The Dissertation Committee for David Frederic Cauble, Jr. certifies that this is
the approved version of the following dissertation:
TRANSITION METAL AND ORGANO-CATALYZED CYCLIZATIONS, CYCLOADDITIONS AND COUPLINGS
Committee:
Michael Krische, Supervisor
Eric Anslyn
Stephen Martin
Philip Magnus
Christian Whitman
TRANSITION METAL AND ORGANO-CATALYZED CYCLIZATIONS, CYCLOADDITIONS AND COUPLINGS
David Frederic Cauble, Jr., B.S
by
DissertationPresented to the Faculty of the Graduate School of
the University of Texas at Austinin Partial Fulfillment of the Requirements
for the Degree ofDoctor of Philosophy
The University of Texas at AustinDecember 2004
UMI Number: 3150558
31505582005
UMI MicroformCopyright
All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code.
ProQuest Information and Learning Company 300 North Zeeb Road
P.O. Box 1346 Ann Arbor, MI 48106-1346
by ProQuest Information and Learning Company.
Dedication
To my parents, David and Alice Cauble, whose support and encouragement have made
all the difference.
Acknowledgements
I am grateful to my mentor, Professor Michael J. Krische, for his support and
guidance and for providing a challenging environment within which to grow personally
and intellectually. I am indebted also to the members of the Krische group, with whom I
spent much time and from whom I learned a great deal. Finally, special thanks are due to
those who helped proof-read this dissertation: Alice Cauble, Diane Lam, Wendy Mariner,
Susan Garner and Pablo Mauleon.
iv
TRANSITION METAL AND ORGANO-CATALYZED CYCLIZATIONS, CYCLOADDITIONS AND COUPLINGS
Publication No.
David Frederic Cauble, Jr., Ph.D.The University of Texas at Austin, 2004
Supervisor: Michael J. Krische Transition metal-catalyzed carbon-carbon bond-forming reactions are attractive
methodological targets, as they enable the rapid build-up of molecular complexity.
Herein is described research directed toward the development of highly practical,
efficient and selective transition metal-catalyzed processes that facilitate the succinct,
sequential formation of multiple chemical bonds: i. Catalysts derived from rhodium and
copper are featured in tandem conjugate addition-electrophilic trapping reactions (tandem
vicinal difunctionalization), leading to products of formal aldol, Dieckmann and Blaise
cyclizations. In this context, the use of diastereotopic 1,3-dione electrophilic acceptors is
examined. ii. Related rhodium catalysts are employed successfully in the catalytic
reductive arylation of 1,3-cyclohexadiene. iii. The classical Gilman reagent
(dimethyllithium cuprate-lithium iodide) is shown to catalyze the [2+2]cycloaddition of
v
bis(enone) substrates in high yield. Effective partitioning between the 1,4-addition and
cycloaddition manifolds is showcased and discussed.
Finally, a strategy for the enantioselective catalysis of photo-mediated reactions in
solution is described, involving the use of chiral molecular receptors possessing
appendant triplet sensitizing moieties. Energy transfer is selectively directed to bound
substrate as a consequence of the distance dependence of triplet-triplet energy transfer.
This effect, which is equivalent to a binding induced rate enhancement, enables
substoichiometric chirality transfer from the receptor template to the substrate, as
observed in the intramolecular enone-olefin photo[2+2]cycloaddition of a quinolone
substrate.
vi
Table of Contents
List of Schemes xiv
List of Tables xviii
List of Figures xix
Glossary xx
Chapter I. Tandem Vicinal Difunctionalization of α,β-Unsaturated Carbonyl
Compounds: Catalytic Tandem Conjugate Addition-Electrophilic Trapping
Reactions
Part 1. Recent Advances 1
A. Introduction 1
B. Reactions Proceeding via Copper Catalysis 4
i. Addition of Grignard Pronucleophiles: The Kharasch Reaction 4
a. Mechanistic Features 4
b. Application to Lycopodine and Prostanoid Syntheses 5
c. Tandem Conjugate Addition-Claisen Rearrangement 6
d. Tandem Conjugate Addition-Intramolecular Alkylation 7
ii. Addition of Organozirconium Pronucleophiles 7
a. Organozirconium Pronucleophiles via Hydrozirconation of Alkynes 7
b. Zirconocyclopentene Pronucleophiles via Oxidative Cyclization 9
c. Organozirconium Pronucleophiles via Hydrozirconation of Alkenes 10
iii. Addition of Organozinc Pronucleophiles 13
a. Mechanistic Features 13
b. Zinc Homoenolate Pronucleophiles 15
c. Organozincate Pronucleophiles 16
d. Diorganozinc Pronucleophiles 18
vii
C. Reactions Proceeding via Rhodium Catalysis 22
i. Additions of Organoboronic Acid and Organoboronate Pronucleophiles 22
a. Background and Mechanistic Features 22
ii. Tandem Reactions Employing Organoborane Pronucleophiles 24
iii. Tandem Reactions Employing Organotitanium and Organozinc 26
D. Reactions Proceeding via Nickel Catalysis 27
i. Additions of Organozinc Pronucleophiles: Background and Mechanistic Features 27
ii. Tandem Reactions Employing Organozinc Pronucleophiles 28
iii. Tandem Reactions Employing Aryl Iodide Pronucleophiles 29
E. Conclusion 30
Part 2: Graduate Research: Metal-Catalyzed Conjugate Addition-Electrophilic Trapping Reactions 32
A. Background: Conjugate Reduction-Electrophilic Trapping Reactions Developed by the Krische Group 32
i. Cobalt-Catalyzed Reductive Aldol and Reductive Michael Cyclizations 32
ii. Cobalt-Catalyzed Intramolecular [2+2] Cycloaddition 33
iii. Borane-Mediated Reductive Aldol Cyclizations 34
iv. Hydrogenative Rhodium-Catalyzed Aldol Cyclizations 35
B. Metal-Catalyzed Conjugate Addition-Aldol, Blaise, Dieckmann and Darzens Condensation Sequences 39
i. Respective Contributions 39
ii. Rhodium-Catalyzed Conjugate Addition-Aldol Cyclizations 39
a. Mono-Enone Mono-Methyl Ketone Substrates 39
b. Conjugate Addition-Aldol Cyclizations Using Symmetrical Dione Acceptors 41
c. Application Towards the Synthesis of Steroidal Ring Systems 42
d. Parallel Kinetic Resolution 43
iii. Cu-Catalyzed Conjugate Addition-Aldol, Dieckmann 43
and Blaise Cyclizations 43
viii
iv. Higher-Order Tandem Reactions 47
a. Latent Functionality and Chemoselectivity 47
b. Cu-Catalyzed Conjugate Addition-Darzens Condensation 48
c. Cu-Catalyzed Conjugate Addition-Aziridination 49
Part 3. References 50
Part 4. Experimental Section 57
A. Synthetic Procedures 57
i. General 57
ii. Representative procedure for the preparation of I-2.7 – I-2.10 58
iii. Representative procedure for the preparation of I-2.11 – I-2.14 58
iv. Representative procedure for the preparation of I-2.1 – I-2.4 59
v. Procedures for the preparation of I-2.19 – I-2.21 59
vi. Procedures for the synthesis of substrates I-2.22 – I-2.24 59
vii. Procedure for Yandem CA-Dieckmann cyclization of I-2.7 and I-2.9 61
viii.Procedure for Tandem CA-Dieckmann cyclization of I-2.8 and I-2.10 61
ix. Procedure for Tandem CA-Blaise cyclization of substrates I-2.11 – I-2.14 62
x. Procedure for Cu-Catalyzed Aldol Cyclizations 62
xi. Procedure for the Preparation of Product I-2.1e 63
xii. Procedure for the Preparation of Products I-2.21, I-2.22 and I-2.25 63
xiii.Procedure for the Preparation of Product I-2.24 64
xiv.Procedure for the Preparation of Substrate I-2.6 64
xv.General procedure for Rh-Catalyzed Aldol Cylizations 64
B. Spectroscopic and Crystallographic Characterization Data 66
ix
Chapter II. Rhodium-Catalyzed Additions to Conjugated Dienes: Reductive Arylation of 1,3-Cyclohexadiene Part 1. Introduction: Metal-Catalyzed Additions to Conjugated Dienes 119
A. Reactions Involving Electrophilic π-Allyl Complexes 119
i. Electrophilic π-Allyl Complexes Derived from Palladium(II) 119
ii. Electrophilic π-Allyl Complexes Derived from Palladium(0) 120
B. Reactions Involving Neutral π-Allyl Complexes 120
i. Mechanistic Features 120
C. Reactions Involving Nucleophilic π-Allyl Complexes 121
i. Tandem Hydrometallation-Aldehyde Additions 121
ii. Carbocyclizations Involving Oxametallocycle Intermediates 122
iii. Carboxylative Processes 123
iv. Coupling of Dienes and Glyoxals Under Catalytic Hydrogenation Conditions 124
Part 2. Rhodium-Catalyzed Reductive Arylation of 1,3-Cyclohexadiene 125
A. Background and Objective 125
B. Results and Discussion 127
i. Initial Results and Mechanistic Hypothesis 127
ii. Optimization 128
a. Counter-ion Effects 128
b. Additive/Solvent/Reaction Time 129
c. Ligand Effects 130
d. Summary 130
iii. Alternative Subtrates 130
a. α-Terpinene and α-Phellandrene 133
b. 2,3-Dimethyl-1,3-Butadiene 133
c. Acyclic Dienes Incorporating Electrophilic (Ketone) Traps 134
d. 2-Phenyl-1,3-cyclohexadiene 134
e. ortho-Acetyl-phenylboronic acid 134
iv. Revised Mechanistic Hypothesis 135
x
Part 3. Conclusion 137
Part 4. References 138
Part 5. Experimental Section 140
A. Synthetic Procedures and Product Characterization 140
i. General 140
ii. Representative procedure for the Rh-catalyzed reductive
arylation of 1,3- cyclohexadiene 140
iii. 4-Phenylcyclohexene 141
iv. 4-Methoxybiphenyl 141
v. Preparation of substrate II-1.1 141
Chapter III: Recent Developments in Catalytic [2+2]Cycloadditions
Part 1. Anion Radical [2+2]Cycloaddition as a Mechanistic Probe: Stoichiometry
and Concentration-Dependant Partitioning of Electron-Transfer (ET) and
Alkylation Pathways in the Reaction of the Gilman Reagent Me2CuLi•LiI
with bis(Enones) 142
A. Introduction and Background 142
i. Early Observations Attributed to Electron Transfer in Gilman Alkylations 142
ii. Accepted Mechanistic Features of Gilman Alkylation 143
iii. Conjugated- bis(Enones) as Mechanistic Probes 144
B. Results and Discussion 146
i. The Anion Radical Probe Reaction 146
ii. Organocuprate Catalyzed [2+2]Cycloaddition 147
a. Partitioning of Reactivity as a Function of Catalyst Loading 147
b. Partitioning of Reactivity as a Function of Catalyst Concentration 147
c. Exploration of Substrate Scope 149
d. Kinetic Studies 149
iii. Mechanistic Proposal 150
a. Concentration-Dependant Speciation 150
xi
b. Role of Lithium Iodide 151
c. Anion Radical Chain Cycloaddition vs. Oxidative Cyclization- Reductive Elimination 152
d. Concentration-Dependant Speciation 153
C. Conclusion 154
D. References 156
E. Experimental Section 158
i. Synthetic Procedures 158
a. General 158
b. Preparation of bis(enone) substrates III-1.1a – III-1.e 159
c. Preparation of dimethyllithium cuprate-lithium iodide (Me2CuLi-LiI) reagent 159
ii. Experimental Procedures 159
a. Procedure for data reported in Table III-1.1 159
b. Procedure for data reported in Table III-1.2 160
c. Procedure for data reported in Table III-1.3 160
iii. Spectroscopic and Crystallographic Data 160
a. Spectroscopic data for cyclobutane products III-1.3a – III-1.3e 160
b. Spectroscopic data for cyclobutane products III-1.2a – III-1.2e 161
c. Crystallographic data for cyclization product III-1.2e 166
Part 2. Studies on the Enantioselective Catalysis of Photochemically Promoted Transformations: “Sensitizing Receptors” as Chiral Catalysts 167
A. Introduction 167
i. Stoichiometric Chirality Transfer in Photo[2+2]cycloadditions 167
ii. Substoichiometric Chirality Transfer 168
B. Sensitizing Molecular Receptors as Enantioselective Catalysts 168
i. Hydrogen Bond-Mediated Host-Guest Complex 168
ii. Triplet Sensitization as Basis for Binding-Induced Rate Enhancement 169
iii. Synthesis of Sensitizing Receptor R (III-2.8) 170
C. Proposed Catalytic Mechanism: Receptor-Directed Energy Transfer 171
xii
D. Evaluation of Organic Chromophore-Mediated Energy Transfer 172
i. Comparison of Exogenous and Receptor-Based Chromophores 172
ii. Identification of the Quenching Chromophore 173
iii. Incorporation of a Non-Quenching Scaffold 174
a. Kinetic Studies 174
E. Characterization of Host-Guest Binding Interactions 176
F. Enantioselective Catalytic Photocycloaddition 176
G. Second-Generation Receptor Design and Synthesis 178
i. Conformational Analysis 178
ii. Incorporation of a tertiary-Butyl Residue 179
iii. Characterization of Host-Guest Binding Interactions 180
H. Conclusion and Outlook 181
I. References 182
J. Experimental Section 186
i. Synthetic Procedures 186
a. General 186
b. Synthesis and Characterization of Cycloaddition Substrate S and Cycloadduct P 187
c. Synthetic Procedures 187
d. Spectroscopic and Crystallographic Data 194
Bibliography 209
Vita 221
xiii
List of Schemes
Scheme I-1.1: Kharasch-Type 1,4-Addition Catalytic Cycle 4
Scheme I-1.2: Stork’s Synthesis of Lycopodine 5
Scheme I-1.3: Prostanoid Synthesis: Tandem 1,4-Addition-Aldol Condensation 5
Scheme I-1.4: Prostanoid Sythesis: Tandem 1,4-Additition Aldol-Condensation via Enolate Derivative 6
Scheme I-1.5: Tandem Conjugate Addition-Peterson Olefination 6
Scheme I-1.6: Tandem Conjugate Addition-Claisen Rearrangement 7
Scheme I-1.7: Tandem Conjugate Addition-Intramolecular Alkylation 7
Scheme I-1.8: Mechanistic Cycle Involving Zirconocene/Cuprate Transmetallation 8
Scheme I-1.9: Tandem Zirconocyclopentene Addition-Electrophile Trapping 10
Scheme I-1.10: Naked Enolate versus Tethered-Zirconium Enolate Trapping 10
Scheme I-1.11 Chemoselective Tethered-Zirconium Enolate Trapping: Aldehyde and Proton 10
Scheme I-1.12: Chemoselective Tethered-Zirconium Enolate Trapping: Aldehyde and Halide 10
Scheme I-1.13: Cu(I)-Catalyzed Alkyl Zirconium 1,4-Addition: Wipf’s Mechanistic Proposal 11
Scheme I-1.14: Tandem Alkylzirconium 1,4-Addition-Aldol Addition 12
Scheme I-1.15: Auxiliary-Directed Alkylzirconium 1,4-Addition-Aldol Sequence 12
Scheme I-1.16: Noyori’s Cu(I)/Sulfonamide Catalyst System: Proposed Bridging Functionality 13
Scheme I-1.17: Alexakis’ Catalytic Mechanism Proposal 14
Scheme I-1.18: Failure of Electrophilic Trapping of Zinc Homoenolate Conjugate Adduct 15
Scheme I-1.19: Tandem Zinc Homoenolate 1,4-Addition- Intramolecular Trapping 15
Scheme I-1.20: Lipshutz’s Cuprate-Catalyzed Organozinc 1,4-Addition-Aldol Sequence 16
Scheme I-1.21: Noyori’s Diethylzinc 1,4-Addition-Aldol Sequence 18
xiv
Scheme I-1.22: Tandem Dialkylzinc 1,4-Addtion-Pd0-Catalyzed Allylic Alkylation 18
Scheme I-1.23: First Highly Enantioselective 1,4-Addition-Aldol Sequence 19
Scheme I-1.24: Feringa’s Synthesis of Prostaglandin E1 Methyl Ester 20
Scheme I-1.25: α,β-Unsaturated Lactams as Conjugate Addition Substrates 20
Scheme I-1.26: Functionalizations of Silyl Enol Intermediates 21
Scheme I-1.27: Hoveyda’s Iminophosphoranes in Enantioselective Sequences 21
Scheme I-1.28: Enantioselective Rhodium-Catalyzed 1,4-Addition of Phenylboronic Acid 22
Scheme I-1.29: Rhodium-Catalyzed 1,4-Addition of Phenylboronic Acid: Catalytic Cycle 23
Scheme I-1.30: Partitioning of Conjugate Addition and Heck Pathways 23
Scheme I-1.31: Rhodium-Catalyzed Arylborane 1,4-Addition-Electrophile Trapping Sequences 25
Scheme I-1.32: Organotitanium Pronucleophiles in Rhodium-Catalyzed Sequences 26
Scheme I-1.33: Organozinc Pronucleophiles in Rhodium-Catalyzed Sequences 26
Scheme I-1.34: Nickel-Catalyzed 1,4-Addition-Alkylation Sequences 27
Scheme I-1.35: Nickel-Catalyzed 1,4-Addition: Schwartz’s Proposed Mechanistic Cycle 27
Scheme I-1.36: Nickel-Catalyzed Conjugate Methylation-Aldehyde Addition 28
Scheme I-1.37: Nickel-Catalyzed 1,4-Addition-Michael and Aldol Cyclizations 28
Scheme I-1.38: Montgomery’s Nickel-Catalyzed 1,4-Addition: Mechanistic Hypothesis 30
Scheme I-2.1: Cobalt-Catalyzed Reductive Aldol and Michael Cyclizations 32
Scheme I-2.2: Basis for Diastereoselection 33
Scheme I-2.3: Bifurcation of Michael Cyclization and [2+2] Manifolds 34
Scheme I-2.4: Catecholborane-Mediated Reductive Aldol Cyclizations 35
Scheme I-2.5: Rh-Catalyzed Hydrogen-Mediated Aldol Additions 36
Scheme I-2.6: Aldol Cyclizations of Enone-Tethered 1,3-Diones 37
Scheme I-2.7: Catalytic Intermolecular Addition of Metalloaldehyde Enolates 37
Scheme I-2.8: Addition of Aldehyde Metalloenolates to Ketones 38
xv
Scheme I-2.9: Formal Heterocyclic Activation of Hydrogen by Enabling Mono-Hydride Pathways 38
Scheme I-2.10: Control: Submitting Product to Equilibrating Conditions 40
Scheme I-2.11: Symmetrical Diones as Electrophilic Acceptors 41
Scheme I-2.12: Entry Into Seco-B Ring Steroidal Systems 43
Scheme I-2.13: Enantioselective 1,4-Addition-Aldol Cyclization 45
Scheme I-2.14: Tandem Kharasch Addition-Aldol Cyclization 47
Scheme I-2.15: Catalytic Conjugate Addition-Darzens Condensation 49
Scheme I-2.16: Catalytic Conjugate Addition-Darzens Aziridination 49
Scheme II-1.1: Electrophilic π-Allyl Complexes Derived from Palladium(II) 120
Scheme II-1.2: Electrophilic π-Allyl Complexes Derived from Palladium(0) 120
Scheme II-1.3: Addition to Conjugated Dienes via Neutral (π-Allyl)Palladium Complexes 121
Scheme II-1.4: Intramolecular Hydroacylation of Conjugated Dienes 121
Scheme II-1.5: Nickel-Catalyzed Reductive Couplings of Conjugated-Dienes and Carbonyls 122
Scheme II-1.6: Nickel-Catalyzed Oxidative Cyclizations of Conjugated Diene-Tethered Aldehydes 122
Scheme II-1.7: Nickel-Catalyzed Bimolecular Oxidative Cyclizations of 1,3-Dienes and Aldehydes 123
Scheme II-1.8: Nickel-Catalyzed Carboxylative Couplings 123
Scheme II-1.9: Nickel-Catalyzed Carboxylative Ring-Forming Coupling of Conjugated Dienes 124
Scheme II-1.10: Coupling of Cyclohexadiene and Glyoxals Under Hydrogenative Conditions 125
Scheme II-2.1: Rhodium-Catalyzed 1,4-Addition of Phenylboronic Acid 126
Scheme II-2.2: Rhodium-Catalyzed 1,4-Addition-Aldol Cyclization Sequences 126
Scheme II-2.3: Rhodium-Catalyzed Coupling of 1,3-Cyclohexadiene and Phenylboronic Acid 127
Scheme II-2.4: Proposed Mechanism 127
Scheme II-2.5: Coupling of 4-Methoxyphenylboronic Acid and 1,3-Cyclohexadiene with a Cationic Rhodium Catalyst 129
Scheme II-2.6: Rhodium-Catalyzed Coupling of 1,3-Cyclohexadiene and Phenylboronic Acid – Optimized Reaction 130
xvi
Scheme II-2.7: Attempted Arylation of α-Terpinene and α-Phellandrene 133
Scheme II-2.8: Attempted Arylation of 2,3-Dimethyl-1,3-Butadiene 133
Scheme II-2.9: Attempted Cyclization of Diene-Ketone II-1.1 134
Scheme II-2.10: Dehydrogenation of 2-Phenyl-1,3-Cyclohexadiene 134
Scheme II-2.11: Attempted Coupling of 1,3-Cyclohexadiene and o-Acetyl Phenylboronic Acid 135
Scheme II-2.12: Attempted Trapping of (π-Allyl)Rhodium Intermediate with Methyl Ethyl Ketone 135
Scheme III-1.1: Gilman 1,4-Addition: Mechanistic Outline 144
Scheme III-1.2: Partitioning of Electron Transfer and Alkylation Pathways 146
Scheme III-1.3: Postulated Stepwise Mechanism for Anion Radical Chain Cyclobutanation 147
Scheme III-1.4: Alternative Cyclobutanation Pathways 153
Scheme III-1.5: Equilibrium Between Solvent-Separated Ion Pairs and Contact Ion Pair Dimer 153
Scheme III-2.1: Synthesis of Sensitizing Molecular Receptor R (III-2.8) 170
Scheme III-2.2: Proposed Catalytic Cycle 172
Scheme III-2.3: Irradiation of Quinolone S in the Presence and Absence of Selected Exogenous Chromophores and Receptors 173
Scheme III-2.4: Identification of Quenching Chromophore in the Receptor R Scaffold 173
Scheme III-2.5: Synthesis of Non-Quenching Receptor RT 174
Scheme III-2.6: Control Experiment - Irradiation of quinolone S in the presence of receptor R 178
Scheme III-2.7: Retrosynthesis of t-Butyl Sensitizing Receptor RtB 179
Scheme III-2.8: Synthesis of Sensitizing Amine III-2.15 180
xvii
List of Tables
Table I-1.1: Lipshutz’s Higher-Order Cuprate-Catalyzed Conjugate Adition- Aldol Sequence 9
Table I-1.2: Crimmins’ Formal [3+2] Cycloadditions 17
Table I-1.3: Oxocarbenium Ions as Electrophilic Traps 20
Table I-1.4: Rhodium-Catalyzed Arylborane 1,4-Addition-Aldol Sequences 24
Table I-1.5: 1,4-Addition-Aldol Sequence Emloying Aryl Iodides 29
Table I-2.1: Rhodium-Catalyzed 1,4-Addition-Aldol Cyclizations 39
Table I-2.2: Enantioselective 1,4-Addition-Aldol Cyclizations of Enone-Tethered 1,3-Dione Substrates 42
Table I-2.3: Tandem 1,4-Addition Dieckmann, Blaise and Aldol Cyclizations 46
Table II-2.1: Rhodium-Catalyzed Arylation of 1,3-Cyclohexadiene: Optimization of Experimental Parameters 131
Table II-2.1 Continued 132
Table III-1.1: Effect of Cuprate-Loading, Concentration and Order of Addition 148
Table III-1.2: Partitioning of Mechanistic Pathways Across a Range of Substrates 149
Table III-1.3: Reaction Kinetics Experiments 150
Table III-2.1: Photocycloaddition in the presence of variable quantities of photo-catalyst R 177
xviii
List of Figures
Figure I-1.1: Convergent Hydrozirconation of Alkenes 11
Figure I-2.1: Bidentate Ligands and Cyclization Transition State 40
Figure I-2.2: Parallel Kinetic Resolutions of Enone-Tethered, Differentiated 1,3-Diones 44
Figure I-2.3: Chemoselectivity and Latent Functionality 48
Figure II-2.1: Proposed Mechanism Involving Non-productive β-Hydride Elimination/Hydrometallation 136
Figure III-2.1: X-Ray crystal structure of mandelamide (R,S) III-2.4 171
Figure III-2.2: Rates of Cycloaddition in the Presence of RT versus Benzophenone 175
Figure III-2.3: Stoichiometry Determination 176
Figure II-2.4: 1H NMR Titration Plot 176
Figure III-2.5: Conformational Basis of Enantiodiscrimination 179
Figure III-2.6: Possible Dimerization Equilibrium 181
xix
xx
Glossary
For questions pertaining to acronyms or abbreviations, see: “The Use of
Acronyms in Organic Chemistry,” Daub, G. H.; Daub, G. W.; Walker, S. B. Aldrichimica
Acta, 1984, 17, 13.
For questions pertaining to chemical nomenclature, see: ‘Systematic
Nomenclature of Organic Chemistry: A Directory to Comprehension and Application of
its Basic Principles,” Hellwinkel, D., Springer-Verlag, Berlin, 2001.
Chapter I: Tandem Vicinal Difunctionalization of α,β-Unsaturated Carbonyl Compounds: Catalytic Tandem Conjugate Addition-Electrophilic Trapping Reactions Part 1. Recent Advances
A. Introduction
Tandem carbon-carbon bond formations are attractive methodological targets as
they enable the rapid build-up of molecular complexity. This is due to the efficiency with
which the reactive potentials of reaction parteners are matched. Central to the
development of highly efficient, sequential processes is the notion of latent functionality,
wherein reaction at one site of a molecule confers reactivity upon another site. Among
functional groups amenable to this technique, conjugated enones (and ynones) represent
versatile platforms for the design of tandem processes involving initial conjugate addition
(CA) and subsequent trapping of the nucleophilic adduct. The first reported instance of
this strategy is a Kharasch-type 1,4-addition/alkylation sequence,1 found in Stork’s
synthesis of Lycopodine (Scheme I-1.2).2 In the following years, as the technologies of
metal-mediated and metal-catalyzed conjugate addition matured, so did the attendant
applications in tandem vicinal difunctionalization. Taylor’s detailed 1985 review3 of
organocopper-based CA/trapping cites instances of catalytically-generated metallo-
enolate and stabilized enolate derivatives trapped with classical (alkyl halide,4
carbonyl,5,6,7 acyl,8,9 Michael,10 oxocarbenium,11 and iminium12) electrophiles. Despite
these developments, greater synthetic versatility and higher yields were, at the time,
associated with the use of stoichiometric cuprate reagents, and this general preference
was reflected by the relatively few instances of catalytic processes in Hulce and
1
Chapdelaine’s 1990 Organic Reactions survey.13 A subsequent mini-review14 in 1994
focused entirely on the use of stoichiometric cuprate reagents. Noyori explains that
“although the combination of Grignard reagents and copper catalysts is often the first
choice, lithium diorganocuprates and higher order cuprates have been used more widely
in view of the higher efficiency, selectivity and reproducibility of the conjugate addition
reactions.”14 For many tandem processes, however, it is conceded that “the utility is
greatly enhanced if the 1,4-addition sequence is made catalytic in such a way as to form a
well-defined, single-metal enolate.”15 From the standpoint of economics and waste
management, furthermore, the benefits of “downsizing”16 the role of metals are obvious.
Ultimately, the most compelling incentive to develop catalytic variants may reside in the
prospect of ligand-mediated, substoichiometric chirality transfer and amplification. To
these ends, catalytic conjugate addition methodologies have unquestionably dominated
the developmental field for the past decade, and the Krische group has been among those
to develop and explore an emergent family of catalytic, tandem carbon-carbon bond-
forming reactions.
The goal of the first part of Chapter I is to review developments in catalytic
tandem vicinal difunctionalization over the past ten years, and in this way contextualize
the author’s research. With regard to the topics reviewed, the intended focus is primarily
the diversity of molecular structures acessible via a wide range of catalysis systems, and
secondarily the evolution of these systems in terms of operational convenience. General
mechanistic features and detailed examples of each catalysis system are presented.
Across the range of systems, yields, selectivites, and substrate/functional group
2
tolerances vary greatly, and as such, do not constitute a basis for the evaluation of relative
merit.
Reactions under consideration are those that i) involve the catalytic 1,4-addition
of organometallic nucleophiles to α,β-unsaturated carbonyls, resulting in the formation of
products embodying both a new β carbon-carbon bond and an enolate or derivative, and
ii) parlay this nascent enolate species (and frequently its associated chirality) into the
formation of new α C-R (R=C,O,N,X) bond. Excluded from consideration are related
cascade Mukaiyama-Michael sequences,17,18 represented also by Shibasaki’s asymmetric
syntheses using heterobimetallic catalysis,19 as well as tandem vicinal
difunctionalizations proceeding from the catalyzed addition of organic radicals, recently
exemplified in the work of Sibi.20
Finally, this section has been organized, primarily with respect to the catalytic
metal, and secondarily with respect to the pronucleophilic organometallic reagent. Within
this framework, an effort has been made to provide relevant background and furthermore,
to partition sections on the basis of terminal electrophiles employed in a given catalytic
system. Most often, the presentation corresponds to the chronology of discovery. The
emphasis, however, is on technological continuity and for this reason some minor
anachronisms may appear.
3
B. Reactions Proceeding via Copper Catalysis
i. Addition of Grignard Pronucleophiles: The Kharasch Reaction
a. Mechanistic Features
Conjugate addition reactions catalyzed by copper(I) are the oldest and most
extensively developed subgroup. First reported by Kharasch1 in the context of Grignard
alkylations, the utility of this chemistry derives from the ability of copper to efficiently
transmetallate a large number of (pro)nucleophilic organometallics,21 thereby promoting
selective 1,4-addition, among other things.22 As the mechanism responsible for classical
Gilman alkylations has begun to yield to extensive theoretical and empirical analysis,23 so
the details of related catalytic cycles have become more clear. A Kharasch 1,4-addition
cycle is depicted in Scheme I-1.1.
Scheme I-1.1: Kharasch-Type 1,4-Addition Cycle
RCu(I)
R2Cu(I)MgX2RMgX + Cu(I)X
RMgX
O
Cu(I)R2
MgX
X2Mg
O
O
Cu(III)R2
MgX
MgX2
O
R
MgX
This simplified cycle involves the formation of magnesium diorganocuprate species,
followed by a “trap-and-bite” π-complexation/oxidative addition sequence resulting in a
β-cuprio(III) intermediate. Reductive elimination results in the β-alkyl magnesium
enolate product and liberates the catalytic alkylcopper(I) residue. In contrast, the
exhaustive mechanism is undoubtedly more complex. Nonlinear effects observed in
4
conjunction with the use of chiral ligands implicate the involvement of copper(I)
aggregates.24
b. Application to Lycopodine and Prostanoid Syntheses
The evolution of the tandem electrophilic trapping implementation began in 1968
(Scheme I-1.2) with Stork’s lycopodine synthesis,2 and to a large extent developed in the
context of prostanoid-related “three-component couplings.”25
Scheme I-1.2: Stork’s Synthesis of Lycopodine
O
H3C
OMgX
H3C
OCH3 O
H3C
OCH3
NH
CH3
OH
N O
H3CH
H
Scheme I-1.3: Prostanoid Synthesis: Tandem 1,4-Addition-Aldol Condensation
7
O
TBSO
1. TBSO(CH2)7MgBr CuI (10 mol %)
Et2O
2. Octanal
O
TBSOOTBS
OH
-H2OCH3
4
7
O
TBSOOTBS
CH3
4
34% Whereas the direct interception of magnesium enolate intermediates is the most
concise approach (Schemes I-1.3),26 it may be advantageous in certain instances to
proceed via a one-pot sequence involving the corresponding silyl enol ether or enol
acetate (Scheme I-1.4).27
5
Scheme I-1.4: Prostanoid Sythesis: Tandem 1,4-Addition-Aldol Condensation via Enolate Derivative
O
O
O
1. n-OctMgBr CuBr-Me2S (0.05 mol%) THF
2. Ac2O
OAc
O
OCH3
7
O
O
OCH3
7
1. MeLi 2. ZnCl2
3. RCHO -H2O
CO2Me
88% 83%
A strategy entailing tandem conjugate addition-Peterson olefination was explored
toward the synthesis of a PG-A2 analogue (Scheme I-1.5),28 currently in pre-clinical trials
as an anticancer agent.29
Scheme I-1.5: Tandem Conjugate Addition-Peterson Olefination O
Me3SiH
H
1. RMgBr CuI (10 mol%) Et2O
2. i PrCHO
OH
HR
R = Me; 86% E:Z - 75:25
R = iPr; 81% E:Z - 58:42R = Vinyl; 94% E:Z - 93:7
2. PhCHO
OH
HR
H3C
CH3
R = Me; 83% E:Z - 30:70R = Vinyl; 88% E:Z - 52:48
O
MeO2C
PG-A2 Analogue
1. RMgBr CuI (10 mol%) Et2O
For a given substrate, considerable differences (in some cases inversions) in olefin
geometry selectivity were observed when comparing Kharasch (catalytic) and Gilman
(stoichiometric) additions of identical alkyl units.
c. Tandem Conjugate Addition-Claisen Rearrangement
Though representing a quantum technological leap in many regards, copper-
catalyzed Grignard additions are liable to suffer from competitive, uncatalyzed 1,2-
addition and may require the presence of stoichiometric additives such as HMPA or
trialkyl chlorosilanes to proceed in high yield. In the latter case, the use of silylating
agents can open the door to new reactivity manifolds. In a unique tandem process, silyl
6
ketene acetals generated in this manner are trapped via [3,3]-sigmatropic rearrangement
(Scheme I-1.6).30
Scheme I-1.6: Tandem Conjugate Addition-Claisen Rearrangement
H3C
O
O
CH3
MeMgBr (150 mol%)TMS-Cl (300 mol%) H3C
OTMS
O
CH3
CH3
H3C
O
OH
CH3
CH3
1. 50 °C
87%
O
N O
NCu
iPr
iPr
CuL2 =
2. H+CuL2 (1 mol%)THF-Et2O
d. Tandem Conjugate Addition-Intramolecular Alkylation
Intramolecular alkylation has been used to access the triquinane subergorgic acid
skeleton (Scheme I-1.7).31 For less reactive halide leaving groups, the use of HMPA or
DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone) was found to be necessary.
Scheme I-1.7 Tandem Conjugate Addition-Intramolecular Alkylation
O
OCH3
CH3
O
HO
O CH3
CH3O
H
Cl
MgBr
CuBr-Me2S (14 mol%)then DMPU (200 mol%)
81%
THF-Et2O
ii. Addition of Organozirconium Reagents
a. Organozirconium Pronucleophiles via Hydrozirconation of Alkynes
The combination of facile hydrozirconation with Cp2Zr(H)Cl32 and
transmetallation from zirconium to copper was reported by Schwartz to provide an
efficient and direct method for the catalytic β-vinylation of enones, starting with terminal
alkynes as pronucleophiles.33 An elegant catalytic implementation by Lipshutz34
7
employed the higher-order cuprate Me2Cu(CN)Li2, and involved initial transmetallation
between the catalyst and a methyl vinylzirconocene, followed by 1,4-addition and a final
transmetallative ligand exchange between the intermediate copper(I) enolate and added
Me3ZnLi (Scheme I-1.8). Notably, at -78 °C, the lithium trimethylzincate does not
compete with the vinyl cuprate as a nucleophile, but is subordinated to the role of a soft
MeLi surrogate. Derivative tandem sequences afforded good yields of structurally
complex products (Table I-1.1).
Scheme I-1.8: Mechanistic Cycle Involving Zirconocene/Cuprate Transmetallation
Cl(Cp)2ZrMe2Cu(CN)Li2
R
Li2Me(CN)Cu
OO
R
LiO
R
Cu(CN)MeLi2Me3ZnLi
R
Me(Cp)2Zr
R R
8
Table I-1.1: Lipshutz’s Higher-Order Cuprate-Catalyzed Conjugate Addition-Aldol Sequence
AlkyneR
n-C6H13
OTIPS
2
OBn
n-C5H11
OTMSn-C4H9
OMEM
n-C5H11
O
O
TBSO O
TBSO
O
OTIPS
2
O
n-C5H11
O
H
O
H
O
H CO2Me
O
H CO2Me
O
H CO2Me5
O
H CO2Me5
O
R
OHH
R'
O
R
R'H OH
O
R
R'H OH
TBSO
"
"
"
Enone Electrophile Product Yield (%)CHO/OTfR'
O
82
80
74
75
79
83
TfOSiMe3
TfOSiMe3
TfO CO2Me3
O
O
TBSO O
TBSO
OBn
n-C5H11
OTMSn-C4H9
OPMB
n-C5H11
O
R
R'H
O
R
R'H
TBSO
"
74
69
71
Entry
1
2
3
4
5
6
7
8
9
b. Zirconocyclopentene Pronucleophiles via Oxidative Cyclization
Zirconocyclopentenes, likewise, engage in vinyl transfer to enones under
copper(I) catalysis, resulting in intermediate tethered zirconium enolates.35 These
bifunctional species represent two nucleophilic organometallic loci that can i) react with
two equivalents of the same electrophile: halides (Scheme I-1.9), or ii) react
chemoselectively with two different electrophiles: aldehyde/proton (Schemes I-1.10 and
9
I-1.11) or aldehyde/halide (Scheme I-1.12). It is notable that the rate of aldehyde addition
was greatly enhanced by converting the tethered zirconium enolate to its corresponding
tetrabutylammonium (naked) enolate (Scheme I-1.11).
