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Indane 2,5-diketopiperazine synthons as probes ofsolid, solution and gas phase supramolecular non-covalent associations: Synthesis, characterization,
and analysis of indane amino acids, unnaturalbis-amino esters, indane 2,5-diketopiperazines,
Item Type text; Dissertation-Reproduction (electronic)
Authors Kloster, Robin A.
Publisher The University of Arizona.
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Download date 11/03/2021 15:48:14
Link to Item http://hdl.handle.net/10150/280299
INDANE 2,5-DIKETOPIPERAZINE SYNTHONS AS PROBES OF SOLID,
SOLUTION AND GAS PHASE SUPRAMOLECULAR NON-COVALENT
ASSOCIATIONS
Synthesis, Characterization, and Analysis of Indane Amino Acids, Unnatural Amino
Esters, Indane 2,5-Diketopiperazines, and Indane bis 2,5-Diketopiperazines
by
Robin A. Kloster
A Dissertation Submitted to the Faculty of the
DEPARTMENT OF CHEMISTRY
In Partial Fulfillment of the Requirements For the Degree of
DOCTOR OF PHILOSOPHY
In the Graduate College
THE UNIVERSITY OF ARIZONA
2 0 0 3
UMI Number: 3089975
UMI UMI Microform 3089975
Copyright 2003 by ProQuest Information and Learning Company.
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THE UNIVERSITY OF ARIZONA ®
GRADUATE COLLEGE
As members of the Final Examination Committee, we certify that we have
read the dissertation prepared by Robin A. Kloster
entitled Indane 2,5-Diketopiperazlne Synthons as Probes of Solid,
Solution, and Gas Phase Supramolecular Non-Covalent Associations.
Synthesis, Characterization»and Analysis of Indane Amino Acids,
Unnatural bis-Amino Esters, Indane 2,5-Diketopiperazines, and
Indane bis 2,5-Diketoplperazines
and recommend that it be accepted as fulfilling the dissertation
requirement for the Degree of Dnrfnr nf Philosophy
^ ^-/Z-c 3 Eugene A. Mash ^ Date
Dr./^ndraneelyGhosh Date ,
linic V. McGrath Date
f/ ^ 2- /^- /P. t {rj. John H. Enemark Date
Dr. Zhiping Zheng Date
Final approval and acceptance of this dissertation is contingent upon
the candidate's submission of the final copy of the dissertation to the
Graduate College.
I hereby certify that I have read this dissertation prepared under my direction and recommend that it be accepted as fulfilling the dissertation
requirement.
•2-'/9--a 3 Disse^ation Director Dr. Eugene A. Mash Date
3
Statement by the Author
This dissertation has been submitted in partial fulfillment of requirements for an advanced degree at the University of Arizona and is deposited in the University Library to be made available to borrowers under rules of the Library.
Brief quotations from this dissertation are allowable without special permission, provided that accurate acknowledgement of the source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the head of the major department of the Dean of the Graduate College when in his or her judgment the proposed use of the material is in the interests of scholarship. In all other instances, however, permission must be obtained from the author.
SIGNED
4
Acknowledgements
Several persons have contributed to this dissertation, and it would be remiss not to
acknowledge their work. Dr. Mike Carducci and Hugh Selby of the Molecular Structure
Laboratory collected all X-ray crystallographic data with the exception of compound 96d
(Appendix A). Dr. Arpad Somogyi, director of the Mass Spectrometry Facility,
conducted the ESI-MS gas phase experiments discussed in Chapter 3. Dr. Neil Jacobsen,
director of the Nuclear Magnetic Resonance Facility, chaperoned most of the two
dimensional NMR data collection (Appendix C). I am indebted to these men for their
work and dedication.
Foremost amongst those to acknowledge and thank is my research advisor.
Professor Eugene A. Mash. Professor Mash is an outstanding mentor who has astutely
guided my graduate education these past SVz years. Of all the positive influences
contributing to my growth as a graduate student and chemist, his is most dominant. This
documented work is a direct result of his unwavering confidence in my abilities.
5
Dedication
If you can keep your head when all about you are losing theirs and blaming it on you;
If you can trust yourself when men doubt you, but make allowance for their doubting too;
If you can wait and not be tired by waiting, or, being lied about, don't deal in lies, or,
being hated, don't give way to hating, and yet don't look too good, nor talk too wise;
If you can dream — and not make dreams your master; If you can think — and not make
thoughts your aim; If you can meet with triumph and disaster and treat those two
imposters just the same; If you can bear to hear the truth you've spoken twisted by
knaves to make a trap for fools, or watch the things you gave your life to broken, and
stoop and build 'em up with worn out tools; If you can make one heap of all you
winnings and risk it on one turn of pitch-and-toss, and lose, and start again at your
beginnings and never breathe a word about your loss; If you can force your heart and
nerve and sinew to serve your turn long after they are gone, and so hold on when there is
nothing in you except the Will which says to them: "Hold on!"; If you can fill the
unforgiving minute with sixty seconds' worth of distance run — yours is the Earth and
everything that's in it, and — which is more ~ you'll be a Man, my son!
"If-" from Rewards and Fairies (1910)
Rudyard Kipling
Dedicated to my parents Frederick Ray Kloster and Barbara Jean Kloster who have
taught me, by example, the importance of working hard and living well
6
Table of Contents
List of Figures 10
List of Schemes 16
List of Tables 18
Abstract 19
Chapter 1. The Importance of Hydrogen Bond Directed Self Assembly 21
Section 1.1. The Role of the Organic Crystal and Crystal Engineering 22
Section 1.2. Intermolecular Forces Defining an Organic Crystal 25
Section 1.3. Predicting Solid State Self Assembly 32
Section 1.4. Design of Hydrogen Bonded Networks 36
Section 1.5. The Indane 2,5-Diketopiperazine 46
Chapter 2. Synthesis of Liquid Crystalline 2,5-Diketopiperazines 52
Section 2.1. Overview of 1,4-Alkyloxy Diketopiperazines 53
Section 2.2. Approaches to the Synthesis of Indane-Derived Amino Acids 56
Section 2.3. Synthesis of Alkyloxy Indane Amino Acids and Diketopiperazines 63
Section 2.4. Differential Scanning Calorimetry and Optical Microscopy of DKP 77
Section 2.5. X-Ray Crystallography of the C12 Diketopiperazine 86
Section 2.6. Conclusions About the 1,4-Alkyloxy DKP Family 98
7
Chapter 3. Synthesis and Characterization of an N-Me Diketopiperazine 99
Section 3.1. The Physical Properties of Amides and Diketopiperazines 100
Section 3.2. Synthesis of the N-Me Diketopiperazine 129 108
Section 3.3. Literature Survey of Some N-Me DKP Crystal Structures 116
Section 3.4. X-Ray Crystallography of the N-Me Diketopiperazine 129 121
Section 3.5. ESI-MS Gas Phase Analysis of the N-Me Diketopiperazine 129 133
Section 3.6. UV-VIS Analysis of the N-Me Diketopiperazinel29 138
Section 3.7. 'H NMR Analysis of the N-Me Diketopiperazine 129 145
Section 3.8. Conclusion 165
Chapter 4. The >«-Diketopiperazine as the New DKP Synthon 166
Section 4.1. Crystal Engineering of Z)/5-Diketopiperazines 167
Section 4.2. Synthetic Developments of Natural and Unnatural bis-Amino Acids .. 174
Section 4.3. Sythesis of Cis and Trans Durene Derived bis Amino Ethyl Esters .... 180
Section 4.4. Synthesis of Trans Cyclohexyl bis Amino Methyl Ester 183
Section 4.5. Synthesis of Spiro[3.3]heptane Amino Methyl Esters 191
Section 4.6. Synthesis of 6w-Diketopiperazines 199
Section 4.7. Physical Characterization of ^w-Diketopiperazines 203
Conclusion and Final Remarks 207
8
Experimental Section 209
Synthesis of 1,4 Methoxy Indane Amino Acids 212
Synthesis of 1,4 Hexyloxy Indane Amino Acids 221
Synthesis of 1,4 Octyloxy Indane Amino Acids 227
Synthesis of 1,4 Dodecyloxy Indane Amino Acids 234
Synthesis of 1,4 Octadecyloxy Indane Amino Acids 240
Synthesis of 1,4 [2-(2-methoxy-ethoxy)-ethoxy] Indane Amino Acids 246
Synthesis of C12 Diketopiperazine 252
Synthesis of C18 Diketopiperazine 254
Synthesis of 2-(2-Methoxy-ethoxy)-ethoxy Diketopiperazine 256
Synthesis of N-Me Diketopiperazine 258
Synthesis of 1,2,3,5,6,7 - Hexahydro-i'-indacene ^w-Amino Acids 260
Synthesis of Cyclohexyl Z)w-Amino Acids 264
Synthesis of Spiro[3.3]heptane ^w-Amino Acids 268
Synthesis of 1,2,3,5,6,7 - Hexahydro-^-indacene /jw-Diketopiperazines 279
Synthesis of Cyclohexyl /)w-Diketopiperazines 294
Appendix A. Crystallographic Data 301
Structural Report of 96d 302
Structural Report of 129a (tape) 325
Structural Report of 129b (dimer) 339
Structural Report of 155b 351
Structural Report of 187 355
9
Structural Report of 188 368
Structural Report of 206 380
Structural Report of 207 390
Crystallization of Compounds Addressed in Chapters 2, 3 and 4 402
Appendix B. Selected'H andNMR Spectra 405
Appendix C. Two Dimensional Spectra of N-Me Diketopiperazine 129 589
One Dimensional 'H NMR 590
One Dimensional '^C NMR 591
'H and '^C One Dimensional Assignments for 129 592
Hetemuclear Single Quantum Coherence (HSQC), Spectra A 593
Partial HSQC, Spectra B 594
Heteronuclear Multiple Bond Coherence (HMBC), Spectra A 595
Partial HMBC, Spectra B 596
Partial HMBC, Spectra C 597
Tabulated HSQC Correlations 598
Tabulated HMBC Correlations 598
Appendix D. Chapter 3 Dependence Studies 599
References 603
10
List of Figures
Figure 1.1. Solid State Photochemistry of cw-Cinnamic Acids 23
Figure 1.2. van der Waals Contacts between Aliphatic and Aromatic Groups 26
Figure 1.3. Relative Distribution of Proton Donors Bonded to Acceptor Oxygen .... 28
Figure 1.4. Supramolecular Hydrogen Bonded Synthons 29
Figure 1.5. Zero, One, Two and Three Dimensional Hydrogen Bonded Motifs 31
Figure 1.6. Reference Code ECPRPROl (Cambridge Structural Database) 34
Figure 1.7. Some Acyclic and Cyclic Amide Synthons 37
Figure 1.8. Whitesides' Cyanuric Acid: Melamine (CA:M) Co-Crystal Synthon .... 38
Figure 1.9. Changes in the CA:M Hydrogen Bonded Tape Morphology 39
Figure 1.10. The weto-Substituted Melamine: Cyanuric Acid Complex 40
Figure 1.11. 2-Benzimidazolone as a More Robust Amide Synthon 41
Figure 1.12. The Offset Hydrogen Bonded Diketopiperazine Tape 43
Figure 1.13. Whitesides' Cycloalkyl Diketopiperazines 44
Figure 1.14. Amide Test Subjects for Computational Prediction 45
Figure 1.15. E. A. Mash's Indane Diketopiperazine as a Versatile Synthon 46
Figure 1.16. Indane DKP Investigated by Mash and Williams 48
Figure 1.17. Interdigitated Tapes of the Tetramethoxy DKP 43 49
Figure 1.18. Edge-to-Face Interactions of the Tetramethoxy DKP 43 49
Figure 1.19. Indane DKP Investigated by Mash, Williams and Jagadish 50
Figure 1.20. Indane DKP Investigated by Mash and Wells 51
11
Figure 2.1. Previously Synthesized 1,4-Alkyloxy Diketopiperazines 53
Figure 2.2. Solid State Organization of 1,4-Ethyloxy Diketopiperazine 52b 55
Figure 2.3. O'Donnell Shiff Bases 59
Figure 2.4. Previously Synthesized Indane Amino Acids 62
Figure 2.5. Nuclear (nb) versus Side Chain (sc) Bromination of Anisoles 64
Figure 2.6. Examples of Liquid Crystalline Materials 78
Figure 2.7. Thermogenic Liquid Crystalline Diketopiperazines 80
Figure 2.8. Differential Scanning Calorimetry of the C12 DKP 81
Figure 2.9. Optical Microscopy of the Cu DKP Phases 82
Figure 2.10. Differential Scanning Calorimetry of the C18 DKP 83
Figure 2.11. Linear Relationship Between Carbon Chain Length and Freezing Point . 84
Figure 2.12. Optical Microscopy of the Cig DKP Phases 85
Figure 2.13. The New 1,4-Alkyloxy Diketopiperazines 86
Figure 2.14. Diketopiperazine Carbon Assignments and Torsion Angles 87
Figure 2.15. C12 Diketopiperazine, Conformer 1 89
Figure 2.16. C12 Diketopiperazine, Conformer 2 90
Figure 2.17. C,2 Diketopiperazine, Conformer 3 91
Figure 2.18. C12 Diketopiperazine, Conformer 4 92
Figure 2.19. Dodecyloxy Chain Carbon Assignments and 8 Torsion Angle 93
Figure 2.20. C12 DKP Tapes with Lateral Edge-to-Face Neighbors 95
Figure 2.21. Vertically Interdigitated and Disordered C12 DKP Tapes 95
Figure 2.22. The C3, C4 and C12 Diketopiperazines 97
12
Figure 3.1. Early Hydrogen Bonding Amide Model Systems 100
Figure 3.2. Cis and Trans Amide Associations 101
Figure 3.3. Cis Amide Kg values from VPO Measurements in Benzene 102
Figure 3.4. Evolution of Amide Model Systems 104
Figure 3.5. Aromatic DKP Conformations in Polar Solvents 105
Figure 3.6. The Indane Derived DKP as a Crystal Engineering Model 106
Figure 3.7. N-Me DKP (R = CH3) as a Model for Hydrogen Bonding 107
Figure 3.8. Phosphonium Peptide Coupling Reagents 112
Figure 3.9. CSD Search Results of Mono N-Methylated DKP 116
Figure 3.10. Increasing DKP N-Methylation 117
Figure 3.11. Increasing Alkyl Bulk to the N-Me DKP 118
Figure 3.12. The DKP Hydrogen Bonded Tape 119
Figure 3.13. Linear Hydrogen Bonded Chains of CMALAL (132) 119
Figure 3.14. Branched Hydrogen Bonded Chains of BAJNOPIO (133) 120
Figure 3.15. The Polymorphic N-Me DKP 121
Figure 3.16. General Peptide Torsion Angles v(/, (j), and co 122
Figure 3.17. General Torsion Angles x and 6 124
Figure 3.18. N-Me DKP Molecules 125
Figure 3.19. Hydrogen Bonded N-Me Dimer 126
Figure 3.20. N-Me DKP Dimer, Edge-to-Face Interactions 127
Figure 3.21. N-Me DKP Dimer, Face-to-Face Interactions 128
Figure 3.22. Interdigitated N-Me DKP Dimer Molecules 128
13
Figure 3.23. A Two Dimensional Sheet of the N-Me DKP Dimer 129
Figure 3.24. Hydrogen Bonded N-Me DKP Tape 130
Figure 3.25. Inverted Face-to-Face Interactions of the N-Me DKP Tape 131
Figure 3.26. The Two Dimensional N-Me DKP Tape 132
Figure 3.27. Concentration Dependence of Gas Phase N-Me DKP 129 134
Figure 3.28. Percent Composition of Gaseous N-Me DKP Oligomers 135
Figure 3.29. A Gas and Solution State Model of N-Me DKP Aggregates 137
Figure 3.30. Spectra and Beer's Law Plot in Ethanol. 11.8|aM - 118 |liM 140
Figure 3.31. Spectra and Beer's Law Plot in Chloroform. 11.0 |aM - 110 |a,M 141
Figure 3.32. Spectra and Beer's Law Plot in Toluene. 10.6 )liM - 116 |jM 142
Figure 3.33. H-type and J-type Aggregation States 143
Figure 3.34. 105.6 mM CDCI3 solution of 129 at 25°C (300 MHz) 145
Figure 3.35. Concentration Dependence of the Aryl and NH protons 147
Figure 3.36. Temperature Dependence of the Aryl and NH protons 147
Figure 3.37. Pertinent HMBC Correlations 148
Figure 3.38. Stereochemical Assignment of the Indane Ring Protons 148
Figure 3.39. Shielding and Deshielding Cones of Benzene 150
Figure 3.40. The N-Me DKP Skeleton Simplified 151
Figure 3.41. 222 mM CDCI3 solution of 69a at 25°C (300 MHz) 152
Figure 3.42. Concentration Dependent Studies of 69a in CDCI3 153
Figure 3,43. Temperature Dependent Studies of 69a at 25°C and 40°C 153
Figure 3.44. A Trifluoroacetic Acid (TFA) Capped DKP 155
14
Figure 3.45. Concentration Invariance of 129 in 0.4% ^/-TFA/CDCls 156
Figure 3.46. 0.4% J-TFA/CDCI3 Solutions of 129 at 25°C and 40°C 156
Figure 3.47. 129b (top) and 129a (bottom) with H® Assignments 158
Figure 3.48. Linear Upfield Movement of the frequency 159
Figure 3.49. Linear Downfield Movement of the NH frequency 159
Figure 3.50. Possible N-Me Diketopiperazines for Solution Phase Analysis 165
Figure 4.1. Zjw-Amide Crystal Engineering Systems 168
Figure 4.2. ftw-DKP Spacer Components and 6^-Amino Esters 169
Figure 4.3. Cis and Trans Durene Derived 1,4-Alkyloxy te-DKP 171
Figure 4.4, (R,R) and (S,S) Spiro[3.3]heptane 1,4-Alkyloxy dw-DKP 172
Figure 4.5. Cis and Trans Cyclohexyl 1,4-Alkyloxy 6w-DKP 173
Figure 4.6. Natural 6/5-Amino Acids, the Diaminopimelic Acids 174
Figure 4.7. Natural to-Amino Acids, Dityrosine and Isodityrosine 175
Figure 4.8. Synthetic Amino Acids as Mimics of Natural Structures 176
Figure 4.9. C4 Bridged 6/5-Amino Acids Resembling Cysteine 177
Figure 4.10. Application of Z)w-Amino Acids as Useful Materials 178
Figure 4.11. The ^/5-Amino Esters as Potential Turn Inducers 179
Figure 4.12. The cis Conformer: N-Boc "Polar" Isomer 187 (with DMF) 182
Figure 4.13. The trans Conformer: N-Cbz "Non-Polar" Isomer 188 182
Figure 4.14. l,4-Diamino-Cyclohexane-l,4-Dicarboxylic Acid Dimethyl Ester 183
Figure 4.15. The trans Cyclohexyl N-Cbz bis Amine Ester 206 190
Figure 4.16. Chiral Spiro[3.3]heptane bis Amino Esters 207 191
15
Figure 4.17. (R,R) and (S,S) Spiro[3.3]heptane bis Amino Ester (HCl salt) 198
Figure 4.18. Synthesized Z)w-Diketopiperazines 202
Figure 4.19. Powder Data from Microcrystalline C(, cw-Durene bis-DK? 155b 205
16
List of Schemes
Scheme 2.1. Formation of a Diketopiperazine From Indane Amino Acids 56
Scheme 2.2. Possible Routes to the Indane Amino Acids 57
Scheme 2.3. Bucherer-Bergs Synthesis of 2-Ind Analogues 58
Scheme 2.4. Kuki Methodology for the Synthesis of Substituted 2-Ind 60
Scheme 2.5. Kotha Methodology for the Synthesis of Substituted 2-Ind 60
Scheme 2.6. Alternative Cyclization Methods for the Synthesis of 2-Ind 61
Scheme 2.7. Nuclear Bromination Under Free Radical Conditions 63
Scheme 2.8. Mechanistic Dichotomy in the Bromination of 2,3 Dimethyl Anisole .... 66
Scheme 2.9. Nuclear and Side Chain Bromination of 1,4-Dialkoxy o-Xylenes 67
Scheme 2.10. Formation of the 1,4-Dimethoxy Isocyanate Ester and Amine 69
Scheme 2.11. Formation of Indane Derived a-Amino Esters 85b-e 70
Scheme 2.12. Mechanistic Considerations in Mono- versus Di- Alkylation 72
Scheme 2.13. Formation of Indane N-Boc Protected Amino Acids 75
Scheme 2.14. Coupling and Thermolysis to Diketopiperazines 76
Scheme 2.15. The Liquid Crystalline Phases 77
Scheme 3.1. Synthesis of N-Me Boc and N-Me Cbz Esters 108
Scheme 3.2. Reactivity Differences in a Sodium Hydride/Iodomethane System 109
Scheme 3.3. N,N-Dimethyliminium Salts from DMF and Methylating Agent 110
Scheme 3.4. Possible N-Me Indane Amino Acid Derivatives for Coupling Ill
Scheme 3.5. Peptide Coupling of the N Me Boc Acid versus N-Me Cbz Acid 113
Scheme 3.6. Decomposition of N-Me Boc Acids 114
17
Scheme 3.7. Cyclization to the N-Me Diketopiperazinel29 115
Scheme 4.1. Progression from the 2,5 DKP to the bis-2,5 DKP Synthon 167
Scheme 4.2. Generation of bis- and tris- Isonitriles Using Kotha Methodology 180
Scheme 4.3. Hydrolysis of Z)w-Isonitrile 183 to Form Isomeric Amine Esters 181
Scheme 4.4. The Cyclohexyl bis Amino Acid via the Bucherer-Bergs Synthesis .... 184
Scheme 4.5. Equilibrium States of the Strecker Reaction 186
Scheme 4.6. Assted Hydrolysis of a-Aminonitriles 187
Scheme 4.7. 1,4-Cyclohexanedione and the Strecker Reaction 188
Scheme 4.8. Synthesis of Cyclohexyl Amino Ester Derivatives 189
Scheme 4.9. Reported Synthesis of Cyclo(propyl, butyl, pentyl) Amino Acids 192
Scheme 4.10. Routes to the Spiro[3.3]heptane System 194
Scheme 4.11. Literature Procedure for the Synthesis of Spiro[3.3]heptanedione 195
Scheme 4.12. Modified Procedure for the Synthesis of Spiro[3.3]heptanedione 196
Scheme 4.13. Synthesis of Spiro[3.3]heptane Amino Ester 197
Scheme 4.14. The Tetrapeptide Precursors of &w-Diketopiperazines 200
18
List of Tables
Table 2.1. Di Alkylation of 2,3-(6w-Bromomethyl)-l,4-dimethoxybenzene 69
Table 2.2. Indane a-Amino Esters 85a-e by the Kuki and Kotha Methods 74
Table 2.3. 1,4-Alkyloxy Diketopiperazine DSC Freezing Temperatures 84
Table 2.4. Diketopiperazine and Indane Ring Torsion Angles 88
Table 2.5. Dodecyloxy Chain Conformations and Torsion Angles 94
Table 2.6. Intermolecular Distances of C2, C4 and C12 Diketopiperazines 97
Table 3.1. Average Dimerization Constants (K°) as a Function of Solvent 103
Table 3.2. Dihedral Angles \|;, (|) and co defining N-Me DKP and N-H DKP 123
Table 3.3. Dihedral Angles x and 5 of the N-Me DKP Tape and Dimer 124
Table 3.4. Hydrogen Bond Parameters for the N-Me DKP Dimer 126
Table 3.5. Arene Parameters for the N-Me DKP Dimer 127
Table 3.6. Hydrogen Bond Parameters for the N-Me DKP Tape 131
Table 3.7. Arene Parameters for the N-Me DKP Tape 132
Table 3.8. Linear Regression Bestfit Analysis of NMR Frequency Data 164
Table 4.1. Conditions for the Coupling of Amino Esters and Indane Acids 201
Table 4.2. Preliminary Thermochemical Characterization of the 6/^-DKP 204
19
Abstract
Non-covalent interactions influence supramolecular organization in the solid,
solution and gaseous state. While intermolecular forces are well understood individually,
it is difficult to predict how their interplay will lead to a highly symmetric and low energy
crystalline solid. Analysis, design, and prediction of crystalline architecture is a recently
popularized sub-field of supramolecular chemistry referred to as 'crystal engineering'.
Crystal engineering seeks to fully understand non-bonding intermolecular forces in order
to build crystalline solids that serve some designed purpose.
Hydrogen bonds are strong and directional intermolecular forces used to build
crystalline solids with desirable supramolecular topography. Much focus has been placed
on cyclic diamides, such as diureas and dioxamides, as robust structural motifs due to
their propensity to form highly rigid hydrogen bonded structures. The diketopiperazine is
an exceptional cyclic diamide synthon due to its planar, inflexible, ring structure and
predictable solid state organization. Professor E. A. Mash has studied the indane
diketopiperazine designed such that hydrogen bonding occurs along one principal axis,
while two orthogonal and linearly independent non-covalent interactions occur 90° offset
from each other. Substitution changes to the indane ring system can explore a range of
non-bonding interactions influencing self-recognition.
Several different 1,4-alkyloxy indane 2,5-diketopiperazines were synthesized
and studied. The 1,4-dodecyloxy and 1,4-octadecyloxy diketopiperazines are liquid
crystalline as observed by differential scanning calorimetry and optical microscopy. The
1,4-dodecyloxy diketopiperazine crystal structure, while exhibiting much alkyl chain
disorder, indicated the supramolecular construct remained constant throughout the 1,4-
alkyloxy indane diketopiperazine series. In order to better understand non-bonding
associations of the indane diketopiperazines in the solid, solution and gas phase, an N-
methylated 1,4-methyloxy 2,5-diketopiperazine was synthesized and studied by X-ray
crystallography, ESI mass spectrometry, and by UV-VIS and NMR spectroscopy. While
the solid state N-Me diketopiperazine is polymorphic, existing as hydrogen bonded dimer
and polymer, the gas and solution phase experiments indicated predominant dimeric
associations. 1,4-Dialkyloxy indane Z>w-diketopiperazines were envisioned as the next
generation of robust indane targets, and their synthesis required construction of novel
unnatural ^/5-amino esters. All of the 6w-diketopiperazines exhibited extremely high
melting points and low solubilities. Microcrystalline ^^-diketopiperazine material was
analyzed by X-ray powder diffraction.
21
Chapter 1
The Importance of Hydrogen Bond Directed Self Assembly
22
Section 1.1. The Role of the Organic Crystal and Crystal Engineering
Synthetic chemistry involves purposeful construction of increasingly complex
molecules via covalent bond formation between lesser molecules and atoms. The
supermolQcuXe. and intermolecular bond are analogous to this relationship between the
molecule and covalent bond. Supramolecular chemistry, encompassing both inorganic
and organic disciplines, involves intermolecular non-covalent associations of molecules
to form highly complex supermolecules. An ideal crystal is a perfect supermolecule. It is
an assembly of molecules self-crafted by mutual recognition at an amazing level of
precision. Crystal engineering, the focus of solid state supramolecular chemistry, seeks to
harness the information stored in the structural features of molecules and supermolecules
and use that knowledge towards the construction of crystalline materials, whether
inorganic or organic, with specific physical and chemical properties.'"''
The term 'crystal engineering' was established over 30 years ago by G. M.
Schmidt to describe the future of solid state organic chemistry. In his seminal report,
Photodimerization in the Solid State, Schmidt proposed four phases in the development
in the field of topochemistry.^ Phase one, the Phase of the Topochemical Principle,
correlated the crystal structure of the alkene reactant (1 and 3) with the photodimerized
product (2 and 4) (Figure 1.1). The Topochemical Principle states that the
stereochemistry of the product dimer is determined by the contact geometry of the tt
bonds (parallel or antiparallel) provided that the center to center distance {d) of these
double bonds is within 4 A. Phase Two, the Phase of the Locus of the Solid State
23
Reaction, explored the relationship between the crystal structure and its reactivity under
different excitation conditions.
R . /
CO2H
R^ /
CO2H
HO2C
=/"r
HO2C
/ R
1 a type crystal structure
^C02H hv,
CO2H
R
3 P type crystal structure
CO2H
CO2H
Figure 1.1. Solid State Photochemistry of cw-Cinnamic Acids
The next two phases, the Phase of Crystal Engineering (Phase three) and the
Phase of Systematic Solid State Chemistry (Phase four), were ~ in Schmidt's opinion ~
still in their infancy. Minor scaffolding changes to the starting material would
unexpectedly result in a lack of photoactivity, or formation of unexpected products. A
posteriori, these seemingly simple structural changes were discovered to have drastically
24
altered the crystalline arrangement, prohibiting formation of the desired (predicted)
photodimerized product. Schmidt saw an immediate deficiency in the practice of
topochemical photochemistry which could be only be satisfied by a deeper appreciation
of the organic crystal: "The systematic development of our subject will be difficult if not
impossible until we understand the intermolecular forces responsible for the stability of
the crystalline lattice of organic compounds. A theory of the organic solid state is a
requirement for the eventual control of the molecular packing arrangement. Once such a
theory exists we shall, in the present context ...be able to 'engineer' crystal structures
having intermolecular contact geometry appropriate for the chemical reaction, much as,
in other contexts, we shall construct organic conductors, catalysts, etc. In short, any
rational development of the physics and chemistry of the solid state must be based upon a
theory of molecular packing."
Schmidt recognized this concept of 'crystal engineering' would have wide appeal.
Functional solid state organic materials possessing porosity,^"'^ demonstrating liquid
• 13 16 17 25 crystalline " or non-linear optical properties, " or modeling solution phase
interactions (such as biomolecular recognition and catalysis) are all well grounded in this
understanding of intermolecular forces and solid state organization. Yet Schmidt's
fundamental Theory of Molecular Packing is only slightly beyond the empirical stage for
the organic crystalline solid. Establishing reliable connections between molecular and
supramolecular structure on the basis of intermolecular interactions is still, to this day, a
current focus. His 'Call to Arms', optimistic of an immediate solution in predicting
crystalline packing, is just as meaningful today as it was 30 years ago.
25
Section 1.2. Intermolecular Forces Defining an Organic Crystal
Intermolecular forces influence molecular shape and conformation and ultimately
define the bulk whether in the gas, liquid, or solid phase. The organic crystalline solid is
that still-life portrait of these equilibrating intermolecular repulsions and attractions, the
molecules closely and symmetrically (some might say aesthetically) arranged while
maintaining an energetic balance. Understanding this complex picture of the crystalline
solid and appreciating the forces involved is important to any student of crystal design.
Any theory that attempts to predict, design and eventually exploit crystalline patterns
must refer to these intermolecular forces.
Intermolecular forces are divided into two categories: long-range (r"' to r'^) and
1 2 * ^ short-range (r" ) intermolecular forces (r = distance between non-bonded atoms). Long-
range forces are categorized into three types: electrostatic (Coulombic) interactions (r"')
between sites of permanent charge distribution; induction or dipole induced dipoles (r"^)
between polarizable atoms; and dispersive (attractive) forces (r"^) involving non-polar
functionalities. Short-range forces (r"'^) are e' cloud repulsive interactions which have
been used to rationalize molecular conformations and steric hindrance. In an increasingly
compressed system (gas^liquid^solid), the attractive energy gradually builds between
molecules while at shorter intermolecular distances the repulsive energy rapidly
increases. This complex interplay between long-range dispersion forces and short-range
forces defines what is known as van der Waals (London dispersion) forces. The
26
crystalline solid ~ void of any strong, directional intermolecular associations - is a
compromise between these attractive and repulsive components.
Hydrocarbon functionalities self associate in the solid state by van der Waals
interactions (Figure 1.2). Long chained aliphatic groups 5 (> C7H14) align in a "zig zag"
• 3 26 27 • conformation. ' ' Aromatic groups associate either in a planar (face-to-face) 6 or
herringbone (edge-to-face) 7 fashion.^'^^"^' Carbon and hydrogen atoms within 4 A of
each other are related by van der Waals contacts.
all-trans (aliphatic)
stacked (arene) herringbone (arene)
Figure 1.2. van der Waals Contacts between Aliphatic and Aromatic Groups
Long range and short range forces are treated as central and isotropic. Forces
directional in nature, such as hydrogen bonding and charge-transfer, are the
exceptions.Hydrogen bonding is an electrostatic interaction either strongly (15-40
1 11 9 kcal/mol"), moderately (4-15 kcal/mol" ), or weakly (1-4 kcal/mol") held. Strong
hydrogen bonds (ionic hydrogen bonds) are found between groups bearing substantial
charge density. Acid-base reactions generate salts tightly held together by these strong
forces. Moderate hydrogen bonds are the most commonly encountered and exist between
neutral donors and acceptors such as O-H, N-H, and 0=C groups. Weak hydrogen bonds
are formed when a hydrogen atom, covalently bonded to a more electroneutral atom
(such as C or Si), associates with acceptor n electrons. Strong hydrogen bonds are
approximately linear (180°), while weak hydrogen bonds and moderate hydrogen bonds
tend to deviate from linearity. Moderate hydrogen bonds are generally oriented toward
the lone pair of the neutral acceptor atom, and thus depend upon the hybridization order
o f tha t accep to r (F igu re 1 .3 ) . ^ ' ^^"^^ Whi l e hydrogen bond l eng ths va ry (be tween 1 .2 -3 .2
A), those characterized as moderate fall within 1.6 - 1.8 A for OH—O bonds, and 1.8 -
2.0 A for NH—O bonds.
28
ethers
region in which lon« pairs conwpniion.illy driiwn
oxygeo
Figure 1.3. Relative Distribution of Proton Donors Bonded to Acceptor Oxygen.
(Borrowed from Desiraju; The Design of Organic Solids', Elsevier: New York. 1989. p 119)
From study of hydrogen bonded systems (such as 8 to 13), solid state bonding
patterns and selectivity preferences were established (Figure 1.4). Foremost amongst
investigators was the late Professor Margaret Etter who established a set of rules ~
dubbed "fitter's Rules" by contemporaries -- from an exhaustive survey of hydrogen
bonded crystal structures.^^'^^ Three of these rules are universal to all hydrogen bonded
structures: (1) All acidic hydrogens available in a molecule will be used in hydrogen
bonding in the crystal structure of that compound; (2) All acceptors will be used in
hydrogen bonding when there are available donors; and (3) The best hydrogen bond
donor and best hydrogen bond acceptor will preferentially form hydrogen bonds to one
->7 another.
29
13
Figure 1.4. Supramolecular Hydrogen Bonded Synthons
Hydrogen bonded solid state structures are defined by the number of non-covalent
vectors, and are categorized as zero, one, two or three dimensional (Figure 1.5).^^ A zero
dimensional hydrogen bonded network describes closed loop systems, such as the
centrosymmetric benzoic acid (14) ^ and 5-valerolactam (15) dimers. N-methyl
acetamide (16), with aligned dipoles, assembles as a one dimensional hydrogen bonded
tape.'^^ Ureylene dicarboxylic acid 17 self associates in a two dimensional hydrogen
bonded sheet, with lateral hydrogen bonding between dicarboxylic acids and vertical
hydrogen bonding between internal urea groups.Three dimensional hydrogen bonded
30
diamandoid structures are formed from tetra-substituted "tectons", such as 3,3-
bis(carboxymethyl)-glutaric acid (18), possessing both hydrogen donating and accepting
ability at the four corners of the molecular tetrahedron.^"''
Most of these hydrogen bonded networks have been designed a priori with the
immense knowledge of the hydrogen bonding geometry and directionality at hand. Yet
even carefully planned designs can go awry. The hydrogen bond is only one of a
multitude of non-covalent intermolecular associations making up the crystal structure.
The presence of competing dipoles, multiple hydrogen bond sites, conformational
flexibility, steric overcrowding, and even different crystallization conditions, adds to the
complexity and can lead to a multitude of energetically similar crystalline structures.
Polymorphism, defined by differing connectivity (constitutional polymorphism) or shape
(conformational polymorphism), is deleterious to the design process and, unfortunately,
quite prevalent.^^'"^^ Clearly further research concerning competing weak non-covalent
forces is required before a claim can be made that crystal structures are indeed
predictable.
31
.0. .Ph ,.H Y O O
pr o -H
14 15
Zero dimensional
H3C CH3 H3C J \ /J ^ \ >=0 H-N >=0---
jj ^ \ Q H—N dimensional
CH3 H3C CH3
16
O
.-•O-t^n'-n'vO-Ho fi' 'i. nH-" u-0 H H 0„ V y Y
'O If O" Two dimensional O p
,Q 17 ''
CH2C02H
H02CH2C '^"""CH2C02H , ^ CH2CO2H ^ Three dimensional
Figure 1.5. Zero, One, Two and Three Dimensional Hydrogen Bonded Motifs
Section 1.3. Predicting Solid State Self Assembly
Linus Pauling was one of the first to show interest in the prediction of
supramolecular architecture. The early 1920's ushered in the development of the X-ray
diffraction technique for determination of crystal structures. Yet solving an x-ray crystal
structure required detailed x-ray photographs, use of complex algorithms and extensive
calculations. By the late 1920's Pauling was working toward developing a prediction
method he believed would be more generally and easily applicable than X-ray
47 • crystallography. The Nature of the Chemical Bond addressed Pauling's attempts, from
the classification of inorganic crystal structures into ionic radii, interatomic distances and
bond angles as determined by X-ray methods, the prediction of new inorganic crystal
structures without X-ray diffraction."^^ A method for the organic solid, at that time, was
not addressed. Eventually Kitaigorodskii, in the late 1950's to early 1960's, developed a
prediction method for the organic crystal which he later summarized in his text
Molecular Crystals and Molecules.Kitaigorodskii proposed that the most likely
packing arrangement of the arbitrarily shaped organic molecule would fill as much space
as possible and leave the minimum of void density.The application of his close
packing theory, or Kitaigorodskii's Aufbau Principle (KAP), consists of a "building up"
process - in zero, one, two and three dimensions or stages ~ of one molecule into an
assembly of symmetry related molecules. A directional non-covalent bond (such as a
hydrogen bond) no matter how strong a vector in one stage will have no effect on the
arrangement of the later stages. The KAP begins by isolating a single molecule or array
of molecules, bound or unbound, and not necessary related by symmetry, from which the
whole crystal structure can be constructed. This simple "packing unit", defined as stage
zero, undergoes a single translational repeat distance to stage one, making up an array of
symmetry related chains. There are more than 75 ways to pack a stage zero cluster in one
dimension, but there are only four symmetry elements which are statistically significant
for the semi-rigid organic molecule: the translation, the two fold screw axis, the glide
plane and the inversion.^*' Repeating stage one in a second dimension generates an
infinite two dimensional sheet (stage two) related by one of these four symmetry
elements. Out of the 80 symmetry types which define stage two, only 7 types make up
92% of all two dimensional monolayers. Stage three - a combination of symmetrically
related stage two layers - completes the three dimensional molecular array. The majority
of organic molecules will organize in three dimensions in either the P2i/c, PI, P2i2|2i,
P2i or C2/c space group.
This simplified progression from stage zero to stage three, when applied to a "real
life" example, marks the difficulty in this type of prediction. A semi-rigid organic
molecule containing 10 internal rotational degrees of freedom, or 10 sp^ bonds, with each
bond assuming 3 possible orientations, would have up to 3'° (or 59,000) possible
conformations. Considering both orientational and translational components, two
dimensional layers will contain more than 10^ potential conformations. For the case of
the semi-rigid molecule ECPRPROl (19) (Figure 1.6), formation of a two dimensional
• • 1 ^ sheet will result in 5.9 x 10 layer geometries. One or two of these layers will serve as a
repeat template to generate the three dimensional crystalline solid. While these numeric
34
projections sound overwhelming, computational methods have been successful in the
prediction of stage one and stage two layers for the semi-rigid small molecule containing
<12 rotational degrees of freedom.
Figure 1.6. Reference Code ECPRPROl (Cambridge Structural Database)
The difficulties in predicting the full three dimensional crystal structure stem from
this "multiple minima problem". Empirical energy force fields are not yet accurate
enough to distinguish conformational differences within a few kcals/mol. The many
degrees of freedom for rigid body translations and rotations intrinsic to the solution
phase, and inclusion of any "soft" internal degrees of freedom (e.g. torsions), contribute
to a large number of possible arrangements that must be sorted in order to find the one
that is thermodynamically preferrable in the crystalline state. The "dynamic approach"
seeks complete prediction of a crystal structure with the use of molecular dynamics and
35
ab initio calculations, yet reproduction of crystal structures of only simple rigid organic
molecules has been achieved."^^'^^"^^ The "static approach" involves the examination or
synthesis of homologous crystal structures to eventually, with strategic shortcuts, predict
the full crystal structure, and has been moderately successful with semi-rigid small
molecules when applied against auxiliary crystallographic information (powder or partial
diffraction data).'^^'^^ These computational approaches are unfortunately inadequate for
the degree of dimensionality inherent to most organic molecules. Without the aid of
accurate prediction methods, the crystal engineer must make use of simplified, rigid,
molecules possessing functionalities which can constrain self-assembly via strong
intermolecular forces to more predictable solid state architectures.
36
Section 1.4. Design of Hydrogen Bonded Networks
The goal of crystal engineering is to recognize and design synthons that are robust
enough to be exchanged from one supramolecular network to another, and to use these
synthons in the construction of materials with desirable superstructure and bulk
properties. The term synthon, coined by Corey and used by synthetic and structural
chemists alike, is that "structural unit within molecules which can be . . . assembled by
known or conceivable synthetic operations".^' What is inferred from the descriptor robust
synthon, implying "hardiness", is a re-defmition by the structural chemist to connote a
"persistence" and "predictability" of a particular motif Robust (and thus successful)
synthons usually contain strong directional forces, such as hydrogen bonding, to enforce
predictable self-organization in the crystalline state. Etter's Rules [Section 1.2] and
Kitagorodskii's Principle [Section 1.3] are not in conflict. ' The most stable crystalline
packing arrangement is the one maintaining a minimum of free volume while
simultaneously satisfying every hydrogen donor site.
A significant effort has been made in construction of amide synthons (such as 20
to 27) and their assembly into hydrogen bonded networks (Figure i 7)^-"'39,43,44,5i,58-74
Notable investigators include Desiraju,^""^'"*^''^ Lehn,''^^ and Whitesides,^^"^^"'^ who have
contributed much toward the development of hydrogen bonded networks, and ultimately
to the field of crystal engineering. It is the latter, G. M. Whitesides, whose work bears the
most pertinence to the thesis topic at hand, in which the following discourse is concerned.
37
Acyclic Amides q
V RHN
,0
NHR 20
bis amides
Fused Amides O
HN NH
W
21
cyclic ureas
O H N.
O
22
cyclic imides
Directly Joined Amides
Ov P
M HN NH \_y
23
cyclic oxamides
HN—^NH
O >=0
24
cyclic diacylhydrazides
O,
V -NH
HN
V
=0
25
cyclic acyl ureas
Amides separated by more than one atom
O-^ ^ /.O
HN^^^NH
26
cyclic diamides
0>
HN
' N H
O 27
diketopiperazines
Figure 1.7. Some Acyclic and Cyclic Amide Synthons
38
Whiteside's primary interest in crystal engineering was three fold: (1) To design
new molecules that would crystallize in unique hydrogen bonded arrays; (2) To
rationalize the organic crystal structure from the molecular structure; and (3) To
eventually predict the crystal structures of new molecules. His initial work centered upon
the 1:1 co-crystal cyanuric acid (29) and melamine (28) complex (CAiM) (Figure
I g) 65,69,71 packing via triply hydrogen bonded tapes with rigid and parallel axes
would minimize free volume and lead to a self assembling system sensitive to steric
perturbations at R| and R2.
R2 R2
. N . / N
" " ^ ^ 28
para-melamine
R-) R2
. N . . N . . N .
29 cyanuric acid
. - N N.
Figure 1.8. Whitesides' Cyanuric Acid: Melamine (CA:M) Co-Crystal Synthon
39
In fact, while the majority of co-crystal CA:M complexes were insensitive to R|
(present on cyanuric acid), the nature of the R2 group (present on melamine) had a
dramatic effect on the tape morphology (Figure 1.9). The hydrogen bonded motif
progressed from a linear tape 30 for small R2 groups, to a "crinkled" tape 31 for medium
R2 groups, and finally to a cyclic pseudo C3 "rosette" 32 for very large R2 groups.
30 31
Linear tape
R2 = H, F, CI, Br, I, CH3
Crinkled tape
R2 = CO2CH3
melamine derivative
diethyl cyanuric acid
32
Rosette R2 = ^Bu
Figure 1.9. Changes in the CA:M Hydrogen Bonded Tape Morphology
40
Minor modifications to the melamine scaffolding created major differences in
CAM crystalline architecture (Figure 1.10)7^ Co-crystals of meto-substituted melamine
33 and cyanuric acid 29 produced linear and "crinkled" hydrogen bonded tapes
unperturbed by sterics, tending toward polymorphism, and occasionally containing
included solvent. The number of orientational options for the meta- CA:M system over
the para- CA:M, simply by rotation about the N-phenyl bond, produced unpredictable
motif patterns which precluded further systematic investigation.
• R. -R.
V/ Vx N, .N.
. H H . .
33 R ' meta-melamine i
29
cyanuric acid
Figure 1.10. The weto-Substituted Melamine : Cyanuric Acid Complex
While the /?ara-CA'M system established a correlation between the sterics and
hydrogen bonded tape patterns, it was difficult to study the effects of different molecular
41
shape on intertape packing. />arfl-Substitution changes resulted in one or zero
dimensional hydrogen bonded tapes rather than different two dimensional sheets. From a
survey of amide synthons,^^ Whitesides identified two structurally simpler systems — 2-
benzimidazolone and 2,5-diketopiperazine ~ as more robust targets. Substituted 2-
benzimidazolones 34 would form rigid and linear hydrogen bonded tapes, with the planar
molecular lengths parallel (Figure 1.11). Unlike the para-CA'M system, changes in
aromatic substitution would effect differences about the edges of the hydrogen bonded
tape, and thereby modify the packing of adjacent tapes.
R R R R
R R R R
34 2-benzimidazolone
Figure 1.11. 2-Benzimidazolone as a More Robust Amide Synthon
42
Whitesides found 2-benzimidazolones formed two types of hydrogen bonded
tapes, parallel (||) and non-parallel (x), or three dimensional (3-D) hydrogen bonded
networks, all of which depended upon the R group substitution. Generally, parallel tapes
associated via van der Waals interactions when the R group was sufficiently bulky (R = i-
Pr, CI, and Br), and non-parallel tapes formed when the R group was small (R = H) and
could not associate. 3-D networks were stabilized by weak hydrogen bonding between N-
H and fluorine substituents. Thus Coulombic interactions were more important than van
der Waals interactions for molecules with small substituents (R = H, F), but the reverse
for molecules with large substituents (R = /Pr, CI, Br). Much to his satisfaction, the
molecular structure was related to the crystal structure. Proper identification of the
influences of weak interactions at the edges of tapes provided the best chance for
predicting their packing arrangements.
Whitesides judged the 2,5-diketopiperazine (DKP) synthon 35 (or 2,5-
piperazinedione) to be an even more promising candidate than 2-benzimidazolones.
Diketopiperazines, the condensation result of two amino acids, have been studied
extensively in both solid and solution phase.More than 40 diketopiperazine crystal
structures have been reported.^^ In fact, the first X-ray crystal structure of a peptide
containing compound was cyclo{G\y)2 (Ri=R2=H), the simplest of these cyclic
dipeptides.^^'^^ While at least half of these diketopiperazine crystal structures formed
hydrates or solvates, or have competing hydrogen bonding functionalities, the remainder
formed linear and offset hydrogen bonded tapes with their long axes parallel (Figure
1.12). The diketopiperazine ring system adopts either a planar, flattened boat or chair
43
conformation, depending upon the number and bulk of the a-substituents.
Tetrasubstitution limits hydrogen bond interactions between amide groups to one
dimension.
2,5-diketopiperazine
Figure 1.12. The Offset Hydrogen Bonded Diketopiperazine Tape
Whitesides designed a series of symmetrically tetrasubstituted diketopiperazines
such that there would be a limited number of conformations, but a maximum range in
molecular volume and shape (Figure 1.13). All compounds crystallized to form one
dimensional hydrogen bonded tapes related to each other by interdigitated van der Waals
contacts. Polymorphism was ruled out for all but one diketopiperazine (Ind-DKP 36). X-
ray powder diffraction experiments on crystals obtained from different solvent systems
verified one crystal structure for each compound. Two different types of hydrogen bond
tapes, both a consequence of ring puckering, were identified from their structural
characterization. Cycloalkyl diketopiperazines 37a-c and 37e, and DMeCeDKP 38 have
44
planar diketopiperazine rings, and form planar tapes. Cycloalkyl DKP 37d, TMeCeDKP
39 and Ind DKP 36, as boat conformers, form non-planar tapes. While the boat
conformer is more stable, all possible conformations of the diketopiperazine ring are
energetically close (within 6 kcal/mol).^^
•NH •NH
Cycloalkyl DKP
HN-HN-)n
36
Ind DKP
37a n = 1 37d n = 4 37b n = 2 37e n = 5 37c n = 3
DMeC^DKP TMeC.DKP
Figure 1.13. Whitesides' Cycloalkyl Diketopiperazines
From this study of the 2,5-diketopiperazines, Whitesides developed an optimized
simulated annealing Monte Carlo (SAMC) procedure for systems containing hydrogen
45
bonded tapes.The correctly predicted crystal structures of the test subjects, cycloalkyl
C5 DKP 37c, DMe DKP 40 and DMeCe DKP 38 of the 2,5 diketopiperazine family and
DMe 2-benzimidazolone 41, attest to the potential of this computational approach (Figure
1.14).
•NH
HN-
O 37c
Cycloalkyl C5 DKP
40
DMeDKP
38
DMeC^DKP
41
DMe 2-benzimidazolone
Figure 1.14. Amide Test Subjects for Computational Prediction
46
Section 1.5. The Indane 2,5-Diketopiperazine
E. A. Mash was also interested in the indane 2,5-diketopiperazine 42 synthon
0*7 Q 1 (Figure 1.15). " The diketopiperazine ring takes on a fairly planar conformation, with
the spiro-fused indane ring re-enforcing planar rigidity along the molecular length. This
system organizes as a one dimensional rod-like hydrogen bonded tape, with non-bonding
interactions occurring perpendicular to the tape. Depending upon the nature of the
aromatic substituents Ri, R2, R3 and R4, a range of non-bonding interactions can be
explored. One can ascertain from a survey of appropriately engineered indane
diketopiperazine crystal structures whether a prediction of the supramolecular framework
can be made from molecular structure.
Figure 1.15. E. A. Mash's Indane Diketopiperazine as a Versatile Synthon
The first diketopiperazines synthesized in the Mash group incorporated dialkyl
and dialkyloxy aryl substituents ortho or para to each other (Figure 1.16).^^"^^ Their
47
supramolecular constructs indicated that while the hydrogen bonded tape motif remained
constant, the vertical and lateral neighboring associations were highly dependant upon the
location of the substituents. If the system contained para substituents (43, 46, and 47) the
vertical tapes interdigitate, with the para substituents occupying the space provided
above and below the DKP ring (Figure 1.17). If the system contained only ortho
substituents (44 and 45), it was impossible for vertical interdigitation, and so tapes
packed together in a less dense fashion. Laterally, the hydrogen bonded tapes associated
via face-to-face interactions if all substituents were hydrogen (36), and by edge-to-face
interactions for those containing only para substituents (43 and 46) (Figure 1.18). There
were no arene associations observed systems bearing ortho substituents (44 and 45). Yet
these arene associations were not always predictable. For the ortho and para
tetrasubstituted hybrid 47, the para substituted arene rings oriented in a familiar
herringbone motif, but were not close enough for edge-to-face associations.
The next group of designed indane DKP systems bore para substituents since
such a molecular arrangement provided the most efficiently packed structures (Figure
1.19). The crystal structure of weakly dipolar diketopiperazine 48 formed hydrogen
bonded tapes, much like other DKP systems, with vertical interdigitating substituents and
lateral edge-to-face associations.^^ The bulk crystal, due to inversion, was not dipolar.
The more strongly dipolar diketopiperazine 49 formed crystals of included
dimethylsulfoxide (DMSO) molecules instead of a self associated hydrogen bonded
an
network.
Figure 1.16. Indane DKP Investigated by Mash and Williams
49
MM
Figure 1.17. Interdigitated Tapes of the Tetramethoxy DKP 43
Figure 1.18. Edge-to-Face Interactions of the Tetramethoxy DKP 43
50
CN
NH
HN
CN
49
NH
HN
48
Figure 1.19. Indane DKP Investigated by Mash, Williams, and Jagadish
The more recently studied of indane diketopiperazines built on the initial work of
Mash and Williams (Figure 1.20). A series of para alkyloxy DKP systems (from
ethyloxy to nonyloxy) were synthesized in order to further explore van der Waals
associations. Unfortunately, only two of the series formed crystals of sufficient quality
for X-ray analysis.^' Similar to the methyloxy DKP 43, the ethyloxy DKP 50 and
butyloxy DKP 51 solid state structures organized as hydrogen bonded tapes vertically
associating by interdigitated alkyloxy substitents. Yet while the butyloxy DKP 51 crystal
structure organized in herringbone fashion between lateral neighboring tapes, only the
methyloxy 43 and ethyloxy DKP 50 contained arene contacts close enough for edge-to-
face associations.
51
NH
HN
OC4H,
51
NH
HN
50
Figure 1.20. Indane DKP Investigated by Mash and Wells
The present thesis begins where this last work ends. Chapter 2 addresses an
optimized synthesis of 1,4 alkyloxy diketopiperazines, and compares their crystal
structures and liquid crystalline behaviour. Chapter 3 concerns the synthesis and solid,
solution and gas phase behavior of an N-methylated diketopiperazine. Chapter 4
concentrates on the synthesis of Z)w-diketopiperazines, and concludes with a discussion of
their preliminary characterization. This thesis completes solid-state investigations of 1,4
alkyloxy diketopiperazines, and works towards an understanding of their solid - solution
phase relationship.
52
Chapter 2
Synthesis of Liquid Crystalline 2,5-Diketopiperazines
53
Section 2.1. Overview of 1,4-Alkyloxy Diketopiperazines
Previous work in the Mash laboratory described a synthesic protocol toward the
construction of 1,4-alkyloxy diketopiperazines sharing the general structure 52.
These sytems were designed such that hydrogen bonding, arene to arene, and van der
Waals interactions between alkyl tails of increasing carbon length C| to C9 would occur,
independant of each other, along the x, y and z direction (Figure 2.1).
OR OR
H,
O H OR OR
52a R = CH3 methyloxy 52b R = C2H5 ethyloxy 52c R = C4H9 butyloxy 52d R = C5H13 hexyloxy 52e R ^ ^ C g H j y o c t y l o x y 5 2 f R = C 9 H ] 9 n o n y l o x y
van der Waals A y
X arene
hydrogen bonding
Figure 2.1. Previously Synthesized 1,4-Alkyloxy Diketopiperazines
The X-ray crystal structures of the methyloxy 52a and ethyloxy 52b
diketopiperazines conform with this design principle.The diketopiperazines organize
as hydrogen bonded tapes, with adjacent lateral neighboring tapes associating via edge to
face arene interactions, and vertical neighboring tapes above and below the plane of the
54
DKP ring associating by van der Waals interactions between the closely interdigitated
alkyl chains (Figure 2.2). The butyloxy 52c diketopiperazine (DKP) crystal structure,
unlike the methyloxy 52a DKP and ethyloxy 52b DKP, possessed no edge to face lateral
arene associations. Additionally, it was found that while the methyloxy 52a DKP and
ethyloxy 52b DKP alkyloxy substituents extended in an oW-trans fashion, the butyloxy
D K P 2 5 c c r y s t a l s t r u c t u r e , s t r u c t u r a l l y s i m i l a r t o o t h e r l i p i d l i k e s y s t e m s , c o n t a i n e d
both trans and gauche alkyl chain conformations. There was interest in completing the
DKP series to see if structural differences became more prevalent as the alkyloxy chain
length increased (R = C6H13, CgHn, and C9H19), yet attempts in obtaining single crystals
for X-ray analysis met with little success. Several questions remained from this initial
work. Would an increase in alkyloxy chain length propagate further disorder? Would a
substantial increase in chain length overcome the dominant organizational role of the
hydrogen bond? What is the length limit in obtaining good crystals of this DKP family?
Obviously there are both positives and negatives upon increasing the alkyl chain length.
Increasing the alkyl chain to too great a length would lead to material amorphous, waxy
and non-crystalline, but moderately increasing the alkyl chain length would result in
more soluble (and easier to crystallize) materials. To this end, the alkyloxy DKP family
was extended to include the dodecyloxy (R = C12H25) and octadecyloxy (R = C18H37)
diketopiperazines. This chapter concerns their synthesis and physical characterization.
hydrogen bonded tapes
interdigitation
edge to face associations
Figure 2.2. Solid State Organization of 1,4-Ethyloxy Diketopiperazine 52b
56
Section 2.2. Approaches to the Synthesis of Indane-Derived Amino Acids
The methodology for construction of indane diketopiperazines is well
established.^^'^' The procedure calls for the synthesis of orthogonally protected indane
amino acids 53 and 54 (Scheme 2.1). Peptide coupling, followed by thermally induced
intramolecular cyclization, yields the 2,5-diketopiperazine 55.
Scheme 2.1. Formation of a Diketopiperazine From Indane Amino Acids
OEt BocHN
NH HO R
•NH
HN
55
57
Several approaches have addressed the synthesis of 2-aniino indane acid
derivatives (Ain or 2-Ind) 56 (Scheme 2.2). Interest in the development of new synthetic
methods grew upon recognition of the indane topography as a conformationally restricted
phenylalanine (Phe) mimic. 2-Aminoindane-2-carboxylic acid (56) (R = H) has been
used as a component of oligopeptides in order to introduce constraints that could lead to
higher bio-active potency and in vivo resiliency of the ligand.^"^"^'
Scheme 2.2. Possible Routes to the Indane Amino Acids
CO^H
R
±>
Bucherer Bergs or Strecker Reaction
R
NH,
CO2R
Diels Alder
Br
Br
Bis-Alkylation
NH2
CO2H
Early attempts in the formation of the 2-Ind (56) and related derivatives employed
the Bucherer Bergs synthesis, yet hydrolysis of the intermediate hydantoin to the desired
amino acid required harsh reaction conditions (excess barium hydroxide, 140 °C or
concentrated hydrochloric acid, 160 °C) which were incompatible with sensitive side
58
chain functionalities (Scheme 2.3).^^'^^ Furthermore, synthesis of the indanone starting
material 57 was a lengthy, and at times low yielding, multi-step sequence.'""'""
Considering these problems, it was little wonder that new synthetic methods were sought.
Scheme 2.3. Bucherer-Bergs Synthesis of 2-Ind Analogues
KCN, (NH4)2C03, EtOH, H2O
Bucherer Bergs conditions
OH NH H^ or "OH
NH
58 56
In the late 1970's to early 1980's, M. O'Donnell and co-workers investigated the
use of stable ketimine 59 and aldimine 60 glycine ethyl esters and alkyl halides to
generate a,a-dialkylated amino esters (Figure 2.3).'"^"'°^ While the ketimine derivatives
tended toward mono-alkylation, the aldimines —presumably due to diminished steric
hindrance ~ were more successful in di-alkylations.'"^ '°^ Additionally, O'Donnell
reported the formation of three and five membered ring systems using a highly active
59
ketimine nitrile and appropriate dihalide, but elaboration of the procedure to form other
Figure 2.3. O'Donnell Shiff Bases
Other groups optimized the O'Donnell methodology for generation of acyclic
amino esters,but was not until the work of S. Kotha and A. Kuki that the
O'Donnell method was used to form indane amino acids.Intramolecular cyclization of
a,a'-dibromo-o-xylenes 61 with aldimine derivatives using lithium or sodium
hexamethyldisilazane (NaHMDS) as a base easily generated the N-protected indane
amino esters 62 (Scheme 2.4). However, substrates containing electron withdrawing
aromatic groups were found, via a single electron transfer, to give unwanted side
products instead of the di-alkylation product."''
An entirely new method based on the early efforts of U. Schollkopf"^ employed
ethyl isocyanoacetate as alkylating agent to generate from substituted a,a'-dibromo-o-
xylene 61 the isocyanate ester 63 (Scheme 2.5).'" "'^""^ The commercial availability of
ethyl isocyanoacetate, the operational simplicity of the reaction setup, compounded with
a similarity in yield made this new methodology competitive with the Kuki's O'Donnell
cyclic systems yielded unsatisfactory results.
Ph
60
protocol. Kotha demonstrated its versatility in the synthesis of indane derivatives
c o n t a i n i n g e i t h e r e l e c t r o n w i t h d r a w i n g o r e l e c t r o n d o n a t i n g s u b s t i t u t e n t s . M o r e
recently, Kotha's use of 2+2+2 cycloadditions and the Diels Alder have resulted
in alternative synthetic strategies for substituted indane derivatives 64 and 65 (Scheme
2.6).
Scheme 2.4. Kuki Methodology for the Synthesis of Substituted 2-Ind
Ph =N COjEt
NaHMDS THF, -78 °C
Scheme 2.5. Kotha Methodology for the Synthesis of Substituted 2-Ind
Br c=N COjEt
Br K2CO3, TBAHS, ACN N = C
61
Scheme 2.6. Alternative Cyclization Methods for the Synthesis of 2-Ind
NH 2+2+2
CO.Et 64
NH
CO.Et
R
+
R
NHAc Diels-Alder ^
COjEt
NHAc
COsEt
The Mash Laboratory has found utility in the O'Donnell method originally
employed by Kuki - that is, the alkylation of dibromo-o-xylenes with aldimine glycine
esters to form indane amino acids. This chemistry was employed in the synthesis of 4,7-
Z)w-alkyloxy indane N-Boc amino acid derivatives 66a-f (R = CH3, C2H5, C4H9, CeHu,
CgHn, CgHig),^' dipolar 4,7 ^/^--substituted indane N-Boc acid derivatives 67a-c,^''^^ and
5,6-&z.s'-methyl-indane N-Boc acid derivatives 68 (Figure 2.4).^^'^° It was of interest to
apply the alternative di-alkylation method championed by Kotha, using ethyl
isocyanoacetate as alkylating agent, toward the synthesis of 4,7-&«'-alkyloxy-indan-2,2-
N-Boced acid derivatives in order to compare the two synthetic methodologies.
62
CO.H BocHN,
OR
NHBoc NHBoc
CH OR OR
66
66a R = CH3 66b R = C2H5 66c R = C4H9 66d R = C6Hi3 66g R —CgHj-y 66f R = C9H,9
67
67a X = 0CH3; Y = Br 67b X = CN; Y = Br 67c X=N02, Y = Br
68
Figure 2.4. Previously Synthesized Indane Amino Acids
63
Section 2.3. Synthesis of Alkyloxy Indane Amino Acids and Diketopiperazines
A series of l,4-6w-alkyloxy-2,3-dimethybenzenes 69, synthesized from
commercially available 2,3 dimethylhydroquinone, were brominated using NBS and
120 121 either BPO or light as radical initiator (Scheme 2.7). ' It was found that nuclear
bromination significantly competed with side chain bromination as the alkyl substitution
length increased. In particular, when R = CH3 (69a) only side chain bromination was
observed, but when R = CgHiy (69c) nuclear bromination predominated. Under forced tri-
bromination conditions, the reaction time, amount of NBS required, and the presence of
unidentified impurities increased with the length of the alkyl chain R group.
Scheme 2.7. Nuclear Bromination Under Free Radical Conditions
69a R = CH3 70a R = CH3 93% 71a R = CH3 0% 69b R = «-C6H,3 69c R = «-C8H,7 70c R = n-C8H,7 25% 71c R = «-C8H,7 60% 69d R = «-Ci2H25 69e R = «-CigH37 69f R = [CH2CH20]20CH3
64
This competition between nuclear bromination of the aromatic ring versus side
121126 chain bromination is a phenomena well documented in the chemical literature. " G.
M. Gruter, O. Akkerman and F. Bickelhaupt found that substitution patterns sway
reaction preferences in the NBS bromination of di- and /r/-methyl substituted anisoles (72
to 76) (Figure 2.5).While the methyloxy group activates the para position for nuclear
bromination, ortho methyl groups reduce this pathway, and increase side chain
bromination (see 72, 74 and 75).
72 73 74 75 76
100% sc 75% nb (para) 3% nb (para) 100% sc 100% nb (para) 24% sc 97% sc
Figure 2.5. Nuclear (nb) versus Side Chain (sc) Bromination of Anisoles
124 These marked product ratio differences prompted further investigation. Kinetic
plots of the NBS bromination of 2,3-dimethylanisole (74) indicated that while the first
bromination occurred on the ortho side chain (74—>78), the second bromination competed
either between the side chain (79—>80), or the para position of the aromatic ring
(78-^81) (Scheme 2.8). NBS bromination of 3,5 dimethylanisole (73) with TEMPO as a
radical scavenger resulted in complete suppression of side chain bromination pathway.
65
and formed 100% nuclear brominated product. The nuclear brominated product was
formed by electrophilic aromatic substitution (EAS), most likely with NBS or HBr as the
in situ electrophile.
As a synthetic strategy in circumventing the unproductive nuclear versus side
chain competition of the l,4-6w-alkyloxy-2,3-dimethybenzenes 69 b-f, bromination was
enacted in two sequential steps (Scheme 2.9). Electrophilic aromatic bromination of 69 b-
f with molecular bromine in chloroform required no activating catalyst and produced a
series of clean mono-brominated products 82b-f in excellent yields. The initial mono-
bromination blocked the EAS competition site, and allowed for efficient free radical side
chain bromination, producing tri-brominated materials 83b-f in excellent yields and
purity.
Scheme 2.8. Mechanistic Dichotomy in the Bromination of 2
NBS
hv
74 77
OCH,
Br
Br*
80
67
Scheme 2.9. Nuclear and Side Chain Bromination of 1,4-Dialkoxy o-Xylenes
OR
OR
69
Br^
CHCl,
OR
OR
82
NBS, hv
CCL
69b R = n-C6H,3 69c R = «-CgHi7 69d R = n-C,2H25 69e R = /7-C]gH37 69f R = [CHjCHjOljOCHj
82b R = «-C6H,3 91% 82c R = «-C8H,7 100% 82d R = «-C,2H25 77%
82f R= [CH2CH20]20CH3 86%
83
83b R = n-C6H,3 100% 83c R = «-C8H,7 100% 83d R = n-C,2H25 96% 83e R = «-Ci8H37 83% after two steps
It was with some surprise that the alkylation of 2,3-(^/-s'-bromomethyl)-l,4-
dimethoxybenzene (70a) did not proceed as cited (Scheme 2.10).'" "'^ S. Kotha and E.
Brahmachary report synthesizing isocyanate 84 from 70a in 57% yield in 3.5 hours
(Table 2.1, run 1).""^ Exact repetition of their procedure (albeit at a slightly larger scale)
took 5 times longer than was reported, and yielded a disappointing 24% of 84 (Table 2.1,
run 2). Increasing the scale and amount of base used had little effect on the yield, even
though the reaction time substantially decreased (run 3). Substituting the phase transfer
catalyst tetrabutylammonium iodide (TBAI) for tetrabuylammonium hydrogen sulfate
(TBAHS) produced only a mild enhancement in the yield (from 28% to 33%, compare
runs 3 and 4). The principal influence on yield, from 33% to 47%, was primarily due to a
larger reaction size (compare runs 4 and 5).
It was found upon increasing the R group alkyl chain length that solubility of the
tribromides 88b-e decreased in the reaction solvent acetonitrile and consequently the di-
alkylation yields decreased (Scheme 2.11). The conditions were modified by addition of
chlorobenzene as co-solvent. Despite electronic differences with acetonitrile,'^'
chlorobenzene was an acceptable co-solvent due to its inert nature and its structural
similarity to the aromatic tribromides 83b-e. Typically, the three step combined yield
from alkylation of 83b-e to hydrolysis of the isonitriles 86b-e followed by debromination
to the amine esters 85b-e varied between 26% to 47% yield and depended upon the
nature of the R group.
69
Scheme 2.10. Formation of the 1,4-Dimethoxy Isocyanate Ester and Amine
OCH OCH
CNCHjCOjEt, K2CO3, NBU4I, ACN, reflux
NC
COjEt
OCH,
84
HCl, EtOH
100%
Table 2.1. Di Alkylation of 2,3-(^i'^-Bromomethyl)-l,4-Dimethoxybenzene
Runs Scale time PTC (0.2 eq) K2CO3 CNCHsCOaEt % yield
of 84
1' 300 mg 3h TBAHS 6 eq 1 eq 57%
2 600 mg 1 6 h TBAHS 6 eq 1 eq 24%
3 2g 3.5 h TBAHS 12 eq 1 eq 28%
4 2g 12 h TBAI 12 eq 1 eq 33%
5 l O g 1 8 h TBAI 12 eq 1.1 eq 44-47%
® Reported conditions and yields, S. Kotha, E. Brahmachary, J. Org. Chem. (2000) 65
1359-1365.
70
Scheme 2.11. Formation of Indane Derived a-Amino Esters 85b-e
OR
OR
(1) CNCH2C02Et, K2CO3, NBU4I
ACN:PhCl, reflux C02Et
83
83b R = «-C6H,3 83c R = ^-CgHiv 83d R = "-C12H25 83e R =
83f R = [CH2CH20]20CH3
86 86b R = «-C6H,3 86c R = w-CgHiv 86d R = «-C,2H25 86e R = 18^37 86f R = [CHsCHjOlsOCHg
OR
85
NH,
CO.Et
(2) HCl, EtOH:AcOEt (3 H2, Pd/C, EtOH:AcOEt
85b R = «-C6HJ3 28% 85c R = w-CgHjy 24% 85d R = «-Ci2H25 47% 85e R = n-Ci8H37 33% 00 R = [CH2CH20J20CH3 26% (4 steps from 82f)
The reaction mechanism illustrates why such low <i/-alkylation yields are
generated from the dibromide 70a and tribromides 83b-f (Scheme 2.12). L. Ridvan and
J. Zavada found in the carbanion alkylation of substrate 87 (R = H) that formation of the
oligomerized product 90 competed unfavorably with formation of the di-alkylated
1 198 product 92. ' The success of the reaction was dependant upon the absolute acidity of
the conjugate carbon acid of 88. N-protected glycine esters (pKg = 18-20), such as ethyl
isocyanoacetate or N-Shiff base glycine esters, formed acyclic products and oligomers
(89 and 90) in preference to the desired di-alkylated material 92. Malonic esters and
nitriles, which are more highly acidic (pKa = 8 - 15),'°^ preferred formation of the di-
alkylated product 92. Torsion strain between the bromine atom (oriented for SNi attack)
and the ring substituents (when R 7^ H) in the second alkylation step (91 -^92) was not
considered, and yet might be a contributing deterrent to Jz-alkylation. A case proof was
observed in the JZ-alkylation of 1,2-Z)w-bromomethylbenzene (R = H) with ethyl
isocyanoacetate, which formed the cyclic product at a higher rate and yield (5 h, 66%)
than ^/-alkylation of 2,3-Z)w-bromomethyl-l,4-dimethoxybenzene (R = OCH3) (18 h,
47%).
