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Université de Montréal

Progress Towards a Total Synthesis of

(±)-Longithorone C

Par

Joseph E. Zakarian

Département de chimie,

Faculté des arts et de sciences

Memoire présenté à la Faculté des études supérieures

en vue de l'obtention du grade de

Maître ès sciences (M.Sc.) en chimie

Juillet 2007

© Joseph E. Zakarian, 2007

Université de Montréal

Faculté des études supérieures

Ce mémoire intitulé:

Progress Towards a Total Synthesis of

(±)-Longithorone C

Présenté par

Joseph E. Zakarian

a été évalué par un jury composé des personnes suivantes:

Président-rapporteur: André B. Charette

Directeur de recherche: Shawn K. Collins

Membre du jury : William D. Lubell

Mémoire accepté le:

11

111

To my Wife Araks

For the loving support

IV

Table of Contents

Title Page ..................................................................................................... i

·fi . .. Jury IdentI IcatIon ...................................................................................... 11

Dedication Page .......................................................................................... iii

Summary ................................................................................................. vii

Résumé ................................................................................................... viii

Acknowledgements ................................................................................... .ix

List of Figures ............................................................................................ x

List ofSchemes ......................................................................................... xii

List of Tables ........................................................................................... xv

Abbreviations ........................................................................................... xvi

Chapter 1: Introduction to the Longithorones: Paracyclophane Natural

1.1 1.2 1.2.1 1.2.2 1.2.3 1.2.4 1.2.5 1.3 1.3.1 1.3.2

1.3.3 1.4 1.4.1 1.4.2 1.4.3

1.5

Products .......................................................................... 1

Ring Closing Olefin Metathesis as a Route to Strained Systems .................. . Synthesis of Longithorone A ........................................................... . Introduction and Synthetic Challenges ................................................ . Preparing [12]Paracyc1ophanes by Enyne Metathesis ............................... . Installation ofthe Atropisomeric Control Element. .................................. . Enyne Metathesis Macrocyc1ization using an Atropisomeric Control Element... Conclusion ................................................................................. . Synthesis ofLongithorone B ........................................................... . [3,3]-Rearrangement in Forming Ortho-Allyl PhenoI31 ............................ . Intramolecular Coupling of the Famesylated Side Chain by Friedel-Crafts

Alkylation ................................................................................. . Conclusion ................................................................................ . Longithorone C: A Representative Compound ....................................... . Synthetic Challenges and Goals ........................................................ . Forming [12]Paracyc1ophanes: A Model Study ...................................... . Determining the Optimal Site for Metathesis along the Ansa-Bridge and Formation of Tri-substituted Olefins by RCM ....................................... . Conclusion ................................................................................ .

1 3 3 6 7 9 11 12 13

14 15 16 16 16

21 24

v

Chapter II: Model Studies Directed Towards the Total Synthesis of Longithorone C via Macrocyclic Olefin Metathesis ....................................... 25

II.1 Retrosynthetic Analysis and Model Studies. .............................. ....... .. . .. 25 II.2 Synthesis ofPentafluoro-2,5-dihydroxybenzoate 60................................. 27 II.3 Synthesis of the AHylic AlcohoI61..................................................... 28 II.4 Macrocyclic Olefin Metathesis ofModel System using trans,trans-FamesoI65 ... 30 II.5 Synthesis of cis-Famesol 62.............................................................. 32 11.5.1 First Generation Synthesis of cis-FamesoI62......................................... 32 11.5.2 Second Generation Synthesis of cis-Famesol 62...................................... 33 II.6 Metathesis ofModel System Incorporating cis-FamesoI62......................... 36 II.7 Synthesis ofcis-Olefin 93............................................ ............ ........ 39 II.8 Metathesis ofModel System 94 using cis-Olefin 93.................................. 40 II.9 Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. 42

Chapter III: Attacking the Total Synthesis of (±)-Longithorone C: Attachment of Alkyl Chains via Coupling Reactions ....................................... 43

111.1 Negishi Coupling Reactions.............................................................. 44 111.2 Copper Catalyzed Grignard Reaction. . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 III.2.1 Optimizing Mg-X Exchange............................................................. 48 III.2.2 Optimizing sNi/SN2-type Product Ratio............................................... 50 III.2.3 Mechanism behind the alyProduct Ratios............................................. 53 IIL2.4 Attaching cis-Olefin 93 via the Copper Catalyzed Grignard Reaction..... .......... 56 111.3 Determining Stereochemistry ofthe Side Chains................ ..................... 58 111.4 Conclusion. . .. . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 59

Chapter IV: Improved Gearing Elements for Macrocyclic Olefin Metathesis:

IV.l IV.2 IV.3

IV.4

IV.5

A Mode) Stndy ................................................................... 60

Improved Gearing Element used in Model Systems ................................ .. Molecular Modeling using the Bistrifluoromethyl Auxiliary on Model Systems Molecular Modeling using the Bistrifluoromethyl Auxiliary on an AH Carbon System ...................................................................................... . Determining the Ideal Gearing Element in the Formation of an AH-Carbon [12]Paracyclophane ...................................................................... .. Conclusion ................................................................................. .

60 63

65

66 70

VI

Chapter V: Approach Towards the Total Synthesis of (±)-Longithorone C ...... 72

V.l RRCM in Forming an AlI-Carbon [12]Paracyc1ophane. ............................. 73 V.2 Future Work for Completing the Total Synthesis of Longithorone C............... 76 V.3 Conclusion.............................................. ..................... .............. 80

Chapter VI: Experimental .................................................................... 81

VI. 1 General Experimental Notes. . .. . .. . ... ...... ... ...... ................................... 81 VI.2 Experimental Procedures and Data............. ............................ ............. 85

Vll

Summary

The growing number of cyc10phane containing natural products and total

syntheses that employ cyc10phane intermediates has stimulated renewed interest in their

asymmetric preparation and planar chirality. A synthetic approach is proposed towards

the total synthe sis of longithorone C. This [12]paracyclophane quinone is a member of a

group of macrocyc1ic farnesylated quinones isolated from the tunicate Aplidium

longithorax. The development of an efficient preparative method will be discussed for

the macrocyc1ic ansa-bridge by ring-c1osing olefin metathesis (RCM) in racemic form.

The investigation of various fluorinated auxiliaries as novel gearing elements and their

effect on macrocyc1ization is presented. The mechanism by which these gearing

elements function has been studied by molecular modeling. Copper-catalyzed Grignard

reactions have been optimized in order to selectively couple prenylated side chains to

aromatic halides. Finally, a variety of olefin metathesis catalysts were studied for the

preparation of a [12]paracyclophane containing three stereodefined tri-substituted olefins.

Key Words: gearing elements, longithorone C, paracyc1ophanes, ring-c1osing olefin

metathesis (RCM).

V111

Résumé

Le nombre grandissant de produits naturels contenant des cyclophanes ou de

synthèses totales utilisant des cyclophanes comme intennédiaires a stimulé un nouvel

intérêt pour la synthèse asymétrique de ces molécules possédant une chiralité plane. Une

approche synthétique vers la synthèse totale de la longithorone C a été proposée. Cette

quinone, possédant un [12]paracyclophane, est membre d'un groupe de quinones

macrocycliques contenant une chaîne ressemblant à famesol dans leur squelette et a été

isolée à partir de Aplidium longithorax. Le développement d'une méthode efficace pour

la préparation de ce macrocycle contenant un pont-ansa par métathèse d'oléfines par

fenneture de cycle dans sa fonne racémique sera discuté. L'investigation d'une variété

d'auxiliaires fluorés comme nouveaux éléments directeurs et leur effet sur la

macrocyclisation seront présentés. Le mécanisme par lequel ces éléments directeurs

fonctionnent a été étudié par modélisation moléculaire. Une réaction de Grignard

catalysée par le cuivre a été optimisée dans le but d'installer les châmes latérales

allyliques à l'halogénure aromatique. Finalement, une variété de catalyseurs de

métathèse d'oléfines a été étudié pour la préparation d'un [12]paracyclophane contenant

trois oléfines trisubstitués stéréodéfinies.