Scheme I-1.9: Tandem Zirconocyclopentene Addition-Electrophile Trapping
Cp2ZrCl21. 2EtMgBr
2. PrPr
O
CuCl-2LiCl (7 mol%)
Cp2Zr
PrPr
O ZrCp2
PrPr
O
PrPr
XX
X = Br X = I
(85%)(69%)
NXS
Scheme I-1.10: Naked Enolate versus Tethered-Zirconium Enolate Trapping
additiveTHF
O - Zr(Cl)Cp2
PrPr
+ NBu4
1. PhCHO
2. H+
O
Et
Pr
Pr
HOH
Ph
Additive time(h) Yield (%)
n-Bu4 NCl 1.5 78none 17 63
Cp2Zr
PrPr
Scheme I-1.11: Chemoselective Tethered-Zirconium Enolate Trapping: Aldehyde and Proton O
CuCl-2LiCl
O ZrCp2
PrPr
1. n-Bu4 NCl
2. RCHO
O OH
RH
Pr
PrEt
R = PhR = n-C5H11
(77%)(84%)Cp2Zr
PrPr
Scheme I-1.12: Chemoselective Tethered-Zirconium Enolate Trapping: Aldehyde and Halide
1. n-Bu4 NCl, PhCHO
2. NBS
O OH
RH
Pr
PrBr
(60%)Cp2Zr
PrPr
c. Organozirconium Pronucleophiles via Hydrozirconation of Alkenes
Primary acyclic organozirconocenes are conveniently derived from any number of
corresponding isomeric olefins, (Figure I-1.1)36 and participate in conjugate addition to
10
linear and cyclic enones under copper catalysis.37 In his NMR analyses of the reaction of
n-hexylzirconocene with CuBr•SMe2, Wipf38 detected no evidence for the formation of
intermediate alkylcopper species via zirconium-copper transmetallation. An alternative
mechanism is proposed, involving enone complexation by the Lewis-acidic zirconocene
followed by inner-sphere transfer of the alkyl substituent to chelated copper(I) (Scheme I-
1.13). Figure I-1.1: Convergent Hydrozirconation of Alkenes
Zr
Cl
H
Cp2(Cl)Zr
Scheme I-1.13: Cu(I)-Catalyzed Alkyl Zirconium 1,4-Addition: Wipf’s Mechanistic Proposal
ZrR(Cl)Cp2
enone
O
CuX
OZrCp2
R
Cu X
OZr(Cl)Cp2
ZrR(Cl)Cp2
Cl
OZrCp2
R
Cu X
Cl
Cu
R
X
OZr(Cl)Cp2
Rslow fast
-CuX
ClCp2Zr
RCu X
CuX
very slow
enone
Zirconium enolates that result from 1,4-addition of alkylzirconocenes to enones
may be trapped with benzaldehyde (Scheme I-1.14).34 In Eqn. 1, the overall syn
selectivity of the aldol addition at 22 °C is 3:1, a ratio that is consistent with the
observations of Yamamoto39 and Panek40 on zirconium-mediated aldol reactions. In this
instance the aldehyde is present during the conjugate addition. Notably, if the aldehyde is
added subsequently, at -78 °C, an inversion in selectivity results, favoring the anti
product by 3:1. Cyclopentenone (Eqn. 2) undergoes conjugate addition-benzaldehyde
trapping with a 2:1 ratio syn/anti. Yields in Scheme I-1.14 may appear to be low, but it
11
must be considered that product yield is calculated relative to the alkene precursor of the
alkylzirconocenes (not shown). Here, even under strictly anhydrous conditions, some
product corresponding to enolate protonation is isolated. By way of explanation, it is
postulated that the alkylzirconium reagent undergoes competive decomposition to
generate HCl. Scheme I-1.14: Tandem Alkylzirconium 1,4-Addition-Aldol Addition
n-C6H13Cp2(Cl)Zr
OCuBr-SMe2 (10 mol%)PhCHO, DCM, 22 °C
O
n-C6H13
HPh
OH O
n-C6H13
HPh
OH O
n-C6H13
HPh
OH
66% (9:2:1)
n-C6H13Cp2(Cl)Zr
CuBr-SMe2 (10 mol%)PhCHO, DCM, 22 °C
58% (2:1)
O O
n-C6H13
HPh
OH O
n-C6H13
HPh
OH
O
n-C6H13
15%O
n-C6H1311%
Eqn. 1
+
+
Eqn. 2
Later studies by Wipf undertook the comparison of chiral oxazolidinone- and
camphor sultam-functionalized crotonates in conjunction with catalytic conjugate
addition-enolate trapping. Optimal diastereomeric ratios were obtained using a
phenylglycine-derived auxiliary (Scheme I-1.15). The presence of the hard Lewis acid
BF3•Et2O was essential to achieve good yields in the aldol process.
Scheme I-1.15: Auxiliary-Directed Alkylzirconium 1,4-Addition-Aldol Sequence
ON
O
Ph
O
n-C6H13Cp2(Cl)Zr
CuBr-SMe2 (15 mol%)BF3-Et2O, THF, 40 °C -78°C
ON
O
Ph
O
H13C6-n
Zr
CpCp
BF3Cl+ -
NO
O
Ph
O
Me n-C6H13
HPh
H O
ZrCp2+
BF3Cl -
PhCHO
ON
O
Ph
O
H13C6-n
Me
MeH
OHPhH
ON
O
Ph
O
H13C6-n
Me
64% >97% de 10% 86% de
12
iii. Addition of Organozinc Pronucleophiles
a. Mechanistic Features
Much of the utility of organozinc reagents lies in their inertness to a wide variety
of common functional groups. Alone, they are almost entirely inert even to α,β-
unsaturated carbonyl compounds. It is only through transmetallation to a more
electronegative metal that reactivity is derived.21 Although applications under copper
catalysis are the most widely used, a general mechanism accounting for the behavior of
all known systems has yet to be formulated. Kitamura and Noyori examined the
conjugate addition of diethylzinc catalyzed by CuCN and an N-benzylsulfonamide
(Scheme I-1.16); the kinetic rate was found to be first order in the concentrations of
enone, diethylzinc, and catalytic complex A.41
Scheme I-1.16: Noyori’s Cu(I)/Sulfonamide Catalyst System: Proposed Bridging Functionality
O
ZnEt2 +
OZn
NS
O
O
PhBn
EtCuZnEt3
OZnEtZn
NS
O
O
PhBn
EtCuEt
Et
Zn
NS
O
O
PhBn
EtCuEt
OZnEt
Et
NS
O
O
PhBn
H
ZnEt2
CuCN
C2H6 A B
The nature of the alkylating agent itself is open to some speculation, being
described in this case as the coordination complex B involving the ligand and a cuprous
organozincate.42 Alternatively, Alexakis has invoked the oxidative addition of an
organocopper intermediate, thereupon following the course outlined in Scheme I-1.1.43
The involvement of bifunctional counterions as bridging ligands, mediating a “push-pull”
13
Lewis acid-base interplay is seen above (Scheme 1-1.16) and has been suggested also by
Alexakis (Scheme I-1.17). In terms of a general mechanism, the necessity of a discrete
bidentate ligand-bridge is questionable given the demonstrated utility of copper salts
incorporating only “non-coordinating” anions (e.g. triflate). It is likely that copper and
zinc ultimately “talk” to one another by association in a mixed-metal cluster.44 It is
collectively understood that copper(I) (either utilized as such or generated in situ from
copper(II)) undergoes a metathetic ligand exchange with the organozinc(II) reagent in
virtue of its lower reduction potentials (-0.76 eV for Zn(II) versus 0.52 eV for Cu(I)).45
The transmetallation equilibrium also must be under some degree of enthalpic control; a
review of the relevant literature reveals a pronounced counterion effect. Alone, organo-
copper(I) reagents are inert to conjugated enones,46 but become reactive in the presence
of either strong Lewis acids47 or through the use of additives such as Me3SiI.48
Scheme I-1.17: Alexakis’ Catalytic Mechanism Proposal
O O
Zn
CuL2
R O
+ ZnEt2
O
EtO
O
R
L2Cu
Et
Et
Zn
Et
EtZnEt
ZnO
EtO
O
R
Cu
Et
Et
Zn
Et
L
ZnEtO
O
O R
Cu
Et
Et
Zn
Et
L
OZnEt
"L"Et
"L"
14
b. Zinc Homoenolate Pronucleophiles
The earliest examples of the use of organozinc reagents in copper-catalyzed
conjugate addition is found in the work of Nakamura.49 Although the zinc homoenolate is
endowed with both nucleophilic and electrophilic functionality, the necessary inclusion
of Me3SiCl in the reaction mixture precludes inter-, and even intramolecular trapping
(Scheme I-1.18).
Scheme I-1.18: Failure of Electrophilic Trapping of Zinc Homoenolate Conjugate Adduct
Zn(CH2CH2CO2Et)2
O
O
O
CHO+
CuBr.Me2S (0.12 mol%)TMSCl (240 mol%)HMPA (240 mol%) Et2O
O
CO2Et
OTMS
Ar
OTMS
CO2Et + ArCHO
100% 80%
(120 mol%)
Subsequently, Crimmins disclosed the catalytic conjugate addition of zinc
homoenolates to acetylenic esters, resulting in intermediate silyl allenolate ethers.50 In
what amounts to a formal [3+2] cycloaddition, these intermediate ethers are trapped in
situ by the appendant ethyl ester, affording a variety of substituted
cyclopentenonecarboxylates in good yield (Scheme I-1.19 and Table I-2.2).
Scheme I-1.19: Tandem Zinc Homoenolate 1,4-Addition-Intramolecular Trapping
Zn(CH2CH2CO2Et)2CO2Et
HMPA (200 mol%)Et2O
CuBr-Me2S (2.8 mol%)
O
CO2Et
R R'R
R'
OEtMO
R'
REtO2C
15
The remarkably enhanced nucleophilicity of the silyl allenolate relative to the
silyl ketene acetal may be attributable to a decumulative effect.51 Interestingly, the
corresponding acetylenic ketones, as well as acetylene-1,2-diesters underwent only
conjugate addition, with no cyclization. A complementary procedure leading to the
analogous cyclohexenecarboxylates was reported by Crimmins to take place via
stoichiometric transmetallation between functionalized zinc iodides and CuCN.52
c. Organozincate Pronucleophiles
Building in part upon foundations laid by Knochel,53 Lipshutz developed
conditions for the catalytic conjugate addition of functionalized organozincs involving
zincate/cuprate transmetallation.54 The zinc enolate intermediates tolerate the presence of
primary chloride and various carboxylic acid derivatives (Scheme I-1.20), and are
trapped by aldehydes to afford products of three-component couplings.55
Scheme I-1.20: Lipshutz’s Cuprate-Catalyzed Organozinc 1,4-Addition-Aldol Sequence O 1. R(CH2)4ZnI
MeLi (200 mol%)MeCu(CN)Li (20 mol%)
2. R'(CH2)5CHO
O
(CH2)4R
HOH
(CH2)5R'
R=Cl, R'=CO2CH3 :R=Cl, R'=H :R=CO2Si(iPr)3, R'=CO2CH3 :R=CO2Si(iPr)3, R'=H :R=CON(Bn)2, R'=CO2CH3 :
75%77%70%74%61%
75%R=CH2COSi(iPr)3, R'=CH2CO2CH3:
123456
16
OCO2Et
OR
R'
substrate product substrate product
EtO2C
R'
OR
R = MOMR' = C5H11
R = AcR' = C5H11
R = HR' = C5H11
R = MOMR' = i PrR = AcR' = i PrR = HR' = i PrR = HR' = (CH2)2PhR = HR' = (CH2)2C(CH3)=CH2
R = HR' = (CH2)2(3-furyl)
R = MOMR' = C5H11
R = AcR' = C5H11
R = TMSR' = C5H11
R = MOMR' = i PrR = AcR' = i PrR = TMSR' = i PrR = TMSR' = (CH2)2PhR = TMSR' = (CH2)2C(CH3)=CH2
R = TMSR' = (CH2)2(3-furyl)
1
2
3
4
5
6
6
8
9
1a
2a
3a
4a
5a
6a
7a
8a
9a
78%
50%
70%
72%
49%
70%
65%
86%
65%
yield
O
OR
R'R'
OH
ON
O
N
R = C5H11R = i PrR = (CH2)2Ph
101112
R = C5H11R = i PrR = (CH2)2Ph
85%40%85%
O
R'R'
O
R
O
R
R = OCH3
R' = C5H11
R = 1-pyrroleR' = C5H11
R = OC6H11
R' = (CH2)2CH=CH2
R = phenylmentholR' = (CH2)2CH=CH2
R = (R,R)-Me2pyrrolidineR' = (CH2)2CH=CH2
R = (R,R)-Me2pyrrolidineR' =
R = (R,R)-Me2pyrrolidineR' =
13
14
15
16
17
18
19OPh
CO2Et
65%
80%
54%
28%
80%
89%
79%
MeO2C
TMSO CH3
OCO2Me
TMSO CH3
MeO2C
TMSO i Pr CO2Me
OCO2Me
TMSO i Pr CO2Me
MeO2C
OR
OCO2Me
OR
R
OR' t Bu
OR
OR' t Bu
OO
R
OR
O R
OR
O O
EtO2C
OH t Bu
OCO2Et
TMSO t Bu
OOO O
OCO2Me
OOMeO2C
O
O
MeO2C
TMSO R
OCO2Me
TMSO R
22 R = H 69%
20a R = H21a R = CH3
20 R = H21 R = CH3
69%67%
23a (syn)24a (anti)
66%66%
25 R = THP (E)26 R = Bn (Z)
51%55%
27 R = OEt R' = MOM (anti)28 R = OEt R' = H (anti)29 R = OEt R' = H (syn)30 R = 1-pyrrole R' = H (2:1 syn:anti)
65%
82%
83%
86%
27a R = OEt R' = MOM 28b R = OEt R' = TMS29b R = OEt R' = TMS30b R = 1-pyrrole R' = TMS
31a R = OMe32a R = NMe2
31 R = OMe32 R = NMe2
51%55%
34a R = OMe35a R = NMe2
34 R = OMe35 R = NMe2
51%55%
33a R = OMe33 R = OMe 51%
yield
10a11a12b
13a
14a
15a
16a
17a
18a
19a
22a R = H
23 (syn)24 (anti)
25a R = THP (E)26b R = Bn (Z)
Table I-1.2: Crimmins' Formal [3+2] Cycloadditions
17
d. Diorganozinc Pronucleophiles
Following Alexakis’ milestone 1993 report describing the enantioselective (32%
ee) conjugate addition of diethylzinc to cyclohexenone, catalyzed by CuI and a trivalent
phosphorous ligand,56 Noyori presented the first related tandem conjugate addition-
electrophilic trapping sequence.57 The one-pot conjugate addition-aldol sequence utilized
cyclopentenone and benzaldehyde and was found to proceed optimally as a single step
manipulation (Scheme I-1.21).
Scheme I-1.21: Noyori’s Diethylzinc 1,4-Addition-Aldol Sequence
O
Ligand (2 mol%)+
PhCHO Et2Zn (100 mol%)
(100 mol%) CuMes (2 mol%)
O
Et
OH
PhH
91% (1.2:1)
O
Ligand (2 mol%)
2. PhCHO
1. Et2Zn (100 mol%)
(100 mol%)
CuMes (2 mol%) O
Et
OH
PhH
28% Ligand = BnNHSO2Ph
Preformation (prior to addition of aldehyde) of the β-alkyl zinc enolates of
cyclopentanone (via catalytic conjugate addition) led to large amounts of homo-
condensation product. This is not an uncommon observation in five-membered ring
substrates.58 Better yield and selectivity (>95%, 5.3:1) was observed for the
corresponding cyclohexenone-based system. In the same report, zinc enolates undergo
stereoselective allylation in the presence of zero-valent palladium (Scheme I-1.22).
Scheme I-1.22: Tandem Dialkylzinc 1,4-Addition-Pd0-Catalyzed Allylic Alkylation O
CuCN (0.5 mol%)Ligand (0.5 mol%)Et2Zn (100 mol%)
OZnEt
Et
OAc
Pd(PPh3)4(2 mol%
O
Et90% (9:1)
18
Feringa59 investigated the effect of added Lewis acids (BF3•Et2O and ZnCl2•Et2O)
on tandem 1,4-addition-aldol reactions featuring his versatile phosphoramidite ligand LF,
and found variable advantage in their use. In this work, the number of viable
diorganozinc reagents was expanded to include dimethylzinc (Scheme I-1.23).
Scheme I-1.23: First Highly Enantioselective 1,4-Addition-Aldol Sequence O
R2Zn (150 mol%)Toluene
Cu(OTf)2 (1.2 mol%)LF (2.4 mol%)
OZnEt
R
1. R'CHO
2. [O]
O
R
O
R'H
O
OP N
Ph
Ph
CH3
CH3
R = Me, EtR' = Et, Vinyl, Ph, mBrC6H4ee 91-95%
Feringa's Phosphoramidite LigandLF
Given that much early development of tandem vicinal difunctionalization strategy
was directed toward prostaglandin syntheses, it is tempting to revisit the target in the
context of modern catalytic enantioselective synthesis. To this end, prostaglandin E1
methyl ester was efficiently accessed from a cyclopentenedione mono-acetal (Scheme I-
1.24).60
Scheme I-1.24: Feringa’s Synthesis of Prostaglandin E1 Methyl Ester
SiMe2Ph
CO2MeZn
+
Cu(OTf)2 (3 mol %)LF (6 mol%)
Toluene, -40 °C
O
CO2MeH
HOH SiMe2Ph
OO
PhPh
OO
O
PhPh
60% (83:17)2
OH
CO2MeH
HOH
O
6 stepsee 94%
O
H
Prostaglandin E1 Methyl Ester
19
In a recent report from Feringa et al., an important extension of substrate scope is
represented by the use of α,β-unsaturated lactams (Scheme I-1.25), although yields are
generally lower.61
Scheme I-1.25: α,β-Unsaturated Lactams as Conjugate Addition Substrates
N
OPhO2C
Cu(OTf)2 (1.5 mol%)LF (3 mol%)Et2Zn (150 mol%)Toluene
X
Pd0 (4 mol%)X = OAc, -Br
CH3CHO
N
OPhO2C
Et 89% ee25-35% (>9:1)
N
OPhO2C
Et
OHH
94% ee64% (>95:5)
An alternative to the conventional preparation of aldol products is represented by
the alkylation of zinc enolates with oxocarbenium ions formed via acetal or orthoformate
decomposition in the presence of a strong Lewis acid (Table I-1.3).62 This method leads
to syn or anti aldols of high enantiomeric and diastereomeric purity when used with
acetals derived from homochiral glycols.
Table I-1.3: Oxocarbenium Ions as Electrophilic Traps
O O
Et
HOR1
R3
n n
R2
1. 16 (1 mol%) Et2Zn (120 mol%) Cu(OTf)2 (0.5 mol%)
2. BF3. Et2O (150 mol%)
E+ (150 mol%)
n
111122
Electrophile
PhCH(OMe)2MeCH(OEt)2Me2C(OMe)2(MeO)3CHPhCH(OMe)2(MeO)3CH
R1
MeEtMeMeMeMe
R2
HHMeOMeHOMe
R3
PhMeMeHPhH
%
626254665859
Entry
123456
While many common electrophiles react with catalytically generated zinc enolates
in situ, it may be advantageous to employ a proxy electrophile, in the form of an O-
silylating agent, before introducing the terminal electrophile (Scheme I-1.26). This
strategy has led to the incorporation of electrophilic oxygen (Rubottom),63 iminium
(Mannich),48 and Simmons-Smith64 traps into tandem processes.
20
Scheme I-1.26: Functionalizations of Silyl Enol Intermediates
OZnEt
Et
1. H2C=NMe2 I-+
2. MCPBA
OCH2
Et
OSiMe3
Et
Me3SiX
X = Cl,OTf
MCPBA
OOSiMe3
Et
Me3SiO
Et
n
n
CH2I2
72%
74%
n = 1 95% (77:1)n = 2 97% (84:1)
Studies on the inter- and intramolecular alkylation of zinc enolates were
undertaken by Hoveyda. Generally high levels of enantioselectivity derived from the use
of his modular, peptide-based iminophosphorane ligands LHa and LHb (Scheme I-1.27).65
Scheme I-1.27: Hoveyda’s Iminophosphoranes in Enantioselective Sequences
O
Me
n
OTsO
Me
R n
n=1, R=Me n=1, R=Et n=2, R=Me n=2, R=Et n=2, R=i Pr
(CuOTf)2 C6H6 (1 mol%)
Et2Zn (300 mol%)
LHa (5 mol%)
Ph
O
Ph
(CuOTf)2 C6H6 (1 mol%)1. Et2Zn (300 mol%)
LHa (2.4 mol%)
2. BnBr (1000 mol%) HMPA (1000 mol%)
Ph
O
Ph
Et
Bn72% (3.2:1) 93% ee
O(CuOTf)2 C6H6 (1 mol%)
1. Me2Zn (300 mol%)
2. (1000 mol%) HMPA (1000 mol%)
I
O
Me 80% (>15:1) 97% ee
N
PPh3
R
O
NH O
NHBu
R'LHaLHb
R=t Bu, R'=Ot BuR=i Pr, R'=H
LHb (2.4 mol%)
67%78%75%81%81%
80% ee85% ee95% ee95% ee74% ee
(>98:1)(>98:1)(>98:1)(>98:1)(>98:1)
21
C. Reactions Proceeding via Rhodium Catalysis
i. Additions of Organoboronic Acid and Organoboronate Pronucleophiles
a. Background and Mechanistic Features
In 1997, Miyaura reported the first examples of the formal 1,4-addition of aryl-
and alkenylboronic acids to α,β-unsaturated ketones under rhodium catalysis.66 The
reaction responded with sensitivity to the choice of rhodium(I) catalyst, the nature of the
phosphine ligand, and the amount of water in the reaction solvent, but led to generally
good yields of β-arylated cyclic and acyclic ketones. In quick succession, an
enantioselective variant was reported by the Hayashi group. Good to outstanding yields
and enantioselectivities for a variety of enones and aryl/vinylboronic acids were
obtainable using Rh(acac)(C2H4)2 in conjunction with BINAP (Scheme I-1.28).67
Scheme I-1.28: Enantioselective Rhodium-Catalyzed 1,4-Addition of Phenylboronic Acid O
PhB(OH)2
(500 mol%)+Rh(acac)(C2H4)2 (3 mol%)
(S)-BINAP (3 mol%)Dioxane/H2O, 100 °C
O
Ph
> 99% (97% ee)
Valuable NMR studies from the same researchers corroborate a proposed
mechanism (Scheme I-1.29) involving initial transmetallation of the rhodium(I)
precatalyst with phenylboronic acid, followed by enone complexation to yield a
tetracoordinate phenylrhodium(I) complex.68 Olefin insertion into the rhodium(I)-
carbon(sp2) bond leads to formation of the η3 oxy(π-allyl)rhodium intermediate. Finally,
proteolysis liberates the conjugate adduct and regenerates the catalytically active
rhodium(I) hydroxide.
22
Scheme I-1.29: Rhodium-Catalyzed 1,4-Addition of Phenylboronic Acid: Catalytic Cycle O
(BINAP)Rh Ph
O
Rh(BINAPPh
Rh(BINAP)O
Ph
O
Ph
(BINAP)Rh OH
PhB(OH)2
B(OH)3
H2O
The mode of reactivity embodied in this cycle invites comparison to classical
Heck enone-arylation, wherein an arylpalladium(II) species, isoelectronic with
arylrhodium(I), coordinates and inserts into a carbon-carbon double bond. The unique
synthetic utility of the rhodium(I)-catalyzed process lies in the fact that the nascent
rhodium enolate exists as a stable η3 haptomer, not labile toward β-hydride elimination.
However, this outcome is not general for all α,β-unsaturated carbonyls. Mori has
demonstrated highly selective partitioning of rhodium(I)-catalyzed Heck and conjugate
addition manifolds in the reaction of arylsilanols with acrylates and acrylamides (Scheme
I-1.30).69 These results suggest that the presence of π-donating acyl substituents inhibit
enolate isomerization with the effect of enabling the Heck pathway. In aqueous media,
proteolysis of the carbon-bound rhodium enolate occurs faster than β-hydride
elimination. This interpretation does not, however, account for Zou’s observation of
β-hydride elimination in a related procedure using aryl boronic acids in aqueous media.70
Scheme I-1.30: Partitioning of Conjugate Addition and Heck Pathways
23
ArSiEt(OH)2 +O
Ot Bu
[Rh(COD)OH]2 O
Ot Bu
Ar O
Ot Bu
Ar+
Ar = 4Me-Ph
Conditions YieldsTHF, 70 °C 99% (based on silane)-THF/H2O (2:1) 70 °C 5%83%
β-hydride elimination is not observed following the carborhodation of α,β-
unsaturated ketones. The practical implications include not only the simultaneous
formation of two new stereocenters from the prochiral enone, but also the possibility of
intercepting the reactive metalloenolate in a tandem bond-forming process. The necessity
of an aqueous reaction media, however, would be expected to preclude the use of most
exogenous carbon electrophiles. ii. Tandem Reactions Employing Organoborane Pronucleophiles
Whereas the ability to use a wet solvent may constitute an advantage in some
cases, the necessity of water is clearly a disadvantage if one seeks to incorporate an
intermolecular terminal electrophile into the preceding type of catalytic process. With this
limitation in mind, Hayashi developed complementary, non-aqueous conditions that use
B-aryl and –alkenyl-9BBN derivatives in place of boronic acids or boronates (Table I-
1.4).71
Table I-1.4: Rhodium-Catalyzed Arylborane 1,4-Addition-Electrophile Trapping Sequences
R
O
BR'
O
HR"
O
R
R'
OH
R"1. [Rh(COD)OMe]2
2. H2O2/NaOH
+ +
R = t Bu R = t Bu R = t Bu R = t Bu R = t Bu R = Ph R = Ph R = Me
R = t Bu
96% (9.6:1)97% (10.7:1)99% (8.9:1)85% (21.4:1)72% (12.4:1)88% (9.0:1)93% (9.0:1)99% (5.7:1)
Toluene; 20 °C
R' = 4-FC6H4 R' = Ph R' = 4-MeOC6H4 R' = 1-heptenyl R' = 4-FC6H4 R' = 4-FC6H4 R' = 4-FC6H4 R' = 4-FC6H4
R' = 4-FC6H4
R" = PhR" = PhR" = PhR" = PhR" = EtR" = PhR" = i PrR" = Ph
R" = Ph
(1)(2)(3)(4)(5)(6)(7)(8)
(9)
O
R
R'
OH
R"
O
R
R'
OH
R"
44% (0.8:1)syn 41% ee anti 94% ee
1. [Rh(S-BINAP)OH]2
2. H2O2/NaOHDMF; 20 °C
24
It is significant to note that this reaction takes place via the intermediacy of a
rhodium enolate, as opposed to a boron enolate. Evidence for this interpretation resides in
the observation of enantioselective aldol addition in the presence of the chiral complex
[Rh(S-BINAP)OH]2 (Table I-1.4, Entry 9). For one system (Table I-1.4, Entry 1), it was
observed that no reaction takes place at all in the absence of aldehyde, suggesting the
existence of a termolecular aggregate in which conjugate addition and aldolization are
promoted sequentially by the same catalytic metal.
At an elevated temperature, cyclohexenone undergoes catalytic enantioselective
conjugate addition in the presence of only B-Ph-9BBN and [Rh(COD)OMe]2/(S)-BINAP,
affording the corresponding boron enolate in high optical purity.72 Products of enolate
alkylation (via Li/B transmetallation), deuteration, and aldolization have been described
(Scheme I-1.31). This method is not generally applicable, however, as cyclopentenone
and acyclic enones fail to yield the corresponding boron enolates under identical
conditions.
Scheme I-1.31: Rhodium-Catalyzed Arylborane 1,4-Addition-Electrophile Trapping Sequences
BO
Arn
O
Ph
HOH
n = 1 46% (98% ee)n = 2 47% (96% ee)
O
Ar
n
Ar = Ph Ar = 4-FPh Ar = 4-MeOPh
71% (98% ee)71% (98% ee)65% (>99% ee)
1. n-BuLi2. Allyl-Br
O
MeOD
O
Ph
D
nn = 1 81% (98% ee)n = 2 82% (96% ee)
25
iii. Tandem Reactions Employing Organotitanium and Organozinc Pronucleophiles
The Hayashi group has been prolific in the development of adjuvant
organometallics for rhodium catalysis. Aryl titanium alkoxides (Scheme I-1.32) and aryl
zinc halides (Scheme I-1.33) have been employed in the corresponding enantioselective
rhodium(I)-catalyzed transformations.73,74
Scheme 1-1.32: Organotitanium Pronucleophiles in Rhodium-Catalyzed Sequences
O
Ph
Ti(Oi Pr)3O
PhTi(Oi Pr)3
OSiMe3
Ph
1. LiOiPr
2. Me3SiCl
Br2.
O
Ph2. ClCOt Bu
OCOt Bu
Ph
82%
79%
84% (99.5% ee)
EtCHO
O
Ph45%
[Rh(S-BINAP)OH]2
Scheme I-1.33: Organozinc Pronucleophiles in Rhodium-Catalyzed Sequences
N
OZnCl
PhN
O
[Rh(S-BINAP)Cl]2
N
O
Ph2. Allyl-Br
2. ClCOtBu
N
OCOt Bu
Ph
97%
83%
PhZnCl
Bz Bz(>99% ee)
Bz
Bz
26
D. Reactions Proceeding via Nickel Catalysis
i. Additions of Organozinc Pronucleophiles: Background and Mechanistic Features
In 1985, Luche reported a nickel-catalyzed conjugate addition of diphenylzinc to
enones and enals with tandem alkylation of the zinc enolate (Scheme I-1.34). Earlier
investigations by Schwartz on nickel-catalyzed organozirconium 1,4-additions strongly
implicated a mechanism involving rate-determining SET from in situ generated nickel(I),
leading to the formation of a β-nickel(III) intermediate, followed by transmetallation and
reductive elimination (Scheme I-1.35). The mechanism of Luche’s methodology was
presumed to occur in an analogous fashion.
Scheme I-1.34: Nickel-Catalyzed 1,4-Addition-Alkylation Sequences
O
1. Ni(acac)2 (1 mol%) Ph2Zn, THF
2. MeI (1000 mol%)
O
Ph
Me71%
O O
PhMe 51%
CHO
1. Ni(acac)2 (1 mol%) (Tol)2Zn, THF
2. MeI, HMPACHO
Tol
Me
49%
Scheme I-1.35: Nickel-Catalyzed 1,4-Addition: Schwartz’s Proposed Mechanistic Cycle
O
Ni(I)
O -
Ni(II)+
O -
Ni(III)
Zr R
OZr
Ni(III)
R
OZr-
RNi(I) +
27
ii. Tandem Reactions Employing Organozinc Pronucleophiles
Over the past decade there have been relatively few instances of tandem vicinal
difunctionalizations initiated by the nickel-catalyzed 1,4-addition of preformed, main-
group organometallics. In a recent report, conjugate methylation based on nickel catalysis
was found to afford more consistently reproducible results than the corresponding
Gilman methylation (Scheme I-1.36).75
Scheme I-1.36: Nickel-Catalyzed Conjugate Methylation-Formaldehyde Addition
O 1. Ni(acac)2, Me2Zn LiBr, Et2O
2. HCHO
O
OH
52%
Montgomery employed aryl- and alkylzinc organometallics in tandem conjugate
addition-Michael and aldol cyclizations (Scheme I-1.37). Appendant nitriles reportedly
fail to intercept the zinc enolate,76,77 an observation of significance when considered
alongside the Blaise cyclizations reported by Krische (vide supra).
Scheme I-1.37: Nickel-Catalyzed 1,4-Addition-Michael and Aldol Cyclizations
R
O
CH2
2
cat. Ni(COD)2
Ph2Zn, PhZnCl
CORPh
COR
CORPh
COR
R = Ph (65%)R = Me (58%)
Ph
OCHO cat. Ni(COD)2
CORPh OH (41%)
Ph
OCN cat. Ni(COD)2
MeLi, ZnCl2
Ph
OCN
Me
(73%)
R = Me (12%)
Ph2Zn, PhZnCl
28
iii. Tandem Reactions Employing Aryl Iodide Pronucleophiles
A novel conjugate addition-aldol sequence was recently disclosed by
Montgomery, involving the one-step coupling of alkyl acrylates, aryl iodides and
carbonyls under nickel catalysis.78 Generally good yields and diastereoselectivities were
observed in conjunction with a range of components (Table I-1.5).
Table I-1.5: 1,4-Aryl-Aldol Sequence Employing Aryl Iodides
O
OR
+ R'I+ R"CHO (E)+ Me2Zn
Ni(COD)2
(10 mol%)
THF0-25 °C
O
OR
OH
R"
R'
entry R R' R" Yield % (dr)
123456789101112
PhPhPhPhPhPhPhPh1-Naphthyl4-Me-Ph3-CO2Et-Ph3-(CH2OTBS)Ph
t-BuCH3
t-But-But-But-But-But-But-But-But-But-Bu
PhPh4-MeO-Ph2-furylCH2CH3
CH(CH3)2
C(CH3)3
E = acetonePhPhPhPh
88 (86:14)76 (89:11)73 (82:18)76 (84:16)75 (85:15)78 (88:12)71 (66:34)5471 (87:13)79 (88:12)54 (87:13)73 (88:12)
The use of aromatic iodides as conjugate addition synthons offers unquestionable
advantages in terms of experimental simplicity. Some degree of substitution of the aryl
moiety is tolerated. Terminal electrophiles include aryl and aliphatic aldehydes, as well as
acetone. Montgomery’s analysis implicates a nickel(0)/nickel(II) catalytic cycle (Scheme
I-1.38) in which dimethylzinc operates in two distinct capacities: primarily, by interacting
with the arylnickel(II) iodide and the enoate substrate in a push-pull, Lewis-acid/base
relay, and secondarily by reducing nickel(II) back to the catalytically active, zero-valent
oxidation state.
29
Scheme I-1.38: Montgomery’s Nickel-Catalyzed 1,4-Addition: Mechanistic Hypothesis
CH3
Zn CH3NiPh
I
O
OR
ZnCH3
NiCH3
I
Ph
O
OR
Zn
CH3
CH3
NiI
Ph
O
OR
NiL2PhI + Zn(CH3)2
PhCHO + Zn(CH3)2
O
OR
Ph
Ph
CH3ZnO
E. Conclusion
The preceding catalytic implementations of vicinal difunctionalization offer
certain advantages over their stoichiometric progenitors: Foremost, metal catalysts
promote the metathetic conversion of non- or weakly nucleophilic organometallics into
chemoselective nucleophiles, setting the stage for programmed reaction sequences.
Milder pronucleophilic organometallics are more stable and consequently more
conveniently used and stored for use, and are generally more “forgiving” reagents.
Enolates resulting from catalytic conjugate additions, furthermore, usually are
coordinated by a single metal, facilitating subsequent electrophilic trapping. By contrast,
mixed-metal enolates generated via stoichiometric metal-mediated processes are often
intractable in tandem aldolizations. Finally, the use of chirally-modified catalysts allows
the propagation of asymmetry over the course of several bond formations, leading to
products rich in structural and stereochemical complexity.
30
The challenges of developing practical, broadly applicable catalytic processes,
however, are considerable. Variations in enone electronics (due to acyl, alpha or beta
substitution), in ring size or in substitution patterns are not equally well tolerated without
some optimization of experimental parameters. Indeed, many important recent advances
in the field of catalytic conjugate addition address issues of scope. Catalytic turnover
itself frequently depends upon the presence of stoichiometric additives, oxidants, or
reductants, each constituting a new permutable variable. Ultimately, the number of
proven catalytic systems is exceeded in size by the number of those yet to be explored,
and for this reason the development of tandem vicinal difunctionalizations should remain
fertile ground for research in the foreseeable future.
31
Part 2. Graduate Research: Metal-Catalyzed Conjugate Addition-Electrophilic Trapping Reactions
A. Background: Conjugate Reduction-Electrophilic Trapping Reactions
Developed in the Krische Group i. Cobalt-Catalyzed Reductive Aldol and Reductive Michael Cyclizations
A prevailing theme in the Krische group has been the utilization of enones as
latent enolates. Seminal studies by Stork establish tandem enone reduction-enolate
alkylation as an effective means of directing regiochemistry in enolate-mediated C–C
bond formations.79 When electrophilic functionality is tethered to enone pronucleophiles,
catalytic conjugate addition/reduction-electrophillic trapping strategies are enabled.
Furthermore, by varying the means of enone activation and the nature of the electrophile,
dozens of permutations are accessible, leading to interesting and useful molecular
architectures. Much of the research in our labs seeks to capitalize on this platform, and
early work centered on identifying versatile conditions for the reductive aldol
cyclization.80 Predicated on the work of Mukaiyama,80c our successful implementation of
the tandem conjugate reduction-aldol cyclization method involved the treatment of mono-
ketone, mono-aldehyde substrates with phenylsilane in the presence of [cobalt(II)(dpm)2]
(Scheme I-2.1, Eqn 1)).81 Five, six and seven-membered ring products were formed in
good yields with complete syn-diastereoselectivity.
Scheme 1-2.1: Cobalt-Catalyzed Reductive Aldol and Michael Cyclizations
Ar
O
O
O
ArCo(dpm)2
PhSiH3
n n
OH
n = 1,2: 68-87% n = 3: 35%
Eqn 1
Ar
O O
ArCo(dpm)2
PhSiH3
n n
ArO O Ar
n = 1,2: 52-73%
Eqn 2
32
Whereas diastereoselectivity is problematic for catalytic intermolecular reductive
aldol couplings catalyzed by cobalt,80c the geometric constraints intrinsic to cyclization
confer exceptionally high diastereoselectivities for the cobalt-catalyzed aldol
cycloreduction. This reagent system was also found to promote tandem conjugate
reduction-Michael cyclizations of symmetrical bis(enone) substrates (Scheme I-2.1, Eqn
2), an outcome which was not certain a priori given that Co-catalyzed
hydrodimerizations of α,β-unsaturated carbonyl compounds that employ zinc as the
terminal reductant exclusively yield β, β -coupled dimers.82, 83 In both cases, the observed
syn-diastereoselectivities may be explained on the basis of a Zimmerman–Traxler type
transition state (Scheme I-2.2).
Scheme I-2.2: Basis for Diastereoselection
PhO
H
OPh
OO
CoLnCoLn
PhO
H
OCoLn
H
Ph
O CoLn
O
PhPh
O CoLn
O
Ph
Ph
O CoLnO
Ph
ii. Cobalt-Catalyzed Intramolecular [2+2] Cycloadditions Competitive hydrometallative and anion radical/oxy-π-allyl pathways are
observed in the catalytic Michael cycloreduction. By substituting phenylmethylsilane for
phenylsilane in conjuction with Co(dpm)2 and the bis(enone) substrate, products of
anion-radical chain [2+2] cycloaddition were obtainable in good yield and complete cis
diastereoselectivity (Scheme I-2.3).84 Competitive formation of the [2+2]cycloaddition
and Michael cycloreduction products, and the partitioning of these reaction manifolds as
a function of silane is consistent with the proposed Co(I)-Co(III) cycle.