Scheme 2.12. Mechanistic Considerations in Mono- versus Di Alkylation
72
R
Br
Br
R
87
V /COiEt ©(
NC 88
Q^COsEt COjEt
COjEt
COsEt C02Et
COoEt
Table 2.2 summarizes the yields of indane derived a-amino esters obtained
previously under Kuki conditions (using N- benzylidine glycine ethyl ester as alkylating
agent) and those obtained via the Kotha method (using ethyl isocyanoacetate as
alkylating agent). Kuki chemistry appears to generate the indane amino acids in a higher
yield. While the methyl 85a, dodecyl 85d, and octadecyl 85e yields obtained using Kotha
chemistry are comparable with typical Kuki yields (between 30% to 40%), the hexyl 85b
and octyl 85c yields obtained by the Kotha method are lower. Generation of the indane
amino acid 85b-e from the tribromide 83b-e using the Kotha method takes 3 steps;
alkylation, hydrolysis of the isonitrile, and hydrogenation. Kuki chemistry requires only 2
steps: alkylation and hydrogenation. A preference for Kotha over Kuki chemistry lies
soley in the ease and economy of the alkylation conditions. Kuki conditions are
rigorously anhydrous, require a strong and expensive base (NaHMDS), and have an
extremely high dilution ratio (200 mL dry THF/mmol of tribromide). A typical Kuki
procedure called for 15 g of tribromide (R = C2H5) in 1.8 L of dry THF solvent to obtain
4 g of the indane amino ester. On the other hand, while the Kotha alkylations were
conducted under inert atmosphere, the procedure did not require dry solvent, the base
used was mild and inexpensive (K2CO3), and the dilution ratio was reasonable (20 mL
solvent/mmol of tribromide).
The amino esters 85a-f, N-Boc protected to 93a-f, were hydrolyzed to the N-Boc
acid 94a-f (Scheme 2.13). Under standard peptide coupling conditions the C12 acid 94d
with C12 amine 85d, the Cig acid 94e with C18 amine 85d, and PEG acid 94f with PEG
amine 85f, cleanly generated the coupled products 95d-f (Scheme 2.14). The coupled
material 95d-f, each vacuum sealed in a Pyrex® glass tube, were thermolyzed to the
diketopiperazines 96d-f. While the utility of the PEG DKP 96f has not yet been
explored, production of such a diketopiperazine bearing sensitive functionality should
endorse the mildness of this optimized synthetic protocol.
74
Table 2.2. Indane a-Amino Esters 85 by the Kuki and Kotha methods
OR
NH
OR
R Kuki' Kotha"'®
85a CHs 35%' 47%"
85b C6H13 46% 28%
85c C8H17 34% 24%
30%®
85d C12H25 47%
85e C,8H37 33%
^Reaction conditions: (1) Benzylidine glycine ethyl ester, NaHMDS, di/tribromide, THF,
-78 °C to RT; (2) H2, 10% Pd/C, EtOH ''Reaction conditions : (1) CNCH2C02Et, K2CO3,
di/tribromide, acetonitrile, (PhCl), reflux 80-90 °C (2) HCl, EtOH, (AcOEt) (3) H2, 10%
Pd/C, EtOH, (AcOEt) ^Reaction conditions: (1) Benzylidine glycine ethyl ester,
NaHMDS, di/tribromide, THF, -78 °C to RT; (2) HCl, Et20 ''Reaction conditions: (1)
CNCH2C02Et, K2CO3, dibromide, acetonitrile, (PhCl), reflux 80-90 °C (2) HCl, EtOH,
(AcOEt) ®Yields obtained by the author
75
Scheme 2.13. Formation of Indane N-Boc Protected Amino Acids
NH,
COjEt
B0C2O, DCM
heat
NHBoc
C02Et
85a r = CH3 93a r = ch3 88%
85b r = «-c6h,3 93b r = "-c6h,3 99%
85c r = ^-cghjy 93c R = n-cghjv 57%
85d r = "•c12h25 93d r = ""c12h25 92%
85e r = n-cjghsy 93e r = "'"c]8h37 98%
85f r = [ch2ch20]20ch3 93f r = [ch2ch20]20ch3 47%
OR
KOH, HjOiEtOH
heat
OR
94
94a r = CH3 75%
94b r = «-C6H,3 91% 94c r = n-CsHn 86% 94d r = n-ci2h25 68% 94e r = '^-ci8h37 98% 94f r = [ch2ch20]20ch3 92%
NHBoc
76
Scheme 2.14. Coupling and Thermolysis to Diketopiperazines
OR OR
NHBoc
CO2H
EtOjC
94d R = n-C,2H25 85d R = «-C,2H25
BOP, DABCO, DMF
OR OR
265 °C
NH
OR OR
95d R = n-Ci2H25 77% 95e R = «-C,sH,7 68%
OR OR
HN
OR OR
•NH
OR
96
96d R = n-C,2H25 79% 96e R = «-C|8H37 72% 96f R = [CH2CH20]20CH3 8% two steps
77
Section 2.5. Differential Scanning Calorimetry and Optical Microscopy of DKP
The liquid crystal is that so-called "fourth state of matter" between the highly
ordered crystalline solid (anisotropic) and the highly disordered liquid (isotropic), and
129 130 possess gradations of order termed mesophases (chlolesteric, smectic and nematic). "
The smectic mesophases (>13 classifications) display both positional and directional
order. The most disordered of all the mesophases, the nematic, has only directional order
(Scheme 2.15).
Scheme 2.15. The Liquid Crystalline Phases
Increasing disorder
M i l M M M i l n i l
SoHd
M M Liquid Crystal Liquid
Smectic C Smectic A Nematic
78
Liquid crystalline compounds typically have long chain aliphatic substituents
attached to a rigid molecular axis.'^"'^ This rigid core possesses a directional capability
which aids in keeping the organized supermolecules' alkyl substituents in close
proximity. Such liquid crystalline compounds are classified according to their chemical
structure as a rod-like97, discotic 98, or polymeric 99 (Figure 2.6).
N III C
97
C s H i ,
(CH2)rro
n-hexyl
^n-hexyl O O
n-hexyl .0
T o o
o o
O n-hexyl
n-hexyf O
98
0.^0
n-hexyl
\ . / CN
99
Figure 2.6. Examples of Liquid Crystalline Materials
79
It is with little surprise that the 1,4-alkyloxy diketopiperazines exhibit liquid
crystalline properties (Figure 2.7). The diketopiperazine organize as hydrogen bonded
tapes with aliphatic side chains extending outward and perpendicular to the tape. Close
packing of adjacent hydrogen bonded tapes keeps the alkyl substituents in interactive
proximity. Energy input (heat) to the DKP solid initially disrupts this ordering of the
alkyl chains via van der Waals (solid^liquid^crystalline). As energy input to the DKP
increases, the alkyl substituents disorder increases. The hydrogen bond is the strongest of
the diketopiperazines associations and the melting point marks its complete disruption
(liquid crystalline^liquid).
This energy interchange between the solid, liquid crystalline and liquid phases is
monitored primarily by three techniques. Differential scanning calorimetry (DSC) is used
to detect small energy differences associated with modifications in the molecular
ordering. Polarized optical microscopy visually detects liquid crystalline phases by
changes in birefringence (reflection of cross polarized light). Powder X-ray diffraction is
a more recent technique used to identify X-ray scattering diffraction patterns associated
with different phase transitions.
The liquid crystalline C12 DKP 96d and Cig DKP 96e were characterized using
DSC and optical microscopy. DSC data was collected under nitrogen (N2) beginning
with the second heating run at 5 °C per minute from - 20 °C to 200 °C, and cooling at 5
°C per minute to -20 °C. The optical microscopy studies were conducted with thin films
of the diketopiperazine prepared between two glass plates. The sample was heated under
80
Na above the isotropic phase (215 °C), held for 5 minutes, and then cooled slowly. Aided
by the DSC data, photographs were taken before and after each apparent phase transition.
The Ci2 DKP 96d underwent an initial phase transition at 39 °C, and then a
second transition (melt) at 199 °C to the isotropic phase (Figure 2.8).
movement of alkyl tails
'slippage" of alkyl tails (mesogen)
doubly enforced hydrogen bonded tape (rigid rods)
Figure 2.7. Thermogenic Liquid Crystalline Diketopiperazines
81
The cooling curve of the C12 DSC spectra corresponds with the changes in
birefringence recorded by optical microscopy (Figure 2.9). As the temperature dropped,
a dramatic transformation occurred from the isotropic liquid to a birefringent liquid
crystal between 190 °C to 187 °C. A more gradual change was noted from that first
transition at 187 °C to the second at 29 °C. These texturation and coloration differences,
while subtle, are indications of changes in molecular ordering.
33.25 °C AH = 14.72 J/g
cooling 191.10 °C AH = 13.52 J/g
38.89 °C AH= 13.75 J/g
heating
198.82 °C vy AH = 13.52 J/g
Figure 2.8. Differential Scanning Calorimetry of the C12 DKP
82
/
N
/ •
/ '
• I'' *
29 °C
Figure 2.9. Optical Microscopy of the C12 DKP Phases
The C18 96e DSC trace (Figure 2.10), similar to the C12, contains lower
temperature phase transitions, yet the Cig DSC spectra is disappointingly asymmetric and
lacks a melt transition. Repeated attempts with larger or smaller sample sizes did not
83
improve the obtained results. In fact, the small cooling transition at 141 °C was not
typically observed in repeated DSC experiments.
Freezing point DSC data (isotrope^liquid crystal) of the entire 1,4 alkoxy-DKP
family^' was plotted against the length of the carbon chain (R) and an equation of the line
was obtained by linear regression analysis (Microsoft Excel) (Figure 2.11). The
calculated Cig 96e freezing point temperature of 138 °C correlates well with the actual
phase temperature at 140 °C (Table 2.5). The optical microscopy photographs indicate a
phase transition occurred between 140 °C to 138 °C upon cooling from the isotropic
liquid to a birefringent liquid crystal, followed by more gradual phase transitions at a
lower temperatures (picture taken at 36 °C) (Figure 2.12).
64.05 °C AH = 14.18 J/g
S i-lU o x; w 140.2rc
AH = 1.40 J/g
65.65 °C ' AH = 17.60
Figure 2.10. Differential Scanning Calorimetry of the Ci8 DKP
84
310
290
S5 270
JJ a> U 250
230 o a. bJ)
.E 210 N a> 0) £ 190
170
150
10 12 14
carbon chain length
Figure 2.11. Linear Relationship Between Carbon Chain Length and Freezing Point
Table 2.3. 1,4-Alkyloxy Diketopiperazine DSC Freezing Temperatures
Carbon chain length (R) Freezing point (°C)
25b C2H5 281 °C
25c C4H9 271 °C
25d CeHis 247 °C
25e CgHn 233 °C
68d C12H25 191 °C
68e C,8H37 138 °C (calcd)'
'^calculated from the equation of the line y = - 9.18x + 303 (R^ = 0.99), x = carbon chain
length and y = Freezing Point (Celsius). Obtained from fitting the experimental data by
linear regression (Microsoft Excel).
200 °C 134 °C
36 °C
Figure 2.12. Optical Microscopy of the CigDKP Phases
86
Section 2.5. X-Ray Crystallography of the C12 Diketopiperazine
While crystallization attempts with Cig DKP 96e generally led to waxy and
amorphous residues, it was possible with some effort to obtain microcrystalline C12 DKP
96d. Since there was difficulty in obtaining meaningful data by X-ray crystallography
(most likely due to the small size of the crystals ~ 0.07mm x 0.03mm x 0.02mm), a
microcrystalline sample was sent to the Argonne National Laboratory DND-CAT
(DuPont-Northwestern-Dow Collaborative Access Team) Synchotron Research Center,
Argonne, IL (Figure 2.13). Data collection provided reflections which allowed for the
determination of the C12 DKP crystal structure.
HN- HN-
•NH •NH
96d 96e
Figure 2.13. The New 1,4-Alkyloxy Diketopiperazines
Surprisingly, the crystal is made up of four conformationally different C12 DKP
molecules (their relative ratios undetermined) containing either planar or flattened boat
diketopiperazine rings, and with varying degrees of alkyl chain disorder. One can
speculate that this disordered conglomerate is a result of poorly controlled (fast)
87
crystallization conditions. The C12 DKP conformers have been assigned on the basis of
DKP ring planarity, indane ring puckering and conformations of the dodecyloxy
substituents, with Conformer 1 being the most ordered and Conformer 4 being the least
ordered.
The dihedral angles, v|/, (j), co, commonly used in the characterization of amide
bonds in peptides, define the DKP ring (Figure 2.14).'^^ Conformer 1 and 2 are identical,
with virtually flat DKP ring systems (v|/ = (|) = © = 0.32°) (Table 2.4). Conformer 3 and 4
both deviate from this planarity and take on a flattened boat conformation, with
Conformer 4 departing most significantly from planarity. The dihedral angle x, measured
from both the DKP ring nitrogen (N) and the gamma carbon (C^), define the relative
orientation of the indane ring to the DKP ring (x*^) and the cyclopentane conformation of
the indane ring system (for flat rings, x^ = 0°) (Figure 2.14). Conformer 1 through 4
share similar x torsion parameters, with the spiro-fused indane ring oriented
perpendicular (x"^ = 78.3° - 85.4°) to the DKP ring, and slightly puckered (x*" = 29.8° -
32°) towards the DKP carbonyl carbon (C').
Figure 2.14. Diketopiperazine Carbon Assignments and Torsion Angles
88
Table 2.4. Diketopiperazine and Indane Ring Torsion Angles
Dihedral Conformer Conformer Conformer Conformer
angle 1 2 3 4
NC^C'N (V|/) 0.32° 0.32° -4.83° -4.83°
C'NC"C' ((|)) 0.32° 0.32° 3.88° 12.9°
C"NC'C" (0) -0.32 ° -0.32 ° 5.51° -4.09°
Nc«cPc^
(X^)
83.5°, -84.5°,
84.5°, -83.5°
83.5°, -84.5°,
84.5°, -83.5°
-85.0°, 85.2°,
-78.3°, 85.4°
-85.0°, 85.2°,
84.5°, -83.5°
CYCPC«CP
(x^)
30.8°, -32.0°,
30.8°, 32.0°
30.8°, -32.0°,
-30.8°, 32.0°
29.9°, -30.6°,
29.0°, -30.0°
29.9°, -30.6°,
-30.8°, 29.8°
Long chain aliphatic systems (R > C7H15) typically adopt zig-zag (all trans)
conformations which serve to maximize close packing between molecules.^'
Conformers 1 to 4 adopt a mixture of all trans with end-tail "kinks", and gauche turns.
Conformer 1 is the most ordered of the series with a symmetric assemblage of all trans
chains with "kinks" and gauche turns starting at the aryl ether oxygen (Figure 2.15).
Conformer 2 is much like Conformer 1, sporting the same symmetric disordered
compilation of all trans with end tail "kinks", and aryl ether gauche turns (Figure 2.16).
Conformer 2 is different from Conformer 1 in that the gauche turned alkyl chains are
rotated out of the plane of aromatic indane ring system.
89
all trans
gauche
gauche
all trans
Front View
Figure 2.15. C12 Diketopiperazine, Conformer 1
90
all trans
)
r all trans
rotated out of plane
rotated out of plane
kink
r-gauche
' gauche
kink
Front View Side View
Figure 2.16. C12 Diketopiperazine, Conformer 2
While the alkyl conformations (the all trans, "kinks" and gauche turns) of
Conformers 1, 2 and 3 are similarly related, Conformer 3 is extremely disordered (Figure
2.17). The all trans alkyl chains are canted oppositely from the all trans chains of
Conformers 1 and 2, and the gauche turn begins in-chain instead of at the aryl ether.
Additionally, a small segment of one alkyl chain is twisted out of the plane of the other
substituents.
91
all trans
gauche
gauche rotated out of
all trans
slight kink
%
kink
Front View Side View
Figure 2.17. C12 Diketopiperazine, Conformer 3
Conformer 4 differs from the rest by containing asymmetric gauche turns and
asymmetric dW-trans conformations laterally related (Figure 2.18). Assuredly, Conformer
4, with the most significant DKP ring bend, is the highest energy and most disordered C12
DKP conformer. Above the plane of the DKP ring, one alkyl substituent (left, above) is
rotated out of the plane of the indane ring system, and contains an aryl ether gauche turn.
The other alkyl substituent (right, above) contains an in-chain gauche turn. Below the
plane of the DKP ring, two alkyl substituents exist in the d\\-trans conformation, with one
92
(left, below) rotated out of plane and the other (right, below) containing an end tail
"kink".
rotated out of plane
gauche
all trans rotated out of plane
gauche
kink
Front View Side View
Figure 2.18. C12 Diketopiperazine, Conformer 4
Figure 2.19 and Table 2.5 quantify the disordered alkyl groups of Conformer 1, 2,
3 and 4 into dihedral angle measurements. The dihedral angle 6 (Figure 2.19) describes
93
the substituent orientation relative to the flat indane aromatic system (for an in-plane
substituent, 5 = 180 °). From the tabulated results, it becomes clear that while Conformer
1 through 4 are dissimilar, their conformational differences are subtle and regular (Table
2.5). Out of plane rotations (5) are generally between 161° to 168°, the end "kinks" range
between 74° to 87°, and gauche turns — whether measured from the aryl ether or
carbon ~ fall between 61° to 67°.
,H lOc
OA/X/XAAAA^
Figure 2.19. Dodecyloxy Chain Carbon Assignments and the 5 Torsion Angle
94
Table 2.5. Dodecyloxy Chain Conformations and Torsion Angles
Dihedral angle Conformer
1
Conformer
2
Conformer
3
Conformer
4
C^-C-O-C'" 174.4°, 174°, 161.2°, 173.3°, 168.6°, 176.6°, 168.6°, 176.6°,
(5) 173.3°, 174.4° 173.3°, 161.2° 169.0,173.9° 163.9°, 157.2°
^ 1 c^2c^3c^4c
(all trans)
-179.0°, 180° -179.0°, 180° -177.8°, 176.1° -177.7°, 138.0°
(kink)
74.8°, -74.8° 74.8°, -74.8° 87.6°, 112.5° 87.6°
OC"C^'C^'
{gauche)
63.0°, -63.0° 67.6°, -67.6° -87.4° -67.8°
{gauche)
61.2° 61.2°
The C\2 DKP supermolecule organizes much like the other members of the 1,4-
dialkyloxy DKP family [Section 2.1] by forming one-dimensional hydrogen bonded tapes
laterally related to each other in a herringbone fashion (Figure 2.20), and vertically
associating via van der Waals interactions with interdigitated dodecyloxy substituents
(Figure 2.21). However, it is not surprising that the C12 DKP crystal structure, as a
consequence of its disorder, displays some minor organizational differences from the
other alkyloxy diketopiperazine crystal structures.
95
Figure 2.20. C12 DKP Tapes with Lateral Edge-to-Face Neighbors
Figure 2.21. Vertically Interdigitated and Disordered C12 DKP Tapes
96
Table 2.6 is a summary of the important non-bonding distances obtained from the
C2 (ethyloxy) DKP 52b, C4 (butyloxy) DKP 52c and C12 (dodecyloxy) DKP 96d crystal
structures (Figure 2.22).^' The C2 and C4 diketopiperazines form identically spaced
hydrogen bonded tapes, with an N—O distance of 2.8 A. The C12 DKP, on the other
hand, forms longer (weaker) and canted hydrogen bonded tapes, with N—O distances of
2.9 A and 3.7 A. Upon a close perusal of the Cn DKP crystal structure (not shown),
conformers of low disorder (Conformers 1 or 2) are hydrogen bonded to conformers of
high disorder (Conformers 3 or 4).
The arene-to-arene and van der Waals tabulated measurements indicate that the
C2 DKP supermolecular structure is more closely packed than the C4 DKP or C12 DKP
supermolecule (Table 2.6). The C2 DKP tapes are laterally related by close arene-to-arene
contacts (H-to-centroid 2.67 A), while the C4 DKP and Cn DKP hydrogen bonded tapes
are too far away for arene associations (H-to-centroid 3.1 A - 4.7 A) and can only mimic
the C2 diketopiperazines' familiar herringbone motif. The C2 DKP interdigitated ethyloxy
chains closely pack together in an a\\-trans fashion, with measured hydrogen-to-hydrogen
distances falling roughly between 2.57 A - 3.12 A. The C4 DKP, on the other hand,
contains interdigitated butyloxy chains with minor gauche disordering resulting in
lengthier hydrogen-to-hydrogen intermolecular distances of 2.60 - 3.48 A. Not
surprisingly, the highly disordered C12 DKP supermolecule contains a varied collection of
hydrogen-to-hydrogen intermolecular distances. Adjacent aW-trans substituents are
closely related (1.97 - 3.73 A), but adjacent gauche containing substituents are too far
away (5.57 - 7.33 A) for these van der Waals associations.
Table 2.6. Intermolecular Distances of C2, C4 and C12 Diketopiperazines
Measured values C2 DKP 52b C4 DKP52C C12 DKP 96d
4N,0) 2.84 A 2.81 A 2.91 A, 3.65 A
H-to-centroid 2.67 A 3.53 A 3.10 A, 4.69 A
Centroid to-
centroid
4.89 A 5.77 A 5.40 A
4H,H)
(van der Waals)
2.57-3.12 A 2.60-3.48 A 1.97-3.73 A (all-?ra«5)
5.57 - 7.33 A {gauche)
OR OR
OR OR
52b R = C2H5 ethyloxy 52c R = c4h9 butyloxy 96d R = C]2H25 dodecyloxy
Figure 2.22. The C3, C4 and C12 Alkyloxy Diketopiperazines
98
Section 2.6. Conclusions About the 1,4-Alkyloxy DKP Family
Does an increase in alkyloxy length propagate further disorder? Most certainly
this is the case. While this might be a circumstance of poorly controlled nucleation and
crystal growth, increased alkyl chain disorder is observed progressing from the C4 DKP
to C12 DKP crystal structure. Did a substantial growth in alkyl chain length overcome the
dominant organizational role of the hydrogen bond? In this case, hydrogen bonding is the
strongest of the non-bonding interactions and no matter the alkyl length - from
methyloxy (Ci) to dodecyloxy (Cn) ~ this motif remained constant. What is the length
limit in obtaining good crystals of this DKP family? Crystallization attempts of the
octyldecyloxy (Cig) DKP were unsuccessful. Dodecyloxy might be the alkyloxy chain
length limit for this series of diketopiperazines.
Chapter 3
Synthesis and Characterization of an N-Me Diketopiperazine
100
Section 3.1. The Physical Properties of Amides and Diketopiperazines
It is well known that strong associations via hydrogen bonding exist between the
donor NH and acceptor C=0 functionalities of amides, lactams, amino acids and the like,
I 0-3 and that these associations are fundamental in influencing protein secondary structure.
Investigators have worked to define non-covalent interactions, such as hydrogen bonding,
through simplified model systems in the interest of better understanding protein structure
and the thermodynamics of protein folding (Figure 3.1). N-methyl acetamide (100), a
trans-mudc system, and the cw-amide lactams, y-butyrolactam (101), 5-valerolactam
(102), and s-caprolactam (103), were popular early prototypes and were generally
evaluated against each other.'*®''*^''^'^''^^
100 101 102 103
Figure 3.1. Early Hydrogen Bonding Amide Model Systems
Near-infrared (IR) studies involving 6-valerolactam (102), 8-caprolactam (103),
and N-methylacetamide (100) (NMA) indicated there is a strong tendency toward
molecular association amongst cis amides.At low concentrations, 6-valerolactam and
s-caprolactam molecules (1.5 mM and 0.7 mM in CCI4, respectively) were seen as
101
predominantly associated, while at an equivalent dilution (1.4 mM in CCI4) NMA
molecules were monomeric. Consistently larger values of cis amide systems reflected
a decrease in free energy associated with formation of an intramolecular hydrogen bond
(104a^l04b) (Figure 3.2).'*'^''^^ Deviation from linearity of the NH absorption band
upon changing the temperature or concentration indicated a preference of NMA to form
oligomeric hydrogen bonded chains 105 in solution."^^ '^^ '^^ Dielectric studies confirmed
this assumption. A slight increase in the concentration of NMA caused a substantial
increase in the dipole moment, indicating an expansive self-association leading to highly
polar multimers."^^
T H
104b 105
Figure 3.2. Cis and Trans Amide Associations
102
Other geometric factors affected hydrogen bonded associations within the lactam
model systems. Vapor pressure osmometry (VPO) measurements indicated that hydrogen
bonding associations were highly dependent on ring size (Figure 3.3).'^^ The smaller the
ring size, the greater the association equilibrium constant (Kg) (106 > 107 > 102). This
trend in Kg values was attributed to the growing polarization of NH and C=0 groups
induced by increased ring strain. Additional differences in Ka values were observed upon
addition of methyl ring substituents. While N-Me lactams (such as 109) showed a
negligible amount of association, Ka values with a-methyl ring substituents (108) were
lower than their unsubstituted counterparts (107). Inductive effects as well as sterics were
argued responsible for this lowered self-association.'^^
Figure 3.3. Cis Amide Ka values from VPO Measurements in Benzene
Not surprisingly, amides in different solvents show large variations in self-
association (Table 3.1). For solvent systems with acidic or basic character, there is a
tendency to associate with either the basic C=0 or acidic NH sites of the monomer, thus
103
inhibiting dimerization."^' '^^ The equilibrium in such cases can be more accurately
described as the dissociation of a monomer-solvent complex to the association of a dimer.
M[solvent] + M[solvent] — M 2 + 2 [ s o l v e n t ]
Non-associating apolar aprotic solvent systems (CCI4, CS2) allow for the maximum in
association between monomers. It is important to remember it is the chemical nature of
the solvent that controls the equilibrium. While carbon tetrachloride (CCI4) and benzene
(C6H6) have similar dipole moments, the dimerization constant is smaller in benzene
1 (Table 3.1). Presumably, the solvation of the acidic NH group with the aromatic n
electrons hinders self-association.
Table 3.1. Average Dimerization Constants (K°) as a Function of Solvent
solvent Dielectric constant Cis lactams (K, M"')" NMA (K, M-')
CCI4 2.23 1 0 0 - 1 5 0 24
CeUe 2.28 2 0 - 4 5 6.1
CHCI3 4.70 1 - 3 2 . 7 - 2 . 8
dioxane 2.21 0.4 0.5
H2O 78.5 0.014 0.005
^ average K values obtained for a range of cis lactams systems. Table taken verbatim
from reference S. Krikorian, J P/ZJV5. C/zew. (1982) 86 1881-1885.
104
'H Nuclear Magnetic Resonance (NMR) spectroscopy is a more modern
technique used to examine hydrogen bond associations in amide model systems.
Elucidating the equilibrium has not been limited to observed changes in the NH
frequency as a function of temperature, concentration, and Small side chain
frequency temperature and concentration dependant shiftings occur relative to
conformational changes, and these minor frequency changes have been used to generate
equilibrium and association constants. ' '
Over time there has been a gradual progression to more complex amide model
systems (102^112) (Figure 3.4). The 2,5-diketopiperazine (DKP) (110), as a cyclic
dipeptide, was considered a more relevant hydrogen bonding model for proteins than the
• « 77 78 • • » simple cyclic amide 6-valerolactam (102). ' Enhanced acidic and basic rate constant
data of 110 over 102 indicated through-space electrostatic stabilizations existed similar
to those imbedded in the secondary structure of proteins. The ubiquitous DKP sub
structure can be found in biologically active compounds such as the antibiotics gliotoxin,
sporidesmin,'"^^ bicyclomycin,'"^'^ and albonoursin.
H3C T O
R R
102 110 111 112
5-valerolactam DKP 3,6 alkyl DKP 3,6 alky I N-Me DKP
Figure 3.4. Evolution of Amide Model Systems
105
The study of amide and DKP systems is not restricted to hydrogen bonding self-
associations. More complex N-Me DKP systems have been used to explore side chain
positioning in peptides and proteins. Due to the static nature of the diketopiperazine ring,
rotational freedom is limited to the substituents. 'H NMR and Circular Dichroism (CD)
studies indicate that alkyl substituents can take on axial, intermediate or equatorial
positions, depending upon their steric environment.'"'^ Interestingly enough, 'H
and CD'"'^ evidence suggest that aromatic substituents (113a versus 113b)
prefer to "hover" over the diketopiperazine ring in polar solvents (Figure 3.5). One theory
advocates the generation of a dipole-induced-dipole between the local dipole of the DKP
ring and the polarizable n electron cloud of the aromatic ring. A more plausible
argument suggests that this folding of the phenyl ring in polar solvent systems helps to
achieve minimum non-polar surface exposure with minimal solvent disruption.'''^
favored form
113a
CO HN. H
H disfavored form
113b
Figure 3.5. Aromatic DKP Conformations in Polar Solvents
106
The diketopiperazine 114 has held considerable interest in the Mash laboratory
from the perspective of crystal engineering. These amide systems have been designed
such that there can exist three linearly independent non-bonding interactions in the x, y
and z dimensions (Figure 3.6). X-ray crystal data of these systems indicates that
hydrogen bonding is the principal organizational element along the y molecular axis, with
the substitution pattern and chemical nature of the aryl R groups playing a more
secondary organizational role along the x and z axes.
O, H
R
O
R
H 114
hydrogen bonding
dipole-dipole arene-arene
van der Waals
van der Waals dipole-dipole arene-arene
Figure 3.6. The Indane-Derived DKP as a Crystal Engineering Model
107
There was an interest in correlating this solid phase understanding of the indane
DKP system to the solution phase. The initial study took on a minimalist position and
focused on the tetramethoxy indane diketopiperazine scaffold 115 (Figure 3.7). The
tetramethoxy DKP (R = H) is one of the simplest synthesized, but has low solubility in
both aqueous and organic solvents. Mono N-methylation (R = ch3) of this system had a
two-fold purpose. It increased solubility in more organic solvents, and it simplifed
analysis by limiting the number of hydrogen bonded dimerization sites. The synthesis
and solid, liquid, and gas phase analysis of cyclo - [(2 -methylamino - 4,7 -
dimethoxyindan - 2 - carboxylic acid)(2 - amino - 4,7 - dimethoxy indan - 2 -carboxylic
acid)] (115, R = ch3) is the subject of the current chapter.
O H
115
Figure 3.7. N-Me DKP (R = ch3) as a Model for Hydrogen Bonding
108
Section 3.2. Synthesis of the N-Me Diketopiperazine 129
Initial construction of the N-Me diketopiperazine followed synthetic protocols
88 90 established for the synthesis of other indane diketopiperazines (Scheme 3.1). ' The
indane amine ester 85a, generated under Kotha conditions (Chapter 2, Section 2.3),"'*
was originally protected as the N-Boc carbamate 93a. Generation of the N-Cbz
carbamate 116 was later found to be necessary.
Scheme 3.1. Synthesis of N-Me Boc and N-Me Cbz esters
OCH
NH
OCH
NHR
R7O = CBZ7O, B0C9O
85a 93a R = Boc, 88% 116 R = Cbz,84%
Surprisingly, the N-methylation of carbamates 93a and 116 was dependent upon
the sequence of addition (Scheme 3.2). It was found that injection of iodomethane into a
slurry of the carbamate and sodium hydride in DMF gave little to no reaction despite
prolonged heating and reaction times. On the other hand, when iodomethane was injected
into a gently heated solution of the N-carbamate in DMF followed by addition of sodium
109
hydride, an immediate and vigorous exothermic reaction occurred. Verification of a
complete reaction was noted by thin layer chromatography (TLC) in less than 1 hour.
Scheme 3.2. Reactivity Differences in a Sodium Hydride/Iodomethane System
OCH
NHR
CO,Et
OCH,
93a R = Boc 116 R = Cbz
(1)NaH, DMF (2) Mel
(1) Mel, DMF/THF (2) NaH
No Reaction
OCH
C02Et
OCH,
117 R = Boc 76% 118R = Cbz 80%
The peculiar circumstances involved in the N-methylation of the carbamates 93a
and 116 is unusual, but not unheard of in the chemical literature. In the N-methylation of
N-acetyl, N-benzoyl and N-carbobenzoxy amino acids, N. Benoiton and J. Coggins
reported the N-alkylation yields of N-Boc leucine increased from 37% to 96% upon
reversal of the normal sequence of addition.While the authors did not speculate on this
enhancement in yield, it can be argued that an alkoxymethylene-N,N-dimethyliminium
salt 119 is generated in situ from the reaction of DMF and iodomethane (Scheme 3.3).
Preparation of a similar reagent 120 from dimethyl sulfate and DMF has been reported in
148 the catalysis of Beckmann rearrangements.
110
Scheme 3.3. N,N-Dimethyliminium Salt From DMF and Methylating Agent
Me^
II Mel V A ^ A "I
H NMe, H NMej
119
O " Me^
X X H NMej H^^NMej SOjCg)
120
Two different synthetic routes, commensing with N-methylated carbamates 117
and 118, could be taken in the construction of the N-Me diketopiperazine (Scheme 3.4).
Either the carbamate protecting group (N-Boc or N-Cbz) could be removed to generate a
2° N-methyl amine 121, or the ester could be hydrolyzed to the acids 122 and 123.
Typically, peptide couplings of N-Me amino esters with acids are difficult and slow,
requiring use of expensive, albeit reactive, peptide coupling reagents which may or may
not generate the desired product in a reasonable yield.Saponification of 117 and
118 to their respective acids 122 and 123 was considered the more reliable route. Peptide
coupling of an amine to an a,a-disubstituted acid is less sterically demanding compared
to the coupling of an acid to an a,a-disubstituted secondary amine.
I l l
Scheme 3.4. Possible N-Me Indane Amino Acid Derivatives for Coupling
OCH CH
NH -Boc or -Cbz removal
OCH OCH CH 121
NR
OCH CH OCH
NR KOH, H2O, EtOH 117 R = Boc
118 R = C b z CO.H
och3
122 R = Boc, 87% 123 R = Cbz, 81%
Peptide coupling between the N-protected acids 122 or 123 and the amine ester
85a required a highly reactive coupling reagent due to steric congestion at the reaction
site. In general, phosphonium salt reagents such as BOP (124) and PyBOP (126) share a
lower reactivity in contrast to the halogenated analogues BroP (125), PyBroP (127) and
PyCloP (128) (Figure 3.8).Generation of toxic HMPA (129) as a coupling by
product makes use of BOP and BroP less attractive. Both PyBroP and PyCloP have been
112
found to be effective in coupling reactions involving either a,a-disubstituted amino
acids or N-Me amino acids.'^^''^'
r R
\ N-
/ L R
124 BOP R = R' = CH3,Y- OBt
125 BrOP R = R' = ch3, Y = Br
126 PyBOP R, R' = (CH2)4Y = OBt
127 PyBroP R, R' = (CH2)4 Y = = Br
128 PyCloP R, R' = (CH2)4 Y = - C I
Figure 3.8. Phosphonium Peptide Coupling Reagents
The reaction of the N-protected acids 122 or 123 with the amine ester 85a using
PyBroP (127) as activating agent yielded a surprising result ~ efficient peptide coupling
was dependent upon the N-protecting group (Scheme 3.5). The N-Boc acid 122 under
these conditions produced trace amount of coupled product, along with the symmetric
anhydride and other unidentified by-products. On the other hand, the N-Cbz acid 123
reacted quickly to form the coupled product 124 in high yield.
+ -P-
PF; -Y OBt =
H3C O CH3 ^ \ II / ^
N—P—N / I \
h3c a ch3 H.C CH,
HMPA 129
113
Scheme 3.5. Peptide Coupling of the N-Me Boc Acid versus N-Me Cbz Acid
OCH CH
85a, PyBroP, DIEA, DCM
NR
OCH OCH
OCH
122 R = Boc 123 R = Cbz
OCH OCH
124 R = Cbz97%
The literature documents a wide variety of cases where N-Boc amino acids tend
toward decomposition to N-carboxyanhydrides (NCA).'^'"'^^ J. Coste, E. Frerot, and P.
Jouin report in PyCloP mediated activation of N-Boc amino acids and N-Me Boc amino
acids that decomposition occurred more quickly and easily for N-Me Boc amino acids
(125^128) (Scheme 3.6).'^' Little to no NCA formation was observed in the PyCloP
activation of N-Cbz and N-Fmoc amino acids. The authors speculate that the extensive
NCA formation seen with N-Boc amino acids is due to the greater stability of the tert-
butyl cation over benzyl or fluorenylmethyl cations.
Scheme 3.6. Decomposition of N-Me-Boc acids
R . . R
'N
- P F 6
- Y
^ DIEAH+
O O
R
t-Bu^ 0^+ r / 0 ^ 0 P 4 N
125
activated N-Me N-Boc acid
R BocN
O R
R \ BocN.
CH, ^CH3
126
symmetric anhydride
+ t-Bu
128
N-Me N-carboxyanhydride (N-Me NCA)
127
115
The final steps of the synthesis of the N-Me DKP were straightforward.
Deprotection of the N-Cbz dipeptide 124 by catalytic transfer hydrogenation,'^'^ followed
by thermolysis, cleanly generated the desired N-Me DKP 129 (Scheme 3.7).
Scheme 3.7. Cyclization to the N-Me Diketopiperazinel29
OCH
124
OCH,
u C Et02C
NCbz
(1) 10% Pd/C, cyclohexene, EtOH (2) sealed tube, 260-265 °C
43%
OCH 3 H,C O OCH,
129
116
Section 3.3. Literature Survey of Some N-Me DKP Crystal Structures
A search of the Cambridge Structural Database (CSD) for cyclic dipeptides
possessing the parent structure N-Me 2,5 diketopiperazine 130 resulted in four N-
methylated DKP analogues with differing substitution patterns (Figure 3.9).'^^"'^^
O
H ,N
N
CH3
130
MPPAZD
O
131
CSARVAL CMALAL
BAJNOPIO FIFMEM
Figure 3.9. CSD Search Results of Mono N-Methylated DKP
117
An analysis of crystal structure parameters and crystal morphology revealed
several interesting features about N-methylation effects on the diketopiperazine ring
system. Comparison of cyclo(Gly-Sar) (MPPAZD) (130)'^^ with cyclo{G\y)2 (135)^^'^*'
and cyc/^ar) 2 (136)'^*' indicated that increased N-methylation of the DKP results in
significant deviations to ring planarity (Figure 3.10). The dihedral angle ((02) between
atoms c3-C1-N1-c4 increased from an approximately 0° in cydifAy) 2 to 4.7° and 7.1° in
cyclo{G\y-Sar) and cyclo{Sar)2 respectively.
H
•^3 2
H
135
cyclo(Gly)2
H N^O
I ch3
130
cyclo (Gly-Sar)
ch3
ch3
136
cyclo(Sar)2
Figure 3.10. Increasing DKP N-Methylation
Increasingly bulky alkyl substituents created additional structural deviations to the
DKP ring system (Figure 4.11). cjc/(Gly -Sar) (130) exits in a flattened chair
conformation.^^ Cyc/o(Sar-Z-Val) (CSARVAL) (131) (002 = 0.5°, 12.5°)'-"^ and cyclo(N-
Me-Z-Ala-Z-Ala) (CMALAL) (132) (02 = 5.3°)'^^ are boat conformers, with quasi-axial
substituents. Deviation of the DKP ring from planarity corresponds, from the cyclo(Sar-
Z-Val) (131) to the cyclo(N-Me-Z-Ala-Z-Ala) (132), with an increase of bulky
118
substituents. Considering the effect of N-methylation and alkyl ring substitution, it is with
little surprise that these DKP systems have been described as "flexible".^^
H
I CH3
130
cyclo(Gly-Sar)
H
1 ch3
131
cyclo(Sar-L- Val)
I ch3
132
cyclo (N-Me-L-A la-L-A la)
Figure 3.11. Increasing Alkyl Bulk to the N-Me DKP
2,5-Diketopiperazines generally organize in the crystalline state to form "ladder
like" hydrogen bonded tapes (Figure 3.12).^^'^^ Crystalline mono-N-methylated
diketopiperazines typically do not form cyclic hydrogen bonded interactions between two
molecules, but instead form linear chains. Of the mono-N-methlyated piperazinediones
studied, only cyc/o-(N-Me-Z-Phe-Z-Phe) (FIFMEM) (134)'^' forms cyclic dimers in the
solid state.
119
Figure 3.12. DKP Hydrogen Bonded Tape
When not impeded by steric bulk about the DKP ring, mono N-methylated
piperazinediones prefer to form linear hydrogen bonded tapes. Cyc/o(N-Me-Z-Ala-I-Ala)
(CMALAL) (132)'^^ and c;;c/o(Sar-I-Val) (CSARVAL) (131)'^'^ organize as simple
chains, with one molecule participating as both a donor and acceptor (Figure 3.13).
Adjacent hydrogen bonded chains associate via van der Waals interactions.
H'
Figure 3.13. Linear Hydrogen Bonded Chains of CMALAL (132)
120
Crystals of c>^c/o(Z-Phe-N-Me-Z-Abu) (BAJNOPIO) (133)'^^ form more complex
hydrogen bonded chains (Figure 3.14). The linear array contains two molecules (A and
B) with different hydrogen bonding requirements. Molecule A participates with one
donor site, and molecule B with 1 donor and 2 acceptor sites.
CH
O
Ph-Ph
H'
Ph Ph
'H
CH
Figure 3.14. Branched Hydrogen Bonded Chains of BAJNOPIO (133)
121
Section 3.4. X-Ray crystallography of N-Me Diketopiperazinel29
Polymorphic x-ray crystal structures were obtained from crystalline samples of
the N-Me Diketopiperazine 129 (Figure 3.15). The N-Me DKP molecule organizes as an
infinitely hydrogen bonded DKP chain (129a) (upon crystallization from chloroform and
diffusing diethyl ether) or as a cyclic hydrogen bonded dimer (129b) (from an
evaporating mixture of ethanol, chloroform and benzene). The polymorphic crystals
appeared dimensionally similar, and crystallized in the monoclinic space groups P2i/c
(dimer) versus P2i/n (tape). The N-H (uncapped) DKP analogue (43)^^ forms ladder-like
hydrogen bonded tapes (similar to other indane DKP systems), and crystallizes in the
monoclinic C2 space group.
OCH
versus
och3 ^ ^^3 och3 och3 ^ och3
Polymorphic N-Me DKP linear tape(129a) and dimer (129b)
43
Figure 3.15. The Polymorphic N-Me DKP
The general torsion angles v|/, (|), and co measure the degree of planarity of the
1 t 1 diketopiperazine ring (Figure 3.16). With the exception of v|/2, torsion angles
122
corresponding to i|/i, (|) and co are all slightly larger for the N-Me DKP 129a (tape) versus
N-Me DKP 129b (dimer), indicating that there is a greater deviation from planarity for
the linear hydrogen bonded tape (Table 3.2). Comparison of the dihedral angles y and (j)
of N-Me DKP 129b (dimer) and 129a (tape) to N-H DKP 137 (ribbon) shows that N-
methylation actually increases DKP ring planarity for this system. The torsion angle co,
defining the peptide bond, is similarly small for the N-Me DKP 129b (dimer) and N-H
DKP 105 (ribbon), but is slightly larger for the N-Me DKP 129a (tape). Despite these
differences, the bond angles for N-Me DKP 129a, 129b, and N-H DKP 43 deviate within
± 9 ° from each other, indicating a similar degree of planarity.
Figure 3.16. General Peptide Torsion Angles v|/, (j) and co
123
Table 3.2. Dihedral angles ij;, (j) and co defining N-Me DKP and N-H DKP
Dihedral angle N-Me DKP 129b
(dimer)
N-Me DKP 129a
(tape)
N-H DKP 43
N,-C,"-C,-N, (v|/,) 2.3° 1.5° 6.4°, 8.0°
N2-C2"-C2-N, (V|;2) -0.75° 3.7°
C2-N,-C,"-C, (^,) -7.2° -6.5° -12.1°,-10.3°
C,-N2-C2"-C2((t)2) -10.6° -4.1°
C,«-N,-C2-C2" (0,) 6.3° 3.9° 2.8°, 4.7°
C,"-C,-N2-C2" (®2) 9.9° 1.3°
Additional torsion angles describe the indane portion of the ring system. Torsion
angle x defines the degree of ring puckering to the DKP ring and torsion angle 5 the
orientation of the methyloxy substituent relative to the plane of the benzene ring (Figure
3.17). N-Me DKP 129a and 129b share similar 6 torsion angles, with the methyloxy
substituent oriented 160° - 180° away from the center of the molecule (Table 3.3).
Interestingly, N-Me DKP 129a and 129b are dramatically different in x- The N-Me DKP
129b (dimer) has a considerably smaller dihedral angle corresponding to the C2"-C2'^
bond (X2'), implying significant cyclopentane puckering of the C2 indane ring system.
124
C4 O4 o 3 o
\ ^ox,
Ci 0 / N2 cTvv c -2 _ C,
Figure 3.17. General Torsion Angles % and 5
Table 3.3. Dihedral angles x and 5 of the N-Me DKP Tape and Dimer
Dihedral angle N-Me DKP 129b
(dimer)
N-Me DKP 129a
(tape)
N,-C,"-C,P-C/(xi') 114.0°,-114.5° 108.6°, -108.4°
N2-C2''-C2^-C2HX2') 81.8°,-80.8° 138.4°,-138.9°
C,^-Ci'-03-C3(5,) 179.5°, 174.2° 163.0°, 174.5°
C2^-C2'-04-C4(62) 171.7°, 176.0° 167.4°, 169.8°
Reduced to their asymmetric units, visual comparison of N-Me DKP 129b
(dimer) and 129a (tape) indicate the indane ring conformations are dramatically different
125
(Figure 3.18). The N-Me DKP 129b (dimer) has one indane ring considerably bent
toward the hydrogen bonding side of the molecule, and the N-Me DKP 129a (tape) has
both indane rings slightly bowed toward its N-methylated side. This rigid and planar
indane ring system is reasonably flexible at the position and is oriented in different yet
energetically similar conformations to attain a closely packed supramolecular structure.
* ' V Front View N-Me DKP 129b (dimer)
Side View N-Me DKP 129b (dimer)
Figure 3.18. N-Me DKP Molecules
p
Front View N-Me DKP 129a (tape)
•V « > I V ^
Side View N-Me DKP 129a (tape)
126
The N-Me DKP 129b forms a C2 symmetric hydrogen bonded dimeric structure
(Figure 3.19). Based on the bond lengths and torsion angles tabulated (Table 3.4), the
two molecules are non-covalently bound between atom Ci and atom N2 by two very
linear and moderately strong hydrogen bonds.
Figure 3.19. Hydrogen Bonded N-Me DKP Dimer
Table 3.4. Hydrogen Bond Parameters for the N-Me DKP Dimer
N-Me DKP 129b (dimer) Measured Values
6(N2,0,) 3.65 A
KHi,0,) 1.94 A
N2-H1-O1 177.7°
H,-N2-CI-0, 0.9°
127
The interesting feature of the N-Me DKP dimer 129b is the symmetric edge-to-
face interactions of the C2 indane hydrogens with the Ci indane aromatic ring (Figure
3.20). The H to centroid distances (3.02 A and 3.48 A) are well within the accepted
limits of arene-to-arene associations (< 4 A) (Table 3.5).^
Co indane
Figure 3.20. N-Me Dimer, Edge-to-Face Interactions
Table 3.5. Arene Parameters for the N-Me DKP Dimer
N-Me DKP 129b (dimer) Measured Values
Edge-to-face (H to centroid) 3.02 A, 3.48 A
Face-to-face (centroid to centroid) 3.81 A
128
Lateral N-Me DKP dimeric neighbors closely pack in face-to-face fashion
between proximate Ci indane ring systems (Figure 3.21). Interdigitated methyloxy
substituents vertically fit within neighboring DKP ring cavities (Figure 3.22).
Figure 3.21. N-Me Dimer, Face-to-Face Interactions
I I *
Figure 3.22. Interdigitated N-Me DKP Dimer Molecules
129
The supramolecular structure of the N-Me DKP dimer 129b cohesively melds
these non-bonding interactions in three dimensions. Hydrogen bonded dimerization and
arene associations participate in a one-dimensional alternately hydrogen bonded and face-
to-face tape (Figure 3.23). Adjacent tapes closely pack to form a two dimensional sheet.
Interdigitated substituents associating by van der Waals interactions occur in the third
dimension (not shown).
close packing
X dimerization arene to arene
Figure 3.23. A Two Dimensional Sheet of the Dimer N-Me DKP Dimer
130
The N-Me DKP hydrogen bonded tape 129a contains a much more complex
infrastructure (Figure 3.24). The N-Me DKP forms a twisting and infinite hydrogen
bonded array involving atom Na of one DKP molecule and atom O2 of the other. The
hydrogen bond is of moderate length, yet considerably weaker in comparison to the dimer
form 129b due to its bent geometry (Table 4.6). The other acceptor atom Oi is left
unbound in this hydrogen bonded network.
Figure 3.24. Hydrogen bonded N-Me DKP Tape
Neighboring hydrogen bonded tapes are inverted, and associate via face-to-face
interactions with one another (Figure 3.25 and Table 3.7). In this way, hydrogen bonding
131
and arene-to-arene associations stabilize the N-Me DKP network in two dimensions.
Stacked closely packed two dimensional sheets make up the three dimensional
supramolecular structure (Figure 3.26).
Table 3.6. Hydrogen Bonding Parameters for the N-Me DKP Tape
N-Me DKP 129a (tape) Measured Values
b(N2,02) 3.61 A
KHi,02) 2.62 A
N2-H,-02 104.0°
H1-N2-C1-O1 -25.8°
I I I
Figure 3.25. Inverted Face-to-Face Interactions of N-Me DKP Tape
Table 3.7. Arene parameters for the N-Me DKP Tape
N-Me DKP 129a (tape) Measured Values
Face-to-face (centroid to centroid) 3.60 A, 3.73 A
hydrogen bonding
Ay
X • arene to arene
Figure 3.26. The Two Dimensional N-Me DKP Tape
133
Section 3.5. ESI-MS Gas Phase Analysis of the N-Me Diketopiperazine 129
"Soft" ionization mass spectrometric methods (those which produce little to no
fragmentation of parent ions) have, in recent years, proved to be invaluable in elucidating
the primary structure of large bio-molecules and polymers.'^' Electrospray Ionization
(ESI) and Matrix Assisted Laser Desorption Ionization (MALDI) are two "soft"
techniques which are used to analyze macromolecules larger than 10,000 Da. In contrast
to MALDI-MS, ESI-MS is performed in a homogenous solution and experiments can be
conducted under near physiological conditions of pH, concentration and temperature. The
ESI method surpasses MALDI in the ability to characterize supramolecular complexes
bound by non-covalent interactions, such as ion-ion, dipole-dipole, hydrogen bonding
and van der Waals.'^^"'^^ While the initial concentration of the solution unavoidably
increases during the spray and subsequent processes, gentle de-solvation of the ionized
vapor favors the detection of intact gas phase complexes structurally similar to complexes
formed in the liquid phase. From the stoichiometric composition and distribution of the
aggregates, one obtains information on the existence, aggregation state, and stability of
aggregates in the gas phase. The gaseous ion populations, in tandem with X-Ray crystal
structures, are used to indirectly verify solution state structural models and support
solution phase equilibrium distributions.'^^"'^^
Micromolar samples of the N-Me DKP were prepared in a 1:1:1 acetonitrile -
methanol - water solvent system, and analyzed by ESI-MS. Standard tuning conditions
using a Finnigan (Thermoquest) ICE Ion trap MS were employed for the experiment
134
(flow rate = 8 (j,L/min, spray voltage = 4.57 kV, sheath gas flow rate = 60, capillary
voltage = 26.05 V, capillary temperature = 200.3 °C). The relative intensity of the peaks
in the ESI spectra indicate a significant presence of hydrogen bonded dimer and
oligomeric ionized complexes in the 0.8 |j,M to 100 j^M concentration range (Figure
3.27).
[M +Hr
(O c (U
<u .> TO CD
Dfl
100-1
8 0 -
6 0 -
40-2 0 -
0 -
100 80 60 40-] 20
OH
100 8 0 -
6 0 -
40-2 0 -
0 -
100-. 8 0 -
6 0 -
40-2 0 -
0 -
[2M+Na]^
[2M +H]+ [3M+Na]+ [4M+Na]+
1 1 1 1 1 1
100 wM •1 T- T 1
20 [iM
9 n M
0.8 \iM
1 1 1 1 1 1 1 1 200 400 600 800 1000 1200 1400 1600 1800 2000
m/z
Figure 3.27. Concentration Dependence of Gas Phase N-Me DKP 129
135
For each concentration, the percent composition of the monomer, dimer, trimer
and tetramer hydrogen bonded states were obtained (Figure 3.28). An increase of the
dimer and trimer populations met with a decay of monomer from 0.8 |j,M to 20 |iM.
Population differences from 20juM to lOOjiM were less dramatic. A consistently small
amount (~1%) of tetramer (not shown) was present from 9 p.M to 100 |a.M, and did not
appear to increase or decrease with concentration.
100
r— 80 >
[2M+H]^ [2M+Na]
[M+H]
[3M+Na]
0
0 20 40 60 80 100
Concentration (}aM)
Figure 3.28. Percent Composition of Gaseous N-Me DKP Oligomers
136
Some conclusions can be made based on the ESI experiments. The remarkable
abundance of N-Me DKP hydrogen bonded dimer, trimer and tetramer gaseous ions at
very low concentrations argues that these are very stable aggregates in both the gas and
solution phase. X-ray crystallographic data supports this assumption. Polymorphic linear
hydrogen-bonded oligomers and cyclic dimers have been observed in the crystalline state
[Section 4.4]. It is interesting that the trimer and tetramer differ from the monomer and
dimer in that they are observed only as sodiated ions. The monomer and dimer are
arguably the predominant species throughout the concentration range, with the dimeric
species siphoning to minor amounts of trimer siphoning to even more minor amounts of
tetramer aggregate. Certainly there are several aggregation states likely for the dimer
(138 and 139), trimer (137 and 140) and tetramer population (Figure 3.29). While it is
possible that the gaseous and solution state dimers contains only one intermolecular
hydrogen bond (139), this is doubtful since formation of the second m/ramolecular
hydrogen bond is much more easily formed than the first m^ermolecular bond.'^^ The
added energy requirement to form a cylic dimer 138 is minimal considering the
stabilization the extra hydrogen bond will give to the aggregate. It is reasonable to
conclude that the solution state N-Me DKP exists chiefly in this cyclic state, with perhaps
minor amounts existing in the linear form 139. More direct solution state studies [Section
3.6 and 3.7] address this assertion.
137
Figure 3.29. Gas and Solution State Model of N-Me DKP Aggregates
138
Section 3.6. UV-VIS Analysis the N-Me Diketopiperazinel29
UV-VIS spectroscopy is a sensitive technique used to detect molecular
interactions at very low concentration levels.Spectral change, peak shifts and
deviations from the Beer-Lambert law occur when the analyte undergoes association or
dissociation to give species with different absorption characteristics.Calculation of
association constants can be extracted from experimental data. Use of computational
programs such as 'Ensfitter' from Biosoft and 'Origin 4.1' from Microcal Software allow
for the calculation of equilibrium constants, but this data requires knowledge of upper
and lower concentration limits (ie concentrations in which the analyte is in the fully
associated and fully dissociated form) and molar absorptivity values sq (monomer) and Sn
(associated species). One assumes that below the concentration where deviation
from Beer's law initially occurs there exists only monomer. If associations occur even in
very dilute solutions extrapolation of the experimental data to infinite dilution is a
1 lf\ necessary compromise.
UV-VIS experiments were conducted on solutions of the N-Me DKP in ethanol,
chloroform, and toluene at approximately the same concentration scale (10 )J,M to 100
|a,M). A range of solvents with different polarity and functionality is desirable in study of
the factors effecting self-association. In this case, the choice of solvents was limited by
the solubility of the N-Me diketopiperazine 129. The absorption measurements were
performed in the range 0.1<A<1.2, according to the general rule for photometric
measurements. Available quartz cuvettes with different pathlengths (1 mm and 10 mm)
139
were used to maximize values of absorbance. All UV-VIS experiments were conducted
on a Shimadzu spectrophotometer. Data acquisition was performed with Shimadzu
UVPC Photometric (version 3.9) software. The digitized data was converted in Microsoft
Office Excel to generate the overlayed absorption spectra and Beer's law plots (Figure
3.30-Figure 3.32).
Assignment of the n—>7r* and transitions were made based on differences
in the absorption spectra in ethanol (Figure 3.30) and toluene (Figure 3.32). The most
definitive criterium in assignment of the n—>7t* band is its complete disappearance in acid
media, or if in non-aqueous media, a corresponding decrease in the absorbance band with
an increase in solvent polarity.^^' The absorption band at 287 nm, diminished in ethanol
versus that in toluene, corresponds to the n-^Ti* transition.
No significant spectral shift changes are observed for experiments conducted in
chloroform (Figure 3.31) or toluene (Figure 3.32). In both cases the increasing absorption
with concentration is linear, conforming to Beer's law. More concentrated solutions of
the N-Me DKP 129 in chloroform (1.11 mM to 11.1 mM with a 1 mm quartz cuvette)
produced similar results (not shown). Of note is the missing transition band in
toluene. Presumably solvent complexation interferes with arene-to-arene associations.
140
Tt - 7t
<u o c XI
94.64
47.32
23.66
11.83
0.6
J 0.4
0.2
290 310 270 230 250 210
-0.2
Wavelength (nm)
200.5 nm
0.6 193.5 nm o C/3 <
286.5 nm
80 100 120 20 40 60 0
Concentration (hM)
Figure 3.30. Spectra and Beer's Law Plot in Ethanol. 11.8 |j,M - 118 ^iM
141
0.8
c 0.6
S 0.4
0.2
0.4
88.32
44.16
22.08
.04
235 255 275 295
Wavelength (nm)
315
287 nm
240 nm
0 20 40 60 80 100 120
Concentration (nM)
Figure 3.31. Spectra and Beer's Law Plot in Chloroform. 11.0 jaM - l lO^ iM
142
220 240 260 280
Wavelength (nm)
n - n
84.96
42.48
y 0.6 21.24
300 320
0.8
o 0.6 c cd X)
0.4
0.2
20 40 60 80
Concentration (nM)
286.5 nm
100 120
Figure 3.32. Spectra and Beer's Law Plot in Toluene. 10.6 )iM - 106 i^M
143
Ethanol, a polar protic solvent, inhibits hydrogen bonding between DKP
monomers. Consequently while the n—>71* transition at 287 nm is diminished, the
experimental data agrees with Beer's law. The transition, on the other hand, is
large and undergoes a small red shift fi-om 194 nm to 201 nm upon increasing the
concentration. Changes in 7t—>7t* transitions are consistent with aggregation phenomena
found in the UV absorption spectra of aromatic compounds.High energy parallel
associations (H-type, 141) result in blue shifts, while low energy co-linear associations
(J-type, 142) result in red shifts (Figure 3.33).
141 142 parallel, face-to-face, H-type colinear, edge-to-face, J-type
Figure 3.33. H-type and J-type Aggregation States
144
Edge-to-face n stacking interactions (J-type, 142) are predominant between
crystalline indane diketopiperazine tapes [Section 1.5], and are observed in the dimer N-
Me DKP crystal structure 129b [Section 3.4].^^ It is reasonable to conclude that these
interactions also exist in solution. Unfortunately calculation of the association constant
(Ka) in ethanol was difficult, requiring experimental (non-extrapolated) molar
absorptivity of the monomer species (so)-'^^ Future studies must work to isolate the
concentration range in which only monomer N-Me DKP exists.
145
Section 3.7. 'H NMR Analysis of the N-Me Diketopiperazine 129
Serially diluted 10.6 mM to 105.6 mM CDCI3 solutions were prepared of the N-
Me diketopiperazine 129 (Figure 3.34). The use of chloroform (an associating solvent
system) over a preferably inert solvent (such as CCI4) was necessary due to lack of
solubility of 129.
Figure 3.34. 105.6 mM CDCI3 solution of 129 at 25 °C (300 MHz)
146
While the '^C NMR data appeared unaffected by changes in concentration and
temperature, the 'H NMR spectra of the N-Me DKP 129 in CDCI3 was found to be both
concentration and temperature dependant. In particular, spectral shifts were noted for the
amide proton and aryl protons upon varying the concentration and temperature (Figure
3.35 and Figure 3.36). The chemical shifts (5H) of NH protons are generally
concentration and temperature dependant, and in amide systems are directly (and
mathematically) correlated to hydrogen bonding between the 0=C and NH moieties on
different molecules.^"^ '^^"''^'''^^''^^ This downfield movement, or deshielding, of the NH
proton is proportional to a rise in concentration (Figure 3.35) and decrease in temperature
(Figure 3.36), and reflects the increasing degree of NH hydrogen bonding with
electronegative carbonyl oxygens. The atypical result is the noticeable upfield movement
of one aryl proton to the other stationary, chemically different, aryl proton upon
increasing the concentration (Figure 3.35) and decreasing the temperature (Figure 3.36).
147
105.6 mM
79.2 mM
NH 59.4 mM
NH 44.6 mM
NH 33.4 mM
NH 25.1 mM
NH 14.1 mM
NH 10.6 mM
T—rn—I—I—I—I—I—!—I—I—I—I—I—I—I—I—I—r~j—i \ i—r*"]—r-r T T "H" T r~T T~i p~r
105.6 mM J \ l
79.2 mM / Vy \ /
59.4 mM yj Vy \/ NH^
44.6 mM
33.4 mM ^pXJ
25.1 mM / \ y N H
14.1 mM
10.6 mM
I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I r I I I I I I I I I I I I I I I I I I I I I I I I I I I I I
6 . 7 5 6 . 7 0 6 . 6 5 6 . 6 0 6 . 5 5 6 . 5 0 6 . 4 5 6 . 4 0 6 . 3 5 6 . 3 0 6 . 2 5 p p m
Figure 3.35. Concentration Dependence of the Aryl and NH Protons
105.6mMat40°C
NH 105.6 mMat25
105.6 mM at-22 "C
T—j—I—I—I—I—I—I—I—I—I—]—1—I—I' '"I" {—I—\—r •m—r ! ' ' ' ' I ' ' ' -}—I—I—r T—I—!—r 1—J—r T T
7 . 1 7 . 0 6 . 9 6 . B 6 , 7 6 . 6 6 . 5 6 , 4 6 . 3 p p i t i
Figure 3.36. Temperature dependence of the Aryl and NH Protons
HSQC and HMBC 2D NMR experiments conducted on the 105.6 mM CDCI3 N-
Me DKP sample (10 °C, Briiker DRX-500) allowed for the complete 'H and '^C
148
assignment. Figure 3.37 depicts only the pertinent HMBC correlations. The moving aryl
proton, assigned as H2®, is present on the C2 indane ring system. Of note are the strong
correlations between each carbonyl carbon and a single H'^ proton (Figure 3.38). This
'J ^ o '2 170 , , large Jch coupling, based on the Karplus relation ( Jtrans> Jgauche), indicates 0° or 180°
orientation of the proton bond relative to the carbonyl carbon bond. These selective
interactions allowed for stereospecific assignment of the indane ring protons.
OCH OCH
6.55 ppm H
(moving)
HN-
,H 6.59 ppm
(stationary)
OCH OCH
Figure 3.37. Pertinent HMBC correlations of 129
3.03
11 pgauche "2
170.8 //
3.68
,0 H
H 3.18
' N H1
O CH3
3.63
Figure 3.38. Stereochemical Assignment of the Indane Ring Protons
149
The proton chemical shifts of other aromatic molecules have been found to
similarly move to higher fields upon increased concentration. These small upfield shifts
have been attributed to the magnetic anisotropy associated with the ring currents in
neighboring molecules. In an aromatic system, a ring current is induced above and below
the ring by an external magnetic field Bo when Bo is perpendicular to the plane of the
molecule (Figure 3.39).'^^ This rotating ring current induces a secondary magnetic field
opposing Bq above and below the plane of the ring, and reinforcing Bo at the periphery.
These differences in the effective magnetic field Beff give rise to anisotropic effects. The
shielding or de-shielding of a proton depends upon its orientation relative to the induced
magnetic current. The probability of a neighboring aromatic molecule habituating in or
near the "shielding cone" of another aromatic molecule is greater than at the "de-
shielding" periphery, and the resulting edge-to-face interaction is energetically
favorable. As the concentration of the aromatic solution increases, so the distance
between neighboring molecules decreases, and the protons of a neighboring molecule
will feel an increased "shielding" effect. The magnitude of these shifts vary with the
degree of aromaticity and ring size, but is generally on of the order of 1 ppm going from
180 a neat liquid to infinite dilution. For smaller concentration changes the differences in
chemical shift is less significant. Azulene in dioxane, from 3 mol % to 20 mol %
concentration units, shifts upfield between 0.1 ppm - 0.25 ppm, depending upon the ring
proton. For the N-Me DKP in CDCI3, even smaller shift changes of the motile aryl peak
were observed. From 10.5 mM (~ 0.1 mol %) to 105.6 mM (~ 1 mol %) the aryl proton
150
chemical shift moved upfield by 0.09 ppm (-20 °C), 0.06 ppm (25 °C), and 0.04 ppm
(40°C) with the respective increases in temperature.
shielding cone +
+ shielding cone
Figure 3.39. Shielding and Deshielding Cones of Benzene
Dramatic upfield shifts with only slight increases in concentration have been
attributed to more than just magnetic anisotropy. 'H NMR investigations of
181 182 183 porphyrins, cyclophanes, flourescent markers, and dyes have ascribed these
chemical effects to non-covalent molecular associations.Others have used the
observed shifts to rationalize conformational changes.Given that the upfield
shifting is due to the postulated assumptions (ti-tz stacking, intercalations, etc.),
manipulation of the chemical shift data can generate pertinent association (Kg) constants.
151
Questions arose concerning the exact nature of the upfield H2® proton shift upon
increasing concentration. While this movement is quite normal for aromatic containing
compounds, could these small spectral shifts ~ indicative of an increasingly shielded
environment ~ be due to minor tc-tt edge-to-face associations related to hydrogen bonded
interactions between molecules? What impact would the arene portion of the N-Me DKP
have on the spectral shifting without influence of a strongly associating hydrogen
bonding functionality? Upon visual dissection, the N-Me DKP scaffold can be divided
into simpler components: the chemically available l,4-dimethoxy-2,3-dimethylbenzene
(69a), dimethoxy indan (143) and the diketopiperazine cycle (N-Me-Aib Aib) (144)
(Figure 3.40).
OCH3 ^ OCH3
OCH3 ^ *^^3 OCH3
1,4-Dimethoxy-2,3 dimethyl benzene
O CH. 144
c>^c/o(N-Me-Aib-Aib) OCH3
143
4,7-Dimethoxy-indan
Figure 3.40. The N-Me DKP Skeleton Simplified
152
Solutions of l,4-dimethoxy-2,3-dimethylbenzene (69a) in CDCI3 were prepared
by serial dilution, the concentration range employed (1.11 mM to 222 mM) comparable
in mol % to that used in the analysis of the N-Me DKP 129. The 'H NMR spectra of 1,4-
dimethoxy-2,3-dimethylbenzene (69a) is quite simple due to the symmetry of the
compound, and has one aryl peak at 6.65 ppm corresponding to the two aryl protons
(Figure 3.41).
OCH
69a
OCH,
7. 5
' I ' I 7 . 0 6 . 5 6 . 0 5 . 5 5 , 0 4 . 5 4 . 0 3 . 5 3 . 0 2 . 5 p p m
Figure 3.41. 222 mM CDCI3 solution of 69a at 25 °C (300 MHz)
The 'H NMR spectra of l,4-dimethoxy-2,3-dimethylbenzene (69a) in CDCI3 does
display a slight concentration dependence (0.015 ppm shift at 25 °C and 40 °C) but little
153
to no temperature dependence (Figures 3.42 and Figure 3.43). Interestingly, the aryl peak
moves oppositely from what was predicted and shifts downfield upon increase of
concentration (Figure 3.42). These molecules, deprived of hydrogen bond associations,
do not organize (at least in solution) in an edge-to-face fashion.
222 mM at 25 "C
11.1 mMat25'>C
"nn I I I I I r~i i ' i i | 1 I
6 . 9 5 6 . 9 0 6 . B 5 6 . 8 0 6 . 7 5 6 . 7 0 6 . 6 5 6 . 8 0 6 . 5 5 6 . 5 0 6 . 4 5 p p m
Figure 3.42. Concentration Dependance Studies of 69a in CDCI3
222mM at 40°C
222 mM at 25°C
• • j I I r~! j I I I ' I' [ I I T r*~| I I I F~1" r""!"'! "1"-j—1—1—1—1—j—1—i j \ | 1 1 1 r "j—m—1—1—| 1 1—1 1 | 1 1 1—r~
6 . 9 5 6 . 9 0 6 , 8 5 6 . 8 0 6 . 7 5 6 . 7 0 6 . 6 5 6 . 6 0 8 . 5 5 6 . 5 0 6 . 4 5 p p m
Figure 3.43. Temperature Dependant Studies of 69a at 25 °C and 40 °C
154
Early crystallography efforts of indane diketopiperazines indicated that solvent
systems with strong hydrogen donating and accepting capabilities prevented the
formation of hydrogen bonded tapes between DKP molecules. The X-ray crystal structure
of the /e/ra-(2,3-methyl) DKP 145 with included trifluoroacetic acid (TFA) explains this
trend: per one DKP molecule two TFA molecules are hydrogen bonded, effectively
capping the amide moieties of the DKP ring (Figure 3.44). If the N-Me DKP 129 aryl
movement is due to the hydrogen bonding associations between DKP molecules, the
addition of an appropriate amount of t/-TFA to the CDCI3 samples would result in little to
no concentration or temperature dependence.
Twenty microliters of J-TFA (0.4%) was added to the N-Me DKP CDCI3
samples, enough to prevent hydrogen bonding but not enough to not have an
overwhelming solvent effect. It was gratifying to see that upon addition of J-TFA, the
predicted outcome was observed. The increase in concentration resulted in static aryl
protons, with both aryl peaks, corresponding to H2'' and Hi^, shifting upfield only very
slightly at the highest concentration (Figure 3.45). Additionally there was no apparent
movement upon increasing the temperature (Figure 3.46). Most likely the miniscule up-
field shifting observed with increasing concentration is due to that concentration
dependent phenomena, previously mentioned, which is so typical of aromatic molecules.
155
145
2 . 5 8 0
2.890
Figure 3.44. Trifluoroacetic Acid (TFA) Capped DKP
156
105.6 mM with d-TFA
59.4 mM with d-TFA
44.6 mM with d-TFA
33.4 mM with d-TFA
18.8 mM with d-TFA
14.1 mM with d-TFA
10.6 mM with d^TFA
JVA
JVA_ 25.1 mM with d-TFA J\J\
JVA.
JVA_
JV7V_ 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 6.95 6.90 6.85 6.80 6.75 6.70 6.65 6.60 6.55 6.50 6.45 ppm
Figure 3.45. Concentration Invariance of 129 in 0.4% J-TFA/CDCls
105.6 mM wfth d-TFA at ACC
105.6 mM with d-TFA at 25°C
T ' ! I I t rn—r—|—i i i i }—i—i—i—i—|—j—i—i—i—j—i—i—i—i—[—i—i—i—i—]—i—i—i—i—j—i—rn—i—|—i—i—m—|—!—i—i—i—|—i—i—i—i—[
6 . 9 5 6 . 9 0 6 . 8 5 6 . 8 0 6 . 7 5 6 . 7 0 6 . 6 5 6 . 6 0 6 . 5 5 6 . 5 0 6 . 4 5 p p m
10.6 mM with d-TFA at 40'='C
10.6 mM with d-TPA at 25®C
"TT I I ' I rn I m I r-| i—m—i—^—i—m—i—| i >—i—i—pi—i t i—| i i—i—i—|—m—i—i—["n—rn—> \ i—\—i—r-pn—i—i—i—\
6 . 9 5 6 . 9 0 6 . 8 5 6 . 8 0 6 . 7 5 6 . 7 0 6 . 6 5 6 . 6 0 6 . 5 5 6 . 5 0 6 . 4 5 p p m
Figure 3.46. 0.4% J-TFA/CDCI3 Solutions of 129 at 25 °C and 40 °C
157
It is understood from the J-TFA data that the small upfield H2^ aryl shifts must be
an indirect result of hydrogen bonding associations between N-Me DKP molecules. The
exact nature of the hydrogen bond (ie whether the N-Me DKP molecules associate as
dimers, oligomers or both) is nicely solved by the X-ray crystal data. The N-Me DKP
129, depending upon the solvent system, crystallizes as the polymorphic hydrogen
bonded dimer 129b and hydrogen bonded tape 129a (Figure 3.47). The supramolecular
structure of the N-Me DKP tape 129a contains bent and twisted hydrogen bonds with
face-to-face associations between neighboring tapes. On the other hand, the N-Me DKP
dimer 129b strongly associates, with linear hydrogen bonds and edge-to-face arene
interactions stabilizing the dimer infrastructure and face-to-face arene stabilizing
associations between neighboring dimers. In fact, only the dimer crystal structure
displays that key edge-to-face conformation (with the aryl protons Hi® sitting in the
shielding cone of the Ci indane aromatic ring) deemed necessary for the observed upfield
proton movement.