Mots clés: éléments directeurs, longithorone C, paracyclophanes, métathèse d'oléfine par

fenneture de cycle (RCM).

IX

Acknowledgements

1 would like to express my sincere gratitude to Professor Shawn K. Collins for

giving me the opportunity to work in his group. He is an excellent teacher who has

guided me throughout my degree.

1 would also like to thank past and present members of the Collins group who

have contributed to the research projects that 1 have been involved with, namely, Pierre­

André Fournier and Alain Grandbois.

Thanks to the assistance provided by Dr. Min Tan Phan Viet, Sylvie Bilodeau,

and Cedric Malveau for the help they have provided in acquiring sorne of the NMR data

that have been presented here, as weIl as for their patience in answering my questions.

Thanks to Alexandra Furtos, Karine Venne, and Dalbir Sekhon for the help in

acquiring mass spectral data, for the patience in answering my questions, and for letting

me know when my lab coat needed replacement.

To aIl my mends who have made this such a pleasurable experience: thanks for

the good times!

Last but not least, 1 would like to thank my family. My parents and two sisters

have al ways supported aIl of my endeavors, and my lovely wife Araks Malkhassian for

the patience through aIl those long hours of work. 1 am grateful for their unconditional

love and support. 1 would not have been able to do this without you.

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure Il

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

Figure 18

x

List of Figures

The Longithorone Family ofNatural Products. ...... ...... ... ... .... .......... 3

Retrosynthetic Analysis ofLongithorone A Involving Molecular and

Transannular Diels-Alder Reactions..... .................................................. 4

Retrosynthetic Analysis of Longithorone A Involving Enyne

Metathesis.. ... ... ..... ....... ...... ...... .......... ............... ... ... ..... ..... 5

Intramolecular and Intermolecular Enyne Metathesis Reactions.... . . . . . . . . 6

Retrosynthetic Analysis of Longithorone B........ ........ .......... ......... 12

Structural Similarities Between Longithorone A, B, and C........ ......... 16

Initial Retrosynthetic Analysis of Longithorone C. ... ....... ...... ..... ..... 17

Retrosynthetic Analysis ofa Model System using cis-Farneso162.. ..... 26

Retrosynthetic Analysis of Revised Model System using

trans-Farneso165. ....... ............... ......... .............. .............. ...... 26

Revised Model System.......................................................... 32

Stereocontrol During Triflation of p-Ketoester 81 using DMF as Solvent. 34

Proposed Model Study using Disubstituted Olefin 93.... ... ................ 39

Retrosynthetic Analysis of Longithorone C. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 43

Copper Catalyzed Grignard Reactions ... , ........................ ". ... ....... 46

Retrosynthetic Analysis using Copper Catalyzed Grignard Reactions.... 46

Magnesium-Halogen Exchange................... ............................. 47

Role of Copper Catalyst in Organomagnesium Cross-Coupling Reactions. 48

Proposed Synthetic Pathway for Copper Catalyzed Coupling of

Grignard Reagents ..... , ........................................ , . . . .. . . . . . . . . . . .. 48

Figure 19

Figure 20

Figure 21

Figure 22

Figure 23

Figure 24

Figure 25

Figure 26

Figure 27

Figure 28

Figure 29

Figure 30

Figure 31

Figure 32

Xl

Regiocontrol in Copper Catalyzed Grignard Reactions. ... ... ....... ... .... 53

Formation of cr-Allyl Copper Species 129 with Acetate 126..... ............ 54

Formation of 1l'-Allyl Copper Species 130 with Acetate 126....... ........ 55

Stereochemistry of Relay Side Chain.. ........ ... ... .......... ......... ....... 58

Quadrupolar Interactions using a CF3-Based Gearing Element............ 63

Results of Higher Drder DFT Calculations on Model System (Red color

denotes areas of increased electron density due to fluorine atoms)........ 64

Results of Higher Drder DFT Calculations on AH Carbon System (Red

color denotes areas of increased electron density due to fluorine atoms). 65

Model System used in Determining the Ideal Gearing Element. . .. . . . . . . . . 66

Retrosynthetic Analysis for the Model System used for Determining the

Ideal Gearing Element. .. .. . . . . .. .. . . . . .. . .. . .. . ... .. .. . .... .. . .. . ... .. . .. . .. . ... 67

Retrosynthetic Analysis for Longithorone C. ... .... ...... ..... .......... .... 72

Proposed Reaction Steps for the Completion of

Longithorone C.................................................................... 76

Proposed Mechanism for Dxidation of Benzaldehydes to Phenols.. .. . ... 78

Proposed Chiral Catalysts for the Asymmetric Synthesis of

Longithorone C.................................. ................................. 79

Proposed Chiral Auxiliaries for the Asymmetric Synthesis of

Longithorone C......................... ... ............................... .. ...... 79

Xll

List of Schemes

Scheme 1 Studies of Enyne Metathesis in Macrocyc1ization Reactions..... ............ 7

Scheme 2 Preparation of Enyne Precursor 3 ..................................... , . .. . .. . . 8

Scheme 3 Enyne Metathesis using an Atropisomeric Control Element............... 10

Scheme 4 Removal of the Atropisomeric Control Element.. .............. " .. , . .. . .. . . 10

Scheme 5 Enyne Metathesis Lacking an Atropisomeric Control Element. .. , . . .... ... Il

Scheme 6 Additive Effect on the Transition States of the [3,3]-Sigmatropic

Rearrangements.. .. . .. . .. . .. ... ... ... . .. .... .. . .. . .. . .. . .. . .. . .. . .. . . . . . . . . . . . . . .. 13

Scheme 7 Preparation of [12]Paracyc1ophanes by Friedel-Crafts Alkylation......... 14

Scheme 8 Initial Attempts in Forming [12]Paracyclophanes. ... ....... ................. 18

Scheme 9 Benzylesters as Gearing Elements. ... ... .... ..................... ............. 19

Scheme 10 Pentafluorobenzylesters as Gearing Elements................. .......... ..... 19

Scheme Il Energy Minimization using AMI and MP2 Methods........... ............. 20

Scheme 12 Determining the Ideal Site for Metathesis ........................... , .... .... 21

Scheme 13 Attempted Formation of a Tri-substituted Olefin by RCM................. 22

Scheme 14 Relay-Ring Closing Metathesis............................... ...... ........... 23

Scheme 15 Model Study Incorporating Relay-Ring Closing Metathesis.. ..... ... ..... 24

Scheme 16 Synthesis ofPentafluoro-2,5-dihydroxybenzoate 60 via Mitsunobu

Chemistry........... ........................... .................................... 27

Scheme 17 Synthesis ofPentafluoro-2,5-dihydroxybenzoate 60 via an Alkylation

Procedure ....................................................... , .............. .... 28

Scheme 18 Synthesis of Allylic Side Chain 61.... ...................... ......... .......... 29

Scheme 19 Alkylation using trans,trans-FarnesoI65 and Allylic AlcohoI61.... ..... 30

xm

Scheme 20 RRCM ofMacrocycle 63.............................................. . .. ....... 31

Scheme 21 Gibbs' Synthesis of cis,trans-FarnesoI62........ ............... ...... ....... 33

Scheme 22 Synthesis of cis-Famesol 62 using Geranylacetone 86...................... 34

Scheme 23 Synthesis of Geranylacetone 86................................................ 33

Scheme 24 Preparation of cis,trans-Fameso162 from Geranylacetone 86. ............ 36

Scheme 25 Alkylation using cis,trans-Fameso162 and Allylic Alcohol61. .... ....... 37

Scheme 26 RRCM ofMacrocycle 58.. ...................................................... 38

Scheme 27 Preparation of Olefin 93 Following Modified Corey Procedure........... 39

Scheme 28 Alkylation using Side Chain 93 and Allylic AlcohoI61.................... 41

Scheme 29 RRCM ofModel System 94.................................................... 42

Scheme 30 Negishi Coupling using Prenylbromide 102.................................. 44

Scheme 31 Negishi Coupling using Iodide 80............................................. 45

Scheme 32 Negishi Coupling using Alkyl Bromide 107................ ............. ...... 45

Scheme 33 Synthesis ofi-Propyl-2,5-diiodobenzoate 120.... ........................... 50