Scheme I-2.3: Bifurcation of Cobalt-Catlayzed Reductive Michael Cyclization and [2+2] Manifolds
O
Ph
CoIII
SiR3 O
Ph
LnCoIII(H)(SiR3)
LnCoI
Ln
O PhOPh
CoIII
R3Si-H -R3Si-HO
Ph
O
Ph
O
Ph
O
Ph
O
Ph
O
Ph
In order to corroborate the notion that cyclobutanation was proceeding via the
intermediacy of anion radical intermediates, selected bis(enones) were subjected to
cathodic reduction under conditions promoting radical chain processes.85 The
electrochemically-promoted and metal-catalyzed transformations exhibited parallel trends
in reactivity and substrate scope.
iii. Borane-Mediated Reductive Aldol Cyclizations The cobalt(II)-catalyzed reductive aldol cyclizations were limited in certain
important regards: viable substrates were characterized by aromatic acyl substituents on
the enone moiety (a methyl enone-tethered aldehyde led to a 33% yield of cyclized
product). Furthermore, ketone acceptors were not tolerated. A modest increase in
substrate scope and reductant scope resulted from our research into borane mediated and
catalyzed reductive aldol cyclizations.86 Exposure of mono-enone mono-methyl ketones
to catecholborane in THF at ambient temperature resulted in tandem 1,4-reduction-aldol
34
cyclization. For aromatic and heteroaromatic enones, six-membered cyclic aldol products
are formed in excellent yield with exceptionally high levels of syn diastereoselectivity.
Five-membered ring formation preceded less readily, but the yield of cyclized product
was improved through introduction of Rh(I) salts (Scheme I-2.4).
Scheme I-2.4: Catecholborane-Mediated Reductive Aldol Cyclizations of Mono-enone Mono-ketones
Ph
O O
CH3 OBH
O
THF, 25 °C
O
Ph
HOCH3
89 %
Ph
OO CH3
"O
Ph
HOCH3
5 %
Ph
OO CH3
O
Ph
HOCH3 32 %
OBH
O
[Rh(COD)Cl]2 THF, 25 °C
Uncatalyzed
Catalyzed
iv. Hydrogenative Rhodium-Catalyzed Aldol Cyclizations Catalytic hydrogenation has been practiced routinely for over a century.87,88,89
Despite this, use of hydrogen as a terminal reductant in catalytic carbon-carbon bond
formation has been limited to transformations involving migratory insertion of carbon
monoxide: alkene hydroformylation and Fischer-Tropsch type reactions.90,91 Krische et
al have developed a catalytic system which enables capture of the organometallic
intermediates that appear transiently during the course of catalytic hydrogenation.92 The
rhodium-catalyzed, hydrogen-mediated reductive aldol reaction has been applied to the
formation of both inter-93 and intramolecular addition products (Scheme I-2.5).
35
Scheme I-2.5: Rh-Catalyzed Hydrogen Mediated Aldol Additions
O
Ph
Rh(COD)2OTf (10 mol%)
(p-CF3Ph)3P (24 mol%)
O
Ph
KOAc (300 mol%)
H2 (1 atm), DCE, 25 oC
O
H
OH
89% (10:1)
O
PhRh(COD)2OTf (5 mol%)
(Ph)3P (12 mol%)
CH3
O
PhH2 (1 atm)DCE, 25 oC
O
H
OH
NO2 NO2
Without Added KOAc, 79% YieldWith 50 mol% KOAc, 92% Yield
150 mol% 100 mol% syn:anti (1.8:1)
An especially challenging variant of the aldol reaction involves the use of ketones
as electrophilic partners. Aldolizations onto ketone acceptors are intrinsically less
exergonic than corresponding aldehyde additions - evidence indicates that aldolization is
driven by chelation.94,95 As such, intramolecular condensation to form a robust transition
metal aldolate should favorably bias the enolate-aldolate equilibria. Indeed, catalytic
hydrogenation of mono-ketone mono-enone substrates results in formation of five and
six-membered aldol cyclization products with >95:5 syn-diastereoselectivity under mild
conditions; however, competitive 1,4-reduction in response to reduced reactivity of the
electrophilic partner is generally observed. Diones are more labile toward addition in
virtue of inductive effects and relief of dipole-dipole interactions. Accordingly, rhodium-
catalyzed hydrogenation of dione-containing substrates affords the corresponding aldol
products in good yield and with excellent syn-diastereoselectivity (Scheme I-2.6).96
The use of metalloaldehyde enolates as nucleophilic partners in aldehyde
additions typically suffers from polyaldolization, product dehydration, and competitive
36
Scheme I-2.6: Aldol Cyclizations of Enone-Tethered 1,3-Diones
HO
CH3
OPh
CH3 OO
O
n
mn
m
O
Ph
HO
CH3
OPh
O
HO
CH3
OPh
O
HO
CH3O
O Ph
HO
CH3O
O Ph
84%d.e. >95:5
86%d.e. >95:5
81%d.e. >95:5
65%, d.e. >95:5(15%1,4-reduction)
Rh(COD)2OTf (10 mol%)(Ph)3P (24 mol%)
H2 (1 atm)K2CO3 (80 mol%)
DCE, 25 oC
Tishchenko-type processes.97 Under rhodium-catalyzed hydrogenation conditions, enals
serve as metalloaldehyde enolate precursors and participate in cross-aldolization with α-
ketoaldehydes.98 The resulting β-hydroxy-γ-ketoaldehydes are highly unstable, but may
be condensed in situ with hydrazine to afford 3,5-disubsituted pyridazines (Scheme I-
2.7).
Scheme I-2.7: Catalytic Intermolecular Addition of Metalloaldehyde Enolates to α-Ketoaldehydes
KOAc (100 mol%)DCE, 25 oC; H2 (1 atm)
Rh(COD)2OTf (1-5 mol%)PPh3 (2.4-12 mol%)
(100 mol%)(500 mol%)
H
O
HO
OR2
O
OHR2
O
H
H2NNH2
N NR2
R1
R1 Exclusive Cross-Aldolization30-62% Yield of Pyridazine
Over Two-Step Sequence- 3 H2O
R1
+
Historically. the addition of metalloaldehyde enolates to ketones is an even more
elusive variant of the aldol reaction. A single, stoichiometric instance of this
transformation is known.99 Under Krische’s conditions, the intramolecular addition of
metalloaldehyde enolates to ketones proceeded well, though aldolization was
accompanied by competitive 1,4-reduction (Scheme I-2.8).100
37
Scheme I-2.8: Catalytic Addition of Metalloenolates to Ketones
HO
CH3
OH
CH3 OO
O
n
Rh(COD)2OTf (10 mol%)(2-furyl)3P (24 mol%)
H2 (1 atm)K2CO3 (100 mol%)
THF, 40 oC
n
O
H
n = 1, 72%, 2:1, syn:anti(16% 1,4-reduction)
n = 2, 73%, 10:1, syn:anti(21% 1,4-reduction)
The important effect of basic additives on the partitioning of aldolization and 1,4-
reduction manifolds suggests that enolate-hydrogen reductive elimination pathways are
disabled via deprotonation of the (hydrido)metal intermediates LnRhIIIX(H)2 or
(enolato)RhIIIX(H)Ln. It is reasonably assumed then, as previously reported by Osborn
and Schrock,101 that deprotonation changes the catalytic mechanism from a dihydride-
based cycle to a monohydride-based cycle. In the former case 1,4-reduction products
predominate, while in the latter case aldolization is promoted (Scheme I-2.9).
Scheme I-2.9: Formal Heterolytic Activation of Hydrogen by Enabling Mono-Hydride Pathways
LnRhIHMono-Hydride Catalytic Cycle
Di-Hydride Catalytic Cycle LnRhIII(H)2
- HX (Base)
LnRhIX
HX
H2
- HX (Base)
H2
O
R1O R2
n
HO R2
n
O
R1
O
R1
O
R1
O
H
RhI
RhI
Ln
Ln
O R2
R2
n
n
O
R1
H
RhIIILn
O R2
n
X H
Start Here!
O
R1O R2
n
O
R1
ORhIII
HLn H
R2
n
X
38
B. Metal-Catalyzed Conjugate Addition-Aldol, Blaise, Dieckmann and Darzens Condensation Sequences i. Respective Contributions
Development of the rhodium-catalyzed conjugate addition-aldol cyclizations of
simple monoketone-tethered enones was initiated and performed in its entirety by the
author. Extension of this strategy to incorporate 1,3-dione acceptors was conducted by
Dr. Brian Bocknack. Complementary copper-catalyzed tandem conjugate addition-aldol,
Dieckmann and Blaise methods were developed by the author in partnership with
Kyriacos Agapiou. Investigations of the tandem conjugate addition-Darzens condensation
methodology was initiated by the author, and extended by Kyriacos Agapiou to
incorporate the corresponding aziridination.
ii. Rhodium-Catalyzed Conjugate Addition-Aldol Cyclizations
a. Mono-Enone, Mono-Methyl Ketone Substrates
With regard to electrophilic trapping, the author circumvented the issue of
competitive enolate hydrolysis in a series of tandem conjugate addition-aldol cyclizations
by employing ketone-tethered enone cyclization substrates (Table I-2.1).102
Table I-2.1: Rhodium-Catalyzed 1,4-Addition-Aldol Cyclizations
39
O
PhO CH3
nI-2.1, n = 1I-2.2, n = 2
O
PhH3C
nPh
OH
I-2.1aI-2.2a
O
CH3O CH3
n
I-2.4, n = 1I-2.3, n = 2
O
CH3
H3C
nPh
OH
I-2.4aI-2.3b
O O
CH3R'
I-2.2I-2.3
Nap
H3C OHO
R'
O
N
O
CH3PhN
Ph
H3C OHO
Ph
TsTsI-2.6aI-2.6
78% (77 ee)88% (88 ee)
88% (94 ee)69% (95 ee)
40%70%
84%
Representative Conditions: [Rh(COD)Cl]2 (2.5 mol%), Ligand (7.5 mol%), PhB(OH)2 (200 mol%), H2O (500 mol%), KOH (10 mol%), Dioxane, 95 °C
R' = PhR' = CH3
I-2.2bI-2.3a
In the presence of either dppb (1,4-bis-diphenylphosphinobutane) or homochiral
BINAP, the diastereo- and enantioselective cycloreductions proceed in generally good
yield. A model accounting for the observed relative stereochemistry invokes the
intermediacy of a Z-enolate and a Zimmerman-Traxler-type transition state (Figure I-2.1,
Eqn. 1).103
Figure I-2.1: Bidentate Ligands and Cyclization Transition State
R
P(Ph)2P(Ph)2 P(Ph)2
P(Ph)2
OO
Ar
CH3
RhIL
R
OO
ArCH3
RhIL
n n
(R) binap dppb Eqn. 1
Although diastereoselectivity is established at the stage of the rhodium enolate by
the adoption of a closed transition state, the product configuration seems also to represent
a thermodynamic minimum, as no isomerization is observed upon submitting I-2.2a to
equilibrating conditions of KOtBu/THF at 95 °C (Scheme I-2.10). This observation
confirms that conjugate addition/carbometallation is the diastereo-differentiating, as well
as the enantiodetermining step.
Scheme II-2.10: Control Experiment: Submitting Product to Equilibrating Conditions
O
Ph
Ph
OHCH3
KOtBu/THF
95 °C
O
Ph
Ph
OCH3
KO
CH3
OK
Ph
O
Ph
Ph
OHCH3
H2O
I-2.2a I-2.2a
It was found that the addition of 10 mole percent KOH resulted in significantly
improved yields. This observation may be attributable to the increased transmetallation
aptitude of rhodium(I) hydroxide relative to its rhodium(I) chloride precursor. The
40
addition of 500 mole percent water was found to promote catalytic turnover at a
maximum rate, but not to compete with the appendant electrophilic ketone – none of the
corresponding, uncyclized conjugate addition product was observed.
b. Conjugate Addition-Aldol Cyclizations Using Symmetrical Dione Acceptors
When related cyclization substrates consisting of both enone and symmetrical 1,3-
dione functionality (Scheme I-2.11) were submitted to the conditions of asymmetric
rhodium(I)-catalyzed carbometallation, the chiral rhodium(I) enolate was found to
effectively discriminate between the four diastereotopic π-faces of the appendant dione.
Scheme I-2.11: Symmetrical Diones as Electrophilic Acceptors
nCH3
OO RhLn
Ar
H
O
H3C m
nCH3
OO RhLn
Ar
H
O
H3Cm
R1
O
n
O
H3C
[Rh(COD)(OCH3)]2 (2.5mol%)(S)-BINAP (7.5 mol%)
ArB(OH)2 (200 mol%)KOH (10 mol%), H2O (500 mol%)
Dioxane (0.1 M), 95 oC
HO
H3C
Ar
R1
O
n
n = 1,2O
R3
R2
R3
O
R2
Eqn 1
Eqn 2
Thus, although a total of 16 possible diastereoisomers are possible, a single stereoisomer
predominated. Such polycyclic adducts contain four contiguous stereocenters, including
two adjacent quaternary centers, and were obtained with quantitative diastereoselection
and high levels of enantioselectivity (Table I-2.2).104 Initial experiments using the
[Rh(COD)Cl]2 precatalyst resulted in yields that were somewhat variable and
irreproducible. Based on the observation that this organometallic is relatively sensitive
with respect to oxidation, the corresponding methoxy-bridged dimer was prepared.105
41
Accordingly, transformations performed in conjunction with this new catalyst proved to
be both more reproducible and higher-yielding.
Table I-2.2: Enantioselective 1,4-Addition-Aldol Cyclizations of Enone-Tethered 1,3-Dione Substrates
Substrate Product Yield (de) ee
OH
H3C O
RO
R'
OH
H3C
RO
R'
OH
H3C O
H3C OO
R = CH3, R' = OCH3 83% (>99:1), 90% ee
R = CH3, R' = H 87% (>99:1), 90% ee
R = CH3, R' = Br 88% (>99:1), 94% ee
R = CH3, R' = OCH3 97% (>99:1), 90% ee
R = Ph, R' = H 86% (>99:1), 85% eeR = CH3, R' = Br 77% (>99:1), 92% ee
R = OCH3; 80% (>99:1), 88% ee
R = H; 82% (>99:1), 85% ee
R
OO
OH3C
R
O
H3C O
O
O
OH3C
OH3C
OH
H3C
H3C O
l. 65% (>99:1), 88% ee
O
m. 93% (>99:1), 88% ee
H3C
OH3C
O
O
H3C
OO
OH3C
OH
H3C O
H3CO
OH
H3C
H3CO
n. 95% (>99:1), 87% eeH3C
O
H3C
CH3
CH3
O
O
CH3
CH3
R
R = Br; 85% (>99:1), 86% ee
R = Ph, R' = H 94% (>99:1), 87% ee
R = CH3 R' = H 87% (>99:1), 91% ee
O
1
2
3
4
5
6
Entry
a.
b.
c.
d.
e.
f.
g.
h.
i.
j.
k.
c. Application Towards the Synthesis of Steroidal Ring Systems
The hydrindanone products of entry 3 are of particular interest because they
represent seco-B ring steroids. The unusual 14-hydroxy cis-fused C-D ring junction is
consistent with the structure of the cardiotonic steroid digitoxin, which is an active
constituent of digitalis, one of the most broadly prescribed treatments for congestive
42
heart failure and cardiac arrhythmias, including atrial fibrillation.106 Application of this
catalytic enantioselective tandem conjugate addition-aldol cyclization methodology
toward the synthesis of digitoxin and related cardiac steroids is a possibility and requires
much further investigation (Scheme I-2.12).
Scheme I-2.12: Entry Into Seco-B Ring Steroidal Systems
StandardConditions
O
OH
H3C
OH3C
A
C D
BH3CO
80% Yield, 88% ee (>99:1)
H3C
OH
H3C
ROH
H
O
O
HH
Digitoxin: R = (Digitoxose)3Digitoxigenin, R = H
OH3C
O CH3
OH3CO
B(OH)2
+
d. Parallel Kinetic Resolution
The enantioselective desymmetrization of dione-based electrophiles suggests the
possibility of conducting parallel kinetic resolutions of chiral racemic enone-diones.107 In
such reactions, the absolute stereochemistry of the nascent conjugate adduct dictates
which of the two nonequivalent carbonyl moieties of the appendant dione participates in
aldolization. When racemic enone-dione 1 (Figure I-2.2) was exposed to standard
reaction conditions, the regioisomeric products 1a and 1b were obtained as single
diastereomers in 43% and 41% chemical yield and >99% and 87% enantiomeric excess,
respectively. The differential degree of asymmetric inductions observed for compounds
1a and 1b suggests that substrate stereochemistry only modestly affects the π-facial
selectivity of the enantiodetermining carbometallation event. On the other hand, substrate
stereochemistry strictly directs the regiochemistry of dione addition. In cases where the
43
matched carbonyl moiety of the dione is recalcitrant with respect to addition, addition to
the mismatched carbonyl to form the epimeric alcohol does not occur.
Figure I-2.2: Parallel Kinetic Resolutions of Enone-Tethered, Differentiated 1,3-Diones
H3C
O
H3C
1 (racemate) 1a, 43% Yield(86% of theoretical)>99:1 de, >99% ee
O
O
OH
H3C O
H3CO
CH3
CH3
1b, 41% Yield(82% of theoretical)
>99:1 de, 87% ee
OH
H3C O
H3CO
CH3
CH3
CH3CH3
N
O
O
H3CCH3
N
OH3CCH3
OHN
OH3C
2 (racemate) 2a, 46% Yield(92% of theoretical)
>99:1 de, 85% ee
2b, 38% Yield(76% of theoretical)
>99:1 de, 64% ee
OCH3
OH3C OH3C OH3C
iii. Cu-Catalyzed Conjugate Addition-Aldol, Dieckmann and Blaise Cyclizations
A measure of any synthetic methodology’s usefulness lies in the extent to which it
is applicable to a generally broad group of substrates. In the context of tandem sequences
proceeding from copper-catalyzed conjugate addition of organozinc reagents, variables of
consequence include the nature of the diorganozinc, the nature of the primary electrophile
(enone), and the nature of the terminal electrophile. If a catalytic system is sufficiently
robust, then an unlimited number of permutations are imaginable. The author employed
catalytic CA-cyclization of modularly bifunctionalized precursors as a point of entry into
molecular architectures rich in structural and stereochemical complexity. The use of
appendant nitriles, ketones, and esters as electrophiles was found to furnish the
corresponding vinylogous amides, tertiary alcohols, and β-diketones – products
44
representing as many as four contiguous stereocenters (Table I-2.3).109 Throughout this
series, a range of dialkylzincs were assayed – all performed well.
It is notable that the phenyl ketone-containing, six-membered ring enamine (Entry
6) was not isolable, but was instead hydrolyzed under chromatographic conditions to the
corresponding β-diketone. Interestingly, the corresponding methyl ketone-containing
enamine was stable and isolable (Entry 7). Five-membered ring β-diketone products
(Entries 1 and 3) were isolated as a mixture of tautomeric isomers. Both tautomers were
recognizable in the respective proton NMR spectra. Six-membered β-diketone products
(Entry 2) did not undergo tautomerization under neutral conditions or on the time scale of
the NMR experiment. In general, mono-enone ketone/diketone substrates in Table I-2.3
exhibited a strong preference for syn-aldolization, with phenyl enones giving syn aldols
exclusively and methyl enones leading to a diastereomeric ratio of 2-3:1. This trend
reflects the relative contribution of transition states embodying Z versus E enolates,
respectively. Notably, mono-phenyl enone-tethered 1,3-dione substrate I-2.15 yielded
two isomeric products representing cis and trans-fused ring junctions in a 10:1 ratio and
nearly quantitative yield. In the presence of the Feringa phosphoramidite LF,108 conjugate
addition-aldol cyclization generated products in excellent yield and good to excellent
enantioselectivity, albeit with low diastereoselectivity (Scheme I-2.13).
Scheme I-2.13: Enantioselective 1,4-Addition-Aldol Cyclization
45
OPh
H3C
O
O
LF (5 mol%)Cu(OTf)2 (2.5 mol%)
Et2Zn (150 mol%)PhCH3, -40 °C H3C O
OH
OPh
CH3
H3C O
OH
OPh
CH3
99% Yield 80% ee 98% ee(2.3:1)
I-2.17 I-2.17a
Table I-2.3: Tandem 1,4-Addition Dieckmann, Blaise and Aldol Cyclizations
Substrate Product
87%
Yield (%)
93%
O
PhO OCH3
O
Ph
O
OCH3
O
R'
O
R'
Et
90%
O
H3CO OCH3
O
H3C
R
O
Et
O
O
O
Ph
O
Ph
O
Ph
O
Ph
84%91%87%
Et
O
H3C
O
H3C
O
H3C
O
H3C
Et
R
X
Et
NH2
NH2
NH2
N
N
N
N
X=NH2X=OH
Substrate Product
98%
Yield (%)
96%
99%
96%
(d.r.)*
(2.2:1)
(2:1)
(10:1)**
(>95:1)(>95:1)(>95:1)
(>95:1)
(>95:1)
84% (8:1)
94% (>95:1)
O
PhO CH3
O
Ph
O
CH3
O
R'
O
R'
83%81%91%
Et
O
H3CO CH3
O
H3C
OH3C
OHOPh
Et
R'
OO
OH3C
O
OH3C
OPh
R'
OO
OH3C
OH
H3C O
Et
R'O
OH
H3C O
R'O
Et
OH
H3C O
OPhO
OH3C
OPh
99%
78% (3:1)
R
OH
R
CH3
OHCH3
OHCH3
R=MeR=EtR=nBu
Et
* Reflects ratio of syn-aldol to anti-aldol product; ** Reflects ratio of cis-fused to trans-fused hydrindane
R'=PhR'=Me
R'=PhR'=Me
Procedure: To solution of substrate (0.5 mmol), CuOTf2 (0.0125 mmol) and P(OEt)3 (0.025 mmol) in DCM (0.5 ml) wasadded R2Zn (0.75 mmol). Reaction was stirred at -20 °C for 24h.
Entry Entry
8
9
10
11
12
13
14
I-2.8 I-2.8a
I-2.9 R'=Ph I-2.9aI-2.10 R'=Me I-2.10a
I-2.11 R=Me R=Et R=nBut
I-2.11aI-2.11bI-2.11c
93%88%88%
I-2.7 R=Me I-2.7a R=Et I-2.7b R=nBut I-2.7c
73%I-2.13 I-2.13a
98%I-2.12 I-2.12a
85%I-2.14 I-2.14a
I-2.1 I-2.1bI-2.1cI-2.1d
77% (3:1)I-2.4 I-2.4b
I-2.2I-2.3
I-2.2cI-2.3c
R'=PhR'=Me
I-2.15I-2.16
I-2.15aI-2.16a
I-2.17 I-2.17a
I-2.18 I-2.18aI-2.19 I-2.19a
I-2.20 I-2.20a
1
2
3
4
5
6
7
46
Finally, under copper catalysis, isopropyl Grignard reagents were found to add
selectively to enones with appendant carbonyl functionality. Trapping of the intermediate
magnesium enolate leads to products representing aldol cyclizations in high yield and
diastereoselectivity (Scheme I-2.14).109
Scheme I-2.14: Tandem Kharasch Addition- Aldol Cyclization
O
PhO CH3
O
Ph
76% (95:1)
i Pr
OHCH3CuCl (3 mol%)
Me3SiCl (120 mol%)i PrMgCl (104 mol%)THF
I-2.1 I-2.1e
iv. Higher-Order Tandem Reactions
a. Latent Functionality and Chemoselectivity
The tandem vicinal difunctionalization of activated carbon-carbon double bonds
is possible in virtue of their primary electrophilicity and latent, or secondary
nucleophilicity. The incorporation of a secondary C=X (X = C,N,O) electrophile (itself
inert to the action of the primary organometallic nucleophile) likewise leads directly to
the formation of tertiary nucleophile, and so on. Strategies for the programmed formation
of multiple chemical bonds and stereogenic centers, therefore, are feasible to the extent
that the sequenced unmasking of latent functionality occurs chemoselectively. From this
point of view, the evolution of catalytic conjugate addition technology can be demarcated
in terms of the efficiency with which it employs its own reactive intermediates in situ.
47
b. Cu-Catalyzed Conjugate Addition-Darzens Condensation
An approach to the catalytic conjugate addition-Darzens condensation that
embodies this notion of efficiency has been developed by the author.110 By endowing the
α-carbon of an olefin (cyclohexenone) with both latent nucleophilicity and latent
electrophilicity, the reactive potential of the substrate complements the reactive potential
of an aldehyde or ketone partner (Figure I-2.3).
Figure I-2.3: Chemoselectivity and Latent Functionality
O
Electrophile
O
R
PrimaryElectrophile
Secondary/Terminal Electrophile
H
O O
R
OH
R"+R'
O
R"
Latent Nucleophile
Latent Nucleophile
Secondary/TerminalNucleophile
OX
Latent Nucleophile
PrimaryElectrophile
Terminal Electrophle
R' R"
X
1. M R
2. H
1. M R
2. H
M R
SecondaryElectrophile
SecondaryNucleophile
+
O
R
O R'
R"
Conjugate Addition Three Component Coupling
Higher-Order Tandem Processes
OR
O
R
N R'
R"
Z
α-Tosyloxycyclohexenone, an air/moisture stable, crystalline solid is obtained in good
yield from the corresponding vicinal dione. In the presence of diethylzinc, copper-
catalyzed conjugate addition precedes inter- or intramolecular trapping with an aldehyde
or ketone and Darzens-type epoxidation (Scheme I-2.15). Isolated yields are good;
diastereoselectivity is modest, but somewhat erratic at this stage of development.
48
Notably, under the present conditions unactivated aromatic aldehydes such as
benzaldehyde fail to react. The intramolecular process is viable and offers the advantages
of being operationally more simple and more diastereoselective. In the latter case, the
absence of HMPA results in the formation chlorohydrin only – no epoxide is obtained.
Scheme I-2.15: Catalytic Conjugate-Addition-Darzens Condensation
OOTos
1. Cu(OTf)2 (2.5 mol%) P(OEt)3 (5 mol%) Et2Zn/Hex (150 mol%) Tol, -20 °C
2. ArCHO (75 mol%) HMPA (150 mol%)
89% (1:1)
O
PhCl
CH3
O
1. Cu(OTf)2 (5 mol%) P(OEt)3 (10 mol%) Et2Zn/Hex (150 mol%) Tol, 0 °C
2. HMPA (500 mol%)
OO
Ph
CH3
CH3
87%
Ar = 4-NO2Ph 85% (2:1)Ar = 4-Pyridyl
I-2.21:I-2.22:
I-2.23 I-2.24
O
CH3
O
Ar
O
CH3
O
Ar+
(R,R,R) (S,R,R)
(R,R,R)-I-2.21
c. Cu-Catalyzed Conjugate Addition-Aziridination
(R,R,R)-I-2.25
This concept has been shown to be amenable to tandem aziridination as well
(Scheme I-2.16). Although optimization is still in progress, this methodology can
conceivably be extended to encompass a number of analogous applications, including
oxirane formation (by way of epoxide trapping) and cyclopropanation (by trapping with a
suitably activated olefin).
Scheme I-2.16: Catalytic Conjugate Addition-Aziridination
(R,R,R) (S,R,R)
OOTos
O
CH3
N
Ar
O
CH3
N
Ar
1. Cu(OTf)2 (2.5 mol%) P(OEt)3 (5 mol%) Et2Zn/Hex (150 mol%) Tol, -20 °C
2. HMPA (150 mol%)+
Ar = 4-NO2Ph 63% (3:1)I-2.25:Ar
NSO2Tol
H (75 mol %)
SO2Tol SO2Tol
49
50
Part 3. References
1 Kharasch, M. S.; Tawney, P. O. J. Am. Chem. Soc. 1941, 63, 2308. 2 Stork, G. Pure Appl. Chem. 1968, 17, 383. 3 Taylor, R. J. K. Synthesis 1985, 364. 4 (a) Naf, F.; Decorzant, R. Helv. Chim. Acta. 1974, 57, 1317; (b) Bornack, W. K.;
Bhagwat, S. S.; Ponton, J.; Helquist, P. J. Am. Chem. Soc. 1981, 103, 4647; (c) Ito, Y.;
Nakatsuka, M.; Saegusa, T. J. Am. Chem. Soc. 1982, 104, 7609. 5 Tandem CA-intermolecular aldehyde trapping: a. Stork, G.; d’Angelo, J. J. Am. Chem.
Soc. 1974, 96, 7114; (b) Johnson, C. R.; Meanwell, N. A. J. Am. Chem. Soc. 1981, 103,
7667; (c) Piers, E.; Lau, C. K. Synth. Commun. 1977, 7, 495; (d) See also Ref. 4a. 6 Tandem CA-intramolecular ketone trapping: (a) Alexakis, A.; Chapdelaine, M. J.;
Posner, G. H.; Runquist, A. W. Tetrahedron Lett. 1978, 19, 4205. 7 For Ni-catalyzed Conjugate Addition of vinylzirconocenes followed by carbonyl
addition: Schwartz, J; Loots, M. J. J. Am. Chem. Soc. 1980, 102, 1333. 8 Tandem CA-intermolecular enolate acylation: (a) Beck, A. K.; Hoekstra, M. S.;
Seebach, D. Tetrahedron Lett. 1977, 18, 1187; (b) Marshall, J. A.; Jochstetler, A. R. J.
Am. Chem. Soc. 1969, 91, 648; (c) Danishefsky, S.; Kahn, M.; Sivestri, M.
Tetrahedron Lett. 1982, 23, 703; (d) Jackson, W.P.; Ley, S. V. J. Chem. Soc. Perkins
Trans. 1, 1981, 1516; (e) Salomon, R. G.; Salomon, M. F. J. Org. Chem. 1975, 40,
1488. 9 Tandem CA-intramolecular enolate acylation (Dieckmann): Pearson, A.J. Tetrahedron
Lett. 1980, 21, 3929. 10 Kretchmer, R.A.; Mihelich, E. D.; Waldron, J. J. J. Org. Chem., 1972, 37, 4483; and
references therein. 11 Mukaiyama, T., Seigo, K., Takazawa, O. Chem. Lett., 1976, 1033. 12 Danishefsky, S.; Kahn, M.; Sivestri, M. Tetrahedron Lett. 1982, 23, 1419. 13 Chapdelaine, M. J.,; Hulce, M. Org. React. 1990, 38, 225.
51
14Suzuki, M.; Noyori, R. “Conjugate Addition-Enolate Trapping Reactions” in
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31 Dragojlovic, V. Molecules, 2000, 5, 674. 32 Hart, D. W.; Blackburn, T. F.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 679. 33 Yoshifuji, M.; Loots, M. J.; Schwartz, J. Tetrahedron Lett. 1977, 18, 1303. 34 (a) Lipshutz, B. H.; Wood, M. R. J. Am. Chem. Soc. 1993, 115, 12625; (b) Lipshutz, B.
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53
53 (a) Knochel, P.; Yeh, M. C. P.; Berk, S.; Talbert, J. J. Org. Chem. 1988, 53, 2390; (b)
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Int. Ed. 1997, 36, 2620. 60 Arnold, L. A.; Naasz, R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2001, 123,
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2004, 1244. 62 Alexakis, A.; Trevitt, G. P.; Bernardinelli, G. J. Am. Chem. Soc. 2001, 123, 4358. 63 Knopff, O.; Alexakis, A. Org. Lett. 2002, 4, 3835. 64 Alexakis, A.; March, S. J. Org. Chem. 2002, 67, 8753. 65 (a) Mizutani, H.; Degrado, S.; Hoveyda, A. J. Am. Chem. Soc. 2001, 124, 779; (b)
Degrado, S.; Mizutani, H.; Hoveyda, A. J. Am. Chem. Soc. 2001, 124, 755. 66 Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16, 4229. 67 Takaya, Y.; Ogasawara, M.; Hayashi, T. J. Am. Chem. Soc. 1998, 120, 5579. 68 Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc., 2001, 124,
5052. 69 Mori, A.; Danda, Y.; Fujii, T.; Hirabayashi, K.; Osakada, K. J. Am. Chem. Soc. 2001,
123, 10774. 70 Zou, G.; Wang, Z.; Zhu, J.; Tang, J. Chem. Commun. 2003, 19, 2438. 71 Yoshida, K., Ogasawara, M., Hayashi, T. J. Am. Chem. Soc. 2002, 124, 10984. 72 Yoshida, K., Ogasawara, M., Hayashi, T. J. Org. Chem. 2003, 68, 1901.
54
73 Hayashi, T., Tokunaga, N., Yoshida, K., Han, J-H. J. Am. Chem. Soc. 2002, 124,
12102. 74 Shintani, R., Tokunaga, N., Doi, H., Hayashi, T. J. Am. Chem. Soc. 2004, 126, 6240. 75 Diaz, S., Cuesta, J., Gonzalez, A., Bonjoch, J. J. Org. Chem. 2003, 68, 7400. 76 Savchenko, A.V., Montgomery, J. J. Org. Chem. 1996, 61, 1562. 77 Montgomery, J., Oblinger, E., Savchenko, A.V. J. Am. Chem. Soc. 1997, 119, 4911. 78 Subburaj, K., Montgomery, J. J. Am. Chem. Soc. 2003, 125, 11210. 79 (a) Stork, G.; Rosen, P.; Goldman, N. L. J. Am. Chem. Soc. 1961, 83, 2965. (b) Stork,
G.; Rosen, P.; Goldman, N.; Coombs, R. V.; Tsuji, J. J. Am. Chem. Soc. 1965, 87, 275. 80 For catalytic reductive aldol processes, see: (a) Revis, A.; Hilty, T. K. Tetrahedron
Lett. 1987, 28, 4809. (b) Matsuda, I.; Takahashi, K.; Sato, S. Tetrahedron Lett. 1990,
31, 5331. (c) Isayama, S.; Mukaiyama, T. Chem. Lett. 1989, 2005. (d) Kiyooka, S.;
Shimizu, A.; Torii, S. Tetrahedron Lett. 1998, 39, 5237. (e) Ooi, T.; Doda, K.; Sakai,
D.; Maruoka, K. Tetrahedron Lett. 1999, 40, 2133. (f) Taylor, S. J.; Morken, J. P. J.
Am. Chem. Soc. 1999, 121, 12202. (g) Taylor, S. J.; Duffey, M. O.; Morken, J. P. J.
Am. Chem. Soc. 2000, 122, 4528. (h) Zhao, C.-X.; Duffey, M. O.; Taylor, S. J.;
Morken, J. P. Org. Lett. 2001, 3, 1829. 81 (a) Baik, T-G.; Luis, A. L.; Wang, L-C.; Krische, M. J. J. Am. Chem. Soc. 2001, 123,
5112; (b) Wang, L-C.; Jang, H-Y.; Roh, Y.; Lynch, V.; Schultz, A. J.; Wang, X.;
Krische, M. J. J. Am. Chem. Soc. 2002, 124, 9448. 82 For examples of Co-cat. acrylate hydrodimerization see: (a) Kanai, H.; Okada, M.
Chem. Lett. 1975, 167. (b) Kanai, H.; Ishii, K. Bull. Chem. Soc. Jpn. 1981, 54, 1015. 83 For examples of cobalt catalyzed enone hydrodimerization see: Kanai, H. J. Mol. Cat.
1981, 12, 231. 84 Baik, T-G.; Luis, A. L.; Wang, L-C.; Krische, M. J. J. Am. Chem. Soc. 2001, 123, 6716. 85 Roh, Y.; Jang, H-Y.; Lynch, V.; Krische, M. J.; Bauld, N. L. Org. Lett., 2002, 4, 611. 86 Huddleston, R. H.; Cauble, D. F.; Krische, M. J. J. Org. Chem. 2003, 68, 11.
55
87 For the first example of catalytic homogeneous hydrogenation, see: M. Calvin,
Homogeneous Catalytic Hydrogenation. Trans. Faraday Soc. 1938, 34, 1181-1191. 88 For early examples of catalytic heterogeneous hydrogenation, see: (a) Loew, O.
Darstellung Eines Sehr Wirksamen Platinmohrs. Ber. 1890, 23, 289-290. (b) Sabatier,
P. Senderens, J.-B.. C. R. Acad. Sci. Paris 1897, 124, 1358-1361. 89 For the first practical heterogeneous catalyst system for hydrogenation at ambient
temperature, see: Voorhees, V.; Adams, R. J. Am. Chem. Soc. 1922, 44, 1397-1405. 90 For recent reviews on alkene hydroformylation, see: (a) Breit, B. Acc. Chem. Res.
2003, 36, 264-275. (b) Breit, B.; Seiche, W. Synthesis 2001, 1-36. 91 For reviews on the Fischer-Tropsch reaction, see: (a) Herrmann, W. A. Angew. Chem.,
Int. Ed. 1982, 21, 117-130. (b) Rofer-Depoorter, C.-K. A Chem. Rev. 1981, 81, 447-
474. 92 For a Recent Review, see: Jang, H-Y.; Krische, M. J. Acc. Chem. Res. 2004, 9, 653. 93 Jang, H.-Y.; Huddleston, R. R.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 15156-
15157. 94 Arnett, E. M.; Fisher, F. J.; Nichols, M. A.; Ribeiro, A. A. J. Am. Chem. Soc. 1989,
111, 748-749. 95 Lack of reactivity of tris(dialkylamino)sulfonium enolates: (a) Noyori, R.; Sakata, J.;
Nishizawa, M. J. Am. Chem. Soc. 1980, 102, 1223-1225. (b) Noyori, R.; Nishida, I.;
Sakata, J. J. Am. Chem. Soc. 1981, 103, 2106-2108. (c) Noyori, R.; Nishida, I.;
Sakata, J. Synthesis, Structure, and Reactions. J. Am. Chem. Soc. 1983, 105, 1598-
1608. 96 Huddleston, R. R.; Krische, M. J. Org. Lett. 2003, 5, 1143-1146. 97 (a) Heathcock, C. H. in Comprehensive Organic Synthesis: Additions to C-X Bonds
Part 2.; Trost, B. M.; Fleming, I.; Heathcock, C. H., Ed. Pergamon Press: New York.,
p. 181-238. (b) Alcaide, B.; Almendros, P. The Direct Catalytic Asymmetric Cross-
Aldol Reaction of Aldehydes. Angew. Chem. Int. Ed. 2003, 42, 858-860.
56
98 Marriner, G. A.; Garner, S. A.; Jang, H.-Y.; Krische, M. J. J. Org. Chem. 2004, 69,
1380. 99 Yachi, K.; Shinokubo, H.; Oshima, K. J. Am. Chem. Soc. 1999, 121, 9465-9466. 100 Koech, P. K.; Krische, M. J. Org. Lett. 2004, 6, 691. 101 Monohydride formation by deprotonation of a dihydride intermediate is known for
cationic Rh-complexes: (a) Schrock, R. R.; Osborn, J. A. J. Am. Chem. Soc. 1976, 98,
2134-2143. (b) Schrock, R. R.; Osborn, J. A. J. Am. Chem. Soc. 1976, 98, 2143-2147.