A linear relationship exists between the shifting and NH proton frequencies
(Hz) and concentration (M), indicating that the solution phase dynamic ~ upon increasing
the concentration - primarily exists between monomer and dimer (Figure 3.48 and 3.49).
Since non-linearity at high concentrations would imply significant oligomer formation, it
can be inferred that the oligomer (trimer and tetramer) contribution to the equilibrium
process is negligible.
158
Ci indane ring system
Hj'^ (static aryl protons)
H2'^ (moving aryl protons)
C2 indane ring system
C2 indane ring system
aryl protons (moving)
linear hydrogen bond
C] indane ring system
Hi'^aryl protons (static)
Figure 3.47. 129b (top) and 129a (bottom) depicted with H*" Assignments
159
Concentration (M)
Figure 3.48. Linear Upfield Movement of the li2^ frequency
2150 -I
2100 -
2050 -
25 °C
40 °C
1950 -
1900 -
1«50
0 0.02 0.04 0.06 0.08 0.1 0.12
Concentration (M)
Figure 3.49. Linear Downfield Movement of the NH frequency
160
Since there are no separate signals for the monomer or dimer aggregate, one can
assume that the N-Me DKP dynamic process is rapid on the NMR time scale, with the
chemical shift as the weighted average of the contributing species. Analysis of this self-
association is made difficult due to the inaccuracy in isolating the dilute concentration in
which only monomer exists. Most experimental procedures require a direct measurement
of 5ni, the chemical shift of the monomer species, to be used as the reference in
determining complexation-induced chemical shift displacements (6m - 6obs)- Despite this
complication, methods are available which can generate physical data, such as the
dimerization constant K°, from the observed NMR frequency shifts 6obs without direct
measurement of 5m- From a curve obtained by plotting frequency data 5obs versus the
concentration [C]o, early treatments manual extrapolated to zero to provide the estimated
monomer shift 5m.With 6m in hand, the dilution shift data was fitted by
regression algorthm to obtain the dimer shift 6d, and This method has been found to
lack accuracy in the calculation of due to its unusual sensitivity to error in the
extrapolated value 5m.. At any concentration of [C]o, a quantity of dimer will always be
present, so any measured value of 5obs can never be equal to 5m. It was the goal of later
methods to alleviate this overly weighted importance of the extrapolated 6m, a goal
tackled more extensively than judiciously by investigators.The especial
nuances of each approach has made selection of the best computational method rather a
daunting task.
A recently developed method has been employed by Horman and Dreux in their
study of the dimerization of caffeine in water, and is the preferred method for analysis of
161
the dimerization of the N-Me DKP 129.'^" There are several reasons for this choice.
There are no apriori assumptions of Sm or 5d before treatment. Rather, K° is arbitrarily
chosen, and 5m and 5d are determined simultaneously by a linear regression best fit
procedure of Sobs versus the concentration [C]o. By increasing or decreasing the value K°,
the generated physical constants 6m and 6d are a result of the bestfit of the data set. Of
late, this method has been successfully employed in the study of other ti-ti self
182 194 195 associatmg systems. ' '
The Horman-Dreux method is as follows:
The law of mass action expression for K° is defined in the equation:
K'^ = [C2]/([C]o-2[C2])'
Where [C2] is the dimer concentration and [C]o is the nominal concentration of C in
solution. Rearrangement of the equation gives:
l/2K''[C]o = 2[C2]/[C]o + [C]o/2[C2] - 2
or
y = x + l / x - 2
162
For any arbitrary value of K , a set of yi values corresponding to different [Cjjo can be
calculated:
yi = 1/(2 K° [C]o)
For every value of y\, there is a value Xi, relating to the measured chemical shift 6j and
corresponding to the dimer fraction, where:
Xi = (5m - 5obs)/(5m - 5d)
5m is the monomer frequency, and 6d is the dimer frequency. For each [Ci]o, a Xj value can
be calculated from the corresponding value yj and plotted against the measured Sobs^
Xi = (l+yi/2) - [ ( l +yi/2)'-l]'''
The equation of the line from this plot conforms to the rearranged equation:
5obs "" 5m ~ Xj(5m ~ 5d)
where the slope of the line is -(6m - 5d), and the intercept is 6m. For any value of other
than the correct one, the equation of the line cannot be linear. The optimum is defined
as that value giving the best straight line fit for Sobs versus Xj. Using a standard linear
163
regression algorithm (Microsoft Excel), the best value of K° is determined by obtaining
the largest value (R^ < 1) from the equation of the line.
Table 3.8 is a list of the results obtained by the Horman-Dreux method. Of note
are the low Revalues (0.1 to 0.9) for the NH and frequencies. Low values are typical
of self associating cis lactams in chloroform [Section 4.1, Table 4.1]."^'''^^ Recall the
monomer-dimer equilibrium (Section 4.1):
M[solvent] + M[solvent] M2 + 2[solvent]
The self-association of two N-Me DKP molecules is impeded by complexing CHCI3 to
the basic C=0 sites. The values in Table 3.8 are a reflection of two dynamic processes
~ the dissociation of a monomer-solvent complex and association to the dimer. The
values, with the exception of NH at -20 °C, decrease with an increase in temperature, and
reflect that disassociating ability of an increasing input of energy (heat) to the
environment. However, the similar results for both the NH and the H2'^ frequencies at 25
°C and 40 °C indicate that there is a leveling point reached at which the fast equilibrium
is less affected by a further increase in temperature.
The work to be done in this particular area needs to be addressed before a
conclusion is met. While these 'H NMR shiftings were observed multiple times in
different experiments, the tabulated results insofar are a reflection of one data collection.
Repetitive experiments would provide a means of calculating error. As well, a more
164
expansive temperature range is believed necessary for van Hoff plots, from which
enthalpy (AH), entropy (AS) and the overall free energy (AG) can be calculated. Accurate
extraction of these physical constants would require data collection at more than three
different temperatures. Finally, repetition of the NMR concentration and temperature
experiments in an assortment of solvent systems (with differing polarity) would provide a
range of values further validating the presently reported data.
Table 3.8. Linear Regression Bestfit Analysis of NMR frequency data
°c NH H2^
-20 °C K"" = 0.4
y = 266x+ 1924; R^ = 0.9975
5n,= 1924 Hz, 6d= 1658 Hz
K" = 0.8-0.9
y = -300x+ 1987; r2 = 0.9920
6ni= 1987 Hz, 6d= 1687 Hz
o n K"" = 0.6 - 0.7
y= 1252X+ 1862; R^ = 0.9997
5m = 1862 Hz, 5d = 610Hz
K" = 0.05 -0.1
y = -958x+ 1985; R^ = 0.9981
5m- 1985 Hz, 5d = 1027 Hz
40 °C K"" = 0.6 - 0.7
y- 1083X+ 1850; R^ = 0.9997
§ni= 1850 Hz, 5d = 767 Hz
K^ = 0.1 -0.2
y = -419x+ 1984; R^ = 0.9905
§m= 1984 Hz, 5d= 1565Hz
165
Section 3.8. Conclusion
The N-Me tetramethoxy diketopiperazine provided the means of exploring the
1,4-alkyloxy diketopiperazine family in the solution phase. Gas and solid phase analysis
correlated nicely with the solution phase results. However, solubility issues made
analysis of the N-Me DKP (R = CH3) limited to the protic solvent systems chloroform
and ethanol. Synthesis of more widely soluble N-Me diketopiperazines 146 with
increasing alkyl chain lengths (R = C2H5, C4H9, CeHia, etc.) would allow for solution
phase studies in such desirable non-associating aprotic solvent systems as CCI4 or CS2
(Figure 3.50). In conjunction with their X-ray crystal structures, a more complete
understanding of the non-bonding dynamic between these indane diketopiperazine
molecules should be possible.
OR OR
CH OR OR
146
Figure 3.50. Possible N-Me Diketopiperazines for Solution Phase Analysis
Chapter 4
The 6/5-Diketopiperazine as the New Indane DKP Synthon
167
Section 4.1 Crystal Engineering of ftw-Diketopiperazines
The design idea of the diketopiperazine 147 (DKP) as a supramolecular synthon
has progressed from one diketopiperazine unit into two covalently linked
diketopiperaines containing a spacer unit of differing character and length (Scheme 3.1).
The indane Z)w-diketopiperazine synthon 148 should organize similarly to the original
model, forming one dimensional "double wide" hydrogen bonded tapes along the
principal molecular axis.
Scheme 4.1. Progression from the 2,5 DKP to the bis-2,5 DKP Synthon
147
linker
linker
148
168
Multiple recognition sites have been found to increase the robust and predictable
nature of self-associating systems. The Z)w-amied synthons, N,N-dimethyl-
arenedicarboxamides 149,^' Z>/i'-(amidopyridines) 150/^ and the Zjw-diketopiperazine
were prepared with (aryl) spacer units of increasing length in order to explore
solid state structural and recognition possibilities.
/ \ >=N
0.
-N
H 150
Figure 4.1. /)w-Amide Crystal Engineering Systems
169
In like manner and purpose, the indane Z?/5-diketopiperazines were designed to
incorporate a rigid cyclic alkyl or aryl spacer unit of increasing length (Figure 4.2). The
spacers, incorporated into the Z)w-diketopiperazine scaffold as bis amino esters 152, 153,
and 154, were thought to pose a manageable synthetic challenge to the design process.
linker
i=^
bis amino ester
H.N
RO.C
NH.
CO2R
152
H2N
RO2C
HjN
RO2C
NH,
CO2R
153
.NH2
CO2R
154
Figure 4.2. 6w-DKP Spacer Components and Z)w-Amino Esters
cis and trans
R,R and S,S
cis and trans
Synthesis of the 6/5-diketopiperazines also utilized the available stock of 1,4-
alkyloxy indane N-Boc amino acids 85a-e (R = CH3, CeHn, CgHn, C12H25 and C18H37)
[Section 2.3]. Cis 155 and trans 156 durene /)w-diketopiperazines (Figure 4.3), (R,R) and
(S,S) spiro[3.3] heptane ^w-diketopiperazines (157a,b) (Figure 4.4) and cis 158 and trans
170
159 cyclohexyl bis-diketopiperazines (Figure 4.5) were envisioned as 1,4-alkyloxy
derivatives. The cis and trans durene and cyclohexyl ^/^-diketopiperaines should
similarly organize in the solid state, forming double wide hydrogen bonded DKP tapes
stabilized by edge-to-face interactions between lateral neighboring tapes and van der
Waals associations between intertigitated vertical neighboring tapes (Figure 4.3 and
Figure 4.5). The spiro[3.3]heptane 6w-DKP, with 90° offset diketopiperazine rings,
should associate in a dramatically different fashion, forming a two dimensional hydrogen
bonded sheet with abutting sheets stabilized by edge-to-face and van der Waals
associations (Figure 4.4).
171
OR OR
OR OR cis 155
OR OR
OR OR trans 156
OR
supramolecular trans 156 RO
OR
RO
OR OR
RO RO'
OR OR
RO RO
OR
RO OR
RO
Figure 4.3. Cis and Trans Durene Derived 1,4-Alkyloxy bis-DKP
OR
RO OR
(R,R) 157a
OR
RO OR
(S,S) 157b
OR
OR
RO
OR
OR RO
OR
A/.
RO OR
OR
supramolecular (R,R) 157a
Figure 4.4. (R,R) and (S,S) Spiro[3.3]heptane 1,4-Alkyloxy bis-DKP
173
OR OR
OR OR cis 158
OR OR
OR OR trans 159
OR supramolecular trans 159
OR RO
RO OR
OR RO OR
OR RO RO
RO OR
OR RO
RO
Figure 4.5. Cis and Trans Cyclohexyl 1,4-Alkyloxy /)w-DKP
174
Section 4.2. Synthetic Developments of Natural and Unnatural 6w-Amino Acids
It is imperative before addressing the construction of Z)w-piperazine-2,5-diones to
digress and consider the importance of &w-amino acids outside the context of crystal
engineering. Given the enormous amount literature on this topic, the departure will be
necessarily abbreviated, but pertinent to the understanding that utility of Z)w-amino acids
is significant throughout the physical sciences.
Interest in production of synthetic variants grew upon recognition of natural bis-
amino acids as important biological agents. Diaminopimelic acids (DAP) are the simplest
bis-amino acids found in nature, and play an integral role in bacterial biosynthesis (Figure
(2S, 6S)-Diaminopimelic acid (160) is essential for the growth of bacteria and
plants and aids in the production of the diamine Z-lysine. Meso (2S, 6R)-diaminopimelic
acid (161) is a cross-linking component of the peptidoglycan layer of bacterial cell walls.
DAP-containing peptides exhibit diverse biological activity, including cytotoxicity and
anti-tumor behavior.
160 161
(2S, 6S)-Diaminopimelic acid (2S, 6R)-Diaminopimelic acid
Figure 4.6. Natural ^iw-Amino Acids, the Diaminopimelic Acids
175
Dityrosine (162) and isodityrosine (163) represent a group of naturally occurring
tyrosine-derived Z)w-amino acids containing oxidatively coupled aromatic nuclei (Figure
4.7).'^^'^®^ Dityrosine and isodityrosine both act as stabilizers of structural proteins in
bacteria and plants. Isodityrosine is present a number of bio-active peptides, which
include the ACE inhibitor K-13, aminopeptidase inhibitor OF4949-III, and the anti-tumor
antibiotic deoxy-bouvardin.^'^' A higher bi-aryl homologue of dityrosine, actinoidic acid,
is a component of the antibiotic vancomycin?*^^
CO2H
CO.H
OH
O.
Y NH,
CO2H HjN^ CO2H
162
Dityrosine
163
Isodityrosine
Figure 4.7. Natural bis-Amino Acids, Dityrosine and Isodityrosine
Following these natural templates, the synthesis of unnatural bis-amino acids was
advanced in the interest in generating better cross-linking elements for stablilization of
peptide secondary structures.^"^ Incorporation of unnatural Z)/i'-amino acids into
biologically active peptides could control spatial requirements at the recognition site, and
176
thus have enhancing (or detracting) consequences. Bis-amino esters 164 and 165 were
designed, using Cinchona alkaloid derivatives as chiral control elements, to possess the
natural Z-configuration (Figure 4.8).^®*^'^®^ 5w-amino ester 164 is similar to meso-
diaminopimelic acid, ^/i'-amino ester 165 is analogous to both dityrosine and
isodityrosine. The ^w-armed di-phenyl amino acid 166 was designed as a structural
variation of the n-n geometries found in peptides. ' Interest in 167, a ferrocenylene
"707 no • • bis-almine, stemmed from its likeness to other P-sheet mimics. " 5w-amino acids
containing metals allowed for greater conformational contraint and order between stacked
arene rings. Bis-amino acid metal complexes have found some use as simplified models
for bio-moleular recognition.
t-BuO,C
H.N
164
•/ CO.H
CO,H
COot-Bu
/ \
C02t-Bu
HjN" C02t-Bu
165
\ /
Bn02C NHBoc BocHN COjBn
166
Figure 4.8. Synthetic Amino Acids as Mimics of Natural Structures
177
Cystine (168) is a four-atom bridged 6/5-amino acid (Figure 4.9). Isosteric
structures have been designed to impart an even greater rigidity to cystine-containing
peptoid bioorganics. Insertion of double bonds (such as compounds 169 and 170), triple
bonds, aryl moieties (such as 171), and cyclic structures (such as 172 and 173) have
induced even more conformational constraints.^'^"^'^ a,a'-Dialkylated C4 ring annulated
systems, such as the a^'-indacene-bridged bis-amino acid 173, represent the most rigid in
91 T 91^ this class of compounds. ' C2 bridged systems have been studied, but to a lesser
extent.^'^'^'^
CO2H
-2 170 171
U02^
,\\C02H
nh2 H02C NH2 172 173
Figure 4.9. C4 Bridged Amino Acids Resembling Cystine
178
Of course, bis-amino acids have applications outside of the biological sphere. Alkyne-
bridged amino acid 174, along with tri- and tetra- podal systems, show nonlinear optical
(NLO) activity (Figure 4.10).^'^ A novel type of bis-amino acid 175, a bis-{ammo acid)
• • 91S oxalyl amide, is a unique coagulant gellating both organic and aqueous solvents.
/CO2CH3 H3CO2C
BocHN ( A ^ / V y NHBoc
174
N OH
R
N' H
O
HO.
O
175
Figure 4.10. Application of bis-Amino Acids as Useful Materials
In light of the preceding discussion, the proposed cyclic a,a-dialkylated bis-
amino acids 179, 180 and 181 have some unique features (Figure 4.11). While C2 and C5
bridged systems (such as 180 and 181) are not as well studied, C3 bridged systems (such
as 179) are diaminopimelic acid analogues. Interestingly, solution and solid state
evidence of oligopeptides containing the a,a-dialkylated AC3 (176), Acs (177) and Ace
(178) demonstrate a marked tendency to contain p bends, 310 helical conformations, and
179
219 y-turns. Ac3 ring systems show a conformational preference (attributed to geometrical
factors induced by ring strain) for the y-turn. ' Considering the current interest in bis
amino acids as cross-linkers and a-helix, p- or y-tum inducers, it would be worthwhile to
examine the proposed bis amino acids (179, 180 and 181) as conformationally restricted
components of oligopeptides.
HO2C. .NH2
178 Acgc
HO2C / \ NH2
H2N ^ / CO2H 181
C2 bridge
H02C^ ^NH2 HO.C
H,N
177
Acsc
NH,
CO2H
180
C5 bridge
HO2C. /NH2
176 Ac^c
HOoC
HoN
NH,
CO.H
179 C5 bridge
Figure 4.11. The Amino Esters as Potential Turn Inducers
180
Section 4.3. Synthesis of Cis and Trans Durene-Derived bis Amino Ethyl Esters
S. Kotha and E. Brahmachary demonstrated the versatility of their di-alkylation
protocol in the synthesis of novel bis- and tris- isonitrile esters 183 and 185 from the
respective alkylbromides 182 and 184 [Chapter 1, Section 1.2] (Scheme 4.2)."'^
Scheme 4.2. Generation of bis- and tris- Isonitriles Using Kotha Methodology
Br Br
CN C02Et K,CO,, TBAHS
2 isomers 2 isomers 42% combined yield Br Br
182 183
Br-CN^ ^COjEt
Br
Br
CN COjEt K2CO3, TBAHS
ACN Br
Et02C///,, NC
Br CN COjEt
184 185
181
Following their reported protocol, hydrolysis of the isonitrile 183 under acidic
conditions generated two isomeric amino esters (Scheme 4.3). While the amine isomers
were isolated as a "polar" isomer 179a and "non-polar" isomer 179b (the relative
positions determined by thin layer chromatography), their stereochemistry had not been
determined.
Scheme 4.3. Hydrolysis of bis- Isonitrile 183 to F orm Isomeric Amine Esters
The N-carbamate ethyl esters 187 (N-Boc) and 188 (N-CBz), formed from the
respective "polar" 186a and "non-polar" 186b amine esters, were highly soluable, and X-
ray quality crystals were easily obtained. The X-ray structure of the N-Boc "polar"
isomer 187 was confirmed as the cis conformer (Figure 4.12) and the N-Cbz "non-polar"
isomer 188 (Figure 4.13) as trans.
conc HCl, EtOH
183
1 (polar amine 186a) : 1.2 (non-polar amine 186b)
182
Figure 4.12. The cis Conformer: N-Boc "Polar" Isomer 187 (with DMF)
Figure 4.13. The trans Conformer: N-CBz "Non-Polar" Isomer 188
183
Section 4.4. Synthesis of Trans Cyclohexyl bis Amino Methyl Ester
The chemical literature records the synthesis of bis amine ester 189, albeit by a
dated protocol (Figure 4.14). ' Difficulties in repeating the procedure prompted
development of a different synthetic method.
Figure 4.14. 1,4-Diamino-Cyclohexane-l ,4-Dicarboxylic Acid Dimethyl Ester
One of the most convenient routes to a-amino acids involves the reaction of
acidic^^^ hydrolysis to the amino acid. Synthesis of the crude hydantoin under Bucherer-
Bergs conditions from 1,4 cyclohexanedione (190) produced a product which, by 'H and
NMR, appeared as one isomer (Scheme 4.4). Basic hydrolysis generated the bis-
amino acid 193, but in low yield (24%). Unfortunately, attempts to esterifiy the isolated
amino acid produced only minimal amounts of material.
HjN CO2CH3
189
ketones via the Bucherer-Bergs reaction to form the hydantoin, followed by basic • or
184
The Edward and Jitrangsri (EJ) rule states that the Bucherer-Bergs reaction of
substituted cyclohexanones yields the a hydantoin isomer as the major product, with the
C4 carbonyl group of the spiro-hydantoin ring in the less sterically hindered (equatorial)
position. " If this rule holds true, then the isolated hydantoin isomer was the trans
conformer 191(Scheme 4.4).
Scheme 4.4. The Cyclohexyl bis Amino Acid via the Bucherer Bergs Synthesis
O
KCN, (NH4)2C03, EtOH, HjO
90%, crude
190 n
m
cw-hydantoin ?rara-hydantoin
20% NaOH glyme, heat
t NH
193
24%, crude
185
The alternative to the Bucherer-Bergs Reaction, the Strecker reaction generates
the amino nitrile from the ketone. Strecker yields are typically poorer than the yields
obtained by the Bucherer-Bergs reaction, and this is primarily due to several equilibration
states between the starting material ketone 190, the imine intermediate 194, the amine
nitrile products 188 and 189 (Scheme 4.5). The EJ rule predicts preferential formation of
the /? isomer, the trans amino nitrile 195, based on the smaller steric requirements of the
228 229 nitrile group. ' Thus, while the Strecker product preferably generates the p isomer,
and Bucher-Bergs reaction the a isomer, both reactions should generate the trans
conformer.
Not surprisingly, generation of the Strecker product was found to be problematic.
The isolated di-amino nitrile material had a tendency to decompose over time to mono
amine nitrile and starting material. Conversion of the di-amino nitrile to the a-amino acid
met, as well, with poor results. It appeared that the nitrile moiety was resistant to
hydrolysis, even under harshly acidic conditions.
186
Scheme 4.5. Equilibrium States of the Strecker Reaction
NH KCN, nh4ci, h2o
HN 194 190
NH NH
CN CN NC
196 195
trans isomer kinetic control
NH CN CIS isomer
CN
NH
CN 195 trans isomer
thermodynamic control
A suitable solution to this problem was an aldehyde- or ketone- assisted
hydrolysis of the di-amino nitrile 198 to the di-amino acid 202 (Scheme 4.6).^^'^ Not only
would the amino nitrile be stable for storage as a N-carbonyl protected nitrile 199, the N-
carbonyl group would anchimerically assist in the acidic hydrolysis of the nitrile 199
187
from the oxazoline intermediate 200 to the amide 201. Acidic hydrolysis of the amide
and N-carbonyl functionalities of 201 to the amino acid 202 would be slow, but feasible.
Scheme 4.6. Assisted Hydrolysis of a-Aminonitriles
CN CN 198 199 197
anchimeric assistance hydrolysis
HO'
O^ O NH, O O NH NH
202 201 200
Following work by M. Paventi et. al., a two step one pot protocol quickly
generated the a-benzamido nitrile 203 (Scheme 4.7). Acidic hydrolysis to the cir-amino
acid hydrobromide salt 204 required harshly acidic conditions, but generated the product
in reasonable yield. Similar to the Bucherer-Bergs synthesis of the Z)w-hydantoin, only
188
one isomer was observed by 'H and '^C NMR for isolated intermediates 203 and 204.
Based on the EJ premise they were assumed to be in the trans conformation.
Scheme 4.7. 1,4-Cyclohexanedione and the Strecker Reaction
O 190
.0 Ph H
(1) KCN, nh4ci, H2O; (2) PhCOCl, K2C03,THF/H20,
100% two steps
CN
O n
Ph' "N H
CN
203 one isomer
HO2C. NHgBr
conc HBr 86%
BrHgN CO2H
204 one isomer
Since the amino acid hydrobromide salt 204 was absolutely insoluable in organic
solvents (and unreactive to Fischer esterification in absolute ethanol or methanol)
formation of the cyclohexyl bis amino ester 189 relied on means of making its precursors
more soluable (Scheme 4.8). Protection of the amino acid salt 204 to the N-Cbz acid 205,
followed by alkylation of the prepared cesium salt, generated the N-carbamate ester 206.
Hydrogenation of the material yielded the free amino ester 189 in good yield.
189
Scheme 4.8. Synthesis of Cyclohexyl bis Amino Ester Derivatives
BrHjN. .CO2H
BrHgN CO2H
204
NaHCOs, CbzCl,H20
63% '
CbzHN. /CO2H CS2CO3;
Mel, DMF
50%
CbzHN CO2H
205
H2N. /CO2CH3 CbzHN. .CO2CH3
H2 (55 psi), 10% Pd/C, ch3oh, EtOAc
93%
H2N CO2CH3
189
CbzHN CO2CH3
206
190
Fortuitously, generation of the N-Cbz protected methyl ester 206 produced
material that generated X-ray quality crystals. The X-ray crystal structure confirmed the
postulated trans stereochemistry (Figure 4.15).
Figure 4.15. The trans Cyclohexyl N-Cbz bis Amino Ester 206
191
Section 4.5. Synthesis Spiro[3.3]heptane Amino Methyl Esters
Construction of the chiral spiro[3.3]heptane bis-dmino esters 207a (R,R) and
207b (S,S) posed a difficult synthetic challenge due to their highly strained helical
architecture (Figure 4.16). Cyclobutanes contain greater strain energy than larger ring
systems (such as cyclopentane and cyclohexane) due to small-angle strain.^^' Ring
puckering alleviates some torsional strain between substituents. The spiro[3.3]heptane
system suffers from small-angle strain and torsional strain, but it additionally suffers
from A''^ strain occurring between eclipsed hydrogens.
H3CO2C ^C02CH3 H3CO2C NH2 \ / \ -s \ / \
H 2 N ^ N H 2 H 2 N ^ C O 2 C H 3
(R,R) 207a (S,S) 207b
Figure 4.16. Chiral Spiro[3.3]heptane Amino Esters 207
It was desirable to construct the spiro[3.3]heptane scaffold in 1 to 2 steps from the
protocols established for small ring systems. O'Donnell and co-workers demonstrated
synthesis of cyclopropane 208a and cyclopentane 208b amino acids under phase transfer
conditions using the appropriate alkyl halide and a highly activated ketimine acetonitrile
as alkylating agent, yet attempts to form four-membered rings (n = 2) led to mixtures of
oligomeric products (Scheme 4.9).'^^ The cyclopropane amino acid 209 was synthesized
192
using the less sterically hindered, yet comparably less activated, benzylidine glycine ethyl
ester. ' Cyclobutane amino acid 210 was assembled using a similar alkylation
234 protocol with ethyl isocyanoacetate as a alkylating agent.
Scheme 4,9. Reported Synthesis of Cyclo (-propyl, -butyl, -pentyl) Amino Acids
Br
Br
NaOH, Ph NC^N=(
Ph_ PTC,PhCH3
N:
CN
Ph
Ph 208a n = l , 8 0 % 208b n = 3,73%
rt: Br LDA, Ph
Et02C^N=/
Br THF,-78°C ^
N=\
Ph
COsEt
209 n = 1 28%
Br
Br
NaH,
EtOjC^N^C
DMS0:Et,0
N = C
CO.Et
210 n = 2, 48%
Unfortunately, use of either benzylidine glycine ethyl ester (212) or ethyl
isocyanoacetate (214) as alkylating agent to form the spiro[3.3]heptane N-protected
amino esters 213 or 215 met with poor results (Scheme 4.10). The starting material
pentaerythritol (211) either did not react, or decomposed to polar oligomeric material. A
193
lengthier route was thus employed. Early work had established conditions in the synthesis
of Fecht's Acid (217) from diethyl malonate (216), and from Fecht's Acid, to
'yin spiro[3.3]cycloheptanedione (218) (Scheme 4.10). " Formation of the ftw-hydantoin
under Bucherer-Bergs conditions, followed by hydrolysis and esterification, would
generate the desired ^w-amino ester 207.^^^"^'^''
194
Scheme 4.10. Routes to the Spiro[3.3]heptane System
EtOjC
215
C02Et
'cOjEt
216
NC
214
,^^2Et cOjEt
NC
fOjEt
Br^^X^^Br
Br^.^^V-Br
211
pentaerythritol tetrabromide
EtOjC
212
COsEt
HO2C CO2H
217
Fecht's Acid
218
spiro [3.3 ] cycloheptanedione
H2N
H3CO2C
*
^:O2CH3
NH.
207a,b
195
Following the literature procedure, production of the N-oxide 220 was
straightforward (Scheme 4.11).^^^'^^^ Unfortunately, thermally induced elimination
(220^221), while consuming starting material, yielded no diene. The difficulty in
isolating the diene 221 was thought to be due to high volatility.
Scheme 4.11. Literature Procedure for the Synthesis of Spiro[3.3]heptanedione
(C0C1)2, DCM; Fecht's HN(CH3)2 Acid
(l)LiAlH4, THF ^ (2) 30% H2O2, N(CH3)2 CH3OH
56%
219 217
-O o-
54% CH
221 220
The procedure was modified in order to generate a higher molecular weight diene
(Scheme 4.12). Grignard addition to the ester 222 (from Fecht's Acid) yielded the
benzylic diol 223Thermolysis generated the diphenylene product 224 as an oily
solid.^'*^'^'^^ While oxidation of similar systems yielded Pinacol rearranged products,
oxidative cleavage of this particular diene generated the spiro[3.3]heptanedione (218) in
good yield.^"^''^"^^
196
Scheme 4.12. Modified Procedure for the Synthesis of Spiro[3.3]heptanedione
Fecht's Acid
(COCl)2, DCM; CH^OH
100% H3C02C C02CH3
217 222
oxalic acid, sodium oxalate, 175-180°C
70%
J*hMgBr, Et20
98%
223
Ph RuCl3(H20)2,Nal04 <5 ACN:CCl4:H20 _ Q "
51% ^
224 218
The 6/5-hydantoin 225 formed under Bucherer-Bergs reaction conditions was
hydrolyzed to the amino acid and protected as the N-Cbz acid 226 in a two step one pot
procedure (Scheme 4.13). Fisher esterification of the intermediate amino acid was
discarded due to the system's lability to acid and heat.^'^^ Base-induced esterification,
followed by N-Cbz deprotection, engendered the racemic spiro[3.3]heptane &«-amino
ester 207. An X-Ray crystal structure of the HCl salt unambiguously confirmed the
racemate product (Figure 4.17).
197
Scheme 4.13. Synthesis of Spiro[3.3]heptane bis Amino Ester
HN NH O
100%
225
O
(1) CS2CO3; Mel, DMF (2)H2, 10%Pd/C, AcOEt HO2C ^ (3)HCl(g),Et,0
61% CbzHN
226
CO2H
NHCbz
3 M NaOH, reflux; PhCOCl, acetone :H20
73%
H3CO2Q
CIH3N
CO2CH3
NH3CI
207a,b racemate
198
R,R
Figure 4.17. (R,R) and (S,S) Spiro[3.3]heptane bis Amino Esters (HCl salt)
Unfortunately, the lengthy and difficult synthesis of this bis amino ester made its
use in the preparation of 6/s-diketopiperazines untenable. The four final steps (225^
207) were difficult to repeat, and the reaction size had to be restricted to a fairly small
scale (150 to 200 milligrams). Attempts in modestly increasing the reaction size met with
decreases in yield. Optimization of these final steps is necessary before use of
spiro[3.3]heptane bis amino ester as a synthetic intermediate can be justified.
199
Section 3.6. Synthesis of Z)/5-Diketopiperazines
The cis durene amine ester 186a, trans durene amine ester 186b and trans
cyclohexyl amine ester 189 were iteratively combined with indane N-Boc acids 85a-e (R
= CH3, CeHis, CgHn, C12H25, C18H37) (Chapter 2, Section 2.3) to form their respective
peptide coupled products 227, 228 and 229 (Scheme 4.14). While peptide coupling is
well documented and the process facile, the synthesis of these particular materials was
initially challenging. Monitoring the course of the reaction by thin layer chromatography
(TLC) indicated, after 24 hours, complete disappearance of the bis amine ester,
appearance of what was isolated as the intermediate mono-coupled product, and
significant presence of the indane acid 85 and its symmetric anhydride. The bis coupled
product (227, 228 or 229) was not observable by TLC. Interestingly, a thick white
precipitate gradually formed over the course of the reaction, and this was later determined
to be pure ^w-coupled material. Isolation and purification was very simple. Upon
complete reaction (determined by disappearance of mono-coupled material) the solvent
was removed in vacuo, and the reaction contents triturated and filtered to obtain pure bis-
coupled product. Acetonitrile was found to be a universally successful triturant. In fact,
the same reaction conditions were employed for all the couplings with the exception of
the solvent, this usually either THF or DMF (Table 4.1). The reaction yields were
moderate and found to be dependant upon the reaction size and nature of the indane N-
Boc acid 85.
200
Scheme 4.14. The Tetrapeptide Precursors of iw-Diketopiperazines
186a + 85a-d
NHBoc
EtOsQ, >NH
OR
H02C
BocHN
85a-e OR
189 + 85b-e
NHBoc
Et02C^''' 'NH
NHBoc
BocHN
H3CO2C. ^NH
HN TO2CH3
OR
186b+ 85a-d
NHBoc
EtOX/,. ^NH
HN'^"'' "C02Et
BocHN
227a R = ch3
227b R = C6H,3 227c R = C8H,7 227d R = C,2H25
229b R=C6H,3 229c R^CgHiv 229d R = C,2H25 229e R = C,8H37
228a R = ch3
228b R = C6H,3 228c R = C8H,7 228d R=C,2H25
201
Table 4.1. Conditions^ for the Coupling of bis Amino Esters and Indane Acids
Amine Acid Solvent Rxn time Purification % yield Product
186a 85a THF 4 days Column 5 2 % 227a
186a 85b THF 5 days Hot ACN 6 6 % 227b
186a 85c THF 4 days Hot ACN 54% 227c
186a 85d THF 4 days Hot ACN 7 8 % 227d
186b 85a THF 3 days Column 55 % 228a
186b 85b THF 4 days Hot ACN 5 0 % 228b
186b 85c THF 4 days Hot ACN 66 % 228c
186b 85d THF 4 days Hot ACN 6 7 % 228e
189 85b DMF 2 days Hot ACN 6 3 % 229b
189 85c DMF 2 days Hot ACN 6 9 % 229c
189 85d DMF 2 days Hot ACN 63 % 229d
189 85e DMF 2 days Hot ACN 4 8 % 229e
® Standard reaction conditions: BOP, DABCO, 186a, 186b or 189, N-Boc acid 85,
solvent
Following Mash laboratory synthetic protocols,the tetrapeptides 227, 228 and
229 were thermally cyclized in a vacuum sealed Pyrex ® glass tube (265 °C to 270 °C for
1 hour) to the ^w-diketopiperazines (bis-DKP) 155,156 and 159 (Figure 4.18).
202
OR OR
•NH
HN HN-
OR OR
OR OR
-NH
HN
OR OR
•NH
-NH
155a R=CH3 155b R = C6H,3 155c R = C8Hi7 155d R = C,2H25
156a R = CH3 156b R = C6H,3 156c R = C8H]7 156d R = C,2H25
OR OR
159b R = C6H,3 159c R = C8Hi7 159d R = Ci2H25 159e R = C,8H37
77%
48%
71%
73%
80% 44% 63% 73%
60% 62% 56% 78%
Figure 4,18. Synthesized Z)w-Diketopiperazines
203
Section 4.7. Physical Characterization of Z)w-Diketopiperazines
The 1,4-alkyloxy Z)w-diketopiperazines, like the wowo-diketopiperazines [Chapter
2], displayed extremely high decomposition or melting temperatures (>300 °C) atypical
for most organic solids. Yet the Z>/i'-diketopiperazines, dissimilar to the mono-
diketopiperazines, were not liquid crystalline (DSC results) (Table 4.2). A structural
feature necessary for liquid crystallinity is close proximity of the 1,4-alkyloxy
substituents [Chapter 2, Section 2.5]. Closely packed Z)w-diketopiperazines would
naturally have diminished interactions between neighboring alkyl groups compared to
their mono-diketopiperazine analogues. Additionally, the d/.s'-diketopiperazines were
markedly insoluble in the majority of organic solvents. In fact, it was extremely difficult
to obtain single crystals, and in only a few select cases were microcrystalline samples
obtained (Table 4.2). Unfortunately, these microcrystals were not of good enough quality
for X-ray (Synchotron) analysis.
204
Table 4.2. Preliminary Thermochemical Characterization of the Z)/5-DKP
bis DKP R group DSC'/TGA" Microcrystals
155a CHs 420 °C decomp'^
155b CfiHn 355 °C decomp DMF
155c CgHn 293 °C meh
155d C12H25 261 °C melt
156a CH3 485 °C decomp'^
156b C6HB 402 °C decomp'^ DMSO
156c CgHn 396 °C decomp DMF
156d C,2H25 342 °C decomp
159b C6H,3 389 °C decomp TFA/EtOH
159c CgHn 369 °C decomp TFA/CH2CI2
159d C12H25 245 °C decomp
159e C18H37 106 °C decomp
^Differential Scanning Calorimetry (DSC); Thermogravimetric Analysis (TGA); '^Due to
the temperature limits of the DSC instrument (<400 °C), these decomposition
temperatures were estimated from TGA results.
Microcrystalline Ce cis durene Zj/s-DKP 155b was obtained from slow
evaporation of DMF, and the ground 20 mg sample was analyzed by powder X-ray
diffraction (Figure 4.18). The indexed diffraction pattern indicated that the C(, cis durene
Z)w-diketopiperazine crystallized in a monoclinic space group, (most likely P2i based on
systematic absences observed), and shared cell parameters, such as a 6 A cell axis length,
typical of indane mono-diketopiperazines.
205
Powder X-ray diffraction data of €5 cyclohexyl bis-DKP 159b microcrystalline
material was less successful (Figure 4.19). There was little similarity to the Ce cis durene
bis-DKP 155b powder diffraction data, and in particular there were no obvious signs of a
6 A cell axis. Indexing the diffraction pattern was, as well, very difficult. Since the
microcrystals were obtained from an evaporating solution of trifluoroacetic acid (TFA)
and ether, the discrepant data could be due to included (hydrogen bonded) trifluoroacetic
acid solvent molecules present, creating an unstable cyclohexyl bis-DKP crystalline
lattice.
Counts
10000
5000
0
0
Figure 4.19. Powder Data from Microcrystalline C(, cis Durene Z)w-DKP155b
-2Theta
206
Cell parameters obtained from powder diffraction data have been used, via
computational methods, to successfully predict the crystal structure of organic
molecules. Of course, obtaining powder data is not as appealing as obtaining the desired
crystal structure, but it does indicate that these Z^w-diketopiperazine systems are capable
of forming organized crystalline lattices that, with some effort, could yield good quality
single crystals for X-ray analysis. It remains the effort of future investigators to see the
6w-diketopiperazine project to its ultimate fruition.
Conclusions and Final Remarks
208
In his seminal paper Photodimerization in the Solid State,^ Schmidt was
concerned with the fimdamental practice of crystal engineering - establishing reliable
connections between molecular and supramolecular solid state structure on the basis of
intermolecular interactions. Yet there exists amongst practitioners of crystal engineering,
despite feigned optimism, a pervading fear that this goal set out by Schmidt is still a long
way off. A Theory of Molecular Packing is left wanting.
This dissertation perhaps contributes a small portion to that big picture. A reliable
synthetic method toward the construction of 1,4-dialkyloxy diketopiperazines,
encompassing N-Methylated diketopiperazines and 6z5-diketopiperazines, has been
established and their supramolecular non-bonding associations - whether in the solid,
solution or gas phase - have been studied. The indane diketopiperazine is a remarkably
predictable scaffold in which the computational approach should hold some measure of
success. Future production of indane diketopipiperazines purposefully engineered to
possess desirable bulk properties may make viable and useful materials. The possibilities
of the diketopiperazine synthon, with a bit of creativity and hard work, seem endless.
Experimental Section
210
General Procedures
Dry reactions were conducted with flame-dried glassware under a positive
pressure of argon. Hydroscopic solvents were transferred via an oven-dried syringe or
cannula. Hydroscopic liquids were treated as the chemical literature dictates: methanol
(CH3OH), dichloromethane (CH2CI2), and dimethylsulfoxide (DMSO) were distilled
from CaH2; amyl alcohol (98% Aldrich), ether (EtaO), and tetrahydrofuran (THF) were
distilled from Na° and benzophenone; pyridine (py) and triethylamine (NEta) were
distilled from potassium hydroxide and stored over 4 A molecular sieves; N,N-
dimethylformamide (DMF) was obtained 99.8% anhydrous from an Aldrich Sure Seal ®
container. Other solvents used include spectrograde acetonitrile (ACN), chlorobenzene
(PhCl, 99+%, Aldrich), absolute ethanol (EtOH, 200 Proof), and carbon tetrachloride
(CCI4, 99.9%, Aldrich). Solutions were concentrated in vacuo using a Biichi ® rotary
evaporator. Aqueous solutions were concentrated using an FTS Systems Lyopholizer.
Reactions monitored by gas chromatography-mass spectrometry (GC-MS) were
conducted on a Varian 3800 instrument using a HP-5 MS Hewlett-Packard capillary
column. Analytical thin-layer chromatography (TLC) was performed on pre-coated silica
gel 60 F-254 glass plates. TLC visualization required using UV light and/or staining. The
anisaldehyde stain (100 mL anisaldehyde, 50 mL glacial AcOH, 100 mL conc H2SO4,
1000 mL 95% EtOH), ninhydrin stain (2.25 g ninhydrin, 22.5 mL glacial AcOH, 750 mL
n-butanol), and PMA stain (5 g phosphomolybdic acid, 100 mL 95% EtOH) were three of
the most commonly used TLC stains. Flash and gravity chromatography were performed
211
using Merck silica gel 60 (230-400 mesh). Melting points were taken for every solid
sample using a Mel-Temp ® apparatus. Infrared characterization was conducted on a
Nicloet Impact 410 Infrared Spectrometer for all samples, whether as solids (KBr pellet)
or oils (NaCl plate). Nuclear Magnetic Resonance (NMR) experiments were performed
on either a 200 MHz Varian Spectrometer, 300 MHz Varian Spectrometer, or a 500 MHz
Briicker Spectrometer. NMR spectra were referenced to either CDCI3 (7.24 ppm, 77.0
ppm), J-TFA (11.5 ppm, 164.4 ppm), c/-DMSO (2.49 ppm, 39.7 ppm), cZ-acetone (2.04
ppm, 29.8 ppm), or tZ-CHsOH (3.30 ppm, 49.0 ppm). Mass characterization was
conducted by the Mass Spectrometry Laboratory of the Department of Chemistry at the
University of Arizona, Tucson, AZ using FAB+, EI, ESI, or MALDI in either CCA (a-
cyano ciimamic acid matrix) or DTH (dithranol matrix) mass spectrometric technique.
Elemental analyses were performed by Desert Analytics, Tucson, AZ. Crystal structures
were obtained either from the Molecular Structure Laboratory of the Department of
Chemistry, Tucson, AZ or from the DND-CAT Synchotron Research Center, Sector 5,
Argonne National Laboratories, Argonne, IL.
Differential scanning calorimetry (DSC) experiments were conducted on a TA
Instruments 2920 Modulated DSC. Thermograms were run on 1 - 5 mg samples in sealed
aluminum pans under nitrogen at heating and cooling rates of 5 °C per minute.
Birefringence experiments (optical microscopy) were conducted using a Nikon
Eclipse ME 600 microscope fitted with a Nikon CoolPix 950 digital camera. Creative
Devices West 2050 controller, and hot stage. A sample was prepared as a thin film
between two glass VWR microslides cut to 10 x 10 mm.
212
Synthesis of 1,4 Methoxy Indane Amino Acids
l,4-Diniethoxy-2,3-dimethylbenzene (69a). Reported previously: L. Williams; Ph.D.
Dissertation, University of Arizona, 2001. A solution of 2,3-dimethylhydroquinone (10.0
g, 72 mmol) in dry THF (100 mL) was slowly added via cannula to a slurry of sodium
hydride (5.78 g, 0.24 mol) in THF (150 mL) under argon. The cannula was rinsed with
THF (2 X 10 mL). Upon injection, an exothermic reaction was observed, and the
resulting green colored solution was allowed to stir at room temperature. After 20 min,
iodomethane (10.4 mL, 0.17 mol) was added via syringe and the reaction was brought to
reflux for 24 h. The solution was cooled to room temperature, slowly quenched with
water (15 mL), and concentrated to a brown residue. The material was dry loaded to
silica, purified by flash chromatography (230-400 mesh silica) in a 15% AcOEt/hexanes
elutant, and further purified by recrystallization from methanol to give 6.1 g (37 mmol,
53%) of 69a as a white solid, Rf 0.63 (20% AcOEt/hexanes, brown in anisaldehyde
stain).
Spectral Data for 69a: ^H NMR (200 MHz, CDCI3) 5: 2.16 (6H, s), 3.77 (6H, s), 6.65
(2H, s); NMR (50 MHz, CDCI3) 5: 12.0, 56.0, 107.8, 126.7, 151.9.
2,3-Bis-bromoinethyl-l,4-dimethoxybenzene (70a). Reported previously: L. Williams;
Ph.D. Dissertation, University of Arizona, 2001. To a dried flask under argon, 1,4
dimethoxy-2,3-dimethylbenzene 69a (13.2 g, 80 mmol), N-bromosuccinimide (28.3 g,
0.16 mol), and benzoyl peroxide (BPO) (0.19 g/hour, 0.79 mmol) were added. The
mixture was solvated with CCI4 (200 mL), and heated to a gentle reflux. Every additional
hour a portion of BPO (0.191 g/hour, 0.79 mmol) was added until complete
disappearance of starting material by TLC was noted. After 2 h, the solution was cooled
to room temperature, filtered, washed with CCI4 (20 mL), and concentrated to a yellow
solid. The material was recrystallized from a minimum amount of CH2CI2. The
recrystallizing solution was cooled in a freezer (-22 °C), and filtered cold, washing with
hexanes, to obtain 23.6 g (73 mmol, 93%) of 70a as an off-white solid, Rf 0.17 (10%
AcOEt/hexanes, black in anisaldehyde stain).
Spectral data for 70a: 'H NMR (200 MHz, CDCI3) 5: 3.86 (6H, s), 4.75 (4H, s), 6.84
(2H, s);'^C NMR (50 MHz, CDCI3) 6: 23.9,56.2,112.1,126.4,151.8.
2-Isocyano-4,7-dimethoxyindan-2-carboxylic acid ethyl ester (84). Reported
previously: S. Kotha, E. Brahmachary; J. Org. Chem. (2000) 6^ 1359-1365. Dry
acetonitrile (600 mL) was added in one portion to a flask containing 2,3-bis-
bromomethyl-l,4-dimethoxybenzene (70a) (8.65 g, 27 mmol), tetrabutylammonium
iodide (1.99 g, 5.4 mmol), and finely ground potassium carbonate (45 g, 0.32 mol) under
argon, and the slurry was heated at reflux in an oil bath heated to 85 -90 °C. Ethyl
isocyanoacetate (3.2 mL, 0.03 mol) was injected. Vigorous stirring was essential for an
efficient and complete reaction. After 15 h, the reaction was cooled to room temperature
and filtered, washing the salts thoroughly with CH2CI2. The solvent was concentrated
under vacuum to a brown residue, which was purified by flash chromatography (230-400
mesh silica) in a 20% AcOEt/hexanes elutant to obtain an off-white solid. The material
214
was further purified by trituration with hexanes. The solution was filtered to obtain 3.5 g
(13 mmol, 47%) of 84 as a white solid, Rf 0.27 (20% AcOEt/hexanes, pink in ninhydrin
stain).
Spectral data for 84: 'H NMR (200 MHz, CDCI3) 6: 1.34 (3H, t, J = 7.14 Hz), 3.50 (2H,
d, J = 16.77 Hz), 3.63 (2H, d, J = 16.77 Hz), 3.78 (6H, s), 4.31 (2H, q, J = 7.13 Hz), 6.70
(2H, s); "C NMR (50 MHz, CDCI3) 6: 13.7, 43.8, 55.3, 62.7, 67.5, 109.7, 127.1, 158.3,
168.3.
2-Amino-4,7-dimethoxy-indan-2-carboxylic acid ethyl ester (85a). Reported
previously: L. Williams; Ph.D. Dissertation, University of Arizona, 2001. Cone HCl
(4mL) was added to a solution of 2-isocyano-4,7-dimethoxyindaH2- carboxylic acid ethyl
ester (84) (2.35 g, 8.5 mmol) in absolute EtOH (100 mL), and the solution stirred
overnight at room temperature. After 15 h the solvent was removed under vacuum to
obtain a white solid, which was taken up in water (100 mL) and basified with conc
NH4OH. The aqueous solution was extracted with AcOEt (3 x 100 mL), and the organic
phase dried (MgS04), and concentrated to obtain 2.25 g (8.5 mmol, 100%) of 85a as a
yellow oil, Rf 0.28, (50% AcOEt/hexanes, rose in ninhydrin stain).
Spectral data for 85a: 'H NMR (200 MHz, CDCI3) §: 1.27 (3H, t, J = 7.14 Hz), 1.79 (2H,
broad s), 2.89 (2H, d, J = 16.19 Hz), 3.45 (2H, d, J = 16.19 Hz), 4.21 (2H, q, J = 7.09
Hz), 6.64 (2H, s); '^C NMR (50 MHz, CDCI3) 6: 14.0, 43.6, 55.4, 61.1, 64.6, 109.1,
129.8, 150.3, 176.5.
2-te/'^Butoxycarbonylamino-4,7-dimethoxyindan-2-carboxylic acid ethyl ester (93a).
Reported previously: L. Williams; Ph.D. Dissertation, University of Arizona, 2001. Di-
/er/-butyl dicarbonate (2.0 g, 9.2 mmol) was added to a solution of 2-amino-4,7-
dimethoxyindan-2-carboxylic acid ethyl ester (85a) (1.62 g, 6.1 mmol) in CH2CI2 (25
mL), and the reaction heated to a gentle reflux overnight. An extra portion of di-^er/-butyl
dicarbonate (0.5 g, 2.3 mmol) was added to the solution after 20 h, and the reaction was
allowed to reflux an additional 5 h. The solution was diluted with CH2CI2 (150 mL), and
washed with brine (lOOmL). The organic phase was dried (MgS04) and concentrated
under vacuum to a yellow solid which was purified by flash chromatography (230-400
mesh silica, pretreated with 1% NEta) in a 30% AcOEt/hexanes elutant to obtain 1.96 g
(5.4 mmol, 88%)) of 93a as an off-white solid, Rf 0.45 (50% AcOEt/hexanes, dark rose in
ninhydrin stain).
Spectral Data for 93a: 'H NMR (200 MHz, CDCI3) 5: 1.26 (3H, t, J = 7.12 Hz), 1.42
(9H, s), 3.18 (2H, broad d, J = 17.13 Hz), 3.54 (2H, d, J = 16.85 Hz), 3.77 (6H, s), 4.22
(2H, q, J = 7.15 Hz), 5.30 (IH, broad s), 6.64 (2H, s); '^C NMR (50 MHz, CDCI3) 5:
14.1, 28.2, 41.61, 55.6, 61.4, 65.6, 80.0, 109.3, 150.1, 154.8, 173.5.
2-/^r^-Butoxycarbonylamino-4,7-dimethoxyindan-2-carboxylic acid (94a). Reported
previously: L. Williams; Ph.D. Dissertation, University of Arizona, 2001. Potassium
hydroxide (2.0 g, 30 mmol) was added to a solution of 2-ter^butoxycarbonylamino-4,7-
dimethoxyindan-2-carboxylic acid ethyl ester (93a) (1.5 g, 4.1 mmol) in absolute EtOH
(50 mL) followed by addition of water (10 mL). The solution gradually went from
216
opaque to a clear yellow solution upon heating to a gentle reflux. After 1 h, the reaction
was cooled to room temperature and the solvent removed under vacuum to obtain a white
solid. The solid was dissolved in water (100 mL) and the solution acidified with conc
HCl to a pH of 2. The aqueous solution was extracted with AcOEt (3 x 100 mL), and the
organic phase washed with brine (100 mL), dried (MgS04) and concentrated under
vacuum to obtain 1.1 g (3.3 mmol, 80%) of 94a as an off-white solid, Rf 0.10 (20%
AcOEt/hexanes, brown in ninhydrin stain).
Spectral data for 94a: 'H NMR (300 MHz, J-CH3OH) 6: 1.42 (9H, s), 3.15 (2H, d, J =
16.60), 3.46 (2H, d, J = 17.09), 3.74 (6H, s), 6.68 (2H, s); '^C NMR (75 MHz, tZ-CHaOH)
6: 28.7, 42.2,56.0, 66.5, 80.4, 110.3, 130.6, 151.3, 151.4, 177.7.
2-(ter^-Butoxycarbonyl-methylainino)-4,7-dimethoxyindan-2-carboxyIic acid ethyl
ester (117). lodomethane (1.2 mL, 0.02 mol) was injected via syringe to a solution of 2-
^er^butoxycarbonylamino-4,7-dimethoxyindaf2- carboxylic acid ethyl ester (93a) (0.87
g, 2.4 mmol) dissolved in a 10:1 THF:DMF solvent system (20 mL) under argon, and
reaction mixture was brought to reflux for 30 min. The heat source was removed and
sodium hydride (0.17 g, 7.2 mmol) was slowly added to the hot solution (exothermic).
The reaction was refluxed for 1 h. Sodium hydride (0.17 g, 7.2 mmol) was again added,
and the reaction was refluxed for 30 min. After verifying the reaction was complete by
TLC, the solution was slowly quenched with water (1.5 mL), and the solvent removed
under vacuum. The resultant residue was taken up in water (100 mL), and extracted with
AcOEt (3 x 100 mL). The organic phase was dried (MgS04), treated with charcoal.
217
filtered and concentrated to obtain 0.69 g (0.18 mmol, 76%) of 117 as a light yellow oil,
Rf 0.43 (30% AcOEt/hexanes, light purple in ninhydrin stain).
Spectral Data for 117: IR (NaCl) cm : 1739, 1696; 'H NMR (300 MHz, CDCI3) 6: 1.21
(3H, t, J = 7.08 Hz), 1.42 (9H, s), 2.88 (3H, s), 3.27 (2H, d, J = 17.09 Hz), 3.54 (2H, d, J
= 17.09 Hz), 3.73 (6H,s), 4.13 (2H, q, J = 7.08 Hz), 6.59 (2H, s); NMR (75 MHz,
CDCI3) 6: 14.0, 28.2, 32.0, 40.2, 55.5, 61.0, 70.8, 80.5, 109.1, 129.5, 149.6, 155.5,
173.9; HRMS (FAB+) calcd for C20H30NO6 (M^ +H) 380.2073, found 380.2077 (+1.1
ppm).
2-(#ert-ButoxycarbonyI-methyIamino)-4,7-dimethoxyindan-2-carboxyIic acid (122).
Potassium hydroxide (0.18 g, 3.2 mmol) was added to a solution of 2-(tert-
butoxycarbonyl-methylamino)-4,7-dimethoxyindar2- carboxylic acid ethyl ester (117)
(0.16 g, 0.41 mmol) in a 1:5 H20:Et0H (6 mL) mixed solvent system, and the reaction
was heated to reflux overnight. The reaction was judged complete by TLC after 22 h. The
solution was cooled to room temperature, the solvent was removed under vacuum to
obtain a white salt, which was dissolved in water (100 mL). Upon acidification with conc
HCl to a pH of 2, the aqueous solution was extracted with AcOEt (3 x 1 OOmL), and the
organic phase dried (MgS04), treated with charcoal, filtered and concentrated to a sticky
oil. The oil was treated several times by azeotroping with benzene to obtain 0.13 g (0.37
mmol, 87%) of 122 as a sticky off-white solid, Rf 0.49 (50% AcOEt/hexanes, brown in
ninhydrin stain).
218
Spectral Data for 122: mp: 188 °C decomposition; IR (KBr) cm 3172, 1746, 1702; 'H
NMR (300 MHz, CDCI3) 6: 1.44 (9H, s), 2.91 (3H, s), 3.30 (2H, d, J = 17.09 Hz),
3.61 (2H, d, J = 17.09 Hz), 3.75 (6H, s), 6.61 (2H, s), 11.72 (IH, broad s); '^C NMR
(75 MHz, CDCI3) 5; 28.4, 32.14, 40.2, 55.6, 70.8, 81.2, 109.3, 129.26, 149.7, 155.7,
180.2; HRMS (FAB+) calcd for CigHzeNOe (M^ +H) 352.1760, found 352.1754 (-
1.7ppm).
2-Benzyloxycarbonylainino-4,7-dimethoxyindan-2-carboxylic acid ethyl ester (116).
Dibenzyl dicarbonate (1.68 g, 5.89 mmol) was added to a solution of 2-amino-4,7-
dimethoxyindan-2-carboxylic acid ethyl ester (85a) (0.52 g, 1.96 mmol) in CH2CI2 (15
mL), and the solution gently refluxed overnight. After 19 h, solution diluted with CH2CI2
(200 mL) and washed with brine (100 mL). The organic phase was dried (MgS04),
concentrated to a yellow oily residue, which was purified by gravity chromatography
(230-400 mesh silica, pretreated with 1% NEts) in a 30% AcOEt/hexanes elutant to
obtain 0.66 g (1.6 mmol, 84%) of 116 as an off-white solid, Rf 0.71 (50%
AcOEt/hexanes, light pink in ninhydrin stain).
Spectral Data for 116: mp:l 13-114 °C; IR(KBr)cm'': 33567,1741,1701; 'HNMR
(300 MHz, CDCI3) 8: 1.18 (3H, broad s), 3.25 (2H, broad d, J = 16.85 Hz), 3.54 (2H,
d, J = 16.84 Hz), 3.73 (6H, s), 4.17 (2H, broad s), 5.06 (2H, s), 5.54 (IH, broad s),
6.62 (2H, s), 7.29 (5H, s); '^C NMR (75 MHz, CDCI3) 8: 13.9, 41.4, 55.4, 61.5, 65.7,
66.5, 109.2, 127.9, 128.3, 129.1, 136.2, 149.9, 155.2, 173.2; HRMS (FAB+) calcd for
C22H26NO6 399.1682 (M^), found 399.1683 (+0.2 ppm).
219
2-(Benzyloxycarbonyl-methyl-amino)-4,7-dimethoxy-indan-2-carboxylic acid ethyl
ester (118). lodomethane (0.74 mL, 11.9 mmol) was injected to a solution of 2-
benzyloxycarbonylaniino-4,7-dimethoxy-indan-2-carboxylic acid ethyl ester (116) (0.59
g, 1.5 mmol) dissolved in a 10:1 THF:DMF solvent system (20 mL) under argon, and
reaction mixture was brought to reflux for 45 min. The heat source was removed, sodium
hydride (0.18 g, 7.4 mmol) was slowly added to the hot solution (caution: exothermic),
and the reaction mixture was reheated to reflux for another 20 min. After verifying the
reaction was complete by TLC, the solution was slowly quenched with water (1.5 mL),
further diluted with water (200 mL), and extracted with AcOEt (3 x 200 mL). The
organic phase was washed with NaiSOa (sat) (150 mL) and brine (150 mL), then dried
(MgS04) filtered and concentrated to obtain 0.49 g (1.2 mmol, 80%) of 118 as a light
yellow oil, Rf 0.41 (30% AcOEt/hexanes, black in PMA stain).
Spectral Data for 118: IR (NaCl) cm 1741, 1693; 'H NMR (300 MHz, CDCI3) 6: 1.12
(3H, broad s), 2.98 (3H, s), 3.36 (2H, d, J = 17.34 Hz), 3.61 (2H, d, J = 17.09 Hz), 3.74
(6H, s), 4.12 (2H, broad s), 5.14 (2H, s), 6.63 (2H, s), 7.34 (5H, m); '^C NMR (75
MHz, CDCI3) 5: 13.9, 32.2, 39.9, 55.5, 61.1, 67.2, 71.2, 109.2, 127.7, 127.9, 128.3,
129.3, 136.3, 149.6, 156.3, 173.4; HRMS (FAB+) calcd for C23H28NO6 (M+ +H)
414.1917, found 414.1924 (+1.8ppm).
220
2-(Benzyloxycarbonyl-methylamino)-4,7-diinethoxyindan-2-carboxylic acid (123).
Potassium hydroxide (0.67 g, 12 mmol) was added to a solution of 2-
(benzyloxycarbonyl-methylamino)-4,7-dimethoxy-indan-2-carboxylic acid ethyl ester
(118) (0.48 g, 1.2 mmol) in a 1:4 H20:Et0H (25 mL) mixed solvent system, and the
reaction heated to reflux. After 4 h, the reaction was judged complete by TLC. The
solution was cooled to room temperature and the solvent was removed under vacuum to
obtain a white salt, which was dissolved in water (50 mL) and acidified with conc HCl to
a pH of 2. The aqueous solution was extracted with AcOEt (3 x 50 mL). The organic
phase washed with brine (150 mL), treated with charcoal, dried (MgS04), filtered and
concentrated to a sticky oil. The oil was treated several times by azeotroping with
benzene, and then triturated in hot hexanes to give an off-white solid. The solution was
cooled to room temperature and filtered to obtain 0.37 g (0.96 mmol, 81%) of 123 as a
dry white solid, Rf 0.21 (50% AcOEt/hexanes, black in PMA stain).
Spectral Data for 123; mp: 171-172 °C; IR (KBr) cm 3421, 1709, 1685; 'H NMR (300
MHz, CDCI3) 5: 2.99 (3H, s), 3.34 (2H, d, J = 16.94 Hz), 3.65 (2H, broad d, J = 19.83
Hz), 3.75 (6H, s), 5.13 (2H, s), 6.63 (2H, s), 7.32 (5H, s), 10.44 (IH, broad s);
NMR (75 MHz, CDCI3) 5: 32.6, 40.08, 55.5, 62.0, 67.6, 71.1, 109.3, 127.94, 128.4,
129.2, 136.2, 149.6, 156.7, 179.2; HRMS (FAB+) calcd for C21H23NO6 (M+) 385.1525,
found 385.1526 (+0.1ppm).
221
Synthesis of 1,4 Hexyloxy Indane Amino Acids
l,4-6«-Hexyloxy-2,3-dimethylbenzene (69b), A solution of 2,3-dimethylhydroquinone
(2.48 g, 18 mmol) in dry THF (35 mL) was slowly added via cannula to a slurry of
sodium hydride (0.95 g, 0.04 mol) in THF (35 mL) under argon. The cannula was rinsed
with THF (2x10 mL). Upon injection, an exothermic reaction was observed, and the
resulting green colored solution was allowed to stir at room temperature. After 20 min,
iodohexane (5.3 mL, 36 mmol) was added via syringe and the reaction was brought to
reflux for 72 h. The solution was cooled to room temperature, slowly quenched with 15
mL of water, and concentrated under vacuum to a brown residue. The material was dry
loaded to silica, purified by flash chromatography (230-400 mesh silica) in 100%
hexanes elutant to give 3.9 g (0.13 mol, 71%) of 69b as a yellow oil, Rf 0.73 (40%
AcOEt/hexanes, purple in anisaldehyde stain).
Spectral Data for 69b: IR (NaCl) cm 1468, 1252; 'H NMR (300 MHz, CDCI3) 5: 0.91
(6H, t, J = 6.83), 1.35 (8H, m), 1.48 (4H, pentet, J = 7.20), 1.77 (4H, pentet, J = 6.76),
2.17 (6H,s), 3.88 (4H, t, J = 6.35), 6.63 (2H, s), '^C NMR (75 MHz, CDCI3) 5: 12.1,
14.0, 22.6, 25.8, 29.5, 31.6, 68.9, 109.1, 126.9, 151.2; HRMS (FAB+) calcd for
C20H34O2 (M^) 306.2559 , found 306.2563 (+1.2 ppm)
l-Bromo-2,5-to-hexyloxy-3,4-dimethylbenzene (82b). A solution of bromine (1.6 mL,
0.032 mol) in CHCI3 (75 mL) was added dropwise over a 30 min period to a solution of
l,4-Z?/5'-hexyloxy-2,3-dimethylbenzene (8.92 g, 29 mmol) (69b) in CHCI3 (75 mL) at
room temperature under argon. The reaction was monitored by GCMS. After 45 min, the
222
reaction was diluted with CH2CI2 (100 mL) and washed successively with NaHCOs (sat)
(100 mL), NaaSOs (sat) (100 mL), and brine (100 mL). The organic phase was dried
(MgS04) and concentrated under vacuum to 10.1 g (26 mmol, 91%) of 82b as a light
yellow oil.
Spectral Data for 82b: IR (NaCl) cm 1462, 1375, 1227, 1103; 'H NMR (300 MHz,
CDCI3) 6: 0.92 (6H, m), 1.35 (8H,m), 1.49 (4H, septet, J = 7.44), 1.79 (4H, septet, J =
7.07), 2.09 (2H, s), 2.22 (2H, s), 3.78 (2H, t, J = 6.60), 3.86 (2H, t, J = 6.47), 6.85 (IH,
s); '^C NMR (75 MHz, CDCI3) 6: 12.1, 13.4, 14.0, 14.1, 22.6, 22.6, 25.7, 25.8, 29.2,
30.1, 31.5, 31.7, 68.6, 73.2, 113.1, 113.5, 126.0, 132.3, 147.9, 153.4; HRMS (FAB+)
calcd for CaoHsaOaBr (M^) 384.1664, found 384.1672 (+2.1 ppm).
l-Bromo-3,4-6/5-bromomethyl-2,5-6/s-hexyloxybenzene (83b). N-bromosuccinimide
(9.8 g, 0.06 mol) was added in one portion to a solution of l-bromo-2,5-6w-hexyloxy-
3,4-dimethylbenzene (82b) (10.1 g, 30 mmol) in CCI4 (150 mL) under argon. A 250 W
(115 -125 V) IR heat lamp was positioned near the reaction flask to ensure a gentle
reflux. The reaction was monitored by GCMS. After 24 h, the solution was cooled to
room temperature and filtered, washing with CCI4 (20 mL). The solution was diluted with
CH2CI2 (100 mL), and washed successively with NaHCOa (sat) (100 mL), Na2S03 (sat)
(100 mL), and brine (100 mL). The organic phase was dried (MgS04), and concentrated
under vacuum to 14.0 g (60 mmol, 99%) of 83b as a yellow oil.
Spectral Data for 83b; IR (NaCl) cm 1455, 1245, 1011; 'H NMR (300 MHz, CDCI3)
5: 0.91 (6H, m), 1.34 (8H, m), 1.48 (4H, m), 1.83 (4H, septet, J=7.20,; 3.95 (2H, t.
223
J=6.35), 4.023 (2H, t, J=6.59), 4.69 (2H, s), 4.70 (2H, s), 7.02 (IH, s), (75 MHz,
CDCI3) 5: 14.0, 14.05, 22.6, 22.6, 23.5, 23.7, 25.5, 25.7, 29.0, 30.0, 31.4, 31.6, 69.0,
74.2, 117.1, 118.4, 125.8, 132.7, 148.6, 153.7; HRMS (FAB+) calcd for C2oH3i02Br3
(M^ +H) 541.9855, found 541.9850 (-0.7 ppm).
2-Amino-4,7-6/5-hexyloxyindaii-2-carboxylic acid ethyl ester (85b). Dry acetonitrile
(850 mL) was added in one portion to a flask containing l-bromo-3,4-Zjw-broniomethyl-
2,5-^w-hexyloxybenzene (83b) (14.2 g, 26 mmol), tetrabutylammonium iodide (1.9 g,
5.0 mmol), and finely ground potassium carbonate (43 g, 0.31 mol) under argon, and the
slurry was refluxed in an oil bath heated to 85 -90 °C. Ethyl isocyanoacetate (3.1 mL,
0.029 mol) was injected. Vigorous stirring was essential for an efficient and complete
reaction. After 15 h, the solution was cooled to room temperature and filtered, washing
the salts thoroughly with CH2CI2. The solvent was concentrated under vacuum to a brown
residue, which was purified by flash chromatography (230-400 mesh silica) in a 10%
AcOEt/hexanes elutant to obtain 9.0 g of a crude yellow oil, Rf 0.38 (10%
AcOEt/hexanes, light pink in ninhydrin stain). The crude isocyanate was dissolved in a
mixture of absolute EtOH (80 mL) and conc HCl (5 mL), and stirred overnight at room
temperature. After 18 h the solvent was removed under vacuum to obtain a white solid,
which was taken up in water (250 mL) and basified with conc NH4OH. The aqueous
solution was extracted with Et20 (3 x 200 mL), and the organic phase dried (MgS04),
and concentrated under vacuum to a crude yellow residue. The material was purified by
flash chromatography (230-400 silica mesh, pretreated with 1% NEta) in a 10%
224
AcOEt/hexanes elutant until all yellow non-polar impurities were removed, and then the
solvent polarity was ramped to 30% AcOEt/hexanes elutant to obtain 5.0 g of a crude
brown oil, Rf 0.29 (30% AcOEt /hexanes, rose in ninhydrin stain). The crude amine with
10% Pd/C (2.4 g) in absolute EtOH (50 mL) was hydrogenated in a Parr hydrogenator at
55 psi (H2 gas). The reaction was monitored by GCMS. Each day a small portion of 10%
Pd/C (0.1 g) was added to the reaction flask. After 4 d, the reaction contents were filtered,
washing with CH2CI2, and concentrated under vacuum to an orange residue, which was
purified by gravity chromatography (40% AcOEt/hexanes, pretreated with 1% NEts) to
obtain 1.97 g (4.0 mmol, 28% for 3 steps) of 85b as a yellow oily solid, Rf 0.48 (50%
AcOEt/hexanes, rose in ninhydrin stain).
Spectral Data for 85b: mp: 35-36 °C; IR (KBr): 1727; 'H NMR (200 MHz, CDCI3) 5:
0.87 (6H, t, J = 6.60), 1.13 (15H, m), 1.71 (6H, m), 2.88 (2H, d, J = 16.4), 3.42 (2H, d, J
= 16.4), 3.86(4H, dt, J = 2.20, 6.41), 4.18 (2H, q, J = 7.17), 6.58 (2H,s); '^C (50 MHz,
CDCI3) 5: 13.9, 14.1, 22.5, 25.6, 29.7, 31.5, 43.8, 61.1, 64.6, 68.3, 110.4, 130.1, 149.8,
176.7; HRMS (FAB+) calcd for C24H40NO4 (M^ +H) 406.2957, found 406.2952 (-1.3
ppm).
2-ter/-Butoxycarbonylamino-4,7-Aw-hexyloxyindaii-2-carboxylic acid ethyl ester
(93b). Di-ter/-butyl dicarbonate (1.47 g, 6.7 mmol) was added to a solution of 2-amino-
4,7-bis-hexyloxyindan-2-carboxylic acid ethyl ester (85b) (1.81 g, 4.0 mmol) in a
mixture of CH2CI2 (25 mL) and brine (5 mL), and the reaction was heated to a gentle
reflux overnight. An extra portion of di-terr-butyl dicarbonate (0.5 g, 2.3 mmol) was
225
added to the solution after 24 h, and the reaction was allowed to reflux an additional 6 h.