Scheme 34 Synthesis ofBromide 125 and Acetate 126........ ........................... 52

Scheme 35 Optimized Reaction Conditions in Forming Aryl.iodide 124............... 56

Scheme 36 Formation of the Allylic Acetate 131 Derived from cis-Olefin 93........ 69

Scheme 37 Optimized Reaction Conditions in Forming Ole fin 132.......... ........... 69

Scheme 38 Synthesis of Acetate 136 and Stereochemistry ofOlefin 153.............. 59

Scheme 39 Preparation of Bistrifluoromethyl Benzyl Ester 139........................ 61

Scheme 40 Improved Bistrifluoromethyl Gearing Element on Model System..... .... 62

Scheme 41 Synthesis of Bromide 161........................................................ 67

XIV

Scheme 42 Synthesis ofPentafluorobenzyl ester 155 and Trifluoromethylbenzyl

ester 156. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Scheme 43 NOESY ofMacrocycle 157.............. .... ................................... 70

Scheme 44 Synthesis ofMacrocyclization Precursors 174 and 176..................... 74

Scheme 45 Optimum Reaction Conditions for RRCM on Real System................ 90

Table 1

Table 2

Table 3

Table 4

xv

List of Tables

Effeet of Ester Group, Halide, and Grignard on Mg-X exehange......... 49

Optimizing y / cr Produet Ratio. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 51

RRCM ofModel Compound [12]Paraeyelophane 157 and 158. ........... 69

RRCM in forming Cyc10phanes 173 and 177.............. ................... 75

XVI

Abbreviations

Ac acetyl

ACN acetonitrile

Ar aryl

COSY correlation spectroscopy

d doublet

dba dibenzylideneacetone

DCM dichloromethane

dd doublet of doublets

DIAD isopropyldiazodicarboxylate

DIBAL-H diisobutylaluminum hydride

DMF dimethylformamide

dppf (diphenylphosphino )ferrocene

dt doublet of triplets

ee enantiomeric excess

eq equivalent

FePc iron tetrasulfophthalocyanine

g gram

GC gas chromatography

h hour

HM half-metathesis

HMPA hexamethylphosphoramide

HRMS high resolution mass spectrometry

XVll

Hz hertz

HWE Homer-Wadsworth-Emmons

imid. imidazole

J coupling constant

kcal kilocalorie

KHMDS potassium hexamethyldisilazide

m multiplet

mm minute

mL milliliter

mol mole

mmol millimole

NBS N-bromosuccinimide

NMP N-methylpyrrolidone

NMR nuc1ear magnetic resonance

NOESY nuc1ear overhauser enhancement spectroscopy

PG protecting group

ppm parts per million

py pyridine

q quartet

RCM ring-c1osing olefin metathesis

RRCM relay ring-c1osing metathesis

r.t. room temperature

s singlet

XVlll

t triplet

TBAF tetrabutylammonium floride

TBDMS tert-butyldimethylsilyl

TBDPS tert-butyldiphenylsilyl

TFA trifluoroacetic acid

TLC thin layer chromatography

UV ultraviolet

Chapter 1:

Introduction to the Longithorones: Paracyclophane Natural

Products

This chapter will focus on the longithorone family of natural products that contain

a paracyclophane core and the synthesis of these macrocyclic natural products.

1.1 - Ring Closing Olefin Metathesis as a Route to Strained Systems.

The olefin ring-closing metathesis (ReM) reaction has emerged as one of the

most powerful transforms in organic synthesis. 1 Indeed, the broad scope and reliability of

this reaction has greatly simplified the total synthesis of a wide variety of architecturally

complex natural and unnatural products.2 For example, Smith and co-workers developed

in 1999, the first total synthesis of cylindrocyclophane F, a unique natural product

possessing a 22-membered [7, 7]paracyclophane ring.3

Recent advancements in metathesis catalyst design have allowed chemists to re-

examine olefin metathesis as a route to systems bearing strained olefins embedded in

1 (a) Trnka, T. M.; Grubbs, R. H. Ace. Chem. Res. 2001,34, 18. (b) FÜfstner, A. Angew. Chem., Int. Ed. 2000,39,3012. (c) Nicolaou, K. c.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005,44,4490-4527. (d) Grubbs, R. H. Handbook ofMetathesis, Three Volume Set 2003. 2 Fürstner, A; Langernann, K. J. Org. Chem, 1996,6/,8746-8749. 3 Smith, A B. III; Kozmin, S. A; Paone, D. V. J. Am. Chem. Soc. 1999, /2/, 7423-7424.

2

their skeletons.4 The variety of different catalysts that have been developed allows for

the possibility to select a catalyst having the necessary level of reactivity to access a

strained system but also to avoid catalysts which may be so reactive as to favor ring-

opening ofthe desired ring system.5

Ring closing metathesis (ReM) is now a standard method for the preparation of

both carbocyclic and heterocyclic ring systems in sizes ranging from five- and six-

membered cycles to macrocyclic compounds.6 Despite its popularity, the preparation of

certain molecules via olefin 'metathesis remains a challenge. In particular, strained ring

systems are problematic. In sorne cases, the ring opening process can be far more

thermodynamically favorable than ring closing while in other cases the system may be

too strained to permit cyclization.6 .::

A fascinating challenge for olefinmetathesis could be the preparation of strained

macrocyclic structures such as the longithorone natural products. In 1997, Schmitz and

co-workers isolated a group of nine ,famesylated quinones isolated from a tunicate

Aplidium longithorax that featured·new macrocyclic skeletons. Their carbon skeletons

resemble a farnesyl unit bridginga quinone at either the meta- or para-positions (Figure

4 (a) Scholl, M.; Ding, S.; Lee, C. W.; Gmbbs, R. H. Org. Lett. 1999, l, 953-956. (b) Ackermann, L.; Filistner, A.; Weskamp, T.; Kohl, F. J.; Herrmann, W. A. Tetrahedron Lett. 1999, 40, 4787-4790. (c) Huang, J. K.; Schanz, H.-J.; Stevens, E. D.; Nolan, S. P. Organometallics. 1999, 18, 5375-5380. (d) Jafarpour, L.; Schanz, H.-J.; Stevens, E. D.; Nolan, S. P. Organometallics. 1999, 18, 5416-5419. (e) Fürstner, A.; Thie1,-O. R.; Ackermann, L.; Schanz, H.-J.; Nolan, S. P. 1. Org. Chem. 2000,65,2204-2207. (1) Collins, S. K. J. Organomet. Chem. 2006, 691, 5122-5128. 5 Tang, H.; Yusuff, N.; Wood, J. L. Org. Lett .. 2001, 3,1563-1566. 6 (a) Paquette, L. A.;. Basu, K.; Eppich, J. C.; Hofferberth, J. E. He/v. Chim. Acta 2002,10,3033-3051. (b) Deiters, A.; Martin, S. F. Chem. Rev. 2004,5,2199-2238. (c) Nakamura, 1.; Yamamoto, Y. Chem. Rev. 2004,5,2127.-2198. , .

3

1).7 To date, the only biological adivityreported for these marine compounds pertains to

longithorone A. 8

longlthorone J longithorone K longlthorone 1

o

longlthorone B longlthorone C longithorone A

Figure 1 - The Longithorone Family' or"Natural Products.

lU l'· ,.:!

1.2 - Synthesis of Longithorone A.

1.2.1 - Introduction and Synthetic Challenges.

In 2002, Shair and co-workers reported an elegant synthesis of the cytotoxic

marine natural product longithorone A, based on the original proposed biosynthesis by

Schmitz and co-workers.9,10 The Shair group proposed the following retrosynthetic

J:

analysis comprised of both intermo.1~C,IJJ.ar . and transannular Diels-Alder reactions in the

• 1 ... ""

7 Fu, X.; Hossain, B.; Schmitz, F. J.; van der,Helm, D. J. Org. Chem. 1997,62,3810-3819. 8 For· information on the biological activity oflongithorone A, see: (a) Fu, X.; Ferre ira, M. L. G.; Schmitz, FJ. J. Nat. Prad. 1999,.62, 1306-1310. (b) Davidson, B. S. Chem. Rev. 1993,93,1771-1791. (c) Faulkner, D. J. Nat. Prad. Rep.1998, /5, .113:158. . 9 Layton, M. E.; Morales, C. A; Shair, M. D. J. Am. Chem. Soc. 2002, /24, 773-775. 10 Fu, x.; Hossain, M. B.; van Der Helm, D.; Schmitz, F. J. J. Am. Chem. Soc. 1994, //6, 12125-12126.