(c) Schrock, R. R.; Osborn, J. A. J. Am. Chem. Soc. 1976, 98, 4450-4455. 102 Cauble, D. F.; Gipson, J. D.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 1110. 103 Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920. 104 Bocknack, B. M.; Wang, L. -C.; Krische, M. J. Proc. Nat. Acad. Sci. 2004, 101, 5421. 105 Uson, R.; Oro, L. A. Inorg. Synth. 1985, 23, 126. 106 Aronson, J.K “An Account of the Foxglove and Its Medicinal Uses: 1785-1985”
Oxford Univ. Press: London, 1985. 107 a) Dehli H.R., Gotor, V. Chem. Soc. Rev. 2002, 31, 365; b) Martin, S.F., Spaller, M.
R., Liras, S., Hartmann, B. J. Am. Chem. Soc. 1994, 116, 4493; c) Vedejs, E., Chen,
X. J. J. Am. Chem. Soc. 1997, 119, 2584; d) Cardona, F., Valenza, S., Goti, A.,
Brandi, A. Eur. J. Org. Chem. 1999, 1319; e) Pederson, T. M., Jensen, J. F., Humble,
R. E., Rein, T., Tanner, D., Bodmann, K., Reiser, O. Org. Lett. 2000, 2, 535; f)
Bertozzi, F., Crotti, P., Macchia, F., Pineschi, M., Feringa, B. Angew. Chem. Int. Ed.
2001, 40, 930; g) Vedejs, E., Rozners, E. J. Am. Chem. Soc. 2001, 123, 2428; h) Al-
Sehemi, A. G., Atkinson, R. S., Meades, C. K. Chem. Commun. 2001, 2684; i) Dehli,
J. R., Gotor, V. J. Org. Chem. 2002, 67, 1716; j) Tanaka, K., Fu, G. C. J. Am. Chem.
Soc. 2003, 125, 8078. 108 Feringa, B. L. Acc. Chem. Res. 2000, 33, 346, and references therein. 109 Agapiou, K.; Cauble, D. F.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 4528. 110 Unpublished results
Part 4. Experimental A. Synthetic Procedures
i. General
All reactions were run under an atmosphere of argon, unless otherwise indicated.
Anhydrous solvents were transferred by an oven-dried syringe. Flasks were oven-dried
and cooled in a dessicator.
Analytical thin-layer chromatography (TLC) was carried out using 0.2 mm
commercial silica gel plates (DC-Fertigplatten Krieselgel 60 F254). Preparative column
chromatography employing silica gel was performed according to the method of Still.1
Melting points were determined on a Thomas-Hoover melting point apparatus in sealed
capillaries and are uncorrected. Infrared spectra were recorded on a Perkin-Elmer 1420
spectrometer. High-resolution mass spectra (HRMS) were obtained on a Karatos MS9
and are reported as m/e (relative intensity). Accurate masses are reported for the
molecular ion (M+1).
Unless otherwise noted, proton nuclear magnetic resonance (1H NMR) spectra
were recorded with a Varian Gemini (300 MHz) spectrometer or a Mercury (400 MHz)
spectrometer. Chemical Shifts are reported in delta (δ) units, parts per million (ppm)
downfield from trimethylsilane. Coupling constants are reported in Hertz (Hz). Carbon-
13 nuclear magnetic resonance (13C NMR) spectra were recorded with a Varian Gemini
300 (75 MHz) spectrometer and a Mercury 400 (100 MHz) spectrometer. Chemical shifts
are reported in delta (δ ) units, parts per million (ppm) relative to the center of the triplet
57
at 77.0 ppm for deuteriochloroform. 13C NMR spectra were routinely run with broad
brand decoupling.
ii. Representative procedure for the preparation of I-2.7 – I-2.10. Cyclization substrates were prepared via Wittig olefination of the corresponding
aldehydes (Fleming, I.; Kilburn, J.D. J. Chem. Soc. Perkins Trans. 1, 1998, 17, 2663.) in
refluxing chloroform. Reaction mixtures were concentrated onto silica gel and purified by
chromatography, eluting over silica gel with ethyl acetate/hexanes to afford product in
greater than 80% yield. Characterization data for substrate I-2.10 was consistent with that
reported in the literature. See: Durman, J.; Elliot, J.; McElroy, A.B.; Warren, S. J. Chem.
Soc., Perkin Trans. 1, 1985, 1237.
iii. Representative procedure for the preparation of I-2.11 – I-2.14. Cyclization substrates were prepared via tandem ozonolytic cleavage – Wittig
olefination of the corresponding unsaturated nitriles. Accordingly, ozone was bubbled
through a solution of 4-pentenonitrile (1 g, 12.0 mmol, 100 mol%) in dichloromethane
(60 ml) at –78 ºC. Upon consumption of 4-pentenonitrile, nitrogen was bubbled though
the mixture followed by the addition of triphenylphosphine (3.15 g, 12.0 mmol, 100
mol%). The mixture was gradually warmed to room temperature and allowed to stir for
1h. The Wittig reagent, 1-phenyl-2-(triphenyl-λ5-phosphanylidene)-ethanone (2.64 g,
6.93 mmol, 200 mol%), was added and the reaction mixture was allowed to stir under
gentle reflux for 16h. The solvent was removed in vacuo and the crude product was
58
subjected to chromatography over silica gel with 10% ethyl acetate in hexanes to give I-
2.5 as a dark red solid (1.58 g, 71%).
iv. Representative procedure for the preparation of I-2.1 – I-2.4.
Cyclization substrates were prepared via tandem ozonolytic cleavage – Wittig
olefination of the corresponding unsaturated methyl ketones as described in the literature.
Spectroscopic characterization data was found to be consistent with reported values. See:
Huddlesston, R. R.; Cauble, D. F.; Krische, M. J. J. Org. Chem. 2003, 68, 11.
v. Procedures for the preparation of I-2.15 – I-2.17.
(Mono)enone-tethered 1,3-cyclopentandione substrates I-2.15 – I-2.17 were
prepared according to literature procedures. Spectroscopic characterization was found to
be consistent with reported values. See: Huddleston, R. R.; Jang,H.-Y.; Krische, M. J. J.
Am. Chem. Soc. 2003, 125, 11488.
vi. Procedures for the synthesis of substrates I-2.18 – I-2.20.
59
2-Methyl-2-(4-oxo-4-phenyl-but-2-enyl)-indan-1,3-dione (I-2.18): Ozone was
bubbled through a solution of 2-allyl-2-methyl-1,3-indandione (Bloch, R.; Orvane, P.
Synthetic Communications 1981, 11, 913.) (1 g, 5.00 mmol, 100 mol%) in
dichloromethane (25 ml) at –78 ºC. Upon consumption of 2-allyl-2-methyl-1,3-
indandione, nitrogen was bubbled though the mixture followed by the addition of
triphenylphosphine (1.3 g, 5 mmol, 100 mol%). The mixture was gradually warmed to
room temperature and allowed to stir for 1h. The solvent was removed in vacuo to give
an oil (637 mg, 63% yield) of sufficient purity for the next step. This product (960 mg,
4.75 mmol, 100 mol%) was taken up in chloroform (24 ml) and stirred under reflux with
the wittig reagent 1-phenyl-2-(triphenyl-λ5-phosphanylidene)-ethanone (2.71 g, 7.12
mmol, 150 mol%) for 12h. The solvent was removed in vacuo and the crude product was
subjected to chromatography over silica gel with 10% ethyl acetate in hexanes to give I-
2.16 as a yellow oil (1.32 g, 87% yield).
2-Methyl-2-(5-oxo-phenyl-pent-3-enyl)-indan-1,3-dione (I-2.19): To stirred
solution of 2-methyl-1,3-indandione1 (1 g, 6.25 mmol, 100 mol%) in H2O (15 ml) was
added acrolein (0.6 ml, 9.37 mmol, 150 mol%). The reaction mixture was allowed to stir
for 18h at room temperature and then extracted with dichloromethane. The combined
extracts were dried over sodium sulphate and concentrated in vacuo to give a yellow oil
(1.24 g, 92% yield) of sufficient purity for the next step. This product (1 g, 4.62 mmol,
100 mol%) was taken up in chloroform (23 ml) and stirred under reflux with the wittig
reagent 1-phenyl-2-(triphenyl-λ5-phosphanylidene)-ethanone (2.21 g, 6.94 mmol, 150
mol%) for 18h. The solvent was removed in vacuo and the crude product was subjected
to chromatography over silica gel with 20% ethyl acetate in hexanes to give I-2.18 as a
yellow oil (1.06 g, 72% yield).
2-Methyl-2-(4-oxo-but-2-enyl)-indan-1,3-dione (I-2.20). The preparation is
identical to the procedure described for I-2.18 except for the use of the Wittig reagent 1-
(triphenyl-λ5-phosphanylidene)-propan-2-one in place of 1-phenyl-2-(triphenyl-λ5-
hosphanylidene)-ethanone. The product I-2.20 was isolated as a yellow oil (1.04 g, 86%).
60
vii. Procedure for tandem CA-Dieckmann cyclization of I-2.7 and I-2.9.
Substrate (1 mmol, 100 mol%), copper (II) triflate (0.05 mmol, 5 mol%), and
triethylphosphite (0.01 mmol, 10 mol%) were combined in anhydrous dichloromethane
(1 ml) and allowed to stir at room temperature for 15 minutes. The mixture was cooled to
0 °C, and a 1M solution of dialkylzinc in hexanes (1.5 ml, 1.5 mmol, 150 mol%) was
added. The reaction mixture was allowed to stir at 0 °C for 24h or until consumption of
the starting material was observed. The reaction was quenched by addition of 50 µl
saturated aqueous ammonium chloride solution, diluted with 5 ml Et2O, and filtered. The
filtrate was extracted twice with aqueous 2M KOH solution, and pooled aqueous extracts
were washed once with Et2O. The aqueous phase was then acidified with aqueous 1 M
HCl, and extracted twice with Et2O. This organic solution was finally dried with brine
and Na2SO4, filtered and evaporated onto silica. Chromatography over silica gel with
ethyl acetate/hexanes eluant mixture afforded cyclized products I-2.7a-c and I-2.9a.
viii. Procedure for tandem CA-Dieckmann cyclization of I-2.8 and I-2.10.
Substrate (1 mmol, 100 mol%), copper (II) triflate (0.025 mmol, 2.5 mol%), and
triethylphosphite (0.05 mmol, 5 mol%) were combined in anhydrous dichloromethane (1
ml) and allowed to stir at room temperature for 15 minutes, at which point a 1M solution
of dialkylzinc in hexanes (1.5 ml, 1.5 mmol, 150 mol%) was added. The reaction mixture
was allowed to stir for 24h or until consumption of the starting material was observed.
The reaction was quenched by addition of 50 µl saturated aqueous ammonium chloride
solution, diluted with 5 ml Et2O, filtered, and evaporated onto silica. Chromatography
61
over silica gel with ethyl acetate/hexanes eluant mixture afforded cyclized products I-
2.8a and I-2.10a.
ix. Procedure for tandem CA-Blaise cyclization of substrates I-2.11 – I-2.14.
Substrate (0.5 mmol, 100 mol%), copper (II) triflate (0.0125 mmol, 2.5 mol%),
and triethylphosphite (0.025 mmol, 5 mol%) were combined in anhydrous
dichloromethane (0.5 ml) and allowed to stir at room temperature for 15 minutes. The
mixture was cooled to –20 ºC, and a 1.0 M solution of diethylzinc in hexanes (0.75 ml,
0.75 mmol, 150 mol%) was added. The reaction mixture was allowed to stir while
gradually warming to room temperature for 24h or until consumption of the starting
material was observed. The reaction was quenched by addition of 50 µL saturated
aqueous ammonium chloride solution, diluted with 5 ml Et2O, filtered, and evaporated
onto silica. Chromatography over silica gel with ethyl acetate/hexanes eluant mixture
afforded cyclized products I-2.11a-c, I-2.12a, I-2.13a and I-2.14a.
x. Procedure for Cu-catalyzed aldol cyclizations
62
Substrate (0.5 mmol, 100 mol%), copper (II) triflate (0.0125 mmol, 2.5 mol%),
and triethylphosphite (0.025 mmol, 5 mol%) were combined in anhydrous
dichloromethane (0.5 ml) and allowed to stir at room temperature for 15 minutes. The
mixture was cooled to –20 ºC, and a 1M solution of dialkylzinc in hexanes (0.75 ml, 0.75
mmol, 150 mol%) was added. The reaction mixture was allowed to stir at –20 ºC for 24h
or until consumption of the starting material was observed. The reaction was quenched by
addition of a saturated aqueous ammonium chloride solution, filtered, and evaporated on
to silica. Chromatography over silica gel with ethyl acetate/hexanes eluant mixture
afforded cyclized products.
xi. Procedure for the preparation of product I-2.1e.
Enone I-2.1 (101 mg, 0.5 mmol, 100 mol %), copper (I) chloride (1.5 mg, 0.015
mmol, 3 mol %) and chlorotrimethylsilane (65 mg, 0.6 mmol, 120 mol%) were combined
in anhydrous tetrahydrofuran (0.7 ml) and allowed to stir at room temperature for 10
minutes. The mixture was cooled to 0 °C, and a 2M solution of isopropylmagnesium
chloride in diethyl ether (0.26 ml, 0.52 mmol, 104 mol%) was added. The reaction
mixture was allowed to warm to room temperature and stirred until consumption of the
starting material was observed. The reaction was quenched by addition of a saturated
aqueous ammonium chloride solution, filtered, and then the aqueous layer was extracted
with diethyl ether. The combined extracts were dried over sodium sulfate, and
concentrated under reduced pressure. Chromatography over silica gel (1% ethyl acetate
in hexanes) afforded cyclized product I-2.1e.
xii. Procedure for the preparation of products I-2.21, I-2.22 and I-2.25
α-Tosyloxycyclohexenone (0.5 mmol, 100 mol%), Cu(OTf)2 (2.5 mol%) and
P(OEt)3 (5 mol%) were combined in toluene (0.2M). This solution was cooled to -20 °C
before adding 1M Et2Zn/Hexane (150 mol%). Stirring was maintained until complete
consumption of enone was observed – usually 12-18 hours. A solution of aldehyde (or
aldimine) (75 mol %) and HMPA (150 mol %) was prepared and added in one portion to
63
the first solution. Stirring at -20 °C was maintained for 7-12 hours. The reaction mixture
was evaporated onto silica gel and purified by chromatography, eluting with a mixture of
ethyl acetate and hexane.
xiii. Procedure for the preparation of product I-2.24
Chloroenone-tethered methyl ketone substrate I-2.23 (0.5 mmol, 100 mol%),
Cu(OTf)2 (5 mol%) and P(OEt)3 (10 mol%) were combined in toluene (0.2M). This
solution was cooled to 0 °C before adding 1M Et2Zn/Hexane (150 mol%). Stirring was
maintained until complete consumption of enone was observed – usually 12-14 hours.
HMPA (500 mol%) was added to the reaction mixture and stirring was continued for 7-
10h. The reaction mixture was evaporated onto silica gel, the purified by
chromatography, eluting with a mixture of ethyl acetate and hexane.
xiv. Procedure for the preparation of substrate I-2.6
Tosylamine-tethered enone-methyl ketone substrate I-2.6 was prepared in
accordance with a literature procedure. Spectroscopic characterization data were
consistent with reported values. See: Huddlesston, R. R.; Cauble, D. F.; Krische, M. J. J.
Org. Chem. 2003, 68, 11.
xv. General procedure for Rh-catalyzed aldol cyclizations
64
[Rh(COD)Cl]2 (6.16 mg, 2.5 mol%) and a bidentate phosphine ligand (7.5 mol%)
were combined in 5 ml of 1,4-dioxane. The solution was allowed to stir at ambient
temperature for thirty minutes, at which point ArB(OH)2 (200 mol%) was added followed
by KOH(aq) [KOH (2.81 mg, 0.05 mmol, 10 mol%), H2O (45 µl, 2.5 mmol, 500 mol%)]
and, finally, substrate (0.5 mmol, 100 mol%). The flask was immediately placed in a 95
°C oil bath and allowed to stir. Upon complete consumption of substrate, the reaction
mixture was partitioned between H2O and Et2O and the aqueous layer was washed
several times with Et2O. The organic extracts were combined, washed with brine, dried
over Na2SO4, concentrated and finally subjected to silica gel chromatography (SiO2:
EtOAc/Hexane) to yield the purified product.
65
B. Spectroscopic and Crystallographic Characterization Data
O
O OCH3
I-2.7
1H NMR (400 MHz, CDCl3): δ 2.51 (t, J = 7.9 Hz, 2H), 2.61 (q, J = 6.5 Hz, 4H), 3.66 (s, 3H), 6.89 (d, J = 15.4 Hz, 1H), 6.96 (m, 1H), 7.42 (t, J = 7.5 Hz, 2H), 7.51 (m, 1H), 7.88 (d, J = 7.2 Hz, 2H). 13C NMR (75 MHz, CDCl3): 27.7, 32.3, 51.7, 126.5, 128.5, 128.5, 132.7, 137.6, 146.8, 172.7, 190.4. HRMS: Calcd [M+1] for C13H15O3: 219.1021; Found: 219.1023. FTIR (film): 3055, 2987, 2953, 2361, 2306, 1734, 1652, 1437, 1277, 1003, 731 cm-1.
66
H3C
O
O OCH3
I-2.8
1H NMR (400 MHz, CDCl3): δ 2.2 (s, 3H), 2.44-2.58 (m, 4H), 3.65 (s, 3H), 6.05 (d, J = 17.2 Hz, 1H), 6.70-6.78 (m, 1H). 13C NMR (75 MHz, CDCl3): 26.8, 27.2, 32.1, 51.7, 131.7, 145.5, 172.5, 198.2. HRMS: Calcd [M+1] for C8H13O3: 157.0865; Found: 157.0865. FTIR (film): 3055, 2987, 1736, 1675, 1438, 1422, 1266, 739, 705 cm-1.
67
O O
OCH3
I-2.9
1H NMR (400 MHz, CDCl3): δ 1.82 (m, 2H), 2.32 (m, 4H), 3.62 (s, 3H), 6.85 (d, J = 15.4 Hz, 1H), 6.96 (m, 1H), 7.41 (m, 2H), 7.5 (m, 1H), 7.87 (d, J = 7.5 Hz, 2H). 13C NMR (75 MHz, CDCl3): 23.2, 31.8, 33.1, 51.4, 126.4, 128.4, 128.4, 132.6, 137.7, 148.0, 173.4, 190.4. HRMS: Calcd [M+1] for C14H17O3: 233.1178; Found: 233.1180. FTIR (film): 3055, 2987, 2953, 2361, 2306, 1734, 1652, 1437, 1277, 1003, 731 cm-1.
68
CN
O
I-2.11
1H NMR (400 MHz, CDCl3): δ 2.56 (m, 2H), 2.65 (t, J = 6.5 Hz, 2H), 6.96 (m, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.55 (t, J = 7.3 Hz, 1H), 7.91 (d, J = 7.2 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 16.0, 28.0, 118.5, 127.6, 128.3, 128.4, 132.8, 137.0, 143.1, 189.6. HRMS: Calcd [M+1] for C12H12NO: 186.0918; Found: 186.0919. FTIR (film): 3055, 2986, 2684, 2688, 1675, 1626, 1446, 1422, 1346, 1263, 897 cm-1. mp 38-40 ºC
69
CNH3C
O
I-2.12
1H NMR (400 MHz, CDCl3): δ 2.25 (s, 3H), 2.54 (m, 4H), 6.16 (d, J = 16.0 Hz, 1H), 6.72 (dt, J1 = 16.0 Hz, J2 = 6.2 1H). 13C NMR (75 MHz, CDCl3): δ 15.9, 27.1, 27.7, 118.3, 132.7, 141.9, 197.6. HRMS: Calcd [M+1] for C7H10NO: 124.0762; Found: 124.0763. FTIR (film): 3059, 2990, 2685, 1699, 1679, 1630, 1419, 1364, 1270, 980, 897 cm-1.
70
CN
O
I-2.13
1H NMR (400 MHz, CDCl3): δ 1.88 (m, 2H), 2.39 (t, J = 7.2 Hz, 2H), 2.48 (m, 2H), 6.96 (m, 2H), 7.45 (t, J = 7.5 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.91 (d, J = 7.2 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 16.6, 23.8, 31.2, 118.9, 127.3, 128.5, 128.6, 132.9, 137.5, 145.9, 190.1. HRMS: Calcd [M+1] for C13H14NO: 200.1075; Found: 200.1084. FTIR (film): 3055, 2986, 2684, 2522, 1671, 1642, 1623, 1419, 1260, 900 cm-1.
71
H3C
O
CN
I-2.14
1H NMR (400 MHz, CDCl3): δ 1.73 (m, 2H), 2.13 (s, 3H), 2.29 (m, 4H), 6.00 (d, J = 16.0 Hz, 1H), 6.63 (dt, J1 = 16.0 Hz, J2 = 6.8 1H. 13C NMR (75 MHz, CDCl3): δ 11.8, 18.5, 25.8, 32.2, 39.2, 40.9, 59.8, 69.2, 88.3, 123.4, 125.2, 129.9, 135.5, 135.5, 153.0, 208.4, 209.1. HRMS: Calcd [M+1] for C8H12NO: 138.0919; Found: 138.0916. FTIR (film): 3056, 2983, 2689, 1703, 1675, 1630, 1419, 1360, 1260, 1153, 980, 893 cm-
1.
72
OO
I-2.1
1H NMR (300 MHz, CDCl3): δ 2.13 (s, 3H), 2.5 (m, 2H), 2.6 (m, 2H), 6.8 (m, 1H), 6.9 (m, 2H), 7.4 (m, 2H), 7.5 (m, 1H), 7.9 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 26.5, 29.9, 41.5, 126.5, 128.4, 132.6, 137.6, 147.4, 190.5, 206.7. HRMS: Calcd [M+1] for C13H14O2: 203.1064; Found: 203.1072. FTIR (film): 3054, 2986, 2685, 2410, 2305, 1716, 1671, 1650, 1622, 1447, 1421, 1365, 1265, 1161, 978, 896, 737, 704 cm-1.
73
H3C
OO CH3
I-2.4
1H NMR (300 MHz, CDCl3): δ 2.12 (s, 3H), 2.18 (s, 3H), 2.45 (m, 2H), 2.58 (t, J = 7.2 Hz, 2H), 6.72 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 26.1, 27.0, 41.5, 131.5, 146.0, 198.1, 206.4. HRMS: Calcd [M+1] for C8H12O2: 141.0916; Found: 141.0913. FTIR (film): 3054, 2986, 2685, 2305, 1716, 1673, 1628, 1421, 1363, 1265, 1161, 978, 896, 738, 704 cm-1.
74
O O
CH3
I-2.2
1H NMR (300 MHz, CDCl3): δ 1.78 (qt, J = 7.3Hz, 2H), 2.11 (s, 3H), 2.29 (m, 2H), 2.46 (t, J = 7.2 Hz, 2H), 6.85 (m, 1H), 7.43 (m, 2H), 7.52 (m, 1H), 7.88 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 21.9, 29.9, 31.8, 42.6, 126.4, 128.4, 132.6, 137.7, 148.5, 190.6, 208.0. HRMS: Calcd [M+1] for C14H16O2: 217.1229; Found: 217.1229. FTIR (film): 2935, 2253, 1713, 1670, 1620, 1598, 1578, 1448, 1357, 1288, 1227, 1159, 907, 740, 650 cm-1. MP: 61-62 °C.
75
H3C
O O
CH3
I-2.3
1H NMR (300 MHz, CDCl3): δ 1.65 (qt, J = 7.2 Hz, 2H), 2.03 (s, 3H), 2.13 (m, 3H, 2H), 2.37 (t, J = 7.2 Hz, 2H), 5.96 (m, 1H), 6.66 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 21.7, 26.7, 29.8, 31.4, 42.3, 131.5, 147, 198.2, 207.8. HRMS: Calcd [M+1] for C9H14O2: 155.1072; Found: 155.1067. FTIR (film): 3054, 2986, 2685, 2305, 1714, 1673, 1626, 1422, 1361, 1265, 1158, 980, 896, 734, 704 cm-1.
76
OO
OH3C
I-2.18
1H NMR (400 MHz, CDCl3): δ 1.29 (s, 3H), 2.72 (d, J = 7.5 Hz, 2H), 6.61 (dt, J1 = 15.4 Hz, J2 = 7.5 Hz, 1H), 6.77 (d, J = 15.4 Hz, 1H), 7.31 (t, J = 7.9 Hz, 2H), 7.43 (t, J = 7.5 Hz,1H), 7.67 (d, J = 7.2 Hz, 2H), 7.78 (m, 2H), 7.90 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 19.6, 37.7, 53.5, 77.2, 123.4, 128.3, 128.3, 129.6, 132.6, 136.0, 137.1, 140.7, 141.5, 190.0, 202.8. HRMS: Calcd [M+1] for C20H17O3: 305.1178; Found: 305.1175. FTIR (film): 3060, 2986, 2932, 2878, 2680, 1748, 1713, 1674, 1628, 1596, 1449, 1421, 1375, 1328, 1262, 1017, 986, 901 cm-1.
77
H3C
OO
OCH3
I-2.19
1H NMR (400 MHz, CDCl3): δ 1.12 (s, 3H), 1.91 (s, 3H), 2.47 (d, J = 7.7 Hz, 1H), 5.86 (d, J = 15.9 Hz, 1H), 6.39 (dt, J1 = 15.9 Hz, J2 = 7.4 Hz, 1H), 7.69-7.81 (m, 4H). 13C NMR (75 MHz, CDCl3): δ18.9, 26.6, 36.9, 52.9, 123.2, 134.1, 135.7, 140.2, 140.3, 197.3, 202.3. HRMS: Calcd [M+1] for C15H15O3: 243.1021; Found: 243.1016. FTIR (film): 3060, 2986, 2932, 2874, 2684, 1744, 1713, 1673, 1627, 1600, 1456, 1417, 1359, 1336, 1184, 1150, 1021, 986, 893 cm-1.
78
O
O
O
CH3
I-2.120
1H NMR (400 MHz, CDCl3): δ 1.28 (s, 3H), 2.01 (m, 2H), 2.11 (m, 2H), 6.63(d, J = 15.4 Hz, 2H), 6.81 (dt, J1 = 15.4 Hz, J2 = 6.8 Hz, 1H), 7.38 (t, J = 7.9 Hz, 2H), 7.49 (t, J = 7.5 Hz, 1H), 7.76 (d, J = 6.8 Hz, 2H), 7.80 (m, 2H), 7.94 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 19.9, 28.2, 33.2, 53.4, 77.2, 123.4, 126.4, 128.4, 128.4, 132.6, 135.9, 137.5, 141.0, 147.4, 190.2, 203.9. HRMS: Calcd [M+1] for C21H19O3: 319.1334; Found: 319.1338. FTIR (film): 3060, 2990, 2924, 2684, 1744, 1709, 1670, 1616, 1596, 1445, 1417, 1266, 994, 901 cm-1.
79
OOH
OO
H3CH3C I-2.7a
1H NMR (400 MHz, CDCl3): δ 0.99 (d, J = 6.5 Hz, 0.93H), 1.12 (d, J = 6.5Hz, 2.43H), 1.57 (m, 0.97H), 1.97-3.38 (m, 4H), 3.84 (d, J = 9.9 Hz, 0.72H), 7.41-7.57 (m, 3H), 7.71-7.73 (m, 0.45H), 7.95 (d, J = 8.5 Hz, 1.56H). 13C NMR (75 MHz, CDCl3): δ 19.5, 29.2, 35.5, 39.4, 65.4, 128.4, 129.2, 133.3, 137.1, 195.8, 213.0. HRMS: Calcd [M+1] for C13H15O2: 203.1072; Found: 203.1070. FTIR (film): 3048, 2963, 2928, 2870, 1740, 1678, 1596, 1448, 1270, 1219, 897 cm-1.
80
OOH
CH3
OO
CH3 I-2.7b
1H NMR (400 MHz, CDCl3): δ 0.78 (t, J = 7.1 Hz, 0.98H), 0.89 ((t, J = 7.3 Hz, 2.02H), 1.18-3.22 (m, 7H), 3.92 (d, J = 9.8 Hz, 0.69H), 7.43-7.59 (m, 3H), 7.7-7.72 (m, 0.47H), 7.96 (d, J = 8.2 Hz, 1.4H) 13C NMR (75 MHz, CDCl3): 11.6, 12.0, 25.3, 26.9, 27.4, 27.9, 35.2, 39.3, 40.3, 42.4, 64.0, 114.2, 127.8, 128.4, 128.6, 129.2, 130.8, 133.3, 135.0, 137.2, 171.5, 196.2, 209.4, 213.1. HRMS: Calcd [M+1] for C14H17O2: 217.1229; Found: 217.1233. FTIR (film): 2967, 2361, 2338, 2249, 1732, 909, 738, 645 cm-1
81
OOH
nBu
OO
nBut I-2.7c
1H NMR (400 MHz, CDCl3): δ 0.75 (t, J = 6.5 Hz, 0.52H), 0.82 (t, J = 6.8 Hz, 2.71H), 1.14-3.29 (m, 12H), 3.91 (d, J = 9.9 Hz, 0.83H), 7.41-7.58 (m, 3H), 7.70-7.73 (m, 0.29H), 7.95 (d, J = 8.5 Hz, 1.72H). 13C NMR (75 MHz, CDCl3): δ 13.9, 22.6, 27.2, 29.7, 34.9, 39.3, 40.7, 64.3, 128.5, 129.2, 133.3, 137.2, 196.1, 213.1. HRMS: Calcd [M+1] for C16H21O2: 245.1542; Found: 245.1543. FTIR (film): 3056, 2982, 2963, 2932, 2862, 1744, 1678, 1448, 1425, 1266, 897 cm-1.
82
OO
H3C
CH3
OHO
H3C
CH3 I-2.8a
1H NMR (400 MHz, CDCl3): δ 0.89 (t, J = 7.5 Hz, 3H), 1.3-1.56 (m, 2.6H), 1.67-1.75 (m, 0.7H), 1.9-2.2 (m, 2H), 2.12-2.64 (m, 4.7 H), 2.68-2.78 (m, 0.5 H), 3.0 (d, J = 10.3 Hz, 0.5 H). 13C NMR (75 MHz, CDCl3): 11.7, 11.8, 20.4, 25.4, 26.3, 27.7, 28.1, 31.0, 35.2, 39.0, 39.9, 40.4, 69.1, 114.6, 175.9, 203.0, 206.2, 212.7. HRMS: Calcd [M+1] for C9H15O2: 155.1072; Found: 155.1072. FTIR (film): 3157, 2967, 2365, 2334, 2252, 1709, 1383, 1231, 913, 742, 649 cm-1.
83
O
CH3
O
I-2.9a
1H NMR (400 MHz, CDCl3): δ 0.87 (t, J = 7.5 Hz, 3H), 1.2-1.46 (m, 2H), 1.74-1.82 (m, 1H), 1.98-2.17 (m, 2H), 2.38-2.14 (m, 2H), 2.5-2.57 (m, 1H), 4.16 (d, J = 9.2, 1H), 7.42 (t, J = 7.5, 2H), 7.5 (m, 1H), 7.85 (d, J = 7.2, 2H). 13C NMR (75 MHz, CDCl3): 11.1, 24.2, 27.3, 27.9, 41.8, 42.3, 63.9, 128.2, 128.6, 133.1, 137.5, 198.1, 208.7. HRMS: Calcd [M+1] for C15H19O2: 231.1385; Found: 231.1387. FTIR (film): 3049, 2986, 2361, 2338, 1712, 1418, 1262, 897, 734 cm-1
84
OHO
H3C
CH3
OO
H3C
CH3 I-2.10a
1H NMR (400 MHz, CDCl3): δ 0.91 (t, J = 7.5 Hz, 3H), 1.3-1.86 (m, 7H), 2.13 (s, 3H), 2.28-2.41 (m, 3 H). 13C NMR (75 MHz, CDCl3): 12.4, 16.5, 23.8, 24.7, 27.8, 31.2, 34.9, 112.9, 184.1, 197.8. HRMS: Calcd [M+1] for C10H17O2: 169.1229; Found: 169.1233.
85
O NH2
H3C I-2.11a
1H NMR (400 MHz, CDCl3): δ 0.73 (d, J = 6.63 Hz, 3H), 1.41 (m, 1H), 2.11 (m, 1H), 2.45 (m, 1H), 2.61 (m, 1H), 3.27 (br m, 1H), 7.35 (m, 3H), 7.53 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 22.7, 30.3, 33.0, 37.7, 111.4, 126.7, 128.0, 129.4, 142.4, 166.8, 192.9. HRMS: Calcd [M+1] for C13H16NO: 202.1232; Found: 202.1232. FTIR (film): 3474, 3052, 2986, 2687, 1615, 1421, 1262, 901 cm-1. mp 148-151 °C
86
CH3
O NH2
I-2.11b
1H NMR (400 MHz, CDCl3): δ 0.60 (t, J = 7.2 Hz, 3H), 0.96 (m, 1H), 1.13 (m, 1H), 1.52 (m, 1H), 2.01 (m, 1H), 2.40 (m, 1H), 2.54 (m, 1H), 3.10 (br m, 1H), 7.33 (m, 3H), 7.52 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 11.3, 26.6, 28.2, 33.0, 44.4, 109.7, 126.6, 127.9, 129.4, 142.4, 167.5, 192.7. HRMS: Calcd [M+1] for C14H17NO: 216.1388; Found: 216.1380. FTIR (film): 3471, 3055, 2982, 2684, 2681, 1616, 1419, 1260, 897 cm-1. mp 104-106 ºC
87
nBut
O NH2
I-2.11c
1H NMR (400 MHz, CDCl3): δ 0.64 (t, J = 6.8, 3H), 0.92-1.08 (m, 6H), 1.52 (m, 1H), 2.02 (m, 1H), 2.40 (m, 1H), 2.57 (m, 1H), 3.14 (m, 1H), 7.33 (m, 3H), 7.51 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 13.8, 22.3, 27.1, 29.2, 33.1, 35.1, 42.7, 110.1, 126.6, 127.9, 129.3, 142.4, 167.1, 192.9. HRMS: Calcd [M+1] for C16H21NO: 244.1701; Found: 244.1714. FTIR (film): 3479, 3056, 2990, 2687, 1623, 1425, 1266, 897 cm-1. mp 113-115 °C
88
CH3
H3C
O NH2
I-2.12a
1H NMR (400 MHz, CDCl3): δ 0.86 (t, J = 7.2 Hz, 3H), 1.25 (m, 2H), 1.47-1.63 (m, 2H), 1.92 (m, 1H), 2.01 (s, 3H), 2.26 (m, 1H), 2.59 (m, 1H), 2.77 (t, J = 7.8 Hz,1H). 13C NMR (75 MHz, CDCl3): δ 11.7, 26.3, 27.3, 28.0, 32.8, 44.2, 110.5, 164.6, 195.2. HRMS: Calcd [M+1] for C9H16NO: 154.1232; Found: 154.1233. FTIR (film): 3485, 3055, 2979, 2681, 2524, 1627, 1585, 1499, 1419, 1264, 897 cm-1. mp 49-51 ºC
89
CH3
H3C
O NH2
I-2.14a
1H NMR (400 MHz, CDCl3): δ 0.86 (t, J = 7.3 Hz, 3H), 1.22-1.42 (m, 3H), 1.50 (m, 2H), 1.62 (m, 1H), 1.75 (m, 1H), 2.08 (s, 3H), 2.13 (m, 1H), 2.24 (m, 1H), 2.36 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 12.4, 16.6, 25.1, 26.7, 28.3, 30.3, 35.4, 107.7, 158.6, 198.3. HRMS: Calcd [M+1] for C10H18NO: 168.1225; Found: 168.1013. FTIR (film): 3467, 3045, 2982, 2955, 2678, 1713, 1613, 1571, 1485, 1416, 1257, 1184, 893 cm-1. mp 90-92 ºC
90
HO CH3
H3C
O
I-2.1b
1H NMR (400 MHz, CDCl3): δ 0.99 (d, J = 6.6 Hz, 3H), 1.27 (s, 3H), 1.34 (m, 1H), 1.79 (m, 1H), 1.89 (m, 1H), 2.17 (m, 1H), 2.66 (m, 1H), 3.30 (d, J = 10.6 Hz, 1H), 4.12 (br s, 1H), 7.48 (t, J = 8.1 Hz, 2H), 7.59 (t, J = 7.5 Hz, 1H), 7.94 (d, J = 7.2 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 20.2, 27.5, 31.7, 39.5, 41.0, 61.6, 82.4, 128.4, 128.7, 133.6, 138.6, 206.4. HRMS: Calcd [M+1] for C14H19O2: 219.1385; Found: 219.1393. FTIR (film): 3052, 2990, 2687, 1681, 1421, 1266, 901 cm-1.
91
HO CH3
CH3
O
I-2.1c
1H NMR (400 MHz, CDCl3): δ 0.75 (t, J = 7.5 Hz, 3H), 1.23 (s, 3H), 1.32 (m, 2H), 1.73 (m, 1H), 1.87 (m, 1H), 2.13 (m, 1H), 2.53 (m, 1H), 3.38 (d, J = 10.3, 1H), 7.44 (t, J = 7.7, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.93 (d, J = 7.2, 2H). 13C NMR (75 MHz, CDCl3): δ 12.6, 27.2, 28.4, 28.9, 40.8, 46.4, 60.0, 81.8, 128.3, 128.6, 133.5, 138.3, 206.2. HRMS: Calcd [M+1] for C15H21O2: 233.1072; Found: 233.1065. FTIR (film): 3460, 3052, 2986, 2683, 2368, 2302, 1654, 1596, 1421, 1262, 897 cm-1.
92
HO CH3
nBut
O
I-2.1d
1H NMR (400 MHz, CDCl3): δ 0.75 (t, J = 7.1 Hz, 3H), 1.06-1.21 (m, 4H), 1.24 (s, 3H), 1.30-1.40 (m, 3H), 1.77 (m, 1H), 1.90 (m, 1H), 2.15 (m, 1H), 2.62 (m, 1H), 3.39 (d, J = 10.5 Hz, 1H), 3.84 (s, 1H), 7.45 (t, J = 7.9 Hz, 2H), 7.59 (t, J = 7.3 Hz, 1H), 7.95 (d, J = 7.2 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 19.9, 22.6, 27.4, 29.4, 30.4, 35.5, 41.0, 44.7, 60.6, 81.8, 128.4, 128.7, 133.6, 138.5, 206.2. HRMS: Calcd [M+1] for C17H25O2: 261.1855; Found: 261.1863. FTIR (film): 3056, 2982, 2683, 1429, 1652, 1262, 901 cm-1.