The solution was diluted with CH2CI2 (150 mL), and washed with brine (100 mL). The
organic phase was dried (MgS04) and concentrated under vacuum to a yellow solid
which was purified by flash chromatography (230-400 mesh silica, pretreated withl%
NEts) in a 20% AcOEt/hexanes elutant to obtain 1.99 g (3.9 mmol, 99%) of 93b as an
off-white solid, Rf 0.55 (purple in ninhydrin stain).
Spectral Data for 93b: mp: 63-64 °C; IR (KBr pellet): 3363 (b), 1733, 1709; 'H NMR
(300 MHz, CDCI3, B0C2O contaminant) 5; 0.87 (6H, t, J = 6.35,; 1.26 (IIH, m), 1.39
(9H, s), 1.50(s,Boc20), 1.70 (4H, pentet, J = 6.78), 3.17 (2H, broad d, J = 17.09), 3.51
(2H, d, J = 16.85), 3.86 (4H, t, J = 6.35), 4.20 (2H, q, J = 7.08), 5.09 (IH, broad s),
6.58 (2H, s); '^C (75 MHz, CDCI3, B0C2O contaminant) S; 14.0, 14.1, 22.6, 25.7, 27.3
(B0C2O), 28.1, 29.3, 31.5, 41.5, 61.4, 65.7, 68.4, 79.8, 85.1 (B0C2O), 110.5, 129.6, 146.7
(B0C2O), 149.5, 154.8, 173.5; HRMS (FAB+) calcd for C29H47NO6 (M^) 505.3403, found
505.3403 (-0.1 ppm).
2-fer^-Butoxycarbonylamino-4,7-6w-hexyIoxyindaii-2-carboxylic acid (94b).
Potassium hydroxide (2.0 g, 30 mmol) was added to a solution of 2-tert-
butoxycarbonylamino-4,7-Z)w-hexyloxyindan-2-carboxylic acid ethyl ester (93b) (1.83 g,
3.6 mmol) in absolute EtOH (60 mL) followed by addition of water (15 mL). The
solution gradually went from opaque to a clear yellow solution upon heating to a gentle
reflux. After 1 h, the reaction was cooled to room temperature and the solvent removed
under vacuum to obtain a white solid. The solid was dissolved in water (100 mL) and the
226
solution acidified with conc HCl to a pH of 2. The aqueous solution was extracted with
AcOEt (3 X 100 mL), and the organic phase washed with brine (100 mL), dried (MgS04)
and concentrated under vacuum to obtain 1.57 g (3.3 mmol, 91%) of 94b as an off-white
solid, Rf 0.56 (20% AcOEt/hexanes, brown in ninhydrin stain)
Spectral Data for 94b: mp=116 °C; IR (KBr): 3351 (b), 3086 (b), 1746, 1672; 'H NMR
(300 MHz, CDCI3) 6: 0.88 (6H, t, J - 6.49), 1.37(17H,m), 1.72 (4H, pentet, J = 6.83),
3.22 (2H, broad d, J = 15.42), 3.58 (2H, d, J = 16.94), 3.87 (4H, t, J = 6.49), 5.18 (IH,
broads), 6.585 (2H, s), 11.87 (IH, broad s); '^C NMR (75 MHz, CDCI3) 6: 14.0,22.6,
25.7, 28.2, 29.3, 31.6, 41.4, 65.4, 68.5, 80.3, 110.6, 129.5, 149.5, 155.4, 178.8; HRMS
(FAB+) calcd for C27H43NO6 (M^) 477.3090, found 477.3089 (-0.3 ppm).
227
Synthesis of 1,4 Octyloxy Indane Amino Acids
2,3-Diniethyl-l,4-6/s-octyloxybenzene (69c). A solution of 2,3-dimethylhydroquinone
(10.0 g, 73 mmol) in dry THF (150 mL) was slowly added via cannula to a slurry of
sodium hydride (3.8 g, 0.16 mol) in THF (80 mL) under argon. The cannula was rinsed
with THF (20 mL). Upon injection, an exothermic reaction was observed, and the
resulting green colored solution was allowed to stir at room temperature. After 20 min,
iodooctane (26.2 mL, 0.15 mol) was added via syringe and the reaction was brought to
reflux for 72 h. The solution was cooled to room temperature, slowly quenched with 15
mL of water, and concentrated under vacuum to a brown residue. The material was dry
loaded to silica, purified by gravity chromatography (230-400 mesh silica) in a 100%
hexanes elutant and concentrated under vacuum to an oil which was freeze-pump-thawed
(3 x) to give 14.8 g (40 mmol, 57%) of 69c as a yellow oil, Rf 0.96 (40% AcOEt/hexanes,
purple in anisaldehyde stain).
Spectral Data for 69c: IR (NaCl) cm 1460, 1243, 1106; 'H NMR (300 MHz, CDCI3)
S: 0.92 (6H, t, J = 6.72), 1.33 (16H, m), 1.49 (4H, pentet, J = 7.16), 1.79 (4H, pentet, J
= 6.89), 2.19 (6H,s), 3.89 (4H, t, J = 6.35), 6.64 (2H, s); '^C NMR (75 MHz, CDCI3)
5: 12.1, 14.1, 22.7, 26.2, 29.3, 29.4, 29.6, 31.9, 68.9, 109.1, 126.9, 151.2; HRMS
(FAB+) cacld for C24H42O2 (M+) 362.3185, found 362.3178 (-1.8 ppm).
l-Bromo-3,4-dimethyl-2,5-6/5-octyloxybenzene (82c). A solution of bromine (2.6 mL,
51 mmol) in CHCI3 (50 mL) was added dropwise over a 30 min period to a solution of
228
2,3-dimethyl-l,4-Z)w-octyloxybenzene (69c) (16.8 g, 47 mmol) in CHCI3 (150 rtiL) at
room temperature under argon. The reaction was monitored by GCMS. After 3 h, the
reaction was washed successively with NaHCOs (sat) (100 mL), NaaSOs (sat) (100 mL),
and brine (100 mL). The organic phase was dried (MgS04) and concentrated under
vacuum to an oil, which was freeze-pump-thawed (3 x) to obtain 20.7 g (50 mmol, 100%)
of 82c as a yellow oil, Rf 0.79 (40% AcOEt/hexanes, purple in anisaldehyde stain)
Spectral Data for 82c; IR (NaCl) cm 1468, 1227, 1103; 'H NMR (300 MHz, CDCI3)
5: 0.87 (6H, t, J - 5.98), 1.28 (16H, m), 1.47 (4H, septet, J - 6.92), 1.78 (4H, septet, J =
6.96), 2.08 (3H,s), 2.20 (3H, s), 3.76 (2H, t, J = 6.72), 3.85 (2H, t, J = 6.35), 6.83 (IH,
s); '^C NMR (75 MHz, CDCI3) 5: 12.2, 13.4, 14.1, 22.7, 26.1, 26.11, 29.2, 29.3, 29.5,
30.1, 31.8, 31.8, 68.6, 73.3, 75.8, 113.2, 113.5, 126.0, 132.3, 148.0, 153.5; HRMS
(FAB+) cacld for C24H4i02Br (M^) 440.2290, found 440.2287 (-0.7 ppm).
l-Bromo-3,4-6/5-bromomethyl-2,5-Z>is-octyloxybenzene (83c). N-bromosuccinimide
(14.2 g, 80 mmol) was added in one portion to a solution of l-bromo-3,4-dimethyl-2,5-
^«-octyloxybenzene 82c (16.9 g, 38 mmol) in CCI4 (150 mL) under argon. A 250 W
(115 to 125 V) IR heat lamp was positioned near the reaction flask to ensure a gentle
reflux. The reaction was monitored by GCMS. After 24 h, the solution was cooled to
room temperature and filtered, washing with CCl4(50 mL). The solution was diluted with
CH2CI2 (50 mL), and washed successively with NaHCOs (sat) (100 mL), Na2S03 (sat)
(100 mL), and brine (100 mL). The organic phase was dried (MgS04), and concentrated
under vacuum to a yellow oil, which was freeze-pump-thawed (3 x) to obtain 22.6 g (40
229
mmol, 100%) of 83c as a sticky yellow solid, Rf 0.61 (5% AcOEt/hexanes, purple in
anisaldehyde stain).
Spectral Data for 83c: mp: 31-32 °C; IR (KBr); 1455, 1245; 'H NMR (300 MHz, CDCI3)
5: 0.87 (6H, t, J = 5.86), 1.28 (16H,m), 1.48 (4H,m), 1.83 (4H, septet, J = 7.20), 3.95
(2H, t, J = 6.35), 4.01 (2H, t, J = 6.59), 4.68 (2H, s), 4.70 (2H, s), 7.01 (IH s); '^C NMR
(75 MHz, CDCI3) 5: 14.1, 22.7, 23.505, 23.7, 25.9, 26.0, 29.1, 29.2, 29.3, 29.4, 30.0,
31.8, 31.824, 69.1, 74.2, 117.2, 118.4, 125.9, 132.7, 148.6, 153.8; HRMS (FAB+) calcd
for C24H3902Br3 (M"") 596.0500, found 596.0501 (+0.2 ppm).
2-Amino-4,7-6/5-octyloxyindan-2-carboxylic acid ethyl ester (85c). (Kotha
conditions): Dry acetonitrile (150 mL) was added in one portion to a flask containing
tetrabutylammonium iodide (3.5 g, 9.6 mmol), and finely ground potassium carbonate
(53 g, 0.38 mol) under argon. l-Bromo-3,4-Z)w-bromomethyl-2,5-Z)«-octyloxybenzene
(83c) (18.8 g, 0.032 mol) in chlorobenzene (150 mL) was added to the flask in one
portion, and the slurry was refluxed in an oil bath heated to 85-90 °C. Ethyl
isocyanoacetate (3.8 mL, 0.035 mol) was injected. Vigorous stirring was essential for an
efficient and complete reaction. After 19 h, the solution was cooled to room temperature
and filtered, washing the sahs thoroughly with CH2CI2. The solvent was concentrated
under vacuum to a brown residue, which was purified by flash chromatography (230-400
mesh silica) in a 10% AcOEt/hexanes elutant to obtain a mixture of isocyanates as a
brown oil, Rf 0.41 and Rf 0.47 (10% AcOEt/hexanes, light pink in ninhydrin stain). The
crude isocyanates were dissolved in a mixture of absolute EtOH (150 mL) and conc HCl
230
(5 mL), and stirred overnight at room temperature. After 18 h, the solvent was removed
under vacuum to obtain a white solid, which was taken up in water (200 mL) and basified
with conc NH4OH. The aqueous solution was extracted with AcOEt (3 x 200 mL), and
the organic phase was washed with brine (200 mL), dried (MgS04) and concentrated
under vacuum to a crude brown residue. This material was purified by flash
chromatography (230-400 silica mesh, pretreated with 1% NEts) in a 5% AcOEt/hexanes
elutant until all yellow non-polar impurities were removed. The solvent polarity was then
ramped to a 20% AcOEt/hexanes elutant to obtain 7.1 g of a brown oil, Rf 0.36 (10%
AcOEt /hexanes, rose in ninhydrin stain). The crude amine in absolute EtOH (100 mL)
with 10% Pd/C (4.0 g) was hydrogenated in a Parr hydrogenator at 55 psi (H2 gas). Each
day a small portion of 10%) Pd/C (0.1 g) was added to the reaction flask. After 5 d, the
reaction contents were filtered, washing with CH2CI2, and concentrated under vacuum to
a brown residue, which was purified by gravity chromatography (30%) AcOEt/hexanes,
pretreated with 1% NEts) to obtain 3.5 g (7.6 mmol, 24% for 3 steps) of (85c) as a brown
oil, Rf 0.36 (10% AcOEt/hexanes, rose in ninhydrin stain).
(Kuki conditions): NaHMDS (130 mL, 1 M solution in THF) was injected to a -78 °C
solution of N- benzylidene glycine ethyl ester (12.5 g, 70 mmol) in dry THF (4000 mL)
under argon. A solution of l-bromo-3,4-&w-bromomethyl-2,5-Z)/5'-octyloxybenzene (83c)
(30 g, 0.05 mol) in THF (50 mL) was injected after 30 min at -78 °C, and the reaction
was allowed to warm to room temperature. The reaction was too dilute to monitor by
TLC. After 24 h, the reaction was quenched by addition of water (10 mL), and the
solution was concentrated under vacuum to a reasonable volume (1000 mL). The solution
231
was washed with brine (250 mL), dried (MgS04) and concentrated to a brown oil. This
crude material in absolute EtOH (100 mL) with 10% Pd/C (3.6 g) was hydrogenated in a
Parr hydrogenator at 55 psi (H2 gas). Each day a small portion of 10% Pd/C (0.1 g) was
added to the reaction flask. After 4 d, the reaction contents were filtered, washing with
CH2CI2, and concentrated under vacuum to a brown residue, which was purified by
gravity chromatography (30% AcOEt/hexanes, pretreated with 1% NEts) to obtain 7.0 g
(15 mmol, 30% for two steps) of a brown oil 85c, Rf 0.42 (2% EtOH, CH2CI2, rose in
ninhydrin stain).
Spectral Data for 85c: IR (NaCl) cm 1733; 'H NMR (200 MHz, CDCI3) 6: 0.86 (6H,
t, J = 6.69), 1.26 (23H, m), 1.73 (6H, m), 2.89 (2H, d, J = 16.20), 3.43 (2H, d, J =
16.19), 3.87(4H, dt, J = 2.17, 6.37), 4.19 (2H, q, J = 7.12), 6.58 (2H, s); NMR (50
MHz, CDCI3) 8: 14.0, 14.1, 22.6, 26.0, 29.2, 29.3, 31.7, 43.7, 61.1, 64.6, 68.3, 110.3,
130.0, 149.7, 176.7; HRMS (FAB+) calcd for C28H48O4N (M+ +H) 462.3583, found
462.3588 (+1.1 ppm).
2-/er/-Butoxycarbonylamino-4,7-6w-octyloxyindan-2-carboxylic acid ethyl ester
(93c). Di-ter^-butyl dicarbonate (4.9 g, 0.023 mol) was added to a solution of 2-amino-
4,7-^/5-octyloxyindan-2-carboxylic acid ethyl ester (85c) (6.97 g, 15 mmol) in a mixture
of CH2CI2 (100 mL) and brine (50 mL), and the reaction was heated to a gentle reflux
overnight. An extra portion of di-ter/^-butyl dicarbonate (0.5 g, 2.3 mmol) was added to
the solution after 15 h, and the reaction was allowed to reflux an additional 6 h. The
solution was diluted with CH2CI2 (150 mL), and washed with brine (100 mL). The
232
organic phase was dried (MgS04) and concentrated under vacuum to a yellow solid
which was purified by gravity chromatography (230-400 mesh silica, pretreated with 1%
NEts) in a 5% AcOEt/hexanes elutant to obtain 4.8 g (8.6 mmol, 57%) of 93c as a light
yellow oily solid, Rf 0.63 (2% EtOH/CH2Cl2, dark rose in ninhydrin stain).
Spectral Data for 93c: mp: 52-53 °C; IR (KBr): 1733, 1702; 'H NMR (300 MHz, CDCI3,
contaminated with B0C2O) 5: 0.86 (6H, t, J = 6.71), 1.27 (23H, m), 1.397 (9H, s), 1.50
(s, B0C2O), 1.71 (4H, pentet, J = 6.90), 3.17 (2H, d, J = 16.85), 3.52 (2H, d, J = 16.85),
3.86 (4H, dt, J = 1.22, 4.97), 4.20 (2H, q, J = 7.08), 5.07 (IH, bs), 6.58 (2H, s);
NMR (75 MHz, CDCI3, contaminated with B0C2O) 6: 14.1, 14.2, 22.6, 26.1, 27.4
(B0C2O), 28.2, 29.2, 29.4, 31.8, 41.6, 61.4, 65.6, 68.5, 79.8, 85.1 (B0C2O), 110.6,
129.6,146.7 (B0C2O), 149.5, 154.9,173.5; HRMS (FAB+) calcd for C33H55O6N (M^)
561.4029, found 561.4031 (+0.4 ppm).
2-fer/-Butoxycarbonylamino-4,7-6is-octyloxyindan-2-carboxylic acid (94c).
Potassium hydroxide (3.8 g, 70 mmol) was added to a solution of 2-tert-
butoxycarbonylamino-4,7-Z)w-octyloxyindan-2-carboxylic acid ethyl ester (93c) (4.22 g,
7.5 mmol) in absolute EtOH (100 mL) followed by addition of water (50 mL). The
solution gradually went from opaque to a clear yellow solution by heating to a gentle
reflux. After 1 h, the reaction was cooled to room temperature and the solvent removed
under vacuum to obtain a white solid. The salts were dissolved in water (150 mL) and the
solution acidified with conc HCl to a pH of 2. The aqueous solution was extracted with
AcOEt (3 x 100 mL), and the organic phase washed with brine (100 mL), dried (MgS04)
233
and concentrated under vacuum to a yellow sticky solid. The solid was dried by
azeotroping with benzene to obtain 3.42 g (6.4 mmol, 86%) of 94c as a light yellow solid,
Rf 0.41 (30% AcOEt/hexanes, brown in ninhydrin stain)
Spectral Data for 94c: mp: 64 °C; IR (KBr): 1720, 1652; 'H NMR (300 MHz, CDCI3) 6:
0.86 (6H, t, J = 6.60), 1.27 (20H, m), 1.40 (9H, s), 1.71 (4H, pentet, J = 6.835), 3.211
(2H, broad d, J = 16.84), 3.58 (2H, d, J = 16.84), 3.87 (4H, t, J = 6.47), 5.14 (IH, broad
s), 6.59 (2H, s); NMR (300 MHz, CDCI3) 6: 14.1, 22.6, 26.1, 28.2, 29.2, 29.4,
31.8, 41.3, 65.6, 68.5, 81.4, 110.6, 129.3, 149.5, 155.6, 178.1; HRMS (FAB+) calcd for
C31H51O6N (M+) 533.3716, found 533.3715 (-0.2 ppm).
234
Synthesis of 1,4 Dodecyloxy Indane Amino Acids
l,4-fi/s-dodecyloxy-2,3-dimethylbenzene (69d). A solution of 2,3-
dimethylhydroquinone (10.28 g, 74 mmol) in dry THF (120 mL) was slowly added via
cannula to a slurry of sodium hydride (3.9 g, 0.16 mol) in THF (150 mL) under argon.
The caimula was rinsed with THF (30 mL). Upon injection, an exothermic reaction was
observed, and the resulting green colored solution was allowed to stir at room
temperature. After 20 min, iodododecane (40.5 mL, 0.16 mol) was added via syringe and
the reaction was brought to reflux. Each additional day, a portion of sodium hydride (0.5
g, 0.02 mol) was added to the reaction until complete reaction. After 4 d, the solution was
cooled to room temperature, slowly quenched with water (1000 mL), and the aqueous
solution was extracted with EtiO (4 x 500 mL). The organic phase was washed with brine
(250 mL), dried (MgS04) and concentrated to a brown solid, which was purified by
gravity chromatography (230-400 mesh silica) in a 100% hexanes elutant to give 25.3 g
(53 mmol, 72%) of 69d as a white solid, Rf = 0.32 (100% hexanes, purple by
anisaldehyde stain).
Spectral Data for 69d: mp 41 °C; IR (KBr) cm "':1468, 1252; 'H NMR (300 MHz,
CDCI3) 5: 0.87 (6H, t, J = 6.59), 1.25 (32H, m), 1.45 (4H, pentet, J = 6.83), 1.76 (4H,
pentet, J = 6.89), 2.15 (6H, s), 3.86 (4H, t, J = 6.47), 6.61(2H, s); '^C NMR (75 MHz,
CDCl3)5; 12.2,14.1,22.7, 26.2, 29.4, 29.4, 29.6, 29.6, 29.7, 29.7, 31.9, 69.0,
109.2, 126.9, 151.2; HRMS (FAB+) calcd for C32H58O2 (M^^) 474.4437, found 474.4439
(+0.4 ppm).
l-Bromo-2,5-6/s-dodecyloxy-3,4-dimethylbenzene (82d). A solution of bromine (3.3
mL, 64 mmol) in CHCI3 (200 mL) was added dropwise over a 30 min period to a solution
of l,4-6w-dodecyloxy-2,3-dimethylbenzene (69d) (23.19 g, 49 mmol) in CHCI3 (200
mL) at room temperature under argon. The reaction was monitored by GCMS. After 6 h,
the reaction solution was washed successively with NaHCOs (sat) (200 mL), NaiSOs
(sat) (200 mL), and brine (200 mL). The organic phase was dried (MgS04) and
concentrated under vacuum to 26.6 g (0.48 mol, 77%) of 82d as a white solid.
Spectral Data for 82d: mp 38 °C; IR (KBr) cm1474, 1375, 1233; 'H NMR (300 MHz,
CDCI3) 5: 0.87 (6H, t, J = 6.59), 1.25 (32H, multiplet), 1.46 (4H, pentet, J = 7.4), 1.77
(4H, septet, J = 6.88), 2.08 (3H, s), 2.20 (3H, s), 3.76 (2H, t, J = 6.59), 3.85 (2H, t, J =
6.47), 6.83 (IH, s); NMR (75 MHz, CDCI3) 6: 12.2, 13.4, 14.1, 22.7, 26.07, 26.1,
29.3, 29.34, 29.5, 29.6, 29.6, 30.1, 31.9, 68.6, 73.3, 113.2, 113.5, 126.0, 132.4, 147.9,
153.5; HRMS (FAB+) calcd for C32H5802Br (M^) 553.3620, found 553.3560 (-2.8 ppm).
l-Bromo-3,4-/>/s-bromomethyl-2,5-6w-dodecyloxybenzene (83d).
N-bromosuccinimide (17.0 g, 0.095 mol) was added in one portion to a solution of 1-
bromo-2,5-Z)w-dodecyloxy-3,4-dimethylbenzene (82d) (26.3 g, 48 mmol) in CCI4 (650
mL) under argon. A 250 W (115 to 125 V) IR heat lamp was positioned near the reaction
flask to ensure a gentle reflux. After 24 h, the solution was cooled to room temperature
and filtered, washing with CCI4 (20 mL). The solution was washed successively with
NaHC03 (sat) (200 mL), NaiSOs (sat) (200 mL), and brine (200 mL). The organic phase
236
was dried (MgS04), and concentrated under vacuum to 33.2 g (47 mmol, 96%) of 83d as
an off-white sohd.
Spectral Data for 83d: mp 41-42 °C; IR (KBr) cm 1455, 1245; 'H NMR (200 MHz,
CDCI3) 6: 0.87 (6H, t, J = 6.41,; 1.25 (32H, s), 1.50 (4H, m), 1.82 (4H, m), 3.95 (2H, t, J
= 6.39), 4.02 (2H, t, J = 6.61), 4.68 (2H, s), 4.70 (2H, s), 7.02 (IH, s); '^C NMR (50
MHz, CDCI3) 5: 14.1, 22.7, 23.5, 23.7, 25.9, 26.0, 29.1, 29.2, 29.3, 29.5, 30.0, 31.9, 69.1,
74.2, 117.2, 118.4, 125.9, 132.7, 148.6, 153.8; HRMS (FAB+) calcd for C32H5502Br3
(M^ +2) 710.1734, found 710.1738 (+0.8 ppm).
2-Amino-4,7-to-dodecyloxyindan-2-carboxylic acid ethyl ester (85d).
Dry acetonitrile (300 mL) was added to a flask containing tetrabutylammonium iodide
(3.0 g, 8.0 mmol), and finely ground potassium carbonate (66 g, 0.48 mol) under argon.
l-Bromo-3,4-Z)w-bromomethyl-2,5-6/5-dodecyloxybenzene (83d) (29.2 g, 0.040 mol) in
chlorobenzene (300 mL) was added to this flask in one portion, and the slurry was
refluxed in an oil bath heated to 85 -90 °C. Ethyl isocyanoacetate (5.0 mL, 0.045 mol)
was injected. Vigorous stirring was essential for an efficient and complete reaction. After
6 h, the solution was cooled to room temperature and filtered, washing the salts
thoroughly with CH2CI2. The solvent was concentrated under vacuum to a brown residue,
which was purified by flash chromatography (230-400 mesh silica) in a 5%
AcOEt/hexanes elutant to obtain the crude isocyanate as a brown oil, Rf 0.21 (5%
AcOET/hexanes, pink in ninhydrin stain). The material was dissolved in a mixture of
AcOEt (50 mL), absolute EtOH (100 mL) and conc HCl (20 mL), and stirred overnight at
237
room temperature. After 18 h, the solvent was removed under vacuum to obtain a white
solid, which was taken up in water (250 mL) and basified with conc NH4OH. The
aqueous solution was extracted with AcOEt (3 x 250 mL), and the organic phase was
washed with brine (200 mL), dried (MgS04) and concentrated under vacuum to a brown
oil, Rf 0.36 (20% AcOEt/hexanes, rose in ninhydrin stain). The crude amine was purified
by flash chromatography (230-400 silica mesh, pretreated with 1% NEts) through a silica
gel plug in a 100%) AcOEt elutant. The crude mixture was hydrogentated in EtOAc (200
mL) with 10%) Pd/C (4.0 g) in a Parr hydrogenator at 55 psi (H2 gas). Each day a small
portion of 10%) Pd/C (0.1 g) was added to the reaction flask. After 5 d, the reaction
contents were filtered, washing with CH2CI2, and concentrated under vacuum to a brown
residue. The crude amine was purified by gravity chromatography in a 20%
AcOEt/hexanes elutant until most of the non-polar impurities were removed. The solvent
polarity was then ramped to 50% AcOEt/CH2Cl2 elutant and finally to a 100% CH2CI2
elutant to obtain 10.8 g (19 mmol, 47%) for 3 steps) of 85d as a brown oil, Rf 0.21 (20%
AcOEt/hexanes, rose in ninhydrin stain).
Spectral Data for 85d: IR (NaCl) cm 1733; 'H NMR (300 MHz, CDCI3) 6; 0.86 (6H,
t, J = 6.47), 1.26 (40 H, m), 1.71 (4H, pentet, J = 6.78), 1.82 (2H, bs), 2.89 (2H, d, J =
16.36), 3.43 (2H, d, J = 16.36), 3.87 (4H, sextet, J = 6.35, 11.47), 4.19 (2H, q, J = 7.08),
6.58 (2H, s); NMR (75 MHz, CDCI3) 5: 14.0, 14.1, 22.6, 26.0, 29.3, 29.4, 29.5, 29.6,
31.8, 43.7, 61.1, 64.6, 68.3, 110.3, 130.0, 149.7, 176.6; HRMS (FAB+) calcd for
C36H64NO4 (M"" +H) 574.4835, found 574.4822 (-2.4 ppm).
238
2-ter/-Butoxycarbonylamino-4,7-A/s-dodecyloxyindan-2-carboxylic acid ethyl ester
(93d). Di-/er/-butyl dicarbonate (6.2 g, 28 mmol) was added to a solution of 2-amino-
4,7-Z)/5-dodecyloxyindan-2-carboxylic acid ethyl ester (85d) (10.8 g, 19 mmol) in CH2CI2
(100 mL) and the reaction was heated to a gentle reflux overnight. An extra portion of di-
tert-h\xXy\ dicarbonate (0.5 g, 2.3 mmol) was added to the solution aliter 24 h, and the
reaction was allowed to reflux an additional 6 h. The solution was diluted with CH2CI2
(150 mL), and washed with brine (100 mL). The organic phase was dried (MgS04) and
concentrated under vacuum to a yellow oil which was purified by flash chromatography
(230-400 mesh silica, pretreated with 1% NEta) in a 5% AcOEt/hexanes elutant to obtain
a yellow oil which was freeze-pump-thawed (3 x) to obtain 11.8 g (0.18 mol, 92%) of
93d as a light yellow solid, Rf 0.77 (20% AcOEt/hexanes, dark rose in ninhydrin).
Spectral Data for 93d: mp: 46 °C; IR (KBr) cm 1752, 1721; 'H NMR (300 MHz,
CDCI3) S: 0.86 (6H, t, J = 6.35), 1.24 (39H, bs), 1.40 (9H, s), 1.71 (4H, pentet, J = 6.72),
3.17 (2H, d, J = 17.09), 3.52 (2H, d, J = 17.09), 3.86 (4H, t, J = 6.35), 4.20 (2H, q, J =
7.08), 5.07 (IH, bs), 6.59 (2H, s); '^C NMR (75 MHz, CDCI3) 5: 14.1, 22.7, 26.1, 28.3,
29.3, 29.4, 29.6, 29.7, 31.9, 41.5, 61.4, 65.6, 68.5, 75.1, 110.5, 129.6, 149.5, 154.9,
173.5; HRMS (FAB+) calcd for C41H71NO6 (M^) 673.5281, found 673.5278 (-0.5 ppm).
2-/er/-Butoxycarbonylainino-4,7-6»-dodecyloxyindan-2-carboxylic acid (94d).
Potassium hydroxide (2.4 g, 42 mmol) was added to a solution of 2-tert-
butoxycarbonylamino-4,7-Z)w-dodecyloxyindan-2-carboxylic acid ethyl ester (93d) (2.84
g, 4.2 mmol) in absolute EtOH (75 mL) followed by the addition of water (25 mL). The
239
solution gradually went from opaque to a clear yellow solution after heating to a gentle
reflux. After 1.5 h, the reaction was cooled to room temperature and the solvent removed
under vacuum to obtain a white solid. The solid was dissolved in water (100 mL) and the
solution acidified with conc HCl to a pH of 2. The aqueous solution was extracted with
AcOEt (3 X 100 mL), and the organic phase washed with brine (100 mL), dried (MgS04)
and concentrated under vacuum to a sticky yellow solid. The solid was further dried by
azeotroping with benzene to obtain 1.83 g (2.8 mmol, 68%) of 94d as a dry off-white
solid, Rf 0.26 (20% AcOEt/hexanes, brown in ninhydrin stain).
Spectral Data for 94d; mp; 60-62 °C; IR (KBr pellet) cm 1721, 1653; 'H NMR (300
MHz, CDCI3) 6: 0.86 (6H, t, J = 6.64), 1.24 (36H, bs), 1.39 (9H, s), 1.71 (4H, pentet, J
= 6.27), 3.23 (2H, d, J = 16.48), 3.52 (2H, d, J = 17.09), 3.86 (4H, t, J = 6.41), 5.14 (IH,
bs), 6.58 (2H, s); '^C NMR (75 MHz, CDCI3) 5: 14.1, 22.7, 26.1, 28.2, 29.3, 29.4, 29.4,
29.6, 29.7, 31.9, 41.3, 65.5, 68.5, 80.6, 110.6, 129.4, 149.5, 155.6, 178.2; HRMS
(FAB+) calcd for C39H67N06(M'^) 645.4968, found 645.4965 (-0.5 ppm).
240
Synthesis of 1,4 Octadecyloxy Indane Amino Acids
2,3-Dimethyl-l,4-6w-octadecyloxybenzene (69e). A solution of 2,3-dimethyl
hydroquinone (9.90 g, 72 mmol) in dry THF (100 mL) was slowly added via cannula to a
slurry of sodium hydride (4.35 g, 0.18 mol) in THF (50 mL) under argon. The cannula
was rinsed with THF (10 mL). Upon injection, an exothermic reaction was observed, and
the resulting green colored solution was allowed to stir at room temperature. After 20
min, a solution of iodooctadecane (60.0 g, 0.16 mol) in THF (80 mL) was added via
syringe, and the reaction was brought to reflux for 72 h. The solution was cooled to room
temperature, slowly quenched with 250 mL of water, and the aqueous solution was
extracted with CHCI3 (10 x 500 mL). The organic phase was washed with brine (1000
mL), dried (MgS04) and concentrated to a brown solid. The crude material was
recrystallized from absolute EtOH to yield 35.9 g (56 mmol, 78%) of 69e as a light
yellow solid, Rf 0.81 (40% AcOEt/hexanes, blue in anisaldehyde stain).
Spectral Data for 69e: mp: 64-65 °C; IR (KBr) cm 1480, 1258, 1116; 'H NMR (300
MHz, CDCI3) 8: 0.87 (6H, t, J = 6.59), 1.25 (56H, s), 1.45 (4H, pentet, J = 6.67), 1.76
(4H, pentet, J = 6.90), 2.153 (6H, s), 3.861 (4H, t, J = 6.47), 6.611 (2H, s); '^C NMR
(75 MHz, CDCI3) 5: 12.1, 14.1, 22.7, 26.2, 29.4, 29.437, 29.5, 29.6, 29.7, 31.9, 69.0,
109.2, 126.9, 151.2; HRMS (FAB+) cacld for C44H82O2 (M^^) 642.6315, found 642.6320
(+0.8 ppm).
241
l-Bromo-3,4-6/s-bromomethyl-2,5-6w-octadecyloxybenzene (83e). A solution of
bromine (3.3 mL, 60 mmol) in CHCI3 (400 mL) was added dropwise over a 3.5 h period
to a solution of 2,3-dimethyl-l,4-Z)w-octadecyloxybenzene (69e) (37.2 g, 60 mmol) in
CHCI3 (500 mL) at room temperature under argon. After 22 h, the reaction washed
successively with NaHCOs (sat) (250 mL), NaaSOs (sat) (250 mL), and brine (250 mL).
The organic phase was dried (MgS04) and concentrated under vacuum to a yellow solid,
which was purified by recrystallization from absolute EtOH to obtain 39.4 g (0.05 mol,
94%) of a light yellow solid. N-bromosuccinimide (19.4 g, 0.11 mol) was added in one
portion to a solution of this yellow solid (38.3 g, 53 mmol) in CCI4 (1000 mL) under
argon. A 250 W (115 to 125 V) IR heat lamp was positioned near the reaction flask to
ensure a gentle reflux. After 24 h, the solution was cooled to room temperature and
filtered, washing with CCI4 (50 mL). The solution was washed successively with
NaHCOs (sat) (500 mL), Na2S03 (sat) (500 mL), and brine (500 mL). The organic phase
was dried (MgS04), and concentrated under vacuum to an orange residue, which was
purified by trituration with hot acetonitrile to obtain 42.4 g (50 mmol, 83% for two steps)
of 83e as a light yellow solid, Rf 0.90 (10% AcOEt/hexanes, colorless in ninhydrin stain,
black in anisaldehyde stain).
Spectral Data for 83e: mp: 53-56 °C; IR (KBr) cm 1468, 1252, 1085; 'H NMR (300
MHz, CDCI3) S: 0.86 (6H, t, J = 6.11), 1.24 (56H, broad s), 1.49 (4H, m). 1.83 (4H,
septet, J = 7.32), 3.95 (2H, t, J - 6.23), 4.02 (2H, t, J = 6.47), 4.69 (2H, s), 4.70 (2H, s),
7.02 (IH, s); '^C NMR (75 MHz, CDCI3) 6: 14.1, 22.7, 23.4, 23.7, 25.9, 26.0, 29.1,
242
29.3, 29.4, 29.5, 29.7, 30.0, 31.9, 69.1, 74.2, 117.2, 118.4, 125.9, 132.7, 148.6, 153.7;
HRMS (FAB+) cacld for C44H7902Br3 (M+) 876.3630, found 876.3609 (-2.4 ppm).
2-Amino-4,7-6w-octadecyloxyindan-2-carboxylic acid ethyl ester (85e). A mixture of
dry acetonitrile (300 mL) and chlorobenzene (300 mL) was added in one portion to a
flask containing l-bromo-3,4-^w-bromomethyl-2,5-Z)Z5-octadecyloxybenzene (83e) (25.6
g, 29 mmol), tetrabutylammonium iodide (2.1 g, 6.0 mmol), and finely ground potassium
carbonate (48 g, 0.35 mol) under argon, and the slurry was refluxed in an oil bath heated
to 85 -90 °C. Ethyl isocyanoacetate (3.5 mL, 32 mmol) was injected. Vigorous stirring
was essential for an efficient and complete reaction. After 4.5 h, the solution was cooled
to room temperature and filtered, washing the salts thoroughly with CH2CI2. The solvent
was concentrated under vacuum to obtain a brown residue, which was triturated in
hexanes, re-filtered to remove ammonium salts, and re-concentrated to obtain the crude
isocyanate as a brown oily solid, Rf 0.65 (10% AcOEt/hexanes, light pink in ninhydrin
stain). To this material was added a mixture of absolute EtOH (80 mL) and conc HCl (5
mL), and the solution was heated to reflux overnight. After 20 h, to solution was cooled
to room temperature, and the solvent was removed under vacuum to obtain a white solid,
which was taken up in water (250 mL) and basified with conc NH4OH. The aqueous
solution was extracted with CH2CI2 (3 x 300 mL), and the organic phase dried (MgS04),
and concentrated under vacuum to a crude brown residue. This material which was
purified by flash chromatography (230-400 silica mesh, pretreated with 1% NEta) in a
20% AcOEt/hexanes elutant until most of the non-polar impurities were removed, and
243
then the solvent polarity was then ramped to a 100% AcOEt elutant to obtain 19.4 g of a
crude orange solid, Rf 0.41 (20% AcOEt /hexanes, rose in ninhydrin stain). The crude
amine with 10% Pd/C (6.0 g) in AcOEt (150 mL) was hydrogenated in a Parr
hydrogenator at 55 psi. Each day a small portion of 10% Pd/C (0.1 g) was added to the
reaction flask. After 5 d, the reaction contents were filtered, washing with CH2CI2, and
concentrated under vacuum to an orange residue, which was purified by gravity
chromatography (200-430 mesh silica) in a 20% AcOEt/hexanes elutant until most of the
non-polar impurities were removed. The solvent polarity was then ramped to a 100%
CH2CI2 elutant to obtain 7.2 g (9.7 mmol, 33% for 3 steps) of 85e as a yellow solid, Rf
0.41 (20% AcOEt /hexanes, rose in ninhydrin stain).
Spectral Data for 85e: mp: 37-38 °C; IR (KBr) cm •':1733; 'H NMR (300 MHz, CDCI3)
5: 0.86 (6H, t, J = 6.23); 1.24 (59H, broad s), 1.41 (4H, m), 1.71 (4H, m), 2.89 (2H, d, J
= 16.36), 3.43 (2H, d, J = 16.36), 3.87 (4H, sextet, J = 5.86), 4.20 (2H, q, J = 7.16), 6.59
(2H, s); NMR (75 MHz, CDCI3) 8: 14.1, 14.2, 22.7, 26.1, 29.3, 29.4, 29.7, 31.9.
43.8, 61.2, 64.6, 68.4, 110.4, 130.1, 14 9.8, 176.8; HRMS (FAB+) cacld for C48H88NO4
(M^ +H) 742.6713, found 742.6726 (+1.7 ppm).
2-te/'/-Butoxycarbonylamino-4,7-6is-octadecyloxyindan-2-carboxyIic acid ethyl ester
(93e). T>i-tert-h\xiy\ dicarbonate (0.45 g, 2.1 mmol) was added to a solution of 2-amino-
4,7-&;>y-octadecyloxyindan-2-carboxylic acid ethyl ester (85e) (1.02 g, 1.4 mmol) in
CH2CI2 (50 mL), and the reaction was heated to a gentle reflux overnight. An extra
portion of 6\-tert-h\xty\ dicarbonate (0.5 g, 2.3 mmol) was added to the solution after 18
244
h, and the reaction was allowed to reflux an additional 6 h. The solution was diluted with
CH2CI2 (150 mL), and washed with brine (100 mL). The organic phase was dried
(MgS04) and concentrated under vacuum to a yellow solid which was purified by flash
chromatography (230-400 mesh silica, pretreated with 1% NEts) in a 10%
AcOEt/hexanes elutant to obtain 1.13 g (1.3 mmol, 98%) of 93e as a light yellow solid,
Rf 0.72 (20% AcOEt/hexanes, dark rose in ninhydrin stain).
Spectral Data for 93e: mp: 54-56 °C; IR (KBr) cm •':1733, 1709; 'H NMR (300 MHz,
CDCI3 with B0C2O contaminant) 6: 0.86 (6H, t, J = 6.60), 1.24 (63H, broad s), 1.40 (9H,
s), 1.51 (s, B0C2O), 1.71 (4H, pentet, J = 6.835), 3.17 (2H, d, J = 16.84), 3.52 (2H, d, J
= 16.85), 3.86 (4H, dt, J = 1.22, 5.99), 4.20 (2H, q, J = 7.16), 5.06 (IH, broad s), 6.59
(IH, s); "C NMR (75 MHz, CDCI3 with B0C2O contaminant) 6: 14.0, 14.1, 22.7, 26.1,
27.4 (B0C2O), 28.2, 29.3, 29.4, 29.7, 31.9, 41.6, 61.4, 65.6, 68.5, 79.8, 85.1 (B0C2O),
110.6, 129.6, 146.7 (B0C2O), 149.5, 154.9, 173.5; HRMS (FAB+) cacld for C53H95NO6
(M+) 841.7159, found 841.7169 (+1.2 ppm).
2-ter^-Butoxycarbonylamino-4,7-6«-octadecyIoxyindan-2-carboxylic acid (94e).
Potassium hydroxide (1.0 g, 18 mmol) was added to a solution of 2-tert-
butoxycarbonylamino-4,7-6/5-octadecyloxyindan-2-carboxylic acid ethyl ester (93e) (1.0
g, 2.1 mmol) in absolute EtOH (150 mL) followed by addition of water (30 mL). The
solution gradually went from opaque to a clear yellow solution by heating to a gentle
reflux. After 3 h, the reaction was cooled to room temperature and the solvent removed
under vacuum to obtain a white solid. The solid was dissolved in water (200 mL) and the
245
solution acidified with conc HCl to a pH of 2. The aqueous solution was extracted with
AcOEt (3 X 200 mL), and the organic phase washed with brine (200 mL), dried (MgS04)
and concentrated under vacuum to a yellow sticky solid. The material was further dried
by azeotroping with benzene to obtain 0.97 g (1.2 mmol, 98%) of 94e as a dry light
yellow solid, Rf 0.41 (30% AcOEt/hexanes, brown in ninhydrin stain).
Spectral Data for 94e: mp: 38-40 °C; IR (KBr) cm "':1717; 'H NMR (300 MHz, CDCI3)
6: 0.86 (6H, t, J = 6.59), 1.24 (60H, broad s), 1.40 (9H,s), 1.72 (4H, pentet, J = 6.75),
3.21 (2H, d, J = 17.34), 3.58 (2H, d, J = 17.09), 3.87 (4H, t, J = 6.35), 5.15 (IH, broad
s), 6.59 (2H,s); '^C NMR (75 MHz, CDCI3) 5: 14.1,22.7,26.1,28.2,29.4,29.4,29.7,
31.9, 41.4, 65.5, 68.5, 73.3, 80.5, 110.6, 129.4, 149.5, 155.6, 178.4; HRMS (FAB+)
cacld for C51H92NO6 (M^ +H) 814.6925, found 814.6954 (ppm).
246
Synthesis of 1,4- [2-(2-Methoxy-ethoxy)-ethoxy] Indane Amino Acids
[2-(2-methoxy-ethoxy)-ethoxy] tosylate. Reported previously: J. Am. Chem. Soc.
(1979) 101 4948. j!7-Toluenesulfonyl chloride (31.3 g, 0.16 mol) was added to a solution
of 2-(2-methoxy ethoxy)-ethanol (13 mL, 0.11 mol) in dry pyridine (60 mL, 0.74 mol)
cooled to 0 °C under argon. The reaction was gradually warmed to room temperature
over a 2 h time period. Crushed ice (10 g) was then added to the reaction, and stirred for
5 min. The solution was diluted with water (150 mL) and extracted with CH2CI2 (4 x 100
mL). The organic phase was washed with a cold 15% HCl solution (2 x 100 mL), dried
(MgS04), and concentrated under vacuum to a yellow oil. The material was purified by
flash chromatography (230-400 mesh silica) in a 40% AcOEt/hexanes elutant to obtain
27.7 g (0.10 mol, 93%) of [2-(2-methoxy ethoxy)-ethoxy] tosylate as a light yellow oil,
Rf 0.44 (30% AcOEt/hexanes, blue in anisaldehyde stain).
Spectral Data for [2-(2-methoxy-ethoxy)-ethoxy] tosylate: IR (NaCl) cm 1355, 1178,
913, 825, 768; 'H NMR (300 MHz, CDCI3) 5: 2.43 (3H, s), 3.33 (3H, s), 3.46 (2H, t, J =
4.15), 3.56 (2H, t, J = 4.40), 3.67 (2H, t, J = 4.76), 4.16 (2H, t, J = 4.76), 7.34 (2H, d, J =
8.06), 7.78 (2H, d, J = 8.06); '^C NMR (75 MHz, CDCb) 5: 21.3, 58.7, 68.4, 69.0, 70.3,
71.5, 127.7, 129.6, 132.7, 144.6; HRMS (FAB+) cacld for CiiH.gOsS (M^ +H) 275.0953,
found 275.0952 (-0.4 ppm).
l,4-fi/5-[2-(2-niethoxy-ethoxy)-ethoxy]-2,3-dimethyI-benzene (69f). A solution of 2,3-
dimethylhydroquinone (6.21 g, 50 mmol) in dry THF (50 mL) was slowly added via
lAl
cannula to a slurry of sodium hydride (3.2 g, 0.14 mol) in THF (150 mL) under argon.
The cannula was rinsed with THF (2x10 mL). Upon injection, an exothermic reaction
was observed, and the resulting green colored solution was allowed to stir at room
temperature. After 30 min, [2-(2-methoxy-ethoxy)-ethoxy] tosylate (25.8 g, 90 mmol)
was added via syringe and the reaction was brought to reflux for 21 h. The solution was
cooled to room temperature, slowly quenched with water (2 mL), and concentrated to a
brown residue. The material was dry loaded to silica, purified by flash chromatography
(230-400 mesh silica) in a 50% AcOEt/hexanes elutant to obtain 13.2 g (40 mmol, 86%)
of 69f as a yellow oil, Rf 0.28 (50% AcOEt/hexanes, purple in anisaldehyde stain).
Spectral Data for 69f: IR (NaCl) cm 1480, 1449, 1257; 'H NMR (300 MHz, CDCI3)
5: 2.16 (6H, s), 3.39 (6H, s), 3.56 (4H, t, J = 4.30), 3.73 (4H, t, J = 4.58), 3.84 (4H, t, J =
4.77), 4.06 (4H, t, J = 4.95), 6.63 (2H, s); '^C NMR (75 MHz, CDCI3) 5: 12.1, 59.0,
68.6, 70.0, 70.7, 71.9, 109.6, 127.1, 151.2; HRMS (FAB+) cacld for CigHsoOe (M^)
342.2042, found 342.2039 (-1.0 ppm).
1 -Bromo-2,5-Z>w- [2-(2-methoxy-ethoxy)-ethoxy] -3,4-dim ethyl-benzene (82f). Bromine
(0.085 mL, 0.02 mol) in CHCI3 (200 mL) was added dropwise to a cooled solution (0 °C)
of l,4-Z)w-[2-(2-methoxy ethoxy)-ethoxy]-2,3-dimethyl-benzene (69f) (5.08 g, 20 mmol)
in CHCI3 (100 mL) over 1.5 h under argon. The solution was allowed to warm gradually
to room temperature. The reaction was judged complete by GCMS 30 min after addition.
The solution was washed successively with NaHCOs (sat) (100 mL), Na2S03 (100 mL)
248
and brine (100 mL). The organic phase was dried (MgS04) and concentrated under
vacuum to obtain 6.4 g (20 mmol, 100%) of 82f as a yellow oil.
Spectral Data for 82f: IR (NaCl) cm 1455, 1230, 1109; 'H NMR (300 MHz, CDCI3)
6: 1.97 (3H, s), 2.12 (3H, s); 3.27 (6H, m), 3.45 (4H, m), 3.60 (4H, m), 3.72 (4H, m),
3.86 (2H, m), 3.92 (2H, m), 6.75 (IH, s); NMR (75 MHz, CDCI3) 6: 11.9, 13.0, 58.6,
68.0, 69.3, 69.8, 70.2, 70.3, 71.5, 71.6, 71.8, 112.9, 113.3, 126.0, 132.2, 147.6, 152.9;
HRMS (FAB+) cacld for Ci8H2906Br (M"") 420.1148, found 420.1154 (+1.6 ppm).
2-Amino-4,7-6w-[2-(2-methoxy-ethoxy)-ethoxy]-indan-2-carboxylic acid ethyl ester
(85f). N-bromosuccinimide (5.68, 30 mmol) was added in one portion to a solution of 1-
bromo-2,5-/)Z5'-[2-(2-methoxy-ethoxy)-ethoxy]-3,4-dimethyl-benzene (82f) (6.4 g, 0.02
mol) in CCI4 (75 mL) in a cooled jacketed flask (15 °C) under argon. A 250 W (115 to
125 V) IR heat lamp was applied approximately 1.5 inches from the reaction flask. After
4 d, another portion of N-bromosuccinimide (1.35 g, 7.6 mmol) was added to the
solution. After 6 d the reaction was judged complete by GCMS. The solution was
filtered, washing with CCI4 (20 mL). The solution was diluted with CH2CI2 (200 mL),
and washed successively with NaHCOs (sat) (100 mL), NaaSOs (sat) (100 mL), and brine
(100 mL). The aqueous phases were combined and back extracted with CH2CI2 (100
mL). The organic fractions were dried (MgS04), and concentrated under vacuum to
obtain 9.64 g of a crude yellow oil. The yellow oil, in a mixture of dry acetonitrile (150
mL) and chlorobenzene (150 mL), was added in one portion to a flask containing
tetrabutylammonium iodide (1.17 g, 3.2 mmol) and finely ground potassium carbonate
249
(26 g, 0.19 mol) and the slurry was refluxed in an oil bath heated to 85-90 °C. Ethyl
isocyanoacetate (1.9 mL, 17.5 mmol) was injected. Vigorous stirring was essential for an
efficient and complete reaction. After 5 h, the reaction was cooled to room temperature
and filtered, washing the salts thoroughly with CH2CI2. The solvent was concentrated
under vacuum to a brown residue, which was purified by flash chromatography (230-400
mesh silica), slowly ramping the solvent polarity from 40% AcOEt/hexanes to 100%
AcOEt elutant, to obtain 3.48 g of the crude isocyanate as an orange oil, Rf 0.24 (40%
AcOEt/hexanes, pink in ninhydrin stain). Cone HCl (1 mL) was added to a solution of the
isocyanate in absolute EtOH (150 mL), and the solution stirred for 6 h at room
temperature. The solvent was removed under vacuum to obtain a yellow residue, which
was taken up in water (100 mL) and basified with conc NH4OH. The aqueous solution
was extracted with AcOEt (3 x 100 mL), and the organic phase dried (MgS04), and
concentrated to obtain 3.19 g of the crude brominated amine as an orange oil. The amine
with 10% Pd/C (1.5 g) in AcOEt (100 mL) was hydrogenated in a Parr hydrogenator at
55 psi (H2). The reaction was monitored by GCMS. After 24 h, the reaction contents
were filtered, washing with CH2CI2, and concentrated under vacuum to an orange
residue, which was purified by flash chromatography (230-400 mesh silica) in a 100%
AcOEt elutant, until the non-polar impurities were removed. The solvent polarity was
slowly ramped from a 5% to a 20% EtOH/AcOEt elutant to obtain 1.82 g (4.1 mmol,
26% for 4 steps) of 85f as a yellow oily solid, Rf 0.39 (20% MeOH/AcOEt, rose in
ninhydrin stain).
250
Spectral Data for 85f: IR (NaCl) cm 3365, 3300, 1733; 'H NMR (300 MHz, CDCI3)
5: 1.21 (3H, t, J = 7.08), 1.94 (2H, bs), 2.85 (2H, d, J = 16.36), 3.31 (6H, s), 3.37 (2H, d, J
= 16.35), 3.498 (4H, t, J = 4.52), 3.63 (4H, t, J=4.64), 3.74 (4H, t, J = 5.01), 3.99 (2H, t, J
= 4.90), 4.04 (2H, t, J = 4.89), 4.14 (2H, q, J = 7.08), 6.55 (2H, s); NMR (75 MHz,
CDCI3) 5: 14.0, 43.6, 58.8, 61.1, 64.5, 67.9, 69.7, 70.5, 71.1, 110.7, 130.2, 149.5, 176.4;
HRMS (FAB+) cacld for C22H36NO8 (M^+H) 442.2441, found 442.2449 (+1.8 ppm).
2-/e/'#-Butoxycarbonylainino-4,7-6is-[2-(2-methoxy-ethoxy)-ethoxy]-indan-2-
carboxylic acid ethyl ester (93f). Di /er/-butyl dicarbonate (0.44 g, 2.0 mmol) was
added to a solution of 2-amino-4,7-Z)w-[2-(2-methoxy ethoxy)-ethoxy]-indan-2-
carboxylic acid ethyl ester (85f) (0.59 g, 1.3 mmol) in CH2CI2 (20 mL) and the reaction
was heated to a gentle reflux overnight. An extra portion of di-/er^butyl dicarbonate
(0.22 g, 1.0 mmol) was added to the solution after 24 h, and the reaction was allowed to
reflux an additional 3 h. The solution was diluted with CH2CI2 (150 mL), and washed
with brine (lOOmL). The organic phase was dried (MgS04) and concentrated under
vacuum to a yellow oil which was purified by flash chromatography (230-400 mesh
silica, pretreated 1% NEts) in a 60% AcOEt/hexanes elutant to obtain 0.34 g (0.63 mmol,
47%) of 93f as light yellow oil, Rf 0.72 (brown in ninhydrin stain).
Spectral Data for 93f; IR (NaCl) cm 3340, 1734, 1717; 'h NMR (300 MHz, CDCI3)
5: 1.24 (3H, t, J = 7.08), 1.48 (9H, s), 3.20 (2H, d, J = 17.09), 3.37 (6H, s), 3.49 (2H, d, J
= 16.85), 3.54 (4H, t, J = 4.40), 3.68 (4H, t, J = 4.64), 3.78 (4H, t, J = 4.77), 4.07 (4H, t, J
= 4.40), 4.19 (2H, q, J = 7.16), 5.25 (IH, bs), 6.60 (2H, s); NMR (75 MHz, CDCI3) 5;
251
14.1,28.2,41.4, 59.0,61.4, 65.6, 68.1,69.7, 70.7,71.9, 79.6, 111.0, 130.0, 149.3, 155.0,
173.5; HRMS (FAB+) cacld for C27H43NO,o (M+) 541.2887, found 541.2907 (+3.7 ppm).
2-te/"/-Butoxycarbonylamino-4,7-te-[2-(2-methoxy-ethoxy)-ethoxy]-indan-2-
carboxylic acid (94f). Potassium hydroxide (0.4 g, 7.1 mmol) was added to a solution of
2-/er/-butoxycarbonylamino-4,7-6/5-[2-(2-methoxy-ethoxy)-ethoxy]-indan-2-carboxylic
acid ethyl ester (93f) (0.33 g, 0.61 mmol) in absolute EtOH (50 mL) and water (5 mL).
After 1 h, the reaction was cooled to room temperature and the solvent removed under
vacuum to obtain a yellow oily residue. The material was dissolved in water (100 mL)
and the solution acidified with conc HCl to a pH of 2. The aqueous solution was
extracted with AcOEt (3 x 100 mL), and the organic phase washed with brine (100 mL),
dried (MgS04) and concentrated under vacuum to obtain a yellow oil. Trace amounts of
solvent were removed by the freeze-pump-thaw method (2 x) to obtain 0.29 g (0.57
mmol, 92%) of 94f as a yellow oil, Rf 0.12 (100% AcOEt, brown in ninhydrin stain).
Spectral Data for 94f: IR (NaCl) cm 3316, 1717; 'H NMR (300 MHz, CDCI3) 5: 1.34
(9H, s), 3.21 (2H, d, J = 16.64), 3.32 (6H, s), 3.50 (4H, t, J = 4.58), 3.53 (2H, d, J =
14.50), 3.65 (4H, t, J = 4.28), 3.74 (4H, t, J = 4.35), 4.01 (4H, t, J = 4.50), 5.44 (IH, bs),
6.55 (2H, s), 10.85 (IH, bs); '^C NMR (75 MHz, CDCI3) 6: 28.1, 41.2, 58.8, 65.1, 67.1,
69.6, 70.5, 71.7, 79.8, 110.8, 129.8, 149.1, 155.2, 177.6; HRMS (FAB+) cacld for
C25H39NO10 (M^) 513.2574, found 513.2559 (-2.9 ppm).
252
Synthesis of Cn Diketopiperazine
2-[(2-te/*/-Butoxycarbonylainino-4,7-6/s-dodecyloxyindane-2-carbonyl)-amino]-4,7-
Z>/5-dodecyloxyindan-2-carboxylic acid ethyl ester (95d). A solution of 2-amino-4,7-
Z)/5'-dodecyloxyindan-2-carboxylic acid ethyl ester (85d) (222 mg, 0.39 mmol) in dry
DMF (5 mL) was injected to a flask containing 2-^ert-butoxycarbonylaniino-4,7-6w-
dodecyloxyindan-2-carboxylic acid (94d) (234 mg, 0.36 mmol), BOP (161 mg, 0.36
mmol) and DABCO (61 mg, 0.55 mmol) under argon and the reaction was monitored by
TLC. After 17 h, the reaction was diluted with brine (200 mL), and the solution extracted
with AcOEt (3 x 150 mL). The organic phase was dried (MgS04) and concentrated to a
crude yellow residue which was purified by gravity chromatography (230-400 mesh
silica, pretreated withl% NEt3) in a 15% AcOEt/hexanes elutant to obtain 0.336g (0.28
mmol, 77%) of 95d as an off-white solid, Rf 0.75 (30% AcOEt/hexanes, light rose in
ninhydrin stain).
Spectral Data for 95d: mp: 90-91 °C; IR (KBr) cm 1746, 1709, 1672; 'H NMR (300
MHz, 40 °C in CDCI3) 5: 0.87 (12H, t, J = 6.35), 1.31 (84H, m), 1.71 (8H, sextet, J =
6.41), 3.22 (4H, d, J = 17.09), 3.56 (4H, d, J = 17.09), 3.85 (8H, t, J = 6.35), 4.17 (2H, q,
J = 7.08), 6.53 (2H, s), 6.57 (2H, s); (75 MHz, 40 °C in CDCI3) §: 14.0, 22.7, 26.0,
26.1, 28.1, 29.3, 29.4, 29.5, 29.6, 29.7, 41.4, 61.4, 65.4, 68.5, 68.7, 110.6, 111.0, 129.7,
129.9, 149.6, 149.8, 154.8, 173.0; HRMS (FAB+) calcd for C75H129N2O9 (M^ +H)
1201.9698, found 1201.9722 (+2.0 ppm).
Cyclo-6/s-(2-aiiiino-4,7-6w-dodecyloxyindaii-2-carboxylic acid) (96d). 2-[{2-tert-
butoxycarbonylamino-4,7-Z)w-dodecyloxyindane-2-carbonyl)-amino]-4,7-6/,s'-dodecyloxy
indan-2-carboxylic acid ethyl ester (95d) (83 mg, 69 mmol) was thermolyzed in a sealed,
evacuated tube for 30 min in an oil bath heated to 260 °C. After cooling to room
temperature, the solid was dissolved in 50% TFA / CH2CI2, and the solution was treated
with charcoal, filtered and concentrated under vacuum to a sticky yellow solid. This
crude material was purified by trituration with hot EtaO. The solution was cooled to room
temperature and filtered to obtain 57 mg (0.05 mmol, 79%) of 96d as an off-white solid.
Spectral Data for 96d: mp: 180-182 °C; IR (KBr) cm 3184, 3055, 1665; 'H NMR
(300 MHz, CDCI3) 5: 0.86 (12H, t, J = 6.35), 1.24 (72H, m), 1.73 (8H, pentet, J = 6.84),
3.15 (4H, d, J = 16.36), 3.69 (4H, d, J = 16.36), 3.88 (8H, t, J = 6.47), 6.38 (2H, bs), 6.62
(4H, s); '^C (75 MHz, CDCI3) 6: 14.2, 22.7, 26.0, 29.3, 29.4, 29.6, 29.7, 31.9, 44.6,
66.7, 68.5, 111.1, 128.1, 149.7, 169.3; HRMS (FAB+) calcd for CagHusNiOa (M^ +H)
1055.8755, found 1055.8702 (-5.0 ppm).
254
Synthesis of Cig Diketopiperazine
2-[(2-ter^-Butoxycarbonylamino-4,7-6w-octadecyloxyindane-2-carbonyl)-ammo]-4,7-
6is-octadecyloxy iiidan-2-carboxylic acid ethyl ester (95e): Dry CH2CI2 (12 mL) was
injected to a flask containing 2-amino-4,7-Z)w-octadecyloxyindan-2-carboxylic acid ethyl
ester (85e) (305 mg, 0.41 mmol), 2-rer?-butoxycarbonyl amino A,l-bis-
octadecyloxyindan-2-carboxylic acid (94e) (350 mg, 0.43 mmol), BOP (275 mg, 0.62
mmol) and DABCO (72 mg, 0.62 mmol) at room temperature under argon. The reaction
was monitored by TLC. After 24 h, a small portion of BOP (100 mg, 0.23 mmol) and
DABCO (20 mg, 0.18 mmol) were added to the flask contents, and the reaction was
stirred an additional 2 d. The reaction was diluted with brine (50 mL), and the aqueous
solution extracted with AcOEt (3 x 100 mL). The organic phase was dried (]V[gS04) and
concentrated to a crude yellow residue, which was purified by gravity chromatography
(230-400 mesh silica, pretreated 1% with NEts) in a 10% AcOEt/hexanes elutant to
obtain a light pink solid. This crude material was further purified by trituration in hot
acetonitrile. The solution was cooled in a freezer (-22 °C), and filtered cold in order to
obtain 0.433 g (0.28 mmol, 68%) of 95e as an off-white solid, Rf 0.59 (20%
AcOEt/hexanes, light rose in ninhydrin stain)
Spectral Data for 95e; mp: 68-70 °C; IR (KBr) cm "':1733, 1701, 1683; 'h NMR (300
MHz, CDCI3) 5; 0.86 (12H, t, J = 6.23), 1.24 (129H, m), 1.70 (8H, pentet, J = 6.34),
3.21 (4H, broad d, J = 14.25), 3.56 (4H, broad d, J = 17.09), 3.84 (8H, t, J = 6.11), 4.17
(2H, q, J = 6.84), 6.53 (2H, s), 6.57 (2H, s); '^C NMR (75 MHz, CDCI3) 5: 14.1, 22.7,
255
26.1, 28.0, 29.3, 29.4, 29.5, 29.7, 31.9, 41.4, 61.4, 68.5, 80.0, 110.7, 110.7, 129.7, 129.7,
149.5, 149.7, 154.7, 172.9, 172.9; HRMS (MALDI) calcd for C99H,76N209Na (M^ +
Na) 1560.3269, found 1560.3215 (-3.4ppm).
Cyclo-bis-(2-amino-4,7-bis-octadecyloxyindan-2-carboxylic acid) (96e). 2-[{2-tert-
butoxycarbonylamino-4,7-6w-octadecyloxyindane-2-carbonyl)-amino]-4,7-Z)w-octadecyl
oxyindan-2-carboxylic acid ethyl ester (95e) (196 mg, 0.13 mmol) was thermolyzed in a
sealed, evacuated tube for 30 min in an oil bath heated to 260 °C. The product was
dissolved in 50% TFA/CH2CI2, and the solution was treated with charcoal, filtered and
concentrated under vacuum to a sticlcy yellow solid. This crude material was purified by
trituration with hot acetonitrile. The solution was cooled to room temperature and filtered
to obtain 129 mg (0.09 mmol, 72%) of 95e as an off-white solid.
Spectral Data for 95e: mp: 96-98 °C; IR (KBr): 1677; 'H NMR (300 MHz, CDCI3): 0.88
(12H, t, J = 6.59), 1.25 (120H, m), 1.75 (8H, pentet, J = 6.96), 3.18 (4H, d, J = 16.36),
3.91 (8H, t, J = 6.47), 6.29 (2H, broad s), 6.65 (4H, s); '^C NMR (75 MHz, CDCI3):
14.1,22.7,26.0,29.3,29.4,29.6,29.7,31.9,44.6,66.8, 68.6, 111.1, 128.0, 149.7, 169.2;
HRMS (MALDI) calcd for CgiHisaNiOgNa (M"" +Na) 1414.2325, found 1414.2324
(+0.0ppm)
256
Synthesis of 2-(2-Methoxy-ethoxy)-ethoxy Diketopiperazine
Cyclo 6/s-(2-amino-4,7-6/5-[2-(2-methoxy-ethoxy)-ethoxy]-indan-2-carboxylic acid)
(96f). A solution of 2-rert-butoxycarbonylaniino-4,7-d/5-[2-(2-methoxy ethoxy)-ethoxy]-
indan-2-carboxylic acid (94f) (192 mg, 0.35 mmol) in dry DMF (4 mL) was injected to a
flask containing BOP (226 mg, 0.51 mmol) and DABCO (57 mg, 0.51 mmol) at room
temperature under argon. This was followed by injection of 2-amho- A,l-bis-{2-{2-
methoxy-ethoxy)-ethoxy]-indan-2-carboxylic acid ethyl ester (85f) (115 mg, 0.34 mmol)
in dry DMF (4 mL). The reaction was monitored by TLC. After 2 d, the solvent was
removed in vacuo. The reaction contents were dry loaded to silica, and purified by flash
chromatography (230-400 mesh silica, pretreated 1% NEts) in a 100% AcOEt elutant to
obtain 89 mg of 2-({2-/er^butoxycarbonylamino-4,7-bis-[2-(2-methoxy ethoxy)-ethoxy]-
indane-2-carbonyl}-amino)-4,7-&w-[2-(2-methoxy-ethoxy)-ethoxy]-indan-2-carboxylic
acid ethyl ester as a crude yellow oil. Rf 0.48 (20% MeOH/AcOEt, light rose in ninhydrin
stain). The crude coupled product was transferred to a glass Pyrex tube in CH2CI2, and
the solvent removed in vacuo overnight. The tube was evacuated and sealed, and the
material thermolyzed for 30 min in an oil bath heated to 260 °C. The solid was dissolved
in CH2CI2 (25 mL) and treated with charcoal for 24 h. The solution was then filtered and
concentrated under vacuum to a sticky yellow solid. This crude material was further
purified by trituration with hot Et20 (2 x). The solution was cooled to room temperature
and decanted to obtain 17 mg (0.02 mmol, 8% for two steps) of 96f as a clear oil.
257
Spectral Data for 96f: IR (NaCl) cm 3043, 1677; 'H NMR (300 MHz, CDCI3) 6: 3.14
(4H, d, J = 16.60), 3.35 (12 H, s), 3.53 (8H, m), 3.67 (12 H, m), 3.79 (8H, t, J = 5.01),
4.08 (8H, t, J = 4.88), 6.35 (2H, s), 6.64 (4H, s); NMR (75 MHz, CDCI3) 5: 44.7,
59.1, 66.7, 68.1, 69.8, 70.7, 71.9, 111.5, 128.3, 149.7, 169.1; HRMS (FAB+) cacld for
C40H59N2O14 (M^+H) 791.3966, found 791.3976 (+1.2 ppm).
258
Synthesis of N-Me Diketopiperazine
2-{2-(Benzyloxycarbonyl-methylamino)-4,7-dimethoxyindane-2-carbonyl}-amino}-
4,7-dimethoxyindan-2-carboxylic acid ethyl ester (124). DIEA (0.1 mL, 0.63 mmol)
was injected to a solution of 2-aniino-4,7-dimethoxyindan-2-carboxylic acid ethyl ester
(85a) (56 mg, 0.21 mmol), 2-(benzyloxycarbonyl-methylamino)-4,7-dimethoxyindaH2-
carboxylic acid (123) (123 mg, 0.32 mmol), and PyBroP (150 mg, 0.32 mmol) in dry
CH2CI2 (4 mL) at 0 °C under argon. The reaction solution was warmed to room
temperature. After 1.5 d, the reaction contents were dry loaded to silica, and purified by
flash chromatography (230-400 mesh silica, pretreated with 1% NEts) in a 50%
AcOEt/hexanes elutant to obtain a sticky solid. This material was triturated with hot
hexanes, and the solution cooled to room temperature and decanted to obtain 130 mg
(0.21mmol, 97%) of 124 as a white solid, Rf 0.42 (50% AcOEt/hexanes, colorless in
ninhydrin stain and black in PMA stain).
Spectral Data for 124: mp: 145-146 °C; IR (KBr) cm 1741, 1701; 'H NMR (300
MHz, CDCI3) 5: 1.13 (3H, t, J = 6.96), 2.95 (3H, s), 3.09 (2H, d, J = 17.33 Hz), 3.19
(2H, d, J = 16.85 Hz), 3.49 (2H, d, J = 16.84 Hz), 3.71 (12H, s), 3.79 (2H, d, J = 17.33
Hz), 4.09 (2H, q, J = 6.84 Hz), 5.03 (2H, s), 6.59 (4H, s), 6.95 (IH, broad s), 7.28 (5H,
m); '^C NMR (75 MHz, CDCI3) 6: 13.9, 33.1, 39.7, 41.3, 55.5, 55.5, 61.3, 64.9, 67.4,
72.1, 109.1, 109.3, 127.8, 128.4, 129.3, 129.4, 136.2, 149.6, 149.9, 157.0, 172.7, 173.1;
HRMS (FAB+) calcd for C35H41N2O9 633.2812 (M^+H), found 633.2805 (-1.2ppm).
259
Cyclo[(2-methylamino-4,7-dimethoxyindan-2-carboxylicacid)(2-ainino-4,7-
dimethoxy indan-2-carboxylic acid)] (129). After 2-{2-(benzyloxycarbonyl-
methylamino)-4,7-dimethoxyindane-2-carbonyl}-amino}-4,7-dimethoxy-indan-2-
carboxylic acid ethyl ester (124) (0.209 g, 0.33 mmol) was solvated in hot absolute
EtOH, the solution was cooled to room temperature, and cyclohexene (0.7 mL, 6.6 mmol)
and 10% Pd/C (0.21 g, 1:1 catalyst: substrate) were added. The reaction was refluxed for
40 min, and at that time the reaction was judged complete by TLC. The reaction mixture
was filtered, washing with CH2CI2, and concentrated to obtain a sticky oil. The oil was
triturated in a 1:1 mixture of hot Et20 and hexanes to a solid. The solution was cooled in
a freezer (-22 °C), and filtered cold to obtain a crude off white solid (147 mg). The solid
(100 mg) was thermolyzed in a sealed, evacuated tube for 50 min in an oil bath heated to
260-265 °C. The product was taken up in CH2CI2, treated with charcoal, filtered and
concentrated to a yellow solid. The solid was purified by trituration in a 10%
Et20/hexanes solution (2x5 mL). The solvent was decanted to obtain 65 mg (0.14 mmol,
43% for two steps) of 129 as an off-white solid.
Spectral Data for 129: mp: 278 °C decomposition; IR (KBr) cm 3188, 3051, 1669,
1660; 'H NMR (300 MHz, 105.6 mM in CDCI3) 5: 2.82 (3H, s), 3.08 (2H, d, J = 16.11),
3.23 (2H, d, J = 17.58), 3.71 (16H, m), 6.60 (2H, s), 6.64 (2H, s), 6.76 (IH, bs); '^C
NMR (75 MHz, 105.6 mM in CDCI3) 6; 29.9, 43.3, 44.9, 55.5, 55.6, 66.2, 69.2, 109.3,
128.0, 129.5, 149.4, 150.3, 167.7, 170.8; HRMS (FAB+) calcd for C25H28O6N2 (M^)
452.1947, found 452.1935 (-2.8 ppm).