4

presence of two macrocyc1ic ring systems which are strained and extremely rigidified

(Figure 2).

Diels-Alder

o 1 > --~-'-':: 1 -_ h F

0"" ~ Q.. 0

longithorone A 2

Figure 2 - Retrosynthetic Analysis of Longithorone A Involving Molecular and Transannular Diels-

AIder Reactions.

Both the macrocyc1es 1 and 2 are tied across quinone ring systems, where the

hindered rotation of the macrocyc1e results in atropisomerism. It was believed by the

Shair group that the absolute and relative stereochemistry of the stereocenters found in

the C, D, and E ring systems of longithorone Amay be derived from the planar chirality

of both 1 and 2 (Figure 2). It was therefore necessary to prepare enantioenriched

paracyc10phanes 1 and 2 possessing a 1,3-diene functionality embedded in the ansa-

bridge. Consequently, Shair and co-workers envisioned using a macrocyc1ic enyne

metathesis reaction to install the necessary diene functionality (Figure 3).

5

A(1,3) Straln

("""" Ene-Yne Metathesls MeO?" :-O:: OTBS ~'=:--_

========:» "H ~ TBSO

/, Il ~ OTBS

(""

if MeO"";-_" OTBS

OTBS

/, Il ~ OTBS

4

A(1 ,3) Straln

~ (Me~"'''?- ~ OTBS

~ F _ Ene-Yne Metathesis TBSO "H o ..§... O· ;, /,

~ Il ~ 2 3

Figure 3 - Retrosynthetic Analysis of Longithorone A Involving Enyne Metathesis_

Although dilution, templates and slow-addition techniques can improve some

macrocyclizations, Il typically chemists resort to the installation of conformational control

elements to favor cyclization. 12 Most often, this takes the form of a large substituent on

the methylene group adjacent to the aromatic moiety. Consequently, in the Shair

synthesis, a t-butyldimethylsilyloxy (OTBS) group was strategically placed adjacent to

the aromatic ring of enynes 3 and 4 as a conformational control element. Minimization

of the A 1,3 strain was believed to be responsible for the gearing of the alkenyl and alkynyl

side chains (Figure 3).

Il Chuchuryukin, A. V.; Dijkstra, H. P.; Suijkerbuijk, R. 1. M.; van Klink, G. P. M.; Mills, A. M.; Spek, A. L.; van Koten, G. Angew. Chem., Int. Ed. 2003, 42, 228-230. 12 Sello, 1. K.; Andreana, P. R.; Lee, D.; Schreiber, S. L. Org. Lett. 2003,22,4125-4127.

6

1.2.2 - Preparing [12]Paracyclophanes by Enyne Metathesis.

Relatively little use has been reported in the literature on macrocyc1ization via

enyne metathesis. 13 However, it is known that intramolecular enyne metathesis affords

1,2-disubstituted dienes (5) and intermolecular enyne metathesis reactions afford 1,3-

disubstiuted dienes (6) (Figure 4).14

~ V)O-4

1,2-disubstituted diene 5

•

1,3-disubstituted diene 6

Figure 4 - Intramolecular and Intermolecular Enyne Metathesis Reactions.

The Shair group used model structures to determine the optimum enyne

metathesis conditions. 15 It was found that under an ethylene atmosphere, ethylene-yne

cross metathesis of 7, 8, and 9 occurs first using catalyst 14, affording a terminal 1,3-

diene followed by terminal olefin-olefin metathesis macrocyc1ization, affording the

desired 1,3-disubstituted olefins 10, 11, and 12. No 1,2-disubstiuted olefin 13 was

observed (Scheme 1).

13 Hensen, E. c.; Lee, D. J. Am. Chem. Soc. 2003, 125, 9582-9583. 14 Mori, M.; Kitamura, T; Sato, Y. Synthesis 2001, 654-664. 15 Morales, C. A.; Layton, M. E.; Shair, M. D. Proc. Nat/. Acad. Sei. 2004, lOI, 12036-12041.

OR 0l ~O~ ~V 7: R = Me 8: R= TBS 9: R= H

" Mes-NyN'Mes

CI,I Ru~

Cl .... 1 Ph

PCY3

14

Grubbs Il (10 mol %)

ethylene (1 atm) DCM, 45°C, 24h

..

10: R = Me, 92% 11: R = TBS, 97% 12: R = H, 71%

1 ,3-d isubstituted

Scheme 1 - Studies of Enyne Metathesis in Macrocyclization Reactions.

1.2.3 - Installation of the Atropisomeric Control Element.

7

13 not observed

1,2-disubstituted

The enantioselective synthesis of enyne 3 was achieved following a nine-step

reaction sequence (Scheme 2).15

~ TlPS 1

16 +

Br

Meo~

Mr Br OMe

15

TIPS:xl.

Zn, Pd(PPh3)4 MeO '-"::

-----.. 1 THF, 23

cC BOOM

98% r 17 e

1. n-BuLi, El20, -7ac C

2.DMF 94%

TIPS---==-----

.. H

o 18

j 1. BBr3, DCM

2. TBSOn, i-Pr2NEI DCM

88% over two steps

TIPS == t-BuU, ZnBr2 TIPS == TMS ~ TBSO

1. TBAF, THF 2. 5% Pd/BaS04

quinoline, H2 3. TBAF, THF

OH

4. TBSCI, Imid., DMF

63% yleld over four steps

21

f MeO .;;:-_ '" f""'"

TBSO

Il ~ 3

OMe

OTBS

h

(1 S,2R)-N-melhylephedrine .. PhMe,OcC

91% yleld, 95% ee

TMS~I

20 \

Scheme 2 - Preparation of Enyne Precursor 3.

H OMe

19

8

Pd-mediated cross coupling ofvinyl-iodide 16 and a benzylic zinc reagent derived

from 15 afforded aromatic bromide 17 in 98% yield. Formylation of the aromatic

bromide 17 with n-BuLi and DMF delivered aldehyde 18 in 94% yield. Selective

demethylation was achieved by treating aldehyde 18 with BBr3 followed by silylation

with TBSOTf to afford silyl ether 19 in 88% yield over two steps. Enantioselective

alkylation of silyl ether 19 using a bromozinc reagent derived from 20 in combination

with the lithium alkoxide of (lS,2R)-N-methylephedrine provided benzylic alcohol 21 in

9

91 % yield and in 95% ee. Benzylic alcohol 21 was treated with TBAF where the

simultaneous deprotection ofboth the>TMS and TBS group was carried out. Subsequent

Lindlar·hydrogenation of the terminalacetylene, TBAF promoted removal of the TIPS

group and silylation of the phenol and benzylic alcohol with TBSCI afforded enyne 3 in

63% yield over four steps.

1.2.4 - Enyne Metathesis Macrocyclizatlon using an Atropisomeric Control Element.

Both enyne 3 and 4 were taken up in CH2Clz and treated with Grubbs first

generation catalyst 22 under an ethylene atmosphere to afford the desired macrocyc1es 23

and 24. High dilution conditions and extended reaction times were necessary in order to

obtain the macrocyc1ic products. Despite optimizing the conditions, enyne 4 cyc1ized to

afford macrocyc1e 23 in only 31 % yield. Furthermore the E:Z ratio was 3.9:1 and the

atropdiastereoselectivity was modest at 2.8:1. It is important to note that the nature of the

substrate controlled the resulting E:Z ratios and atropdiastereoselectivity.15 For example,

when enyne 3 was subjected to nearly identical reaction conditions, the yield of

macrocyc1e 24 was 42%. However, both the E:Z ratio and atropdiastereoselectivity had

increased to greater than 25:1 in the formation of24 (Scheme 3).