93
HO CH3O
iPr I-2.9e
1H NMR (400 MHz, CDCl3): δ 0.72 (d, J = 6.7 Hz, 3H), 0.84 (d, J = 6.7 Hz, 3H), 1.25 (s, 3H), 1.49 (m, 2H), 1.72 (m, 1H), 1.89 (m, 1H), 2.06 (m, 1H), 2.59 (m, 1H), 3.37 (br s, 1H), 3.55 (d, J = 10.2 Hz, 1 H), 7.47 (t, J = 7.2 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.97 (d, J = 7.2 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 19.9, 21.6, 26.5, 27.4, 29.7, 32.3, 41.5, 51.3, 58.2, 81.9, 128.4, 128.8, 133.5, 138.2, 205.7. HRMS: Calcd [M+1] for C16H23O2: 247.1698; Found: 247.1709. FTIR (film): 3052, 2979, 2632, 2687, 1654, 1421, 1266, 901 cm-1.
94
HO CH3
CH3
H3C
O
syn I-2.4b
1H NMR (400 MHz, CDCl3): δ 0.81 (t, J = 7.5 Hz, 3H), 1.17-1.28 (m, 2H), 1.27 (s, 3H), 1.40-1.60 (m, 1H), 1.57-1.74 (m, 2H), 1.93-2.0 (m, 1H), 2.18 (s, 3H), 2.30-2.33 (m, 1H), 2.40 (d, J = 10.3 Hz, 1H), 3.62 (bs, 1H). 13C NMR (75 MHz, CDCl3): δ 12.3, 27.5, 28.4, 28.6, 32.8, 40.7, 44.4, 66.5, 81.0, 213.7. HRMS: Calcd [M+1] for C10H19O2: 171.1385; Found: 171.1393. FTIR (film): 3492, 3054, 2934, 2878, 2306, 1690, 1462, 1421, 1359, 1267, 1178, 1046, 950, 731 cm-1.
95
HO CH3
CH3
H3C
O
anti I-2.4b
1H NMR (400 MHz, CDCl3): δ 0.81 (t, J = 7.5 Hz, 3H), 1.17-1.28 (m, 2H), 1.27 (s, 3H), 1.40-1.60 (m, 1H), 1.57-1.74 (m, 2H), 1.93-2.0 (m, 1H), 2.18 (s, 3H), 2.30-2.33 (m, 1H), 2.40 (d, J = 10.3 Hz, 1H), 3.62 (bs, 1H). 13C NMR (75 MHz, CDCl3): δ 12.3, 27.5, 28.4, 28.6, 32.8, 40.7, 44.4, 66.5, 81.0, 213.7. HRMS: Calcd [M+1] for C10H19O2: 171.1385; Found: 171.1393. FTIR (film): 3492, 3054, 2934, 2878, 2306, 1690, 1462, 1421, 1359, 1267, 1178, 1046, 950, 731cm-1.
96
HO CH3
CH3
O
I-2.2c
1H NMR (400 MHz, CDCl3): δ 0.74 (t, J = 7.4 Hz, 3H), 0.92 (m, 2H), 1.02 (s, 3H), 1.16 (m, 1H), 1.28 (dt, J1 = 13.1,J2 = 3.8 1H), 1.72-2.04 (m, 4H), 3.23 (d, J = 11.0, 1H), 4.12 (br, 1H), 7.46 (t, J = 7.9 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.96 (d, J = 8.2, 2H). 13C NMR (75 MHz, CDCl3): δ 11.3, 20.8, 27.7, 29.6, 30.2, 38.9, 39.0, 56.6, 70.8, 128.2, 128.8, 133.6, 138.9, 209.2. HRMS: Calcd [M+1] for C16H23O2: 247.1704; Found: 247.1698. FTIR (film): 3480, 3052, 2967, 2936, 2854, 2679, 2361, 2307, 1654, 1596, 1581, 1449,1371, 1266, 1212, 1045, 944, 897 cm-1.
97
HO CH3
CH3
H3C
O
syn I-2.3c
1H NMR (400 MHz, CDCl3): δ 0.64-0.75 (m, 1H), 0.74 (t, J = 7.5 Hz, 3H), 0.90-1.19 (m, 3H), 1.0 (s, 3H), 1.35-1.76 (m, 4H), 2.14 (s, 3H), 2.22 (d, J = 10.9 Hz, 1H), 3.42 (bs, 1H). 13C NMR (75 MHz, CDCl3): δ 10.8, 20.5, 26.9, 29.5, 29.6, 34.8, 37.8, 38.5, 63.0, 69.9, 217.8. HRMS: Calcd [M+1] for C11H21O2: 185.1542; Found: 185.1543. FTIR (film): 3492, 3054, 2934, 2878, 2306, 1690, 1462, 1421, 1359, 1267, 1178, 1046, 950, 731 cm-1.
98
HO
CH3
H3C
O CH3
anti I-2.3c
1H NMR (400 MHz, CDCl3): δ 0.64-0.75 (m, 1H), 0.74 (t, J = 7.5 Hz, 3H), 0.90-1.19 (m, 3H), 1.0 (s, 3H), 1.35-1.76 (m, 4H), 2.14 (s, 3H), 2.22 (d, J = 10.9 Hz, 1H), 3.42 (bs, 1H). 13C NMR (75 MHz, CDCl3): δ 10.8, 20.5, 26.9, 29.5, 29.6, 34.8, 37.8, 38.5, 63.0, 69.9, 217.8. HRMS: Calcd [M+1] for C11H21O2: 185.1542; Found: 185.1543. FTIR (film): 3492, 3054, 2934, 2878, 2306, 1690, 1462, 1421, 1359, 1267, 1178, 1046, 950, 731 cm-1.
99
O
CH3CH3
HO
O
I-2.15a
1H NMR (400 MHz, CDCl3): δ 0.74 (t, J = 7.5 Hz, 3H), 1.13 (s, 3H), 1.35-1.76 (m, 4H), 2.14 (s, 3H), 2.22 (d, J = 10.9 Hz, 1H), 3.42 (bs, 1H). 13C NMR (75 MHz, CDCl3): δ 12.4, 16.3, 28.0, 31.0, 35.4, 39.8, 45.4, 58.1, 60.0, 88.8, 128.3, 129.0, 134.0, 137.9, 204.1, 220.9. HRMS: Calcd [M+1] for C18H23O3: 287.1647; Found: 287.1646. FTIR (film): 3483, 3054, 2967, 2937, 2877, 2851, 2306, 1655, 1596, 1579, 1448, 1375, 1264, 1211, 1075, 945, 703 cm-1.
100
H3C
O
CH3CH3
HO
O
I-2.19a
1H NMR (400 MHz, CDCl3): δ 0.74 (t, J = 7.5 Hz, 3H), 1.13 (s, 3H), 1.35-1.76 (m, 4H), 2.14 (s, 3H), 2.22 (d, J = 10.9 Hz, 1H), 3.42 (bs, 1H). 13C NMR (75 MHz, CDCl3): δ 12.2, 15.8, 28.3, 32.0, 33.0, 35.3, 39.6, 43.7, 59.6, 64.5, 88.6, 212.3, 220.4. HRMS: Calcd [M+1] for C13H21O3: 225.1491; Found: 225.1498.
101
O
O
HO
CH3
CH3 cis I-2.17a
1H NMR (400 MHz, CDCl3): δ 0.74 (t, J = 7.5 Hz, 3H), 1.13 (s, 3H), 1.35-1.76 (m, 4H), 2.14 (s, 3H), 2.22 (d, J = 10.9 Hz, 1H), 3.42 (bs, 1H). 13C NMR (75 MHz, CDCl3): δ 11.2, 19.4, 27.2, 27.7, 27.8, 31.3, 34.6, 38.0, 52.3, 53.6, 78.4, 128.0, 129.1, 134.3, 138.6, 208.0, 218.0. HRMS: Calcd [M+1] for C19H25O3: 301.1804; Found: 301.1812. FTIR (film): 3483, 3054, 2967, 2937, 2877, 2851, 2306, 1655, 1596, 1579, 1448, 1375, 1264, 1211, 1075, 945, 703 cm-1. mp 90-91oC
102
O
O
HO
CH3
CH3 trans I-2.17a
1H NMR (400 MHz, CDCl3): δ 0.74 (t, J = 7.5 Hz, 3H), 1.13 (s, 3H), 1.35-1.76 (m, 4H), 2.14 (s, 3H), 2.22 (d, J = 10.9 Hz, 1H), 3.42 (bs, 1H). 13C NMR (75 MHz, CDCl3): δ 11.2, 19.4, 27.2, 27.7, 27.8, 31.3, 34.6, 38.0, 52.3, 53.6, 78.4, 128.0, 129.1, 134.3, 138.6, 208.0, 218.0. HRMS: Calcd [M+1] for C19H25O3: 301.1804; Found: 301.1816. FTIR (film): 3483, 3054, 2967, 2937, 2877, 2851, 2306, 1655, 1596, 1579, 1448, 1375, 1264, 1211, 1075, 945, 703 cm-1.
103
CH3
O HO
CH3O
synI-2.18a
1H NMR (400 MHz, CDCl3): δ 0.75 (t, J = 7.4 Hz, 3H), 1.06-1.30 (m, 3H), 1.32 (s, 3H), 1.84 (dd, J1 = 13.6 Hz, J2 = 10.8 Hz 1H), 2.10 (dd, J1 = 13.6 Hz, J2 = 7.2 Hz 1H), 2.74 (m, 1H), 3.51 (d, J = 11.0 Hz, 3H), 4.82 (br, 1H), 7.16 (d, J = 6.9 Hz, 1H), 7.37 – 7.50(m, 4H), 7.57 (t, J = 7.4 Hz, 3H), 7.72 (d, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 12.2, 19.8, 27.0, 40.1, 48.4, 61.3, 62.3, 88.1, 124.0, 124.5, 128.6, 128.8, 129.4, 133.4, 134.1, 135.3, 137.5, 155.1, 204.4, 208.9. HRMS: Calcd [M+1] for C22H23O3: 335.1647; Found: 335.1649. FTIR (film): 3398, 3056, 2986, 2932, 2870, 2684, 1717, 1654, 1603, 1445, 1421, 1262, 1219, 1025, 900 cm-1.
104
CH3
O HO
CH3O
anti I-2.18a
1H NMR (400 MHz, CDCl3): δ 0.75 (t, J = 7.5 Hz, 3H), 1.09 (m, 1H), 1.20 (s, 3H), 1.31 (m, 1H), 1.44 (t, J = 13.0 Hz, 1H), 1.88 (m, 1H), 2.21 (br s, 1H), 2.51 (dd, J1 = 12.3 Hz, J2 = 5.5 Hz 1H, 1H), 3.95 (d, J = 11.6 Hz, 1H), 6.91 (d, J = 6.5 Hz, 1H), 7.42 (m, 2H), 7.52 (t, J = 7.8 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.71 (d, J = 6.5 Hz, 1H), 8.20 (d, J = 7.5 Hz, 2H) . 13C NMR (75 MHz, CDCl3): δ 12.4, 19.2, 26.4, 40.9, 60.9, 64.1, 89.3, 123.6, 125.7, 128.9, 129.4, 130.1, 133.5, 135.4, 135.8, 138.8, 153.5, 200.2, 208.4. HRMS: Calcd [M+1] for C22H23O3: 335.1647; Found: 335.1649. FTIR (film): 3398, 3056, 2986, 2932, 2870, 2684, 1717, 1654, 1603, 1445, 1421, 1262, 1219, 1025, 900 cm-1. mp 189-190oC
105
CH3
H3C
O HO
CH3O
syn I-2.19a
1H NMR (400 MHz, CDCl3): δ 0.79 (t, J = 7.5 Hz, 3H), 1.11 (m, 1H), 1.22 (s, 3H), 1.29 (m, 1H), 1.69 (dd, J1 = 13.3 Hz, J2 = 10.3 Hz, 1H), 1.97 (dd, J1 = 13.3 Hz, J2 = 7.2 Hz, 1H), 2.21 (s, 3H), 2.54 (m, 1H), 2.65 (d, J = 10.6 Hz, 1H), 4.18 (bs, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.48 (d, J = 10.6 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 12.0, 19.2, 26.8, 33.2, 39.8, 46.6, 61.7, 66.8, 87.6, 123.9, 124.1, 129.5, 133.3, 135.6, 155.3, 208.5, 212.9. HRMS: Calcd [M+1] for C17H21O3: 273.1491; Found: 273.1501. FTIR (film): 3421, 3060, 2986, 2684, 2524, 1713, 1642, 1603, 1421, 1375, 1355, 1262, 1150, 901 cm-1.
106
CH3
H3C
O HO
CH3O
anti I-2.19a
1H NMR (400 MHz, CDCl3): δ 0.64 (t, J = 7.2 Hz, 3H), 0.90 (m, 1H), 0.99 (s, 3H), 1.10-1.25 (m, 2H), 1.35 (m, 1H), 2.09 (s, 3H), 2.22 (m, 1H), 2.80 (br, 1H), 2.88 (d, J = 12.0 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 11.8, 18.5, 25.8, 32.2, 39.2, 40.9, 59.8, 69.2, 88.3, 123.4, 125.2, 129.9, 135.5, 135.5, 153.0, 208.4, 209.1. HRMS: Calcd [M+1] for C17H21O3: 273.1491; Found: 273.1501. FTIR (film): 3421, 3060, 2986, 2684, 2524, 1713, 1642, 1603, 1421, 1375, 1355, 1262, 1150, 901 cm-1. mp 142-143oC
107
CH3
O
OHO
CH3
I-2.20a
1H NMR (400 MHz, CDCl3): δ 0.67 (t, J = 7.2 Hz, 3H), 0.79 (m, 2H), 1.06 (m, 2H), 1.07 (s, 3H), 1.68 (dt, J1 = 9.6 Hz, J2 = 4.4 Hz, 1H), 1.92 (m, 1H), 2.01 (m, 1H), 2.35 (dt, J1 = 14.3 Hz, J2 = 3.8 Hz, 1H), 2.96 (d, J = 11.3 Hz, 1H), 5.57 (s, 1H), 7.05 (d, J = 7.5 Hz, 1H), 7.23 (m, 6H), 7.42 (t, J = 7.2 Hz, 3H), 7.74 (d, J = 7.2 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 11.1, 24.2, 26.5, 27.5, 28.0, 29.6, 38.2, 57.1, 59.8, 79.3, 123.5, 123.8, 127.9, 128.4, 128.5, 133.2, 133.7, 133.8, 138.3, 156.7, 206.0, 208.3. HRMS: Calcd [M+1] for C23H25O3: 349.1804; Found: 349.1809. FTIR (film): 3425, 3060, 2986, 2936, 2683, 1720, 1650, 1600, 1449, 1421, 1266, 1219, 897 cm-1. mp 90-92oC
108
OO H
NO2
CH3 (R,R,R) I-2.19
1H NMR (400 MHz, CDCl3): δ 0.49 (t, J = 7.5 Hz, 3H), 0.98-1.02 (m, 1H), 1.12-1.16 (m, 1H), 1.58-1.61 (m, 1H), 1.8-2.17 (m, 4H), 2.54-2.56 (m, 1H), 2.63-2.66 (m, 1H), 4.66 (s, , 1H), 7.5 (d, J = 4.8 Hz, 2H), 8.2 (d, J = 4.8 Hz, 2H). HRMS: Calcd [M+1] for C15H18NO4: 276.1227; Found: 273.1236.
109
OO H
NO2
CH3 (S,R,R) I-2.19
1H NMR (400 MHz, CDCl3): δ 0.88 (t, J = 7.5 Hz, 3H), 1.25-1.47 (m, 3H), 1.6-1.8 (m, 2H), 1.82-1.93 (m, 2H), 2.38-2.42 (m, 1H), 2.63-2.66 (m, 1H), 3.9 (s, 1H), 7.47 (d, J = 4.8 Hz, 2H), 8.23 (d, J = 4.8 Hz, 2H). HRMS: Calcd [M+1] for C15H18NO4: 276.1227; Found: 273.1234.
110
O CH3O
Ph
CH3 I-2.24
111
O HO CH3
Ph
I-2.1a
1H NMR (300 MHz, CDCl3): δ 1.39 (s, 3H), 1.94-2.16 (m, 3H), 2.48-2.58 (m, 1H), 3.79-3.90 (m, 2H), 4.24 (s, 1H), 7.11-7.33 (m, 7H), 7.48 (m, 1H), 7.61 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 27.2, 31.7, 41.7, 50.1, 62.7, 82.2, 126.5, 127.1, 128.3, 128.4, 128.6, 133.3, 138.0, 144.0, 205.7. HRMS: Calcd [M+1] for C19H20O2: 281.1542; Found: 281.1538. FTIR (film): 3054, 2986, 2685, 2410, 2305, 1655, 1597, 1421, 1265, 896, 737, 705 cm-1. MP: 94-95 °C. [α]22
D (70% ee) = +40.4º (c = 1, CHCl3).
112
Ph
O HO CH3
I-.2a
1H NMR (300 MHz, CDCl3): δ 1.13 (s, 3H), 1.41-2.08 (m, 6H), 3.29-3.38 (m, 1H), 3.65 (d, J = 11.7 Hz, 1H), 4.31 (d, J = 2.6 Hz, 1H), 6.92 (m, 1H), 7.03 (m, 2H), 7.09, (m, 2H), 7.24 (m, 2H), 7.39 (m, 1H), 7.55 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 21.2, 30.3, 33.1, 38.7, 44.2, 57.6, 71.0, 126.4, 127.8, 127.9, 128.2, 133.0, 138.6, 143.0, 208.3. HRMS: Calcd [M+1] for C20H22O2: 295.1698; Found: 295.1701. FTIR (film): 3054, 2986, 2933, 2853, 2683, 2359, 2339, 1656, 1596, 1265, 1128, 1008, 895, 747, 702 cm-1. MP: 109-110 °C. [α]22
D (90% ee) = -7.7º (c = 1, CHCl3).
113
Nap
O
Ph
HO CH3
I-2.2b
1H NMR (300 MHz, CDCl3): δ 1.16 (s, 3H), 1.49-2.13 (m, 6H), 3.53 (m, 1H), 3.81 (d, J = 11.3 Hz, 1H), 4.31 (d, J = 2.4 Hz, 1H), 7.14 (m, 2H), 7.24-7.35 (m, 4H), 7.51-7.63 (m, 6H). 13C NMR (75 MHz, CDCl3): δ 21.4, 30.5, 33.5, 38.8, 44.4, 57.3, 71.1, 125.1, 125.6, 125.7, 126.5, 127.2, 127.3, 127.7, 127.8, 128.0, 132.0, 132.8, 133.1, 138.3, 140.4, 207.8. HRMS: Calcd [M+1] for C24H24O2: 345.1855; Found: 345.1860. FTIR (film): 3054, 2986, 2933, 2853, 2683, 2359, 2339, 1656, 1596, 1265, 1128, 1008, 895, 747, 702 cm-1. MP: 152-153 °C.
114
Nap
O
H3C
HO CH3
I-2.3a
1H NMR (300 MHz, CDCl3): δ 1.20 (s, 3H), 1.38 (m. 1H), 1.57 (s, 3H), 1.61-2.01 (m, 2H, 2H, 1H), 2.88 (d, J = 12.1 Hz, 1H), 3.27 (m, 1H), 4.1 (d, J = 2.4 Hz, 1H), 7.35 (m, 1H), 7.44 (m, 2H), 7.60 (s, 1H), 7.77 (m 3H). 13C NMR (75 MHz, CDCl3): δ 21.0, 29.7, 33.2, 34.5, 38.4, 43.9, 63.3, 70.5, 125.5, 125.6, 126.1, 126.3, 127.6, 127.7, 128.3, 132.4, 133.5, 140.8, 217.3. HRMS: Calcd [M+1] for C19H22O2: 283.1698; Found: 283.1690. FTIR (film): 3054, 2986, 2935, 2685, 2410, 2305, 1694, 1602, 1421, 1265, 1168, 896, 730, 704 cm-1. MP: 91-92 °C.
115
H3C
O HO CH3
Ph I-2.4a
1H NMR (300 MHz, CDCl3): δ 1.43 (s, 3H), 1.76-1.94 (m, 6H), 2.35-2.42 (m, 1H), 2.91 (d, J = 11.3 Hz, 1H), 3.58 (m, 1H), 3.91 (s, 1H), 7.20-7.35 (m, 5H). 13C NMR (75 MHz, CDCl3): δ 27.2, 32.3, 32.9, 40.8, 49.0, 67.9, 81.3, 126.7, 127.1, 128.8, 144.1, 213.9. HRMS: Calcd [M+1] for C14H18O2: 218.1307; Found: 218.1310. FTIR (film): 3471, 3054, 2986, 2685, 2305, 1691, 1421, 1375, 1265, 896, 739 cm-1
[α]22D (94% ee) = +11.4º (c = 1, CHCl3).
116
Ph
O
H3C
HO CH3
I-2.3a
1H NMR (300 MHz, CDCl3): δ 1.16 (s, 3H), 1.26-1.94 (m, 2H, 2H, 2H, 3H), 2.74 (d, J = 11.7 Hz, 1H), 3.06 (m, 1H), 4.03 (d, J = 2.4 Hz, 1H), 7.16 (m, 3H), 7.24 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 21.0, 29.7, 33.0, 34.4, 38.4, 43.8, 63.5, 70.5, 126.8, 127.6, 128.7, 143.5, 217.4. HRMS: Calcd [M+1] for C15H20O2: 233.1542; Found: 233.1546. FTIR (film): 3054, 2986, 2935, 2685, 2410, 2305, 1694, 1602, 1421, 1265, 1168, 896, 730, 704 cm-1. MP: 85-86 °C. [α]22
D (95% ee) = -15.5º (c = 1, CHCl3).
117
PhN
O HO CH3
Tos I-2.6a
1H NMR (400 MHz, CDCl3): δ 1.15 (s, 3H), 2.44 (m, 3H, 1H), 2.60 (m, 1H), 3.63 (m, 2H), 3.85 (m, 1H), 3.96 (m, 1H), 7.0-7.07 (m, 5H), 7.25 (m, 2H), 7.31 (m, 2H), 7.41 (m, 1H), 7.56 (m, 2H), 7.67 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 21.7, 27.0, 42.2, 51.0, 54.8, 55.9, 69.2, 127.3, 127.6, 127.7, 127.8, 128.3, 128.4, 129.5, 133.3, 133.8, 138.0, 138.2, 143.4, 204.1. HRMS: Calcd [M+1] for C26H27NO4S: 450.1739; Found: 450.1737. FTIR (film): 3054, 2986, 2305, 1660, 1597, 1495, 1421, 1348, 1265, 1166, 962, 896, 737, 704 cm-1. MP: 194-195 °C.
118
Chapter II. Rhodium-Catalyzed Additions to Conjugated Dienes: Reductive Arylation of 1,3-Cyclohexadiene Part 1. Introduction: Metal-Catalyzed Additions to Conjugated Dienes
Conjugated-dienes are reactive substrates for metal-catalyzed/mediated formation
of carbon-metal, carbon-hydrogen or carbon-carbon bonds. Known reactions occur via
several distinct mechanisms, but most involve the intermediacy of a (π-allyl)metal
complex. For this reason, regiochemical issues figure prominently.1 The nature of the
coupling partners, furthermore, is determined by the reactivity of the π-allyl intermediate.
An analysis on the basis of reactivity involves partitioning reaction types into three broad
categories – those in which the π-allyl is nucleophilic, electrophilic, or neutral. The latter
two groups encompass a huge number of reactions – too many to enumerate here. The
subject has been extensively reviewed elsewhere,2 so only a cursory outline follows.
A. Reactions Involving Electrophilic π-Allyl Complexes
The most common representatives of the electrophilic family involve (π-
allyl)palladium intermediates. Generally speaking, this family of reactions can be
partitioned into i) those in which the active catalyst has an oxidation state of (II), and ii)
those for which the active catalyst is zerovalent.
i. Electrophilic π-Allyl Complexes Derived from Palladium(II)
In the first class, a palladium(II) complex first coordinates, then oxidizes the
diene. Reoxidation of the catalyst to its +2 state by a stoichiometric additive completes
the cycle. Examples of this category include diacyloxylations and dialkoxylations
119
(Scheme II-1.1).2b In the case of mono-ene substrates, this manifold constitutes the basis
of the Wacker process.3
Scheme II-1.1: Electrophilic π-Allyl Complexes Derived from Palladium(II)
R = Alkyl, Carbonyl
ROPdII X
RO ORPdX2, ROH ROH RO
RO
ii. Electrophilic π-Allyl Complexes Derived from Palladium(0)
The other type of palladium-catalyzed coupling involves initial oxidative addition
of Pd(0) into an RX bond. Insertion of the diene leads to formation of a (π-
allyl)palladium intermediate, which reacts with a nucleophile to form the product and
regenerate the zerovalent palladium catalyst. Reactions of this category involve three-
component couplings of aryl and vinyl halides, and nitrogen, oxygen, or stabilized carbon
nucleophiles (Scheme II-1.2).2b
SchemeII-1.2: Electrophilic π-Allyl Complexes Derived from Palladium(0)
R = Aryl, Vinyl; Nuc = NR2, OR, CZ2
RPdII X
NucR Nuc
R-PdII-XR
Nuc
B. Reactions Involving Neutral π-Allyl Complexes
i. Mechanistic Features
A second category of reactions involves (π-allyl)metal species that behave as
neither nucleophiles or electrophiles. In this regard, they can be considered neutral,
although certainly not unreactive. Reactions involve formation of a catalytically active
hydrido-metal species (Scheme II-1.3) by oxidative addition of the metal pre-catalyst to
an appropriate metal-hydrogen or carbon-hydrogen σ-bond. Hydrometallation yields a (π-
120
allyl)metal complex; finally, reductive elimination occurs to afford the mono-unsaturated
coupling product. Most examples of this category involve palladium-catalysis:
hydrosilation, hydrostannation, hydroboration, and additions across active carbon-
hydrogen bonds.2b
Scheme II-1.3: Addition to Conjugated Dienes via Neutral (π-Allyl)Palladium Complexes PdII HNuc
H NucH
PdII-NucH
Nuc
Recently, complementary rhodium-catalyzed procedures, such as Mori’s
intramolecular hydroacylation of 4,6-dienals, have been reported.4 In this work, seven-
membered unsaturated alkenones are generated along with small amounts of isomeric
cyclopentanones via a common (π-allyl)rhodium intermediate (Scheme II-1.4).
Scheme II-1.4: Intramolecular Hydroacylation of Conjugated Dienes
OR O
R[Rh(dppe)]ClO4
OR
R
O
Rh
R
O
H
R = PhCH2CH2-
10 mol %65 °C, 18h
62% 13% 6%
C. Reactions Involving Nucleophilic π-Allyl Complexes
i. Tandem Hydrometallation-Aldehyde Additions
A final category of diene functionalizations proceeds via nucleophilic (π-
allyl)metal species. This subset is currently under rapid development and, as it constitutes
the context of current Krische group research, will be examined in greater detail. Mori’s
nickel-catalyzed reductive cyclizations and allylations exemplify this reaction manifold,5
in which conjugated dienes undergo regioselective6 hydrometallation followed by
electrophilic trapping with appendant (Scheme II-1.5, Eqn. 1) or exogenous (Scheme II-
121
1.5, Eqn. 2) aldehydes or ketones. In these reactions, the catalytically active species is
nickel(II).
Scheme II-1.5: Nickel-Catalyzed Reductive Couplings of Conjugated-Dienes and Carbonyls
O OM
NiII HM
ONi
Mcat.
R
Ni(COD)2 (20 mol%)PPh3 (40 mol%)
Et3SiH (500 mol%)R
OSiEt3
Ph
Eqn. 1
Eqn. 2RNi
Et3Si
M-H
PhCHO (100 mol%)R = MOM-CH2-Ph- 84%
ii. Carbocyclizations Involving Oxametallocycle Intermediates
Related studies from the same group focus on intramolecular, nickel(0)-catalyzed
oxidative cyclizations, wherein turnover derives from a β-elimination/O-H reductive
elimination sequence (Scheme II-1.6).7
Scheme II-1.6: Nickel-Catalyzed Oxidative Cyclizations of Conjugated Diene-Tethered Aldehydes
Ocat. Ni(COD)2
PPh3
ONi OH OH
O O O O O O O O
91% (1:3.8)
2.5h, 50 °C
Ketone/aldehyde allylation and homoallylation chemistry developed by Tamaru8
(Scheme II-1.7 Eqn. 1) and extended by Loh9 to incorporate cyclohexadiene (Scheme II-
1.7 Eqn. 2) involves formation of a hydrido(π-allyl)nickel(II) species that reductively
eliminates to afford either of two unsaturated alcohol isomers.
122
Scheme II-1.7: Nickel-Catalyzed Bimolecular Oxidative Cyclizations of 1,3-Dienes and Aldehydes
Ni(acac)
OH
Ph
PhCHO
O
Ph
NiOH
Ph
+OMEtn
Ph
NiH
+
Ni(acac)2 (10 mol%)
ZnEt2
EtZnO R
NiII
HO R
+ H
Eqn. 1
Eqn. 2
(2.5 mol%)RT
77%
13%
Et3B
(240 mol%)
PhCHO
(400 mol%)72% syn28% anti62%
iii. Carboxylative Processes
Bimolecular oxidative coupling and transmetallative carbon-carbon bond-forming
manifolds are paired in an impressive tandem manipulation reported by Mori.10 In her
procedure, stoichiometric zerovalent nickel promotes an oxidative cyclization involving a
diene substrate and carbon dioxide. The resulting (π-allyl)nickel(II)carboxylate
undergoes transmetallation with an diarylzinc(II) species followed in one instance by
reductive elimination to afford, regio- and stereoselectively, the syn 1,4-addition product.
Alternatively, if the diarylzinc(II) reagent is replaced with dimethylzinc, products of anti
1,4-carboxylation result (Scheme II-1.8).
Scheme II-1.8: Nickel-Catalyzed Carboxylative Couplings
Me2Zn (5 eq)50%
PhZnCl (5 eq)44-57%O
ONi
DBU (2 eq)
CO2 (1 atm)Ni(COD)2 ( 1 eq)
CO2HPh
CO2HHO2C
A related catalytic carboxylative cyclization of tethered dienes has been
developed (Scheme II-1.9) in which either dimethylzinc or diphenylzinc is reacted with
123
the intermediate (π-allyl)nickel(II) complex, leading to a new carbon-carbon bond and
returning the metal to its active oxidation state.
Scheme II-1.9: Nickel-Catalyzed Carboxylative Ring-Forming Coupling of Conjugated Dienes
TsN TsN
H
H
CO2H
RDBU (2 eq)
CO2 (1 atm)Ni(COD)2 ( 0.1 eq) Me2Zn or
TsN
H
HNi
O
OPh2Zn
R = Me: R = Ph:
RT (5 eq)
94%82%
iv. Coupling of Dienes and Glyoxals Under Catalytic Hydrogenation Conditions
Whereas the previous methodologies derive hydride from organometallic
precursors via β-hydride elimination, Krische’s chemistry successfully employs diatomic
hydrogen at atmospheric pressure to the same end.11 In the presence of a cationic
rhodium(I) catalyst, 1,3-cyclohexadiene and aromatic glyoxals undergo reductive
coupling (Scheme II-1.10). Experiments conducted under D2 reveal incorporation of two
deuterium atoms. This observation is explained by invoking the (π-allyl)rhodium(I)
intermediate C. Detailed mechanistic studies are underway; It is likely that the reaction
involves a termolecular oxidative cyclization, leading to the rhodium(III) alkoxide A.
Carbon-deuterium reductive elimination occurs regioselectively to afford rhodium(I)
alkoxide B. Allylic C-H insertion generates a bicyclic hydrido(π-
allyl)rhodium(III)alkoxide, which undergoes oxygen-hydrogen reductive elimination to
C. Finally, oxidative addition to another equivalent of D2 leads to the formation of
regioisomeric reductive elimination products D and E and regenerates the catalytic
hydridorhodium(I) species.
124
Scheme II-1.10: Coupling of Cyclohexadiene and Glyoxals Under Hydrogenative Conditions
RhI(COD)OTf
O
O
Ar
HO COAr
RhI
D
H
D2
HO COAr
DH
HD
HO COAr
D
HDH
C
O COAr
D
H
B
RhI
D2
O COAr
H
RhIIID
C
A
D E
In addition to 1,3-cyclohexadiene, a range of cyclic and acyclic dienes were assayed -
none underwent comparatively facile coupling. It can be deduced from this observation
that strong pre-coordination between the metal and the diene is an essential factor.
Indeed, in related nickel-catalyzed cyclizations of conjugated diene-tethered aldehydes,
cyclohexadiene has been found to ligate the metal complex strongly, thereby altering the
regiochemical outcome.12 The strength of coordination is clearly a factor of substitution
patterns and relative diene stereochemistry.
Part 2. Rhodium-Catalyzed Reductive Arylation of 1,3-Cyclohexadiene
A. Background and Objective
Formation of phosphine-stabilized rhodium(I)-aryl complexes is easily
accomplished via transmetallation of an arylboronic acid with an appropriate rhodium(I)
salt.13 Insertion into conjugated enones, resulting in β-aryl rhodium enolates (Scheme II-
2.1), occurs in very high yield and enantioselectivity, leading to products of formal
conjugate addition.14
125
Scheme II-2.1: Rhodium-Catalyzed 1,4-Addition of Phenylboronic Acid
O
PhB(OH)2
(500 mol%)+
Rh(acac)(C2H4)2 (3 mol%)
(S)-BINAP (3 mol%)Dioxane/H2O, 100 °C
O
Ph
> 99% (97% ee)
O
Ph
RhIL
Oxy(π-allyl)rhodium intermediates constitute rhodium enolates and exhibit characteristic
reactivity, including electrophilic trapping (Scheme II-2.2).15,16
Scheme II-2.2: Rhodium-Catalyzed 1,4-Addition-Aldol Cyclization Sequences O
PhO CH3
n
O
PhH3C
nAr
OHRhI, ArB(OH)2
R1
O
n
O
H3C
HO
H3C
Ar
R1
O
n
n = 1,2O
R3
R2
R3
O
R2
Eqn. 1
Eqn. 2
n = 1,2
L, Dioxane/H2O
RhI, ArB(OH)2
L, Dioxane/H2O
Recognizing the efficacy of rhodium(I)-catalyzed 1,4-additions of arylboronic
acids to conjugated enone substrates,11-13 as well as the rhodium(I)-catalyzed reductive
diene/glyoxal couplings described above,11 we sought to develop a complementary
process involving the coupling of conjugated diene substrates and organoboronic acids
under rhodium catalysis. We speculated that treatment of suitable dienes with the
rhodium(I)-aryl reagent would result in the formation of an analogous diene
carbometallation intermediate consisting of a new sp3-carbon-aryl bond and (π-
allyl)rhodium bond. Hydrolysis of this intermediate would afford the coupling product
and promote turnover.
126
B. Results and Discussion
i. Initial Results and Mechanistic Hypothesis
Our first experimental attempt involved the use of standard conjugate addition
conditions (Scheme II-2.3), and we were pleased to obtain a 25% yield of 4-
phenylcyclohexene. Aside from this product, a trace amount of biphenyl was observed by
TLC. Unconsumed cyclohexadiene was detected by GC-MS.
Scheme II-2.3: Rhodium-Catalyzed Coupling of 1,3-Cyclohexadiene and Phenylboronic Acid
PhB(OH)2(200 mol%)+
[Rh(COD)Cl]2 (2.5 mol%)(rac)-BINAP (7.5 mol%)
Dioxane, H2O (500 mol%)95 °C Ph
25%
1,3-Cyclohexadiene 4-Phenylcyclohexene
This outcome was consistent with our initial expectations and may be explained by the
following mechanistic model (Scheme II-2.4): Regioselective carborhodation occurs to
generate the resonance-stabilized complex A. Haptomeric isomerization leads to (π-
allyl)rhodium intermediate B, from which point hydrolytic cleavage leads to a single
regioisomeric olefin product C.
Scheme II-2.4: Proposed Mechanism
Ph
RhI
Ph
RhI
HO-RhIL2
PhB(OH)2
Ph
RhI
+
Ph
H2O
A
B
C
127
ii. Optimization
a. Counterion Effects
It is known that the rhodium(I) counterion has a strong effect on the facility of
arylboronic acid transmetallation, with hydroxide allowing the transformation to take
place at a lower temperature than either chloride or acetylacetonate.11 In the context of
tandem conjugate addition-dione trapping, furthermore, we noted that the use of
[Rh(COD)OMe]2 is preferential to [Rh(COD)Cl]2, the former promoting higher chemical
yields.13 Based on these observations, we began the process of optimization by
investigating several different rhodium(I) precatalysts. In this series of experiments
(Table II-2.1, Entries 1-20), minor (and perhaps statistically insignificant) improvements
in yield (2-3%) were attributable to counterion effects, with oxygen-containing ions
outperforming chloride by a small margin. Cationic rhodium complexes (Entries 22,24)
led to slightly anomalous results, in that copious amounts of biphenyl was produced. A
paramount question relates to the origin of this product. Possible sources include i) the
oxidative coupling of phenylboronic acid, and 2) dehydrogenation of the side-product
phenyl-2,4-cyclohexadiene (vide infra). The rhodium-catalyzed oxidative coupling of
boronic acids is not known. Even so, we considered it to be unlikely in this case since this
material was never observed in related rhodium-catalyzed arylative aldol cyclizations
(Scheme II-2.2). In order to elucidate the mechanism of biphenyl formation, an
experiment was conducted in which 4-methoxyphenylboronic acid was substituted for
phenylboronic acid. In this reaction, 4-methoxybiphenyl was formed in 25% yield, to the
exclusion of either biphenyl or the 4-arylcyclohexene (Scheme II-2.5). This result rules
128
out the coupling of boronic acids, and implicates a mechanism involving diene
carbometallation. This mechanism is discussed in greater detail (vide infra).
Scheme II-1.5: Coupling of 4-Methoxyphenylboronic Acid and 1,3-Cyclohexadiene with a Cationic
Rhodium Catalyst
1,3-Cyclohexadiene 4-Methoxybiphenyl(200 mol%)
+Rh(COD)OTf (5 mol%)BINAP (7.5 mol%)
Dioxane, H2O (500 mol%)95 °C
Ph25%
MeO
B(OH)2 MeO
b. Additive/Solvent/Reaction Time
The importance of ligating-cyclooctadiene in the precatalyst is deduced from the
lack of reactivity found with complexes featuring ethylene and CO2 ligands (Table II-2.1,
Entries 1,21,25). Other variables were probed: The addition of exogenous hydroxide did
not result in substantial change (Entry 1 vs. Entry 7), and the addition of triethylamine
was found to preclude reactivity altogether (Entry 17). Likewise, changing the solvent to
toluene or dichloroethane was not tolerated (Entries 5,6). Water content proved to be a
variable of some consequence; across a range of precatalysts a substantial decrease in
yield resulted from an increase in loading from 500 to 2800 mole percent (Entries
4,10,15), while a decrease in loading resulted in an insignificant change (Entry 3).