260
Synthesis of l,2,395,6,7-Hexahydro-5-indacene bis-Amino Acids
2,6-Diisocyano-l,2,395?6,7-hexahydro-s-indacene-2,6-dicarboxyIic acid diethyl ester
(183). Reported previously: S. Kotha, E. Brahmachary; J. Org. Chem. (2000) 6^ 1359-
1365. Dry acetonitrile was added in one portion to a flask containing 1,2,4,5-tetrakis-
(bromomethyl)-benzene (10.0 g, 20 mmol), tetrabutylammonium iodide (4.1 g, 10
mmol), and finely ground K2CO3 (36.5 g, 0.26 mol) and the slurry was refluxed under
argon in an oil bath heated to 80-85 °C. Vigorous stirring was essential for an efficient
and complete reaction. Ethyl isocyanoacetate (4.8 mL, 40 mmol) was injected, and the
reaction was monitored by TLC. After 22 h, the solution was cooled to room temperature,
filtered, washing thoroughly with CH2CI2, and concentrated to a brown foam. This
material was dry loaded to silica and purified by flash chromatography (230-400 mesh
silica, pretreated 1% NEta) in a 20% AcOEt/hexanes elutant to obtain 2.42 g (6.9 mmol,
31%) of 183 as an off-white solid, Rf 0.49 (40% AcOEt/hexanes, light pink in ninhydrin
stain).
Spectral Data for 183: mp: 147-148 °C; IR (KBr) cm 2143, 1749; 'H NMR (200
MHz, CDCI3) 5: 1.35 (6h, t, J = 7.14), 3.43 (4H, d, J - 16.93), 3.68 (4H, d, J = 15.84),
4.31 (2H, q, J = 7.14), 4.33 (2H, q, J = 7.15), 7.12 (2H, m); '^C NMR (50 MHz, CDCI3)
5: 13.9, 45.6, 63.0, 68.0, 68.4, 120.7, 120.9, 137.6, 158.8, 168.1, 168.3; HRMS
(FAB +) calcd for C29H21N2O4 (M"^ +H) 353.1501, found 353.1497 (-1.3 ppm).
261
C/s-2,6-Diainino-l,2,3?5,6,7-hexahydro-s-indacene-2,6-dicarboxyIic acid diethyl ester
(186a) and ^m«s-2,6-Diamino-l,2,355,6,7-hexahydro-s-indacene-2,6-dicarboxylic acid
diethyl ester (186b). Reported previously: S. Kotha, E. Brahmachary; J. Org. Chem.
(2000) ^ 1359-1365. Conc HCl (15 mL) was added to a heterogeneous solution of 2,6-
diisocyano-l,2,3,5,6,7-hexahydro-5'-indacene-2,6-dicarboxylic acid diethyl ester (183)
(5.0 g, 10 mmol) in absolute EtOH (150 mL), and the slurry stirred at room temperature.
The solution gradually became homogeneous with gentle gas extrusion. After 24 h, the
solvent was removed under vacuum to obtain a white solid. This solid was taken up in
water (200 mL), and the solution basified with conc NH4OH, and extracted with AcOEt
(3 X 200 mL). The organic phase was dried (MgS04) and concentrated under vacuum to a
crude yellow solid, which was purified by gravity chromatography (230-400 mesh silica)
in a 30% EtOH/AcOEt elutant to obtain 1.2 g (3.6 mmol) of cz5'-2,6-diamino-1,2,3,5,6,7-
hexahydro-.s'-indacene-2,6-dicarboxylic acid diethyl ester (186a) as an off white solid, Rf
0.20 (30% EtOH/AcOEt, pink in ninhydrin stain), and 1.4 g (4.2 mmol) of trans-2,6-
diamino-l,2,3,5,6,7-hexahydro-5'-indacene-2,6-dicarboxylic acid diethyl ester (186b) as
an off white solid, Rf 0.40 (30% EtOH/AcOEt, pink in ninhydrin stain). A total of 2.6 g
(7.8 mmol, 55%) of cis and ?rara-2,6-diamino-l,2,3,5,6,7-hexahydro-.^-indacene-2,6-
dicarboxylic acid diethyl ester was obtained.
Spectral Data for 186a: mp 134 °C (lit. 123-125°C); IR (KBr) cm 3405, 3381, 1725;
'H NMR (300 MHz, CDCI3) 5: 1.27 (6H, t, J = 7.08), 1.79 (4H, s), 2.80 (4H, d, J =
15.38), 3.51 (4H, d, J = 15.14), 4.20 (4H, q, J = 7.08), 7.04 (2H, s); NMR (75 MHz,
262
CDCls) 6: 14.1, 45.8, 61.2, 65.3, 121.2, 139.1, 176.2; HRMS (FAB+) calcd for
C18H25NO4 (M^ +H) 333.1814, found 333.1822 (+2.2 ppm).
Spectral Data for 186b: mp: 90-91 °C (lit. 91-93 °C); IR (KBr) cm 3373, 3300,
3260, 1741; 'HNMR (300 MHz, CDCI3) 6: 1.25 (6H, t, J = 7.21), 1.78 (4H, s), 2.78 (4H,
d, J = 15.38), 3.45 (4H, d, J = 15.38), 4.18 (4H, q, J = 7.16), 7.02 (2H, s); '^C NMR (75
MHz, CDCI3) 6: 14.0, 45.5, 61.0, 65.0, 121.1, 139.0, 176.3; HRMS (FAB+) calcd for
C18H25NO4 (M^ +H) 333.1814, found 333.1824 (+2.9 ppm).
Oj-2,6-5/y-/'^/-/-butoxycarbonylamino-l,2,3»5,6,7-hexahydro-5-indacene-2,6-
dicarboxylic acid diethyl ester (187). Di-fer/^-butyl-dicarbonate (0.206 g, 0.92 mmol)
was added in one portion to a solution of cw-2,6-diamino-l,2,3,5,6,7-hexahydro-5-
indacene-2,6-dicarboxylic acid diethyl ester (186a) (0.102 g, 0.36 mmol) in CH2CI2 (5
mL), and the solution gently refluxed overnight. After 24 h, the solution was diluted with
CH2CI2 (100 mL) and washed with brine (100 mL). The organic solution was dried
(MgS04) and concentrated to a light yellow solid, which was purified by trituration in hot
hexanes. The solution was cooled to room temperture and filtered to obtain 0.154 g (0.29
mmol, 94%) of 187 as an off-white solid, Rf 0.33 (30% AcOEt/hexanes, light pink in
ninhydrin stain).
Spectral Data for 187: mp: 187-188 °C; IR (KBr) cm 3326, 1727, 1690; 'h NMR (300
MHz, CDCI3) 6: 1.22 (6H, t, J = 7.08), 1.38 (18H, s), 3.09 (4H, d, J = 16.12), 3.53 (4H, d,
J = 16.12), 4.18 (4H, q, J - 7.08), 5.10 (2H, bs), 6.98 (2H, s); '^C NMR (75 MHz,
263
CDCls) 6: 14.1, 28.2, 43.4, 61.4, 66.2, 79.8, 120.6, 138.7, 154.9, 173.3; HRMS (FAB+)
cacld forC28H4iN208 (M"" +H) 533.2863, found 533.2860 (-0.5 ppm).
rrfl/i5-2,6-fi/s-benzyIoxycarbonylamino-l,2,395,6,7-hexahydro-5-indacene-2,6-
dicarboxylic acid diethyl ester (188). Dibenzyl dicarbonate (0.19 g, 0.66 mmol) was
added in one portion to a solution of ^ra«i'-2,6-Diamino-l,2,3,5,6,7-hexahydro-5-
indacene-2,6-dicarboxylic acid diethyl ester (186b) (0.055 g, 0.17 mmol) in CH2CI2 (5
mL), and the solution was heated to a gentle reflux for 1 h. After 2 min, a white
precipitate was observed. The reaction was quenched by removal of the solvent under
vacuum to obtain a crude white solid, which was purified by trituration with hot hexanes.
The solution was cooled to room temperature, and filtered to obtain 0.079 g (0.15 mmol,
90%) of 188 as a white solid, Rf 0.91 (100% AcOEt, light pink in ninhydrin stain).
Spectral Data for 188; mp: 250 °C decomposition; IR (KBr) cm 3340, 1733, 1725;
'HNMR (300 MHz, CDCI3) 5: 1.11 (6H, t, J = 6.96), 3.15 (4H, d, J = 16.35), 3.38 (4H,
d, J = 16.11), 4.07 (4H, q, J = 6.92), 5.01 (4H, s), 6.99 (2H, s), 7.33 (lOH, s), 8.03 (2H,
s); '^C NMR (75 MHz, CDCI3) 5: 13.9, 42.4, 60.7, 65.2, 65.8, 120.4, 127.7, 127.8,
128.3, 136.9, 138.5, 155.6, 173.1; Anal, calcd for C34H36N2O8 C 67.99, H 6.04, N 4.66,
found C 67.50, H 6.18, N 4.87.
264
Synthesis of Cyclohexyl 6/5-Amino Acids
l,4-fi/5-phenyIcarbonylamino-cyclohexane-l,4-diiiitrile (203). Potassium cyanide (5.3
g, 0.081 mol) was added to a cooled (0 °C) aqueous solution (25 mL) of 1,4
cyclohexanedione (4.35 g, 39 mmol) and ammonium chloride (4.3 g, 81 mmol). A thick
white precipitate had formed after 1 min. The ice bath was removed and the reaction was
stirred at room temperature for 2 d. At that time, the solution was filtered and the white
precipitate was washed with a minimum of cold water, then cold CHCI3, and futher dried
in vacuo, to obtain 6.4 g (39 mmol, 100%) of a white dry solid. This material was
immediately deposited into a mixture of K2CO3 (15.6 g, 0.11 mol) in THF (780 mL) and
water (1000 mL). Benzoyl chloride (9.5 mL, 82 mmol) was added to the solution, and the
reaction was vigorously stirred at room temperature. After a few minutes, a white
precipitate formed. After 3 d, the solution was filtered and the white precipitate was
washed with water, and dried in vacuo, to obtain 13.6 g (37 mmol, 100%) of 203 as a
white solid, Rf 0.78 (5% MeOH/AcOEt, hght purple in anisaldehyde).
Spectral Data for 203; mp: 316-318 °C, IR (KBr) cm 1659; 'H NMR (300 MHz, d-
DMSO) 5 : 1.74 (pentet, minor salt impurity), 2.06 (4H, d, J = 10.26), 2.61 (4H, d, J =
10.01), 3.58 (pentet, minor salt impurity), 7.49 (4H, t, J = 7.57), 7.57 (2H, d, J = 7.32),
7.90 (4H, d, J = 7.33); NMR (75 MHz, cZ-DMSO) 5; 30.7, 50.4, 119.4, 127.8, 128.3,
131.9, 133.26, 166.8; HRMS (EI+-) calcd for C22H20N4O4 (M"") 372.1586, found
372.1573 (-3.4 ppm).
l,4-Diammo-cycIohexane-l,4-dicarboxylic acid hydrobromide salt (204). A solution
of l,4-/)w-phenylcarbonylaniino-cyclohexane-l,4-dinitrile (203) (15.8 g, 42 mmol) in
conc HBr (160 mL) was vigorously refluxed over 4 d. Benzoic acid can be observed as a
white crystalline condensant in and around the lip of the flask after 24 h of refluxing. The
solution was cooled to room temperature, and the solvent removed under vacuum, aided
by azeotroping with /BuOH, to obtain a brown solid which was purified by trituration
with absolute EtOH. The solution was filtered, washing thoroughly with EtOH, to obtain
a white solid. Due to the presence of a salt impurity (observable by 'H NMR as 3
symmetric singlets present 6-8 ppm) the white solid must be vigorously stirred in
absolute EtOH (150 mL) overnight. The slurry was filtered to obtain 13.3 g (36 mmol,
86%) of 204 as a white solid.
Spectral Data for 204: mp 303 °C decomposition; IR (KBr) cm 3018 (br), 1715; 'H
NMR (200 MHz, d- CH3OH) S: 2.21 (2H, d, J = 9.44), 2.26 (2H, d, J = 9.61), 2.29 (2H,
d, J = 9.81), 2.34 (2H, d, J = 9.52), 4.95 (6H, s); '^C NMR (50 MHz, t^-CHjOH) 5: 29.2,
58.0, 172.2; HRMS (FAB+) calcd for C8H15N2O4 (M^ +H) 203.1032, found 203.1031 (-
0.5 ppm).
l,4-fi/s-benzyloxycarbonylamino-cyclohexane-l,4-dicarboxylic acid (205). A slurry
of l,4-diamino-cyclohexane-l,4-dicarboxylic acid hydrobromide salt (204) (1.04 g, 2.9
mmol) in NaHCOs (sat) (250 mL) was heated to a boil until the solution became clear.
The solution was cooled to room temperature, and further in an ice bath to 0 °C. Benzyl
chloroformate (3.0 mL, 27 mmol) was slowly added by pipet, and solution was warmed
266
to room temperature. After 48 h, the reaction was diluted with water (250 mL) and
washed with Et20 (250 mL). The organic phase was discarded. The aqueous solution was
acidified with conc HCl to a pH of 2, and the solution extracted with AcOEt (3 x 250
mL). MeOH (200 mL) was added to the opaque AcOEt phase until clear, and the organic
solution was dried (NaiSOa) and concentrated under vacuum to 0.85 g (1.8 mmol, 63%)
of 205 as an off-white solid.
Spectral Data for 205: 254 °C decomposition; IR (KBr) cm 3320, 1733, 1665; 'H
NMR (200 MHz, c/-DMSO) 6: 1.89 (8H, m), 5.20 (4H, s), 7.36 (10, s), 7.59 (2H, s),
12.38 (2H, bs); NMR (50 MHz, d-BMSO) §: 26.4, 57.4, 65.1, 127.6, 127.7, 128.3,
137.0, 155.4, 175.9; HRMS (FAB+) calcd for C24H27N2O8 (M^ +H) 471.1767, found
471.1770 (+0.6 ppm).
l,4-5/s-benzyloxycarbonylamino-cyclohexane-l,4-dicarboxylic acid dimethyl ester
(206). A slurry of 1,4- 6w-benzyloxycarbonylamino-cyclohexane-l,4-dicarboxylic acid
(205) (10.4 g, 22 mmol) in a 5% aqueous CS2CO3 (75 mL) was heated until the solution
cleared. The aqueous solution was lyopholized to a dry white salt. lodomethane (27.4
mL, 0.44 mol) was injected to a slurry of the salt in dry DMF (100 mL) under argon, and
the reaction stirred at room temperature for 48 h. The solvent was removed under vacuum
to obtain a yellow residue, which was taken up in water (200 mL) and extracted with
AcOEt (3 X 200 mL). The organic phase was dried (MgS04) and concentrated to a yellow
solid, which was triturated in hot Et20, cooled to room temperature, and filtered to obtain
a light yellow solid. The material was further purified by trituration in a minimum of cold
267
AcOEt to obtain 5.53 g (11.1 mmol, 50%) of 206 as a white solid, Rf 0.4 (40%
AcOEt/hexanes, black in PMA stain).
Spectral Data for 206: mp: 266 °C; IR (KBr) cm 3307, 1732, 1689; 'H NMR (200
MHz, CDCI3) 6: 2.10 (4H, d, J = 12.73), 2.09 (4H, d, J = 12.46), 3.67 (6H, s), 5.02 (2H,
s), 5.09 (4H, s), 7.35 (lOH, s); '^C NMR (50 MHz, CDCI3) 5: 27.2, 52.6, 58.1, 66.9,
128.1, 128.2, 128.5, 136.0, 155.5, 174.2; HRMS (FAB+) calcd for C26H31N2O8 (M^ +H)
499.2080, found 499.2086 (+1.2 ppm).
7>a«s-l,4-diamino-cyclohexane-l,4-dicarboxylic acid dimethyl ester (189). Reported
previously: J. R. Piper, C. Stringfellow, T. Johnston; J. Am. Chem. Soc. (1966) 911. 1,4-
^w-Benzyloxycarbonylamino-cyclohexane-l,4-dicarboxylic acid dimethyl ester (206)
(1.77 g, 3.6 mmol) with 10% Pd/C (0.42 g) in a mixture of MeOH (50 mL) and AcOEt
(80 mL) was hydrogenated at 55 psi (H2) in a Parr hydrogentator for 20 h. The reaction
solution was treated with charcoal and filtered, washing with CH2CI2. The solution was
concentrated under vacuum to a minimum of solvent (20 mL), and further filtered
through a cotton plug. The solvent was concentrated under vacuum to obtain 0.77 g (3.3
mmol, 93%) of 189 as an off-white solid.
Spectral Data for 189: mp 116-118 °C (lit. 122 °C); IR (KBr) cm 3420, 3359, 3299,
1732; 'H NMR (300 MHz, CDCI3) S: 1.49 (4H, dd, J = 4.03, 13.55), 2.15 (4H, dd, J =
3.91, 13.43), 3.72 (6H, s) ; NMR (75 MHz, CDCI3) 6: 32.1, 52.7, 57.6, 177.9;
HRMS (FAB+) calcd for C10H19N2O4 (M^ +H) 231.1345, found 231.1344 (-0.4 ppm).
268
Synthesis of Spiro [3.3] heptane 6/s-Amino Acids
Spiro[3.3]heptane-2,6-dicarboxylic acid (Fecht's Acid) (217). Obtained from the
literature procedure: L. Rice, C. Grogan. ; J. Org. Chem. (1961) 26 54 - 58. To a
solution of Na(s) (18.2 g, 0.79 mol) in dry amyl alcohol (800 mL) under argon, diethyl
malonate (120 mL, 0.79 mol) was injected and the solution stirred at room temperature
for 5 min. Pentaerythritol tetrabromide (61.5 g, 0.16 mol) was added in one portion, and
the reaction set to reflux. The solvent was distilled (approx 350 mL) until the distillate
temperature reached 129-130 °C, and then the solution was cooled to room temperature
and to it was added an equivalent amount of dry amyl alcohol (approx 350 mL). The
reaction was heated to reflux for 3 d. The reaction was quenched by removal of a
majority of the solvent by distillation, followed by slow addition of water (1000 mL), and
continued distillation until the distillate temperature reached 97-98 °C. The solution was
cooled to room temperature, and extracted with EtiO (3 x 250 mL). The organic phase
was washed with brine (250 mL), dried (MgS04) and concentrated under vacuum to an
orange oil (122 g). Potassium hydroxide (150 g, 2.8 mol) was added to the oil in absolute
EtOH (1000 mL), and the reaction vigorously stirred at room temperature for 2 d, upon
which a thick precipitate had formed. The reaction contents were filtered, washing the
precipitate with absolute EtOH. The yellow solid was dissolved in water (500 mL),
treated with charcoal, vacuum filtrated, and the aqueous filtrate acidified with conc HCl
to a pH of 2, and continuously extracted with EtiO for 24 h. The Et20 solution was dried
(MgS04) and concentrated to a crude yellow solid (43.9 g). This material was
thermolyzed in an oil bath heated to 215 °C for 1 h (or until complete CO2 extrusion).
269
Optimized purification conditions: The thermolyzed material was sublimed (265 °C, 10
mmng) to obtain an off-white solid. The material was triturated with hexanes and filtered
to obtain 11.7 g of 217 as a dry white solid. The hexanes solution was concentrated to a
light yellow oil, which by NMR indicated incomplete hydrolysis to the di-acid. The oil
was resubjected to potassium hydroxide hydrolysis, acidification, Et20 extraction, and
sublimation to obtain 5.77 g of 217 as a dry white solid. Both isolates were combined to
obtain a total of 17.5 g (95 mmol, 60%) of 217 as a dry white solid, Rf 0.71 (100%
AcOEt, light purple in anisaldehyde stain).
Spectral Data for 217: mp: 202 °C (lit 212 °C); IR (KBr) cm 3092, 1702; 'H NMR
(300 MHz, <i-DMSO) 6: 2.14 (8H, m), 2.86 (2H, pentet, J = 8.39), 11.98 (2H, bs);
NMR (75 MHz, t/-DMSO) 5: 32.2, 36.0, 37.1, 37.6, 176.2; HRMS (FAB+) calcd for
C9H,304 (M^+H) 185.0814, found 185.0814 (+0.3 ppm).
Spiro[3.3]heptane-2,6-dicarboxylic acid 6/5^-dimet^amide (219). Reported
previously: L. Rice, C. Grogan. ; J. Org. Chem. (1961) 26 54 - 58. Oxalyl chloride (0.28
mL, 3.19 mmol) was injected to a solution of spiro[3.3]heptane-2,6-dicarboxylic acid
(217) (0.235 g, 1.28 mmol) in dry CH2CI2 (5 mL). After 3.5 h, the solvent was removed
in vacuo, the flask was cooled in an ice bath to 0 °C, and dry CH2CI2 (5 mL) was
injected, followed by slow addition of dimethylamine (2.5 mL, 0.49 mol) (exothermic).
The reaction was stirred for 5 min, and then the solvent was removed under vacuum, and
the material taken up in water (50 mL) and continuously extracted with Et20 overnight.
After 24 h, the Et20 solvent was removed under vacuum to obtain a yellow solid. This
270
material was dissolved in hot MeOH, treated with charcoal, filtered hot and concentrated
to obtain 172.2 mg (0.72 mmol, 56%) of 219 as an off-white solid
Spectral Data for 219: mp: 102-105 °C (lit. 111-112 °C); IR (KBr) cm 1622; 'H
NMR (300 MHz, d- CH3OH) 5: 2.14 (4H, d, J = 8.54), 2.31 (2H, d, J = 8.55), 2.32 (2H,
d, J = 8.30), 2.89 (6H, s), 2.96 (6H, s), 3.26 (2H, pentet, J = 8.49); '^C NMR (75 MHz, d-
CH3OH) 8: 32.8, 35.7, 36.4, 37.1, 38.3, 38.8, 176.3; HRMS (FAB+) cacld for
C13H23N2O2 (M^ +H) 239.1760, found 239.1763 (+1.4 ppm).
2,6-(Dimethyiamino)-spiro[3.3]heptane 2,6-N-oxide (220).
A solution of spiro[3.3]heptane-2,6-dicarboxylic acid ftw-dimethylamide (219) (0.144 g,
0.61 mmol) in dry THF (3 mL) was added to a slurry of LiAlH4 (0.072 g, 1.8 mmol) in
dry THF (2 mL) at 0 °C under argon, and the reaction was warmed to room temperature.
After 1.5 h, the solution was quenched by a successive addition of water (0.07 mL), 15%
NaOH solution (0.07 mL), and finally water (0.2 mL), and the solution was allowed to
stir for 45 min. The reaction contents were vacuum filtrated, washing the salts with THF.
The filtrate was concentrated to a colorless oil which was immediately taken up in a
mixture of 30% H2O2 solution (1 mL) in MeOH (10 mL) and stirred at room temperature
overnight. After 18 h, the reaction was quenched by addition of charcoal, and the solvent
was filtered and concentrated to obtain a watery oil. This oil was dried by azeotroping
with MeOH to an off-white solid. The solid was purified by trituration with AcOEt, and
filtered to obtain 0.080 g (0.33 mmol, 54% for two steps) of 220 as an off-white solid.
271
Spectral Data for 220; mp: 144-146 °C; IR (KBr) cm 3475, 3197, 1480; 'H NMR
(300 MHz, d-MeOH) 5: 1.87 (2H, t, J = 10.26), 2.02 (2H, t, J = 10.01), 2.16 (IH, dd, J =
3.17, 11.23), 2.16 (IH, t, J = 11.84), 2.44 (IH, dd, J = 3.85), 10.87), 2.44 (IH, t, J =
11.72), 2.84 (2H, septet, J = 7.94), 3.27 (12H, s), 3.49 (4H, d, J = 6.59), 5.08 (H2O);
NMR (75 MHz, tZ-MeOH) 8: 25.9, 38.6, 40.0, 41.1, 57.5, 57.6, 75.9; HRMS (FAB+)
cacld for C13H27N2O2 (M^ +H) 243.2073, found 243.2070 (-1.2 ppm).
Spiro[3.3]heptane-2,6-dicarboxylic acid dimethyl ester (222). Reported previously: L.
Rice, C. Grogan. ; J. Org. Chem. (1961) 26 54 - 58. Oxalyl chloride (7 mL, 0.08 mol)
was added to a solution of spiro[3.3]heptane-2,6-dicarboxylic acid (217) (5.71 g, 24
mmol) in dry CH2CI2 (40 mL) under argon, and the solution stirred at room temperature
for 3 h. CO2 extrusion was observed 2 min after addition. The majority of solvent was
removed in vacuo, the flask was cooled in an ice bath to 0 °C, and dry MeOH (40 mL)
was slowly injected. The solution was allowed to warm to room temperature and stirred
overnight. After 18 h, the solvent was removed under vacuum to obtain an oil, which was
taken up in AcOEt (250 mL) and washed with NaHCOs (2 x 250 mL) and brine (250
mL). The organic phase was dried (MgS04) and concentrated to 6.56 g (31 mmol,
>100%) of 222 as a light yellow oil, Rf 0.46 (50% AcOEt/hexanes, blue in anisaldehyde
stain).
Spectral Data for 222: IR (NaCl) cm"': 1733; 'H NMR (300 MHz, CDCI3) §: 2.13 (8H,
m), 2.87 (2H, pentet, J = 8.49), 3.53 (6H, s); NMR (75 MHz, CDCI3) 5: 32.4, 36.5,
272
37.1, 37.7, 51.4, 175.4; HRMS (FAB+) calcd for C11H17O4 (M^ +H) 213.1127, found
213.1134 (+3.2 ppm).
2,6-(Hydroxydiphenylmethyl)-spiro[3.3]heptane (223). Reported previously: H. J.
Backer, H. G. Kemper; Red. Trav. Chim. Pays-Bas. (1938) 1248 - 1258. A 3 M solution
of PhMgBr in Et20 (100 mL, 0.29 mol) was injected to a solution of spire[3.3Jheptane-
2,6-dicarboxylic acid dimethyl ester (222) (12.37 g, 58 mmol) in dry Et20 (100 mL)
cooled in an ice bath to 0 °C under argon. The reaction was warmed to room temperature
and refluxed for 1.5 h. The solution was then cooled in an ice bath to 0 °C and a
saturated solution of ammonium chloride was slowly added until the reaction was
quenched (no exothermic reaction was observed). The solution was stirred for an
additional 10 min at room temperature, diluted with brine (1000 mL), and the aqueous
solution was extracted with AcOEt (5 x 200 mL). The organic phase was washed with
brine (500 mL), dried (MgS04) and concentrated to a yellow oil. The material was
purified by flash chromatography (230-400 mesh silica) in a 100% hexanes elutant until
all UV active by-products were removed, and then the solvent polarity was ramped to a
20% AcOEt/hexanes elutant to obtain 26.4 g (57 mmol, 98%) of 223 as a light yellow
foam, Ri O.13 (10% AcOEt/hexanes, brown in anisaldehyde stain).
Spectral Data for 223: mp: 42^6 °C (lit. 56 °C); IR (KBr) cm 3506 (br), 1449, 751,
702; 'H NMR (300 MHz, t^-DMSO) 8: 1.54 (2H, dt, J = 3.91, 7.20), 1.82 (2H, dt, J =
3.90, 7.32), 1.95 (2H, t, J = 10.14), 2.07 (2H, t, J = 9.89), 3.18 (2H, pentet, J = 8.55), 5.33
(2H, s), 7.12 (4H, m), 7.21 (4H, t, J = 7.45), 7.24 (4H, t, J = 7.41), 7.32 (4H, d, J = 7.81),
273
7.34 (4H, d, J = 7.57); '^C NMR (75 MHz, J-DMSO) 6: 32.6, 34.3, 35.9, 38.3, 76.7,
126.0, 126.1, 126.2, 127.6, 147.4; HRMS (FAB+) calcd for C33H31O (M^ - (HO))
443.2375, found 443.2363 (-2.6 ppm).
2,6-Dibenzhydrylidene-spiro[3.3]heptane (224). Reported previously: H. J. Backer, H.
G. Kemper; Red. Trav. Chim. Pays-Bas. (1938) 1248 - 1258. A ground mixture of
oxalic acid (88.1 g, 71 mmol) and sodium oxalate (15.5 g, 0.12 mol) was deposited in a
beaker containing the oily solid, 2,6-(hydroxydiphenylmethyl)-spiro[3.3]heptane (223)
(22.9 g, 50 mmol), and the contents intermixed. A watch glass was placed over the
beaker and the neat mixture thermolyzed in an oil bath heated to 175-180 °C for 2 hr.
Determination of the reaction time was based on the equation y = 3.76 x + 17.03, where x
= amount of 2,6-(hydroxydiphenylmethyl)-spiro[3.3]heptane (223) (grams), and y =
reaction time (min). The thermolyzed material was cooled to room temperature, and
diluted with water (500 mL) and Et20 (1000 mL). Most of the mixture should be soluble
except for sodium oxalate. The heterogeneous solvent system was vacuum filtrated,
washing thoroughly with Et20. The organic phase was separated, and the aqueous phase
washed with Et20 (3 x 250 mL). The Et20 fractions were combined and washed with
NaHCOs (2 x 250 mL) and brine (250 mL), treated with charcoal and dried (MgS04),
then filtered and concentrated under vacuum to a yellow oil. The oil was dried to a sticky
solid by azeotroping with MeOH, and and the material was purified by trituration with
hot MeOH to a dry yellow solid. The MeOH solution was cooled in a freezer (-22 °C)
overnight, and then filtered, washing sparingly with cold MeOH to obtain 14.9 g (35
274
mmol, 70%) of 224 as a light yellow solid, Rf 0.54 (20% EtiO/hexanes, black in PMA
stain).
Spectral Data for 224: mp: 112-113 °C (lit. 116- 116.5 °C); IR (KBr) cm : 3086,3018,
1499, 1443, 702; 'H NMR (300 MHz, CDCI3) 5: 3.02 (8H, s), 7.22 (20H, m); '^C NMR
(75 MHz, CDCI3) 5: 35.3, 44.9, 126.3, 128.0, 128.8,134.0, 135.2,140.6; Anal, calcd. for
C33H28: C, 93.35, H, 6.65; found C, 90.42, H 6.54.
Spiro[3.3]heptane-2,6-dione (218). Reported previously: J. Gore, J. Denis, P.
Leriverend, J. Conia; Bull. Soc. Chim. France (1968) 6 2432-2437. To a solution of 2,6-
dibenzhydrylidene-spiro[3.3]heptane (224) (7.97 g, 19.0 mmol) in a mixture of
acetonitrile (120 mL), CCI4 (120 mL) and water (180 mL), RuCl3(H20)2 (0.65 g, 3.1
mmol, 16 mol%) and NaI04 (40 g, 0.19 mol) were added in one portion. The solution
was stirred at room temperature for 5 min, and then heated to reflux for 1.5 h. At that
time, the solution was cooled to room temperature and the insoluble salts were filtered,
washing thoroughly with CH2CI2. The salts were extracted from CH2CI2 in a Soxlet
continuous extractor overnight. The CH2CI2 extract and filtrate were combined and
concentrated to a brown residue. The material was dry loaded to silica, and purified by
gravity chromatography (230-400 mesh silica) in a 35% AcOEt/hexanes elutant to obtain
the product as an oil contaminated with I2. The yellow oil was purified by trituration in
hot hexanes to a solid, cooled in the freezer (-22 °C) overnight, and filtered, washing with
hexanes to obtain 1.2 g (9 mmol, 51%) of 218 as a light yellow solid, Rf 0.5 (40%
AcOEt/hexanes, black in anisaldehyde stain).
275
Spectral Data for 218: mp: 64 °C; IR (KBr) cm 1781; 'H NMR (300 MHz, CDCI3) 5:
3.34 (8H, s); '^C NMR (75 MHz, CDCI3) 6: 23.4, 58.6, 204.7; Anal, calcd. for CyHgOi:
C, 67.73, H, 6.50; found C, 66.90, H 6.59.
Spiro[3.3]heptane-spiro-2,6-hydantoin (225). Potassium cyanide (1.65 g, 25 mmol)
and ammonium carbonate (13.3 g, 85 mmol) were added to a solution of
spiro[3.3]heptane-2,6-dione (218) (1.05 g, 8.5 mmol) in absolute EtOH (30 mL) and
water (30 mL), and the solution gently refluxed in an oil bath heated to 60 °C. The
solution cleared after 3 h of heating, and then a white precipitate gradually formed. After
3 d, the reaction was cooled to room temperature, further cooled in an ice bath to 0 °C,
and conc HCl (approx 20 mL) added dropwise to the solution over a 1 h period, or until a
pH of 2. The reaction mixture was cooled in a freezer (-22 °C) overnight. After 24 h,
EtaO (60 mL) was added to the acidified solution, and the cold mixture was vacuum
filtrated, washing the precipitate with EtiO. The white solid was further purified by
vigorously stirring with absolute EtOH (100 mL) at room temperature overnight, and the
mixture was filtered to obtain 2.28 g (8.6 mmol, 100%) of 225 as a white solid.
Spectral Data for 225: mp: 358 °C decomposition; IR (KBr) cm 3188 (br), 1781,
1725; 'h NMR (300 MHz, t/-DMSO) §: 2.21 (2H, d, J = 12.51), 2.28 (2H, d, J = 12.66),
2.39 (2H, dd, J = 3.38, 12.65), 2.54 (2H, dd, J = 3.21, 12.52), 8.15 (2H, s), 10.45 (2H, s);
NMR (75 MHz, t/-DMSO) 8:. 27.4, 44.0, 44.2, 57.1, 156.1, 178.5; HRMS (EI) cacld
for CiiHi2N404(M^ ) 264.0853, found 264.0865 (+4.5 ppm).
276
2,6-fi/5-benzyloxycarbonylamino-spiro[3,3]heptane-2,6-dicarboxylic acid (226).
(Note that this reaction is limited to this particular scale). Spiro[3.3]heptane-spir0 2,6-
hydantoin (225) (0.136 g, 0.52 mmol) was hydrolyzed by vigorously refluxing over 24 h
in a 3 M NaOH solution (1 mL). A trace amount of precipitate developed after this time
period. The solution was cooled in an ice bath to 0 °C, and a mixture of benzyl
chloroformate (1 mL, 7.0 mmol) in acetone (5 mL) was added by pipet. This was
followed by addition of NaOH (0.4 g, 0.01 mol) in water (5 mL), and the reaction was
warmed to room temperature and stirred overnight. After 24 h, the aqueous solution was
washed with EtiO (10 mL), and the EtiO phase back-extracted with water (10 mL). The
aqueous fractions were combined, diluted with water (100 mL) and acidified with conc
HCl until a white precipitate was observed (pH of 2). The acidified solution was
extracted with AcOEt (3 x 100 mL). Extraction forms an emulsion which should be
collected together with the AcOEt layer. The emulsified organic phase was dried
(MgS04) and concentrated to an opaque oil, which was freeze-pump-thawed (2 x) and
triturated with hot hexanes to obtain 0.178 g (0.37 mmol, 73% for two steps) of 224 as a
dry white solid.
Spectral Data for 226: 192-194 °C: IR (KBr) cm 3292, 1709, 1644; 'H NMR (300
MHz, d- CH3OH) 5: 2.37 (4H, t, J = 11.72), 2.74 (4H, d, J = 9.53), 5.05 (4H, s), 7.32
(lOH, m); NMR (75 MHz, d- CH3OH) 8:. 33.0, 45.0, 45.5, 55.4, 67.3, 128.6, 128.9,
129.4, 138.1, 157.8, 177.2; HRMS (FAB+) cacld for C25H27N2O8 (M^ +H) 483.1767,
found 483.1744 (-4.9 ppm).
277
2,6-Diainino-spiro[3.3]heptane-2,6-dicarboxylic acid dimethyl ester (207a,b). 2,6-
6/5'-Benzyloxycarbonylamino-spiro[3.3]heptane-2,6-dicarboxylic acid (224) (190 mg,
0.39 mmol) was solvated in a 5% CS2CO3 solution (15 mL) with heating. The aqueous
contents were removed by lyophilization to obtain a white salt. Dry DMF (10 mL) and
iodomethane (0.5 mL, 8.0 mmol) were injected to the flask containing the salt under
argon, and the reaction stirred at room temperature overnight. After 24 h, iodomethane
(0.5 mL, 8.0 mmol) was again added, and the reaction stirred an additional 24 h. The
solvent was removed under vacuum, and the yellow residue taken up in a mixture of
water (lOOmL) and AcOEt (100 mL), and the aqueous phase was extracted with AcOEt
(3 X 100 mL). The AcOEt fractions were combined, and washed with Na2S03 (100 mL)
and brine (100 mL). The organic phase was dried (MgS04) and concentrated to a yellow
sticky solid which was purified by flash chromatography (230-400 mesh silica, pretreated
1% NEta) in a 50% AcOEt/hexanes elutant to obtain 173 mg of the crude diester as a
sticky clear oil, Rf 0.34 (50% AcOEt/hexanes, blue-yellow in PMA stain). This material
was taken up in AcOEt (10 mL) with 10% Pd/C (0.04 g) and hydrogenated at 55 psi (H2)
in a Parr hydrogenator overnight. After 20 h, the contents were filtered, washing with
CH2CI2, and concentrated to an oil. The oil was dissolved in Et20 (25 mL), and
anhydrous HCl (g) was bubbled through a cooled solution (0 °C) until a white precipitate
was observed. The EtiO solvent was decanted, and the sticky solid dried under vacuum to
a dry tannish solid. The solid was purified by trituration with hot acetonitrile, and the
solution cooled to room temperature and filtered to obtain 74.1 mg (0.24 mmol, 61% for
in
two steps) of 207a,b as an off white HCl salt, Rf 0.13 (50% EtOH/AcOEt, yellow in
ninhydrin stain).
Spectral Data for 207a,b: mp; 226-228 °C; IR (KBr) cm -1: 3421(br), 1741; 'H NMR
(300MHz, d- CH3OH) 5: 2.63 (2H, d, J = 15.14), 2.71 (2H, d, J = 13.67), 2.78 (IH, d, J =
4.40), 2.82 (IH, d, J = 4.39), 2.93 (IH, d, J = 3.41), 2.97 (IH, d, J = 3.42), 3.87 (6H, s);
'^C NMR (75 MHz, d- CH3OH) 6: 31.2, 43.3, 44.1, 54.0, 54.1, 172.3; HRMS (FAB+)
cacld for CnHi9N204 (M+ +H) 243.1345, found 243.1343 (-0.8 ppm).
279
Synthesis of l,2,3?5,6,7-Hexahydro-5-indacene 6w-Diketopiperazines
C/5-[(2,6-6/s-{2-/er/-ButoxycarbonyIamino-4,7-dimethoxy-indane-2-carbonyl}-
amino)-l,2,3,5,6,7-hexahydro-5-indacene-2,6-dicarboxylic acid diethyl ester] (227a).
Dry THF (8 mL) was injected to a flask containing cw-2,6-diamino-l,2,3,5,6,7-
hexahydro-5-indacene-2,6-dicarboxylic acid diethyl ester (186a) (69 mg, 0.21 mmol), 2-
rert-butoxycarbonylamino-4,7-dimethoxy-indan-2-carboxylic acid (85a) (154 mg, 0.46
mmol), BOP (279 mg, 0.63 mmol), DABCO (141 mg, 1.26 mmol), and catalytic amount
of DMAP at room temperature under argon. Gradually, a thick white precipitate formed.
Each additional day, a portion of BOP (279 mg, 0.63 mmol) was added. The reaction was
quenched after 3 d by removal of the solvent in vacuo to an off-white solid. The reaction
contents were dry loaded to silica, and purified by flash chromatography (230-400 mesh
silica) in a 5% EtOH/CH2Cl2 elutant. The product was observed in the collected fractions
as an insoluble white solid. The solid was collected and triturated with hot AcOEt. The
solution was cooled to room temperature and filtered to obtain 105 mg (0.11 mmol, 52%)
of 227a as a white solid.
Spectral Data for 227a: mp: 241 °C decomposition; IR (KBr) cm 3394, 3320, 1727,
1709, 1665; 'H NMR (300 MHz, J-DMSO at 55 °C) 6: 1.06 (6H, t, J = 6.96), 1.24 (18H,
s), 3.01 (4H, bd, J = 17.09), 3.14 (2H, bd, J = 16.60), 3.20 (2H, bd, J = 15.38), 3.41 (4H,
bd, J = 16.60), 3.43 (4H, bd, J = 16.36), 3.70 (2H, s), 3.98 (4H, q, J = 6.93), 6.69 (4H, s),
6.98 (2H, s), 8.08 (2H, bs); NMR (75 MHz, J-DMSO at 55 °C) 5: 13.5, 27.7, 42.3,
55.2, 60.2, 65.0, 65.2, 78.2, 109.3, 119.8, 129.4, 138.3, 149.5, 154.4, 172.9, 173.3;
280
HRMS (MALDI in CCA) calcd for C52H66N4O14K (M^ + K) 1009.4211, found 1009.4177
(-3.3 ppm)
Cy do- [cis-( {2,6-bis-[2-ainino-4,7-dimethoxy-indane-2-carboxylicacid] -amino}-
l,2,355,6,7-hexahydro-5-indacene-2,6-dicarboxylic acid)] (155a). Cis-[(2,6-bis-{2-tert-
Butoxycarbonylamino-4,7-dimethoxy-indane-2-carbonyl}-amino)-l,2,3,5,6,7-hexahydro-
^-indacene-2,6-dicarboxylic acid diethyl ester] (227a) (163 mg, 0.17 mmol) was heated in
a sealed, evacuated tube for 1 h in an oil bath heated to 265 - 270 °C. The sample melted,
evolved gas, and re-solidified. The solid was dissolved in a 50% TFA/CH2CI2 solution,
treated with charcoal, then filtered and concentrated under vacuum to a tan solid. The
material was purified by tituration with hot Et20. The solution was cooled to room
temperature, and filtered to obtain 88 mg (0.13 mmol, 77%) of 155a as a white solid.
Spectral Data for 155a: mp: > 300 °C decomposition; IR (KBr) cm 1685; 'H NMR
(300 MHz, d-TFA) 8: 3.50 (4H, bd, J = 16.66), 3.60 (4H, bd, J = 16.84), 4.11 (20H, m),
7.12 (4H, s), 7.34 (2H, s); '^C NMR (75 MHz, d-T¥A) 5: 46.1, 48.3, 59.0, 68.8, 69.3,
116.1, 123.5, 130.5, 140.2, 152.5, 175.0; HRMS (MALDI in DTH) calcd for C38H39N4O8
(M^+H) 679.2763, found 679.2778 (+2.2 ppm).
rr««s-[(2,6-6is-{2-^erf-Butoxycarbonylamino-4,7-dimethoxy-indane-2-carbonyl}-
amino)-l,2,3?5,6,7-hexahydro-s-mdacene-2,6-dicarboxylic acid diethyl ester] (228a).
Dry THF (8 mL) was injected to a flask containing /ran5'-2,6-diamino-l,2,3,5,6,7-
hexahydro-i'-indacene-2,6-dicarboxylic acid diethyl ester (186b) (83 mg, 0.25 mmol), 2-
281
/^er?-butoxycarbonylamino-4,7-dimethoxy-indan-2-carboxylic acid (85a) (185 mg, 0.55
mmol), BOP (332 mg, 0.75 mmol), DABCO (168 mg, 1.50 mmol), and catalytic amount
of DMAP at room temperature under argon. Gradually, a thick white precipitate formed.
Each additional day, a portion of BOP (332 mg, 0.75 mmol) was added. The reaction was
quenched after 3 d by removal of the solvent in vacuo to an off-white solid. The reaction
contents were dry loaded to silica, and purified by flash chromatography (230-400 mesh
silica) in a 5% EtOH/CH2Cl2 elutant. The product was observed in the collected fractions
as an insoluable white solid. The solid was collected and triturated with hot AcOEt. The
solution was cooled to room temperature and filtered to obtain 134 mg (0.14 mmol, 55%)
of 228a as a white solid.
Spectral Data for 228a; mp: 262 °C decomposition; IR (KBr) cm 3388, 3326, 1721,
1701, 1659; 'H NMR (300 MHz, c/-DMSO at 55 °C) §; 1.06 (6H, t, J = 7.08), 1.17 (18H,
s), 2.98 (4H, bd, J = 17.09), 3.17 (4H, bd, J = 12.70), 3.35 (4H, bd, J = 15.38), 3.40 (4H,
bd, J - 16.61), 3.69 (12H, s), 3.99 (4H, q, J = 7.08), 6.68 (4H, s), 6.93 (2H, bs), 6.98 (2H,
s), 7.96 (2H, bs); '^C NMR (75 MHz, J-DMSO at 55 °C) 5: 13.5, 27.6, 42.1, 55.1, 60.1,
65.1, 65.2, 78.2, 109.2, 120.1, 129.3, 138.2, 149.4, 154.2, 172.6; HRMS (MALDl in
CCA) calcd for C52H66N40i4Na (M^ + Na) 993.4468, found 993.4407 (-6.1 ppm).
Cyclo-[^ra«5-({2,6-6/s-[2-amino-4,7-dimethHy- indane-2-carboxylic acid]-amino}-
l,2,3,5,6,7-hexahydro-5^-indacene-2,6-dicarboxylic acid)] (156a). Trans-\{2,6-his-{2-
fert-Butoxycarbonylamino-4,7-dimethoxy-indane-2-carbonyl}-amino)-l,2,3,5,6,7-
hexahydro-5-indacene-2,6-dicarboxylic acid diethyl ester] (228a) (107 mg, 0.11 mmol)
282
was heated in a sealed, evacuated tube for 1 h in an oil bath heated to 265 - 270 °C. The
sample melted, evolved gas, and re-solidified. The solid was dissolved in a 50%
TFA/CH2CI2 solution, treated with charcoal, then filtered and concentrated under vacuum
to a tan solid. The material was purified by tituration with hot Et20. The solution was
cooled to room temperature, and filtered to obtain 60 mg (0.09 mmol, 80%) of 156a as a
white solid.
Spectral Data for 156a: mp: > 300 °C decomposition; IR (KBr) cm 3180, 3051, 1677;
'H NMR (300 MHz, i/-TFA) 6: 3.48 (4H, bd, J = 16.93), 3.57 (4H, bd, J = 17.24), 4.08
(20H, m), 7.09 (4H, s), 7.30 (2H, s); NMR (75 MHz, t/-TFA) 6: 46.2, 48.3, 59.1,
68.9, 69.5, 116.2, 123.6, 130.6, 140.4, 152.6, 175.0, 175.1; HRMS (MALDI in CCA)
calcd for C38H39N4O8 (M^+H) 679.2763, found 679.2716 (-6.3 ppm).
Cw-[(2,6-Aw-{2-^^/'/-Butoxycarbonylamino-4,7-Z»/5-hexyloxy-indane-2-carbonyl}-
ainino)-l,2,3?5,6,7-hexahydro-s-indacene-2,6-dicarboxylic acid diethyl ester] (227b).
Dry THF (8 mL) was injected to a flask containing cw-2,6-diamino-l,2,3,5,6,7-
hexahydro-.y-indacene-2,6-dicarboxylic acid diethyl ester (186a) (53 mg, 0.16 mmol), 2-
rert-butoxycarbonylamino-4,7-^z5-hexyloxy-indan-2-carboxylic acid (85b) (160 mg, 0.33
mmol), BOP (211 mg, 0.48 mmol), DABCO (107 mg, 0.95 mmol), and catalytic amount
of DMAP at room temperature under argon. Gradually, a thick white precipitate formed.
Each additional day, a portion of BOP (211 mg, 0.48 mmol) was added. The reaction was
quenched after 5 d by removal of the solvent in vacuo to an off-white solid. The solid was
purified by trituration with hot acetonitrile, and the solution was cooled to room
283
temperature and filtered (2 x) to obtain 104 mg (0.08 mmol, 66%) of 227b as a white
solid.
Spectral Data for 227b: mp: 223-224 °C; IR (KBr) cm 3381, 3324, 1725, 1705, 1669;
'H NMR (300 MHz, CDCI3) 5: 0.84 (12H, t, J = 6.59), 1.15 (6H, t, J = 7.08), 1.29 (34H,
m), 1.36 (8H, pentet, J = 6.84), 1.68 (8H, pentet, J = 6.84), 3.15 (8H, bd, J = 16.11), 3.52
(4H, bd, J = 12.45), 3.57 (4H, bd, J = 12.50), 3.84 (8H, t, J = 6.47), 4.12 (4H, q, J = 7.00),
5.09 (2H, bs), 6.57 (4H, s), 6.95 (2H, s), 7.34 (2H, bs); NMR (75 MHz, CDCI3) 5:
14.1, 22.6, 25.7, 28.1, 29.4, 31.6, 43.2, 61.5, 65.6, 68.5, 77.2, 110.7, 120.4, 129.6, 138.7,
149.7, 154.8, 173.0; HRMS (MALDI in CCA) calcd for C72Hio6N40,4Na (M^ + Na)
1273.7598, found 1273.7708 (+8.6 ppm).
Cyclo-[m-({2,6-A/5-[2-amino-4,7-A/s-hexyloxy-indane-2-carboxylic acid]-amino}-
l,2,3?5,6,7-hexahydro-s-indacene-2,6-dicarboxylic acid)] (155b). Cis-{(2,6-bis-{2-
fert-Butoxycarbonylamino-4,7-6w-hexyloxy-indane-2-carbonyl}-amino)-l,2,3,5,6,7-
hexahydro-5-indacene-2,6-dicarboxylic acid diethyl ester] (227b) (90 mg, 0.07 mmol)
was heated in a sealed, evacuated tube for 1 h in an oil bath heated to 265 - 270 °C. The
sample melted, evolved gas, and re-solidified. The solid was dissolved in a 50%
TFA/CH2CI2 solution, treated with charcoal, then filtered and concentrated under vacuum
to a tan solid. The material was purified by tituration with hot acetonitrile. The solution
was cooled to room temperature, and filtered to obtain 69 mg (0.07 mmol, 48%) of 155b
as a white solid.
284
Spectral Data for 155b: mp: > 300 °C decomposition; IR (KBr) cm 3180, 3059, 1669;
'H NMR (300 MHz, d-TFA) 6: 0.79 (12H, t, J = 6.87), 1.25 (16H, m), 1.38 (8H, m), 1.72
(8H, pentet, J = 7.06), 3.24 (4H, bd, J = 16.33), 3.37 (4H, bd, J - 16.79), 3.81 (4H, bd, J =
16.63), 3.85 (4H, bd, J = 16.33), 4.08 (8H, t, J = 6.72), 6.88 (4H, s), 7.07 (2H, s);
NMR (75 MHz, 50% J-TFA in CDCI3) 6: 13.9, 22.6, 25.5, 31.5, 44.2, 46.2, 66.3, 66.8,
70.8, 114.4, 121.4, 128.3, 137.7, 149.4, 171.8, 172.1; HRMS (MALDI in CCA) calcd for
C58H78N408Na (M'^ + Na) 981.5712, found 981.5641 (-7.2 ppm).
7>a«5-[(2,6-6/s-{2-/e/'/-ButoxycarbonyIamino-4,7-6/5-hexyloxy-indane-2-carbonyl}-
ainino)-l,2,3,5,6,7-hexahydro-5-indacene-2,6-dicarboxylic acid diethyl ester] (228b).
Dry THF (5 mL) was injected to a flask containing rra«5-2,6-diamino-l,2,3,5,6,7-
hexahydro-5-indacene-2,6-dicarboxylic acid diethyl ester (186b) (48 mg, 0.14 mmol), 2-
fer?-butoxycarbonylamino-4,7-Z)w-hexyloxy-indan-2-carboxylic acid (85b) (158 mg, 0.33
mmol), BOP (200 mg, 0.45 mmol), DABCO (96 mg, 0.86 mmol), and catalytic amount
of DMAP at room temperature under argon. Gradually, a thick white precipitate formed.
Each additional day, a portion of BOP (200 mg, 0.45 mmol) was added. The reaction was
quenched after 4 d by removal of the solvent in vacuo to an off-white solid. The solid was
purified by trituration with hot acetonitrile, and the solution was cooled to room
temperature and filtered (2 x) to obtain 90 mg (0.07 mmol, 50%) of 228b as a white solid.
Spectral Data for 228b; mp: 234 °C; IR (KBr) cm 3388, 3320, 1727, 1701, 1665; 'H
NMR (300 MHz, CDCI3) 5: 0.92 (12H, t, J = 6.59), 1.20 (18H, s), 1.23 (6H, t, J = 7.32),
1.31 (16H, m), 1.41 (8H, pentet, J = 6.59), 1.70 (8H, pentet, J = 6.84), 4.80 (8H, bd, J =1
285
6.11), 3.52 (4H, bd, J = 13.92), 3.57 (4H, bd, J = 16.85), 3.86 (8H, t, J = 6.47), 4.19 (4H,
q, J = 7.08), 5.05 (2H, bs), 6.59 (4H, s), 7.01 (2H, s), 7.23 (2H, bs); NMR (75 MHz,
CDCI3) 5: 14.0, 22.6, 25.7, 27.8, 29.3, 31.6, 40.3, 43.0, 61.4, 66.1, 66.5, 68.5, 80.3,
110.7, 120.8, 129.6, 138.6, 149.7, 154.6, 172.7; HRMS (MALDI in CCA) calcd for
C72H106N4O14K (M^+ K) 1289.7341, found 1273.7321 (-3.4 ppm).
Cyclo-[^/*a«5-({2,6-6is-[2-amino-4,7-6w-hexyloxy-indane-2-carboxylic acid]-amino}-
l,2,355,6,7-hexahydro-s-indacene-2,6-dicarboxylic acid)] (156b). Trans-{{2,6-bis-{2-
/ert-Butoxycarbonylamino-4,7-Z)/5-hexyloxy-indane-2-carbonyl}-amino)-l,2,3,5,6,7-
hexahydro-^-indacene-2,6-dicarboxylic acid diethyl ester] (228b) (63 mg, 0.05 mmol)
was heated in a sealed, evacuated tube for 1 h in an oil bath heated to 265 - 270 °C. The
sample melted, evolved gas, and re-solidified. The solid was dissolved in a 50%
TFA/CH2CI2 solution, treated with charcoal, then filtered and concentrated under vacuum
to a tan solid. The material was purified by tituration with hot acetonitrile. The solution
was cooled to room temperature, and filtered to obtain 21 mg (0.02 mmol, 44%) of 156b
as a white solid.
Spectral Data for 156b: mp: > 300 °C decomposition; IR (KBr) cm 3421, 3244, 1677;
'H NMR (300 MHz, 50% d-TFA in CDCI3) 6: 0.88 (12H, t, J = 6.79), 1.32 (16H, m),
1.42 (8H, pentet, J = 6.87), 1.76 (8H, pentet, J = 7.17), 3.24 (4H, bd, J = 16.77), 3.30 (2H,
bd, J = 16.78), 3.78 (4H, bd, J = 16.32), 3.83 (4H, bd, J = 15.42), 4.04 (8H, t, J = 6.79),
6.83 (4H, s), 7.13 (2H, s); ^^C NMR (75 MHz, 50% d-T¥A in CDCI3) 5: 13.7, 22.6, 25.6,
29.1, 31.6, 44.3, 46.2, 66.5, 66.9, 71.4, 115.2, 121.4, 128.7, 137.9, 149.5, 172.1, 172.3;
286
HRMS (MALDI in CCA) calcd for C58H78N408Na (M^ + Na) 981.5712, found 981.5748
(+3.6 ppm).
Cw-[(2,6-6/s-{2-ter#-Butoxycarbonylamino-4,7-^/5-octyloxy-indane-2-carbonyl}-
amino)-l,2,3»5,6,7-hexahydro-s-indacene-2,6-dicarboxylic acid diethyl ester] (227c).
Dry THF (5 mL) was injected to a flask containing c/5-2,6-dianiino-l,2,3,5,6,7-
hexahydro-5'-indacene-2,6-dicarboxylic acid diethyl ester (186a) (52 mg, 0.16 mmol), 2-
?er/-butoxycarbonylamino-4,7-6/5-octyloxy indan-2-carboxylic acid (85c) (182 mg, 0.34
mmol), BOP (215 mg, 0.49 mmol), DABCO (109 mg, 0.97 mmol), and catalytic amount
of DMAP at room temperature under argon. Gradually, a thick white precipitate formed.
Each additional day, a portion of BOP (215 mg, 0.49 mmol) was added. The reaction was
quenched after 4 d by removal of the solvent in vacuo to an off-white solid. The solid was
purified by trituration with hot acetonitrile, and the solution was cooled to room
temperature and filtered (2 x) to obtain 120 mg (0.09 mmol, 54%) of 227c as a white
solid.
Spectral Data for 227c: mp: 206-207 °C; IR (KBr) cm 3389, 3324, 1725, 1709, 1660;
'H NMR (300 MHz, CDCI3) S: 0.86 (12H, t, J = 6.32), 1.18 (6H, t, J = 7.08), 1.32 (58H,
m), 1.69 (8H, pentet, J = 6.84), 3.16 (8H, bd, J = 16.11), 3.54 (4H, bd, J = 16.36), 3.58
(4H, bd, J = 16.11), 3.84 (8H, t, J = 6.35), 4.13 (4H, q, J = 7.00), 5.11 (2H, bs), 6.57 (4H,
s), 6.96 (2H, s), 7.36 (2H, bs); '^C NMR (75 MHz, CDCI3) 5: 14.0, 14.1, 22.6, 26.0, 28.0,
29.2, 29.3,31.8,40.5,43.2,61.4, 65.6, 66.6, 68.5, 80.2, 110.7, 120.3, 129.6, 138.7, 149.7,
287
154.8, 173.0, 173.1; Anal, calcd for C8oHi22N40,4 C 70.45, H 9.02, N 4.11; found C
70.56, H 9.32 N 4.22.
CycIo-[c«-({2,6-6w-[2-amino-4,7-6«-octyloxy-indane-2-carboxylic acid]-ainino}-
l,2,3»5,6,7-hexahydro-5-indacene-2,6-dicarboxylic acid)] (155c). Cis-{{2,6-bis-{2-tert-
Butoxycarbonylamino-4,7-Z)w-octyloxy-indane-2-carbonyl}-aniino)-l,2,3,5,6,7-
hexahydro-5-indacene-2,6-dicarboxylic acid diethyl ester] (227c) (201 mg, 0.15 mmol)
was heated in a sealed, evacuated tube for 1 h in an oil bath heated to 265 - 270 °C. The
sample melted, evolved gas, and re-solidified. The solid was dissolved in a 50%
TFA/CH2CI2 solution, treated with charcoal, then filtered and concentrated under vacuum
to a tan solid. The material was purified by tituration with hot acetonitrile. The solution
was cooled to room temperature, and filtered to obtain 157 mg (0.15 mmol, 71%) of 155c
as a white solid.
Spectral Data for 155c: mp: > 300 °C decomposition; IR (KBr) cm 3188, 3067, 1685;
'H NMR (300 MHz, 10% d-TFA in CDCI3) 5: 0.81 (12H, t, J = 6.49), 1.23 (32H, m),
1.36 (8H, m), 1.68 (8H, pentet, J = 6.83), 3.10 (4H, bd, J = 15.56), 3.14 (4H, bd, J =
16.33), 3.67 (4H, bd, J = 16.48), 3.75 (4H, bd, J = 15.87), 3.85 (8H, t, J = 6.49), 6.60 (4H,
s), 7.06 (2H, s), 7.89 (2H, bs), 7.95 (2H, bs); NMR (75 MHz, CDCI3) 5: 14.1, 22.6,
26.0, 29.2, 29.4, 31.8, 44.4, 46.4, 66.5, 66.7, 68.5, 111.0, 121.1, 128.0, 138.2, 149.6,
169.5, 169.8; HRMS (MALDI in CCA) calcd for C66H94N408Na (M^ + Na) 1093.6964,
found 1093.6915 (-4.4 ppm).
288
7m/i5-[(2,6-6w-{2-fei'^-Butoxycarbonylamino-4,7-6«-octyloxy-indane-2-carbonyl}-
amino)-l,2,3,5,6,7-hexahydro-5-indacene-2,6-dicarboxylic acid diethyl ester] (228c).
Dry THF (5 mL) was injected to a flask containing /rara-2,6-diamino-l,2,3,5,6,7-
hexahydro->s'-indacene-2,6-dicarboxylic acid diethyl ester (186b) (52 mg, 0.16 mmol), 2-
rer/-butoxycarbonylamino-4,7-Z)/5-octyloxy indan-2-carboxylic acid (85c) (175 mg, 0.33
mmol), BOP (232 mg, 0.52 mmol), DABCO (105 mg, 0.94 mmol), and catalytic amount
of DMAP at room temperature under argon. Gradually, a thick white precipitate formed.
Each additional day, a portion of BOP (232 mg, 0.52 mmol) was added. The reaction was
quenched after 4 d by removal of the solvent in vacuo to an off-white solid. The solid was
purified by trituration with hot acetonitrile, and the solution was cooled to room
temperature and filtered (2 x) to obtain 139 mg (0.10 mmol, 66%) of 228c as a white
solid.
Spectral Data for 228c: mp: 216-217 °C; IR (KBr) cm 3397, 3316, 1733, 1701, 1677;
'H NMR (300 MHz, CDCI3) 5; 0.86 (12H, t, J = 6.47), 1.27 (64H, m), 1.67 (8H, pentet, J
= 6.83), 3.16 (4H, bd, J = 15.87), 3.49 (2H, bd, J = 14.16), 3.54 (2H, bd, J = 16.60), 3.83
(8H, t, J = 6.47), 4.16 (8H, t, J = 7.08), 5.01 (2H, bs), 6.56 (4H, s), 6.97 (2H, s), 7.20 (2H,
bs); '^C NMR (75 MHz, CDCI3) 5: 14.1, 22.7, 26.1, 27.9, 29.3, 29.4, 1.8, 40.5, 43.1,
61.4, 66.1, 68.5, 81.0, 110.7, 120.9, 129.6, 138.7, 149.7, 154.7, 172.7, 172.8; HRMS
(MALDI in DTK) calcd for C8oH,22N40i4Na (M+ + Na) 1385.8850, found 1385.8725 (-9
ppm).
289
Cyclo-[^ra«s-({2,6-^>/s-[2-amiiio-4,7-6/5-octyloxy-indane-2-carboxylic acid]-amino}-
l,2,3»5,6,7-hexahydro-5-indacene-2,6-dicarboxylic acid)] (156c). Trans-{{2,6-bis-{2-
ter/-Butoxycarbonylamino-4,7-&w-octyloxy indane-2-carbonyl}-amino)-l,2,3,5,6,7-
hexahydro-5'-indacene-2,6-dicarboxylic acid diethyl ester] (228c) (111 mg, 0.08 mmol)
was heated in a sealed, evacuated tube for 1 h in an oil bath heated to 265 - 270 °C. The
sample melted, evolved gas, and re-solidified. The solid was dissolved in a 50%
TFA/CH2CI2 solution, treated with charcoal, then filtered and concentrated under vacuum
to a tan solid. The material was purified by tituration with hot acetonitrile. The solution
was cooled to room temperature, and filtered to obtain 55 mg (0.05 mmol, 63%) of 156c
as a white solid.
Spectral Data for 156c: mp: > 300 °C decomposition; IR (KBr) cm 3180, 3067, 1677;
'H NMR (300 MHz, 10% t/-TFA in CDCI3) 5: 0.86 (12H, t, J=6.56), 1.33 (40H, m), 1.74
(8H, pentet, J = 6.92), 3.20 (4H, bd, J = 15.72), 3.24 (4H, bd, J = 16.48), 3.74 (4H, bd, J =
16.63), 3.82 (4H, bd, J = 16.18), 3.96 (8H, t, J = 6.56), 6.73 (4H, s), 7.13 (2H, s), 8.26
(2H, bs); '^C NMR (75 MHz, 10% J-TFA in CDCI3) 5: 14.0, 22.6, 25.9, 29.1, 29.2, 29.3,
31.8,44.2,46.1,66.1,66.6,69.9, 113.2, 121.3, 127.8, 137.7, 149.4, 171.6, 172.1; HRMS
(MALDI in CCA) calcd for C66H94N408Na (M'^ + Na) 1093.6964, found 1093.6939 (-2.2
ppm).
C/5-[(2,6-6/s-{2-^^r/-Butoxycarbonylamino-4,7-6w-dodecyloxy-indane-2-carbonyl}-
amino)-l,2,3?5,6,7-hexahydro-s-indacene-2,6-dicarboxylic acid diethyl ester] (227d).
290
Dry THF (5 mL) was injected to a flask containing cw-2,6-diamino-l,2,3,5,6,7-
hexahydro-5-indacene-2,6-dicarboxylic acid diethyl ester (186a) (35 mg, 0.11 mmol), 2-
^er?-butoxycarbonylamino-4,7-6z\s'-dodecyloxy-indan-2-carboxylic acid (85d) (143 mg,
0.22 mmol), BOP (140 mg, 0.32 mmol), DABCO (71 mg, 0.63 mmol), and catalytic
amount of DMAP at room temperature under argon. Gradually, a thick white precipitate
formed. Each additional day, a portion of BOP (140 mg, 0.32 mmol) was added. The
reaction was quenched after 4 d by removal of the solvent in vacuo to an off-white solid.
The solid was purified by trituration with hot acetonitrile, and the solution was cooled to
room temperature and filtered (2x) to obtain 131 mg (0.08 mmol, 78%) of 227d as a
white solid.
Spectral Data for 227d: mp: 164-166 °C; IR (KBr) cm 3382, 3314, 1727, 1715, 1665;
'H NMR (300 MHz, CDCI3 at 40 °C) 5: 0.87 (12H, t, J = 6.35), 1.18 (6H, t, J = 7.08),
1.25 (72H, m), 1.31 (18H, s), 1.70 (8H, pentet, J = 6.84), 3.17 (8H, bd, J = 16.36), 3.53
(4H, bd, J = 16.84), 3.58 (4H, bd, J = 16.11), 3.85 (8H, t, J - 6.35), 4.14 (4H, q, J = 7.08),
5.07 (2H, bs), 6.58 (4H, s), 6.95 (2H, s); '^C NMR (75 MHz, CDCI3 at 40 °C) 6: 14.0,
14.1, 22.6, 26.0, 28.0, 29.3, 29.4, 29.5, 29.6, 31.9, 40.0, 43.2, 61.4, 65.6, 66.8, 68.5, 80.0,
110.7, 120.3, 129.6, 138.7, 149.7, 154.8, 173.0; HRMS (MALDI in CCA) calcd for
C96Hi54N40i4Na (M^ + Na) 1610.1354, found 1610.1306 (-2.9 ppm).
Cyclo-[cw-({2,6-6/5-[2-amino-4,7-6/5-dodecyloxy-indane-2-carboxyUc acid]-amino}-
l,2,3,5,6,7-hexahydro-s-indacene-2,6-dicarboxylic acid)] (155d). Cis-[{2fi-bis-{2-
291
fer^Butoxycarbonylamino-4,7-6/5-dodecyloxy-indane-2-carbonyl}-amino)-l,2,3,5,6,7-
hexahydro-5-indacene-2,6-dicarboxylic acid diethyl ester] {221 A) (127 mg, 0.08 mmol)
was heated in a sealed, evacuated tube for 1 h in an oil bath heated to 265 - 270 °C. The
sample melted, evolved gas, and re-solidified. The solid was dissolved in a 50%
TFA/CH2CI2 solution, treated with charcoal, then filtered and concentrated under vacuum
to a tan solid. The material was purified by tituration with hot acetonitrile. The solution
was cooled to room temperature, and filtered to obtain 74 mg (0.06 mmol, 73%) of 155d
as a white solid.
Spectral Data for 155d: mp: 240-242 °C; IR (KBr) cm 3180, 3051, 1677; 'H NMR
(300 MHz,10% J-TFA in CDCI3) 6: 0.85 (12H, t, J = 6.49), 1.24 (72H, m), 1.74 (8H,
pentet, J = 6.92), 3.20 (4H, bd, J = 17.25), 3.26 (4H, bd, J = 16.78), 3.75 (4H, bd, J =
16.48), 3.84 (4H, bd, J = 15.78), 3.98 (8H, t, J = 6.72), 6.77 (4H, s), 7.13 (2H, s); '^C
NMR (75 MHz, 10% J-TFA in CDCI3) 5: 14.0, 22.7, 25.8, 29.1, 29.3, 29.5, 29.6, 29.7,
31.9, 44.2, 46.2, 66.2, 66.7, 70.4, 113.9, 121.3, 128.0, 137.6, 149.4, 171.6, 172.0; HRMS
(MALDI in CCA) calcd for C82Hi26N408Na (M^ + Na) 1317.9468, found 1317.9547
(+5.9 ppm).
Jra«5-[(2,6-6w-{2-#er^-Butoxycarbonylamino-4,7-te-dodecyloxy-indan€2-
carbonyl}-ainino)-l,2,3,5,6,7-hexahydro-5-indacene-2,6-dicarboxylic acid diethyl
ester] (228d). Dry THF (5 mL) was injected to a flask containing /ra«5-2,6-diamino-
1,2,3,5,6,7-hexahydro-^-indacene-2,6-dicarboxylic acid diethyl ester (186b) (55 mg, 0.17
mmol), 2-/ert-butoxycarbonylamino-4,7-^w-dodecyloxy-indan-2-carboxylic acid (85d)
292
(235 mg, 0.35 mmol), BOP (220 mg, 0.50 mmol), DABCO (112 mg, 1.00 mmol), and
catalytic amount of DMAP at room temperature under argon. Gradually, a thick white
precipitate formed. Each additional day, a portion of BOP (220 mg, 0.50 mmol) was
added. The reaction was quenched after 4 d by removal of the solvent in vacuo to an off-
white solid. The solid was purified by trituration with hot acetonitrile, and the solution
was cooled to room temperature and filtered (2 x) to obtain 177 mg (0.11 mmol, 67%) of
228d as a white solid.
Spectral Data for 228d: mp: 176-178 °C; IR (KBr) cm 3382, 3314, 1727, 1709, 1659;
'H NMR (300 MHz, CDCI3 at 40 °C) 6: 0.87 (12H, t, J = 6.35), 1.26 (96H, m), 1.68 (8H,
pentet, J = 5.86), 3.17 (8H, d, J = 15.62), 3.50 (4H, bd, J = 10.25), 3.55 (4H, bd, J =
10.30), 3.84 (8H, t, J = 5.78), 3.50 (4H, bd, J = 10.25), 3.55 (4H, bd, J = 10.30), 3.84 (8H,
t, J = 5.78), 4.17 (4H, q, J = 6.83), 5.02 (2H, bs), 6.56 (4H, s), 6.97 (2H, s); NMR (75
MHz, CDCI3 at 40 °C) 5: 14.0, 22.6, 26.0, 27.9, 29.2, 29.3, 29.4, 29.5, 29.6, 31.9, 40.6,
43.1, 61.3, 66.1, 66.6, 68.6, 80.4, 110.9, 120.7, 129.7, 138.7, 149.8, 154.7, 172.7, 172.9;
HRMS (MALDI in CCA) calcd for C96Hi54N40i4Na (M"^ + Na) 1610.1354, found
1610.1267 (-5.4 ppm).
CycIo-[/ra«5-({2,6-to-[2-amino-4,7-te-dodecyloxy-indane-2-carboxylic acidj-amino}
-l,2,3,5,6,7-hexahydro-s-indacene-2,6-dicarboxylic acid)] (156d). Trans-Y{2,6-bis-{2-
ter?-Butoxycarbonylamino-4,7-Z)/5-dodecyloxy-indane-2-carbonyl}-amino)-l,2,3,5,6,7-
hexahydro-5'-indacene-2,6-dicarboxylic acid diethyl ester] (228d) (155 mg, 0.10 mmol)
was heated in a sealed, evacuated tube for 1 h in an oil bath heated to 265 - 270 °C. The
293
sample melted, evolved gas, and re-solidified. The solid was dissolved in a 50%
TFA/CH2CI2 solution, treated with charcoal, then filtered and concentrated under vacuum
to a tan solid. The material was purified by tituration with hot acetonitrile. The solution
was cooled to room temperature, and filtered to obtain 73 mg (0.06 mmol, 59%) of 156d
as a white solid.