~" ,i

OTBS

rMe'~'''''7 "-': OTBS

TBSO "H

/, Il ~

3

PCY3 CI,I

Ru=--CI"" Ph

PCY3

Grubbs 1 (30 mol %l 22 ethylene (1 atm), DCM, 45°C

[M] = 3.10-3, 40h

31%

2.8: 1 atropdiastereoselectivity

3.9: 1 E: Z

1. Grubbs 1 (30 mol %l 22

ethylene (1 atm), DCM, 45°C

[M] = 3 • 10-3 , 21h .. 2. TBAF, THF

42% > 25: 1 atropdfastereoselectfvity

> 25: 1 E: Z

Scheme 3 - Enyne Metathesis using an Atropisomeric Control Element.

10

23 OTBS

24

The removal of the atropisomeric control element was achieved by hydride

reduction of the benzylic silyloxy group using TFA and NaBH3CN, followed by

silylation of the phenol to afford paracyc10phane 25 in 75% yield (Scheme 4).15,16

24

2. TBSCI, Imid. 75%

Scheme 4 - Removal of the Atropisomeric Control Element.

25

Although Shair and co-workers demonstrated that the formation of macrocyc1es

such as [12]paracyclophanes was possible using RCM, these macrocyc1ization reactions

16 Kursanov, D. N.; Parnes, Z. N. Russ. Chem. Rev. 1969,38,812-821.

11

proved to be difficult due to ring strain and no cyclization was observed in forming 27

without the pendant OTBS group in 26 (Scheme 5).

22

tM:~j'''';;:'' -.;:: OMe Grubbs 1 (30 mol %)

JI'"

• Mixture of Products

Scheme 5 - Enyne Metathesis Lacking an Atropisomeric Control Element.

1.2.5 - Conclusion.

Shair and co-workers have demonstrated the first examples of enyne metathesis in

forming macrocyclic ring structures such as [12]paracyclophanes. These results

demonstrate the ability of substituted methylene groups to act as conformation

controlling groups, and to control the transfer of their chirality to atropisomeric centers.

Although the Shair group successfully applied this methodology towards the asymmetric

total synthesis of longithorone A, large amounts of catalyst were necessary as weIl as

extended reaction times, high dilution and the presence of an ethylene atmosphere in

order to accomplish macrocyclization. Although the control element was easily removed,

the installation process involved difficult reaction steps, and afforded paracyclophanes 23

and 24 in low yields, and variable diastereoselectivity.

12

1.3 - Synthesis of Longithorone B.

Longithorone B is a [12]paracyc1ophane containing a macrocyc1ic structure based

on a famesyl unit, bridging a benzoquinone at the para-position. The macrocycle is

composed of two trans, and one cis double bonds. The hindered rotation of its

macrocyclic structure about the quinone core affords this natural product an element of

planar chirality. The synthetic challenge in synthesizing longithorone B is directly linked

to the difficulty in forming the highly substituted, planar chiral macrocyc1e. These

synthetic challenges had inspired Tadahiro and co-workers to develop an efficient

synthesis of the macrocyc1ic ring structure of longithorone B, by way of intramolecular

Friedel-Crafts alkylation reaction forming the ansa-bridge (Figure 5).17

longithorone B

1. Hydrolysis >

2. CAN Oxidation

Friede/-Crafts

Reduction

HO) ~o '(40~ '<=:: ==

~"O~ PivO

Figure 5 - Retrosynthetic Analysis of Longithorone B.

17 Tadahiro, K.; Kentaro, N.; Masahiro, H. Tetrahedron Lett. 1999,40, 1941-1944.

13

1.3.1 - [3,3]-Rearrangement in Forming Ortho-Allyl Phenol 31.

[3,3]-Sigmatropic rearrangements of aIl yI aryl ethers provide convenient access to

ortho-allyl phenols. 18 However, one of the challenges encountered by the Tadahiro group

was in controlling the E:Z ratios of the products. 17 They determined a strong dependence

of the rearrangement reaction on the reaction conditions (Scheme 6).

OEt

OMe

trans-product 30

D~ DEI ~

EtO o

28 V OMe

AI20 3

xylene. !J., 36h 71% conversion

EtO

~*~ 0 .l'''~ MeO il -- ÀI

29-E 29-Z

1: 4.3 E: Z

o

---

OCOCMe3

OMe o

OEt

cis-product 31

Scheme 6 - Additive Effect on the Transition States of the [3,3)-Sigmatropic Rearrangements.

The rearrangement of28 afforded a 71 % conversion with a low 1 :4.3 E/Z product

ratio. The proposed mechanism inyolved the coordination of the Lewis acid with the

18 Krohn, K.; Bernhard, S. Synthesis 1996, 6,699-701.

14

oxygen atom of phenyl ether 28 forming the two possible transition states 29-E and 29-Z.

In the absence of a Lewis acid, 29-E was the major intermediate leading to the formation

of the trans-olefin 30. In the presence of a Lewis acid su ch as Alz03 or Si02, the Al or Si

atoms complex with the oxygen atom of the ether linkage, increasing the repulsion

between it and the side chain at the equatorial position of transition state 29-E, leading to

the formation of the desired Gis-phenol 31 through transition state 29-Z.

1.3.2 - Intramolecular Coupling of the Farnesylated Side Chain by Friedel-Crafts

Alkylation.

The intramolecular coupling reaction was examined using three types of protected

alcohols (32, 33, and 34) derived from phenol 31 and the ester at the terminal position of

the famesyl chain was reduced to the alcohol using DIBAL-H. The intramolecular

coupling reaction was achieved by way of the Friedel-Crafts alkylation at the C-1

position of the farnesyl moiety in the presence of the acids Hf(OTf)4 and LiCI04 in

CH2Clz (Scheme 7).

OR

Hf(OTf)4

liCI04 • DCM

35 36 37

32: R =TBDMS 8% 1:8 64% traces

33: R = Bn 0%

34: R = COCMe3 --------_ .. 78% 6: 1 13% traces

Scheme 7 - Preparation of [12IParacyclophanes by Friedel-Crafts Alkylation.

15

When silyl ether 32 was treated, with Hf(OTf)4 in the presence of LiCI04, a

mixture of 35 and 36 was obtained, where HPLC purification afforded macrocyc1e 36 in

64% yield. The predominant meta-coupling with respect to the methyl ether of silyl ether

36 was believed to be caused by the,electron-withdrawing nature of the TBDMS group.

When benzyl ether 33 was treated under the same reaction conditions, a complex mixture

was detected without formation of any product. When pivilate 34 was subjected to the

coupling reaction under the same conditions, the desired macrocyc1e 35 was isolated in

78% yield. Steric hindrance as weH' as the electron-withdrawing nature of the pivaloyl

grollP of 34 was believed to control the reaction, leading to the desired para-substituted

(with respect to the macrocyc1ic ring structure) macrocyc1e 35 as the major product.

Hydrolysis of macrocyc1e 35 with KOH; in MeOH followed by CAN oxidation lead to the

formation of longithorone B in 58% yield,over two steps.

1.3.3 - Conclusion.

Although the Tadahiro group demonstrated an efficient synthesis of the

[12]paracyc1ophane longithorone B, the [~,3]-rearrangement as weIl as the intramolecular

cye1iz~tion proved difficult. Complete conversion was never achieved in the

rearrangement step and the Friedel-Crafts alkylation afforded a mixture of ortho- and

meta-substituted products.

In light of the work performed by both the Tadahiro and Shair groups, it is c1ear

that. there is a need for new and more efficient methods for forming highly hindered,

planar chiral macrocyc1i~ ring structures.

16

1.4 - Longithorone C: A Representative. Compound.

1.4.1 - Synthetic Challénges and Goals ..

Longithorone C, a member of a family of nine famesylated quinones, features a

macrocyclic skeleton derived from. a famesyl unit bridging a quinone at the para-

position. Longithorone C a1so exhibit~ atFopisomerism due to the hindered rotation of the

macrocyclic ring structure. Its structural· features resemble those of 10ngithorone B and

the two monomers that make up longithorone A (Figure 6).

longlthorone B longlthorone A

longlthorone C

Figure 6 - Structural Similarities Between Longithorones A, B, and C. .' .