Several alcohols, phenol, methanol, and 2,2,2-trifluoroethanol were screened as
alternatives to water (Entries 26,49-50). Of these, only methanol resulted in a measurable
yield (14%). All other factors being equal, variations in reaction time were
inconsequential (Entry 9 vs. Entry 11).
129
c. Ligand Effects
A series of experiments explored the use of twelve alternative ligands, including
mono- and bidentate phosphines, and an N-heterocyclic carbene. No product was
produced in the presence of monodentate phosphines PPh3 and P(nBu)3 (Table II-2.1,
Entries 27-28). Of the bidentate phosphines, only Biphep (2,2’-
Bis(diphenylphosphino)biphenyl) promoted competitively high yields (32%, Entry 41).
An N,N-dimesitylimidazole carbene-ligated catalyst (generated in situ from N,N-
dimesitylimidazolium chloride) allowed for the formation of trace amounts of product
(Entries 37-39)
d. Summary
Ultimately, the best conditions identified are very similar to those which led to the
first “hit” (Scheme II-2.6). The optimization consisted of substituting the hydroxy-
bridged rhodium(I) dimer for the corresponding chloro-bridged dimer, using Biphep
instead of BINAP and decreasing the reaction temperature to 65 °C. The optimal reaction
system was found to perform consistently across a range of solvent concentrations, water,
and phenylboronic acid loadings (Entries 41,44,45).
Scheme II-2.6: Rhodium-Catalyzed Coupling of 1,3-Cyclohexadiene and Phenylboronic Acid – Optimized Reaction
1,3-Cyclohexadiene 4-Phenylcyclohexene
PhB(OH)2(200 mol%)+
[Rh(COD)OH]2 (2.5 mol%)Biphep (7.5 mol%)
Dioxane/H2O (500 mol%)65 °C Ph
32%
130
Table II-2.1: Rhodium-Catalyzed Arylation of 1,3-Cyclohexadiene: Optimization of Experimental Parametersa,b
Entry Catalystc PhB(OH)2 H2O Additives Solventd Temp Time Yield (mol %) (mol %) (mol%) (M) ( °C) (h) (%)
1 A 200 500 - 0.2 M D 95 2 25 2 A 200 0 - 0.2 M D 95 2 0 3 A 200 250 - 0.2 M D 95 2 24 4 A 200 2800 - 0.4 M D 95 2 12 5 A 200 500 - 0.2 M Tol 95 2 0 6 A 200 500 - 0.2 M DCE 95 2 0 7 A 200 500 10 KOH 0.2 M D 95 2 25 8 A 200 500 10 KOH 0.2 MTol 95 2 0 9 B 200 500 - 0.2 M D 95 2 27
10 B 200 2800 - 0.2 M D 95 2 16 11 B 200 500 - 0.2 M D 95 14 28 12 B 200 500 - 0.2 M D 65 13 22 13 B 200 500 - 0.2 M D 95 2 22 14 B 3 x 100 500 - 0.2 M D 95 16 15 15 C 200 2800 - 0.2 M D 95 2 11 16 C 200 500 - 0.2 M D 65 2 27 17 C 200 500 1000 TEA 0.2 M D 65 2 0 18 C 200 500 10 KHCO3 0.2 M D 95 2 12 19 C 200 500 2000 MEK 0.2 M D 95 2 11 20 C 200 500 100 KOH 0.2 M D 95 2 11 21 D 200 500 - 0.2 M D 95 2 0 22 E 200 500 - 0.2 M D 95 2 0 23 E 200 Ph 0 500 MeOH 0.2 M DCE 95 2 0 24 F 200 Ph 500 - 0.2 M D 95 2 0 25 G 200 Ph 500 - 0.2 M D 65 2 0 26 C 200 Ph 0 500 TFE 0.2 M D 95 4 trace
(a) For detailed procedure see experimental section; (b) Unless otherwise indicated all reactions employ racemic BINAP (7.5 mol%); (c) Catalysts (5 mol% w.r.t. Rh): A = [Rh(COD)Cl]2; B = [Rh(COD)OMe]2; C = [Rh(COD)OH]2; D = [Rh(C2H4)Cl]2; E = Rh(COD)2OTf; F = Rh(COD)(IMes)OTf; G = [Rh(CO)2Cl]2; (d) Solvents: D = 1,4-dioxane; Tol = toluene; DCE = 1,2-dichloroethane
131
Table II-2.1 Continued
Entry Catalyst Ligandf PhB(OH)2 Additives Temp Time Yield (mol %) (mol %) (mol %) ( °C) (h) (%)
27 C 15 PPh3 200 - 65 2 0 28 C 15 PBu3 200 - 65 2 0 29 C 7.5 dppf 200 - 65 2 0 30 C 7.5 dppPh 200 - 65 16 14 31 B 7.5 dppb 200 - 95 14 trace 32 C 7.5 dppe 200 - 65 2 trace 33 C 7.5 dppp 200 - 65 2 13 34 C 7.5 (R)-Phanephos 200 - 65 2 trace 35 C 7.5 (R)-Quinap 200 - 65 2 trace 36 C 7.5 (S,S)-NT 200 - 65 2 trace 37 C 5 IMes 150 5 Cs2C03 65 2 trace 38g C 5 IMes 150 5 Cs2C03 65 2 0 39 A 5 IMes 200 5 KOtBu 95 4 trace 40 C 7.5 Biphep 200 - 65 16 23 41 C 7.5 Biphep 200 - 65 2 32 42 C 7.5 Biphep 200 - 95 2 8 43h C 7.5 Biphep 200 - 65 2 trace 44e C 7.5 Biphep 100 - 65 2 31 45e C 7.5 Biphep 100 - 65 2 29 46 C 7.5 Biphep 200 100 KHCO3 95 2 0 47 A 7.5 Biphep 200 4 Ag2CO3 95 2 0 48 A 7.5 Biphep 200 7.5 AgBF4 95 2 0 49g C 7.5 Biphep 200 500 PhOH 65 2 0 50g C 7.5 Biphep 200 1000 MeOH 65 2 14 51g C 7.5 Biphep 200 o-AcPh - 65 12 0
(e) 1M dioxane was used instead of 0.2M dioxane; (f) Ligands: dppf = 1,1’-bis(diphenylphosphino)ferrocene; dppPh = 1,2-bis(diphenylphosphino)benzene; dppb = 1,4-bis(diphenylphosphino)butane; dppe = 1,2-bis(diphenylphosphino)ethane; dppp = 1,3-bis(diphenylphosphino)propane; Imes = N,N-dimesitylimidazolium chloride; (S,S)-NT = (S,S)-Napthyl Trost Ligand; BIPHEP = 2,2’-bis(diphenylphosphino)biphenyl; (g) No water was used in these reactions; (h) 2800 mol% water was used in this reaction
132
iii. Alternative Substrates
a. α-Terpinene and α-Phellandrene
It was clear, qualitatively (by smell and by GC-MS), that much of the diene was
not being consumed during the reaction. By contrast, complete consumption of
phenylboronic acid was always observed by TLC. Due to difficulties attendant to the
quantification of residual diene, two higher-boiling alternatives were assayed: α-terpinene
and α-phellandrene (Scheme II-2.7). Unfortunately, under the optimized conditions,
neither substrate underwent arylation detectable by NMR or TLC.
Scheme II-2.7: Attempted Arylation of α-Terpinene and α-Phellandrene
alpha-Terpinene
Standard Conditions Standard ConditionsNR
alpha-Phellandrene
b. 2,3-Dimethyl-1,3-Butadiene
It is reasonable to expect that strong pre-coordination in virtue of the S-cis diene
configuration of 1,3-cyclohexadiene plays a role in the observed reactivity. Supporting
this notion is the observation that 2,3-dimethyl-1,3-butadiene (Scheme II-2.8) fails to
react under standard conditions.
Scheme II-2.8: Attempted Arylation of 2,3-Dimethyl-1,3-Butadiene StandardConditions
NR
2,3-Dimethyl-1,3-Butadiene
133
c. Acyclic Dienes Incorporating Electrophilic (Ketone) Traps
End-functionalized acyclic diene II-1.1 could be expected to easily adopt the
requisite conformation (Scheme II-2.9). Substrate II-1.1, furthermore, was designed to
incorporate a third point of chelation. Despite these features, the substrate was unreactive
under standard conditions.
Scheme II-2.9: Attempted Cyclization of Diene-Ketone II-1.1
PhII-1.1
StandardConditions
O
H3C Ph
Ph
RhI O CH3
Ph
Ph
H3CHO
d. 2-Phenyl-1,3-cyclohexadiene
2-Phenyl-1,3-cyclohexadiene (Scheme II-2.10), underwent dehydrogenation to
yield biphenyl, and was the only other diene found to react under standard conditions.
Scheme II-2.10: Dehydrogenation of 2-Phenyl-1,3-Cyclohexadiene
Ph
StandardConditions
Ph
2-phenyl-1,3-cyclohexadiene biphenyl
e. ortho-Acetyl-phenylboronic acid
In an effort to substantiate the proposed mechanism, ortho-acetyl phenylboronic
was employed using standard conditions (Table II-2.1, Entry 51). The expected product
(Scheme II-2.11) was not obtained. Rather, the boronic acid underwent decomposition to
acetophenone.
134
Scheme II-2.11: Attempted Coupling of 1,3-Cyclohexadiene and o-Acetyl Phenylboronic Acid
(OH)2BO
CH3
Standard Conditions
(OH)2BO
CH3
Standard Conditions
H3C
HOO
CH3
+
In a related experiment, the effect of added methyl ethyl ketone was investigated
(Table II-2.1, Entry 19). In this reaction, a low (11%) yield of 4-phenylcyclohexene was
produced, although no product resulting from carbonyl addition was observed (Scheme
II-2.12).
Scheme II-2.12: Attempted Trapping of (π-Allyl)Rhodium Intermediate with Methyl Ethyl Ketone
PhB(OH)2(200 mol%)+
[Rh(COD)Cl]2 (2.5 mol%)(rac)-Binap (7.5 mol%)
Dioxane/H2O (500 mol%)95 °C Ph
11%
O+
Ph
OH
0%
(2000 mol%)
iv. Revised Mechanistic Hypothesis
In terms of substrate scope, these restrictions severely limited applicability and
ultimately provided little incentive to continue the project. Within the narrow framework
of the most successful reaction, however, we were confounded by the apparent “ceiling”
of 32% yield. A hypothesis follows, which accounts for some product formation as well
as the persistence of unconsumed diene across a range of conditions (Figure II-2.1).
135
Figure II-2.1: Proposed Mechanism Involving Non-productive β-Hydride Elimination/Hydrometallation
Ph
RhI
Ph
RhI
HO-RhIL2
PhB(OH)2
Ph
RhI
+
Ph
H2O
Ph
H-RhI
H
RhI
D
I II
C
B
The desired, product-forming manifold II involves hydrolysis of (π-allyl)rhodium
complex B, leading to 4-phenylcyclohexene C. Alternatively, B may undergo
competitive β-hydride elimination, generating phenyl-2,4-cyclohexadiene D and a
hydridorhodium(I) complex. This metal hydride may then enable a non-productive
hydrometallation/ β-hydride elimination cycle (manifold I) for the remaining lifetime of
the catalyst. Notably, D can be produced in no more than five percent yield, since only
five mole percent rhodium catalyst is used. Although this material was not identified in
any reaction mixture, it is possible that any D formed would undergo dehydrogenation to
yield biphenyl, a pervasive byproduct in trace quantities.
136
Part 3. Conclusion
The rhodium-catalyzed reductive arylation of 1,3-cyclohexadiene is
unprecedented. Like its counterpart, the rhodium-catalyzed 1,4- addition of conjugated
enones, this chemistry may lend itself to use with a variety of organometallic partners.
However, compared to related metal-catalyzed transformations, this reaction is probably
not mechanistically unique. Despite our efforts to optimize this procedure, it is not
sufficiently high-yielding in its current form. Ultimately, the restriction to substrates
embodying relatively unsubstituted cyclohexadienes does not allow much versatility and
therefore limits any synthetic potential.
137
138
Part 4. References
1 Backvall, J.-E. in Advances in Metal-Organic Chemistry, Vol. 1, (Ed. Liebeskind,
L.S..) JAI Press: Greenwich, CT, 1989, pp. 135-175. 2 (a) Heumann, A.; Reglier, M. Tetrahedron, 1995, 51, 975; (b) Backvall, J.-E.,
‘Palladium-catalyzed 1,4-Additions to Conjugated Dienes”, Metal-Catalyzed Cross-
Coupling Reactions (Ed. Diederich, F.) Wiley: New York, 1998, pp. 339-385, and
references therein. 3 For the mechanism of the Wacker Process: Backvall, J. -E.; Akermark, B.; Ljunggren,
S. O. J. Am. Chem. Soc., 1979, 101, 2411. 4 Sato, Y.; Oonishi, Y.; Mori, M. Angew. Chem. Int. Ed. 2002, 41, 1218. 5 (a) Sato, Y.; Takimoto, M.; Hayashi, K.; Katsuhara, T.; Takagi, K.; Mori, M. J. Am.
Chem. Soc., 1994, 116, 9771; (b) Takimoto, M.; Hiraga, Y.; Sato, Y.; Mori, M.
Tetrahedron Lett., 1998, 39, 4543. (c) Asymmetric: Sato, Y.; Saito, N.; Mori, M. J.
Am. Chem. Soc., 2000, 122, 2371. 6 Hydrometallation of the opposite regiochemistry is observed in the presence of ligating
dienes such as 1,3-cyclohexadiene. See: Sato, Y.; Takimoto, M.; Mori, M.
Tetrahedron Lett., 1996, 37, 887. 7 (a) Sato, Y.; Takanashi, T.; Hoshiba, M.; Mori, M. Tetrahedron Lett., 1998, 39, 5579.
(b) Sato, Y.; Takanashi, T.; Mori, M. Organometallics, 1999, 18, 4891; (c) Sato, Y.;
Takimotoi, T.; Mori, M. J. Am. Chem. Soc., 2000, 122, 1624. 8 (a) Kimura, M.; Ezoe, A.;Tamaru, Y. J. Am. Chem. Soc., 1998, 120, 4033; (b) Kimura,
M.; Fujimatsu, H.; Ezoe, A.; Shibata, L.; Shimizu, M.; Matsumoto, S.; Tamaru, Y.
Angew. Chem. Int. Ed., 1999, 38, 397; (c) Kimura, M.; Shibata, K.; Koudahashi, Y.;
Tamaru, Y. Tetrahedron Lett., 2000, 41, 6789; (d) Shibata, K.; Kimura, M.; Shimizu,
M.; Tamaru, Y. Org. Lett., 2001, 3, 2181; (e) Kimura, M.; Ezoe, A.; Tanaka, S.;
Tamaru, Y. Angew. Chem. Int. Ed., 2001, 40, 3600. 9 Loh, T. -P.; Song, H. -Y.; Zhou, Y. Org. Lett., 2002, 4, 2715. 10 Takimoto, M.; Mori, M. J. Am. Chem. Soc., 2001, 123, 2895. 11 Jang, H. -Y.; Huddleston, R. R.; Krische, M.J Angew. Chem. Int. Ed., 2003, 42, 4074.
139
12 Sato, Y.; Takimoto, M.; Mori, M. Tetrahedron Lett., 1996, 37, 887. 13 Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16, 4229. 14 Hayashi, T.; Takahashi, M.; Takaya, Y., Ogasawara, M. J. Am. Chem. Soc., 2001, 124,
5052, and references therein. See also Ref. 13. 15 Cauble, D. F.; Gipson, J. D.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 1110. 16 Bocknack, B. M.; Wang, L. -C.; Krische, M. J. Proc. Nat. Acad. Sci., 2004, 101, 5421.
Part 5. Experimental Section
A. Synthetic Procedures and Product Characterization
i. General
All reactions were run under an atmosphere of argon, unless otherwise indicated.
Anhydrous solvents were transferred by an oven-dried syringe. Flasks were oven-dried
and cooled in a dessicator.
Analytical thin-layer chromatography (TLC) was carried out using 0.2-mm
commercial silica gel plates (DC-Fertigplatten Krieselgel 60 F254). Preparative column
chromatography employing silica gel was performed according to the method of Still.*
Melting points were determined on a Thomas-Hoover melting point apparatus in sealed
capillaries and are uncorrected. Infrared spectra were recorded on a Perkin-Elmer 1420
spectrometer. High-resolution mass spectra (HRMS) were obtained on a Karatos MS9
and are reported as m/e (relative intensity). Accurate masses are reported for the
molecular ion (M+1).
Unless otherwise noted, proton nuclear magnetic resonance (1H NMR) spectra
were recorded with a Varian Gemini (300 MHz) spectrometer or a Mercury (400 MHz)
spectrometer.
ii. Representative procedure for the Rh-catalyzed reductive arylation of 1,3- cyclohexadiene
A 25 ml tube was flame dried and allowed to cool in a drybox. Thereupon, the
tube was charged with [Rh(OH)COD]2 (14.3 mg, 0.313 mmol, 2.5 mol%), BIPHEP (49
mg, 0.094 mmol, 7.5 mol%), 1,4-dioxane (12.5 ml, 0.1M) and H2O (112.5 µl, 6 mmol,
140
141
500 mol%). The tube was sealed and the contents were allowed to stir at room
temperature until homogeneous – typically ca. 30 minutes. PhB(OH)2 (305 mg, 2.5
mmol, 200 mol%), and 1,3-cyclohexadiene (119 µl, 1.25 mmol, 100 mol%) were added
and the tube was quickly purged with Ar, resealed, and heated in an oil bath for 2h. After
the allotted time, the tube was allowed to cool to room temperature. The contents were
either analyzed directly via GC-MS or evaporated onto silica gel. Purification by silica
gel chromotagraphy, eluting with a mixture of ethyl acetate and hexanes, yielded the
desired product.
iii. 4-Phenylcyclohexene
4-Phenylcyclohexene was identified by comparison of 1HNMR spectroscopic
data to reported values: Kamigata, N.; Fukushima, T.; Satoh, A.; Kameyama, M. J.
Chem. Soc. Perkin Trans. 1 1990, 549.
iv. 4-Methoxybiphenyl
4-Methoxybiphenyl was identified by comparison of 1HNMR spectroscopic data
to reported values: Spivey, A. C.; Diaper, C. M.; Adams, H.; Rudge, A. J. J. Org. Chem.
2000, 65, 5253.
v. Preparation of substrate II-1.1
Diene-tethered methyl ketone substrate II-1.1 was prepared in accordance with a
literature procedure. Spectroscopic data was consistent with values reported therein. See:
Murakami, M.; Ubukata, M.; Ito, Y. Tetrahedron Lett. 1998, 39, 7361.
Chapter III: Recent Developments in Catalytic [2+2]Cycloadditions Part 1: Anion Radical [2+2]Cycloaddition as a Mechanistic Probe: Stoichiometry and Concentration-Dependant Partitioning of Electron-Transfer (ET) and Alkylation Pathways in the Reaction of the Gilman Reagent Me2CuLi•LiI with bis(Enones) A. Introduction and Background
i. Early Observations Attributed to Electron Transfer in Gilman Alkylations
An electron transfer (ET) mechanism was originally proposed for the alkylation
of conjugated enones by Gilman reagents (formally lithium dialkylcuprates).1 However,
much of the data once believed to support the intermediacy of enone anion radicals in the
Gilman conjugate addition has been subject to debate and in some instances refuted.2 For
example: (a) E/Z isomerization of enones upon exposure to Me2CuLi•LiI, initially
attributed to the formation of anion radical intermediates, is catalyzed by lithium iodide at
temperatures as low as -78 °C.3 (b) Although a correlation between enone reduction
potential and the ability to undergo conjugate addition using Me2CuLi•LiI has been
made,4 subsequent studies reveal this correlation to be superficial, thus disqualifying rate-
determining electron transfer.5 (c) A large number of studies involving the use of
chemical probes were considered to corroborate the intermediacy of anion radicals.7-9
Specifically, upon exposure to Gilman reagents, enones possessing γ-heteroatom
substitution afford products of elimination,6 enones possessing leaving groups at the δ-
position afford products of internal substitution,6a,7 and γ,δ-cyclopropyl enones are
subject to alkylative ring opening.8 While products of ring cleavage potentially could
arise via the intermediacy of a cyclopropylcarbinyl radical, the nucleophilic ring opening
of cyclopropyl esters and ketones using Gilman reagents is known.9 Moreover, elegant
142
studies by Casey demonstrate stereospecific alkylative ring opening, which appears
incompatible with anion radical intermediates.10 Initially, this result was interpreted as
evidence for direct nucleophilic addition to the cyclopropane. Related studies by Bertz
suggest that alkylative ring opening actually occurs through stereospecific rearrangement
of an initially formed β-cuprio adduct.11 Indeed, for all the aforementioned chemical
probes, reactivity once deemed “diagnostic” of the presence of anion radicals is perhaps
better attributed to the action of β-cuprio intermediates. (d) Finally, attempted
spectroscopic detection of anion radicals using electron spin resonance (ESR) and
chemically induced dynamic nuclear polarization (CIDNP) was unsuccessful.12
ii. Accepted Mechanistic Features of Gilman 1,4-Addition
It is now generally believed that the reaction of the Gilman reagent Me2CuLi•LiI
with conjugated enones involves reversible formation of a copper-complexed
intermediate followed by rate-determining carbon-carbon reductive elimination (Scheme
III-1.1). Rate-determining reductive elimination is supported by kinetic isotope effects.13
Additionally, kinetic studies performed by Krauss and Smith reveal reversible formation
of an intermediate that is subject to irreversible rate-determining conversion to product.14
While copper-complexed enone intermediates have been directly observed using low
temperature NMR spectroscopically,15 the precise nature of such enone complexes is the
subject of debate.
143
Scheme III-1.1: Gilman 1,4-Addition: Mechanistic Outline
O
Cu
Li XLi
MeMe
O
MeLi
XLiMeCu
O
CH3
LiLn
RDS
The available theoretical data suggest their structure resides between the limiting,
and perhaps mesomeric, forms represented by unsymmetrical π-complexes and oxy- π -
allyls, enyls(σ+π) and β-cuprio adducts.16 Studies by Boche suggest the copper-
complexed intermediate is a contact ion pair (CIP), rather than a solvent separated ion
pair (SSIP), even in cases when the latter predominates in solution.17
Despite strong evidence against the intermediacy of enone anion radicals in many
Gilman type conjugate additions, the ET properties of Gilman reagents have been clearly
demonstrated in cases involving easily reduced substrates. These include: (a) additions to
doubly activated olefins,18 (b) addition to bromonaphthoquinone,19 (c) polyaddition to
fullerenes, as well as the (d) ketyl anion radical formation and pinacolization of
fluorenone.20 Hence, the formation of anion radicals in a pre-equilibrium preceding the
rate-determining step of the Gilman reaction remains a possibility, especially for easily
reduced systems.
iii. Conjugated bis(Enones) as Mechanistic Probes
Our recent observation that easily reduced bis(enones) are subject to
intramolecular [2+2]cycloaddition upon cathodic reduction or chemically promoted ET
provides a hitherto unavailable means of detecting anion radical intermediates.21 As such,
we became interested in utilizing these anion radical probes in an examination of the
mechanism of the Gilman alkylation of conjugated enones.
144
THF, 0 oCHH
O
R
O
R
III-1.1a-e III-1.3a-eIII-1.2a-e
O
R
O
R(CH3)2CuLi-LiI
H3C
RR
OO
a. R=4-Biphenylyl; b. R = 2-Naphthyl; c. R = 4-Chlorophenyl; d. R = 3,4-Dichlorophenyl; e. R = Phenyl
Eqn. III-1.1
To this end, our investigations have established that exposure of aromatic bis(enones)
III-1.1a-e to the methyl Gilman reagent (Me2CuLi•LiI) at 0 oC in THF results in the
formation of both the products of tandem conjugate addition-Michael cyclization III-
1.2a-e and [2+2]cycloaddition III-1.3a-e. Partitioning of these reaction pathways is
achieved by modulating the concentration and loading of the Gilman reagent. While the
aggregate(s) present at higher concentration induce typical Gilman alkylation en route to
products III-1.2a-e, the aggregate(s) present at lower concentration provide products of
catalytic [2+2]cycloaddition III-1.3a-e. These studies suggest a concentration-dependent
speciation of the Gilman reagent and differential reactivity of the aggregates present at
higher and lower concentrations. Based on these data, along with our prior studies
involving chemically and electrochemically induced anion radical cyclobutanation of the
very same bis(enones),21 the [2+2]cycloadducts III-1.3a-e arising under Gilman
conditions appear to be products of anion radical chain cyclobutanation that derive via
electron transfer (ET) from the Me2CuLi•LiI aggregate(s) present at low concentration
(Scheme III-1.2).
145
Scheme III-1.2: Partitioning of Electron Transfer and Alkylation Pathways
R R
O O
O
R
O
R
O
R
O
R
H3C
HH
R = ArylTHF, 0 oC
(CH3)2CuLi-LiI
200 mol% CuprateHigh Concentration
Fast Addition
25 mol% CuprateLow Concentration
Slow Addition
Electrochemical ReductionET from Arene Anion Radicals
B. Results and Discussion
i. The Anion Radical Probe Reaction
In connection with ongoing studies toward the development of catalysts for
alkene [2+2]cycloaddition,21,22 the belief that Gilman reagents might serve as ET agents
prompted us to examine their capacity to induce anion radical chain cyclobutanation of
bis(enone) substrates. The bis(enone) substrates III-1.1a-e have been shown in this
laboratory to undergo intramolecular cyclobutanation via enone anion radical
intermediates formed initially either by ET from the chrysene anion radical or by
cathodic reduction.21 The available evidence strongly supports a stepwise cycloaddition
mechanism involving the formation of a distonic anion radical intermediate which then
cyclizes to form the anion radical of the cyclobutane product III-1.3, which should be
localized upon the aroyl moiety. Exergonic ET to the more easily reducible substrate III-
1.1 then initiates an anion radical chain reaction (Scheme III-1.3). Since the 4-biphenoyl
moiety of III-1.1a more effectively stabilizes the anion radical moiety than does the
benzoyl moiety of III-1.1e, the former has been found to be a substantially more efficient
146
anion radical probe than the latter. Consequently, bis(enone) III-1.1a was used in the
most extensive series of probe experiments in the present work. The prototypical Gilman
reagent Me2CuLi•LiI, generated through the addition of methyl lithium to a THF solution
of copper(I) iodide, was selected as the specific Gilman reagent for this study.
Scheme III-1.3: Postulated Stepwise Mechanism for Anion Radical Chain Cyclobutanation
O ROR
e-
O ROR O RORO
R
O
R
O
R
O
R
Distonic Anion Radical
III-1.1a-e III-1.3a-e
a. R=4-Biphenylyl; b. R = 2-Naphthyl; c. R = 4-Chlorophenyl; d. R = 3,4-Dichlorophenyl; e. R= Phenyl
ii. Organocuprate-Catalyzed [2+2]Cycloaddition
a. Partitioning of Reactivity as a Function of Catalyst Loading
Toward this end, variable quantities of the methyl Gilman reagent were added to a
THF solution (0.01 M) of the 4-biphenylyl substituted bis(enone) III-1.1a at 0 oC. Using
two equivalents of the Gilman reagent, an 85% yield of the tandem conjugate addition-
Michael cyclization product III-1.2a is obtained (Table III-1.1, Entry 1). Upon use of one
equivalent of the methyl Gilman reagent, both III-1.2a and the [2+2]cycloadduct III-1.3a
are obtained in 64% and 13% yields, respectively (Entry 2). Further decrease in the
loading of Gilman reagent was found to favor the cycloaddition pathway. Using 0.5
equivalents of the Gilman reagent, III-1.2a and the [2+2]cycloadduct III-1.3a are
produced in 38% and 40% yields, respectively (Entry 3), and upon use of 0.25
equivalents of the Gilman reagent, III-1.2a and the [2+2]cycloadduct III-1.3a are
produced in 13% and 84% yields, respectively (Entry 4). Notably, when 0.25 equivalents
of the Gilman reagent is added more slowly (60 sec), the cyclobutanation manifold is 147
favored to the exclusion of III-1.2a, providing the cycloadduct III-1.3a in 91% yield as a
single diastereomer (Entry 5). A further decrease in loading of the Gilman reagent results
in incomplete consumption of III-1.1a (Entry 6).
b. Partitioning of Reactivity as a Function of Catalyst Concentration
Finally, use of one equivalent Gilman reagent at 0.00125 M rather than 0.01 M
concentration inverts the proportion of alkylation product III-1.2a and cyclobutanation
product III-1.3a. The yields of III-1.2a and III-1.3a change from 64% and 13%, to 10%
and 60%, respectively (Table III-1.1, Entry 7). These results demonstrate that, when
suitably dilute, the Gilman reagent becomes ineffective at methylation, and instead serves
as a catalyst for cyclobutanation.
Table III-1.1: Effect of Cuprate-Loading, Concentration and Order of Addition
THF, 0 oCHH
O
R
O
R
1aR = 4-Biphenylyl 3a2a
Entry 3a (Yield)c2a (Yield)c
1234567
200 mol%a
100 mol%a
50 mol%a
25 mol%a
25 mol%b
10 mol%a
100 mol%a
---13%40%84%91%72%60%
85%64%38%13%---7%
10%
O
R
O
R(CH3)2CuLi-LiI
H3C
RR
OO
0.01 M0.01 M0.01 M0.01 M0.01 M0.01 M1.25 mM
Conc. 1a(CH3)2CuLi 1a (Recov.)c
5%5%------
3%16%---
(a) A 0.5 M solution of the Gilman reagent in THF is added over 5 seconds. (b) A 0.5 M solution of the Gilman reagent in THF is added over 60 seconds. (c) Isolated yields afterchromatographic separation.
148
c. Exploration of Substrate Scope
To explore the scope of this partitioning phenomenon, optimum Gilman
alkylation and anion radical cyclobutanation conditions were applied to related
bis(enones) (Table III-1.2). Gratifyingly, complete partitioning of the alkylation and
cyclobutanation manifolds was achieved in most cases. Interestingly, the parent phenyl-
substituted bis(enone) III-1.1e is more resistant to cyclobutanation, suggesting the
Gilman reagent catalyzes only the cycloaddition of easily reduced bis(enones).
Table III-1.2: Partitioning of Mechanistic Pathways Across a Range of Substrates
Substrate III-1.3 (Yield)bIII-1.2 (Yield)b
III-1.1a
III-1.1b
III-1.1c
III-1.1d
III-1.1e
ABABABABAB
---91%
---90%
---80%
---70%
---43%
91%---
89%---
93%---
85%4%
90%12%
Conditions
R = 4-Biphenylyl
R = 2-Naphthyl
R = 4-Chlorophenyl
R = 3,4-Dichlorophenyl
R = Phenyl
R
THF, 0 oCHH
O
R
O
R
III-1.1a-e III-1.3a-eIII-1.2a-e
O
R
O
R(CH3)2CuLi-LiI
H3C
RR
OO
(a) Conditions A for tandem conjugate addition-Michael cyclization employ rapid addition (5 sec)of Me2Culi (200 mol%) to a solution of substrate (100 mol%) in THF at 0 oC. Conditions B foranion radical cyclobutanation employ slow addition (60 sec) of Me2Culi (25 mol%) to a solution of substrate (100 mol%) in THF at 0 oC. (b) Isolated yields after chromatographic separation. Theratio of cis:trans diastereomers for 3a, 3b, 3c, 3d and 3e is >99:1, 44:1, 9:1, 13:1 and 17:1respectively.
d. Kinetic Studies
Reaction kinetics experiments are described in Table III-1.3. With a starting
concentration of the cuprate reagent of 0.01 M, which is injected rapidly to the substrate
solution, and using 25 mol% of the Gilman reagent, III-1.2a is formed almost exclusively
during the initial stages of reaction. However, after the majority of the Gilman reagent is
149
consumed through the conversion of III-1.1a to III-1.2a, the formation of III-1.3a begins
and continues to develop, ultimately becoming the dominant reaction pathway. The
implications of these results will be discussed (vide infra).
Table III-1.3: Reaction Kinetics Experiments
THF, 0 oC(Fast Addition)
HH
O
R
O
R
III-1.1aR = 4-Biphenylyl III-1.3aIII-1.2a
Entry III-1.3a (mol%)aIII-1.2a (mol%)aTime (sec)
1234567
0103060
180480
1200
05.1
11.712.733.243.254.7
016.319.020.318.620.222.0
O
R
O
R(CH3)2CuLi-LiI(25 mol%)
H3C
RR
OO
III-1.1a (mol%)a
10076.366.763.442.033.424.3
(a) Conversion was determined by 1H NMR analysis and the values given are the average of two runs. Total values are under 100 mol% as small quantities of hetero-Diels-Aldercycloadduct are produced.
iii. Mechanistic Proposal
a. Concentration-Dependent Speciation
It is evident from the results presented in Table III-1.1 that the cyclobutanation
reaction is indeed a catalytic or chain process, but that the chain lengths are rather short
(ca. 2-3). These experiments also suggest a concentration-dependent speciation of the
Gilman reagent, as demonstrated by differential reactivity at high and low concentration.
The aggregates present at high concentration favor alkylation, while the aggregates
present at low concentration favor cycloaddition. A corollary to this hypothesis requires
that variation of concentration at constant loading of Gilman reagent should modulate the
ratio of alkylation and cyclobutanation products. Indeed, the yields of III-1.2a and III-
150
1.3a change from 64% and 13%, to 10% and 60%, respectively, when one equivalent
Gilman reagent is used at 0.00125 M rather than 0.01 M concentration (Table III-1.1).
Studies of the time-evolution of products III-1.2a and III-1.3a provide further
insights into the mechanistic dichotomy observed in this work (Table III-1.3). The
alkylation product III-1.2a is formed rapidly early in the reaction, whereas only small
amounts of III-1.3a are generated at this stage. However, after the concentration of
Gilman reagent is lowered through its consumption, the cycloaddition pathway becomes
dominant. These results again suggest that the composition of the Gilman reagent is
concentration-dependent and that the species present at low concentration are relatively
ineffective methyl transfer agents, but are effective agents for chain cycloaddition in the
case of easily reduced bis(enones).
b. Role of Lithium Iodide
A further important consequence of the kinetic studies is the conclusion that
lithium iodide, which is present at constant concentration throughout the reaction period,
is not differentially involved in the competition between methylation and
cyclobutanation. This conclusion is further substantiated by carrying out a reaction in
which 100 mol % of lithium iodide is included with the substrate and 100 mol % of the
Gilman reagent is added in the slow fashion. Instead of favoring the methylation, the
results are essentially the same as when the lithium iodide is omitted. The nature of the
termination step of the anion radical chain process is not currently known, but coupling
of two anion radicals is a possibility.
151
c. Anion Radical Chain Cycloaddition vs. Oxidative Cyclization-Reductive Elimination
A paramount question relates to whether the cycloadducts III-1.3a-e are products
of anion radical chain cycloaddition or instead derive from copper(I)-catalyzed oxidative
cyclization-reductive elimination (Scheme III-1.4). In the latter case, the Gilman
intermediate, be it a π-complex, oxy- π -allyl, enyl(σ+π) or β-cuprio adduct, is required to
insert into the appendant enone. Here, it is especially noteworthy that the biphenoyl
derived bis(enone) III-1.1a is much more efficiently converted to III-1.3a than the
related benzoyl substituted bis(enone) III-1.1e is to III-1.3e. This same reactivity order
has been observed in authenticated anion radical reactions involving ET from chrysene
anion radical,21 and is attributable to the more facile generation of the 4-biphenoyl-type
anion radical moiety, as opposed to a benzoyl-type anion radical moiety, in the second
cyclization step to close the cyclobutane ring. Since the comparison of III-1.1a and III-
1.1e should not involve a significant difference in polar effects (phenyl vs. 4-biphenyl),
the enhancement associated with III-1.1b is presumed to be a conjugative effect, such as
would be present in the delocalization of an anion radical moiety. Further, authenticated
anion radical cyclobutanations involving cathodic reduction typically proceed through
short chains, in the same manner as the currently-observed cyclobutanations. Finally,
when the same solvent (THF) is involved, chemically initiated anion radical
cyclobutanation of substrate III-1.1a affords exclusively the exo,cis-cyclobutane product
III-1.3a, as observed in the present work. The high levels of stereoselectivity suggest the
anion radical intermediates derived from III-1.1a exist as CIPs.
152
Scheme III-1.4: Alternative Cyclobutanation Pathways
HH
O
R
O
RElectronTransferRR
OO O ROR
Anion Radical Chain Cycloaddition
HH
O
R
O
RCu(I)LnRR
OO
Oxidative Cyclization - Reductive Elimination
e
Cu(I)Ln
HH
CuIIIO O
RR
Ln
Eqn. 1
Eqn. 2
d. Concentration-Dependent Speciation
A second important question concerns the composition of the reactive species at
high and low concentration. It has been established that, in THF solution, the methyl
Gilman reagent exists primarily as solvent-separated ion pairs (Li+ // CuMe2־), which are
in rapid equilibrium with the cyclic dimer of lithium dimethylcuprate ([Me2CuLi]2).17
Extensive evidence suggests that the latter dimer is much more reactive than the former
with respect to Gilman methylation. Neither monomer nor dimer is intimately associated
with the lithium halide, which is consistent with our own observation that the product
distribution is insensitive to added lithium iodide (Scheme III-1.5).
Scheme III-1.5: Equilibrium Between Solvent-Separated Ion Pairs and Contact Ion Pair Dimer Me MeCu
Me MeCu
Li Li2 Me2CuLiTHF
(Dimeric CIP)
(Monomeric SSIPs)
Since the equilibrium between the dimer and the monomer would be shifted even
further to the monomer upon dilution, it is reasonable to suggest that the monomeric
solvent-separated ion pairs, which are known to be relatively unreactive toward
153
methylation, may be the species responsible for the initiating electron transfer, while the
dimer is the species which is responsible for methylation. This proposal would explain
why electron transfer chemistry appears to dominate when the Gilman reagent is very
dilute, but methylation dominates when the reagent is more concentrated. Because
products derived via anion radical intermediates may be formed to the exclusion of
methylation products, it appears that these anion radical intermediates are not subject to
Gilman methylation. Hence, the Gilman alkylation and cycloaddition pathways are
mechanistically distinct.