Spectral Data for 156d: mp: > 300 °C decomposition; IR (KBr) cm 3180, 3059, 1677;
'H NMR (300 MHz, 10% J-TFA in CDCI3) 8: 0.86 (12H, t, J = 6.56, 1.25 (72H, s), 1.39
(8H, m), 1.75 (8H, pentet, J = 6.71), 3.22 (4H, bd, J = 15.26), 3.27 (4H, bd, J = 16.02),
3.76 (4H, bd, J = 17.09), 3.82 (4H, bd, J = 18.61), 4.00 (8H, t, J = 6.56), 6.78 (4H, s),
7.13 (2H, s); '^C NMR (75 MHz, 10% d-T¥A in CDCI3) 6: 14.0, 22.7, 25.8, 29.1, 29.4,
29.5, 29.6, 29.7, 32.0, 44.2, 46.1, 66.7, 66.3, 70.6, 114.2, 121.3, 128.2, 137.7, 149.4,
171.8, 172.1; Anal, calcd for C82H,26N408 C 76.00, H 9.80, N 4.32, found C 75.12, H
9.84, N 4.08.
294
Synthesis of Cyclohexyl 6/s-Diketopiperazines
r/*fl«^-[l,4-Z»is-({2-^e/*/-butoxycarbonylamino-4,7-^>/s-hexyloxy-indane-2-carbonyl}-
amino)-cyclohexane-l,4-dicarboxylic acid dimethyl ester] (229b). Dry DMF (5 mL)
was injected to a flask containing ?ra775'-l,4-diamino-cyclohexane-l,4-dicarboxylic acid
dimethyl ester (189) (45 mg, 0.19 mmol), 2-?ert-butoxycarbonylamino-4,7-6/5-hexyloxy-
indan-2-carboxylic acid (85b) (202 mg, 0.42 mmol), BOP (270 mg, 0.61 mmol), and
DABCO (130 mg, 1.16 mmol) at room temperature under argon. Gradually, a thick white
precipitate formed. After 24 h, another portion of BOP (270 mg, 0.61 mmol) was added,
and the reaction stirred an additional 1 d. The reaction was quenched by removal of the
solvent in vacuo to an off-white solid. The solid was purified by trituration with hot
acetonitrile, and the solution was cooled to room temperature and filtered (2 x) to obtain
140 mg (0.12 mmol, 63%) of 229b as a white solid.
Spectral Data for 229b: mp: 254 °C decomposition; IR (KBr) cm 3389, 3332, 1733,
1677; 'H NMR (300 MHz, CDCI3 at 40 °C) 5: 0.87 (12H, t, J - 6.35), 1.30 (16H, m),
1.38 (26H, s), 1.68 (8H, pentet, J = 6.75), 1.91 (4H, bd, J = 9.85), 2.12 (4H, bd, J = 9.76),
3.17 (4H, bd, J = 16.85), 3.45 (4H, bd, J = 17.09), 3.63 (6H, s), 3.83 (8H, t, J = 6.23),
5.46 (2H, bs), 6.55 (4H, s), 7.07 (2H, bs); '^C NMR (75 MHz, CDCI3) 5: 14.0, 22.6, 25.8,
27.2, 28.3, 29.5, 31.6, 40.3, 52.1, 57.5, 66.8, 68.7, 80.2, 110.9, 129.8, 149.8, 155.2, 173.2,
173.9; HRMS (MALDl in CCA) calcd for C64HiooN40,4Na (M^ + Na) 1171.7129, found
1171.7129 (+0.0 ppm).
295
Cy do- [/ra«s-({l ,4-6/5- [amino-4,7-te-hexyloxy-indane-2-carbonyl] -amino}-
cyclohexane-l,4-dicarboxylic acid dimethyl ester)] (159b). Trans-[\,A-bis-{{2-tert-
butoxycarbonylamino-4,7-6/5-hexyloxy-indane-2-carbonyl}-amino)-cyclohexane-l,4-
dicarboxylic acid dimethyl ester] (229b) (114 mg, 0.10 mmol) was heated in a sealed,
evacuated tube for 1 h in an oil bath heated to 265 - 270 °C. The sample melted, evolved
gas, and re-solidified. The solid was dissolved in a 50% TFA/CH2CI2 solution, treated
with charcoal, then filtered and concentrated under vacuum to an off-white solid. The
material was purified by tituration with hot acetonitrile. The solution was cooled to room
temperature, and filtered to obtain 53 mg (0.06 mmol, 60%) of 159b as a white solid.
Spectral Data for 159b; mp: >300 °C decomposition; IR (KBr) cm 3180, 3051, 1660;
'H NMR (300 MHz, 10% J-TFA in CDCI3) 5: 0.87 (12H, t, J = 5.80) 1.31 (24H, m), 1.73
(8H, pentet, J = 6.72), 2.15 (4H, bd, J = 9.92), 2.44 (4H, bd, J = 10.37), 3.23 (4H, bd, J =
16.94), 3.75 (4H, bd, J = 16.79), 4.00 (8H, t, J = 6.34), 6.79 (4H, s); NMR (75 MHz,
10% d-TYA in CDCI3) 6; 13.8, 22.5, 25.5, 29.0, 30.2, 31.5, 44.5, 57.0, 65.8, 70.9, 114.5,
128.4, 149.3, 171.4, 172.7; HRMS (MALDl in DTH) calcd for C52H76N408Na (M^ + Na)
907.5556, found 907.5599 (+4.7 ppm).
7>a«5-[l,4-6/s-({2-ter/-butoxycarbonylamino-4,7-6/s-octyioxy-indane-2-carbonyl}-
amino)-cyclohexane-l,4-dicarboxylic acid dimethyl ester] (229c). Dry DMF (5 mL)
was injected to a flask containing ^ram-l,4-diamino-cyclohexane-l,4-dicarboxylic acid
dimethyl ester (189) (44 mg, 0.19 mmol), 2-^er^butoxycarbonylamino-4,7-Z)/5•-octyloxy-
296
indan-2-carboxylic acid (85c) (220 mg, 0.41 mmol), BOP (270 mg, 0.61 mmol), and
DABCO (128 mg, 1.14 mmol) at room temperature under argon. Gradually, a thick white
precipitate formed. After 24 h, another portion of BOP (270 mg, 0.61 mmol) was added,
and the reaction stirred an additional 1 d. The reaction was quenched by removal of the
solvent in vacuo to an off-white solid. The solid was purified by trituration with hot
acetonitrile, and the solution was cooled to room temperature and filtered (2x) to obtain
166 mg (0.13 mmol, 69%) of 229c as a white solid.
Spectral Data for 229c: mp: 237-238 °C; IR (KBr) cm 3381, 3324, 1725, 1709, 1669;
'H NMR (300 MHz, CDCI3) 6: 0.86 (12H, t, J = 6.35), 1.25 (36H, m), 1.35 (22H, m),
1.66 (8H, pentet, J = 6.59), 1.96 (4H, bd, J = 8.05), 2.17 (4H, bd, J = 8.05), 3.12 (4H, bd,
J = 16.84), 3.41 (4H, bd, J = 16.60), 3.64 (6H, s), 3.78 (8H, t, J = 7.09), 6.50 (4H, s), 7.22
(2H, bs); NMR (75 MHz, CDCI3) §: 14.1, 22.6, 26.1, 27.0, 28.2, 29.3, 29.4, 29.5,
31.8, 40.0, 52.1, 57.3, 66.7, 68.4, 79.8, 110.4, 129.7, 149.7, 155.0, 173.1, 174.3; HRMS
(MALDI in DTH) calcd for C72Hn6N40,4Na (MV Na) 1283.8381, found 1283.8313 (-
5.2 ppm).
Cyclo-[/rfl«s-({l,4-Z>/s-[ainmo-4,7-6/s-octyloxy-in(lane-2-carbonyl]-amino}-
cyclohexane-l,4-dicarboxyiic acid dimethyl ester)] (159c). Trans-[\,A-bis-{{2-tert-
butoxycarbonylamino-4,7-iz5'-octyloxy-indane-2-carbonyl}-amino)-cyclohexane-l,4-
dicarboxylic acid dimethyl ester] (229c) (131 mg, 0.10 mmol) was heated in a sealed,
evacuated tube for 1 h in an oil bath heated to 265 - 270 °C. The sample melted, evolved
gas, and re-solidified. The solid was dissolved in a 50% TFA/CH2CI2 solution, treated
297
with charcoal, then filtered and concentrated under vacuum to an off-white solid. The
material was purified by tituration with hot acetonitrile. The solution was cooled to room
temperature, and filtered to obtain 104 mg (0.10 mmol, 62%) of 159c as a white solid.
Spectral Data for 159c; mp: > 300 °C decomposition; IR (KBr) cm 3188, 3051, 1660;
'H NMR (300 MHz, 15% d-TFA in CDCI3) 5: 0.85 (12H, t, J = 7.02), 1.31 (40H, m),
1.72 (8H, pentet, J = 6.56), 2.11 (4H, bd, J = 10.23), 2.44 (4H, bd, J = 10.37), 3.20 (4H,
bd, J = 16.48), 3.73 (4H, bd, J = 16.64), 3.96 (8H, t, J = 6.33), 6.74 (4H, s); NMR (75
MHz, 15% i/-TFA in CDCI3) 5: 14.0, 22.6, 25.8, 29.1, 29.2, 29.3, 29.7, 30.0, 31.8, 44.5,
49.9, 56.9, 65.7, 70.1, 113.5, 127.9, 149.3, 171.2, 172.6; HRMS (MALDI in DTH) calcd
for C6oH92N408Na (M^ + Na) 1019.6808, found 1019.6847 (+3.8 ppm)
7>flns-[l,4-6/s-({2-ter/-butoxycarbonylamino-4,7-Aw-dodecyloxy-indan^- carbonyl}-
amino)-cyclohexane-l,4-dicarboxylic acid dimethyl ester] (229d). Dry DMF (5 mL)
was injected to a flask containing /rara-l,4-diamino-cyclohexane-l,4-dicarboxylic acid
dimethyl ester (189) (42 mg, 0.18 mmol), 2-/er^butoxycarbonylamino-4,7-Z)w-
dodecyloxy-indan-2-carboxylic acid (85d) (256 mg, 0.40 mmol), BOP (255 mg, 0.58
mmol), and DABCO (124 mg, 1.10 mmol) at room temperature under argon. Gradually, a
thick white precipitate formed. After 24 h, another portion of BOP (255 mg, 0.58 mmol)
was added, and the reaction stirred an additional 1 d. The reaction was quenched by
removal of the solvent in vacuo to an off-white solid. The solid was purified by trituration
with hot acetonitrile, and the solution was cooled to room temperature and filtered (2 x)
to obtain 173 mg (0.12 mmol, 63%) of 229d as an off-white solid.
298
Spectral Data for 229d: mp: 216-218 °C; IR (KBr) cm 3381, 3316, 1725, 1709, 1660;
'H NMR (300 MHz, CDCI3 at 40 °C) 6: 0.86 (12H, t, J = 6.35), 1.25 (72H, m), 1.37
(18H, s), 1.67 (8H, pentet, J = 6.78), 3.14 (4H, bd, J = 17.09), 3.43 (4H, bd, J = 16.84),
3.64 (6H, s), 3.79 (8H, t, J = 6.69), 5.67 (2H, bs), 6.51 (4H, s), 7.15 (2H, bs); '^C NMR
(75 MHz, CDCI3) 6: 14.1, 22.7, 26.1, 27.1, 28.2, 29.3, 29.4, 29.6, 31.9, 40.2, 52.2, 57.4,
66.8, 68.5, 80.0, 110.5, 129.7, 149.7, 155.0, 173.1, 174.2; Anal, calcd for C88H,48N40,4
C 71.12, H 10.04, N 3.77, found C 70.78, H 10.16, N 3.62.
Cyclo-[/ra«s-({l,4-6w-[amino-4,7-6/s-dodecyloxy-indane-2-carbonyl]-amino}-
cyclohexane-l,4-dicarboxylic acid dimethyl ester)] (159d). Trans-[\,4-bis-{{2-tert-
butoxycarbonylamino-4,7-dw-dodecyloxy-indane-2-carbonyl} -amino)-cyclohexane-1,4-
dicarboxylic acid dimethyl ester] (229d) (155 mg, 0.10 mmol) was heated in a sealed,
evacuated tube for 1 h in an oil bath heated to 265 - 270 °C. The sample melted, evolved
gas, and re-solidified. The solid was dissolved in a 50% TFA/CH2CI2 solution, treated
with charcoal, then filtered and concentrated under vacuum to a tan solid. The material
was purified by tituration with hot acetonitrile. The solution was cooled to room
temperature, and filtered to obtain 56 mg (0.0.05 mmol, 56%) of 159d as an off-white
solid.
Spectral Data for 159d; mp: >300 °C decomposition; IR (KBr) cm 1669; 'H NMR
(300 MHz, 5% C/-TFA in CDCI3) 6: 0.86 (12H, t, J = 6.41), 1.24 (72H, m), 1.73 (8H,
pentet, J = 6.94), 2.13 (4H, bd, J = 9.92), 2.45 (2H, bd, J = 10.07), 3.22 (4H, bd, J =
16.48), 3.74 (4H, bd, J = 16.48), 3.98 (8H, t, J = 6.64), 6.77 (4H, s); '^C NMR (75 MHz,
299
5% d-TFA in CDCI3) 5: 14.0, 22.7, 25.8, 29.1, 29.4, 29.6, 29.7, 30.1, 32.0, 44.5, 57.0,
65.8, 70.6, 114.2, 128.2, 149.3, 171.3, 172.7; Anal, calcd for C76H124N4O8 C 74.71, H
10.23, N 4.59, found C 73.02, H 10.33, N 4.35.
7>flns-[l,4-W5-({2-ter/-butoxycarbonylainino-4,7-Z>w-octadecyloxy-indane-2-
carbonyl}-amino)-cyclohexane-l,4-dicarboxylic acid dimethyl ester] (229e). Dry
DMF (5 mL) was injected to a flask containing /ran5-l,4-diamino-cyclohexane-l,4-
dicarboxylic acid dimethyl ester (189) (48 mg, 0.21 mmol), 2-^er^butoxycarbonylamino-
4,7-^/5-octadecyloxy-indan-2-carboxylic acid (85e) (360 mg, 0.44 mmol), BOP (279 mg,
0.63 mmol), and DABCO (141 mg, 1.26 mmol) at room temperature under argon.
Gradually, a thick white precipitate formed. After 24 h, another portion of BOP (279 mg,
0.63 mmol) was added, and the reaction stirred an additional 1 d. The reaction was
quenched by removal of the solvent in vacuo to an off-white solid. The reaction contents
were dry loaded to silica, and purified by flash chromatography (230-400 mesh silica) in
a 100% AcOEt elutant. Gradually, the solvent polarity was ramped to 5% MeOH/CH2Cl2,
and the product was observed in the collected fractions as an insoluble white solid. The
solid was collected and triturated with hot acetonitrile. The solution was cooled to room
temperature and filtered to obtain 185 mg (0.10 mmol, 48%) of 229e as an off-white
solid.
Spectral Data for 229e: mp: 180-186 °C; IR (KBr) cm 3381, 3308, 1725, 1709, 1660;
'H NMR (300 MHz, CDCI3 at 40 °C) 6: 0.86 (12H, t, J = 6.35), 1.24 (120H, m), 1.38
(18H, s), 1.68 (8H, pentet, J = 6.93), 1.91 (4H, bd, J = 9.04), 2.13 (4H, bd, J = 9.28), 3.17
300
(4H, bd, J = 16.60), 3.45 (4H, bd, J = 16.85), 3.63 (6H, s), 3.82 (8H, t, J = 6.46), 5.44
(2H, bs), 6.55 (4H, s), 7.07 (2H, bs); NMR (75 MHz, CDCI3) 5: 14.1, 22.7, 26.1,
28.2, 29.4, 29.5, 29.7, 31.9, 40.1, 52.2, 57.4, 66.8, 68.5, 80.0, 110.5, 129.7, 149.7, 155.0,
173.1,174.2; Anal, calcd for C112H196N4O14 C 73.80, H 10.84, N 3.07, found C 73.66,
H 10.86, N 3.24.
Cy do- ,4-6/5- [amino-4,7-to-octadecyloxy-indane-2-carbonyl] -amino}-
cyclohexane-l,4-dicarboxyIic acid dimethyl ester)] (159), Trans-{\,A-bis-{{2-tert-
butoxycarbonylamino-4,7-6z.s'-octadecyloxy-indane-2-carbonyl}-amino)-cyclohexane-
1,4-dicarboxylic acid dimethyl ester] (229e) (125 mg, 0.07 mmol) was heated in a sealed,
evacuated tube for 1 h in an oil bath heated to 265 - 270 °C. The sample melted, evolved
gas, and re-solidified. The solid was dissolved in a 50% TFA/CH2CI2 solution, treated
with charcoal, then filtered and concentrated under vacuum to a tan solid. The material
was purified by tituration with hot acetonitrile. The solution was cooled to room
temperature, and filtered to obtain 82 mg (0.05 mmol, 78%) of 159 as an off-white solid.
Spectral Data for 159: mp: > 300 °C decomposition; IR (KBr) cm 3180, 3043, 1669;
'H NMR (300 MHz, 5% J-TFA in CDCI3) 5: 0.88 (12H, t, J = 6.18), 1.26 (120H, s), 1.76
(8H, pentet, J = 6.56), 2.18 (4H, bd, J = 10.22), 2,47 (4H, bd, J = 9.92), 3.26 (4H, bd, J =
16.48), 3.78 (4H, bd, J = 16.63), 4.02 (8H, t, J = 6.64), 6.82 (4H, s); '^C NMR (75 MHz,
5% d-TFA in CDCI3) §: 13.9, 22.7, 25.8, 29.1, 29.4, 29.5, 29.6, 29.7, 29.8, 30.2, 32.0,
44.5,57.0,65.9,71.1, 114.7, 128.5, 149.4, 171.4, 172.7; Anal, calcd for C,ooH|72N408 C
77.07, H 11.12,N3.60, found C 76.80, H 11.20, N 3.41.
Appendix A
Crystallographic Data
Structural Report of 96d
0C,2H25 o 0C,2H25
0C,2H25 0C,2H25
303
NOTES
This written report is accompanied by an electronic Crystallographic Information File (GIF) which should be supplied to any journal publishing these results. It contains calculated distances and angles beyond those in the attached tables and all needed crystallographic information for generating other needed results. With modifications it is suitable for electronic submission to Acta Crystallographlca Section C as a structure report. Observed and calculated structure factors are in the file fofc. Publications arising from this report must either 1) include the preparer(s) as coauthors when significant contributions were made and/or 2) acknowledge the Molecular Structure Laboratory and NSF grant CHE9610374 which provided the diffractometer. A copy of any paper reporting these results should be provided to MSL after publication.
The following acknowledgement needs to appear on publications, etc per DND and Argonne requests: We thank DND-CAT staff for their help. Portions of this work were performed at the DuPont-Northwestern-Dow Collaborative Access Team (DND-CAT) Synchrotron Research Center located at Sector 5 of the Advanced Photon Source. DND-CAT is supported by the E.I. Du Pont de Nemours & Co., The Dow Chemical Company, the U.S. National Science Foundation through Grant DMR-9304725, and the State of Illinois through the Department of Commerce and the Board of Higher Education Grant IBHE HECA NWU 96. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under Contract No. W-31-109-Eng-38.
EXPERIMENTAL
A Colorless Prism of C68 H114 N2 06 having approximate dimensions of 0.02 x 0.03 x 0.07 mm was mounted on a glass fiber in a random orientation. Examination of the crystal was performed at the Advanced Photon Source at Argonne National Lab at the DND-CAT 5-ID-B beamline. A temperature of 100(2)K was maintained using an Oxford Cryonics Cryostream. Initial images showed measurable diffraction to at least theta = 29.0978deg. Data were collected on a 165mm Mar detector set at a distance of 50mm using monochromated radiation with a wavelength of (A =0.71 OA).
A total of 1200 frames at 1 detector setting covering -70 < 2theta < 70 deg were collected, having a phi scan width of 0,3 and an exposure time of 0.5 seconds. The frames were integrated using the Rigaku Corporations CrystalClear software package. A total of 111186 reflections were integrated and retained of which 25086 were unique (<redundancy> = 4.0, Rint = 4.5%, Rsig = 2.3% ). Of the unique reflections, 20440 (81.5%) were observed l>2sigma(l). The final Monoclinic cell parameters of a = 21.981 (4), b = 18.298(4), c = 24.801(5), alpha = 90, beta = 108.72(3), gamma = 90, volume = 9447(3) A^3 are based on the refinement of the XYZ-centroids of 53897 reflections with I > 3 sigma(l) covering the range of 1.7328 < theta < 29.0978. Empirical absorption and decay
304
corrections were applied using the program dTScale via the method of Semi-empirical from equivalents. The absorption coefficient is 0.069 mm-1, Tmin = 0.5915, and Tmax = 1.0000. ForZ = 6 and F.W. = 1055.61 the calculated density is 1.113g/cm3. Systematic absences and intensity statistics indicate the space group to be P2(1)/c (#14) which was consistent with refinement.
The structure was solved using SHELXS in the Bruker SHELXTL (Version 5.0) software package[1]. Refinements were performed using SHELXL and illustrations were made using XP. Solution was achieved utilizing direct methods followed by Fourier synthesis. Hydrogen atoms were added at idealized positions, constrained to ride on the atom to which they are bonded and given thermal parameters equal to 1.2 or 1.5 times Uiso of that bonded atom. The final anisotropic full-matrix least squares refinement based on F'^2 of all reflections converged (maximum shift/esd = 0.707) at R1 = 0.1160, wR2 = 0.2971 and goodness-of-fit = 1.098. "Conventional" refinement indices using the 20440 reflections with F > 4 sigma(F) are R1 0.0992, wR2 = 0.2806. The model consisted of 1417 variable parameters, X constraints and 2060 restraints. There were 24 correlation coefficients greater than 0.73 involving thermal and/or positional parameters of overlapping atoms in the disordered regions. A simularity constraint was applied to the thermal parameters of neighboring atoms. Chemically equivalent fragments were constrained to have similar geometries The highest peak on the final difference map was 1.141 e/A'^3 located 1.11 A from 050_3. The lowest peak on the final difference map was -1.036 e/A^3 located 0.24 A from C61_2. Scattering Factors and anomalous dispersion were taken from International Tables Vol C Tables 4.2.6.8 and 6.1.1.4.
STRUCTURE The molecule has the structure proposed by the submittor. There are 1.5 independent molecules in the asymmetric unit and a total of 6 in the unit cell. Each of the two independent molecules contains two disordered conformers. One sits on a center of inversion and has a planar central ring while the other displays a marked deviation from planarity. The disorder essentially bends one piperazinedione ring so that the attached alkyi chains shift register by one atom position.
FIGURES
EQUATIONS
Rin. = E|FoMFo2)|/nFo^]
Rsig = E[a(Fo^)]/I[Fo2]
R, = I||Fol-|Fc||/E|Fo|
WR2 = {E[w(FO2-FC^)^]/E[W(FO^)^]}^'^
305
w=1/[a2{Fo2)+(0.1719P)^+4.648P] where P={?o^+2?c^)l3
GOF = S = {X[w(Fo2-Fc2)V(n-p)}'''
REFERENCES
Bruker (1997) SAINT Reference Manual Version 5.0, Bruker AXS Inc. , Madison, Wisconsin, USA.
Bruker (1997) SHELXTL Reference Manual Version 5.0, Bruker AXS Inc. , Madison, Wisconsin, USA.
Bruker (1997) SMART Reference Manual Version 5.0, Bruker AXS Inc. , Madison, Wisconsin, USA.
306
Table 1. Crystal data and structure refinement for rksyn. Identification code rksyn Empirical formula C68H114N2 06 Formula weight 1055.61 Temperature 100(2) K
Wavelength 0.7100 A Crystal system Monoclinic Space group P2(1)/c Unit cell dimensions a = 21.981 (4) A a=90°.
b = 18.298(4) A b=108. c = 24.801(5) A g = 90°.
Volume 9447(3) A3 z 6 Density (calculated) 1.113 Mg/m^ Absorption coefficient 0.069 mm"^ F(OOO) 3504 Crystal size 0.07 X 0.03 X 0.02 mm3 Theta range for utilized data 1.73 to 29.06°. Limiting indices -30<=h<=28, 0<=k<=24, 0<=l<=33
Reflections utilized 25086 Independent reflections 25086 [R(int) = 0.0000] Completeness to theta = 29.06° 99.4 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 1.0000 and 0.5915
Refinement method Full-matrix least-squares on F^ Data / restraints / parameters 25086/2060/1417 Goodness-of-fit on 1.098 Final R indices [l>2sigma(l)] R1 = 0.0992, wR2 = 0.2806
R Indices (all data) R1 =0.1160, wR2 = 0.2971
Largest diff. peak and hole 1.141 and -1.036 e.A-3
RMS difference density 0.063e.A-3
Table 2. Atomic coordinates (x 10") and equivalent isotropic displacement parameters (A^x 10®) for rksyn. U(eq) Is defined as one third of the trace of the orthogonalized U'' tensor.
X y z U(eq)
0012 335(1) 7853(1) 9480(1) 30(1) C012 223(1) 7316(1) 9733(1) 24(1) N022 172(1) 7361(1) 10253(1) 25(1) C032 -2(1) 6784(1) 10581(1) 24(1) C042 -684(1) 6940(1) 10617(1) 28(1) C052 -542(1) 7447(1) 11118(1) 25(1) C062 -962(1) 7920(1) 11260(1) 27(1) C072 -722(1) 8371(1) 11727(1) 28(1)
C082 -76(1) 8339(1) 12058(1) 28(1)
C092 337(1) 7849(1) 11925(1) 25(1) CI 02 96(1) 7405(1) 11447(1) 24(1) C112 443(1) 6850(1) 11206(1) 25(1) 0302 974(1) 7758(1) 12234(1) 30(1) 0502 -1592(1) 7893(1) 10915(1) 35(1) C312 1215(1) 8179(1) 12742(1) 33(1) C322 1918(1) 7990(1) 13021(1) 36(1)
C332 2191(1) 8412(2) 13563(1) 54(1) C342 2884(1) 8203(2) 13899(1) 52(1) C352 3378(1) 8326(2) 13604(2) 60(1) C362 4063(1) 8207(2) 13992(2) 58(1) C372 4577(1) 8276(2) 13713(2) 72(1) C382 5254(1) 8192(2) 14122(2) 63(1) 0392 5780(2) 8239(2) 13863(2) 73(1) 0402 6452(1) 8195(2) 14285(2) 63(1) 0412 6985(2) 8234(2) 14033(2) 73(1) 0422 7653(2) 8248(2) 14465(2) 75(1) 0512 -2053(1) 8266(1) 11109(1) 36(1) 0522 -2708(1) 8000(2) 10754(1) 43(1)
0532 -3239(1) 8272(2) 10973(1) 45(1) 0542 -3897(1) 7978(2) 10627(2) 51(1) 0552 -4436(1) 8221(2) 10850(2) 51(1) 0562 -5088(1) 7925(2) 10497(2) 59(1) 0572 -5639(1) 8158(2) 10710(2) 57(1) 0582 -6276(1) 7855(2) 10343(2) 68(1) 0592 -6847(2) 8070(3) 10534(2) 78(1) 0602 -7472(2) 7738(4) 10153(3) 124(2) 0612 -8079(3) 7805(5) 10507(5) 231(6) 0622 -8195(3) 8407(3) 10284(3) 138(3) 0011 -196(1) 11195(1) -656(1) 29(1) 0011 -105(1) 10648(1) -350(1) 23(1) N021 -172(1) 10660(1) 168(1) 26(1) 0031 -85(1) 10056(1) 569(1) 23(1) 0041 416(1) 10284(1) 1143(1) 26(1) 0051 17(1) 10701(1) 1425(1) 25(1) 0061 212(1) 11231(1) 1848(1) 29(1) 0071 -249(1) 11564(1) 2037(1) 34(1) 0081 -887(1) 11355(1) 1818(1) 37(1) 0091 -1084(1) 10826(1) 1397(1) 32(1)
C101 -620(1) 10508(1) 1198(1) 26(1) cm -710(1) 99600) 7270) 26(1) 0301 852(1) 11383(1) 2038(1) 38(1) 0501 -1701(1) 10577(1) 1152(1) 430) 03111 982(4) 12084(6) 2328(5) 36(2)
C3211 1612(2) 12330(3] 2246(2) 40(1) 03311 2209(3) 11893(3) 2546(3) 43(1) C3411 2795(3) 12076(4) 2411(3) 57(2) 03511 3417(2) 11793(3) 2752(3) 51(1) C3611 3981(3) 11990(4) 2557(3) 56(2) C3711 4623(2) 11746(4) 2910(3) 53(1) C3811 5175(4) 11955(5) 2694(4) 57(2) 03911 5818(3) 11694(4) 3059(3) 54(1) 04011 6376(4) 11893(7) 2853(4) 69(3) 04111 7016(3) 11598(4) 3206(3) 58(2) 04211 7569(4) 11789(9) 2997(5) 63(3) 03121 1144(4) 11946(6) 2430(5) 40(2) 03221 1894(4) 11912(4) 2565(4) 77(3) 03321 2085(4) 12048(5) 2059(6) 103(3) 03421 2697(4) 11757(5) 2012(6) 94(3) C3521 3310(3) 12032(4) 2376(3) 61(2) C3621 3913(4) 11749(6) 2335(5) 73(2) C3721 4531(3) 12047(5) 2589(5) 87(3) C3821 5122(4) 11746(6) 2528(6) 68(3) C3921 5733(4) 12051(5) 2741(6) 101(3) C4021 6314(5) 11747(7) 2662(6) 68(3) C4121 6943(4) 12029(6) 2867(6) 125(4) 04221 7528(6) 11692(9) 2811(6) 83(5) 0511 -2192(1) 10948(2) 1302(1) 47(1) 0521 •2827(1) 10619(2) 961(2) 53(1) C531 -3v374(1) 10945(2) 1135(2) 51(1) C541 -4030(1) 10622(2) 799(2) 54(1) C551 •4574(1) 10933(2) 987(2) 59(1) C561 •5226(1) 10606(2) 665(2) 580) 0571 -5773(1) 10919(2) 851(2) 61(1) C581 -6422(1) 10576(2) 541(2) 58(1) 0591 -6969(1) 10872(2) 731 (2) 55(1) C60t -7804(1) 10473(2) 4430) 54(1) 0611 -8151(1) 10695(2) 666(1) 49(1) 0621 -8439(2) 11431(2) 465(2) 66(1) 0013 -31(1) 5489(1) 10605(1) 41(1) cot 3 15(1) 6034(1) 10329(1) 280) N023 52(1) 5987(1) 9804(1) 29(1)
C033 133(1) 6577(1) 9443(1) 29(1) C043 613(3) 6384(3) 9149(2) 32(1) C053 221(1) 5912(1) 8661(1) 310) C063 416(1) 5354(2) 8372(1) 38(1) C073 -34(2) 4995(1) 7926(1) 42(2) C083 -678(2) 5194(2) 7768(1) 45(1) C093 -872(1) 5752(2) 8056(1) 43(1) 0103 -422(2) 6111(1) 8502(1) 35(1) C113 -524(3) 6659(3) 8903(3) 33(1) 0503 -1500(2) 5976(2) 7939(2) 560)
309
0303 1058(2) 5139(2) 8593(2) 44(1)
C313 1191(2) 4408(2) 8439(2) 48(1)
C323 1836(2) 4166(3) 8843(2) 52(1) C333 2412(3) 4569(3) 8790(3) 56(1) C343 3058(4) 4196(4) 9058(4) 60(2) C3S3 3612(3) 4620(4) 9006(4) 69(2) C363 4267(3) 4256(4) 9235(3) 60(2)
G373 4811(4) 4656(5) 9162(5) 76(2) C383 5469(3) 4299(4) 9372(3) 66(2)
C393 6009(5) 4698(8) 9305(7) 94(3)
C403 6670(3j 4356(4) 9511(4) 79(2)
C413 7201(5) 4659(6) 9315(7) 126(5)
C423 7768(6) 4518(9) 9203(10) 233(10)
C513 -2017(2) 5552(3) 7605(2) 43(1) C523 -3194(5) 5563(7) 7288(5) 80(3)
C533 -2670(3) 5893(5) 7650(3) 88(2)
C543 -3843(3) 5357(5) 7541P) 79(2) C553 -4490(4) 5607(7) 7212(8) 70(3)
C563 -5024(2) 5337(4) 7424(2) 66(2)
C573 -5687(4) 5601 (5) 7047(6) 73(3)
C583 -6205(2) 5301(4) 7317(2) 63(1)
C593 -6860(4) 5533(6) 7034(3) 59(2) C603 -7382(2) 5233(5) 7236(3) 78(2)
C613 -8040(3) 5406(5) 7045(5) 109(4) C623 -8496(12) 5243(18) 7318(12) 560(30) C043 811(4) 6338(5) 9348(3) 31(2)
C053 554(2) 5825(2) 8850(2) 29(1)
C063 868(2) 5274(2) 8658(2) 40(2)
C073 533(2) 4851(2) 8191(2) 41(1)
C083 -117(2) 4978(2) 7918(2) 44(3) C093 -431(2) 5529(2) 8111(2) 40(1) C103 -96(2) 5952(2} 8577(2) 27(1)
C113 -333(5) 6619(4) 8876(4) 32(2) 0503 -1084(3) 5679(3) 7869(2) 64(2)
0303 1508(2) 5146(2) 8989(2) 44(1) C313 1880(3) 4640(3) 8788(3) 46(2) C323 2573(4) 4689(5) 9186(4) 57(2) C333 3040(5) 4413(6) 8891(6) 65(3) C343 3749(5) 4494(8) 9251(6} 94(5)
C353 4219(5) 4319(8) 8933(6) 79(3) C363 4916(6) 4466(10) 9321(8} 104(6) C373 5396(5) 4349(9) 9000(7} 97(4) C383 6083(7) 4540(15) 9368(11} 125(8)
C393 6599(5) 4414(10) 9105(8) 113(5) C403 7236(6) 4813(7) 9546(6) 68(3) C413 7873(5) 4480{7) 9696(7) 99(5) C423 8382(6) 4876(9) 9481(11} 195(11) C513 -1513(4) 5212(5) 7453(4) 65(2) C523 -2188(4) 5524(5) 7242(5) 68(2)
C533 -2626(3) 5321(5) 7597(4) 67(2) C543 -3299(3) 5495(6) 7363(4) 34(2) C553 -3817(3) 5869(6) 7392(4) 62(2) C563 •4460(5) 5455(10) 7154(7) 66(5)
310
C573 -5008(3) 5906(6) 7206(4) 68(2)
C583 -5647(6) 5489(9) 7119(9) 83(5)
C593 -6192(3) 6009(6) 7035(4) 67(2)
C603 -6861(5) 5674(7) 6835(5) 59(3)
C613 -7377(3) 6167(5) 6895(3) 59(2)
C623 -8039(4) 5817(6) 6812(4) 62(3)
Table 3. Bond lengths [A] and angles [°] for rksyn.
0012-C012 1.232(2) C061-0301 1.361(3)
C012-N022 1.334(2) C061-C071 1.386(3)
C012-C033 1.513(3) C071-C081 1.386(3)
N022-C032 1.456(2) C081-C091 1.388(3)
C032-C013 1.512(3) C091-0501 1.373(3)
C032-C112 1.549(3) C091-C101 1.394(3)
C032-C042 1.557(3) C101-C111 1.504(3)
C042-C052 1.500(3) 0301-C3121 1.422(12)
C052-C102 1.381(3) 0301-C3111 1.454(12)
C052-C062 1.391(3) 0501-C511 1.423(3)
C062-0502 1.375(2) C3111-C3211 1.530(10)
C062-C072 1.382(3) C3211-C3311 1.513(7)
C072-C082 1.395(3) C3311-C3411 1.469(7)
C082-C092 1.389(3) C3411-C3511 1.453(8)
C092-0302 1.373(2) C3511-C3611 1.511(8)
C092-C102 1.393(3) C3611-C3711 1.471(9)
C102-C112 1.505(2) C3711-C3811 1.525(10)
0302-C312 1.427(2) C3811-C3911 1.493(10)
0502-C512 1.427(2) C3911-C4011 1.518(10)
C312-C322 1.517(3) C4011-C4111 1.498(10)
C322-C332 1.497(3) C4111-C4211 1.488(10)
C332-C342 1.533(4) C3121-C3221 1.574(10)
C342-C352 1.508(5) C3221-C3321 1.466(11)
C352-C362 1.521(4) C3321-C3421 1.486(10)
C362-C372 1.506(5) C3421-C3521 1.450(10)
C372-C382 1.515(4) C3521-C3621 1.456(9)
C382-C392 1.493(5) C3621-C3721 1.411(10)
C392-C402 1.514(4) C3721-C3821 1.462(10)
C402-C412 1.495(5) C3821-C3921 1.392(10)
C412-C422 1.515(5) C3921-C4021 1.463(11)
C512-C522 1.507(3) C4021-C4121 1.408(11)
C522-C532 1.520(3) C4121-C4221 1.473(13)
C532-C542 1.525(4) C511-C521 1.507(4)
C542-C552 1.525(4) C521-C531 1.524(4)
C552-C562 1.520(4) C531-C541 1.533(4)
C562-C572 1.530(4) C541-C551 1.525(4)
C572-C582 1.510(5) C551-C561 1.522(4)
C582-C592 1.529(4) C561-C571 1.528(4)
C592-C602 1.522(6) C571-C581 1.524(4)
C602-C612 1.821(12) C581-C591 1.524(4)
C612-C622 1.222(8) C591-C601 1.534(4)
0011-C011 1.232(2) C601-C611 1.530(4)
C011-N021 1.337(2) C611-C621 1.503(4)
C011-C031#1 1.510(2) 0013-C013 1.231(2)
N021-C031 1.458(2) C013-N023 1.335(2)
C031-C011#1 1.510(2) N023-C033 1.450(2)
C031-C041 1.550(3) C033-C113 1.453(10)
C031-C111 1.555(3) C033-C043 1.503(6)
C041-C051 1.495(3) C033-C113 1.631(7)
C051-C101 1.376(3) C033-C043 1.641(10)
C051-C061 1.391(3) C043-C053 1.513(6)
312
C053-C063 1.3900 C393-C403 1.645(13) C053-C103 1,3900 C403-C413 1.463(13) C063-C073 1.3900 C413-C423 1.561(15)
C063-0303 1.396(4) C513-C523 1.518(11) C073-C083 1.3900 C523-C533 1.542(11)
C083-C093 1.3900 C533-C543 1.442(9)
C093-0503 1.379(5) C543-C553 1.349(10)
C093-C103 1.3900 C553-C563 1.545(13) C103-C113 1.478(6) C563-C573 1.501(14)
0503-C513 1.405(5) C573-C583 1.551(14) 0303-C313 1.447(5) C583-C593 1.492(13) C313-C323 1.516(7) C593-C603 1.521(12) C323-C333 1.507(7) C603-C613 1.493(12)
C333-C343 1.523(8) C613-C623 1.542(10) C343-C353 1.483(9) C353-C363 1.521(8) 0012-C012-N022 122.33(17) C363-C373 1.462(10) 0012-C012-C033 119.20(16) C373-C383 1.519(9) N022-C012-C033 118.47(16) C383-C393 1.448(11) C012-N022-C032 127.88(15) C393-C403 1.512(11) N022-C032-C013 112.47(14) C403-C413 1.507(11) N022-C032-C112 107.96(15) C413-C423 1.384(12) C013-C032-C112 113.14(16) C513-C533 1.601(8) N022-C032-C042 109.19(15)
C523-C533 1.355(11) C013-C032-C042 109.93(16) C523-C543 1.774(9) C112-C032-C042 103.75(14) C543-C553 1.466(11) C052-C042-C032 102.30(16) C553-C563 1.517(10) C102-C052-C062 121.01(18) C563-C573 1.535(10) C102-C052-C042 110.93(16) C573-C583 1.591(11) C062-C052-C042 128.06(18) C583-C593 1.449(9) 0502-C062-C072 125.43(18) C593-C603 1.495(9) 0502-C062-C052 115.97(18) C603-C613 1.406(8) C072-C062-C052 118.61(18) C613-C623 1.411(16) C062-C072-C082 120.66(18) C043-C053 1.509(9) C092-C082-C072 120.52(18) C053-C063 1.3900 0302-C092-C082 124.95(17)
C053-C103 1.3900 0302-C092-C102 116.43(17) C063-C073 1.3900 C082-C092-C102 118.62(18)
C063-0303 1.402(6) C052-C102-C092 120.53(17) C073-C083 1.3900 C052-C102-C112 110.47(16) C083-C093 1.3900 C092-C102-C112 128.99(18) C093-C103 1.3900 C102-C112-C032 102.32(15) C093-0503 1.394(7) C092-0302-C312 116.83(16) C103-C113 1.465(7) C062-0502-C512 117.11(17) 0503-C513 1.436(10) 0302-C312-C322 108.44(17) 0303-C313 1.426(7) C332-C322-C312 110.36(19) C313-C323 1.529(10) C322-C332-C342 113.7(2) C323-C333 1.527(12) C352-C342-C332 116.4(3) C333-C343 1.535(13) C342-C352-C362 113.1(3) C343-C353 1.521(14) C372-C362-C352 115.7(3) C353-C363 1.549(14) C362-C372-C382 113.8(3) C363-C373 1.527(15) C392-C382-C372 115.8(3) C373-C383 1.534(15) C382-C392-C402 114.8(3) C383-C393 1.497(16) C412-C402-C392 115.6(3)
C402-C412-C422 114.7(4) 0301-C3121-C3221 109.2(7) 0502-C512-C522 107.30(19) C3321-C3221-C3121 112.3(7) C512-C522-C532 112.7(2) C3221-C3321-C3421 121.4(10) C522-C532-C542 112.6(2) C3521-C3421-C3321 120.7(9) C532-C542-C552 113.6(3) C3421-C3521-C3621 121.2(7) C562-C552-C542 112,6(3) C3721-C3621-C3521 126.7(8) C552-C562-C572 114.0(3) C3621-C3721-C3821 124,6(9) C582-C572-C562 111.9(3) C3921-C3821-C3721 126,2(9) C572-C582-C592 114.4(3) C3821-C3921-C4021 125,1(10) C602-C592-C582 111.8(4) C4121-C4021-C3921 127,6(10) C592-C602-C612 109.2(5) C4021-C4121-C4221 126.7(12) C622-C612-C602 85.5(7) 0501-C511-C521 107.8(2) 0011-C011-N021 122.17(16) C511-C521-C531 110,9(2) 0011-C011-C031#1 118.63(16) C521-C531-C541 112.7(3) N021-C011-C031#1 119.20(15) C551-C541-C531 112.5(3) C011-N021-C031 127.77(15) C561-C551-C541 113.1(3) N021-C031-C011#1 113.03(14) C551-C561-C571 113.2(3) N021-C031-C041 108.72(15) C581-C571-C561 113.2(3) C011#1-C031-C041 111.31(15) C591-C581-C571 113.7(3) N021-C031-C111 109.00(15) C581-C591-C601 112.1(3) C011#1-C031-C111 111.32(15) C611-C601-C591 114.2(3) C041-C031-C111 102.95(14) C621-C611-C601 114.5(3) C051-C041-C031 102.55(15) 0013-C013-N023 122.14(18) C101-C051-C061 120.97(18) 0013-C013-C032 119.21(17) C101-C051-C041 110.44(16) N023-C013-C032 118,59(16) C061-C051-C041 128.58(18) C013-N023-C033 127,83(16) 0301-C061-C071 125.48(19) N023-C033-C113 110,7(4) 0301-C061-C051 115.93(18) N023-C033-C043 111,6(3) C071-C061-C051 118.6(2) C113-C033-C043 84.3(4) C081-C071-C061 120.32(19) N023-C033-C012 113.24(15) C071-C081-C091 121.23(19) C113-C033-C012 118.0(3) 0501-C091-C081 126.06(19) C043-C033-C012 115.8(3) 0501-C091-C101 115.88(18) N023-C033-C113 108,9(3) C081-C091-C101 118.1(2) C113-C033-C113 18,0(3) C051-C101-C091 120.79(18) C043-C033-C113 101,5(3) C051-C101-C111 110.64(16) C012-C033-C113 104.7(2) C091-C101-C111 128.55(19) N023-C033-C043 100.8(3) C101-C111-C031 102.28(15) C113-C033-C043 103.4(4) C061-0301-C3121 125.0(4) C043-C033-C043 19,5(2) C061-0301-C3111 111.5(3) C012-C033-C043 108,7(3) C3121-0301-C3111 17.7(4) CI 13-C033-C043 120,8(4) C091-0501-C511 116.78(18) C033-C043-C053 102,4(4) 0301-C3111-C3211 103.6(7) C063-C053-C103 120,0 C3311-C3211-C3111 117.3(5) C063-C053-C043 130,0(3) C3411-C3311-C3211 116.9(5) C103-C053-C043 110,0(3) C3511-C3411-C3311 121.0(6) C073-C063-C053 120,0 C3411-C3511-C3611 116.4(6) C073-C063-0303 123.3(2) C3711-C3611-C3511 117.8(6) C053-C063-0303 116.4(2) C3611-C3711-C3811 115.8(6) C063-C073-C083 120.0 C3911-C3811-C3711 114.3(8) C073-C083-C093 120.0 C3811-C3911-C4011 115.4(7) 0503-C093-C103 115.8(2) C4111-C4011-C3911 115.1(8) 0503-C093-C083 124.2(2) C4211-C4111-C4011 114.8(8) C103-C093-C083 120.0
314
C093-C103-C053 120,0 C083-C073-C063 120.0
C093-C103-C113 129.4(3) C073-C083-C093 120.0
C053-C103-C113 110.3(3) C103-C093-C083 120.0
C103-C113-C033 101.8(3) C103-C093-0503 116.5(3)
C093-0503-C513 121.7(4) C083-C093-0503 123.5(3)
C063-0303-C313 115.0(4) C093-C103-C053 120.0
0303-C313-C323 108.7(4) C093-C103-C113 129.5(5)
C333-C323-C313 115.7(4) C053-C103-C113 110.4(5)
C323-C333-C343 115.8(4) C033-C113-C103 106.7(5)
C353-C343-C333 113.9(5) C093-0503-C513 122.6(6)
C343-C353-C363 116.3(6) C063-0303-C313 118.9(5)
C373-C363-C353 116.7(6) 0303-C313-C323 107.5(6)
C363-C373-C383 118.0(7) C333-C323-C313 110.8(7)
C393-C383-C373 118.0(7) C323-C333-C343 113.8(10)
C383-C393-C403 119.2(10) C353-C343-C333 114.2(12)
C413-C403-C393 119.9(9) C343-C353-C363 110.0(11)
C423-C413-C403 146.8(12) C373-C363-C353 111.3(13)
0503-C513-C533 108.5(4) C363-C373-C383 111,8(12)
C533-C523-C543 118.0(8) C393-C383-C373 116.4(16)
C523-C533-C513 111.7(7) C383-C393-C403 104,1(11)
C553-C543-C523 118.9(8) C413-C403-C393 121.6(10)
C543-C553-C563 115.2(9) C403-C413-C423 116.9(11)
C553-C563-C573 112.0(7) 0503-C513-C523 111,5(7)
C563-C573-C583 107.6(8) C513-C523-C533 115.7(8)
C593-C583-C573 115.5(6) C543-C533-C523 117.7(9)
C583-C593-C603 118.7(6) C553-C543-C533 149.9(9)
C613-C603-C593 128.4(8) C543-C553-C563 114.4(9)
C623-C613-C603 127.1(17) C573-C563-C553 111.0(12)
C053-C043-C033 99.4(5) C563-C573-C583 115.7(10)
C063-C053-C103 120.0 C593-C583-C573 110.901)
C063-C053-C043 129.4(4) C583-C593-C603 116.0(10)
C103-C053-C043 110.6(4) C613-C603-C593 114.2(9)
C073-C063-C053 120.0 C603-C613-C623 116,8(8)
C073-C063-0303 124.0(3)
C053-C063-0303 115.8(3)
Symmetry transformations used to generate equivalent atoms: #1 -x,-y+2,-2
315
Table 4. Anisotropic displacement parameters (A^x 10®) for rksyn. The anisotropic
displacement factor exponent takes the form: •2p^[ h^ a*®U" + ... + 2 h k a* b* j
U" U22 U33 U23 U13 U12
0012 50(1) 20(1) 28(1) 0(1) 22(1) -1(1) C012 31(1) 20(1) 23(1) 0(1) 13(1) 1(1) N022 40(1) 16(1) 23(1) -2(1) 15(1) -2(1) C032 34(1) 18(1) 23(1) 0(1) 14(1) -1(1) C042 33(1) 28(1) 27(1) -5(1) 14(1) -3(1) C052 32(1) 23(1) 24(1) 0(1) 14(1) -1(1) C062 30(1) 29(1) 25(1) 2(1) 13(1) 2(1) C072 35(1) 27(1) 27(1) 0(1) 17(1) 3(1) C082 37(1) 27(1) 23(1) -3(1) 15(1) 1(1) C092 31(1) 24(1) 21(1) 2(1) 12(1) -1(1) CI 02 33(1) 20(1) 22(1) 1(1) 14(1) 0(1) C112 33(1) 21(1) 24(1) 0(1) 12(1) 2(1) 0302 31(1) 33(1) 25(1) -5(1) 9(1) 1(1) 0502 28(1) 45(1) 34(1) -6(1) 12(1) 3(1) C312 34(1) 33(1) 31(1) -8(1) 9(1) -3(1) C322 33(1) 33(1) 39(1) -3(1) 11(1) 0(1) C332 37(1) 57(2) 56(2) -22(1) -1(1) 8(1) C342 37(1) 53(2) 56(2) -14(1) 0(1) 5(1) C352 34(1) 57(2) 76(2) 13(2) 1(1) 0(1) C362 33(1) 49(2) 80(2) 7(1) 1(1) . 3(1) C372 34(1) 84(3) 88(3) 23(2) 5(2) 0(1) C382 36(1) 56(2) 86(2) 14(2) 4(1) 2(1) C392 37(2) 86(3) 86(3) 12(2) 6(2) -4(2) C402 38(1) 54(2) 90(2) 10(2) 9(1) 3(1) C412 42(2) 73(2) 96(3) -3(2) 12(2) -4(2) C422 41(2) 66(2) 112(3) -1(2) 18(2) 8(1) C512 31(1) 38(1) 43(1) -1(1) 18(1) 4(1) C522 30(1) 46(1) 54(1) -7(1) 15(1) 2(1) C532 33(1) 43(1) 61(2) -2(1) 20(1) 2(1) C542 31(1) 46(1) 77(2) -9(1) 19(1) -1(1) C552 33(1) 50(2) 74(2) 1(1) 22(1) 3(1) C562 33(1) 53(2) 95(2) -5(2) 25(1) -2(1) C572 34(1) 65(2) 74(2) 8(2) 22(1) 5(1) C582 34(1) 75(2) 100(3) 2(2) 26(2) 0(1) C592 31(1) 124(3) 81(2) -2(2) 19(2) 6(2) C602 34(2) 219(7) 122(4) -44(4) 28(2) -5(3) C612 67(3) 209(8) 328(12) 184(9) -60(5) -57(4) C622 97(4) 92(4) 169(6) 46(4) -35(4) -43(3) 0011 48(1) 18(1) 25(1) 1(1) 17(1) 2(1) C011 31(1) 18(1) 23(1) -2(1) 12(1) -1(1) N021 41(1) 16(1) 25(1) -1(1) 17(1) 1(1) C031 31(1) 18(1) 22(1) -1(1) 13(1) -1(1) C041 30(1) 24(1) 26(1) -6(1) 12(1) 0(1) C051 35(1) 21(1) 20(1) 1(1) 12(1) 3(1) C061 39(1) 25(1) 22(1) -1(1) 10(1) 4(1) C071 50(1) 29(1) 26(1) -5(1) 14(1) 8(1) C081 44(1) 37(1) 34(1) -4(1) 19(1) 13(1) C091 35(1) 31(1) 32(1) -1(1) 16(1) 6(1)
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Table 5. Hydrogen coordinates (x 10^) and Isotropic displacement parameters (A^x 10 for rksyn.
x y z U(eq)
H02A2 253 7792 10419 30 H04A2 -962 7176 10266 34 H04B2 -892 6485 10686 34
H07A2 -1000 8708 11824 34
H08A2 83 8654 12377 33
H11A2 483 6376 11408 30 H11B2 876 7024 11226 30
H31A2 970 8068 13005 40
H31B2 1169 8707 12650 40
H32A2 1962 7460 13104 43 H32B2 2161 8108 12758 43 H33A2 1917 8329 13806 64 H33B2 2175 8939 13472 64
H34A2 3016 8485 14259 63 H34B2 2892 7680 14001 63 H35A2 3336 8832 13455 72 H35B2 3290 7989 13275 72
H36A2 4155 8565 14308 70
H36B2 4092 7713 14161 70 H37A2 4537 8760 13527 87 H37B2 4503 7899 13412 87
H38A2 5326 8575 14418 75 H38B2 5286 7713 14315 75
H39A2 5735 8706 13652 87 H39B2 5723 7838 13584 87 H40A2 6507 8599 14562 76 H40B2 6493 7731 14498 76 H41A2 6927 8680 13795 88 H41B2 6952 7808 13780 88 H42A2 7972 8271 14266 112 H42B2 7721 7804 14698 112 H42C2 7698 8678 14710 112 H51A2 -2019 8801 11064 43 H51B2 -1978 8159 11516 43 H52A2 -2709 7459 10753 52 H52B2 -2796 8166 10357 52 H53A2 -3249 8813 10959 53
H53B2 -3142 8122 11375 53 H54A2 -3880 7437 10629 61 H54B2 -3999 8143 10228 61 H55A2 -4338 8052 11249 61 H55B2 -4453 8761 10851 61 H56A2 -5067 7384 10496 71 H56B2 -5182 8093 10099 71 H57A2 -5551 7986 11106 68 H57B2 -5663 8699 10711 68 H58A2 -6246 7315 10341 82
H58B2 -6358 8026 9947 H59A2 -6768 7905 10931 H59B2 -6887 8609 10527 H60A2 -7403 7219 10077 H60B2 -7618 8001 9785 H61A2 -8435 7449 10372 H61B2 -7904 7816 10928 H62A2 -8547 8634 10386 H62B2 -8320 8354 9870 H62C2 -7811 8715 10418 H02B1 -281 11083 279 H04C1 616 9852 1370 H04D1 755 10596 1081 H07B1 -126 11936 2318 H08B1 -1196 11579 1959 H11C1 -1096 10073 399 H11D1 -747 9457 861 H31C1 1031 12030 2737 H31D1 632 12437 2154 H32C1 1552 12323 1833 H32M1 1690 12844 2375 H33C1 2302 11953 2962 H33D1 2112 11370 2457 H34C1 2724 11919 2013 H34D1 2829 12615 2416 H35C1 3388 11254 2762 H35D1 3508 11972 3147 H36C1 3898 11788 2170 H3SM1 3991 12529 2525 H37C1 4616 11208 2944 H37M1 4711 11952 3297 H38C1 5087 11752 2306 H38D1 5187 12494 2664 H39C1 5803 11155 3089 H39D1 59G3 11897 3446 H40C1 6282 11712 2458 H40D1 6406 12432 2842 H41C1 7113 11783 3599 H4iyi 6985 11059 3220 H42D1 7957 11575 3251 H42E1 7604 12321 2992 H42F1 7476 11596 2612 H31E1 1036 11882 2785 H31F1 981 12428 2266 H32D1 2099 12281 2860 H32E1 2051 11424 2721 H33E1 2095 12585 2013 H33F1 1735 11861 1728 H34E1 2696 11222 2075 H34N1 2685 11830 1614 H35E1 3320 11961 2774 H35N1 3311 12566 2312 H36D1 3940 11237 2471
82 94 94
149 149 277 277 207 207 207 31 31 31 41 44 31 31 43 43 47 47 52 52 69 69 61 61 67 67 64 64 68 68 65 65 71 71 69 69 95 95 95 48 48 92 92
124 124 113 113 74 74 88
H36N1 3854 11721 1922 88 H37D1 4598 12067 3003 104 H37N1 4507 12561 2457 104 H38E1 5159 11246 2687 82 H38N1 5038 11688 2114 82 H39E1 5824 12095 3157 121
H39N1 5694 12556 2591 121 H40E1 6345 11241 2810 82 H40N1 6217 11702 2245 82 H41D1 7031 12105 3281 150 H41N1 6919 12522 2698 150 H42G1 7900 12001 2999 124 H42H1 7484 11642 2407 124 H42i1 7589 11208 2990 124 H51C1 -2185 11476 1216 56 H51D1 -2123 10892 1715 56 H52C1 -2813 10083 1022 64 H52D1 -2904 10710 551 64 H53C1 -3385 11480 1075 61 H5301 -3291 10856 1546 61 H54C1 -4119 10724 389 65 H54D1 -4016 10085 850 65 H55C1 -4479 10841 1399 71 H55D1 -4592 11469 928 71 H56C1 -5208 10071 725 69 H56D1 -5320 10697 253 69 H57C1 -6672 10842 1265 73 H67D1 •5799 11453 781 73 H58C1 -6525 10662 127 69 H58D1 -6392 10041 604 69 H59C1 -7025 11399 639 66 H59D1 •6854 10819 1149 66 H60C1 -7738 10570 29 65 H60D1 -7531 9940 499 65 H61C1 -8494 10321 545 59 :H6101 7988 10695 1087 59 H6201 -8785 11531 624 99 H62E1 -8613 11434 49 99 H62F1 -8107 11808 592 99 H02C3 24 5544 9659 34 H04E3 981 6110 9406 38 H04F3 775 6827 9010 38 H07C3 98 4613 7729 51 H08C3 •985 4948 7463 54 H11E3 -908 6544 9012 39 H11F3 -567 7158 8739 39 H31G3 1200 4402 8042 58 H31H3 850 4069 B464 58 H32F3 1829 4223 9238 62 H32G3 1891 3639 8780 62 H33G3 2428 5057 8967 67 H33H3 2349 4646 8381 67 H34F3 3121 4111 9466 72
322
H34G3 3050 3714 8875 72 H35F3 3630 5091 9207 83 H35P3 3530 4733 8598 83 H36E3 4357 4164 9646 72 H36P3 4242 3775 9047 72 :H37E3 4840 5132 9358 92 H37P3 4712 4761 8751 82 H38F3 5566 4191 9782 79 H38P3 5441 3825 9173 79 H39F3 6034 6172 9502 113 H39P3 5910 4806 8894 113 H40F3 6819 4377 9932 95 H40P3 6621 3833 9404 95 H41E3 6945 4880 8948 152 H41P3 7336 5081 9576 152 H42J3 7912 4963 9061 349 H42K3 7696 4132 8915 349 H42L3 8097 4359 9554 349 H51E3 -1969 5041 7742 51 H$1F3 -2025 55S4 7203 51 H52E3 '3052 5101 7159 96 H52Q3 -3360 5880 6948 96 H53E3 -2877 5838 8045 105 H53Q3 -2684 6422 7562 105 H54E3 -3860 4819 7578 94 H54Q3 -3739 5564 7929 94 H55E3 -4583 5446 6812 84 H55Q3 -4493 6148 7213 84 H56E3 -4946 5513 7818 79 H56F3 -5020 4796 7432 79 H57E3 -5779 5413 6654 87 H57F3 -5699 6142 7033 87 H58E3 -6192 4761 7314 75 H58F3 -6078 5460 7719 75 H59E3 -6968 5411 6625 70 H59Q3 -6872 6073 7062 70 H60L3 -7362 4697 7193 94 H60M3 -7238 5328 7651 94 H61L3 -8062 5942 6988 131 H61M3 -8211 5188 6660 131 H60L3 -8850 4961 7059 671 H60M3 •8664 5698 7422 671 H60N3 -8292 4955 7662 671 H04G3 1036 6762 9250 37 H04H3 1103 6086 9686 37 H07D3 748 4475 8060 49 H08D3 -346 4689 7600 52 HI 1G3 -373 6991 8673 38 H11H3 -759 6382 8900 38 H31!3 1859 4765 8394 55 H31J3 1712 4138 8789 55 H32H3 2676 5202 9306 68 H32i3 2620 4392 9531 68
H33I3 2964 4686 8530 78 H33J3 2949 3891 8793 78 H34H3 3825 5002 9394 112 H34I3 3839 4166 9585 112' Hsses 4121 4625 8586 95 H35H3 4174 3799 8814 95 H36F3 4950 4975 9463 125 H36R3 5022 4135 9653 125 H37F3: 5273 4658 8654 117 H3;7G3 5380 3832 8879 117 H38G3 6093 5062 9476 150 H38R3 6189 4251 9724 150 H39G3 6483 4637 8722 136 H39H3 6676 3885 9074 136 H40G3 7259 5302 9387 81 H40R3 7143 4895 9907 81 H41F3 7822 3975 9545 119 H41G3 8048 4446 10116 119 H42M3 8787 4604 9608 293 H42N3 84'"i1 5372 9637 293 H4203 8226 4898 9065 293 H51G3 -1524 4724 7623 78 H51H3 -1351 5150 7126 78 H52F3 -2397 5356 6846 82 H52G3 -2157 6063 7233 82 H53F3 -2588 4788 7668 80 H53G3 -2455 5566 7971 80 H54F3 -3316 5629 6971 40 H54G3 -3479 4994 7323 40 H55F3 -3847 6333 7179 75 H56G3 -3751 5996 7795 75 H56G3 -4535 5334 6748 79 H56H3 -4436 4991 7365 79 H57G3 -5090 6306 6924 81 H57H3 -4875 6132 7589 81 H58G3 -5734 5166 6783 100 H58H3 -5607 5179 7456 100 H5SF3 -6167 6381 6754 80 H59G3 -6136 6265 7400 80 H60H3 -696§ 5534 6430 71 H60I3 -6858 5222 7056 71 H61I3 -7435 6569 6616 71 H61J3 -7225 6388 7280 71 H62J3 6185 6877 93 H62K3 -7992 S415 7084 93 H62L3 -8214 5628 6423 93
324
Tables. Hydrogen bonds with H..A< r(A) + 2.000 Angstroms and <DHA>110deg.
oTi d(D-H) d(H..A) <DHA d(D..A) A
N02-H02A_2 0.880 1.962 164.53 2.820 001_1 [-x,-y+2,-z+1 ]
N02-H02B_1 0.880 2.051 166.58 2.914 001_2 [-x,-y+2,-z+1 ]
N02-H02C_3 0.880 2.003 174.48 2.880 001_3 [-x,-y+1,-z+2 ]
325
Structural Report of 129a (tape)
OCH OCH
•NH
OCH OCH
326
NOTES
This written report is accompanied by an electronic Crystallographic Information File (CIF) which should be supplied to any journal publishing these results. It contains calculated distances and angles beyond those in the attached tables and all needed crystallographic information for generating other requested results. With modifications it is suitable for electronic submission to Acta Crystallographica Section E as a structure report. Observed and calculated structure factors are in the file fofc.txt and RKlSts.fcf. Publications arising from this report must either 1) include the preparer(s) as coauthors when significant contributions were made and/or 2) acknowledge the Molecular Structure Laboratory and NSF grant CHE9610374 which provided the diffractometer. A copy of any paper reporting these results should be provided to MSL after publication.
EXPERIMENTAL
A colorless plate of C25 H28 N2 06 having approximate dimensions of 0.25 x 0.1 x 0.05 mm was mounted on a glass fiber in a random orientation. Examination of the crystal on a Bruker SMART 1000 CCD detector X-ray diffractometer at 170(2)K and a power setting of 50KV, 40mA showed measurable diffraction to at least theta = 23.576°. Data were collected on the SMART1000 system using graphite monochromated Mo Ka radiation (A =0.71073A).
Initial cell constants and orientation matrix were determined from reflections obtained in three orthogonal 6° wedges of reciprocal space. A total of 3686 frames at 1 detector setting covering 0 < 20 < 60°were collected, having an u) scan width of 0.2° and an exposure time of 40 seconds. The frames were integrated using the Bruker SAINT software package's narrow frame algorithm. A total of 19204 reflections were integrated and retained of which 3314 were unique (<redundancy> = 5.795, Rmt = 6.8%, Rsig = 4.5%). Of the unique reflections, 2550 (76.95%) were observed l>2o{l). The final Monoclinic cell parameters of a = 17.118(3), b = 12.253(3), c = 10.721 (2)A, a = 90, [3 = 105.56(3), y = 90°, volume = 2166.4(7) A^ are based on the refinement of the XYZ-centroids of 3435 reflections with I > 4 a(l) covering the range of 2.47 < 6 < 23.576°. An empirical absorption correction was applied using the program SADABS. The absorption coefficient is 0.100 mm"\ Tmin = 0.725906, and Tmax = 1. For Z = 4 and F.W. = 452.49 the calculated density is 1.387g/cm^. Systematic absences and intensity statistics indicate the space group to be P2(1)/c (#14) which was consistent with refinement.
The structure was solved using XS in the Bruker SHELXTL (Version 5.0) software package. Refinements were performed using XL and illustrations were made using XP. Solution was achieved utilizing direct methods followed by Fourier synthesis. Hydrogen atoms were added at idealized positions, constrained to ride on the atom to which they are bonded and given thermal parameters equal to 1.2 or 1.5 times U|so of that bonded atom. The final anisotropic full-matrix least squares refinement based on of all reflections converged (maximum shift/esd = 0.000) at R1 = 0.1062, wR2 = 0.1972 and goodness-of-
327
fit = 1.070. "Conventional" refinement indices using the 2550 reflections with F > 4 a(F) are R1 = 0.0810, wR2 = 0.1836. The model consisted of 301 variable parameters, 0 constraints and 0 restraints. There were no correlation coefficients greater than 0.50. The highest peak on the final difference map was 0.732 e/A^ located 0.53 A from H1C. The lowest peak on the final difference map was -0.327 e/A^ located 0.77 A from 016. Scattering Factors and anomalous dispersion were taken from International Tables Vol C Tables 4.2.6.8 and 6.1.1.4.
There were two moderate problems with this structure. The first was the weakly diffracting sample. Although some reflections were measured to 0.88 A, the average best resolution was closer to 1 A. This fact is reflected in the somewhat poor refinement statistics and higher than average residual electron density. In addition to weak diffraction, the sample was observed to shift midway through data collection, requiring the integration of each half of the data with different orientation matrices as well as the subsequent loss of the latter portion (-2/3) of the third set of 909 frames. The orientation matrix of the second half of the data set was transformed to match the first and both halves were merged using SADABS during the application of an absorption correction. It is likely that the merging and absorption corrections were not ideal, as suggested by a slightly uneven distribution of residual electron density peaks and holes. The imperfect absorption correction also resulted in small deviations from ideal "rigid bond" thermal parameters and contributed to the degradation of refinement quality.
The methyl site bound to the amide nitrogen N2 was found to be conformationally disordered, with residual electron density located ~60°away from the (calculated) normal hydrogen atom sites. The disorder was treated with an "ideal disordered methyl" model, which placed six half occupied H-atom sites appropriate C-H bond distance from the carbon and exactly 60° apart from each other. Subsequent refinements were improved.
STRUCTURE
The title compound, C25 H28 N2 06, has the structure proposed by the submitter. Its molecular structure is identical to that reported previously as rk14. The current sample is a polymorph of rk14, which crystallizes in the same (monoclinic) system as rk14, is in a closely related space group (P2i/c vs P2i/n (rk14)), and both have very similar cell parameters. As observed in rk14, the current structure has one complete molecule in the asymmetric unit and four in the unit cell. The principal difference between the two is the hydrogen bonding/packing mode observed in both. In rk14, the molecules formed discrete hydrogen bonded dimers, with the methylated nitrogen atom barred from participating in further non-covalent interactions. In the current structure, the non-methylated nitrogen participates in very weak (r(D-A) > 2.6A) hydrogen bonding with neighboring molecules to form a hydrogen bonded polymer which extends in the c-direction (figure 2). This bonding mode requires the packing of the molecules to be different from that observed in rk14, and the slight differences in cell parameters and volume are the result of this subtle difference.
FIGURES
Fig. 1 A thermal ellipsoid rendering of the molecule with 50% probability ellipsoids. Fig. 2 A partial packing diagram indicating the H-bonding chain in the c-direction.
EQUATIONS
Rin. = Z|Fo^-{Fo2)|/I[Fo2]
Rsig = i:[a(Fo^)]/L[Fo^]
R, = I||Fol-|Fc||/I|Fo|
wRa = {1:[W(Fo^-FC2)VL[W(FO2)2]}''2
w=1/[a^(Fo^)+(0.0761P)2+5.9862P] where P=(Fo^+2Fc^)/3
GOF = S = {X[w(Fo2-Fc2)2]/(n-p)}''^
REFERENCES
Bruker (1997) SAINT Reference Manual Version 5.0, Bruker AXS Inc., Madison, Wisconsin, USA.
Bruker (1997) SHELXTL Reference Manual Version 5.0, Bruker AXS Inc., Madison, Wisconsin, USA.
Bruker (1997) SMART Reference Manual Version 5.0, Bruker AXS Inc., Madison, Wisconsin, USA.
SADABS: Area-Detector Absorption Correction. (1996) Siemens Industrial Automation, Inc.: Madison, Wl..
329
Table 1. Crystal data and structure Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions
Volume z Density (calculated) Absorption coefficient F(OOO) Crystal size Theta range for utilized data Limiting Indices Reflections utilized Independent reflections Completeness to theta = 23.86° Absorption correction Max. and min. transmission Refinement method Data / restraints / parameters Goodness-of-fit on Final R indices [l>2sigma(l)] R indices (all data)
Largest diff. peak and hole
RMS difference density
a= 90°. b= 105.56(3)°. 9 = 90°.
refinement for rk13ts. rklSts C25 H28 N2 06 452.49 170(2) K 0.71073 A Monoclinic P2(1)/c a = 17.118(3) A b= 12.253(3) A c = 10.721(2) A 2166.4(7) A3 4 1.387 Mg/m® 0.100 mm"'' 960 0.25 X 0.1 X 0.05 mm® 1.23 to 23.86°. .19<=h<=19, -13<=k<=13, -11<=l<=12
19204 3314[R(int) = 0.0680] 99.3 % None 1 and 0.725906 Full-matrix least-squares on F^ 3314/0 /301 1.070 R1 =0.0810, wR2 = 0.1836 R1 =0.1062, wR2 = 0.1972
0.732 and -0.327 e.A'^
0.068e.A-3
330
'C(26)O(30)
33^
.O '
o
Table 2. Atomic coordinates (x 10") and equivalent isotropic displacement parameters (A^x 10^)
for rkl 3ts. U(eq) is defined as one third of the trace of the orthogonalized U'' tensor.