1 .,'

The synthetic challenge associated with the synthesis of longithorone C was

linked to the difficulty in forming the highly strained, planar chiral macrocycle that l'

contains three stereodefined tri-substituted olefins. It has been reported that heating

longithorone C at reflux for 7 days in toluene resulted in no racemization of its

17

macrocyc1ic structure.7 These synthetic challenges inspired our group to develop an

efficient synthesis towards longithorone C using ring c10sing olefin metathesis (RCM) in

forming the ansa-bridge (Figure 7).

/RCM ,

metathesis/ oxidation

;. ~:~ OPG

Me

Longithorone C

Figure 7 - Initial Retrosynthetic Analysis of Longithorone C.

The ultimate goal would be to install the planar chirality in this molecule via an

enantioselective ole fin metathesis reaction using a chiral catalyst. Since the formation of

[12]paracyc1ophanes had been achieved using enyne metathesis, it was therefore

necessary to determine whether RCM could be used in forming the macrocyc1ic ring

structure of longithorone C. Other synthetic variables to optimize included determining

the ideal site for macrocyc1ization, and stereoselectively forming the tri-substituted

olefins within the macrocyc1e.

1.4.2 - Forming [12]Paracyclophanes: A Model Study.

[12]Paracyc1ophanes are relatively strained macrocyc1ic structures. Chiral

gearing elements such as the benzylic silyl ether group used by Shair and co-workers

18

have been employed In directing macrocyc1ization processes to form

[12]paracyc1ophanes. However, since the ultimate goal would entail using asymmetric

olefin metathesis, the substituted methylene gearing elements located on the side chains

would be undesirable (i.e. leading to diastereoselective cyc1ization in place of an

enantioselectively cyc1ization). Yassir EI-Azizi, a member of the Collins group,

investigated whether RCM could be used to access strained macrocyc1ic systems in the

absence.of gearing elements on the side chains (Scheme 8).19

OH HO~ H.Y

h~~ 39 a 22

~ PPh3, DIAD

~ Grubbs 1 (10 mol %)

~ ~

MeO Il PhMe, 8, 1.5h

MeO Il DCM, 8, 15h

MeO Il MeO ~ 50- 90% [M] = 0.4 * 10-3

OH O~ 26% O~O

38 40 41

Scheme 8 - Initial Attempts in Forming [121Paracyclophanes.

Unfortunately, numerous attempts ta cyc1ize vanous substituted

[12]paracyc1ophanes using Grubbs first generation catalyst 22 lead to the preferential

formation of the dimer 41, demonstrating the importance of controlling the orientation of

the side chains. It was believed that the use of a benzyl ester would allow the formation

of the "stacked" conformer 43-8 in solution, which in tum would "gear" the two side

chains together through steric bias facilitating macrocyc1ization (Scheme 9).

19 EI-Azizi, Y.; Schmitzer, A.; Collins, S. K. Angew. Chem., ln!. Ed. 2006, 6, 968-973_

19

~~ ~4 o~

-~~4 0

B~ 22

o~~ ~A Grubbs 1 (10 mol %) ..

DCM.1.\.15h Bn02C /; Bn02C ~

0 o~ 26%

O<o:~ oo~ O~O

42 "slacked" 44

43-0 43-5

Scheme 9 - Benzyl Esters as Gearing Elements.

Despite varying the concentration and mode of addition, the use of the benzyl

ester did not form the desired macrocyclic product, and once again the dîmer was

obtained as the major product. Consequently, a strategy employîng pentafluorophenyl-

phenyl interactions as a novel gearing element to favor the desired intramolecular

macrocyclization was envisioned (Scheme 10).

~4 o 22 o Grubbs 1 (10 mol %~

CaFsHzCOiH DCM. L'.. 15 h

41% o o~

~4 ~

F o~ ~F~Fh F~O~ FOOO~

/~j\F "open" "stacked" F 46-0 46-5

45 47

Sc he me 10 - Pentafluorobenzylester as a Gearing Elements.

When olefin 45 was treated with catalyst 22, cyclophane 47 was isolated in 41 %

yield. Rence the formation of [12]paracyclophanes by RCM was made possible using

novel gearing elements such as the pentafluorobenzyl ester 45. The quadrupolar non-

20

bonding interactions between pentaflp.oroarenes and arenes are the result of the

orthogonal densities of aromatics and pentafluoroaromatics.20 These interactions have

spiked significant interest in medicinal chemistry and materials science due to the

predictable preference for the face-to-face stacking with the aromatics in the solid state.21

However, relatively littIe use of these non-bonding interactions has been reported in

catalysis.22 The pentafluorobenzyl ester 45 has been predicted through molecular

modeling to prefer the solution state conformation 46-8 to a much greater degree than 46-

o (Scheme Il).23

"open" 43-0 "stacked" 43-5

ÀHstaek - ÀHopen = -3.9 kcal/mol

~4 o F o~

F.too"'~ 1 \J4"

F ~ F "open" 46-0 F

Scheme 11 - Energy Minimization using AMI and MP2 Methods,z3

...

20 Brown, N. M. D.; Swinton, F. L. J. Chem.,Soc., Chem. Comm. 1974, 19,770-771. 21 Mann, E.; Mahia, J.; Maestro, M. A.; Hetradon, B. 1. Mol. Struct. 2002,641,101-107.

"stacked" 46-5

22 POI1;Zini, F.; Zagha, R.; Hardcastle, K.; Siegel, J. S. Angew. Chem., fnt. Ed. 2000, 39, 2323-2325. 23 For a complete list ofmethods and results used in the molecular modeling studies see: Collins, S.; EI­Azizi, Y.; Schrnitzer, A. R. 1. Org. Chem. 2007, 72,6397-6408.

21

1.4.3 - Determining tbe Optimal Site for Metatbesis along tbe Ansa-Bridge and

Formation of Tri-substituted Olefins by ReM.

Previously it had been demonstrated by Yassir El-Azizi that moving the site of

metathesis c10ser to the aromatic core resulted in a higher reaction yield when forming

[12]paracyc1ophanes via olefin metathesis (Scheme 12).24

Mk& 22 Grubbs 1 (10 mol %) Ml DCM,~, 15 h

[M] = 0.5' 10.3

01 41% O~ooJ FO O~ 4":::

45 Il 47

ftf 22

Grubbs 1 (10 mol %) F 0

DCM,~, 15 h

~ [M] = 0.5 * 10.3

~ Ol 48% FO O~ ~ 0 0 3":::

48 49

Scheme 12 - Determining the Ideal Site for Metathesis.

When olefin 45 was subjected to metathesis conditions using catalyst 22 under

di lute conditions, macrocyc1e 47 was obtained in 41 % yield. When moving the site of

metathesis c10ser to the central arene in olefin 48, the reaction yield had increased from

41 to 48% yield un der the same reaction conditions, indicating that the site of metathesis

for the formation macrocyc1es should be performed c10ser to the aromatic core.

24 Collins, S. K.; EI-Azizi, Y. Pure Appl. Chem. 2006, 78, 783-789.

22

Our group subsequently attempted to prepare even more strained macrocycles

incorporating a stereodefined tri-substituted olefin similar to those present in

longithorone C (Scheme 13).19

Fi 22 Fi \ F FA

~A Grubbs 1 (10 mol %) »J ~~»J DCM, 6,15 h

64% F 0 0 F 0 0 OOF FOO 50 51 Not observed

Scheme 13 - Attempted Formation of a Tri-substituted Olefin by ReM.

Unfortunately, cyclization of olefin 50 led to the preferred formation of the dimer

51 and no macrocyc1ic product was isolated, ev en in the presence of the

pentafluorobenzyl ester. Recently, Hoye and co-workers had developed an efficient

method for forming highly substituted olefins by RCM called relay-ring c10sing

metathesis (RRCM) (Scheme 14).25

25 Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J,; Zhao, H. J. Am. Chem. Soc. 2004, 126,10210-10211.

23

:r5o

22 Grubbs 1 (10 mol %)

+-------------------,... DCM, 1'.,15 h

No Reaction

52

fVo)- 22 0 Grubbs 1 (10 mol %) ):50 ..