The possibility that small amounts of extraneous impurities could be responsible
for the initiation of the anion radical chemistry observed in the present work has been
extensively considered. The following reagents (acting alone, under the typical conditions
of the reaction) have been shown not to initiate anion radical chemistry in the case of III-
1.1a, or in any of the substrates of this study: MeLi, MeCu, and LiI. Further, the reagent
lithium trimethyldicuprate reacts in essentially the same manner as lithium
dimethylcuprate. This reagent was specifically considered because it could be generated
from lithium dimethylcuprate and methylcopper, which is released upon Gilman
methylation.
C. Conclusion
The now well-established intramolecular anion radical chain cyclobutanation
reactions of 1,7-bis(aroyl)-1,6-heptadienes have been employed as anion radical probes in
the reactions of these enones with the Gilman reagent. When the Gilman reagent is
present in the reaction solution at low concentrations, either via slow addition of the
154
reagent to a solution of the bis(enone), or by use of a sub-stoichiometric amount of the
reagent (25 mol%), the intramolecular [2 + 2] cycloaddition products are formed in good
yield. In contrast, when a stoichiometric (or greater) amount of the reagent is added
rapidly to a solution of the enone, tandem Gilman methylation-intramolecular Michael
addition occurs in high yield. Under suitable conditions, complete partitioning of the
anion radical and conventional Gilman methylation pathways is observed. These results
indicate that anion radical intermediates are generated in competition with Gilman
methylation products, and that the anion radical mechanism is independent of the
methylation mechanism. That is, under ideal anion radical conditions (low concentration
of the Gilman reagent), no methylation is observed; conversely, under ideal methylation
conditions (high concentration and an excess of the Gilman reagent), no anion radical
products are formed. The powerful dependence of the competition between ET chemistry
and Gilman methylation upon the concentration of the Gilman reagent, coupled with the
generally acknowledged greater methylation reactivity of the dimeric, rather than
monomeric, Gilman reagent, suggests that the species responsible for methylation is
probably the CIP dimer, while the species responsible for electron transfer is probably the
Gilman monomer, which is present in tetrahydrofuran solutions as the solvent-separated
ion pair.
155
156
D. References
1 For a review, see: House, H. O. Acc. Chem. Res. 1976, 9, 59. 2 For reviews covering the mechanism of the Gilman conjugate addition, see: (a)
Nakamura, E.; Mori, S. Angew. Chem. Int. Ed. 2000, 39, 3750. (b) R. A. J. Smith, A.
S. Vellekoop in Advances in Detailed Reaction Mechanisms, Vol. 3 (Ed.: J. M.
Coxon), JAI: Greenville, CT, 1994, pp. 79-130. (c) Perlmutter, P., in Conjugate
Addition Reactions in Organic Synthesis (Baldwin, J. E. and Magnus, P. D., Eds),
Pergamon Press, Oxford, 1992, pp 10-13. 3 Corey, E. J.; Hannon, F. J.; Boaz, N. W. Tetrahedron 1989, 45, 545. 4 House, H. O. Umen, M. J. J. Am. Chem. Soc. 1972, 94, 5495. 5 Krauss, S. R.; Smith, S. G. J. Am. Chem. Soc. 1981, 103, 141. 6 (a) Ruden, R. A. Litterer, W. E. Tetrahedron Lett. 1975, 16, 2043. (b) Logusch, U. W.
Tetrahedron Lett. 1979, 20, 3365. (c) Ibuka, T.; Chu, G.-N.; Yoneda, F. Tetrahedron Lett. 1984, 25, 3247.
7 (a) Hannah, D. J.; Smith, R. A. J.; Teoh, I.; Weavers, R. T. Aust. J. Chem. 1981, 34,
181. (b) Smith, R. A. J.; Vellekoop, A. S. Tetrahedron 1989, 49, 517. 8 (a) Marshall, J. A.; Ruden, R. A. J. Org. Chem. 1972, 37, 659. (b) House, H. O.;
Snoble, K. A. J. Org. Chem. 1976, 41, 3076. 9 For classic examples, see: (a) Corey, E. J.; Fuchs, P. L. J. Am. Chem. Soc. 1972, 94,
4014. (b) Daviaud, G.; Miginiac, P. Tetrahedron Lett. 1972, 13, 997. (c) Grieco, P. A.;
Finkelhor, R. J. Org. Chem. 1973, 38, 2100. (d) Miyaura, M.; Itoh, M.; Sasaki, N.;
Suzuki, A. Synthesis 1975, 317. (e) House, H. O.; Prabhu, A. V.; Wilkins, J. M.; Lee.
L. F. J. Org. Chem. 1976, 41, 3067. (f) House, H. O.; McDaniel, W. C.; Sieloff, R. F.;
Vanderveer, D. J. Org. Chem. 1978, 43, 4316. 10 Casey, C. P.; Cesa, M. C. J. Am. Chem. Soc. 1979, 101, 4236. 11 Bertz, S. H.; Honkan, V. J. Org. Chem. 1984, 49, 1739. 12 (a) Hannah, D. J.; Smith, R. A. J. Tetrahedron Lett. 1975, 16, 187. (b) Smith, R. A. J.;
Mannah, D. J. Tetrahedron 1979, 35, 1138. 13 Frantz, D. E.; Singleton, D. A. Snyder, J. P. J. Am. Chem. Soc. 1997, 119, 3383.
157
14 Krauss, S. R.; Smith, S. G. J. Am. Chem. Soc. 1981, 103, 141. 15 (a) Bertz, S. H.; Carlin, C. M.; Deadwyler, D. A.; Murphy, M. D.; Ogle, C. A.;
Seagle, P. H. J. Am. Chem. Soc. 2002, 124, 13650. (b) Vellekoop, A. S.; Smith, R. A.
J. J. Am. Chem. Soc. 1994, 116, 2902. (c) Bertz, S. H.; Smith, R. A. J. Am. Chem. Soc. 1989, 111, 8276. (d) Ullenius, C.; Christianson, B. Pure Appl. Chem. 1988, 60,
57. 16 (a) Snyder, J. P. J. Am. Chem. Soc. 1995, 117, 11025. (b) Snyder, J. P.; Bertz, S. H. J.
Org. Chem. 1995, 60, 4312. (c) Nakamura, E.; Mori, S.; Morokuma, K.; J. Am .Chem. Soc. 1997, 119, 4900. (d) Mori, S.; Nakamura, E. Chem. Eur. J. 1999, 5, 1534. (e)
Nakamura, E.; Yamanaka, M. J. Am. Chem. Soc. 1999, 121, 8941. (f) Yamanaka, M.;
Kato, S.; Nakamura, E. J. Am. Chem. Soc. 2004, 126, 6287. 17 John, M.; Auel, C.; Behrens, C.; Marsch, M.; Harms, K.; Bosold, F.; Gschwind, R. M.;
Rajamohanan, P. R.; Boche, G. Chem. Eur. J. 2000, 6, 3060. 18 (a) Chounan, Y.; Ibuka, T.; Yamamoto, Y. J. Chem. Soc. Chem. Commun. 1994, 2003.
(b) Yamamoto, Y.; Nishii, S.; Ibuka, Y. J. Am. Chem. Soc. 1988, 110, 617. 19 (a) Chounan, Y.; Horino, H.; Ibuka, T.; Yamamoto, Y. Bull. Chem. Soc. Jpn. 1997, 50,
1953. (b) Wigal, C. T.; Grunwell, J. R.; Hershberger, J. J. Org. Chem. 1991, 56, 3759.
(c) Anderson, S. J.; Hopkins, W. T.; Wigal, C. T. J. Org. Chem. 1992, 57, 4304. 20 House, H. O.; Respess, W. L.; Whitesides, G. M. J. Org. Chem. 1966, 31, 3128. 21 (a) Roh, Y.; Jang, H.-Y.; Lynch, V.; Bauld, N. L.; Krische, M. J. Org. Lett. 2002, 4,
611. (b) Yang, J.; Felton, G.; Bauld, N. L.; Krische, M. J. J. Am. Chem. Soc. 2004,
126, 1634. 22 (a) Baik, T.-G.; Wang, L.-C.; Luiz, A.-L.; Krische, M. J. J. Am. Chem. Soc. 2001, 123,
6716. (b) Wang, L. -C.; Jang, H.-Y.; Roh, Y.; Schultz, A. J.; Wang, X.; Lynch, V.;
Krische, M. J. J. Am. Chem. Soc. 2002, 124, 9448.
E. Experimental Section
i. Synthetic Procedures
a. General
All reactions were run under an atmosphere of argon, unless otherwise indicated.
Anhydrous solvents were transferred by an oven-dried syringe. Flasks were oven-dried
and cooled in a dessicator.
CuI (99.999%) was obtained from Strem chemical company. Tetrahydrofuran was
distilled from sodium benzophenone ketyl immediately prior to use. All reactions were
conducted in oven-dried glassware, under an inert atmosphere of Argon.
Analytical thin-layer chromatography (TLC) was carried out using 0.2-mm
commercial silica gel plates (DC-Fertigplatten Krieselgel 60 F254). Preparative column
chromatography employing silica gel was performed according to the method of Still.*
Melting points were determined on a Thomas-Hoover melting point apparatus in sealed
capillaries and are uncorrected. Infrared spectra were recorded on a Perkin-Elmer 1420
spectrometer. High-resolution mass spectra (HRMS) were obtained on a Karatos MS9
and are reported as m/e (relative intensity). Accurate masses are reported for the
molecular ion (M+1).
158
Unless otherwise noted, proton nuclear magnetic resonance (1H NMR) spectra
were recorded with a Varian Gemini (300 MHz) spectrometer or a Mercury (400 MHz)
spectrometer. Chemical Shifts are reported in delta (δ) units, parts per million (ppm)
downfield from trimethylsilane. Coupling constants are reported in Hertz (Hz). Carbon-
13 nuclear magnetic resonance (13C NMR) spectra were recorded with a Bruker
spectrometer (63 MHz). Chemical shifts are reported in delta (δ ) units, parts per million
(ppm) relative to the center of the triplet at 77.0 ppm for deuteriochloroform. 13C NMR
spectra were routinely run with broad brand decoupling.
b. Preparation of bis(enone) substrates III-1.1a – III-1.e
Cyclization/cycloaddition substrates III-1.1a – III-1.e were prepared according to
literature procedures. Sprectroscopic data was consistent with reported values. See: Yang,
J.; Felton, G.; Bauld, N. L.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 1634.
c. Preparation of dimethyllithium cuprate-lithium iodide (Me2CuLi-LiI) reagent
Dimethyllithium cuprate-lithium iodide (Me2CuLi-LiI) reagent was prepared by
adding 200 mol% MeLi (1.6 M in Et2O) to a suspension of 100 mol% CuI in 0 °C THF.
Stirring for approximately 30 minutes at 0°C resulted in a homogeneous solution. The
reagent solution was used immediately.
ii. Experimental Procedures
a. Procedure for data reported in Table III-1.1
Data was obtained using the following procedure: Me2CuLi-LiI reagent solution
(0.5 M in Et2O/THF) was added at the indicated rate to a solution of (bis)enone substrate
(0.25 mmol) in 25 ml 0 °C THF. The reaction was stirred at 0 °C for 25 minutes, and then
quenched with several drops of saturated aqueous NH4Cl solution. The residue was
concentrated and purified via silica gel chromatography, eluting with a mixture of ethyl
acetate and hexane.
159
b. Procedure for data reported in Table III-1.2
Data was obtained using the following representative procedures:
(A) Me2CuLi-LiI (15.7 ml; 0.0032 M in Et2O/THF; 200 mol%) was added over 5s to a solution of
substrate (0.26 mmol; 100 mol%) in 5 ml 0 °C THF. Stirring was maintained for 25 minutes and
then was worked up and purified as described above.
(B) Me2CuLi-LiI (0.125 ml; 0.5 M in Et2O/THF; 25 mol%) was added over 60s to a solution of
substrate (0.25 mmol; 100 mol%) in 25 ml 0 °C THF. Stirring was maintained for 25 minutes and
then was worked up and purified as described above.
c. Procedure for data reported in Table III-1.3
Data represents measurements from separate, parallel reactions conducted using the
following procedure: Me2CuLi-LiI (0.98 mL; 0.034 M in Et2O/THF; 25 mol%) was added over
5s to a solution of substrate (0.1316 mmol; 100 mol%) in 3.5 ml 0 °C THF. Stirring was
maintained for the indicated time before work up and purification as described above.
iii. Spectroscopic and Crystallographic Data
a. Spectroscopic data for cyclobutane products III-1.3a – III-1.3e
1HNMR data for cyclobutane products III-1.3a – III-1.3e was consistent with
values reported in the literature. See: Yang, J.; Felton, G.; Bauld, N. L.; Krische, M. J. J.
Am. Chem. Soc. 2004, 126, 1634.
160
b. Spectroscopic data for cyclobutane products III-1.2a – III-1.2e
H3C
O
O
III-1.2a
1HNMR (300 MHz, CDCl3): δ 8.1-8.12 (d, J = 8.4 Hz, 2H), 7.86-7.89 (d, J = 8.4 Hz, 2H), 7.66-7.67 (d, J = 8.4 Hz, 2H), 7.55-7.63 (m, 6H), 7.36-7.47 (m, 6H), 3.12-3.19 (t, J = 9.9 Hz, 1H), 2.90-3.0 (q, J = 8.7 Hz, 1H), 2.42-2.57 (m, 2H), 1.72-1.87 (m, 4H), 1.36-1.49 (m, 1H), 1.06-1.27 (m, 2H), 0.80-0.82 (d, J = 6.3 Hz, 3H). 13CNMR (63 MHz, CDCl3): δ 205.7, 198.9, 145.9, 145.5, 139.9, 139.7, 137.9, 135.4, 128.9, 128.8, 128.2, 128.1, 127.4, 127.3, 127.2, 127.2, 56.6, 44.1, 38.5, 36.9, 34.9, 31.5, 25.4, 21.1 HRMS: Calc. [M+1] for C34H32O2: 473.2481; Found: 473.2460. IR (KBr): 3060, 3031, 2950, 2921, 2848, 1674, 1601, 1601, 1553, 1403, 1212, 1193, 1003, 761, 746, 695 cm-1.
161
H3C
O
O
III-1.2b
1HNMR (300 MHz, CDCl3): δ 8.56 (s, 1H), 8.27 (s, 1H), 8.12-8.15 (dd, J1 = 8.7 Hz, J2 = 1.8 Hz, 1H), 7.99-8.03 (m, 1H), 7.77-7.91 (m, 6H), 7.46-7.61 (m, 4H), 3.28-3.34 (t, J = 9.9 Hz, 1H), 3.02-3.09 (q, J = 9 Hz, 1H), 2.52-2.66 (m, 2H), 1.72-1.97 (m, 4H), 1.14-1.45 (m, 3H), 0.80-0.83 (d, J = 6.9 Hz, 3H). 13CNMR (63 MHz, CDCl3): δ 206.1, 199.4, 136.6, 135.64, 135.4, 133.9, 132.6, 132.4, 130.1, 129.7, 129.7, 128.7, 128.6, 128.3, 128.3, 127.7, 127.6, 126.8, 126.5, 123.9, 56.6, 44.2, 38.7, 37.1, 34.9, 31.5, 25.4, 21.1. HRMS: Calc. [M+1] for C30H28O2: 421.2168; Found: 421.2168. IR (KBr): 3453, 3057, 2950, 2925, 2848, 1674, 1626, 1461, 1373, 1270, 1179, 1120, 819, 753 cm-1.
162
H3C
O
O
Cl
Cl III-1.2c
1HNMR (300 MHz, CDCl3): δ 7.96-7.93 (d, J = 8.7 Hz, 2H), 7.70-7.73 (d, J = 8.7 Hz, 2H), 7.42-7.45 (d, J = 8.7 Hz, 2H), 7.35-7.38 (d, J = 8.7 Hz, 2H), 3.10-3.08 (t, J = 9.9 Hz, 1H), 2.75-2.82 (q, J = 11.1Hz, 1H), 2.38-2.45 (m, 2H), 1.70-1.84 (m, 4H), 1.31-1.40 (m, 1H), 1.10-1.23 (m, 2H), 0.73-0.75 (d, J = 6.6 Hz, 3H). 13CNMR (63 MHz, CDCl3): δ 204.9, 197.9, 139.8, 139.4, 137.4, 134.9, 129.6, 129.1, 128.8, 56.3, 43.8, 38.2, 37.0, 34.8, 31.3, 25.3, 21.0. HRMS: Calc. [M+1] for C22H22O2Cl2: 389.1075; Found: 389.1081. IR (KBr): 3071, 2955, 1932, 2850, 1877, 1850, 1685, 1662, 1588, 1565, 1401, 1211, 1087, 982, 898, 815 cm-1.
163
H3C
O
O
Cl
Cl
Cl
Cl
III-1.2d
1HNMR (300 MHz, CDCl3): δ 8.05-8.05 (d, J = 2.1 Hz, 1H), 7.84-7.85 (d, J = 2.1 Hz, 1H), 7.79-7.83 (dd, J1 = 8.4 Hz, J2 = 2.1 Hz, 1H), 7.46-7.60 (m, 3H), 2.98-3.05 (t, J = 10.2 Hz, 1H), 2.71-2.77 (dd, J1 = 14.1 Hz, J2 = 2 Hz, 1H), 2.34-2.51 (m, 2H), 1.70-1.78 (m, 4H), 1.33-1.46 (m, 1H), 1.03-1.24 (m, 2H), 0.73-0.76 (d, J = 6.3 Hz, 3H). 13CNMR (63 MHz, CDCl3): δ 203.8, 196.8, 138.4, 138.1, 137.6, 136.2, 133.6, 133.3, 130.9, 130.7, 130.2, 130.1, 127.2, 127.2, 56.3, 43.5, 38.1, 37.2, 34.8, 31.4, 25.3, 21.0. HRMS: Calc. [M+1] for C22H20O2Cl4: 457.0296; Found: 457.0299. IR (film): 3423, 3090, 3068, 2950, 2928, 2848, 1681, 1678, 1652, 1582, 1557, 1454, 1381, 1204, 1028 cm-1.
164
H3C
O
O
III-1.2e
1HNMR (300 MHz, CDCl3): δ 7.99-8.03 (d, J = 8.4 Hz, 2H), 7.77-7.79 (d, J = 8.7 Hz, 2H), 7.36-7.58 (m, 6H), 3.06-3.13 (t, J = 9.9 Hz, 1H), 2.82-2.92 (q, J = 11.1 Hz, 1H), 2.38-2.51 (m, 2H), 1.63-1.88 (m, 4H), 1.32-1.42 (m, 1H), 1.02-1.233 (m, 2H ), 0.75-0.77 (d, J = 6.6 Hz, 3H). 13CNMR (63 MHz, CDCl3): δ 206.2, 199.3, 139.3, 136.7, 133.2, 132.9, 128.7, 128.5, 128.2, 56.5, 44.0, 38.3, 36.9, 34.9, 31.4, 25.3, 21.0. HRMS: Calc. [M+1] for C22H24O2: 321.1855; Found: 321.1853. IR (KBr): 3082, 3067, 3024, 2958, 2939, 2932, 2914, 2851, 2833, 1678, 1593, 1450, 1362, 1201, 999, 970, 889, 786, 750, 706, 684 cm-1.
165
c. Crystallographic data for cyclization product III-1.2e
View of molecule III-1.2e showing the atom labeling scheme. Displacement
ellipsoids are scaled to the 50% probability level.
166
Part 2. Studies on the Enantioselective Catalysis of Photochemically Promoted Transformations: “Sensitizing Receptors” as Chiral Catalysts A. Introduction
i. Stoichiometric Chirality Transfer in Photo[2+2]cycloadditions
Many important classes of chemical transformations exist for which catalytic
enantioselective variants do not exist or have not been optimally developed.
Photocycloadditions represent a powerful means of stereogenic carbon-carbon and
carbon-oxygen bond formation that have found extensive use in synthesis,1 yet generally
effective strategies for catalytic asymmetric induction in photochemically mediated
transformations are largely undeveloped.2 Thus far, methods affording useful
enantiomeric excess have been restricted to stoichiometric chirality transfer from
preexisting stereocenters in the substrate3 and the use of chiral auxiliaries4 (i.e.
diastereoselection), solid-state photochemical transformations5 including clathrates,6 and
unimolecular photochemical reactions in chirally modified zeolites.7 Most recently, chiral
molecular receptors have been shown to serve as highly effective “noncovalent chiral
auxiliaries” for enantioselective photo[2+2]cycloadditions.8
The use of asymmetric media (e.g. chiral solvents,9 chiral liquid crystalline
phases,10 and chiral polymer matrices11) embodies another approach to stoichiometric
chirality transfer in photo-mediated transformations.12 However, in contrast to
photochemical reactions that take place in the well-defined chiral microenvironment of
non-centrosymmetric crystal lattices13 and synthetic host-guest complexes,8 the “loose”
asymmetric environment of chiral solvents and liquid crystals confers low levels of
enantioselection.
167
ii. Substoichiometric Chirality Transfer
Methods for substoichiometric chirality transfer have met with limited success.
The use of circularly polarized lasers (i.e. so-called absolute asymmetric synthesis) gives
disappointing enantiomeric enrichments.14 Chiral photosensitizers provide modest
enantiomeric enrichments for a limited range of substrates.15 The asymmetric protonation
of dienols generated via photodeconjugation of γ,γ-disubstituted enones or enoates in the
presence of sub-stoichiometric amounts of chiral aminoalcohols proceeds with
synthetically-useful enantioinduction.16 For this process, enantiodiscrimination does not
occur in the excited state, but in the tautomerization of the photochemically produced
ground-state dienol.
B. Sensitizing Molecular Receptors as Enantioselective Catalysts
As for any catalytic enantioselective process, a generally effective approach to the
enantioselective catalysis of photo-mediated transformations in solution will require: i.
that the substrate be placed in a well-defined chiral microenvironment upon binding to
the template and, ii. that substrate-template binding confer a kinetic advantage to the
transformation of interest. In principle, chiral molecular receptors that incorporate triplet-
sensitizing residues meet these requirements.
i. Hydrogen Bond-Mediated Host-Guest Complex
With regard to the first requirement, the high levels of asymmetric induction
observed for solution state photo[2+2]cycloadditions in synthetic host-guest systems
strongly suggest that cycloaddition proceeds in a well-defined chiral microenvironment.8 168
In such a system, hydrogen-bond formation dictates the orientation of the substrate with
respect to the chiral receptor template in a distinct and predictable fashion. In general, the
use of hydrogen-bond interactions as stereochemical control elements in photochemical
cycloadditions is well documented.17
ii. Triplet Sensitization as Basis for Binding-Induced Rate Enhancement
The second requirement is met through the incorporation of a triplet-sensitizing
moiety. The lifetime of the triplet sensitizer, in relation to the rates of diffusion and
sensitization, defines a highly-localized sphere of sensitization within which energy
transfer occurs via intermediacy of a triplet exciplex.18 The stringent distance dependence
of energy transfer is equivalent to a binding-induced rate enhancement, i.e. excitation of
bound substrate should be favored over excitation of exogenous, untemplated substrate. If
the lifetime of the exciplex is comparable to the rate of cyclization, exciplex formation
can be enantiodiscriminating.
Predicated on this simple analysis, “sensitizing receptor” R (III-2.8) is proposed.
The binding motif embodied by R derives from structurally related carboxylic acid
receptors.19 The proposed substrate, 4-butenyloxy-2-quinolone S, embodies an identical
array of hydrogen-bond donor-acceptor sites with respect to carboxylic acid guests and
undergoes quantitative photo[2+2]cycloaddition, making it a suitable test substrate. A
binding-induced rate enhancement is engineered by equipping receptor R with a triplet-
sensitizing moiety in the form of a benzophenone residue. While modeling of the host-
guest complex indicates this first generation receptor R does not optimally obscure an
169
enantiotopic π-face of the bound quinolone, exceptionally high levels of enantiofacial
bias are not necessary to illustrate proof of concept.
iii. Synthesis of Sensitizing Receptor R (III-2.8)
The synthesis of receptor R (III-2.8) is straightforward and involves the modular
introduction of sensitizing and binding residues via amide bond formation. The
sensitizing moiety, optically pure 4-(1-aminoethyl)-benzophenone III-2.3, is prepared
from 4-ethyl-benzophenone as outlined in Scheme III-2.1. Resolution of the racemic
amine is achieved through conversion to the (R)-mandelic acid amide III-2.4, followed
by chromatographic separation of the diastereomers and subsequent amide hydrolysis.
Coupling of the resolved sensitizing amine fragment to the indicated mono-amide mono-
acid III-2.7 provides the sensitizing receptor R (Scheme III-2.1).
Scheme III-2.1: Synthesis of Sensitizing Molecular Receptor R (III-2.8)
Reagents: a) NBS, (BzO)2, CCl4; b) NaN3, DMF; c) THF-H2O, PPh3; d) (R)-mandelic acid, DCC, HOBT, DCM; e) HCl (aq); f) C6H13Br, K2CO3, DMF; g) LiNH-(C5H4N); h) LiOH, THF-MeOH-H2O; i) (S)-III-2.3, EDC, DMAP, DCM
H3C O
a
HN
H3C O
(R,R)-III-2.4 (R,S)-III-2.4
H2N
H3C O
(R)-III-2.3, (S)-III-2.3
O
OHPh
i
OY
O O
CH3O OCH3
O
O O
NH HN
N
CH3
O
O
O O
NH
N
OZ
III-2.1 (X=Br)X
III-2.2 (X=N3)b
(X=H)4-Ethylbenzophenone
cIII-2.3 (X=NH2)
d e
5-Hydroxy-Dimethylisophthalate
(Y=H)
g
III-2.5 (Y=n-hexyl)f
R III-2.8III-2.7 (Z=H)h
III-2.6 (Z=CH3)
170
Figure III-2.1: X-Ray crystal structure of mandelamide (R,S) III-2.4
C. Proposed Catalytic Mechanism: Receptor-Directed Energy Transfer
The proposed catalytic cycle is depicted in Scheme III-2.2. Receptor R binds
quinolone S to form the complex R:S. Energy transfer should be directed to the bound
quinolone S owing to the distance dependence of energy transfer.20 Thus, cycloaddition
should occur in the chiral microenvironment of the R:S host-guest complex to yield
optically enriched cycloadduct P in the form of the R:P complex. Finally, dissociation of
cycloadduct P regenerates the uncomplexed receptor R to complete the cycle. Efficient
templating of the cycloaddition will require the sensitized reaction to be fast relative to
the unsensitized process. In order to suppress the background reaction of untemplated
substrate, the substrate-product exchange equilibrium (R:P + S ⇆ R:S + P) should be
fast, yet the cycloaddition of the templated substrate should be faster than the substrate
off-rate (Scheme III-2.2).
171
Scheme III-2.2: Proposed Catalytic Cycle
O O
N N
NH H
N
OH
CH3
R
O
*
N
OH
O
O O
N N
NH H
CH3
HN
O
O
O O
N N
NH H
N
OH
CH3
R
*
O
R S
R:S
OC6H13
OC6H13 OC6H13
O
P
R:P
D. Evaluation of Organic Chromophore-Mediated Energy Transfer
i. Comparison of Exogenous and Receptor-Based Chromophores
In order to establish the capability of receptor R to mediate energy transfer, and to
assess the sensitivity of the cycloaddition with respect to the presence of exogenous
donor/acceptor chromophores, parallel experiments were conducted in which quinolone S
was irradiated in both the presence and absence of selected additives. Irradiation of S in
the absence of an exogenous chromophore for 15 minutes results in 6% conversion.
When S is irradiated in the presence of sensitizing (benzophenone, triplet energy = 69
Kcal/mol) or quenching (naphthalene, triplet energy = 61 Kcal/mol) chromophores, 58%
conversion and trace conversion are observed, respectively.21 Finally, when S is
irradiated in the presence of sensitizing receptor R and quenching receptor RQ (III-2.9),
which incorporate benzophenone and naphthalene residues respectively, 33% and 0%
conversions are observed. The expectation that sensitization and quenching efficiencies
172
should be augmented in virtue of bringing the donor/acceptor chromophores together in
the form of the R:S and RQ:S complexes is borne out for the irradiation performed in the
presence of RQ. However, irradiation of S in the presence of receptor R resulted in lower
conversions than observed in the irradiation of S in the presence of benzophenone
(Scheme III-2.3).
Scheme III-2.3: Irradiation of Quinolone S in the Presence and Absence of Selected Exogenous Chromophores and Receptorsa
hv
No Sensitizer
HN
O
O
Naphthalene
Benzophenone15 min0
Conversion (%)
6
Trace
33
58
RQ
R
O O
N N
NH H
CH3
R
OC6H13
O
O O
N N
NH H
CH3
RQ
OC6H13
(a) Conditions: [7] = 0.075 M, [Additive] = 0.15 M. Irradiations were performed in CDCl3 for 15 minutes using a medium pressure Hg vapor lamp.
S
III-2.8 III-2.9
ii. Identification of the Quenching Chromophore
The fact that irradiation in the presence of benzophenone induced higher levels of
conversion than irradiation in the presence of sensitizing receptor R suggests that the
receptor scaffold contains a weakly quenching chromophore. Indeed, control experiments
involving irradiation of quinolone S in the presence of structural subunits of receptor R
reveal that the iso-phthaloyl moiety inhibits the cycloaddition (Scheme III-2.4).
Scheme III-2.4: Identification of Quenching Chromophore in the Receptor R Scaffolda
HN
O
O
O
N
NH
O O
N OCH3
NH
OC6H13
hv
No Additive
15 min6
Conversion (%)
6
011I-2.6
S
(a) Conditions: [7] = 0.075 M, [Additive] = 0.15 M; Irradiations were performed in CDCl3 for 15 minutes using a medium pressure Hg vapor lamp.
III-2.6PAP
PAP
173
iii. Incorporation of a Non-Quenching Scaffold
In order to further corroborate these observations, a non-quenching scaffold was
conceived and synthesized (Scheme III-2.5). Proceeding from cis-1,3-
cyclohexanedicarboxylic acid anhydride and sensitizing amine III-2.3, a completely
diastereoselective acylation afforded mono-acid mono-amide intermediate III-2.10 in
good yield. Coupling with 2-aminopyridine completed the synthesis of RT (III-2.11).
Scheme III-2.5: Synthesis of Non-Quenching Receptor RT
O O
NH
N
HN
O
H2N
O
O OO
O O
HO HN
O
2-NH2Py.,EDC, DMAP
DCM/THF, 25 °C 6h, 88%
DCM, DIPEA
25 °C, 10h, 70%
(S)- III-2.3
+
RT III-2.11III-2.10
a. Kinetic Studies
If our assessment regarding the nature of the quenching chromophore was
accurate, then the receptor incorporating a cyclohexane spacer should promote a rate of
cycloaddition comparable to that accompanying benzophenone sensitization. Kinetic
studies depicted in Figure III-2.2 reveal no difference in rates corresponding to 10 mole
percent RT and 10 mole percent benzophenone, respectively.
174
Figure III-2.2: Rates of Cycloaddition in the Presence of RT versus Benzophenone
0
10
2030
40
50
607080
90100
0 1 2 3 4 5
Reaction Time (hours)
Perc
ent C
onve
rsio
n
10% R(T) III-2.11
10% Benzophenone
5% Benzophenone
5% R(T) III-2.11
Control
Rates corresponding to 5 mole percent receptor RT and benzophenone, respectively,
differ only by a very small margin. At room temperature, a significant background
(unsensitized) reaction was observed. In contrast, no background reaction was detected at
temperatures lower than -20 °C. Ultimately, poor solubility of RT at low temperatures (≤
0 °C) precluded implementation of this receptor design. Transparency in the scaffold,
after all, perhaps should not be considered a requisite feature. The presence of a weakly
quenching chromophore in the receptor R scaffold may be advantageous as it provides an
innocuous means of dissipating excitation energy when the binding site is unoccupied or
non-productively occupied by product i.e. energy is transferred to the iso-phthaloyl
residue rather than to exogenous untemplated substrate, which could enhance the rate of
the background reaction.
175
E. Characterization of Host-Guest Binding Interactions With regard to sensitizing receptor R and quinolone S, confirmation of the
anticipated 1:1 binding stoichiometry was obtained by applying Job’s method of
continuous variation to NMR results for species in rapid exchange (Figure III-2.3).22 An
association constant for the formation of the R:S complex was determined via 1H NMR
titration experiments (log Ka = 2.5±0.2 at 23 °C in CDCl3) (Figure III-2.4).23 Based on the
calculated Ka value, complex formation should be quantitative under the following
concentration and stoichiometry: [R]=0.15M, [S]=0.075M. Within this concentration
range, the dimeric association of quinolone S was undetectable via 1H NMR titration in
room temperature CDCl3.
Figure III-2.3: Stoichiometry Determination Figure III-2.4: 1H NMR Titration Plot
F. Enantioselective Catalytic Photocycloaddition
The stage was now set for proof-of-principle experiments. Irradiation of S in the
presence of 2-equivalents of sensitizing receptor R at ambient temperature gave
quantitative conversion to P, but without any detectable asymmetric induction (Table III-
2.1, entry 1). However, for reactions conducted at successively reduced temperatures,
176
enantiodifferentiation became increasing apparent. Specifically, at –20oC and –70oC,
quantitative conversion to P occurred in 8% and 21% enantiomeric excess, respectively.
Notably, the time required for complete conversion to P increases as the rate of
intermolecular exchange decreases in response to temperature. For a catalytic asymmetric
process, the degree of asymmetric induction observed at –70°C should persist upon
successively reduced loadings of sensitizing receptor R. Indeed, reactions performed at –
70°C involving the use of equimolar quantities of sensitizing receptor R and quinolone S
gave quantitative conversion to P with 21% enantiomeric excess. Similarly, for
substoichiometric loadings of sensitizing R, 0.5 equivalent and 0.25 equivalents,
quantitative conversion to P occurred in 20% and 19% enantiomeric excess, respectively.
Table III-2.1: Photocycloaddition in the presence of variable quantities of photo-catalyst Ra,b,c
HN
O
O
HN
O
O
hvNH
O
OChiral SensitizingReceptor R
ENTRY R (mol%) Temp (oC) TIME (h) Conversion (%)a EE (%)b
1 200 30 8 100 0 2 200 -20 12 100 8 3 200 -70 24 100 21 4 100 -70 30 100 22 5 50 -70 40 100 20 6 25 -70 70 100 19
(a) Conditions: [S] = 0.075 M. Irradiations were performed in CDCl3 for 15 minutes using a medium pressure Hg vapor lamp. (b) Reactions were periodically monitored by 1HNMR, which enabled a determination of the percent conversion. The formation of byproducts was not observed by 1HNMR. (c) Enantiomeric excess was determined by chiral stationary phase HPLC analysis using a Chiracel OD column.
177
The persistence of the observed 20% enantiomeric excess across a range of
receptor stoichiometries strongly suggests that the observed level of asymmetric
induction results from the intrinsic enantiofacial bias conferred by the association of
quinolone S to the sensitizing receptor R. In order to support this contention, a control
experiment was performed. Irradiation of S was carried out under conditions identical to
those described in Table III-2.1, but in the presence of receptor fragment RF for which
the binding site has been deleted. Quantitative conversion to cycloadduct P was observed,
but without any detectable asymmetric induction. Collectively, these results establish
substoichiometric chirality transfer from a receptor template to the prochiral substrate
(Scheme III-2.6).
Scheme III-2.6: Control Experiment - Irradiation of quinolone S in the presence of receptor Ra,b
HN
O
O
HN
O
O
hv NH
O
OR or RF
-70oC
O O
CH3O NH
CH3
OC6H13
OBinding SiteDeleted
2 Equivalents of Receptor RF, 0% ee2 Equivalents of Receptor R, 21% ee
O O
N N
NH H
CH3
R
OC6H13
O
RF
Binding SitePresent
(a) Conditions: [7] = 0.075 M, [Additive] = 0.15 M. Irradiations were performed in CDCl3 for 15 minutes using a medium pressure Hg vapor lamp. (b) Enantiomeric excess was determined by chiral stationary phase HPLC analysis using a Chiracel OD column.
S
G. Second-Generation Receptor Design and Synthesis
i. Conformational Analysis
A qualitative analysis of competitive diastereomeric transition states en route to
each enantiomeric cycloadduct reveals differentiation on the basis of the host
conformation relative to the guest. The lowest energy duplex results when the substrate is
distal to the benzylic methyl (Figure III-2.5). The disfavored conformation involves
binding of the guest proximally with respect to the methyl.
178
Figure III-2.5: Conformational Basis of Enantiodiscrimination
O
O
O
CH3
BPH
H
CH3BP
BP H
CH3 ii. Incorporation of a tertiary-Butyl Residue
Based on this analysis, it is reasonable to presume that a more sterically
demanding antipode to hydrogen would shift the conformational equilibrium further to
the left. To this end, receptor RtB (III-2.16) was conceived and synthesized per Scheme
III-2.7.
Scheme III-2.7: Retrosynthesis of t-Butyl Sensitizing Receptor RtB
O
OO
NH HN
N
O
O
OO
NH
N
OH
+
H2N
O
RtB III-2.16 III-2.7 III-2.15
Synthesis of primary amine III-2.15 began with a regioselective acylation of
commercially available neopentylbenzene to afford benzophenone derivative III-2.12.
Benzylic bromination, yielding III-2.13, was initially followed by an unsuccessful
179
attempt at substitution with a homochiral benzylic amine. Ultimately, the corresponding
azide III-2.14 was employed. Reduction of the organic azide under Staudinger conditions
was not successful in this case; instead, catalytic hydrogenation led to good yields of the
racemic base (Scheme III-2.8).
Scheme III-2.8: Synthesis of Sensitizing Amine III-2.15
BzCl, AlCl3, CS2
O
NBS, (BzO)2, CCl4
0-25 °C, 16h, 88%
Br
O
77 °C, 5h, 70%
NH2
NH2
MeO
NR
NR
1. NaN3, DMF
80 °C, 28h, 100%
2. H2, Pd/C 25 °C, 20h, 80%
H2N
O
VI
Neopentylbenzene III-2.12 III-2.13
III-2.15
iii. Characterization of Host-Guest Binding Interactions
1H NMR titration experiments were undertaken to quantify RtB:S binding affinity.
Unfortunately, the observed shift behavior was not consistent with the anticipated mode
of association (did not produce a characteristic curve). A reasonable interpretation of the
data is that very weak binding, or alternatively, unexpected modes of association,
including homodimerization of RtB (Figure III-2.6), predominate under the conditions of
the titration.