X y z U(eq)
0(12) 1268(2) 1818(2) 351(3) 34(1)
0(30) 4015(2) -4937(2) 7048(3) 33(1)
0(14) -488(2) -669(2) 2975(3) 34(1)
0(32) 6104(2) -2653(3) 4850(3) 38(1)
0(29) 1794(2) -2428(3) 972(3) 50(1)
0(16) 3678(2) -1299(3) 5626(3) 44(1)
N(2) 2635(2) -891(3) 3950(4) 34(1)
N(27) 2906(2) -2692(3) 2608(4) 38(1)
C(9) 785(2) 1266(3) 980(4) 25(1)
C(21) 5645(2) -3255(3) 5486(4) 27(1)
C(20) 4808(2) -3156(3) 4986(4) 22(1)
C(25) 4288(2) -3731(3) 5527(4) 23(1)
C(22) 5938(3) -3910(3) 6541(4) 29(1)
C(26) 3418(2) -3543(3) 4798(4) 24(1)
C(23) 5421(2) -4487(3) 7110(4) 27(1)
C(10) 1134(2) 351(3) 1693(4) 28(1)
C(24) 4593(2) -4411(3) 6590(4) 25(1)
C(6) -99(2) 12(3) 2307(4) 25(1)
C(8) -3(3) 1522(3) 919(4) 29(1)
C(28) 2233(3) -2131(4) 2074(5) 35(1)
C(3) 2031(2) -1137(4) 2717(4) 32(1)
C(17) 3267(2) -1529(3) 4559(4) 21(1)
C(19) 4347(2) -2493(4) 3835(4) 30(1)
C(4) 1171(3) -1261(4) 2948(5) 40(1)
C(18) 3450(2) -2545(3) 3908(4) 22(1)
C(7) -440(3) 905(3) 1591(4) 30(1)
C(5) 702(2) -267(3) 2352(4) 28(1)
C(11) 1949(3) -141(4) 1751(5) 38(1)
C(13) 867(3) 2612(4) -594(5) 36(1)
C(15) -1333(3) -493(5) 2750(6) 51(1)
C(1) 2509(3) 63(4) 4678(6) 51(2)
C(31) 4299(3) -5718(4) 8063(5) 39(1)
C(33) 6931(3) -2955(4) 5082(6) 47(1)
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Table 4. Anisotropic displacement parameters (A^x 10®) for rk13ts. The anisotropic
displacement factor exponent takes the form: -2p^l h^ a*^U'^ + ... + 2 h k a* b* ]
U11 U2Z U33 UZ3 Ijia U12
0(12) 26(2) 30(2) 47(2) 17(2) 10(1) 4(1)
0(30) 32(2) 30(2) 39(2) 15(1) 10(1) 7(1)
0(14) 18(2) 43(2) 40(2) 10(2) 10(1) 2(1)
0(32) 27(2) 37(2) 54(2) 5(2) 17(2) 5(1)
0(29) 45(2) 55(2) 38(2) -2(2) -10(2) -1(2)
0(16) 49(2) 39(2) 39(2) -3(2) 1(2) 7(2)
N(2) 32(2) 18(2) 54(3) 1(2) 16(2) 7(2)
N(27) 45(2) 29(2) 27(2) -1(2) -11(2) 8(2)
C(9) 24(2) 22(2) 30(2) 0(2) 7(2) 2(2)
C(21) 26(2) 20(2) 36(3) -4(2) 10(2) 3(2)
C(20) 22(2) 22(2) 22(2) -2(2) 6(2) 5(2)
C(25) 23(2) 18(2) 25(2) -3(2) 4(2) 2(2)
C(22) 20(2) 25(2) 35(3) -7(2) -4(2) 6(2)
C(26) 22(2) 22(2) 26(2) 3(2) 6(2) 4(2)
C(23) 31(2) 23(2) 23(2) 4(2) 1(2) 7(2)
C(10) 17(2) 26(2) 37(3) 7(2) 5(2) 3(2)
C(24) 27(2) 20(2) 27(2) 0(2) 6(2) 2(2)
C(6) 22(2) 27(2) 26(2) -3(2) 6(2) 0(2)
C(8) 29(2) 22(2) 33(3) 6(2) 6(2) 12(2)
C(28) 25(2) 33(3) 37(3) 15(2) -7(2) -5(2)
0(3) 14(2) 42(3) 37(3) 17(2) -2(2) 0(2)
C(17) 15(2) 22(2) 21(2) -5(2) 0(2) -1(2)
0(19) 30(2) 34(2) 27(2) 4(2) 11(2) 13(2)
0(4) 26(2) 38(3) 57(3) 21(2) 12(2) 7(2)
0(18) 24(2) 22(2) 15(2) 0(2) -3(2) 6(2)
0(7) 21(2) 29(2) 39(3) 0(2) 10(2) 9(2) 0(5) 18(2) 28(2) 36(3) 6(2) 4(2) 3(2)
0(11) 27(2) 36(3) 52(3) 23(2) 10(2) 7(2)
0(13) 38(3) 32(3) 36(3) 13(2) 4(2) 2(2)
0(15) 29(3) 66(4) 63(4) 15(3) 22(3) 7(3)
0(1) 55(3) 29(3) 75(4) -15(3) 28(3) 5(2)
0(31) 44(3) 35(3) 38(3) 17(2) 13(2) 10(2)
0(33) 22(2) 44(3) 78(4) -2(3) 18(3) -1(2)
Table 5. Hydrogen coordinates (x 10^) and isotropic displacement parameters (A^x 10
for rk13ts.
X y z U(eq)
H(27) 2710(30) -3420(40) 2130(50) 45
H(22A) 6508 -3973 6895 34 H{26A) 3085 -3375 5399 29
H{26B) 3189 -4191 4277 29 H(23A) 5638 -4929 7849 32
H(8A) -254 2127 413 34
H(19A) 4402 -2814 3016 36
H(19B) 4544 -1730 3899 36 H(4A) 903 -1933 2531 48
H(4B) 1212 -1296 3886 48
H(7A) -982 1105 1554 35
H(11A) 2388 396 2078 46 H(11B) 1972 -393 884 46
H(13A) 1264 2956 -979 54
H(13B) 617 3171 -173 54
H(13C) 448 2251 -1272 54
H(15A) -1553 -1013 3263 76
H(15B) -1602 -598 1828 76
H(15C) -1429 253 3003 76 H(1A) 2042 477 4168 77 H(1B) 2994 525 4864 77 H{1C) 2405 -170 5494 77 H(1D) 2919 78 5516 77
H(1E) 1967 30 4820 77
H(1F) 2556 725 4190 77
H(31A) 3835 -6036 8306 58
H(31B) 4657 -5356 8817 58
H(31C) 4599 -6297 7762 58
H(33A) 7195 -2475 4587 71
H(33B) 6966 -3713 4811 71
H(33C) 7202 -2884 6007 71
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Table?. Hydrogen bonds for rklSts [Aand°].
D-H...A d(D-H) d(H...A) d(D...A) <(DHA)
N{27)-H(27)...0(16)#1 1.04(5) 2.63(5) 3.050(5) 104(3)
Symmetry transformations used to generate equivalent atoms: #1 x,-y-1/2,z-1/2
339
Structural Report of 129b (dimer)
OCH OCH
•NH
OCH OCH
340
NOTES
This written report is accompanied by an electronic Crystallographic Information File (GIF) which should be supplied to any journal publishing these results. It contains calculated distances and angles beyond those in the attached tables and all needed crystallographic information for generating other requested results. With modifications it is suitable for electronic submission to Acta Crystallographica Section E as a structure report. Observed and calculated structure factors are in the file fofc.txt and rk14m.fcf. Publications arising from this report must either 1) include the preparer(s) as coauthors when significant contributions were made and/or 2) acknowledge the Molecular Structure Laboratory and NSF grant CHE9610374 which provided the diffractometer. A copy of any paper reporting these results should be provided to MSL after publication.
EXPERIMENTAL
A colorless block of C25 H28 N2 06 having approximate dimensions of .4 x .4 x .4 mm was mounted on a glass fiber in a random orientation. Examination of the crystal on a Bruker SMART 1000 CCD detector X-ray diffractometer at 170(2)K and a power setting of SOKV, 40mA showed measurable diffraction to at least 0 = 30.626°. Data were collected on the SMART1000 system using graphite monochromated Mo-Kq radiation (A =0.71073A).
Cell constants and an orientation matrix for integration were determined from reflections obtained in three orthogonal 6 ° wedges of reciprocal space. A total of 3656 frames at 1 detector setting covering 0 < 26 < 60 ° were collected, having an w scan width of 0.2° and an exposure time of 20 seconds. The frames were integrated using the Bruker SAINT software package's narrow frame algorithm. A total of 37218 reflections were integrated and retained of which 6975 were unique (<redundancy> = 5.335, Rim = 13.3%, Rsig = 9.4% ). Of the unique reflections, 3746 (53.71%) were observed l>2a(l). The final Monoclinic cell parameters of a = 9.553406), b = 12.199(2), c == 19.099(3)A, a = 90, (3 = 91.436(4), y= 90°, volume = 2225.2(6) A^ are based on the refinement of the XYZ-centroids of 4598 reflections with I > 10 o(l) covering the range of 2.708 < 0 < 30.626°. No absorption nor decay corrections were necessary and were not applied. For Z = 4 and F.W. = 452.49 the calculated density is 1.351g/cm^. Systematic absences and intensity statistics indicate the space group to be P2(1)/n (#14) which was consistent with refinement.
The structure was solved using XS in the Bruker SHELXTL (Version 5.0) software package. Refinements were performed using XL and illustrations were made using XP. Solution was achieved utilizing direct methods followed by Fourier synthesis. Hydrogen atoms were added at idealized positions, constrained to ride on the atom to which they were bonded and given thermal parameters equal to 1.2 or 1.5 times Uiso of that bonded atom. The methyl group bound to N1 (CI m) was found to be disordered. This disorder was treated by splitting the hydrogen atoms into six half occupied sites placed 60° apart about Cim. These six sites were still constrained to ride upon Clm. This "ideal methyl
341
disorder" model improved subsequent refinements and rendered the final difference map essentially featureless. The final anisotropic full-matrix least squares refinement based on
of all reflections converged (maximum shift/esd = 0.000) at R1 = 0.1033, wR2 = 0.1437 and goodness-of-fit = 0.927. "Conventional" refinement indices using the 3746 reflections with F > 4 a(F) are R1 = 0.0494, wR2 = 0.1214. The model consisted of 298 variable parameters, 0 constraints and 0 restraints. There were no correlation coefficients greater than 0.50. The highest peak on the final difference map was 0.366 e/A^ located 0.76 A from C210. The lowest peak on the final difference map was -0.232 e/A® located 1.59 A from C26. Scattering Factors and anomalous dispersion were taken from International Tables Vol C Tables 4.2.6.8 and 6.1.1.4.
STRUCTURE
The title compound, C25 H28 N2 06, has the structure proposed by the submitter. The molecule features a cyclic, six-membered bis-amide core which has had one of the amide nitrogens (N1) methylated. The a-carbons at either end of the core (CI, C21) form spiro-junctions with two five membered rings. These five membered rings are each fused to bis-jt>methoxy benzene rings at C4 and C9, and C24 and C29, respectively. There is one complete molecule in the asymmetric unit, with a total of four in the unit cell. When viewing the packing diagram, it is revealed that the molecules form discrete hydrogen bonded dimers. The hydrogen bond is the expected N-H O mode between pairs of molecules on their non-methylated sides. The methyl group on the non-H-bonding amide projects into a small void in the structure and exhibits "ideal" methyl disorder. The disorder was modeled as described above. One of the bis p-methoxy benzene rings is bent considerably more than the other. Examination of the packing diagram suggests that this is likely to allow for more efficient packing, as no close contacts with the ring or methoxy groups are observed.
FIGURES
Fig. 1 A thermal ellipsoid rendering of the molecule with 50% probability ellipsoids.
EQUATIONS
Rin, = Z|FoMFo^)|/£[Fo2]
Rsig = E[a(FoVl[Fo^]
Ri = I||Fo|-|Fcl|/E|Fol
wR2 = {I[w(Fo^-Fc2)2]/E[w(Fo^)2]} '2
w=1/[o2(Fo^)+(0.0635P)^+0.00P] where P=(Fo^+2Fc^)/3
GOF = S = {I[w(Fo^-Fc^)V(n-P)}'"
Table 1. Crystal data and structure
Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions
Volume z Density (calculated) Absorption coefficient F(OOO) Crystal size Theta range for utilized data Limiting Indices Reflections utilized Independent reflections Completeness to theta = 30.87° Absorption correction Max. and min. transmission Refinement method Data / restraints / parameters Goodness-of-fit on Final R indices [l>2sigma(l)] R indices (all data)
Largest diff. peak and hole
RMS difference density
refinement for rk14m.
rk14m C25 H28 N2 06 452.49 170(2) K 0.71073 A Monoclinic P2(1)/n a = 9.5534(16) A a= 90°. b= 12.199(2) A b= 91.436(4)° c = 19.099(3) A g = 90°. 2225.2(6) A3 4 1.351 Mg/m3 0.097 mm-'' 960 .4 X .4 X .4 mm^ 1.98 to 30.87°. .13<=h<=13, -17<=k<=17, -27<=l<=27 37218 6975 [R(int) = 0.1335] 99.2 % None .955 and .719 Full-matrix least-squares on F^ 6975/0 / 298 0.927 R1 =0.0494, wR2 = 0.1214 R1 =0.1033, wR2 = 0.1437
0.366 and -0.232 e.A'^ 0.062e.A-3
0(212)
344
Table 2. Atomic coordinates (x 10'') and equivalent isotropic displacement parameters (A^x 10®) for rk14m. U(eq) is defined as one third of the trace of the orthogonalized W' tensor.
X y Z U(eq)
0(1) 10865(1) 2642(1) 2398(1) 30(1) N(1) 11661(1) 2361(1) 1312(1) 23(1) C(1) 10941(2) 2941(1) 1785(1) 21(1) C(1M) 12356(2) 1364(1) 1570(1) 32(1) C(2) 11893(2) 2662(1) 576(1) 22(1) C(3) 11470(2) 1702(1) 73(1) 25(1) C(4) 12813(2) 1336(1) -242(1) 22(1) 0(5) 11816(1) -117(1) -888(1) 33(1) C(5) 12997(2) 482(1) -720(1) 26(1) C(6) 14305(2) 322(1) -992(1) 31(1) C(7) 15424(2) 986(2) -785(1) 32(1) 0(8) 16274(1) 2527(1) -64(1) 36(1) C(8) 15246(2) 1822(1) -305(1) 27(1) C(9) 13922(2) 1991(1) -38(1) 23(1) C(10) 13486(2) 2880(1) 452(1) 26(1) C(11) 17606(2) 2446(2) -375(1) 51(1) C(12) 11990(2) -998(2) -1369(1) 45(1) 0(21) 11134(1) 3963(1) -263(1) 40(1) N(21) 10338(1) 4217(1) 817(1) 24(1) C(21) 11079(2) 3676(1) 355(1) 24(1) C(22) 10197(2) 3981(1) 1559(1) 19(1) C(23) 10734(2) 4984(1) 1983(1) 23(1) C(24) 9492(2) 5744(1) 1940(1) 21(1) 0(25) 10731(1) 7386(1) 2090(1) 34(1) C(25) 9462(2) 6881(1) 1978(1) 23(1) C(26) 8192(2) 7411(1) 1882(1) 26(1) C(27) 6968(2) 6817(1) 1748(1) 25(1) 0(28) 5869(1) 5023(1) 1566(1) 32(1) C(28) 7004(2) 5687(1) 1703(1) 23(1) C(29) 8286(2) 5151(1) 1797(1) 20(1) C(210) 8615(2) 3954(1) 1717(1) 24(1) C(211) 4596(2) 5559(2) 1375(1) 37(1) C(212) 10749(2) 8549(2) 2086(1) 42(1)
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. CM ^ T- '-CM CM CM CJ CM CM CM
Table 4. Anisotropic displacement parameters (A^x 10^) for rk14m. The anisotropic
displacement factor exponent takes the form: •2^{ a'^U^^ +... + 2 h k a* b* ]
U" \J22 (j33 u23 (j13 u12
0(1) 38(1) 32(1) 21(1) 8(1) 8(1) 9(1)
N(1) 30(1) 21(1) 19(1) 1(1) 3(1) 10(1)
C(1) 21(1) 21(1) 20(1) 1(1) 2(1) 2(1)
C(1M) 42(1) 25(1) 30(1) 3(1) 0(1) 14(1)
C(2) 26(1) 22(1) 18(1) 0(1) 4(1) 6(1)
C(3) 25(1) 28(1) 23(1) -5(1) 2(1) 4(1)
C(4) 26(1) 22(1) 19(1) 0(1) 2(1) 6(1)
0(5) 40(1) 30(1) 31(1) -11(1) 3(1) -1(1)
C(5) 31(1) 25(1) 20(1) -1(1) 2(1) 4(1)
C(6) 37(1) 28(1) 27(1) -5(1) 7(1) 10(1)
C(7) 29(1) 35(1) 32(1) 0(1) 12(1) 11(1)
0(8) 23(1) 44(1) 41(1) -5(1) 6(1) 0(1)
C(8) 24(1) 29(1) 28(1) 2(1) 2(1) 4(1)
C(9) 24(1) 25(1) 20(1) 0(1) 2(1) 6(1)
C(10) 24(1) 26(1) 28(1) -5(1) 3(1) 2(1)
C(11) 25(1) 65(2) 62(2) -4(1) 12(1) 0(1)
C(12) 60(1) 38(1) 37(1) -17(1) 7(1) -7(1)
0(21) 58(1) 44(1) 19(1) 7(1) 13(1) 26(1)
N(21) 33(1) 22(1) 18(1) 4(1) 6(1) 11(1)
C(21) 28(1) 24(1) 20(1) 1(1) 5(1) 5(1)
C(22) 22(1) 20(1) 15(1) 1(1) 4(1) 4(1)
C(23) 23(1) 22(1) 23(1) -1(1) 1(1) 4(1)
C(24) 24(1) 22(1) 17(1) -1(1) 4(1) 4(1)
0(25) 29(1) 23(1) 49(1) -5(1) -5(1) 0(1)
C(25) 26(1) 24(1) 21(1) -3(1) 1(1) 2(1)
C(26) 34(1) 21(1) 23(1) -3(1) 4(1) 6(1)
C(27) 26(1) 28(1) 22(1) -1(1) 4(1) 8(1)
0(28) 21(1) 29(1) 45(1) 1(1) 2(1) 1(1)
C(28) 21(1) 28(1) 20(1) 0(1) 5(1) 2(1)
C(29) 23(1) 23(1) 16(1) 1(1) 6(1) 4(1)
C(210) 23(1) 23(1) 26(1) 2(1) 5(1) 1(1)
C(211) 24(1) 40(1) 45(1) -6(1) -3(1) 7(1)
C(212) 46(1) 24(1) 56(1) -6(1) -6(1) -3(1)
Table 5. Hydrogen coordinates (x 10^) and isotropic displacement parameters (A^x 10
for rk14m.
X y z U(eq)
H(1l\/11) 12844 1011 1185 48 H(1M2) 11655 859 1752 48 H{1M3) 13033 1554 1944 48
H(1M4) 12177 1271 2069 48 H(1IVI5) 13366 1423 1502 48
H(1M6) 11988 729 1310 48
H(3A) 11037 1096 336 30
H(3B) 10798 1957 -295 30 H(6A) 14443 -246 -1323 37
H(7A) 16320 866 -975 38 H(10A) 13625 3611 240 31
H(10B) 14032 2840 899 31 H(11A) 18244 2987 -161 76 H(11B) 17509 2589 -878 76 H{11C) 17985 1708 -299 76
H(12A) 11090 -1367 -1452 67
H{12B) 12672 -1522 -1174 67
H{12C) 12329 -709 -1813 67
H(21l) 9873 4791 656 29
H(23A) 10970 4783 2474 27
H(23B) 11565 5315 1767 27
H(26A) 8153 8188 1906 31 H(27A) 6102 7191 1688 30 H(21A) 8063 3623 1326 28 H(21B) 8436 3544 2153 28 H(21C) 3862 5011 1290 55 H(21D) 4728 5989 948 55 H(21E) 4321 6047 1755 55 H(21F) 11709 8808 2172 63 H(21G) 10147 8825 2455 63 H(21H) 10404 8816 1630 63
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Table 7. Hydrogen bonds for rk14m [A and °].
D-H...A d(D-H) d(H...A) d(D...A) <(DHA)
N(21)-H(21l)...0(21)#1 0.88 1.94 2.8196(18) 177.6
Symmetry transformations used to generate equivalent atoms; #1 -x+2,-y+1,-2
Structural Report of 155b
•NH •NH
HN- HN-
A sample of approximately 20mg of powder was submitted for analysis by powder X-ray diffraction. The attached diffraction pattern was obtained using the parameters listed in Table 1. Peak fitting within the Philips Analytical program Xpert Plus yielded the 26 peak positions listed in table 2. Indexing of these peaks was performed using the program Treor (as included in Xpert Plus). Refinement of the unit cell parameters and determination of possible space groups were then performed using the Symmetry Explorer module in Xpert Plus.
The results of this analysis indicate that the "0C6 cisdurene" molecule crystallizes in a monoclinic space group with parameters a = 31.24(7), b = 5.68(2),=c 16.38(3)A, a = 90, P = 110.12(2), Y = 90, V = 2730.634A^ The most likely space group is P2i (#4) based on systematic absence observations. For an empirical formula of C58H7808N4, and a Z of 2 (the most common and expected for P2i) the calculated density is 1.167 g/cm3 and the average non-H atomic volume is 19.5. Both of these values are typical of previous hydrogen bonded chains of piperazinediones. A further observation that supports this molecule in this cell is the length of the b axis which for other hydrogen bonded chains of piperazinediones is approximately 6A.
analvsis of RK19 Table 1 Relevant parameters of the Measurement parameters
Sample identification Date and time Generator settings Diffractometer Titel 1 Titel 2 Divergence slit/ ° Receiving slit/ mm Scan-range, step size (2Theta)/ ° Scan time per step/ s Scan type Detector
RK19 (Measl) 8/26/2002 17:15 50 kV, 40 mA XPert MPD Exported by X'Pert SW Generated by carducci in project robin. 0.125 12.750 2.004-38.920, 0.017 50.15 CONTINUOUS X'Celerator
Radiation Cu Ka Global parameters Number of phases 1 Structure and profile data Space group (No.) P 1 21 1 (4) Lattice parameters
a / A 3 1 . 2 4 ( 7 ) b/ A 5.68(2) c/ A 16.38(3) aJ° 90 P / ' 1 1 0 . 1 2 ( 2 )
353
Y / ° 90 V/106 pm3 2730.634
Table 2 Indices. 2Theta values, calculated and observed relative intensities of h k 1 2Theta d-spacing Icalc. lobs. 1 0 0 3.010 29.33289 0 22
1 0 -1 5.489 16.08733 0 1000 0 0 1 5.741 15.38159 0 282
2 0 0 6.021 14.66644 0 308 3 0 -1 8.885 9.94452 0 18 3 0 0 9.037 9.77763 0 45
2 0 1 9.651 9.15721 0 28 2 0 -2 10.991 8.04367 0 49
3 0 -2 11.935 7.40902 0 10 4 0 0 12.059 7.33322 0 20 4 0 -2 13.506 6.55083 0 40 5 0 0 15.090 5.86658 0 28 5 0 -2 15.517 5.70610 0 52 1 1 -1 16.531 5.35825 0 21 0 0 3 17.281 5.12720 0 30 2 1 1 18.359 4.82852 0 66 5 0 -3 18.644 4.75535 0 69 7 0 -2 20.333 4.36408 0 40 7 0 0 21.185 4.19041 0 20 5 1 0 21.756 4.08174 0 12 3 0 3 22.157 4.00885 0 8 5 0 -4 22.860 3.88709 0 4 4 1 -3 23.400 3.79862 0 13 8 0 1 26.844 3.31846 0 4 10 0 -3 29.399 3.03568 0 4 0 0 6 34.972 2.56360 0 6
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Structural Report of 187
EtOjC, HN—
O
356
NOTES
This written report is accompanied by an electronic Crystallographic Information File (GIF) which should be supplied to any journal publishing these results. It contains calculated distances and angles beyond those in the attached tables and all needed crystallographic information for generating other requisite results. With modifications it is suitable for electronic submission to Acta Crystallographica Section E as a structure report. Observed and calculated structure factors are in the file fofc.txt and rk09.fcf. Publications arising from this report must either 1) include the preparer(s) as coauthors when significant contributions were made and/or 2) acknowledge the Molecular Structure Laboratory and NSF grant CHE9610374 which provided the diffractometer, A copy of any paper reporting these results should be provided to MSL after publication.
EXPERIMENTAL
A colorless plate of C28 H40 N2 08, C3 H7 N O having approximate dimensions of 0.37 x .29 X .1 mm was mounted on a glass fiber in a random orientation. Examination of the crystal on a Bruker SMART 1000 CCD detector X-ray diffractometer at 170(2)K and a power setting of 50KV, 40mA showed measurable diffraction to at least 0 = 23.692°. Data were collected on the SMART1000 system using graphite monochromated Mo-Ka radiation (A=0.71073 A).
Cell constants and an orientation matrix for integration were determined from reflections obtained in three orthogonal 6° wedges of reciprocal space. A total of 1868 frames at 1 detector setting covering 0 < 20 < 60 ° were collected, having an w scan width of 0.3° and an exposure time of 20 seconds. The frames were integrated using the Bruker SAINT software package's narrow frame algorithm. A total of 25920 reflections were integrated and retained of which 6928 were unique (<redundancy> = 3.74, R|n, = 12.1%, R^ig = 18.7% ). Of the unique reflections, 2629 (37.95%) were observed l>2a(l). The final Monoclinic cell parameters of a = 10.7517(11), b = 36.694(4), c - 9.4807(10)A, a = 90, p = 115.835(2), y = 90°, volume = 3366.5(6) A® are based on the refinement of the XYZ-centroids of 4893 reflections with I > 4 a(l) covering the range of 2.196 < 0 < 23.692°. No absorption nor decay corrections were applied. For Z = 4 and F.W. = 605.72 the calculated density is 1.195g/cm®. Systematic absences and intensity statistics indicate the space group to be P2(1)/c (#14) which was consistent with refinement.
The structure was solved using SHELXS in the Bruker SHELXTL (Version 5.0) software package. Refinements were performed using XL and illustrations were made using XP. Solution was achieved utilizing direct methods followed by Fourier synthesis. Hydrogen atoms were added at idealized positions, constrained to ride on the atom to which they are bonded and given thermal parameters equal to 1.2 or 1.5 times Uiso of that bonded atom. The final anisotropic full-matrix least squares refinement based on F^ of all reflections converged (maximum shift/esd = 0.001) at R1 = 0.1990, wR2 = 0.2258 and goodness-of-fit = 0.895. "Conventional" refinement indices using the 2629 reflections with F > 4 a(F)
357
are R1 = 0.0678, wR2 = 0.1701. The model consisted of 390 variable parameters, 0 constraints and 1 restraint. There were 24 correlation coefficients greater than 0.50. The highest peak on the final difference map was 0.272 e/A® located 0.97 A from C37. The lowest peak on the final difference map was -0.389 e/A® located 0.43 A from H37B. Scattering Factors and anomalous dispersion were taken from International Tables Vol C Tables 4.2.6.8 and 6.1.1.4.
A small amount of librational disorder was observed in a terminal methyl carbon, C38. The disorder manifested itself as slightly larger than normal anisotropic thermal motion and an abnormally short Csps-Cgps bond length. Attempts to split the atom and/or the entire ethyl group to which it belonged did not satisfactorily resolve the problem, even with bond length constraints applied to the disordered components. The best model simply kept C38 as a single unit with the C37-C38 bond length constrained to 1.54 A. Subsequent refinements were improved.
STRUCTURE
The title compound, C28 H40 N2 08, C3 H7 N O, has the general structure proposed by the submitter. The structure consists of a fused tricyclic core to which are bonded four additional substituents at opposing ends of the core. The tricyclic core is formed from two five-membered rings fused to a central benzene ring at atoms C5, C9 and C3 and C11. The substituents (a /-butoxy carbamate and an ethoxy carbonyl) are bound at the apices of the five-membered rings at CI and C7. The carbamates project above the plane of the core and the ethoxy cabonyls project below the plane. The molecules pack in a lamellar fashion with the layers stacking in the ^-direction. Within a given layer, the amide portions of the carbamates form intermolecular hydrogen bonds which result in infinite chains of hydrogen bonding in the c-direction. Small channels in the structure contain a DMF molecule that is included in a 1:1 stoichiometric ratio with the main residue. This fact is reflected in the title formula.
FIGURES
Fig. 1 A thermal ellipsoid rendering of the molecule with 50% probability ellipsoids.
EQUATIONS
Rin, = IlFo^-(Fo2)|/I[Fo^]
Rs„ = Z[O(Fo')]/UFO']
R, = I1 |FO |-|FC| | / I |FO|
wRa = {L[w(FO^-FC2)VE[W(FO^^} '
w=1/[a^(Fo^)+(0.1078P)^] where P=:(Fo^+2Fc^)/3
0I1SI
C32I
0135) C(37)
CI33I
CI38I
00
359
Table 1. Crystal data and structure Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions
Volume z Density (calculated) Absorption coefficient F(OOO) Crystal size Theta range for utilized data Limiting Indices Reflections utilized Independent reflections Completeness to theta = 27.15° Absorption correction Max. and min. transmission Refinement method Data / restraints / parameters Goodness-of-fit on Final R indices [l>2sigma(l)] R indices (all data)
Largest diff. peak and hole
RMS difference density
refinement for rk09. rk09 C31 H47 N3 09 605.72 170(2) K 0.71073 A Monoclinic P2(1)/c a = 10.7517(11) A a=90°. b = 36.694(4) A b= 115.835(2)° c = 9.4807(10) A g = 90°. 3366.5(6) A3 4 1.195 Mg/m^ 0.088 mm-1 1304 .37 X .29 X 0.1 mm^ 1.11 to 27.15°. .13<=h<=13, -46<=k<=46, -12<=l<=11 25920 6928 [R(int) = 0.1212] 92.9 % None 1 and 0.809879 Full-matrix least-squares on F^ 6928 / 1 / 390 0.895 R1 =0.0678, wR2 = 0.1701 R1 =0.1990, wR2 = 0.2258
0.272 and -0.389 e.A'^
0.074e.A-3
Table 2. Atomic coordinates (x 10^) and equivalent isotropic displacement parameters (A^x 10^) for rk09. U(eq) is defined as one third of the trace of the orthogonal ized U'' tensor.
x y z U(eq)
0(15) 8577(3) 1329(1) 3803(3) 35(1) 0(23) 9271(3) 657(1) 5763(3) 33(1) 0(29) -3271(3) 1465(1) -169(3) 38(1) 0(28) -2511(3) 1179(1) -1776(3) 38(1) N(13) 7314(3) 1151(1) 5089(3) 26(1) N(26) -1372(3) 1138(1) 855(3) 33(1) 0(16) 8547(3) 1654(1) 5833(3) 39(1) 0(36) -2023(3) 445(1) 12(4) 52(1) C(3) 4522(4) 879(1) 2421(4) 27(1) C(14) 8194(4) 1373(1) 4824(4) 28(1) C(2) 5962(4) 872(1) 2521(4) 29(1) C(11) 4513(4) 720(1) 3754(4) 28(1) C(12) 5954(4) 607(1) 4877(4) 28(1) C(10) 3285(4) 671(1) 3875(4) 31(1) C(4) 3314(4) 1003(1) 1222(4) 31(1) C(7) -312(4) 898(1) 838(4) 34(1) 0(22) 8002(3) 291(1) 3782(4) 60(1) C(1) 6895(4) 807(1) 4272(4) 26(1) C(5) 2078(4) 961(1) 1344(4) 31(1) C(27) -2392(4) 1254(1) -477(5) 31(1) C(9) 2077(4) 792(1) 2654(4) 32(1) 0(35) -417(4) 408(1) -896(4) 66(1) C(21) 8119(4) 560(1) 4543(5) 32(1) C(24) 10442(4) 414(1) 6199(5) 34(1) C{34) -914(5) 563(1) -137(5) 39(1) C(6) 665(4) 1091(1) 253(5) 40(1) C(8) 628(4) 776(1) 2535(4) 42(1) C(17) 9573(4) 1921(1) 5875(5) 38(1) C(30) -4395(4) 1662(1) -1405(5) 40(1) C(25) 11732(4) 625(1) 7116(5) 50(1) C(20) 10933(5) 1737(2) 6278(6) 66(2) C(32) -5050(5) 1867(1) -509(6) 56(1) C(33) -5406(5) 1395(2) -2545(6) 61(2) C(38) -4132(6) 127(2) -1164(9) 114(3) C(37) -2637(6) 112(2) -856(8) 86(2) C(18) 9067(6) 2120(1) 4327(6) 71(2) C(31) -3807(5) 1925(1) -2198(6) 62(2) C(19) 9652(6) 2174(2) 7159(7) 83(2) N(1S) 3344(5) 2041(1) 2577(5) 62(1) 0(1S) 3095(6) 2465(1) 737(6) 112(2) C(3S) 2650(8) 1834(2) 3298(7) 102(2) C(2S) 2659(7) 2254(2) 1351(8) 86(2) C(1S) 4838(7) 2054(2) 3325(7) 94(2)
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displacement factor exponent takes the form: -2p^[ h^ + ... + 2 h k a* b* ]
U'' U22 U33 U23 U13 U12
0(15) 34(2) 54(2) 25(2) -7(1) 20(1) -6(1) 0(23) 23(2) 40(2) 31(2) -4(1) 8(1) 8(1) 0(29) 33(2) 57(2) 27(2) 3(1) 17(1) 14(2) 0(28) 38(2) 60(2) 20(2) 0(1) 15(1) 10(2) N(13) 24(2) 34(2) 24(2) -5(2) 16(2) -2(2) N(26) 26(2) 56(2) 16(2) •3(2) 9(2) 5(2) 0(16) 46(2) 39(2) 43(2) -14(1) 31(2) -13(1) 0(36) 45(2) 51(2) 56(2) -12(2) 19(2) -5(2) C(3) 21(2) 39(3) 22(2) -2(2) 10(2) -2(2) C(14) 22(2) 35(3) 22(2) -2(2) 6(2) 3(2) C(2) 21(2) 43(3) 20(2) -5(2) 6(2) 1(2) C(11) 24(2) 37(3) 23(2) 0(2) 9(2) 2(2) C(12) 22(2) 35(2) 25(2) -3(2) 9(2) -3(2) C(10) 29(2) 39(3) 26(2) 5(2) 14(2) 2(2) C(4) 26(2) 47(3) 22(2) -2(2) 13(2) -3(2) C(7) 21(2) 59(3) 26(2) 9(2) 13(2) 8(2) 0(22) 38(2) 60(2) 63(2) -34(2) 3(2) 9(2) C(1) 21(2) 33(2) 26(2) -4(2) 13(2) -1(2) C(5) 20(2) 53(3) 21(2) 5(2) 9(2) 5(2) C(27) 28(2) 45(3) 26(2) 1(2) 17(2) 2(2) C(9) 24(2) 49(3) 24(2) 2(2) 12(2) 3(2) 0(35) 91(3) 70(3) 53(2) 4(2) 44(2) 28(2) 0(21) 27(2) 38(3) 29(2) -5(2) 11(2) 1(2) 0(24) 23(2) 42(3) 34(2) 1(2) 10(2) 10(2) 0(34) 37(3) 48(3) 29(2) 11(2) 12(2) 14(2) 0(6) 25(2) 72(3) 26(2) 14(2) 15(2) 9(2) C(8) 26(2) 75(4) 25(2) 8(2) 10(2) 7(2) 0(17) 42(3) 37(3) 44(3) -4(2) 26(2) -11(2) 0(30) 31(3) 50(3) 36(2) 4(2) 14(2) 14(2) 0(25) 31(3) 70(4) 39(3) -15(2) 7(2) 4(2) 0(20) 42(3) 75(4) 79(4) -10(3) 25(3) -9(3) 0(32) 59(3) 59(3) 59(3) 4(3) 35(3) 23(3) 0(33) 34(3) 81(4) 55(3) -11(3) 7(2) 8(3) 0(38) 115(6) 98(5) 167(7) -75(5) 99(6) -70(5) 0(37) 92(5) 48(4) 99(5) -8(3) 23(4) -6(3) 0(18) 80(4) 55(4) 75(4) 17(3) 30(3) -13(3) 0(31) 72(4) 62(4) 67(4) 21(3) 45(3) 19(3) 0(19) 108(5) 71(4) 101(5) •48(4) 74{4) -43(4) N(1S) 92(4) 53(3) 47(3) 5(2) 35(3) 10(3) 0(1 S) 164(5) 86(3) 97(4) 37(3) 69(3) 23(3) C(3S) 157(7) 89(5) 79(5) -19(4) 68(5) -28(5) C(2S) 99(5) 88(5) 76(5) 5(4) 41(4) 29(4) 0(1 S) 83(5) 129(6) 56(4) 2(4) 18(4) 21(4)
Table 5. Hydrogen coordinates (x 10"*) and isotropic displacement parameters (A^x 10 for rk09.
X y z U(eq)
H{13A) 6993 1217 5762 31 H(26A) -1343 1208 1757 39 H(2A) 6187 1106 2168 35 H(2B) 6060 672 1874 35 H{12A) 6069 340 4861 34 H(12B) 6166 684 5960 34 H{10A) 3273 558 4771 37 H(4A) 3325 1115 324 37 H(24A) 10468 311 5248 41 H(24B) 10361 211 6840 41 H(6A) 435 1021 -842 48 H{6B) 598 1359 310 48 H(8A) 532 943 3302 51 H(8B) 395 526 2725 51 H(25A) 12533 464 7419 74 H(25B) 11702 725 8060 74 H(25C) 11808 825 6473 74 H(20A) 11236 1611 7285 99 H(20B) 11623 1920 6353 99 H(20C) 10828 1560 5459 99 H(32A) -5422 1693 -8 84 H{32B) -5800 2021 -1235 84 H(32C) -4351 2020 295 84 H{33A) -5756 1231 -1981 91 H(33B) -4939 1251 -3044 91 H{33C) -6180 1528 -3349 91 H(38A) -4631 -78 -1840 170 H(38B) -4538 357 -1685 170 H(38C) -4201 110 -169 170 H(37A) -2181 -106 -228 103 H(37B) -2550 104 -1852 103 H(18A) 9024 1950 3510 107 H(18B) 9706 2319 4417 107 H(18C) 8145 2220 4051 107 H(31A) -3392 1787 -2770 93 H(31B) -3101 2078 -1403 93 H(31C) -4551 2080 -2932 93 H(19A) 9982 2039 8148 124 H(19B) 8733 2274 6900 124 H(19C) 10293 2373 7265 124 H(3SA) 1664 1819 2584 153 H(3SB) 2767 1954 4273 153 H(3SC) 3044 1588 3532 153 H(2SA) 1681 2235 904 103 H(1SA) 5169 2156 2596 141 H(1SB) 5204 1806 3622 141 H(1SC) 5153 2207 4264 141
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Table 7. Hydrogen bonds for rk09 [A and °].
D-H...A d(D-H) d(H...A) d(D...A) <(DHA)
N(13)-H(13A)...0(28)#1 0.88 2.16 2.897(4) 140.8 N(26)-H(26A)...0(15)#2 0.88 2.03 2.905(4) 174.1
Symmetry transformations used to generate equivalent atoms: #1 x+1 ,y,z+1 #2 x-1 ,y,z
Structural Report of 188
HN-
•NH
369
NOTES
This written report is accompanied by an electronic Crystaliographic Information File (GIF) which should be supplied to any journal publishing these results. It contains calculated distances and angles beyond those in the attached tables and all needed crystaliographic information for generating other requested results. With modifications it is suitable for electronic submission to Acta Crystallographica Section E as a structure report. Observed and calculated structure factors are in the file fofc.txt and rklTm.fcf. Publications arising from this report must either 1) include the preparer(s) as coauthors when significant contributions were made and/or 2) acknowledge the Molecular Structure Laboratory and NSF grant CHE9610374 which provided the diffractometer. A copy of any paper reporting these results should be provided to MSL after publication.
EXPERIMENTAL
A colorless plate of C34 H36 N2 08 having approximate dimensions of 0.3 x 0.15 x 0.08 mm was mounted on a glass fiber in a random orientation. Examination of the crystal on a Bruker SMART 1000 CCD based X-ray diffractometer at 170(2)K and a power setting of 50KV, 40mA showed measurable diffraction to at least 0 = 26.249°. Data were collected on the SMART1000 system using graphite monochromated Mo-Ka radiation (A=0.71073 A).
Cell constants and an orientation matrix for integration were determined from reflections obtained in three orthogonal 6° wedges of reciprocal space. A total of 3686 frames at 1 detector setting covering 0 < 20 < 60 ° were collected, having an o) scan width of 0.3° and an exposure time of 20 seconds. The frames were integrated using the Bruker SAINT software package's narrow frame algorithm. A total of 8288 reflections were integrated and retained of which 2981 were unique (<redundancy> = 2.780, Rip, = 6.9%, Rgig = 8.8% ). Of the unique reflections, 1822 (61.12%) were observed l>2a(l). The final Triclinic cell parameters of a = 7.7824(8), b = 9.1091 (9), c = 11.1134(11)A, a = 98.037(2), |3= 106.442(2), Y = 100.826(2)°, volume = 726.43(13) A® are based on the refinement of the XYZ-centroids of 2822 reflections with I > 4 a(l) covering the range of 2.3255 <6< 26.249°. The absorption coefficient is 0.098 mm-1, Tmin = 0.899488, and Tmax = 1. However, no decay nor absorption correction was necessary. For Z = 1 and F.W. = 600.65 the calculated density is 1.373g/cm^. Systematic absences and intensity statistics indicate the space group to be P-1 (#2) which was consistent with refinement.
The structure was solved using XS in the Bruker SHELXTL (Version 5.0) software package. Refinements were performed using XL and illustrations were made using XP. Solution was achieved utilizing direct methods followed by Fourier synthesis. Hydrogen atoms were added at idealized positions, constrained to ride on the atom to which they are bonded and given thermal parameters equal to 1.2 or 1.5 times Uiso of that bonded atom. The final anisotropic full-matrix least squares refinement based on F^ of all reflections converged (maximum shift/esd = 0.000) at R1 = 0.0794, wR2 = 0.0864 and goodness-of-
370
fit = 0.867. "Conventional" refinement indices using tine 1822 reflections with F > 4 a(F) are R1 = 0.0418, wR2 = 0.0787. The model consisted of 199 variable parameters, 0 constraints and 0 restraints. There were no correlation coefficients greater than 0.50. The highest peak on the final difference map was 0.301 e/A® located 0.64 A from H7A. The lowest peak on the final difference map was -0.317 e/A^ located 0.27 A from H7A. Scattering Factors and anomalous dispersion were taken from International Tables Vol C Tables 4.2.6.8 and 6.1.1.4.
STRUCTURE
The title compound has the structure proposed by the submitter. The molecule is based on a benzene ring with two five-membered aliphatic rings fused to it at the 1,2 and 4,5 positions. At the apices of the five-membered rings (CI and its symmetry equivalent) are a carboxybenzyl protected amine and an ethyl ester. With the imposition of the
crystallographic inversion symmetry, the amides and esters are trans- to one another with
respect to the plane of the benzene ring. The centroid of the benzene ring sits on the inversion center; only half the molecule is contained in the asymmetric unit. There is one complete molecule per unit cell. The amide hydrogen atoms (H7 and equivalent) undergo intermolecular hydrogen bonding with the ester (C=0) oxygen atoms of neighboring molecules. This hydrogen bonding scheme forms infinite chains parallel to the c-axis (Figure 2).
FIGURES
Fig. 1 A thermal ellipsoid rendering of the molecule with 50% probability ellipsoids.
Fig. 2 A diagram elaborating the hydrogen bonding along c. EQUATIONS
Rin, = Z|Fo2-(Fo2)|/I[Fo2]
Rsig = I[0(F0MF0^]
R, = I||Fo|-|Fc|!/X|Fo|
WR2 = {I:[w(FO^-FC2)VZ[W(FO2)^]} '
w=1/[a2(Fo2)+(0.025400P)2] where P=(Fo2+2Fc2)/3
GOF = S = {X[w(Fo'-Fc')V(n-p)}'"
371
Table 1. Crystal data and structure Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions
Volume Z Density (calculated) Absorption coefficient F(OOO) Crystal size Theta range for utilized data Limiting Indices Reflections utilized Independent reflections Completeness to theta = 26.39° Absorption correction Max. and min. transmission Refinement method Data / restraints / parameters Goodness-of-fit on Final R indices [l>2sigma(l)] R indices (all data)
Largest diff. peak and hole
RMS difference density
refinement for rk17m. rk17m C34 H36 N2 08 600.65 170(2) K 0.71073 A Triclinic P-1 a = 7.7824(8) A b = 9 . 1 0 9 1 ( 9 ) A c = 1 1 . 1 1 3 4 ( 1 1 ) A 726.43(13) A3 1 1.373 Mg/m3 0.098 mm-' 318 0.3 X 0.15 X 0.08 mm^ 1.95 to 26.39°. .9<=h<=9, -11<=k<=11, -13<=l<=13
8288 2981 [R(int) = 0.0688] 99.8 % None 1 and 0.899488 Full-matrix least-squares on F^ 2981 / 0/199 0.867 R1 =0.0418, wR2 = 0.0787 R1 = 0.0794, wR2 = 0.0864
0.301 and -0.317 e.A^
0.043e.A-3
a= 98.037(2)°. b= 106.442(2)°. g = 100.826(2)°.
U) K)
373
374
Table 2. Atomic coordinates (x 10'*) and equivalent isotropic displacement parameters (A^x 10®) for rk17m. U(eq) is defined as one third of the trace of the orthogonalized U'i tensor.
x y z U(eq)
N(7) 1355(2) 4355(2) 1505(1) 23(1) 0(8) 4447(2) 4761(1) 1787(1) 28(1) 0(9) 2363(2) 2872(1) 229(1) 29(1) 0(17) 2060(2) 7070(1) 728(1) 27(1) 0(18) 2488(2) 8439(1) 2675(1) 30(1) C(4) 1818(2) 5018(2) 5711(2) 21(1) C(8) 2857(2) 4070(2) 1223(2) 22(1) C(2) 2736(2) 5797(2) 3768(2) 23(1) C(1) 1481(2) 5748(2) 2387(2) 22(1) C(5) 386(2) 4683(2) 6214(2) 20(1) C(3) 1420(2) 5338(2) 4491(2) 19(1) C(6) -462(2) 5737(2) 2514(2) 22(1) C(17) 2063(2) 7130(2) 1821(2) 23(1) C(11) 3095(2) 1260(2) -1338(2) 26(1) C(19) 2884(3) 9831(2) 2196(2) 32(1) C(20) 3470(3) 11160(2) 3306(2) 43(1) C(16) 3117(2) 1610(2) -2502(2) 32(1) C(12) 2322(3) -223(2) -1313(2) 39(1) 0(10) 3892(3) 2463(2) -135(2) 34(1) 0(15) 2350(3) 498(3) -3618(2) 40(1) 0(14) 1580(3) -964(3) -3577(2) 44(1) 0(13) 1578(3) -1331(2) -2421(2) 47(1)
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C(13)-C(12)-H(12A) 119.4 C(14)-C(15)-H(15A) 119.8 C(11)-C(12)-H(12A) 119.4 C(16)-C(15)-H(15A) 119.8 0(9)-C(10)-C{11) 107.67(14) C(15)-C(14)-C(13) 119.62(19) 0(9)-C(10)-H(10A) 110.2 C(15)-C(U)-H(14A) 120.2 C(11)-C(10)-H(10A) 110.2 C(13)-C(14)-H(14A) 120.2 0(9)-C(10)-H(10B) 110.2 C(14)-C(13)-C(12) 120.0(2) C{11)-C(10)-H(10B) 110.2 C(14)-C(13)-H(13A) 120.0 H(10A)-C(10)-H(10B) 108.5 C(12)-C(13)-H(13A) 120.0 C(14)-C(15)-C{16) 120.41(19)
Symmetry transformations used to generate equivalent atoms; # 1 - x , - y + 1 , - z + 1
Table 4. Anisotropic displacement parameters (A^x 10®) for rk17m. The anisotropic
displacement factor exponent takes the form: -2p^[ +... + 2 h k a* b* ]
y22 U33 U23 U13 U12
N(7) 19(1) 22(1) 26(1) -1(1) 9(1) -2(1) 0(8) 21(1) 31(1) 27(1) 0(1) 5(1) 2(1) 0(9) 25(1) 30(1) 27(1) -5(1) 9(1) 4(1) 0(17) 28(1) 32(1) 19(1) 4(1) 8(1) 2(1) 0(18) 39(1) 24(1) 27(1) 3(1) 14(1) 3(1) C(4) 19(1) 22(1) 19(1) 1(1) 4(1) 5(1) C(8) 27(1) 21(1) 18(1) 5(1) 7(1) 4(1) 0(2) 20(1) 27(1) 20(1) 3(1) 7(1) 4(1) 0(1) 22(1) 24(1) 19(1) 2(1) 7(1) 4(1) 0(5) 21(1) 18(1) 18(1) 1(1) 5(1) 5(1) 0(3) 21(1) 17(1) 18(1) -1(1) 7(1) 3(1) 0(6) 20(1) 27(1) 19(1) 4(1) 6(1) 5(1) 0(17) 16(1) 28(1) 21(1) 1(1) 4(1) 3(1) 0(11) 24(1) 26(1) 28(1) 3(1) 11(1) 8(1) 0(19) 41(1) 27(1) 31(1) 9(1) 14(1) 8(1) 0(20) 60(2) 29(1) 43(1) 5(1) 21(1) 8(1) 0(16) 30(1) 30(1) 39(1) 9(1) 14(1) 8(1) 0(12) 57(1) 33(1) 33(1) 8(1) 23(1) 9(1) C(10) 28(1) 36(1) 35(1) -4(1) 12(1) 9(1) 0(15) 46(1) 53(2) 26(1) 10(1) 13(1) 18(1) 0(14) 48(1) 42(1) 35(1) -10(1) 12(1) 8(1) 0(13) 62(2) 25(1) 49(1) -3(1) 23(1) -1(1)
Tabie 5. Hydrogen coordinates (x 10"*) and isotropic displacement parameters (A^x 10 for rk17m.
X y z U(eq)
H(7A) 284 3689 1152 28 H(4A) 3044 5029 6190 25 H(2A) 3538 5074 3753 27 H(2B) 3523 6837 4166 27 H(6A) -728 6756 2494 27 H(6B) -1430 4977 1808 27 H(19A) 1771 9916 1532 39 H(19B) 3882 9814 1809 39 H(20A) 3747 12113 3008 65 H(20B) 4573 11066 3956 65 H(20C) 2471 11169 3680 65 H(16A) 3663 2620 -2540 38 H(12A) 2302 -486 -519 47 H(10A) 4671 2070 556 41 H(10B) 4667 3370 -283 41 H(15A) 2358 754 -4417 48 H(14A) 1050 -1722 -4343 53 H(13A) 1063 -2349 -2384 56
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Table 7. Hydrogen bonds for rk17m [A and"].
D-H...A d(D-H) d(H...A) d(D...A) <(DHA)
N(7)-H(7A)...0(17)#2 0.88 2.27 2.9963(17) 140.3
Symmetry transformations used to generate equivalent atoms; #1 -x,-y+1 ,-2+1 #2 -x,-y+1 ,-2
Structural Report of 206
H3CO2C COjCH
O^NH
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381
NOTES
This written report is accompanied by an electronic Crystallographic Information File (CIF) which should be supplied to any journal publishing these results. It contains calculated distances and angles beyond those in the attached tables and all needed crystallographic information for generating other needed results. With modifications it is suitable for electronic submission to Acta Crystallographica Section C as a structure report. Observed and calculated structure factors are in the file fofc.txt and rk06m.fcf. Publications arising from this report must either 1) include the preparer(s) as coauthors when significant contributions were made and/or 2) acknowledge the Molecular Structure Laboratory and NSF grant CHE9610374 which provided the diffractometer. A copy of any paper reporting these results should be provided to MSL after publication.
EXPERIMENTAL
A colorless plate of C26 H30 N2 08 having approximate dimensions of 0.05 x 0.15 x 0.20 mm was mounted on a glass fiber in a random orientation. Examination of the crystal on a Bruker SMART 1000 CCD detector X-ray diffractometer at 100(2)K and a power setting of 50KV, 40mA showed measurable diffraction to at least 0 = 25.73°. Data were collected on the SMART1000 system using graphite monochromated Mo Ka radiation ( A=0.71073A ).
Cell constants and an orientation matrix for integration were determined from reflections obtained in three orthogonal 6° wedges of reciprocal space. A total of 3736 frames at 1 detector setting covering 0° < 20 < 60° were collected, having an co scan width of 0.3° and an exposure time of 30 seconds. The frames were integrated using the Bruker SAINT software package's narrow frame algorithm. A total of 11978 reflections were integrated and retained of which 2409 were unique (<redundancy> = 4.97, R|„, = 5.1%, Rgig = 5.0% ). Of the unique reflections, 1621 (67.23%) were observed l>2a{l). The final Monoclinic cell parameters of a = 10.2758(6)A, b = 7.1597(4)A, c = 16,6143(10)A, a = 90°, p = 92.7750(10)°, Y= 90°, volume = 1220.91(12) A® are based on the refinement of the XYZ-centroids of 12592 reflections with I > 10 sigma(l) covering the range of 2.45° < 0 < 25.73°. Decay was measured at regular intervals and found to be 0.24%. The absorption coefficient is 0.101 mm"\ no decay nor absorption correction has been applied. For Z = 2 and F.W. = 498.52 the calculated density is 1.356g/cm^. Systematic absences and intensity statistics indicate the space group to be P2(1)/c (#14) which was consistent with refinement.
The structure was solved using SHELXS in the Bruker SHELXTL (Version 5.0) software package. Refinements were performed using SHELXL and illustrations were made using XP. Solution was achieved utilizing direct methods followed by Fourier synthesis. Hydrogen atoms were added at idealized positions, constrained to ride on the atom to which they are bonded and given thermal parameters equal to 1.2 or 1.5 times Uisj, of that bonded atom. The final anisotropic full-matrix least squares refinement based on F^ of all reflections converged (maximum shift/esd = 0.000) at R, = 0.0734, wRj =
382
0.1043 and goodness-of-fit = 0.997. "Conventional" refinement indices using the 1621 reflections w/ith F > 4 a(F) are R, = 0.0393, wRj = 0.0880. The model consisted of 163 variable parameters, 0 constraints and 0 restraints. There were no correlation coefficients greater than 0.50. The highest peak on the final difference map was 0.441 e/ located 0.63 A from HN. The lowest peak on the final difference map was -0.531 e/ A^ located 0.22 A from HN. Scattering Factors and anomalous dispersion were taken from International Tables Vol C Tables 4.2.6.8 and 6.1.1.4.
STRUCTURE
The title compound, C26 H30 N2 08, was found to have the basic structure suggested by the submitter. The compound consists of a core cyclohexane moiety which is tetra-substituted at the 1 and 4 positions. The substituents are a benzylcarbamate and a methyl ester in the axial and equatorial positions, respectively. The cyclohexane core adopts a boat conformation, yielding an overall trans disposition of the substituents and allowing a center of symmetry at the cyclohexane centroid.
As the molecule is centrosymmetric, only one half is contained in the asymmetric unit. There are two molecules in the unit cell. An intermolecular hydrogen bond exists between a given molecule's amide nitrogen (N1) and a neighbor's methyl ester oxygen (03_$2). The hydrogen bonding scheme extends roughly parallel to the b axis.
FIGURES
Fig. 1 A thermal ellipsoid rendering of the molecule with 50% probability ellipsoids.
EQUATIONS
Ri„, = Z|FoMFo^>|/ZM
Rsig = I[a(FoMFo1
R, = I1 | FO |-|FC ||/I|FO | .
WR2 = {i:[w(Fo2-Fc2)^]/E[w(Fo2)2l} '2
w=1/[a^(Fo')+(0.03770P)^+0.66560P] where P=(Fo^+2Fc^)/3
GOF = S = {INFo^-Fc') V(n-P)}"'
383
Table 1. Crystal data and structure Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions
Volume Z Density (calculated) Absorption coefficient F(OOO) Crystal size Theta range for utilized data Limiting Indices Reflections utilized Independent reflections Completeness to theta = 26.06° Absorption correction Refinement method Data / restraints / parameters Goodness-of-fit on F^ Final R indices [l>2sigma(l)] R indices (all data) Largest diff. peak and hole
RMS difference density
refinement for rk06m. rk06m C26 H30 N2 08 498.52 100(2) K 0.71073 A Monoclinic P2(1)/c a = 10.2758(6) A a= 90°. b = 7.1597(4) A (3=92.7750(10)° c= 16.6143(10) A y = 90°. 1220.91(12) A3 2 1.356 Mg/m3 0.101 mm"'' 528 0.20 X 0.15 X 0.05 mm^ 1.98 to 26.06°. -12<=h<=12, -8<=k<=8, -20<=l<=20 11978 2409 [R(int) = 0.0508] 99.7 % None Full-matrix least-squares on F^ 2409 /0 /163 0.997 R1 = 0.0393, wR2 = 0.0880 R1 =0.0734, wR2 = 0.1043
0.441 and -0.531 e.A-3
0.050e.A-3
Table 2. Atomic coordinates ( x 10") and equivalent isotropic displacement parameters (A^x 10^) for rl<06m. U{eq) is defined as one third of the trace of the orthogonal ized U'i tensor.
x y 2 U(eq)
0(2) 7480(1) 4628(2) -848(1) 20(1) C(2) 7324(2) 3424(3) -230(1) 18(1) C(8) 8099(2) 8149(3) -2820(1) 32(1) C(9) 8132(2) 6746(3) -2247(1) 27(1) C(4) 8648(2) 7066(3) -1474(1) 22(1) C(3) 8740(2) 5538(3) -854(1) 25(1) C(5) 9130(2) 8835(3) -1283(1) 31(1) C(7) 8595(2) 9890(3) -2632(2) 34(1) C(6) 9104(2) 10230(3) -1866(2) 38(1) 0(3) 5688(1) 4602(2) 1170(1) 20(1) 0(4) 5732(1) 1876(2) 1834(1) 22(1) C(13) 6223(2) -202(3) 495(1) 17(1) C(12) 5908(2) -1450(3) -234(1) 17(1) C(10) 5700(2) 2912(3) 1168(1) 17(1) C(1) 5575(2) 1722(3) 403(1) 16(1) 0(1) 8173(1) 3009(2) 268(1) 26(1) N(1) 6079(2) 2776(2) -265(1) 16(1) C(11) 5603(2) 2866(3) 2591(1) 25(1)
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Table 4. Anisotropic displacement parameters (A^x 10®) for rk06m. The anisotropic displacement factor exponent takes the form: -2p2[ h^ + ... + 2 h k a* b* ]
U" u22 (j33 u23 u13 u12
0(2) 21(1) 20(1) 19(1) 4(1) 2(1) -4(1) C(2) 22(1) 16(1) 17(1) -1(1) 4(1) 1(1) C(8) 26(1) 37(1) 32(1) 10(1) 3(1) 2(1) C{9) 25(1) 24(1) 34(1) 2(1) 4(1) -1(1) C(4) 16(1) 22(1) 29(1) 5(1) 6(1) 0(1) C(3) 19(1) 26(1) 30(1) 5(1) 1(1) -4(1) C(5) 28(1) 28(1) 37(1) 0(1) 3(1) -6(1) C(7) 22(1) 33(1) 48(2) 18(1) 7(1) 1(1) C(6) 30(1) 23(1) 63(2) 5(1) 6(1) -7(1) 0(3) 27(1) 14(1) 18(1) 0(1) -2(1) 0(1) 0(4) 36(1) 18(1) 12(1) 1(1) 3(1) 1(1) C(13) 18(1) 16(1) 16(1) 1(1) 0(1) 0(1) C(12) 20(1) 15(1) 16(1) 1(1) 3(1) 1(1) C(10) 16(1) 18(1) 16(1) 2(1) 0(1) 1(1) C(1) 21(1) 15(1) 12(1) 1(1) 1(1) -1(1) 0(1) 21(1) 29(1) 27(1) 8(1) -4(1) -1(1) N(1) 20(1) 18(1) 11(1) 1(1) -1(1) -2(1) C(11) 37(1) 23(1) 14(1) -4(1) 3(1) -3(1)
Table 5. Hydrogen coordinates (x 10"*) and isotropic displacement parameters (A^x 10 for rk06m.
X y z U(eq)
H(8A) 7733 7911 -3346 38 H(9A) 7795 5546 -2385 33 H(3A) 9419 4625 -991 30 H(3B) 8975 6067 -316 30 H(5A) 9476 9090 -754 37 H(7A) 8586 10847 -3028 41 H(6A) 9442 11432 -1732 46 H(13A) 7179 -40 563 20 H(13B) 5921 -818 986 20 H(12A) 6321 -2686 -141 20 H(12B) 6287 -890 -715 20 HN 5571 2995 -696 19 H(11A) 5641 1970 3037 37 H(11B) 4766 3523 2578 37 H(11C) 6314 3770 2666 37
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389
Table 7. Hydrogen bonds for rk06m [A and °].
D-H...A d(D-H) d(H...A) d(D...A) <(DHA)
N(1)-HN...O(3)#2 0.88 2.27 2.969(2) 136.3
Symnnetry transformations used to generate equivalent atoms: #1-x+1,-y,-z #2-x+1,-y+1,-2
Structural Report of 207
H3CO2C
H2N ^ NH2 (R,R)
H2N ^ CO2CH (S,S)
391
NOTES
This written report is accompanied by an electronic Crystallographic Information File (GIF) wliich should be supplied to any journal publishing these results. It contains calculated distances and angles beyond those in the attached tables and all needed crystallographic information for generating other needed results. With modifications it is suitable for electronic submission to Acta Crystallographica Section E as a structure report. Observed and calculated structure factors are in the files rk12m.fcf and fofc.txt. Publications arising from this report must either 1) include the preparer(s) as coauthors when significant contributions were made and/or 2) acknowledge the Molecular Structure Laboratory and NSF grant CHE9610374 which provided the diffractometer. A copy of any paper reporting these results should be provided to MSL after publication.
EXPERIMENTAL
A colorless plate of (C11 H20 N2 04)2+, 2CI- having approximate dimensions of 0.01 x 0.20 X 0.25 mm was mounted on a glass fiber in a random orientation. Examination of the crystal on a Bruker SMART 1000 CCD detector X-ray diffractometer at 293(2)K and a power setting of 50KV, 40mA showed measurable diffraction to at least theta = 16.18deg. Data were collected on the SMART1000 system using graphite monochromated Mo Ka radiation (A=0.71073A).
Initial cell constants and an orientation matrix for integration were determined from reflections obtained in three orthogonal 5 deg wedges of reciprocal space. A total of 1954 frames at 1 detector setting covering 0 < 2theta < 60 deg were collected(one half sphere), having an omega scan width of 0.2 and an exposure time of 60 seconds. The frames were integrated using the Bruker SAINT software package's narrow frame algorithm. A total of 4215 reflections were integrated and retained of which 1307 were unique (<redundancy> = 3.2, Pint = 25.7%, Rsig = 31.7% ). Of the unique reflections, 395 (30.2%) were observed l>2sigma(l). The final Monoclinic cell parameters of a = 8.681(6), b = 16.982(12), c = 11.343(8), alpha = 90, beta = 90.511(13), gamma = 90, volume = 1672(2) A^3 are based on the refinement of the XYZ-centroids of 400 reflections with I > 3 sigma(l) covering the range of 2.40 < theta < 16.18. No absorption or decay corrections were applied. The absorption coefficient is 0.398 mm-1, Tmin = 0.9070, and Tmax = 0.9960 based on crystal size. For Z = 4 and F.W. = 315.19 the calculated density is 1.252g/cm3. Systematic absences and intensity statistics indicate the space group to be P2(1)/c (#14) which was consistent with refinement.
The structure was solved using SHELXS in the Bruker SHELXTL (Version 5.0) software package[1]. Refinements were performed using the freely available SHELXL and illustrations were made using XP. Solution was achieved utilizing direct methods followed by Fourier synthesis. Hydrogen atoms were added at idealized positions, constrained to ride on the atom to which they are bonded and given thermal parameters equal to 1.2 or 1.5 times Uiso of that bonded atom. A parameter describing extintion was included. A rigid bond restraint was applied to all bonded atoms. Because of the limited extent of
392
observable diffraction, this analysis has a suboptimal data to parameter ratio of 7.5 (10 i more typical). With the use of appropriate restraints, there is no sign of parameters being overdetermined. The final anisotropic full-matrix least squares refinement based on F^2 c all reflections converged (maximum shift/esd = 0.000) at R1 = 0.2342, wR2 = 0.1310 and goodness-of-fit = 0.774. "Conventional" refinement indices using the 395 reflections with > 4 sigma(F) are R1 = 0.0643, wR2 = 0.0953. The model consisted of 173 variable parameters, 0 constraints and 54 restraints. There were 7 correlation coefficients greater than 0.50. Only one between the extinction parameter and the scale factor is over 0.6 Tf highest peak on the final difference map was 0.260 e/A^3 located 1.57 A from CL2. The lowest peak on the final difference map was -0.189 e/A^3 located 1.19 A from H24A. Scattering Factors and anomalous dispersion were taken from International Tables Vol C Tables 4.2.6.8 and 6.1.1.4.
STRUCTURE
This compound crystallizes as thin flat plates. It has the structure expected by the submit There are discrete cationic moieties as pictured in Fig. mol. Charge balance is provided by chloride anions. Each of the hydrogens in the NHa"" groups of the cation are hydroger bonded to different CI", as detailed in Table 8. The remainder of the cation consists of twi spiro fused cyclobutane rings. The individual rings are not flat, but slightly puckered. The substituents at the ring ends are rotated by 87.3(5)° from each other.
FIGURES
Fig. mol A thermal ellipsoid rendering of the cation with 50% probability ellipsoids.
Fig. cella A packing diagram of the unit cell contents viewed down the a axis. Atoms rendered with 50% probability ellipsoids.
EQUATIONS
Rin. = I|Fo^-(Fo^)|/i:[Fo2]
Rsig = L[o(Fo')]/Z[Fo']
R, = Z||FoHFc||/Z|Fo|
wRz = {I[w(Fo'-Fc') Vl[w(Fo^)']}^''
W=1/[CT2(FO^)+(0.0000P)2+0.00P] where P=(Fo2+2Fc2)/3
GOF = S = {X[w(Fo'-Fc2)V(n-p)}'"
393
Table 1. Crystal data and structure refinement for rk12m. Identification code rk12m Empirical formula C11 H20 CI2 N2 04 Formula weight 315.19 Temperature 293(2) K Wavelength 0.71073 A Crystal system Monoclinic Space group P2(1)/c Unit cell dimensions a = 8.681 (6) A a= 90°
b= 16.982(12) A b= 90.1 c= 11.343(8) A g = :90'
Volume 1672(2) A3 z 4 Density (calculated) 1.252 Mg/m3 Absorption coefficient 0.398 mm"^ F(OOO) 664 Crystal size 0.25 X 0.20 X 0.01 mm3 Theta range for utilized data 2.16 to 18.85°. Limiting Indices -7<=h<=7, -15<=k<=15, -10<=l<: =8
Reflections utilized 4215 Independent reflections 1307 [R(int) = 0.2568] Completeness to theta = 18.85° 100.0% Absorption correction None Max. and min. transmission 0.9960 and 0.9070 Refinement method Full-matrix least-squares on F^ Data / restraints / parameters 1307/54/173 Goodness-of-fit on P 0.774 Final R indices [l>2sigma(l)] R1 = 0.0643, wR2 = 0.0953 R indices (all data) R1 =0.2342, wR2 = 0.1310 Extinction coefficient 0.0047(12)
Largest diff. peak and hole 0.260 and -0.189 e.A^ RMS difference density 0.045e.A-3
394
395
396
Table 2. Alomic coordinates (x lO"*) and equivalent isotropic displacement parameters (A^x 10^)
for rk12m. U(eq) is defined as one third of the trace of the orthogonalized U'' tensor.
X y 2 U(eq)
Cl(1) 7027(4) 248(2) 1312(3) 78(2)
Cl(2) 12896(6) -2696(3) -3924(4) 157(2)
C(1) 11161(16) -5930(8) -3235(13) 63(4)
C{11) 12917(13) -5821(8) -3032(14) 87(5)
C(12) 11062(12) -5024(6) -3236(12) 73(4)
C(13) 12824(15) -4955(9) -2815(15) 63(4)
N(14) 13741(9) -4483(6) -3658(8) 74(4)
C(15) 13110(20) -4668(12) -1668(18) 92(6)
0(16) 13992(13) -4172(8) -1396(10) 158(6)
0(17) 12239(12) -5040(7) -905(11) 111(4)
C(18) 12407(17) -4754(10) 303(14) 142(8)
C(21) 10487(15) -6425(7) -4207(13) 76(4)
C(22) 10186(14) -6401(7) -2347(12) 77(4)
C(23) 9737(17) -6983(8) -3315(13) 64(4)
N(24) 8016(11) -7077(5) -3461(9) 84(4)
C(25) 10470(20) -7738(11) -3220(18) 105(6)
0(26) 9894(13) -8352(6) -3521(11) 131(5) 0(27) 11964(12) -7676(6) -3004(12) 135(5)
C(28) 12936(17) -8362(9) -3015(18) 196(9)
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398
H(24B)-N(24)-H(24C) 109.5 0(27)-C(28)-H(28B) 109.5
0(26)-C(25)-0(27) 121.7(19) H(28A)-C(28)-H(28B) 109.5
0(26)-C(25)-C(23) 124.8(18) 0(27)-C(28)-H(28C) 109.5
0(27)-C(25)-C(23) 112.1(16) H(28A)-C(28)-H(28C) 109.5
C(25)-0(27)-C(28) 120.5(14) H(28B)-C(28)-H(28C) 109.5
0(27)-C(28)-H(28A) 109.5
Symmetry transfomiations used to generate equivalent atoms;
Table 4. Anisotropic displacement parameters (A^x 10®) for rk12m. The anisotropic
displacement factor exponent takes the form: -2p^[ h^ a*2U" + ... + 2 h k a* b* ]
UZ2 IJ33 U23 U13 U12
Cl(1) 59(3) 94(3) 81(3) 16(3) -16(2) -7(3) Cl(2) 227(6) 137(5) 106(4) -40(4) -2(4) 35(4)
C(1) 50(8) 43(8) 95(13) 21(9) -13(9) 19(7) C(11) 47(7) 93(9) 121(14) -5(10) -9(9) 27(8) C(12) 44(7) 56(7) 119(13) 11(8) -4(8) 2(7) C(13) 40(8) 74(10) 74(9) -3(9) -4(9) 8(8) N(14) 38(7) 123(10) 62(8) 7(8) -10(6) -5(7) C(15) 63(14) 147(17) 66(9) -5(11) 9(9) -9(10)
0(16) 100(10) 271(16) 104(11) -70(10) 8(8) -75(10) 0(17) 85(8) 162(12) 85(8) 23(10) 13(8) 18(8)
C(18) 171(18) 178(19) 76(10) 32(14) 28(14) 41(15)
C(21) 80(11) 61(10) 88(10) 18(7) -3(9) -6(8)
C(22) 84(11) 59(9) 89(10) 9(7) -4(9) 3(8) C(23) 78(9) 38(7) 77(12) 9(7) 11(11) 15(7)
N(24) 88(7) 70(9) 94(11) 32(7) -9(8) -11(7) C(25) 110(10) 38(8) 170(20) 15(10) -25(16) 9(10) 0(26) 161(10) 45(7) 187(12) -11(9) -33(9) 11(8)
0(27) 96(8) 61(8) 247(15) 41(9) -21(11) 29(7)
C{28) 170(13) 142(14) 276(18) 60(14) -12(14) 104(11)
Table 5. Hydrogen coordinates (x 10") and isotropic displacement parameters (A^x 10 ®) for rk12m.