DCM, 1'.,15 h

53 59% 55

OR

or 22 0 Grubbs 1 (10 mol %) ):50 Yo ..

DCM, 1'.,15 h

54 59% 55

Scheme 14 - Relay-Ring Closing Metathesis.

In an attempt to cyclize olefin 52 containing both an electron deficient and a

substituted olefin, the catalyst 22 was not reactive enough to perform the desired

cyclization. When the olefins of the electron deficient (53) or hindered olefin (54) were

appended with a five carbon chain containing a terminal olefin the cyclization was now

successful, affording lactam 55 in 59% yield. The catalyst 22 can now react selectively

at the primary olefin of this "relay chain", producing a very fast intramolecular

cyclization kicking out a cyclopentene, thereby placing the catalyst onto the desired

olefin and allowing facile cyclization to the desired lactam 55.

Exploiting a relay ring closing metathesis protocol in tandem with the gearing

effect of the pentafluorophenyl-phenyl interaction, the cyclophane 57 was isolated in

53% yield on treatment of olefin 56 with catalyst 14 in CH2Ch at reflux (Scheme 15).19

Cyclophane 57 was isolated as a single isomer with the tertiary olefin in the Z

configuration.

14

Grubbs Il (10 mol %)

DCM,6, 16 h

53%

.. F~FA <YrY

F 0 0 ..,;:;

57

Scheme 15 - Model Study Incorporating Relay-Ring Closing Metathesis.

1.5 - Conclusion.

24

These studies suggest that pentafluorophenyl-phenyl interactions represent a

novel 7r-shielding element for application in face selective transformations,24 and with

potential for use as chiral auxiliaries. The following chapters will focus on the model

studies carried out in order to optimize the use of this gearing element for

macrocyclizations with the goal of achieving the total synthesis of longithorone C.

Chapter II:

Model Studies Directed Towards the Total Synthesis of

Longithorone C via Macrocyclic Olefin Metathesis

25

The goal of the following model studies was to study the formation of a

[14 ]paracyc1ophane by ring-c1osing olefin metathesis (RCM).

Il.1 - Retrosynthetic Analysis and Model Studies.

The following retrosynthetic analysis was devised in order to prepare a

macrocyc1e that contained three stereodefined tri-substituted olefins that would resemble

the macrocyc1ic ring of longithorone C (Figure 8).

26

F 0 ~ ~ ~ »lf f;J\' 'M

HO 62

c:=::::::> 1 ~ l' 1 Mitsunobu + ~ tF t-. ,/ t F t-.

F 0 0/ O~ 0 OH SO~ F 0 0 HO 1 ~ '~O . 59~ 58 :/ 60 61

ReM

Figure 8 - Retrosynthetic Analysis of a Model System using cis-Farnesol 62.

The target [14 ]paracyclophane 58 contained a macrocycle with three

stereodefined tri-substituted olefins, coupled to a bis-phenol with the pentafluorobenzyl

ester as functional group. Metathesis of olefin 59 should al10w for the successful

formation ofparacyclophane 58. In this manner, the two side chains 61, and 62 could be

coupled to bis-phenol 60 via the Mitsunobu reaction (Figure 8).

Unfortunately, cis,trans-farnesol 62 required for the formation of 58 in the correct

configuration, was not commercially available. As a result trans,trans-famesol 65 was

used in order to determine whether or not [14 ]paracycIophanes such as 63 could be

generated using the RRCM technique (Figure 9).

f""" Mitsunobu

HO~ F 0 FO~

fiJ »lf »A 65

~ ==:> I~ l' 1 t t-. ==:> ;, F t-.

F /'" Mitsunobu ...Y'

So~ F 00 F 0 0 ' o~ 0 OH HO 1

64~0~ 63 60 61

Figure 9 -Retrosynthetic Analysis of Revised Model System using trans-Farnesol 65.

27

II.2 - Synthesis of Pentafluoro-2,5-dihydroxybenzoate 60.

Installation of the pentafluorobenzyl ester gearing element was initially achieved

Via an esterification procedure. Pentafluorobenzyl ester 60 was formed via the

Mitsunobu reaction using pentafluorobenzyl alcohol 67 and 2,5-dihydroxybenzoic acid

66 with a slight excess ofPPh3 and DIAD in anhydrous THF. Diphenol 60 was obtained

in 46% yield as a white solid (Scheme 16).

F

~' OH F F OH F 0 I~

HoA ':4' ·M .tilt b, + HO 1: F

PPh3• DIAD

THF. 23°C. 10h ;, F ~ F

46% 0, 0, o OH F F 0 OH F 0 OH

66 67 60 68

Scheme 16 - Synthesis of Pentafluoro-2,S-dihydroxybenzoate 60 via Mitsunobu Chemistry.

The low reaction yield was a result of the formation of an undesired byproduct,

dialkyl 68. In addition, purification of pentafluorobenzylester 60 was very difficu1t; the

excess DIAD would always co-elute along with diphenol60.

In contrast to the Mitsunobu alkylation mentioned above (Scheme 16), alkylation

of 2,5-dihydroxybenzoic' acid 66 with pentafluorobenzyl bromide 69 proved to be much

more selective. Diphenol 60 was obtained following a simple column purification in

80% yield (Scheme 17).

HO~ •

o OH'

66

~,Jj F

69

-D-M---'F ,E=:':'~~"'-'~'---C,-1-0h'" il; 6 80% O~

F 0 OH

60

Scheme 17 - Synthesis of Pentafluoro-2,S-dihydroxybenzoate 60 via an Alkylation Procedure.

II.3 - Synthesis of the Allylic Alcohol 61.

28

Our group had previously demonstrated that relay nng closing metathesis

(RRCM) was crucial in forming tri-substituted olefins in macrocyclization?S A

retrosynthetic analysis for the preparation ,of 61 was devised following the precedent by ;-f,!'

Eisenreich and co-workers.26 ' The procedure was slightly modified using a silyl ether

protecting group rather than 'a tetrahydropyranyl protecting group. The volatility of the

products incorporating the latter protectirig group was frequently problematic. The

overall reaction yields in either case were identical (Scheme 18).

26 Amslinger, S.; Kis, K.; Hecht, S.; Adam, P.; Rohdich, F.; Arigoni, D.; Bacher, A.; Eisenreich, W. 1. Org. Chem. 2002, 67, 4590-4594.

o ~OH

70

TBDMSCI 0 ------.. ~OTBDM~. Imid, DMF, 23~C, 10h

71

T ris(triethyl)phosphonoacetate .. NaH, THF, O°C - 30min,

23°C - 10 h

74

Br~

o

EtO~ ~OTBDMS

72 E: Z 87:13

j DIBAL-H

DCM, -78°C, 2h

~o~ .. TSAF ~O---n ~OH THF, 23°C, 5h ~OTBDMS

NaH • HO~ THF, 23°C, 10h ~OTBDMS

30% over 5 steps 61 chromatographie separation 75 73

.,' , ." ,

Scheme 18 - Synthesis of Allylic Side Chain 61.

, ~ . -: , " \. ,

29

The hydroxyl'gr~up '~'fà-hydrdxyketone 70 was protected through etherification

with TBDMSCI affordi~g the silyl ether 71 in quantitative yield. The silyl ether 71 was

used crude in the following Homer-Wadsworth-Emmons reaction (HWE) using tris-

triethylphosphonoacetate and NaH ln' àrlhydrous THF, affording ester 72 as an 87/13

inixture of E/Z isomers. Due' to the difficult separation of the two isomers, the crude

mixture was simply carried over to the next reaction step. Reduction of the E/Z isomers

of ester 72 by DIBAL-H in CH2Ch afforded the allylic alcohol 73 with no

chromatographic purification necessary. Allylic alcohol 73 was alkylated using NaH and

allyl bromide in anhydrous THF affording silyl ether 75 that was immediately carried

over to the next reaction step. The TBAF deprotection of crude silyl ether 75 followed

by chromatographic purification afforded the desired allylic a1cohol 61 in a 30% yield

over five steps as a single trans-isomer according to the IH-NMR spectrum.