180
Figure III-2.6: Possible Dimerization Equilibrium
OO
HN
O
NON
H
OO
NH
O
NO N
H
O
OO
NH HN
N
O
RtB
H. Conclusion and Outlook While the use of transition metal templates in conjunction with chiral ligands has
proven successful for myriad reaction types,24 application of this approach to
photochemical reactions is complicated by two factors: i. most metals possess intense
charge transfer bands in the spectral region of interest for organic photochemistry, and ii.
photochemically-promoted ligand loss is often a consequence of such absorptions, which
disrupts the chiral microenvironment of the metal template at the crucial moment of bond
formation. As supported by the collective results reported herein, a potentially general
strategy for the enantioselective catalysis of photo-mediated transformations involves the
use of molecular receptors equipped with appendant chiral sensitizing moieties. Future
studies will focus on the development and optimization of receptor-sensitizer templates
that confer heightened levels of enantiodiscrimination.
181
182
I. References
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Synthesis 1998, 683. (b) Winkler, J. D.; Bowen, C. M.; Liotta, F. Chem. Rev. 1995, 95,
2003. (c) M.T. Chem. Rev. 1988, 88, 1453. (d) Demuth, M. Pure Appl. Chem. 1986, 58,
1233. 2 For reviews on solution-state asymmetric photochemistry, see: (a) Inoue, Y. Chem. Rev.
1992, 92, 741. (b) Rao, H. Chem. Rev. 1983, 83, 535. 3 For selected examples of diastereoselective photochemical transformations, see: (a)
Crimmins, M. T.; Wang, Z.; McKerlie, L. A. J. Am. Chem. Soc. 1998, 120, 1747. (b)
Alibes, R.; Bourdelande, J. L.; Font, J.; Gregori, A.; Parella, T. Tetrahedron 1996, 52,
1267. (c) Alibes, R.; Bourdelande, J. L.; Font, J.; Parella, T. Tetrahedron 1996, 52,
1279. (d) Carreira, E. M.; Hastings, C. A.; Shepard, M. S.; Yerkey, L. A.; Millward, D.
B. J. Am. Chem. Soc. 1994, 116, 6622. (e) Organ, M. G.; Froese, R. D.; Goddard, J. D.;
Taylor, N. J.; Lange, G. L. J. Am. Chem. Soc. 1994, 116, 3312. 4 For representative examples of chiral auxiliaries in photochemical transformations, see:
(a) Dussault, P. H.; Han, Q.; Sloss, D. G.; Symonsbergen, D. J. Tetrahedron 1999, 55,
11437. (b) Bertrand, S.; Hoffman, N.; Pete, J.-P. Tetrahedron 1998, 54, 4873. (c)
Yamaguchi, T.; Uchida, K.; Irie, M. J. Am. Chem. Soc. 1997, 119, 6066. (d) Faure, S.;
Piva-Le Blanc, S.; Piva, O.; Pete, J.-P. Tetrahedron Lett. 1997, 38, 1045. 5 For selected examples of enantioselective solid state photochemistry, see: (a)
Takahashi, M.; Sekine, N.; Fujita, T.; Watanabe, S.; Yamaguchi, K.; Sakamoto, M. J.
Am. Chem. Soc. 1998, 120, 12770. (b) Leibovitch, M.; Olovsson, G.; Scheffer, J. R.;
Trotter, J. J. Am. Chem. Soc. 1997, 119, 1462. (c) Leibovitch, M.; Olovsson, G.;
Scheffer, J. R.; Trotter, J. Pure Appl. Chem. 1997, 69, 815. (d) Gamlin, J. N.; Jones, R.;
Leibovitch, M.; Patrick, B.; Scheffer, J. R.; Trotter, J. Acc. Chem. Res. 1996, 29, 203. 6 For selected examples of enantioselective photochemistry in clathrates, see: (a) Toda,
F.; Miyamoto, H.; Tamashima, T.; Kondo, M.; Ohashi, Y. J. Org. Chem. 1999, 64,
2690. (b) Toda, F. Acc. Chem. Res. 1995, 28, 480.
183
7 For selected examples of enantioselective photochemistry in zeolites, see: (a) Sen, S. E.;
Smith, S. M.; Sullivan, K. A. Tetrahedron 1999, 55, 12657. (b) Joy, A.; Scheffer, J. R.;
Corbin, D. R.; Ramamurthy, V. J. Chem. Soc., Chem. Commun. 1998, 1379. (c) Joy,
A.; Robbins, R. J.; Pitchumani, K.; Ramamurthy, V. Tetrahedron Lett. 1997, 38, 8825.
(d) Kaprinidis, N. A.; Landis, M. S.; Turro, N. J. Tetrahedron Lett. 1997, 38, 2609. 8 Bach, T.; Bergmann, H; Grosch, B.; Harms, K. J. Am. Chem. Soc. 2002, 124, 7982 and
references therein. 9 For selected examples of photochemical reactions in chiral solvents, see: (a) Boyd, D.
R.; Campbell, R. M.; Coulter, P. B.; Grimshaw, J.; Neill, D. C.; Jennings, W. B. J.
Chem. Soc., Perkin Trans. 1 1985, 849. (b) Seebach, D.; Oei, H.-A.; Daum, H. Chem.
Ber. 1977, 110, 2316. (c) Brittain, H. G.; Richardson, F. S. J. Phys. Chem. 1976, 80,
2590. (d) Seebach, D.; Oei, H. A. Angew. Chem. Int. Ed. 1975, 87, 629-636. (e)
Seebach, D.; Daum, H. J. Am. Chem. Soc. 1971, 93, 2795. 10 For selected examples of photochemical reactions in chiral liquid crystals, see: (a)
Finzi, L.; Maccagnani, G.; Masiero, S.; Samori, B.; Zani, P. Liquid Cryst. 1989, 6, 199.
(b) Hilbert, M.; Solladie, G. J. Org. Chem. 1980, 45, 5393. (c) Eskanazi, C.; Nicoud, J.
F.; Kagan, H. B. 1979, 44, 995-999. (d) Nakazaki, M.; Yamamoto, K.; Fujiwara, K.;
Maeda, M. J. Chem. Soc., Chem. Commun. 1979, 1086. (e) Nakazaki, M.; Yamamoto,
K.; Fujiwara, K.; Chem. Lett. 1978, 863. 11 For selected examples of photochemical reactions in chiral polymer matrices, see:
Tazuke, S.; Miyamoto, Y.; Ikeda, T.; Tachibana, K. Chem. Lett. 1986, 953. 12 For selected reviews on photochemistry in organized media, see: (a) Weiss, R. G.
Photochemistry in Organized and Constrained Media; Ramamurthy, V., Ed.; VCH
Publishers: New York, 1991; Chapter 14. (b) Ganapathy, S.; Weiss, R. G.; Organic
Phototransformations in Non-homogeneous Media; Fox, M. A., Ed., American
Chemical Society: Washington, DC, 1985; Chapter 10. 13 Obata, T.; Tetsuro, S.; Yasutake, M.; Shinmyozu, T.; Kawaminami, M.; Yoshida, R.;
Somekawa, K. Tetrahedron, 2001, 57, 1531 and references therein.
184
14 For selected examples of enantioselective photochemistry via circularly polarized
lasers, see: (a) Feringa, B. L.; van Delden, R. A. Angew. Chem. Int. Ed. 1999, 38,
3418. (b) Salam, A.; Meath, W. J. J. Chem. Phys. 1997, 106, 7865. (c) Salam, A.;
Meath, W. J. Chem. Phys. Lett. 1997, 277, 199. (d) Shimizu, Y. J. Chem. Soc., Perkin
Trans. 1 1997, 1275. (e) Moradpour, A.; Kagan, H.; Baes, M.; Morren, G.; Martin, R.
H. Tetrahedron 1975, 31, 2139. 15 For selected examples of enantioselective photochemistry via chiral photosensitizers,
see: (a) Asaoka, S.; Kitazawa, T.; Wada, T.; Inoue, Y. J. Am. Chem. Soc. 1999, 121,
8486. (b) Inoue, Y.; Matsushima, E.; Takehiko, W. J. Am. Chem. Soc. 1998, 120,
10687. (c) “Optically Active (E/Z)-1,3-Cyclooctadiene: First Enantioselective
Synthesis through Asymmetric Photosensitization and Chirotopical Properties,” Inoue,
Y.; Tsuneishi, H.; Hakushi, T.; Tai, A. J. Am. Chem. Soc. 1997, 119, 472. (d) Inoue,
Y.; Yamasaki, N.; Yokoyama, T.; Tai, A. J. Org. Chem. 1993, 58, 1011. (e) Inoue, Y.;
Yamasaki, N.; Yokoyama, T.; Tai, A. J. Org. Chem. 1992, 57, 1332. (f) Inoue, Y.;
Yokoyama, T.; Yamasaki, N.; Tai, A. J. Am. Chem. Soc. 1989, 111, 6480. 16 For asymmetric photodeconjugation, see: (a) Piva, O.; Mortezaei, R.; Henin, F.;
Muzart, J.: Pete, J.-P. J. Am. Chem. Soc. 1990, 112, 9263. (b) Piva, O.; Pete, J.-P.
Tetrahedron Lett. 1990, 31, 5157. (c) Pete, J.-P.; Heinin, F.; Mortezaei, R.; Muzart, J.;
Piva, O. Pure Appl. Chem. 1986, 58, 1257. 17 “Solvent Effects on Diastereoselective Intramolecular [2 + 2] Photocycloadditions:
Reversal of Selectivity through Intramolecular Hydrogen Bonding,” Crimmins, M. T.;
Choy, A. L. J. Am. Chem. Soc. 1997, 119, 10237 and references therein. 18 Corey, E. J.; Bass, J. D.; LeMahieu, R.; Mitra, R. B. J. Am. Chem. Soc. 1964, 86, 5570. 19 Bilz, A.; Stork, T.; Helmchen, G.; Tetrahedron: Asymmetry 1997, 24, 3999. 20 See Turro, N. “Comparison of the Theoretical Distance Dependencies of Energy-
Transfer Rates and Efficiencies,” in Modern Molecular Photochemistry; University
Science Books: Sausalito, 1991, pp. 319-321. 21 See Birks, J. Photophysics of Aromatic Molecules; John Wiley: New York, 1970. 22 Blanda, M. T.; Horner, J. H.; Newcomb, M. J.Org.Chem. 1989, 54, 4626.
185
23 CHEM-EQUILI is a computer program for the calculation of equilibrium constant and
related values from many types of experimental data (IR, NMR, UV/Vis, and
fluorescence spectrophotometry, potentiometry, calorimetry, conductometry, etc.). It is
possible to use any combination of such kinds of methods simultaneously for reliable
calculations of equilibrium constants. For a detailed description see: (a) Solov’ev, V.
P.; Vnuk, E. A.; Strakhova, N. N.; Raevsky, O. A., “Thermodynamic of complexation
of the macrocyclic polyethers with salts of alkali and alkaline-earth metals” VINTI:
Moscow, 1991. (b) Solov’ev, V. P.; Baulin, V. W.; Strakhova, N. N.;Kazachenko, V.
P.; Belsky, V. K.; Varnek, A. A.; Volkova, T. A.; Wipff, G., J. Chem. Soc. Perkin
Trans. 2 1998, 1489. 24 For an authoritative account, see: Comprehensive Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Heidelberg, 1999.
I. Experimental Section
i. Synthetic Procedures
a. General
All reactions were run under an atmosphere of argon, unless otherwise indicated.
Anhydrous solvents were transferred by an oven-dried syringe. Flasks were oven-dried
and cooled in a dessicator. Analytical thin-layer chromatography (TLC) was carried out
using 0.2-mm commercial silica gel plates (DC-Fertigplatten Krieselgel 60 F254).
Preparative column chromatography employing silica gel was performed according to the
method of Still.* Melting points were determined on a Thomas-Hoover melting point
apparatus in sealed capillaries and are uncorrected. Infrared spectra were recorded on a
Perkin-Elmer 1420 spectrometer. High-resolution mass spectra were obtained on a
Karatos MS9 and are reported as m/e (relative intensity). Accurate masses are reported
for the molecular ion (M+1). Unless otherwise noted, proton nuclear magnetic resonance
(1H NMR) spectra were recorded with a Varian Gemini (300 MHz) spectrometer or a
Mercury (400 MHz) spectrometer. Chemical Shifts are reported in delta (δ) units, parts
per million (ppm) downfield from trimethylsilane. Coupling constants are reported in
Hertz (Hz). Carbon-13 nuclear magnetic resonance (13C NMR) spectra were recorded
with a Varian Gemini 300 (75 MHz) spectrometer and a Mercury 400 (100 MHz)
spectrometer. Chemical shifts are reported in delta (δ ) units, parts per million (ppm)
relative to the center of the triplet at 77.0 ppm for deuteriochloroform. Enantiomeric
purity of sensitizing amines (R)-III-2.3 and (S)-III-2.3 was determined using a Varian
Pro Star HPLC equipped with a Chiracel OD column, eluting with 20% ethanol in
186
hexane. Enantiomeric ratios of photocycloaddition products were likewise determined
using a Chiracel OD column, eluting with 10% isopropanol in hexane.
b. Synthesis and Characterization of Cycloaddition Substrate S and Cycloadduct P
The quinolone photocycloaddition substrate S was prepared in accordance with a
literature procedure. Spectroscopic data for this comound, and photocycloaddition
product P were consitent with reported values. See: Kaneko, C. et al. J. Chem Soc. Chem.
Commun. 1979, 804.
c. Synthetic Procedures
III-2.1: 4-Ethylbenzophenone 1 (15.0 g, 71.36 mmol, 100 mol%) and N-
bromosuccinimide (16.52 g, 92.81 mmol, 130 mol%) were combined in CCl4 (350 ml).
To this solution was added benzoyl peroxide (180 mg, 0.72 mmol, 1 mol%) and the
reaction mixture was heated at reflux for 12h. After reflux, the solution was cooled to 0
°C and the solid precipitate was filtered. The filtrate was washed with 1M Na2CO3(aq),
saturated NaS2O3(aq) and brine. The organic layer was dried (Na2SO4), filtered,
evaporated and the residue was purified via column chromatography (0-2.5% ethyl
acetate-hexane) to provide 4-(1-bromoethyl)-benzophenone as a red oil (15.4 g, 53.3
mmol) in 74% yield.
III-2.2: To a solution of 4-(1-bromoethyl)-benzophenone (14.24 g, 49.24 mmol,
100 mol%) in DMF (100 ml) was added NaN3 (9.6 g, 147.7 mmol, 300 mol%). The
reaction mixture was stirred at ambient temperature for 11h, then partitioned between
187
H2O and Et2O. The aqueous layer was washed with Et2O, then organic fractions were
pooled and washed with brine. Drying over Na2SO4 and concentration in vacuo yielded
4-(1-azidoethyl)-benzophenone as a golden oil (11.9 g, 47.4 mmol) in 96% yield,
requiring no further purification.
III-2.3: To a solution of 4-(1-azidoethyl)-benzophenone (11.9 g, 47.36 mmol, 100
mol%) in THF (400 ml) and H2O (2.5 ml, 142.06 mmol, 300 mol%) was added
triphenylphosphine (18.63 g, 71.03 mmol, 150 mol%). The reaction mixture was heated
at reflux for 20h, then concentrated to 20% volume. The reaction mixture was partitioned
between H2O and Et2O, and the organic phase extracted with three portions of 1M
HCl(aq). Pooled aqueous washes were neutralized with 2M NaOH(aq) and extracted three
times with Et2O. Organic fractions were combined, washed with brine, dried over
Na2SO4 and then evaporated onto silica gel. Column chromatography (0-10% methanol-
dichloromethane) afforded 4-(1-aminoethyl)-benzophenone as a golden oil (7.92 g, 35.2
mmol) in 74.2% yield.
III-2.4: To a 0 °C solution of 4-(1-aminoethyl)-benzophenone (11.88 g, 52.7
mmol, 100 mol%) and (R)-mandelic acid (8.83 g, 58 mmol, 110 mol%) in DCM (250 ml)
was added DCC (11.97 g, 58 mmol, 110 mol%) and HOBT (710 mg, 5.3 mmol, 10
mol%). Stirring was maintained for 14h, allowing reaction to warm to ambient
temperature, then was cooled to 0 °C, filtered, and the filtrate washed with first 1M
Na2CO3(aq), then 1M H2SO4(aq). Washing with brine and drying with Na2SO4 was
followed by concentration and column chromatography (20-40% ethyl acetate-hexane) to
188
yield the upper Rf (R,R) diastereomer (7.4 g, 20.6 mmol) in 78% yield and the lower Rf
(R,S) diastereomer (8.2 g, 22.8 mmol) in 87% yield as white solids.
(R)-III-2.3: Mandelamide (R,R)-III-2.4 (1.0 g, 2.8 mmol, 100 mol%) was heated
at reflux in 20ml concentrated aqueous HCl for 14h. The cooled solution was extracted
with Et2O, then made basic with 3M NaOH(aq) and extracted again with Et2O. The
combined Et2O fractions were washed with brine, dried over Na2SO4, concentrated and
chromatographed (2-7% MeOH-DCM) to yield (R)-III-2.3 as a clear oil (0.4 g, 1.78
mmol) in 64% yield
(S)-III-2.3:The (S) antipode of amine III-2.3 was derived in the same manner as
the (R) antipode.
III-2.5: Dimethyl-5-hydroxyisophthalate (13.07 g, 62.18 mmol, 100 mol%) was
dissolved in DMF (150 ml) before adding 1-bromohexane (9.82 g, 59.22 mmol, 105
mol%) and K2CO3 (9.82 g, 71.06 mmol, 114 mol%) and heating at 65 °C for 14h. The
reaction mixture was partitioned between H2O and Et2O. The aqueous layer was
separated and washed with Et2O. Combined organic fractions were washed with 1M
NaOH(aq) and brine. Drying over Na2SO4 and concentration in vacuo, followed by
purification over silica gel with 10% ethyl acetate-hexane yielded dimethyl-5-
hexyloxyisophthalate (16.84 g, 57.2 mmol) in 92% yield as a pale yellow oil, which
crystallized upon standing.
189
III-2.6: 2-aminopyridine (1.98 g, 21.02 mmol, 100 mol%) was dissolved in 125
ml THF and cooled to -78 °C. A solution of n-butyllithium in hexanes (13.14 ml, 1.6 M,
100 mol%) was added slowly and the solution was allowed to stir for 0.5h, and then
transferred, dropwise, via cannula, into a -78 °C solution of diester III-2.5 (12.37 g,
42.03 mmol, 200 mol%) in 50 ml THF. The solution was stirred for 3h after addition,
then quenched with 150 ml 1M NaHCO3(aq). Partitioning between Et2O and H2O was
followed by two extractions of the aqueous phase with Et2O. Combined organic fractions
were washed with brine and dried over Na2SO4. Purification over silica gel with 0-40%
ethyl acetate-hexane yielded methyl 5-hexyloxy-N-pyridin-2-yl-isophthalamate (5.9 g,
16.6 mmol) in 79% yield as a white solid.
III-2.7: Ester III-2.6 (510 mg, 1.43 mmol, 100 mol%) was dissolved in 14 ml
3:1:1 THF/CH3OH/H2O before adding LiOH monohydrate (90 mg, 2.15 mmol, 150
mol%). The reaction mixture was allowed to stir at room temperature for 14h, at which
point NH4Cl (115 mg, 2.15 mmol, 150 mol%) was added. The solution was concentrated
to dryness and chromatographed over silica gel (0-7% CH3OH-CH2Cl2) to yield 5-
hexyloxy-N-pyridin-2-yl-isophthalamic acid (440 mg, 1.28 mmol) in 90% yield as an
amorphous white solid.
III-2.8: To a solution of acid III-2.7 (1.0 g, 2.92 mmol, 100 mol%) and amine
(S)-III-2.3 (660 mg, 2.92 mmol, 100 mol%) in CH2Cl2 (15 ml) was added EDC (620 mg,
3.21 mmol, 110 mol%) and DMAP (36 mg, 0.292mmol, 10 mol%). The reaction mixture
was stirred at ambient temperature for 14h, then evaporated onto silica gel and
chromatographed using 15-40% ethyl acetate-hexane to yield receptor R (1.06g, 1.9
mmol) in 66% yield as a white solid.
III-2.9: To a solution of acid III-2.7 (1.0 g, 2.92 mmol, 100 mol%) and (R)-1-
(naphthyl)ethylamine (850 mg, 3.21 mmol, 110 mol%) in CH2Cl2 (15 ml) was added
EDC (620 mg, 3.21 mmol, 110 mol%) and DMAP (360 mg, 0.292 mmol, 10 mol%). The
reaction mixture was stirred at ambient temperature for 14h, then evaporated onto silica 190
gel and chromatographed using 10-40% ethyl acetate-hexane to yield receptor RQ (0.99
g, 2.0 mmol) in 68% yield as a waxy white solid.
III-2.10: To a solution of amine (S)-III-2.3 (1.0 g, 4.44 mmol, 100 mol%) and
N,N-diisopropylethylamine (1.15 g, 8.88 mmol, 200 mol%) in dichloromethane (11 ml,
0.4M) was added a solution of 1,3-cyclohexanedicarboxylic acid anhydride (0.685g, 4.44
mmol, 100 mol%) in dichloromethane (1 ml, 0.69M). The reaction mixture was stirred at
room temperature for 10h, then washed with three portions of 0.5M HCl(aq). The organic
solution was concentrated onto silica gel and purified by column chromatography, eluting
with a mixture of methanol and chloroform, to yield the mono-acid product as a white
solid in 70% yield and as a single diastereomer.
III-2.11: (Mono)acid-(mono)amide III-2.10 (500 mg, 1.32 mmol, 100 mol%) was
dissolved in a 1:1 mixture of dichloromethane and tetrahydrofuran (6.5 ml, 0.2M). To
this solution was added 2-aminopyridine (136 mg, 1.44 mmol, 110 mol%), followed by
EDC (276 mg, 1.44 mmol, 110 mol%) and finally DMAP (18 mg, 0.15 mmol, 10 mol%).
The reaction mixture was stirred for 6h, then concentrated to dryness. The residue was
evaporated onto silica gel and purified via column chromatography, eluting with a
mixture of ethyl acetate and hexanes. The receptor RQ was obtained as a white solid in
88% yield.
III-2.12: To a solution of neopentylbenzene (5 g, 33.7 mmol, 100 mol%) in
carbon disulfide (170 ml, 0.2M) is added benzoyl chloride (4.74 g, 33.7 mmol, 100
mol%). This solution was cooled to 0 °C before adding AlCl3 (9 g, 67.5 mmol, 200
mol%) portionwise, over several minutes. The reaction was stirred, warming to room
temperature, for a total of 16h, then recooled to 0 °C and quenched via careful addition of 191
water. The biphasic reaction mixture was then filtered and the organic layer isolated. The
organic layer was washed with several portions of 1M NaOH(aq), dried over Na2SO4 and
concentrated. The residue was purified via column chromatography, eluting with a
mixture of ethyl acetate and hexanes and affording the benzophenone derivative in 88%
yield.
III-2.13: 4-Neopentylbenzophenone III-2.12 (2 g, 8 mmol, 100 mol%) was
dissolved in CCl4 (40 ml, 0.2M). To this solution was added N-bromosuccinimide (1.48g,
8.3 mmol, 1.05 mol%), followed by a catalytic amount of benzoyl peroxide. The reaction
was stirred at reflux for 5h, at which point complete conversion was observed by TLC.
After cooling to 0 °C, the reaction was filtered of succinimide and concentrated. The
residue was purified via column chromatography, eluting with a mixture of ethyl acetate
and hexanes and affording the brominated benzophenone derivative in 70% yield.
III-2.14: Bromide III-2.13 (1 g, 3 mmol, 100 mol%) and NaN3 (0.98 g, 15 mmol,
500 mol%) were dissolved in DMF (30 ml, 1M). The reaction solution was stirred at 80
°C for 28h, at which point 1HNMR analysis revealed quantitative conversion. The
reaction solution was cooled to room temperature and partitioned between ethyl ether and
water. The organic phase was washed with brine, dried over Na2SO4, and concentrated to
afford the target azide in 100% yield.
III-2.15: Azide III-2.14 (4 g, 13.6 mmol, 100 mol%) was dissolved in ethanol
and the solution was degassed with Ar. 10% Pd/C (400 mg) was added in one portion,
and hydrogen gas was bubbled through the reaction mixture for 3 minutes before leaving
the suspension to stir under 1 atm of H2 for 20h. The reaction was filtered through
diatomaceous earth and concentrated to dryness. The residue was purified via column 192
chromatography, eluting with a mixture of isopropyl alcohol and chloroform and
affording the target amine in 80% yield
III-2.16: (Mono)acid-(mono)amide III-2.7 (1 g, 4.1 mmol, 100 mol%) and amine
III-2.15 were combined in dichloromethane (20 ml, 0.2M). To this solution was added
EDC (0.95 g, 5 mmol, 120 mol%) and then DMAP (44 mg, 0.4 mmol, 10 mol%), and the
solution was stirred at room temperature for 12h. The reaction was concentrated and the
residue purified by silica gel chromatography, eluting with a mixture of ethyl acetate and
hexanes. In this manner, a 45% yield of receptor RtB was obtained.
193
d. Spectroscopic and Crystallographic Data
Br
O
III-2.1
1H NMR (400 MHz, CDCl3): δ 2.06 (d, J = 7.2 Hz, 3H), 5.21 (q, J = 6.8 Hz, 1H), 7.43-7.58 (m, 5H), 7.74-7.78 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 26.80, 48.19, 76.68, 70.00, 77.31, 126.28, 127.81, 129.45, 129.94, 132.00, 136.74, 136.76, 146.77. HRMS: Calcd [M+1] for C15H13OBr: 289.0228; Found: 289.0233. FTIR(film): 3019, 2400, 1659, 1608, 1278, 1216, 762, 702, 669, 420 cm-1.
194
N3
O
III-2.2
1H NMR (400 MHz, CDCl3): δ 1.54 (d, J = 6.8Hz, 3H), 4.67 (q, J = 6.8 Hz, 1H), 7.39-7.45 (m, 4H), 7.51-7.55 (m, 1H), 7.74-7.79 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 21.80, 60.49, 76.67, 77.00, 77.32, 125.66, 127.72, 129.36, 129.93, 131.88, 136.55, 136.73, 144.71. HRMS: Calcd [M+1] for C15H13N3O: 252.1137; Found: 252.1130. FTIR(film): 3059, 2979, 2113, 1662, 1609, 1447, 1412, 1279, 1061, 939, 703, 436 cm-1.
195
NH2
O
III-2.3
1H NMR (400 MHz, CDCl3): δ 1.53 (d, J = 6.6Hz, 3H), 1.94 (s, 2H), 4.31 (q, J = 6.6 Hz, 1H), 7.55-7.61 (m, 4H), 7.66-7.72 (m, 1H), 7.88 -7.93 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 25.31, 50.81, 76.57, 77.00, 77.42, 125.38, 127.92, 129.61, 130.11, 131.97, 135.77, 137.43, 152.24, 195.97. HRMS: Calcd [M+1] for C15H15NO: 226.1227; Found: 226.1232. FTIR(film): 3370, 3299, 3058, 2965, 2249, 1658, 1607, 1447, 1280, 939, 852, 734, 443 cm-1.
196
HN
CH3
O
O
OH
(S,R)-III-2.4
1H NMR (400 MHz, CDCl3): δ 1.42 (d, J = 6.8Hz, 3H), 4.43 (d, J = 3.8 Hz, 1H), 4.96 (d, J = 3.4 Hz, 1H), 5.05 (qt, J = 7.2 Hz, 1H), 7.08 (d, J = 7.9 Hz, 1H), 7.22-7.30 (m, 6H), 7.40-7.43 (m, 2H), 7.52-7.56 (m, 1H), 7.62 -7.70 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 22.07, 49.54, 74.08, 76.68, 77.00, 77.31, 125.38, 126.18, 127.81, 127.93, 128.14, 129.50, 130.00, 132.02, 135.86, 136.83, 138.95, 147.10, 170.96, 195.56. HRMS: Calcd [M+1] for C23H21NO3: 360.1600; Found: 360.1596. FTIR(film): 3400, 3018, 2401, 1655, 1518, 1279, 1216, 771, 443 cm-1
MP 121-123 ºC. [α]22
D = -115.6 ( c = 1, CHCl3).
197
HN
CH3
O
O
OH
(R,R)-III-2.4
1H NMR (400 MHz, CDCl3): δ 1.39 (d, J = 6.8Hz, 3H), 4.55 (d, J = 4.1 Hz, 1H), 4.87 (d, J = 4.5 Hz, 1H), 5.00 (qt, J = 7.2 Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H), 7.20-7.31 (m, 6H), 7.39-7.43 (m, 2H), 7.51-7.56 (m, 1H), 7.61 -7.70 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 22.20, 48.66, 73.84, 76.69, 77.00, 77.31, 125.39, 126.15, 127.81, 127.89, 128.11, 129.50, 129.94, 132.04, 135.83, 136.80, 138.95, 147.26, 171.02, 195.60. HRMS: Calcd [M+1] for C23H21NO3: 360.1600; Found: 360.1598. FTIR(film): 3400, 3018, 2401, 1655, 1518, 1279, 1216, 771, 443 cm-1. MP: 123-124 ºC. [α]22
D = -3.9 ( c = 1, CHCl3).
198
NH2
O
[α]22D = -24.9 ( c = 1, CHCl3).
NH2
O
[α]22D = +25.9 ( c = 1, CHCl3).
199
O
OO
CH3O OCH3 III-2.5
1H NMR (300 MHz, CDCl3): δ 0.88 (t, J=6.9 Hz, 3H), 1.29-1.34 (m, 6H), 1.42-1.47 (quintet, 2H), 1.73-1.80 (quintet, J=7.2 Hz, 2H), 3.91 (s, 6H), 4.01 (t, J=6.7 Hz, 2H), 7.71 (s, 2H), 8.23 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 13.92, 22.50, 25.55, 28.96, 31.43, 52.25, 68.49, 119.68, 122.61, 131.56, 159.13, 166.08. HRMS: Calcd [M+1] for C16H22O5: 295.1546; Found: 295.1542. FTIR (film): 3054, 2986, 2685, 2305, 1716, 1673, 1628, 1421, 1363, 1265, 1161, 978, 896, 738, 704 cm-1. MP: 52-53 ºC
200
O
O O
NH OCH3
N III-2.6
1H NMR (400 MHz, CDCl3): δ 0.89-0.93 (t, J=7.1 Hz, 3H), 1.32-1.51 (m, 6H), 1.77-1.84 (quintet, J=7.4 Hz, 2H), 4.04-4.08 (t, 6.8 Hz, 2H), 7.13-7.18 (t, J=6.2 Hz, 1H), 7.76 (s, 1H), 7.84-7.89 (m, 2H), 8.21-8.23 (d, J=5.4 Hz, 1H), 8.69-8.72 (d, J=7.6 Hz, 1H), 9.05 (s, 1H), 11.54 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.04, 22.61, 25.67, 29.12, 31.56, 68.54, 116.24, 119.02, 119.68, 120.07, 121.51, 132.26, 134.76, 140.27, 144.96, 152.16, 159.43, 165.29, 170.93. HRMS: Calcd [M+1] for C20H24N2O4: 357.1814; Found: 357.1812. FTIR(film): 3054, 2986, 2955, 2873, 2306, 1724, 1683, 1595, 1578, 1518, 1434, 1302, 1265, 1046, 896, 747 cm-1. MP: 112-114 ºC.
201
O
O O
NH OH
N III-2.7
1H NMR (400 MHz, DMSO-d6): δ 0.85 (t, J=6.8, Hz, 3H), 1.26-1.37 (m, 4H), 1.39-1.40 (m, 2H), 1.68-1.75 (quintet, J=7.5 Hz, 2H), 4.05-4.08 (t, 6.2 Hz, 2H), 7.11-7.14 (t, J=5.5 Hz, 1H), 7.56 (s, 1H), 7.78-7.82 (m, 2H), 8.12 (s, 1H), 8.17 (d, J=8.2 Hz, 1H), 8.35 (d, J=3.8 Hz, 1H), 10.95 (s, 1H). 13C NMR (75 MHz, DMSO-d6): δ 13.87, 22.07, 25.13, 28.53, 30.97, 38.67, 38.95, 39.23, 39.50, 39.78, 40.06, 40.34, 68.11, 114.85, 117.76, 118.33, 119.90, 121.28, 132.39, 135.81, 138.09, 147.92, 152.09, 158.63, 165.05, 166.62. HRMS: Calcd [M+1] for C19H22N2O4: 343.1658; Found: 343.1661. FTIR(film): 3683, 3614, 3261, 3019, 2958, 2934, 2400, 1672, 1594, 1580, 1470, 1340, 1217, 1045, 929, 750, 669, 419 cm-1. MP: 204-206 ºC.
202
O
OO
NH HN
N
O
III-2.8
1H NMR (400 MHz, CDCl3): δ 0.85 (t, J = 6.5Hz, 3H), 1.26-1.37 (m, 6H), 1.47 (d, J = 6.8 Hz, 3H), 1.68 (qt, J = 6.8 Hz, 2H), 3.86 (t, J = 6.5 Hz, 1H), 5.28 (qt, J = 7.2 Hz, 1H), 6.89-6.92 (m, 1H), 7.24-7.39 (m, 4H), 7.47-7.67 (m, 9H), 7.98-7.07 (m, 2H), 8.21 (d, J = 8.2 Hz, 1H), 9.34 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.42, 21.92, 22.89, 25.90, 29.29, 31.74, 49.61, 68.49, 76.68, 77.00, 77.31, 114.14, 116.22, 116.60, 117.07, 119.60, 125.15, 125.80, 126.87, 128.04, 128.14, 135.09, 135.85, 137.89, 142.44, 147.10, 150.81, 158.94, 164.52, 164.93. HRMS: Calcd [M+1] for C34H36N3O4: 550.2706; Found: 550.2726. FTIR(film) 3370, 3299, 3058, 2965, 2249, 2200, 1658, 1607, 1447, 1412, 1308, 1280, 924, 852, 734, 620, 443 cm-1. MP: 146-147 ºC. [α]22
D = +65.0º ( c = 1, CHCl3).
203
O
OO
NH HN
N
III-2.9
1H NMR (400 MHz, CDCl3): δ 0.91 (t, J = 6.8Hz, 3H), 1.26-1.45 (m, 6H), 1.65 (d, J = 7.2 Hz, 3H), 1.77 (qt, J = 7.2 Hz, 2H), 1.94 (s, 1H), 3.98 (t, J = 6.5 Hz, 1H), 5.45 (qt, J = 7.2 Hz, 1H), 6.74 (d, J = 7.9Hz, 1H), 7.01-7.04 (m, 1H), 7.40-7.53 (m, 5H), 7.68-7.83 (m, 6H), 8.20 (d, J = 4.1Hz, 1H), 8.29 (d, J = 8.6 Hz, 1H), 8.81 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.42, 21.92, 22.89, 25.90, 29.29, 31.74, 49.61, 68.49, 76.68, 77.00, 77.31, 114.14, 116.22, 116.60, 117.07, 119.60, 125.15, 125.80, 126.87, 128.04, 128.14, 135.09, 135.85, 137.89, 142.44, 147.10, 150.81, 158.94, 164.52, 164.93. HRMS: Calcd [M+1] for C31H33N3O3: 496.2600; Found: 496.2607. FTIR(film): 3370, 3299, 3058, 2965, 2249, 2200, 1658, 1607, 1447, 1412, 1308, 1280, 924, 852, 734, 620, 443 cm-1. MP: 146-147 ºC. [α]22
D = -47.0º ( c = 1, CHCl3).
204
O O
NH HN
O
N
III-2.11
1H NMR (500 MHz, CDCl3): δ 1.31-1.58 (m, 2H), 1.52 (d, 3H, J=7.0), 1.72-1.82 (m, 2H), 1.94-2.04 (m, 3H), 2,17-2.25 (m, 2H), 2.31-2.36 (m, 1H), 5.22 (quintet, 1H, J=7.2), 5.97 (d, 1H, J=7.6), 7.03-7.06 (m, 1H), 7.4-7.43 (m, 2H), 7.47-7.51 (m, 2H), 7.58-7.62 (m, 2H), 7.68-7.72 (m, 1H), 7.77-7.81 (m, 4H), 8.2-8.28 (m, 3H). 13C NMR (75 MHz, CDCl3): δ 21.8, 24.9, 28.9, 31.7, 32.0, 44.6, 45.7, 48.8, 114.1, 119.8, 125.9, 128.8, 130.0, 130.5, 132.4, 136.6, 137.6, 138.4, 147.8, 148, 151.3, 173.6, 173.9, 196.3.
205
O
III-2.12
1H NMR (400 MHz, CDCl3): δ 0.94 (s, 9H), 2.58 (s, 2H), 7.22 (d, J = 8.2 Hz, 2H), 7.4 – 7.61 (m, 3H), 7.73 (d, J = 8.2 Hz, 2H), 7.81 (d, J = 7.9 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 29.34, 31.92, 50.13, 128.14, 129.59, 129.89, 130.27, 132.1, 135.1, 137.84, 144.97, 196.51.
206
O
O O
NH HN
O
N
III-2.16
1H NMR (300 MHz, CDCl3): δ 0.86 (t, 3H, J=6.9), 0.96 (s, 9H), 1.2-1.42 (m, 6H), 1.72 (q, 2H, J=6.7), 3.92 (t, 2H, J=6.4), 5.03 (d, 1H, J=11), 6.95-6.99 (m, 1H), 7.11 (d, 1H, J=8.9), 7.34 (d, 2H, J=8.4), 7.39-7.53 (m, 5H), 7.64-7.69 (m, 3H), 7.73 (d, 2H, J=8.4), 7.87 (s, 1H), 8.81 (d, 1H, J=3.8), 8.284 (d, 1H, J=8.4), 9.29 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 13.9, 22.5, 25.5, 26.8, 28.9, 31.38, 34.9, 62.3, 68.5, 114.4, 116.2, 117.1, 117.3, 120.0, 128.1, 128.2, 129.7, 129.9, 132.3, 135.8, 136.3, 136.6, 137.4, 138.3, 144.7, 147.8, 151.4, 159.6, 165.1, 166.1, 196.3. HRMS: Calcd [M+1] for C37H42N3O: 592.3175. Found: 592.3187.
207
208
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VITA
David Frederic Cauble, Jr. was born in Charlotte, North Carolina on September
12, 1973, the son of Alice Harkey Cauble and David Frederic Cauble. After earning his
Bachelor of Science degree in chemistry at North Carolina State University in Raleigh,
he worked for Micell Technologies, Inc from 1996 until enrolling in the graduate
chemistry program at the University of Texas at Austin in 1999.
Permanent Address: 5818 Gate Post Rd Charlotte, NC 28211 This dissertation was typed by the author.
221
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