X y 2 U(eq)
H(11A) 13298 -6110 -2352 105 H(11B) 13516 -5951 -3723 105 H{12A) 10338 -4817 -2668 88 H(12B) 10870 -4802 -4011 88 H(UA) 14712 -4454 -3404 111
H(UB) 13347 -4000 -3710 111 H(14C) 13712 -4711 -4364 111 H(18A) 11740 -5049 810 213 H(18B) 12136 -4207 334 213 H(18C) 13456 -4820 560 213 H(21A) 11259 -6679 -4689 92 H(21B) 9747 -6144 -4695 92 H(22A) 10789 -6636 -1714 93 H(22B) 9322 -6108 -2036 93 H(24A) 7667 -7408 -2916 126 H(24B) 7806 -7268 -4175 126 H(24C) 7562 -6611 -3378 126 H(28A) 13977 -8211 -2834 295 H(28B) 12895 -8601 -3781 295 H(28C) 12583 -8732 -2436 295
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Table 7. Least-squares planes (x,y,z in crystal coordinates) and deviations from them (* indicates atom used to define plane)
6.2661 (0.0454) x -11.6251 (0.0992) y + 1.0833 (0.0521) z = 13.4537 (0.0206)
* -0.0290(0.0066) N14 * 0.0370(0.0093) C13 * 0.0041 (0.0153) CI 5 * 0.0119(0.0065) 016 * -0.0239(0.0074) 017
Rms deviation of fitted atoms = 0.0242
1.6848 (0.0464) x + 2.1840 (0.1286) y - 11.0501 (0.0217) z = 3.6862 (0.0848)
Angle to previous plane (with approximate esd) = 87.30 ( 0.46 )
* -0.0568(0.0076) N24 * 0.0920(0.0104) C23 * -0.0546(0.0184) 025 * 0.0470(0.0072) 026 * -0.0276(0.0091) 027
Rms deviation of fitted atoms = 0.0594
Table 8, Hydrogen bonds with H..A < r(A) + 2.000 Angstroms and <DHA >110
D-H d(D-H) d(H..A) <DHA d(D..A) A
N14-H14A 0.890 2,444 134.85 3.135 CM [ X-H1 ,-y-1/2, z-1/2 ] N14-H14B 0.890 2.260 167.22 3.135 CI2 N14-H14C 0.890 2.297 152.20 3.112 CI1 [-x+2, y-1/2,-z-1/2 ] N24-H24A 0.890 2.203 151.39 3.015 C12 [-x-i-2, y-1/2,-z-1/2 ] N24-H24B 0.890 2.237 159.93 3.088 012 [-x+2,-y-1,-z-1 ] N24-H24C 0.890 2.386 158.93 3.233 CM [ x,-y-1/2, z-1/2 ]
402
Crystallization of Compounds Addressed in Chapters 2, 3 and 4
403
The tabulated data is a compilation of crystallization conditions found to be the most
successful for the compound listed. Temperature was controlled using an Ace Glass
12125-14 Econo Temperature Controller (type J thermocouple). All slow crystallizations
were conducted with Kimble borosilicate glass culture tubes (6 x 50 mm).
Compound Solvents Crystallization Description/Results
187 DMF Slow evaporation; crystals with included YyMV\Xray
188 DMSO Slow evaporation; crystals obtained approx 7 d
188 DMF Slow evaporation; crystals obtained 24 h; XRay
206 MeOH Heated solution then slow evaporation; crystals; Xray
207 MeOH; EtzO Vapor diffusion of ether; star crystals
207 MeOH;THF Vapor diffusion of THF; plate crystals
207 MeOH; AcOEt Vapor diffusion of AcOEt; feathery crystals
207 MeOH;
acetone
Vapor diffusion of acetone; feathery crystals; Xray
129 CHCI3; EtiO Vapor diffusion of ether; crystals; Xray, linear
129 EtOH; PhH;
CHCI3
Slow evaporation; crystals; X-ray; dimer
96d «BuOH Controlled cooling 29 - 25 °C, 0.25 °/h; sm. crystals
96d EtOH Controlled temp 27.3 °C; sm. crystals
96d /PrOH Slow evaporation; sm. crystals; Neutron Scattering
404
Compound Solvents Crystallization Description/Results
155b DMSO Controlled heat 140 °C; branched crystals
155b DMF Heated then slow evaporation; branched crystals; Powder
155c DMSO Heated then slow evaporation; cotton crystals
155c DMF Heated then slow evaporation; cotton crystals
155c nBuOH Heated then slow evaporation; si. crystalline
155d CHCI3;
EtOH
50:50 mix slow evaporation; si. crystalline
156b DMSO Controlled heat 112 °C; microcrystals
156c DMSO Controlled cooling 80 - 25 °C over 3 weeks; microcrystalline
156d DMSO, DMF, HMPA, nBuOH, or iPrOH; soluble in each
with heat but did not produce crystalline material
159b TFA;
EtOH
Slow evaporation; crystalline solid; Powder
159c TFA;
CH2CI2
Slow evaporation; needle-like crystals
159d TFA;
CH2CI2
Soluble, but did not produce crystalline material
159e TFA;
CH2CI2
Soluble, but did not produce crystalline material
405
Appendix B
Selected 'H and '^C NMR Spectra
OCHa
OCH3
69a
zL I I I I r I I I I ' i " T I I I I i " j I i I r I ' I ' I I I I r I ' T I I I 1 1 I I I I I T I ' I I I I ^ 1 I I I - 1
0 PPM
6,18 5.or
O ON
OCHa
69a
{ I I I I I I I I > j I I I I I I > I I } I I I I { I I I 1 [ I I I I I I I > I { I I I I I i I I I I I » I I I I I I I I I I 1 I T I I ' I I ' ' ' ' M ' ' ' I I ' ' ' I ' ' ' > I ' ' ' ' I ' ' <
200 180 160 140 120 100 80 50 40 20 PPM
69b
10
r
r
j l
1—I—I—I—I—I—I—I—I—1—I—I—I—I—I—I—I—!—r
1 ppm
4.10
' I ' I ' — 1 —
6.17' 12.76 4.21 6.22
6017
OCoH
OCgH,
69c
1—r T—I—r T T—I—r T 1 1 T T—I—I—r T—I—I—r T—i—I—r T—r 1—I—r T T T
9 8 7 6 5 4 3 2 1 ppm
2.00 6.83 26,13 4.25 4.86 8.01
69c
Uf ky |y| !^t«^i^ii^i((»il)iii(ii(i(P)ii(i)^fii^^|»>i^iiii>(i)P>i(>)>i^i^i^^iiii^|llii^i^ii^itli^^ I I I M I M I I I I I I I I I I I I I I I M I I I I I j I M I I I I M j I I I I I I I I I I I I I I I I I I I [ I I I I I I I I I I I I I I I I I I I I I I I I I I I I I [ I I I I I I I I I j I
180 160 140 120 100 80 6Q 40 20 ' PPm
6C12H2S
69d
1—I—I—r T—I—I—r "T—!—I—r -i—I—I—r T—I—I—r
10 9 7
g.so
r
r" J
JJL. 1 1—I—I—I—1—I—I—I—I—I—I—I—I—I—[—I—I—I—r ' ' I
ppm.
4,14
' 1—'—I—' 1 —I—' 6.16 37.98
4.27 6.06
4^ K)
9^12^25
6C12H26
69d
M I I I M I M I I I M I I I I I M I I I I I I I M I I I I I I I I I M I I I I I I I r i I I M
200 180 160 140 120 100 20 Dom
OC18H37
OC-igHa?
69e
r
UJdd 03 Ot^ 09 08 OOT 02T Ot^i: 091: 081 I I I I I I I I I I I I I f I I I I I I I I I I I I I I I I i I I I I 1 I I I I I I I I I I I I r I I I I I I I I I r J 1 I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I
<*»
^69
"h®^oo
69f
I I I I I I I I I I I I I I I I I I I I I I I I [ I M I I I r I I I I I I I ' I I ' I ' M ' I I I I ' ' I I I I ' I I I I I I M I ' I I I ' I I I I I ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' 0 9 8 7 6 5 4 3 2 1 PPM 0
i-r-i I . 1 . 1 , 1 , 1 , 1 i _ _ i 2.00 4.31 U.oel 5.87 5.92
4.19 4.23
69f
] I I > I ( I ! I I I I I I I I I I I 1 I I I I I I I I I I ) I > l ' I I I I I I ] I 1 I I I I I I I I 1 1 I 1 I I I I > I I » > 1 I I I 1 I I I I I i I I I I I I I I I I { I I I I l ' I 1 I < I I I I 1 I I > I { I ! I I I I I I I I I I I 1 I I I I I I I I I I j I > l ' I I I I I I I I < I I I I I I I I M I 1 I I I t > I I I > 1 I I I 1 I [ I I I i [ I I I I I I I I I { I I I I [ '
200 180 160 140 120 100 80 60 40 20 PPM
4^ H—k -J
OCHg
OCH3
70a
10 111111111
9 I M I I I I I ' M l I I I • I I I I
6 I I I I I •H"
5 i _
2.00
0 PPM
-1 00
OCH-.
Br
.Br
OCH3
70a
I I I I I [ 1 I 1 ] ' 1 I I I I I I I I I I I r 1 I I I r I I I I " f I I I » t I t I I I [ I I 1 ' 1 I I I I I I I I I 1 ' [ M I I I I 1 I I ' I I I I I 1 I 1 I I I I I I I I I 1 1 I [ I I I I I I I 1 I
200 180 1 50 140 1 20 1 00 8 0 60 4 0 20 PPM
-fi
OCGHIS
82b
1—I—I—I—I—I—I—I—I—I—I—R 9 8 PD!TS
0CEHI3
82b
I
BIILIMNWI I I I I I I I I I I I I I I I I I I I I I I I M I I I I I I I I I I I > I I I I I I t'T I I I I I I I I I I I I I I I I I I M I I I I I I I I I I I I I M [ I I I I I I I M I M I 1 I I I I I [
180 160 140 120 100 80 60 40 20 ppm
4^ K)
0CsH,7
82c
r
Jl VJ 1 "T I I I I I I I I I I I I I I I I F~~| T""! I I
ppm.
2.47 1.99
3.19 23.00 3.46 4,53 6.66
4^ K) TO
ocbhit
Br
OCGHN
82c
xmmIJii i»[jwi|i(i»>»iiwiiwwi>i i III I I I I I I I I I M I I I I I M I I I M I I I n I I I I I I I I I I I I I M I M M I J M I I M M I M I I I I I I I I I I I I I I I M I I I r I I I I I I I I I I I { I M I I I I M I I I I I I'
200 180 160 140 120 lOO 80 60 40 20 ppm
to
82d
lAyui I T [ 1 1 1 1 1 1 1 1 1 1 1 ! 1 1 1 F T—[—I—R T—R 1—,—J—,—J. T T T T T T T T 1
10 9 B 7 6 5 4 3 2 1 ppm I—.—1 I , I • I I I i I I_ J 1.58 2.34 3.10 38.76
1.95 3.24 4.32 6.26
4^ (O -1
6C12H25
82d
IIIFI<MWWWI|NNIIWINM I I I I I I I I I I I I I I I M I I I M I I 1 I I M I M M I M M I M I I I I I I I I I M I I M I I I I I M I I I M I M I I I I I I < { I I I I I I I I I I I I I I I I M I
200 180 160 140 120 100 80 60 40 2 0 p p m
82f
1—;—I—I—I—I—I—I—I—I—I—I—I—I—[—I—I—I—1—I—1—I—I—\—|-9 8 7 6 5
1 . 0 0
T—R T—R T—I—R T—I—1—R T T
4 3 2 1 ppm
4.2a.41 3.22 4.254.406.39 3.23
4^ NJ O N
82f
IIHWMMLLMKIHNLLWW'LIK I I I I I I I I I I I I I M I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I [ I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I •[
180 160 140 120 100 80 60' 40 20 ' ppm
4^ K)
OCEH-S
83b
T 1 1 1 1 1 1 1 1 1 1 T 1 1
1 1 . 0 0
/
"T 1 1 T 1 I I 1 1 1 1 1 T
p p m
13.75 4.78 6.93
K) 00
OCFIHI
83b
<III4K wmm I I M I I M I I I I I M I I M I { I I I I I I I M I M I I I I I I I I I I I I I I M I I I I I I I I I I I I I l|l I I I I I I I I I I I I I I M [ t I I I I I M I I I I M I I < I I
Wi
200 180 160 140 120 100 80 60 40 20 p p m
OCGHN
83c
^ V "1—I—I—I—I—R—I—I—I—I—I—I—I—R -1—I—I—I—p I I • I I
7 '-T-' 1 . 0 0
4.24
' • r
p p m
OCgH
OCGHU
83c
I I M I I ! I I I I M ! I I I T M [ M I I I M M I I I I I } I ! M I I I t ) I M M I t I I I I I I I I I I I M I I I I I I I I I I I I I I I I I M I t M M I I I I I I M 1 I
180 160' 140 120 100 BO 60 40 20 ' ppm
I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I [ I I 1 I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I ' I I ' ' ' ' I I ' ' ' ' I ' '
10 9 8 7 6 5 4 3 2 1 PPM 0 I , I I , I I , I I • , I 1.0 4.2 4.5 41.5 6.4
-1 LA K)
IC12H25
Br
Br
Br
OC12H25
83d
mmm I I I I I I I I I I I I I I I r r I I ' 1 j I I I I I I I I t I ; I [ I I I I I I I ' I I r I ; I r I ! ' [ f I I 1 ' I I 1 I I ' I I I I I I I I I J I I I i I I I I I I ' I I I I I I I I I I I ' I I M I I i 1 '
200 180 160 140 120 100 80 60 40 20 PPM
U)
OCIGHS;
83e
JL •^[—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—R 10 9 8 7 6 5
0.79 4.00
OC18H37
83e
pJLmmmJImmmwmjL - M I I I I M I I I I I I I I I I I I I I I I I I I I I I M I I I I I I I I I I I I I I I I I I
180 160 140 120 100
j Ju .
I I I I I I I I I I I I I { I I I I I I I I I I I I I I I I I I I I I I I I I I I I I
80 60 40 20 ppm
U) LA
OCH:
NC
OCH3
84
jil / I ' L JL I I > I I { 1 I I i j I I I » I I 1 » I I I I I I I t I I i I I 1 ! I I I I I t j I » I n ' ' ' ' } ' ' ' M ' ' ' ' I ' ' ' ' I ' ' ' ' I < ' ' M ' ' ' ' I ' ' ' ' M ' ' ' } ' ' ' M ' ' ' ' } ' ' I I i
10 9 8 7 6 5 4 3 2 1 0 PPM
^ ^04 ' ' 4.17 ' 2.97' 5.89
4^ ON
NC
OCH3
84
I 1 I I I I I I I I I I I M I I 1 iiiii<>/^»iA»iiin«»wiMi'V>»i«i«i»|iii>tyii I MniMiniio
200 180 1 ' I I M
160 I I I I M
140 1 I I I M
120 I I I I I I I I I I I
100 80 I I I I I I I I I I I I '
50 -I-P
40 I I I I I I I I r I I r I I I
20 PPM 0
OCHA ,NH2
OCH3
85a
I I I I I I i I T r"|'T I iT"|"T I I I I I r I I I I 'I T 1 j"i~r
10 9 8 7 I I I ' I M
0 PPM
4s, U> 0 0
,NH2
0CH3
85a
I I I I I f - r - T T " r [ T ! • » I { I r t f | ~ ! " r r t t t i t [ i t 1 i | i i i i [ • • f - r t 1 | 1 1 1 1 [ 1 1 1 t | i 1 1 1 [ 1 1 t 1 f 1 ' ' { 1 1 ' ' [ ' ' ' ' | ^ ' I ' ' ' ' | ' " ' 1 M ' ' '
200 180 160 140 120 100 80 60 40 20 PPM 0
NH;
85b
M I I I I I I I I I I I I I I I I I I I t I I I I I I > I I I I I t I 10 9 8 7
v^uLoJl I I I I I I I I I I I I I I I I I I I I I I I I ' I I I I ' I I ' M I I I I I M I I I I I I I
4 3 2 1 PPM 0 I—, ' , ' , 11
2.09 I 1.90 1.90 3.88
l_, > , }
5.61 ' 5.59 14.12
O
,NH2
OCGHI3
85b
i** W*»>W nAiwiwhi*! I I I I I I [ I I I I I I I I I I I I I I I i I I I M M I I I I
100 1 I I I I I I I I I I I I I I I I I I I I I I I ' I I I I I I I I I I I I I I
20 PPM 200 180 160 140 lEO 80 50 40
NH-
85c
I I t I I { 1 I I I { I I I I I i I > I I I I I 1 I I I M I I M 1 I M I I { I t M } ' ' ' ' I ' ' ' M ' ' ' ' { ' ' ' M ' ' ' ' I ' ' ' M ' ' I ' ' < ' M ' ' ' I ' ' ' ' M ' ' * I ' '
iO 9 8 7 6 5 4 3 2 1 PPM 0 I—,—I I , I , i , I t , t • . ' . ' . «
2,0 2.0 4.0 1.8 2.0 5,9 22.6 5.7
PCGHIY NH,
COJET
OCGHIR
85c
WWNW*MMMW Lj • y T ' T T I I I I > I I I I ' I 1 F ~ T ~ L I I I I I I i 1 I 1 I I I T I I I I I I I I I I I I I ! 1 I t j " T 7 r T T ' l T I I | I > I I } I I I t { I I f I | I I I I | 1 T 1 I T ' T T ' T - T j I I I I | I I T I
200 180 160 140 120 100 80 60 40 20 PPM
4^ U)
,NH
6C^2H25
85d
r
lA ll ll . A A \
J
—I—I—I—I—I—I—I—1—I—I—[—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—R 5 4
4.SS 2.13 1.93
3'
1.98
2 i p p m '—I—'—I • • '
40.48 6.50 6.39
4^ -1
NH.
85d
I I I I I I I I I I I t I I I I I I M M I M I I I I M I [ I I I I I I I I I I I I I I I M I I [ I I I I I I I I I j I I I I I M I I I I I I I I M I I ) I I I I I I I I I I I I I I I I I I
200 180 160 140 120 100 80 60 40 20 PPm
NH.
OC18H37
85e
r
JU_ u "T—I—I—I—I—I—I—I—R -I—I—I—I—I—I—I—I—I—I—I—I—I—F-
2 1 p p m
5.36 2.46 2.52 2.43
94.30 8.33 9.54
O^
ludci OE 017 09 08 O O t 02T 09t 08T I • • I i ' I • 1 1 I ' I • ' 1 1 ' 1 1 1 ' 1 1 I I 1 1 I • 1 1 ' I 1 1 1 1 1 1 1 1 1 1 1 1 1 I ' I 1 1 ' • I ' I ' I ' I ' 1 1 ' I 1 1 I I 1 1 I 1 1 I 1 1 1 1 1 I • 1 1 I I I I 1 1 • I I ' I I ' I I
T
9^8
NH-
85f
r
J\ ^
I r ["~1 r I I I I I I I
10 8
—TT—I—R—(~ T—R—R—T—F—I—I—I—T—["" 6 5 4 3
T—I—I—R- -T—I—r-r-i—r—p
1 p p m
1.99 'TV'TW H-L
4.19 4.63.25 1.85 2.37 4.33.€40l '
3.44 2.24
,NH.
85f
i I I I I ' ' ' I I I I I ' M ' ' I I I ' I I M I I I j ' I I M I I I I I I r I I I I I I I I I
180 160 140 120 100 2 0 p p m
OCHs
NHBcx:
•C02ET
X7V.
ST I I I I I I I I I I I I I I I I [ i I I I I I I 1 I j I I I I I I 9 B 7
I I I I I I I I 5 .
l-r-l 0.96 2.00
M I I ! 1 M [ I I I 1 { t M i 1.1 I 1 f I I I 1 I I I I I I I I M I I M I I I I I I 1 I i r I i
4 3 2 1 0 PPM
2.07 ' ' '2.13' ' 5.84 2,03 6.341
3 = E2
-1^ o
OCH
NHBoc
OCH3
93a
I I r I i I 1 I I I I I I I i j I I > I I I I I I [ 1 1 ! I I I I » I j ! I I I I I I I 1 [ I 1 I > 1 I I I I I I I I 'I I 1 I I 1 j I I 1 I I t I I I I I I I I ( I 1 ! I I ; I I I I I I I I I
200 180 160 140 120 100 80 60 40 20 PPM 0
QCGHIA
NHBoc
OCGHIS
93 b
J JL-
1—I—I—I—I—I—I—I—I—I—R 9 8
"1—I—I—I—I—R
2 , 0 1
1—I—I—I—I—I—I—I—I—I—I—I—1—I—I—R "T—I—I—I—I—I—I—I—I—I—R
1.00 2 .12 2 .09
4 .14 2 .08
! 1 ^-T-" 1 4.24 6 .01
29.51
ppm
-LI.
NHBoc
93b
IIXDWUIRTWKM I I I I I I I I I I I I I I I M I I I [ I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I M I I I I I I I I I I I I I I I I I I I I I I I I I 1
180 160 140 120 100 80 60 40 ppm
U)
OC8HI7
NHBoc
bOzEt
93c
-]—I—I—I—I—I—I—I—T—I—I—T—R 9 8'
I ' ' ' ' I ' ' ' ! I 7 6 5
1.06 1.99
iJjL
r
AJ/'Ul 1—I—I—I—I—I—R
3 I • I—.—I
"T—I—I—I—I—I—I—R
—I— 1 —I— 4.20 6 .23
38 .82
PPrri
20 2.12 4 .17 2 .09
OCGHN NHBoc
OC8H17
93c
II<NN>T«*»A» JMWH* Y'I>WI« LH*WW */IWIWW M I I I I I I I I I I I I I I I I I I I I ] I I I I I I I I I I I I I I I I I I I I I I I I I I I M I M I I I I I I I [ I I' I I I I I I I I I I I I I I I I I I I I I I I t I I I I I I I I I I I I I
180 160 140 120 100 80 60 40 20 ppm
NHBoc
COsEt
6C12H25
93d
-I—I—I—I—I—I—I—I—1—]—I—I—I—R—I—I—I—I—I—I—I—I—I—I—I—R 9 8 7 6 5
2.01 0.91
r
J
r J
v_j I ~i—I—I—I—I—1—I—I—I—I—1—I—I—I—I—I—I—I—I—I—I—I—I—I—t
4 3 ' I ' I • I ' — . —
2.17 1 .92 4 .21 2 .OB
ppm
4.37 B.36 49.96
-LI. ON
V^12"25 NHBoc
COzEt
OC12H25
93d
X [ I I M } I I 1 I I i M I I M I I I I M I I M M I I M 1 I I I I I I M M I I M I I M I I I M M I M I I I M M [ M M I I I I I M I M I I I I I I I I I M
200 180 160 140 120 100 80 60 40 20 ppm
PCISHS? NHBoc
OC18H37
93 e
COoEt
a 1—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—[—I—I—I—I—I—R
7
2.00 I . L.
1.00 2 .44 2 .24
5 .12 2 .44 5 .42 9 .74
104.02
ppm
4^ 00
NHBoc
COaEt
OC-18H37
93e
^ L i. - 1 I I I I I I I M I I I M I I M I I I I I I I I I I I I I I I I I I I M I I I
200 180 160 140 120
I I [ I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I
100 80 60 40 20 ppm
4^
NHBoc
• I
1—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—P 9 8 7 6
' I ' 2 . 0 0
f
J
1—I—I—I—I—I—I—1—I—I—I—!—I—I—I—I—R 1—R 1—I—I—R pprri
0.B9 2 .20 4 .4$ .412.33
4 .334.2-6 .30 4 .86
9 .16
NHBoc
93f
mL "MM I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I M I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I [ I I I I I I I I I I I I I I I I I
180 160 140 120 100 80 60 40 20 ppm
a\
NHBoc
CO2H
1 -|—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—R
9 8 7
2 . 0 0
J
r
I I I I I I I n~i I I I I I I I p~T r~T I [~
4 3 2 1 ppm
2,25 6 ,42 2 .20
10 .04
On TO
OCH:
NHBoc
OCH3
94a
WMIMMP I t I I I I I I I I I I I I I I I I I I I I I I I I I I I I j I M I I I I I I I M I I I I I I I I I
180 160 140 120 100
mttmm mtm F»WIIIIIIMNI»IIN M ' l M I I j I I I I I M I I I I I I I I I I I I I M I I I I I I I I I I I I I I I
80 60 40 20 ppm
4^ ON
NHBoc
T - r > 1 1 1 L I T ! T I L L 1 I I I I I I I L I L T I I I I I I I I 1 1 1 1 T r
12 11 10 9 8 7 6 5 4 3 2 1 ppm 1 I 1 I 1 I 1 '-r-' , 1 • • ' I 1" 1—I
0.80 0 .47 2 .04 4 .16 6 .11 2 .22 4 .66 2 .01 21.5S
-1^ ON
NHBoc
94b
I I I I I I ' ' ' I I I ' > ' M I I I I I I I M > I ' I I > I I M I I I I I I < I I M I ' I I I I I > M I I • I < I ' M I I I t I I I I I I I I I I I I I I I I I I M I I I I I I I I i
180 160 140 120 100 8o' 60 40' 20 ppm
NHBoc
OCGHIY
94c
1—I—I—R 1—I—1—R —I
r
VJl "T—I—I—I—I—I—I—I—I—I—I—I—I—I—R —I—I—I—I—I—I—I—I—I—I—I—R
2 1 Ppm ' • • I '—.—'
27.72 3 .98 5 .78 0 .75
3 .86 1 .99 1 .99
On 0\
OCgH
NHBoc
OCgHn
94c
I I ' ' I I I I I I I I I I ' I I I ' I I I I I I I I I I I I M I I I I I I I I I I I I I I I I I I I M I I I I M I I I M I I M I I I I I I I I I I I I I I I I I I I I I I I I I I I ' I I I I
180 160 140 120 100 80 60 40 20 ppm
o -J
NHBoc
6C12H25
94d
_^L_ I—I—I—I—I—I—|—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I J I—I—I—I—|-12 n ' 10 9 8 7 6
2.00
r
J
T—T—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—R 5 4 3 2 1 ppm
S-" ' • • • ' • ' ' I ' • ' I ' 3.95 1 .87 44 .71
0 .55 1 .86 3 .75 6 .99
-1^ 0\ 00
OC12H25
OC12H25
94d
••aVmnmimmi J k
{ I M I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I M I I I I I I I I I I I I I I I I j I I I I I I I I I I I I I I I I I I I I [ I I I I I I I I I I I I I I I I I
180 160 140 120 100 80 60 40 20 ppm
-1^ •vO
OCIGHAR NHBoc
CO2H
OC18H37
94e
_jL "T 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 T
9 8 7
2.00
_J'V "T—I—I—I—T—I—I—I—I—I—I—1—I—I—I—I—I—I—I—I—R -I—I—I—R
ppm
0.36 5 .60 2 .38
2 .67 133.16
8 .59 13 .32
--J O
NHBoc
OCIGH37
94e
^ I I I I t I I I I I I I I I M I I I M M I I I I I I I I I I I M I I I M I I I I I I I I t l M [ 1 I
180 160 140 120 100
JLL. I I I I I I I M I I I I ' I I I I I I I I I I I I I I I M I I I I I I I I I I I I I I I I
80 60 40 2 0 . p p m
-1^ -J
,NHBoc
94f
I I I I I I I I I I I I I I I I I I I I I I I I I I
11 10 9 8 1
0.91 2.00
F|/
Y
W L
I I I I I I I I ' 'I I I' I I I I I' I I I I I I I I I I I I I ppm
_l I I I I I
0.52 ' I 'I' I 1—
3.65 ,24 3 .65 3 ,46 7-48
9 .94
K)
NHBoc
94f
11 •iiifiihiii<^i*wMMi^««^wi|iiiw»it« ^MiikmiriiwiiinwM* iy mi># mn'tinin rn wn' mr 'wmmm
I I I I I I I I i 1 1 r i I I I i I I I I I I I I I I I I I I I I M I I M I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I
180 160 140 120 100 80 60 40 20 ppm
4^ U)
HN
95d
1 1—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—T—I—R
9 8 7 6 T—'
3.86 '
ppm
liJCld . 08 Ot' 09 ,08 OOT 08t O V l OBt p8t
I I I I I I I I I I I I I I I I ' I I I I I ' I I I I I I I I I I I I I I I I I I I I I ' I I I 1 I I I ' I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I
iMMML M
rf
P^6
PCIAHS? O 9 1®^37
OC18H37 OC18H37
95e
-I—I—I—I—I—I—I—I—I—I—I—I—I—^—I—I—T—I—I—I—[-9 8 7 6
3.45
-I—I—I—I—I—I—R 4
-I—I—I—I—I—R 2
I—, L.
1—R
-i-ppm
T
8.47 3 .68 2 .33 4 .00 '
152.33 9 .96 15.10
OCibH.
HN
95e
I M I I { I I I I I M M I I I M I M I I I M I I I I I I I I I M I I 1 I M I M 1 » I M
180 160 140 120 100
I I I I I I I I I I I I I I M I I M I I I I I I I I I I I I I I M 1 M I
80 60 40 20 ppm
96d
J A_
-|—I—I—I—I—I—I—I—I—I—I—R 9 8
-|—I—I—\—T—I—I—I—I—I—I—R 7 6
' I ' • ' 4.11
1 .92
r J
iUL vj' "1 I I I I I I I I I I I—I—I I I I I I I I—I—I I—I—r
4 3 2 1 ppm
8.42 4 .00 3 .92
—I—• 1 •—I—' 77.01
9 . i i 14 .24
45^ - J 00
>12"25 OCi2^^25
96d
''I I I I I I ' • ' • I • • ' ' I ' ' < ' I ' ' • ' I < ' ' ' I • ' • > I ' ' • • I ' ' ' • M • I ' I I ' I M I I I I I I l| I I I I I I I I I I I I ) I I I I I I I I I I I I I M I I I I I I I I I I I 1 j ' ' ' I I I I I i I I M I I M M I ! I M I
180 160 140 120 100 80 60 40 20 p p m
NH
96e
I i 1
I I 1 I I I I I I I I I I I I I I I I I I I I r
9 8 7 6 '—I—'—I—' 4 .35
1 .94
9^18^37 Q OC18H37
OCfgH37 " OC18H37
96e
I I I I I I I I I I I I M I I M I I I I I M I M M I I I M I I 1 M I I 1 I I I ' I I I I I I I I I M I I I I L { M I M 1 1 I I M I I I M I I I I I I I I I I I I M I I I I I M I I I I
200 180 160 140 120 100 80 60 40 20 ' ppm
00
HN
96f
r
T—I—I—I—I—I—I—I—I—I—I—I—I—R 9 8 7
I ' ' ' ' I 6 5 10
4 .00 2 . 1 1
h
u JL
' ' I ' 4
' ' I ' ' 3
I I I I I I 1 I I
ppm
8 .71 12 .4 f f i .78 9 .139 .15 5 .17
HN
96f
M I I I I I { I I I I I I I » I 1 I I I I
180 160
I I I I I I I I I I I I I I I I I j I I I I I I I I I [ I I I I I ' I I I I I I I I I I I I I I [ I I I I I I I I I I I I I I I I I I
140 120 100 80 60 40 ppm
4^ 00 U)
NHCBz
OCH3
116
[
J J
I T—I—I—I—I—1—I—I—I—R -I—I—I—I—I—I—I—I—I—I—I—I—I—I—[-10
4 .68 0 .93 1 .95 ? . 0 0
(
ULa_ X -|—I—I—I—I—I—I—R 1—I—I—I—I—I—I—I—I—I—I—I—I—I—R
ppm
1 .84 2 .16 6 .0 i 2 .07
3 .11
00
OCH-
NHCBz
116
I i 1 1 I } I I 1 I I t I I I ; 1 1 I I I I I M I I M 1 j I I I 1 } t M I [ M M I
180 160 140 120
JU 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
80 60 40 20 ppm
4^ 00 U>
OCH
COZET
T 1 1 1 1 1 1 1 1 ] 1 1 1 1 [-9 8 7
f
OCH
NBoc
OCH3
117
JU 1)1 1 <MMWI j I I I I I I I I I I I I I I I I I I I I M I t I I I I i I i I I I j I M I I I I I t I I I 1 I I I I I I I I I M ) I I I I I ' ' I rp i 1 r ; 1 i 1 1 | 1 i 1 1 ; M ' ' j ' ' ' ' 1 1 1 [ 1
180 160 140 120 100 80 60 40 20 ppm
OCH
NCBz
OCH3
118
-|—I—I—I—I—I—I—I—I—1—I—I—I—I—I—I—I—I—I—I—I—I—I—I—R
5 .30 •-H
2 . 0 0
5 V
2 .03
r f
J
V.
1—I—I—I—I—I—I—I—I—I—I—I—I—I—I—R
6 .42 2 .22 1 .05 2 .41 3 .12
' I ' ' ' ' I 1 ppm
2 .92
-1 00 00
OCHg
NCBz
I I M ] ! I I I j I I I I } I I M I M I I M I I I I M I I I M M M TTTT M M { M I I TTT rj-VT T T M M I M M M M I M M M M I M M
180 160 140 120' 100 80 60 40 20 ppm
OCH
NBoc
122
JbL J "T—I r~T I i I \ r~| I r~i i [~n
12 11 10 '—^—'
0 .83
" T I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I T
9 .42
B 7 ppm T I
2 .00 5 .87 2 ,13
2 .24 3 .02
OCH.
NBoc
122
<|»\U^HM pn» m 11
I M M I I 1 { t [ 1 i M I } M i [ I 1 M M M { I I M t I I I j ! I I M j } M t ( I i M I I M i t I [ } I j j } I ' M I I M I I i I ( 1 [ M I t I ! M j I } M r }
180 160 140 120 100 80 60 40 20 ppm
J
JL T-I—I : I I I I ! I
5 4 3 2 I , , I , U , - . , i
9.43' 3.47 2.OC 2.37
I I I I I 1 pprrs;
4I. TO
fCH
NCBz
( I#*WWMNI*IIIIILL I)I»W>I»INH|^^
180 60 160 140 120 100 80 40 ppm
-T^ L»J
BzCN
OCH- OCH3
HN
BzCN
OCH3 OCH-
124
1^ Ly|bL|| LdilyliitMJidMtay AilMMLw>.t>L|l u i
I I I I ! I I I I I M I I I I I I I j I I I I I I I I I [ ! I I i I M I I [ I I I I I I I I I I I I I I I I I I I I M I I I i I I I I I M I I I I I I I I M I I i I I I [ I I I I I I I I I I
180 160 140 120 100 80 60 40 20 ppm
-F^ UI
OCH. OCH.
OCH- OCH.
129
JL
-|—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—R 9 8 7 6
i,06 4 .00
' I ' ' ' ' I ' ' 4 3
'-r-VH-' 17 .47 2 .50
2 .62 3 .54
' ' I 2
n I I I I I r
ppm
4^ o\
OCH. OCH
OCH OCH.
129
I I M } I I M [ M M I M M I I I M I M M I 1 I M j I I M I I M I I U M I M
180 160 140 120 100
WWWWF**! M I I I I I I I I I I I I I I I j I M I I I M I I I I I I I I I I I I I I M I I I I I I
80 60 40 20 ppm
- J
OCHa
-NH HN-
HN- -NH
OCH3
155a
?CH,
OCH3
r
L
1 I—I—I—I—I—R-|—I—I—I—I—I—I—N—I—[—1—I—I—I—I—I—I—I—I—|-12 11 10 9 8 7
2 .05 4 .00
(
J /
_A.
T 6
T—T—I—I—[—T" "T—I—I—I—I—R-|—I—I—I—I—I—I—I—I—I—[— 3 2 1 ppm
20 .42 8 .50 •O OC
MIMWJ y
(WMMHMMMIMM X L HIMIIIPII WUMTLINI WINNIIIIIIWRI I M I I M I I I I I I I I TT"rT-()-|-rrrr I i i i i [ i ii i | i i i i | i i F T [ i i i i [ i i i i | i i i i | i i ii | i i il | i i t i | i i T T j-rr-n-|-iTT-1 [ i i i I T T T I T
180 160 140 l'20 100 80 60 40 20 ' ppm SO
•NH HN
HN- •NH
155b
i T—I—I—R—I—I—R
11 -I—I—I—I—I—RN—R—I—I—I—RN—I—I—I—RI—R
10 8 7 ' _ ' '
2.08 3 .90
ppm
PC6H-T3
OCGHIS 0CFTHI3
I I ' I I I I I I I I I I I I I I I I I I I I I I I I M I I I I M I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I
200 180 160 140 120 lOO 80 60 40 20 ppm
o
OCGHN 155c
T T—!
13 12 11 10
DCSHIR
8
1.77
JJLJU
7 6 5
J \J
/
3.99
| -I I- I I-J-I--4 3 2 1 , ppm
9.12 9.85 16>1. 1.93 8.20 8.29 4B. 17
L/) O K)
CO O
02 OF 09 08 PO^ 02T OPL 09T OBT 005 1.1 LLiJ_LL.LLi_l..i..l J.-Ll 1 L 1 I i-l-LliJ_l.LLi I l.l I 1.1 I I 11 L I I I I I I I I I I I I I I f I I I I I I I I I i | | I I I I I i i i I I I I i . I I I I i I I I i i I I i ] i I
nr IFI»I#I»II>N>IIIIMIIIW» 0D#
•NH HN
HN •NH
HN-NH
•NH HN-
155d
I I I I I I I I I I I I I I I
12 11 10
1 I I I I R~| I I I I I 9 8 7
I, • I
1.60' 2 .83
ppm
HN-NH
•NH HN-
155d
I I I I 1 I I I M M [ I I I I i M I I I M M I i I M I I
60 40 20 ' ppm
O
OCHS OCH3
156a
J
r -T-T—J—I I I I—I I ITT'] -I T"i—; I —p T' "I—I I I I I I I [] I—I I I T'l -1 T—f-T—r—T—r-|—1 1 i—r—pT—i—1 1 | 1 1 1
12 11 10 9 8 7 6 5 4 . 3 2 ppm'
1 .95 3 .71
5 4 . 3 •—I—J' 19 .32
8 .02
O
OCHa
156a OCH,
ll I I t I I I I I M I I M I I I M I I I I I 1 I M ! t I 1 1 M i M M I I M I I I I 1 1 I r n I I I M I I I M I { i I M I M M I I I I I I M M I I M ' I I 1 i I I 1 ' ' I I I
180 160 140 120 100 80 60 40 20 ppm
HN NH
HN-
OCGH
156b
f
' I ' ' ' ' I 12 11
t i l l — r - r - "T—I—I—I—R~I—I—[—I—I—I—R"|—I I I—I I I
10 8 7 MS--
2 .13 3 .62
I I I I I I I I I I I I I I I I I I I I I I I I I I I
2 1 ppm • , I
8 .01 8 .42 8 . 8 2
—R 26 .57
8 .51 13 .13 U\ o 00
QCEHIS O
OCGH^A 156 b
i.,. I fmm tmmt
200 180 160 140
<IN(M MMAM J. [TRRRR-RTI I | I N I | I I II | I I M' | I I I I |
100 80 60 40 20 ppm U\ o VO
OC.H OC.H.
•NH HN-
HN- •NH
OC.H
156c
1 ' y J T—I—I—I—I—I—M—I—I—I—I—R
11' ID T—1—I—I—I—I—I—I—I—I—I—I—I—I—R
8
0 .81 1 .93 0 .67 4^00
I ' ' ' M T—I—I—I—I—I—I—I—I—[—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—R
pprri
8 .32 8 .43 0 .34
43 .17 8 .69 12 .52
VYI o
•NH HN-
HN- NH
156c
iIUmJL WIN»WMIMINW> J, I M I I I I I I I I I I I T I I I I I I I M I I M M I I I I I I I I M I I I I I I I M I j
200 180 160 140 120 100
1 WII|M I I I I I I I I I I M I I I M I I I I I I I I I I I I M I I I I I I I |-11 I T
80 60 40 20 ppm
HN-•NH
NH HN-
156cl
r J"
JL -I—I—I—I—I—N—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—R
11 10
2.05 3 .32
"T—I—I I I I—I I I I I—I I I—[—I—r-i—I—[~i—I—I—r-|—I—I—I—r-|-
5 4 3 2 1 ppm
8 .00 9 .03 10 ,03
96 .25 8 .57 17 .69
KJ\
TO
HN-•NH
HN- •NH
156d
I M ' I I I ' ' ' ' I ' ' I I I ' I ' I M ' ' I I I I I M ' I ' I I
60 40 20 pprn
""*""""" *'i ' Vf||ii[lrr"iii-i)iiriyii[-iit,i.r' I M I I I I I I I
200
I I I I I I M I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I
160 140 180 120 100
U)
QCEHIA Q O OCEH-IA
0CEHI3 0 O 0CEHI3
159b
^ II II • • IIIWI !•! rtlrt 111! » H II • I [
I I I I I I I I I I I I I [ I I I I I
11 10 9 B
I I I I I I I
4 . 0 1
uu I I I I T—\—I—R I I I I
6 5 4 3 2 1 p p m ' I ' T '—I—' ' I ' I • I ' I ' I '
4. 46 4. 26 a.78 13 .33-8 .11 4 .35 4 .36 26. 00 ^
•NH HN-
HN- -NH
159b
mitm I<XIKIWYIIIIY<L IIMKIIDKJJYI 11 IKI
I I M I M ' ' ' I ' ' ' ' ^ ' ' ' M ' ' ' ' ^ ' I ' ' ' ' I ' ' ' ' I ' ' ' I ' * ' ' ' M ' ' ' ^ ' ^ ^ ' I ' ' ' ' ^ ' i ' ' ' ' ' I ' ' ' ' I ' ' ' ' 1 ' ' ' ' i ' '
200 180 160 140 120 100 80 60 40 20" ppm Lh LTt
OCgH.
•NH HN
HN •NH
159c
I ' ' ' ' I 1—r—r -I—I—I—R I I I I
12 11 10
4 . 0 0
U V L I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I
2 - I , 1 , 1
4 3 ' I ' • • • ' "-T 1 > 1 r
4 .5B 4 .22 8 .11 13 .38 7 .66 4 .47 4 .45 43 .21
ppm
OS
OCGHIY
159c CGHI/
NHMWLIIFFI U I I I I I I I I I ' I ' I ' I I I ' 'I I I' I ' I I I I I I I I M I I I I I I I I I I I I I I I I I M I I I I ' I I I ' I I I I I I I I I I I I I I M i I I I I I I I I I I I I I I I I I I I I
180 160 140 120 100 80 60 40 20 ppm
OC12H25 Q OC12H25
OC12H25
_R
, 1 •• I I I I I [ I I I I I I I I I I I I I I I I I I I [ I I
12 11 10 9 8 7
3.11
I I I I I I I I I I I I I I I I I I 1 I I I I I I I I I I I I
4 .06 3 .91 8 .99 13 .50 7 .61 4 .00 3 .89 80 .64
00
OCI2H25 OC12H25
INWITIWWI^W» IW>*I LI I* #1 iU I I I I I I I I I I I I I I I I I I I I I I I I 1 I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I M I I I I I I I I I I I I I M I I I I I I I
200 180 160 140 120 100 80 60 40 20 ppm
PC18H37 N
OC-IAHST
O OCIGH37
CIEHA?
159e
1
J
"I—I—I—I—I—R—I—I—I—I—I—I—I—I—I—I—I—R 11 10 9
—PN—I—I—I—I—I—I—I—I—|—I—R 8 7 6
4.00
T—I—I—I—I—(—1—I—I—R—I—R~I—I—I—I—I—'—I—I—I—I—I—N—I I I I ' I ' ' I 1 ppm
4 .37 4 .21 10 .09 16 .02 8 .85 4 .72 4 .60 142 .14
K) O
NH HN-
HN- •NH
OCgH
159e
IWIIIII^I4IIHIWINLI>II^IIN>PLI» NMNWI iL
!
WIN LI WWNWINNWIW<WII»*M^ PMTLNIMFN I I I I I I I M I I I I I I I M I I I M'M I ' I I I I ' ' ' ' I ' ' ' ' I ' I I ' I '"I ' I I I ' I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I M I [ I I I I I I I M I I
200 180 160 140 120 100 80 60 40 20 ppm
TO
183
V U pf > » r{ T t ^ j I i I i { I I I 4 { ( I I I 1 I { t I i ? r r f T » r r I } 1 { I { t < < I I t M i I } ^ t > I t I I M I j j < I t i 1 ( "T'T
i PPN
Lh TO
183
I I I I I I 1 I I I I I I I I ; I I 200 180
I I I ' M I I I I I I I ( I I I I I I I 120
-N-T 100
V' I I M 1 1 { I M I 60
1111111111 20 PPM 160
T-r-pr 140
I I ' ' I I I 80 40
K) U)
"I—I—I—I—I—I—I—J—I—I—I—J—I—I—R 9 8
NH2 HoN,
186a
ETOZC?
.NH2
COJET
186b
—^—I—I—I—I—[—I—I—I—I—I—I—'—I—R 10 9 8
J
"T—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—R—I—I—I—I—R 1 ppm
4 .17 4 .01 3 .90
4 . 2 1 6 . 3 S
to ON
CNI
Wdd 02 Qt ' 09 oa OOT OST Ot'T 09T 0,8T ' I I I I I I I 1 I I I • I I I I I 1 I I I I I I I I I I I I I I I I I I I I I I I , I I I I I I I I I I I I I I I I I I I I I I I . I I I I I I I ] I I I I I I I I I I I I I 1 I I I I I I I I
I
q98 i
•HN
o o
187
1 1 T -I—I—I—R
2 . 0 1
X li I A n I I—I—I I p~i r~T \ I I i~~i—I—I I !—I I I I—I I—V
ppm
2 .03
—I— —I— 1— 4 .26 4 .42
4 .29 ' 7 .45
19 .02
oo
HN-NH
187
>Jm
• I I I I \ I I I I I I I I I I ) I 1 I I [ I M I I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' '"
180 160 140 120 100 80 60 40 20 ppm
Ln TO
/ ETOJCR COAET ^
188
r'
./ W 1 I I I—I R—]—I—T—I—T—]—R--T T"!—I ' RN—I 1 I I I I I
9 0 7 6
1 .50 2 .32 9 .25
1—I I I T—R—R T~T~T—R T
4 3 2 1 ppm — I 1 , 1 , 1 I , — I
4 .14 4 .28 5 .39 ' 6 ,41
U) o
HN NH
COzEt Ph Ph
188
mHim [ 11 M I I I I I j I I I I I I I I I I I M I I I I M I I I t t I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I M I I I I I I I I I I j I I I I I I I I I I
200 ibo 160 140 120 100 80 60 40 20 ppm
HAN /COZCHJ
^COZCHJ
189
•]—I—I—1—I—[—I—I—I—I—I—I—I—I—I—I—1—I—I—I—[• 9 8 7 6
II
A. T—I—I—I—I—I—1—I—R
V 5 .15 '
JUL "I I I I 1 I l~
2 ppm W W
1.99 2.11 2 .14 2 .01
Ut Lk) K)
HzN CO2CH3
H2N COZCHJ
189
[ I I M I I I I I I I I I I 1 M I I I I I I I { I I I 
_CN
O
CN
203
J w VA T T""! I I I I I n~l I P
10
1 . 0 2 6 . 0 7 3 .87
r
J )
I I I I I I I I I I I I I I ] I I I I I I I—I—I—I—I r
4 3 2 1 pprri
4 .56 4 .17
U\ U) -1
203
Wntm miM4 T I Im I I T' I I I I I I I t 1 I I I—I I' I I I I I I I I T" r'T-T •!' T 'r I 11 I' I I I r • 1 • I' '! I ' I i—r-I I I I I I I r I I I I 11 I I I I I I I [ I I I I I I I I I I I I n I I M I j I I I I I I I I I I I I I I I i I I I 'p I I I I I I I I I I I I I I I I I I [ I I I I I I I I I I I I I I I I I'l l I I I I I 11 I I I I I I' I
200 180 160 140 120 lOO' 80 60 40 20 p'p'm
UL U)
BrHgN .CO2H
BrHjN CO2H
204
IV T"T—I—I—I—I—I—R -F—R
PPM
ON
BRU^N. .COJH
BRHAN CO2H
204
JLy I I I I 1 I I > I I I I I I I I M i I ) t I I I I I I I I [ I I I I [ I I I I { I I I I I I I I I I I I I I I I I I > { ! j I I T I I I I I > I I I I I I I 1 I I I 1 I
200 180 150 140 120 100 80 60 40 20 PPM
COZH
COoH
"1 I—I—I—I—I—I—I—I—I—I—I—I—I—I—1—I—I—I—I—I—I—I—R-12 10
1 .19 1.
i d 1—I—I—I—I—I—I—!—I—I—I—I—I—I—I—I—I—I—!—I—R
4 2 PPM • . ' I , I
. 00 7 .70
U) 00
y^ri " CO2H PHT " H
205
r ?OO
fil iliitii iriiii^iiiillilH/il itiiliiiijiiiiijiiiliyt i
180 160 140
OJ
.C02CH3
COOCH,
206
i "M I I I I » { ' ' ' ' I ' ^ ' I ' ' ' ' I ' ' ' M ' ' ' ' } ' ' ' M ' ' ' ' I * ' ' ' M ' ' ' ) ' ' ' M ' ' ' ' I ' ' ' ' I ' ' ' ' 1 ' ' ' ' 1 ' ' ' ' I ' ' ' M ' ' ' ' I ' ' ' ' ^ ' I ^
10 1 PPM 0 9.68
1.88 5.91 3.00
O
/CO2CH3 O ^ O .
^COzCHa Ph'^ " H
206
I I I I I I I I I 1 I I I I I I I I I I I I I I I I I I I I I I I r I' I I I 1 I I I I ! M I I I I I I I ' I ' I ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' 160 140 120 100 80 60 40
I I I < I I I I I I I I I I I I J 20 PPM 0 200 IflO
U) 4^
OCHA
207
,jPL T 1 1 1 1 1 1 1 1—I 1 1 1 1 1 1 1 1 1 1—I 1 T"
4 3 2 1 ppm V
5.79
TO
HgCO OCH.
207
JJML JU. I I M I I I I M I I I I I I I I I I I I I I I I I I I ' I ' ' I M ' I ' I I I I M I I I M I I I M I I I I I I I I I I I M I I [ M I 1 I ' I ' ' I ' ' I ' I ' I ' I I I ' I I I I I I I I I I
180 160 140 120 100 80 60 40 20 ppm
4^ U>
217
1—I—I—I—I—RI—I—I—I—I—1—J—I—I—I—I—R—I—I—I—I—I—I—I—I—1—I—I—P
12 11 10 9 8 7
1.B8
I
I—I—I—I—I—I—R—R-T—I—I—I—R—I—|—I—R'T "T ]—T T"R •I—P I'T-'T—R-Y- T'L 6 5 4 3 2 pp'rfi
^ 't' 8-so
2..00
218
ppm
ON
218
i •*4w*w
M I I I I I M I M M I [ I I I I 1 I I I I I I I I I I 1 I I I M M I I I M n ' ' ' I ' '
200 180 160 140 120
TT I I I I I I I I M I M I I I M I I I I I I I I I I I I I I M I I I I M I I I I I I M I I
100 80 60 40 20 ppm
-1
(HGCJZNOC' C0N(CH3)2
219
T—I—I—I—I—I—I—I—I—[—I—I—I—I—I—I—I—I—I—I—R 9 8 7 6 ppm
1.02 2 .99 3.00
2 .03 2.08
4^ 00
549
N—
220
"I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—F—I—I—I—[—I—R 9 8 7 6
JuLwl-AJWL I I I I I I I I I I I I I I I r~~! I I I r
3 , 2 1 pp'm
5.B1 1 .01 0.98 2.05 1.00 1 .111.00
o
N— /
220
II I JL-JLJllLL-jt
M I I I M I I j 11 I I I 11 I I I I I I I I I M I I I I M I I' 'I I' 'I' I ' ri I I I I i I I I 11 I I I i 11 I I I I 11 I I I I 11 1 I 11 I li I I I I n I I I I I I 11 I I I
180 160 140 120 100 80 60 40 20 ppm
222
/
JLJI -I—I—I—I—I—I—I—I—I—I—I—I—I—R T—I—I—I—R
6
1—I—1—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—R 1 4 3
M 6.24
2.00
r 2
8.6B
1 ppm
K)
H3CO2C'^-S^^<,^^/^C0JCH3
222
1 I I M i I I ! i I I I I I I I I I I I ! I I I ; I I I I [ I M I I [ I I I I I I 1 I t I M I [ 1 M I I I M I I I M I I I I M I M I 1 I I i M I I I I I ( I I M I M I I ( I I M I I
180' 160 140 120 100 80 60 40 20 ppm
U>
OH HQ
Ph-
Ph
223
—T—I—1—I—I—I—!—\—\—I—I—r 10 9 A
r T—R r r (
3 2 ppm '-r-' S-" 2.00 1 .96 1.93
1,991.93
L/\
OH HQ
•Ph
223
M*B WRTIK WLLL»|>W|||LL|L||||^)^^<»^L#YVWLULL^LMLLL<^^^ 11 11 I I J 11 I J I I I 11 I I T J I I 11 11 11 I I I I I I 11 I I I I I I I 111 I I I 11 I I I 11 I I I I I 11 I 11 I I I I I I I I 11 I 11 I I I I I I I I I I I I I I I I 11 I I I I I I
180 160 140 120 100 80 60 40 20 ppm
LTi L/\ Lr\
224
r
Y V_ A
"I I I I I I I—I—I—I—I I—I—I—I—I—I—r
1 ppm
4.00
ON
224
I I I I I I I I I I I I I I I I I I I I I 11 I I I ' I' I [ I I I I I M I I I I I I I I I
180 160 140 120
I I I I I I I I I I I I > I I I I > • I I ' I ' M ' ' ' I I ' ' I ' I ' I I I I ' ' ' M ' I ' '
100 80 60 40 20 ppm
558
E D. a
- C\J
— TN
RU L O)
M
— U3
J A
—
T — CD o
o
— cn
T J
_ O (O . O)
C\J
HN NH
225
HO' OH
NH HN
T ! !—R T—I—I—I—I—R T—I—I—I—I—I—I—I—I—I—I—I—I—R 1—I—I—R T—I—I—R T—R T T
1 0 9 8 7 6 5 4 3 2 i p p m ' —, ' " , ' •—I—• R-5.00 2 .34
4.27 2.45
On O
)>==0 0==^
PH/ 226
1^1*1 M J. I I M > M I i I I 11 I I I I M I I I M I ( M I I I I
180 160 140
I I I I I I I I I I I 120
I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I r
80 60 40 20 ppm
ON
OCH. 'CH3 NH HN-
EfQ DEt NH HN
iCH. OCH.
227a
-I—I—I—I—I—I—I—I—I—I—I—I I I I I I I I I I I F" 9 8 7 6 5
2 .00 4 .65 3 . 6 7
ON
OCHA OCH3
I I M I I I I I I I I M I I I I I I I I M I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I M I I I I I I I I I I I I M I I I I I I I I I I I I I
180 160 140 120 100 80 60 40 20 ppm
L/\ O^
OCEH HN •NH
EfO, pEt HN
€EH'
227b
~i—I—I—I—r -i—I—I—I—I—I—t—r
7
2.37 1 . 8 6 4 . 0 3
OCEHIA q
OCFLH^a
227b
6" 13
0CgHi3
WNWMIIWIMW IIIIWI»<4 I I I I I I I I I 1 I I I M I I M I I I I I I I I I I I I I M I I I I I I I I I I I I I I I I I I ' * ' ' I ' ' ' ' I ' ' ' ' ' ' ' ' ' I I I ' ' ' '
180 160 140 120 100 80 60 40 20 ppm
LN On Lr\
•NH HN-
EtO, OEt NH HN
OCgH
227c
_/v_
-I 1 1 1 ] 1 1 1 1 1 1 1 1 1 j 1 ! 1 1 1-
9 8 ,7 6' i__.i—,—I
' ' ' I
: .06
-I—"—R 1.34 4 .00
2 .36
OCBH
OCeH-o
'CGHIS
OCgH 13
227b
IFW I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I M I I I I I I ! f I I I I I I I I M I I I I I I I I 1 I I I I I I I I I I I I I I I I I I I I I I I I I M I I I I I I I I I I I
180 160 140 120 100 80 60 40 20 ppm
ON
OC.H. ICAH. •NH HN-
EtO, QEt NH HN
OCaH
227c
] 1 1 1 1 j 1 1 1 1 1 1 1 1 1 j 1 ! 1 1 1 1 1 1 1 [•
9 8 7 6 5 '-1-' ' I " I ' «—T—
1.34 4.00 2 .36 2.06
OC.H
•NH HN-
EtO. ,OEt NH HN
OC.H OC.H'
227c
*r] T ri" r) I I I I I I I I I I I I I I I t I I I I M I I I I I I I I I I I I I 1 I I 1 I M I I I 1 I 1 r ] I I MM MM MM MM M M I M M TT
200 180 160 140 120' 100 80 60' 40 20' ppm
ON
HN-•NH
ETA OEt NH HN
227d
JLJ_ 1 "1—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—r—I—I—I—I—I—[~
9 8 7 6 5 M H-" H-"
1 . 7 8 1 . 6 7 2 . 8 1
r
J
A { . A k AV uL___ T I I I I I' I I \ I I I r~~i i~~i 1 I I 1 I I I I I r
ppm
6 . 7 7 7 . 1 2 4 . 0 2 7 . 1 6
'-r-' , '-I-' 8 7 , 1 4
6 , 7 9 1 2 . 2 0
O
•NH HN-
EtO, OEt NH HN
227d
VNFT* i ' ' ' ' i i i i i i i i i I i i 1 I i i r r n i i i i i | i T i i | t i - i i | i i i i | i i i i | i i
ISO 160 140 120 100
•WWILTI P4. *4WLASTIIIIFIIVLU ILAIMHIIITNIFJN -RR-RRI J^RT^N"TTT-T-Q-RT-RL | I I I I | I I I I ( | - | I I | I I I I | I I I I
80 60 40 20 ' ppfn
-J
OCH
NH HN^ EfQ PET
NH HN
OCH; OCH.
228a
/ Y
1 I I \ I I I I \ I I I I I I I I I T -I—I—R 10
I 1^ 2.20 4 . 6 3
4.3B
j J
/V "A 228a
i { I I i' I I r
LLi.IJI ..u.tA^I J ^ iui iiii. ..*11 a 1. . L l L iil^iiiliiillilill''-""*"''^-^''-''"'''^"^'^''-^ Mil • b-iiifcJLjtiiL.i hjJljI.lil .UliL. lii J. uri.iiitiniititiuitjll.ikii U.1
I , . < I I
180 160
I I I . r I . I
140 120 100
L j. ilx... bi.i.il.m^^
Pf 80 60 20 ppm
OCEHIS
OCGHI3 D
AT 7(
CFLH 6" 13
JVJl _a.
T 1 1 1 1 1 1 1 [ 1 1 1 1 j 1 1 1 1 1 1 1 1 1 1-
9 8 7 6 5
2 . 1 7 1 9 7 3 . 9 8
-|—I—I—I—I—I—I—I—R-
8. 6S 7.88 4 . 3 1 8 . 0 3
I—]—I—I—I—I—I—I—I—I—I—I— 2 1 pptn
4 6 . 0 3 8 . 3 4 1 1 . 4 9
•-J
NH HN-
EtO, pEt NH HN
OCgH
228b
160 140 100 60 40 180 120 80 20 ppm
UL
9^8^17 O O 9C8H17
OC8H-I7
228c
_A -I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—R
8 r
7 6 ' I ' . ' 2 . 3 7
4 . 0 0 2 . 1 1
r
OC.H
HN-•NH
EtQ pEt NH HN
OC.H OGbH
228c
I I I I M I I I I I I I I I I I I I I I I I I M I I I I I I I I I I I I I I I I M I I I I
180 160 140 120 60
•NH
OEt EtO, HN NH
228d
-I—I—I—I—I—I—I—R—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—T" 9 8 7 6 5
2 . 1 5 1.26 3 . 0 0
"1—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—R 1—I—R
4 I i_
8 . 4 7 9 . 2 4 4 . 0 0 9 . 6 0
ppm —I—• 1 •—I—'
1 2 6 . 5 7 1 3 . 5 6 1 8 . 3 5
LTl -J 00
OCI2H25 O 0 9C12H25
OC12H25
228d
]"L I I 1 [TTT" 200 180
I I I I I I I I I I ' I I I I I I I I I I R I I I I I I N I I "JT'I R I I I I I I I I I 1 I I I I I I I I I I I I I I 1 I I I I I I I M 1 I I I 7TI FT 7
160 140' 120 100 80 60 40 20' ppm
L/1 -J
OCgH^a
ocgh^a
_L/V, I—I I I I I I I I I j I r~i I I I I I I I I r~i I [~
9 8 7 6 5 LPJ L-T-I I-R-J
1 . 3 0 1 . 7 0 4 . 0 0
/.
jXiv ' I '
4
-I—I—I—R 1—R 3 _j
1
6 . 2 0 4 . 4 1 B . 3 5 4 . 4 2
' I ' I ' I ' . ' I ' I '
4 . 7 4 2 6 . 4 6 1 3 . 0 6 4 . 2 1 9 . 6 2 2 0 . 1 5
ppm
00 o
•NH HN-
OCH. HN
229b
IHHMOHH »»INN>NN<L^I*YI »«LW I I I I I I I I I I j I I I I I I M I j I I I I I I I I I I I I I I I I I M I I I M I I I I I I M I I I I I I I I M I I I I M I I M I I I I I I I I I I I I I I I I I [ I I I I I I I I I [ I I
200 180 160 140 120 100 80 60 40 20 ppm
VYI 00
OCGH-IY O OCGH^
H , C O
OCbHH OC8HI7
229c
Jv T 1 1 1 1—I 1 1 1 1 T
9 8
T—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—R ppm
1 . 7 1 4 . 0 0
7 . 9 8 4 . 1 6 6 . 4 4 4 . 3 7
I I 3 . 8 3 B . 5 2 1 3 . 9 1
4 . 3 6 6 3 . 0 4
OO K>
PCgH
NH HN
OCH. NH HN
OCgH
229c
JiApwf f ' [ 1 I I I M I 1 I I [ I I I I I I M M I I I I I I I I I I I I I I I j I I M I M I I I M I I I I I I I I I M 1 I I M I I I I M I I M I I I I I 1 I I I I I [ I M I 1 I I
180 160 140 120 100 80 60 40' 20 ppm
00 U>
•NH HN-
NH
229d
- T — I — I — — R - [ — R T - I — - T 9 8 7 6
1 . 7 0 1 4 . 0 0
t' 5
T-r~r*' "•Y
I.', I I I 8 . 0 8 5 . 1 6
9 . 3 9 4 . 8 6
••T~|—C= R - -T" »"-P-'T'"R-RT—]—T
2 1 ppm I • < • I -i-
I ' I
5 . 3 5 1 2 2 . 1 0 4 . 3 6 1 0 . 6 9 1 6 . B 2
00
229d
I mLt* MKMM I LJ/IU
I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I 1 I I I j I I I I I M I I I I I M I M I I I I I I I I I I I I I I I I I I I I I I
200 180 160 140 120 100 80 60 40 20 ppm
OC18H37 OC1SH37
Jl.
1—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—[-9 8 7 6 5
S-' H-J I-H 1 .20 1 . 3 5
4.00
1—I—I—I—R 3
-I—I—I—R -|—I—I—R ppm
—I— I I —r
6 . 8 0 4 . 1 9 8 . 4 4 4 . 1 5
4 . 6 8 1 6 1 . 2 6 3 . 4 1 8 . 8 0 1 8 . 4 1
00 O^
OC18H37 O O 9C18H37
OC18H37
229e
JL si. i- JX. I 1 I I iTn-i-nnpT"! i-jTi \ I"]tt I I i ri n -("n 1 r | i 1 M | i 11 1 i 1 1 1 i j j 11 1 | n 1 1 | 1 n nmi"] "i i ! i | 11 n |
200 180 I'eO 140 120' 100 8O' 60 40' 20 ppm
00
588
589
Appendix C
Two Dimensional Spectra of N-Me Diketopiperazine 129
590
One Dimensional 'H NMR (105.7 mM of 129 in CDCI3, 288K, 500 MHz)
U O - 9 1
H.CO
H.CO
OCH.
O^ <N
OCH,
986 "V
160 S^O
T
000 >
006 0
/N V
/N
CO
CNJ
f\l
NO
CO
RO
o 'SR
T
00
CM
ID
CD
ID
O
CD
CO
CD
CO
E A CL
591
One Dimensional '^C NMR (105.7 mM of 129 in CDCI3, 288K, 125 MHz)
O
o
o o
o o
o CO
o
o OCH
-o
O^ (N
HN
o -o
OCH
592
and One Dimensional Assignments for 129
"H NMR (105.7 mM in CDCI3, 288K, 500 MHz) S: 2.77 (3H, s), 3.03 (2H, d, J = 16.03),
3.18 (2H, d, J = 17.55), 3.63 (2H, d J = 16.02), 3.67 (6H, s), 3.68 (2H, d, J = 17.17), 3.72
(6H, s), 6.55 (2H, s), 6.59 (2H, s), 6.78 (IH, bs); NMR (105.7 mM in CDCI3, 288K,
125 MHz) 5: 30.0, 43.3, 44.8, 55.4, 55.5, 66.2, 69.1, 109.1,109.6, 127.9, 129.4, 149.3,
150.2, 167.6, 170.8.
Pgauche
HJPsyn,
CH,
HN
psyn
pgauche
593
Heternuclear Single Quantum Coherence (HSQC), Spectra A
0'0£
ivdd ) uocjUDj
0 * 0 9 O ' O Z 0 * 0 6 O ' O l I
1
CO
F\J
C\J
ro
(O
ro
o
E ^ A
CD §
L f\j Q-
in
CO
in
o CO
T
CO
Partial HSQC, Spectra B
594
2.77, 30.0
• • 3.68, 43.3 3.18,43.3
• • 3.63,44.8 • » 3.03,44.8
3.72, 55.4 ^^3.67,55.5
3.8 3.6 3.4 Pnoton
3.2 3.0 2.8 C ppm )
o RO
CO ro
E A a
f\l c ^ 0
-Q L 0
O ^ 00
ID
595
Heteronuclear Multiple Bond Coherence (HMBC), Spectra A
eTe eTo sTi ^~6 Ze
Pnoton (ppm)
596
Partial HMBC, Spectra B
4 0
4 •
4 I 14 <4 >
4 • ^ 4 '
00
O 1 Q-
ID ^
c 0
O -0 • L
"O 0 CO o
«# 3.63, 66.2 I
••I 3.68,69.1
3.03,66.21
^ 3.18,69.1 T
2.77, 69.1
4 . 0 3 . 8 3 . 6 3 . 4 3 . 2 3 . 0 2 . 8 Proton (ppm)
CO CO
o OJ
Partial HMBC, Spectra C
3.68, 109.1 1
3.18, 109.1 1
1 •n-
1
1 " M
1 1 3.63, 109.6
1 3.03, 109.6
^6.55, 127.9
*
\
3.63, 127.9
1
.1
3.03, 127.9
1
4*
6.59, 129.4 1 3.68, 129.4
1 3.18, 129.4
6.59, 149.3
%
\.55, 150.2
3.72,149.3. 1,
i 3.67, 150.2 ^
3.03, 150.2
1 «« 4*
1 3.18, 149.3
•
3.63, 167.7 !!
3.68,170.8 "
2.77, 167.7
1
6 . 8 6 . 0 5 . 2 4 . 4 3 . 6 2 . 8 Proton ( p p m )
Tabulated HSQC Correlations
H ppm ppm
H5 2.77 C5 30.0
p gauche 3.03 C2P 44.8
h^psyn 3.63 QP 44.8
j^^p gauche 3.18 c.p 43.3
h^Psyn 3.68 C,P 43.3
H4 3.67 C4 55.5
H3 3.72 C3 55.4
H2' 6.55 C2' 109.6
6.59 109.1
Tabulated HMBC Correlations
'H ppm '^C ppm '^C ppm '^C ppm '^C ppm
2.77 (H5) 69.1 (Ci«) 167.7 (C2)
3.03 66.2 (C2") 109.6 (C2®) 127.9 (C2^) 150.2 (C2')
3.63 66.2 (C2") 109.6 (C2^) 127.9 (C2^) 167.7 (C2)
3 18 (H,P gauche) 69.1 (C,") 109.1 (C,®) 129.4 (Ci^) 149.3 (Ci")
3.68 69.1 (€,") 109.1 (Ci^) 129.4 (C,^) 170.8 (C,)
3.67 (H4) 150.2 (C2')
3.72 (H3) 149.3 (C,'^)
6.55 (H2') 127.9 (C2^) 150.2 (C2')
6.59 (H,') 129.4 (C,^) 149.3 (€,')
599
Appendix D
Chapter 3 Dependence Studies
600
A 106 mM CDCI3 stock solution of the N-Me diketopiperazine 129 was prepared,
and solutions ranging from 11 mM to 79 mM were obtained via serial dilution. 5 mL of
each sample was injected into an NMR tube and the glass tube sealed. Dependence
experiments were conducted on a 300 MHz Varian NMR Spectrometer at temperatures of
-20 °C, 25 °C and 40 °C. All 'H NMR spectra were referenced to TMS (0 ppm). The aryl
and NH 'H NMR frequencies appeared to be concentration and temperature
dependant, while the Hi^ 'H NMR frequency along with the remainder of the 'H NMR
spectra, and the '^C NMR spectra, were immobile. Upon completion of the experiment,
each NMR tube was carefully opened, 20 )iL of d-TFA was injected, and the glass tube
again sealed. Within 2 hours of J-TFA injection, 'H NMR experiments were conducted at
25 °C and 40 °C. The following tables summarize the 'H NMR data collection for the
aryl W , aryl H,' and NH protons at 25 °C, 40 °C and -20 °C.
601
N-Me Diketopiperazine 129 in CDCI3 at 25 °C (300 MHz)
M (CDCI3) H2' (Hz) H,^(Hz) NH (Hz) li2^ /TFA (ppm) H,' /TFA (ppm)
0.011 1982.5 1979.1 1881.1 6.75 6.73
0.014 1982.1 1979.2 1887.1 6.75 6.73
0.019 n.f. n.f. n.f. 6.75 6.73
0.025 1979.4 1979.4 1902.2 6.75 6.73
0.033 1978.7 1978.7 1916.9 6.75 6.73
0.045 1976.1 1978.3 1932.1 6.75 6.73
0.059 1973.3 1978.4 1952.0 6.74 6.72
0.079 1970.0 1978.1 1978.1 6.74 6.72
0.106 1965.1 1977.3 2007.8 6.73 6.71
n.f.= data collected but not available
N-Me Diketopiperazine 129 in CDCI3 at 40 °C (300 MHz)
M (CDCI3) W (Hz) H,'=(Hz) NH (Hz) H2' /TFA (ppm) Hi' /TFA (ppm)
0.011 1982.3 1978.6 1866.3 6.75 6.73
0.014 1981.7 1978.5 1870.6 6.75 6.73
0.019 1981.1 1978.7 1877.6 6.75 6.73
0.025 1978.6 1978.6 1884.6 6.75 6.73
0.033 1978.3 1978.3 1896.8 6.75 6.73
0.045 1977.2 1977.2 1910.5 6.74 6.73
0.059 1974.4 1977.8 1928.0 6.74 6.72
0.079 1971.2 1977.0 1949.2 6.74 6.72
0.106 1967.4 1976.9 1976.9 6.73 6.71
602
N-Me Diketopiperazine 129 in CDCI3 at -20 °C (300 MHz)
M (CDCI3) H2^ (HZ) H,^(HZ) NH (HZ) H2' /TFA (ppm) Hi'^ /TFA (ppm)
0.011 1983.1 1981.2 1949.2 n.a. n.a.
0.014 1980.8 1980.8 1962.8 n.a. n.a.
0.019 1981.0 1981.0 1962.9 n.a. n.a.
0.025 1977.7 1977.7 1969.1 n.a. n.a.
0.033 1974.7 1980.8 1992.5 n.a. n.a.
0.045 1971.1 1980.6 2014.3 n.a. n.a.
0.059 1966.7 1980.6 2041.1 n.a. n.a.
0.079 1961.1 1980.2 2074.4 n.a. n.a.
0.106 1954.7 1979.9 2117.1 n.a. n.a.
n.a. = experiments were not conducted
A 222 mM stock solution of 1,4 dimethoxy-2,3-dimethylbenzene (69a) was
prepared, and 111 mM and 11 mM solutions were obtained via serial dilution. 5 mL of
each sample was injected into an NMR tube and the glass tube sealed. 'H NMR
experiments were conducted on a 300 MHz Varian NMR Spectrometer at temperatures of
25 °C and 40 °C. The spectra was referenced to TMS (0 ppm).
69a in CDCI3 at 25 °C and 40 °C(300 MHz)
M (CDCI3) 25 °C (ppm) 40 °C (ppm)
0.011 6.64 6.64
0.111 6.65 6.65
0.222 6.66 6.66
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