'1

30

II.4 - Macrocyclic Olefin Metathesis of Model System using trans,trans-Farnesol 65. . ., l~:-: . :

Olefin 76 was formed as the major product by Mitsunobu coupling of 0.5

equivalent of trans,trans-farnesol 65 to pentafluorobenzylester 60 using PPh3 and DIAD

in anhydrous THF at reflux (SchemJ~ 19) .

FO~V,yF, F ;IH

M~ 01

F 0 OH

60

. . '

HO~ 65 ..

PPh3, DIAD, THF, i'>, 10 h

.. ' 'lI

! 't' ,1

FO~

~ F 0 OH

7

j6 HOSO~

61 PPh3, DIAD, THF, i'>, 10 h

30% over two steps

FO~ F'0F ~ ~SO~

64

Scheme 19 - Alkylation using trans,trans-Farnesol 65 and Allylic Alcohol61.

Unfortunately, due to the presence of the two hydroxyl groups in ester 60, sorne , 't',

, . dialkylated product was isolated along with phenol 76. Both products were very difficult

to separate by silica gel column purification. As a result, cru de olefin 76 was carried over

" ,

to the next reaction sequence. Another Mitsunobu reaction was performed to alkylate

phenol 76 with relay side chain 61. However, this time the desired pentafluorobenzyl

ester 64 was separated from the cru de mixture by flash chromatography and obtained in

31

30% yield over two steps. With both side chains in place, olefin 64 was subjected to

metathesis conditions using 2nd generation Grubbs catalyst 14 as well as 2nd generation

Grubbs-Hoveyda catalyst 77 in attempts to obtain macrocyc1e 63 (Scheme 20).

FO~ FO

F~M'\ F /'1 ______ ~~~~~~~~~~~_~~!_o:o! _____ F+rF 0 M ~ DCM,t.,12h ~~ o ~ 0 0 Grubbs Il (10 mol %) 14 0 1 0 0

-î Grubbs-Hoveyda Il (10 mol %) 77 F

~O~ 64 63

L FO~ #A 0

1°\", 78 Hb

35-37%

Scheme 20 - RRCM of Macrocycle 63.

Grubbs Il (10 mol %)

1\ MesNyNMes

".,CI Ru=-,.

Cl .... 1 Ph

PCY3

14

Grubbs-Hoveyda Il (10 mol %)

1\ MesNyNMes

RUb,:..:·CI Cl.... 1

6 f ~ --\ -

77

Unfortunately, no signs of the desired macrocyc1e were obtained. Only traces of

olefin 78, commonly referred to as a half-metathesis product (HM) was observed by lH_

NMR. The failed macrocyc1ization could be due to the configuration of the olefins or the

substitution pattern in the prenylated side chain. In either case, the configuration about

the allylic double bond on the prenylated side chain should in fact be Gis in order for

macrocyc1e 58 to resemble that of longithorone C (Figure 10).

59

Figure 10 - Revised Model System.

F~~ ~;fi

F 00

58

32

longithorone C

As such, the next target was to prepare cis-farnesol and incorporateit into our model

system.

II.5 - Synthesis of cis-Farnesol 62.

II.5.1 - First Generation Synthesis of cis-FarnesoI62.

(2Z,6E)-Farnesol 62 has been synthesized by a 5 step synthesis developed by

Gibbs and co-workers (Scheme 21).27

27 Gibbs, R. A.; Eummer, J. T.; Shao, y. Org. LeU. 1999, 1,627-630.

33

0 0

HO~ I~ 0 Amberlyst 15 .. NaH, n-BuLi .. Nal, ACN, 23°C, O.5h Ethyl Acetoacetate :::,.. 1

62% THF, O°C, 10min; 79 80 23°C,10h 81

43%

KHMDS

5-CI-2-N(S02CF3hPy DMF, O°C, 10min;

23°C, 10h 45%

AsPh3, Pd(PhCN)2CI2 OTf

?'" DIBAL-H ?'" Cul, SnMe4

.~ .. .. HO PhMe, -78°C, 1h 0 NMP, 100°C, 18h o OEt

• 1 74% 95%

62 83 82 1

Scheme 21 - Gibbs' Synthesis of cis,trans-Farnesol 62.

Geranyl iodide 80 was synthesized from geraniol 79 usmg the acidic resm

Amberlyst 15 and NaI, affording the iodide 80 in 62% yield, Iodide 80 was then

alkylated using the Weiler di anion formed from ethylacetoacetate using NaH and n-BuLi

which afforded the p-ketoester 81 in 43% yield. Ester 81 was then converted to triflate

82 with high stereoselectivity in 45% yield using DMF as solvent. The polar aprotic

solvent disrupts the potassium enolate from coordinating to the carbonyl of the ester,

leading to the cis-isomer (Figure Il).

84

(±) K,

~-: 1

o OEt

85 1

Figure 11 - Stereocontrol During Triflation of ,8-Ketoester 81 using DMF as Solvent,

34

TriJlate 82 was then coupled with tetramethyltin under catalytic amounts of

, , j"" ,0

Pd(AsPh3)2 and Cul as co-catalyst to afford ester 83 in 95% yield. Ester 83 was then

reduced with DIBAL-H to afford the desired (2Z,6E)-famesol 62 in 74% yield. Due to

the overall length of the reaction sequence, low yield, high cost of reagents, and health

hazard, the ab ove procedure was abandoned.

l'. l ' .• :'

II,5.2 - Second Generation Syntbesis of1cis-Farnesol 62.

In order to ob tain a fair amount of cis-olefin 62, Wiemer et al. reported the

following procedure using a.modifiep w~~yg reaction (Scheme 22).28

~O 86

1. (PhhPCH3Br

n-BuLi. THF, -78°C

2, s-BuLi 3. CH20 then LI.

.. ~~ol~ol HO)" - ~2 ~ ~ ,

Scheme 22 - Synthesis of cis-Farnesol 62 using Geranylacetone 86.

28 Yu, J. S.; Kleckley, T. S.; Wiemer, D. F. Org. Lell. 2005, 7,4803-4806.

35

Although geranylacetone 86 was fairly expensive, it could easily be synthesized

starting from commercially available geraniol (Scheme 23).29

~OH DCM. O·C. 1.5h. Dark 79 ~,:, ~" ,~

99%

1 1 1 KOH ~O"""~--­

MeOH, l1, 48h

99%

86

Scheme 23 - Synthesis of Geranylace~one 86 .. . ' ...

~Br 87

j NaH, Methyl Acetoacetate

Aliquot 336, PhH, l1, 8h 80%

~o MeO 0

88

Geraniol 79 was converted to geranyl bromide 87 using PPh3 and CBr4 dissolved

in anhydrous CH2Ch. The bromide was used immediately following the removal of

triphenylphosphine oxide. The 'p:ketoester 88 was prepared by alkylating

methylacetoacetate with bromide 87 using NaH in anhydrous benzene. The phase­

transfer catalyst AÙquot 336 was esseriÙ~l in order for the reaction to progress. Ester 88

was obtained in 80% yield following column purification and removal of excess

methylacetoacetate. . ~, ,::.',

Geranylacetone: :86 was formed from ester 88 following

saponification and decarboxylation of the ester using KOH and MeOH at reflux for 48 h.

Geranylacetone 86 was obtained in 99%:yield.

Geranylacetone 86 was th en converted to cis-famesol 62 in a modified Wittig

procedure which involved deprotonation of the oxaphosphatane 89, generated from

29 Durst, H. D.; Liebeskind, L. J. Org. Chem. 1974; 39, 3271-3273.

36

geranylacetone 86 in the presence ofmethyl triphenylphosphonium bromide and n-BuLi,

with s-BuLi and th en quenchirig inte.rmediate 90 with dry paraformaldehyde, affording

cis-farnesol62 in 26% yield (Scheme 24).

~~-A~~ HO}' ~ ~2 ~ ~ , ..

then RT

1. (Ph)3PCH3Sr n-SuU, THF, -7aoC

2. s-BuU 3. CH20 than RT

26%

. ..

~O 86

1 1. (PhhPCH3Sr

n-SuU, THF, -7aoC

Scheme 24 - Preparation of cis,trans-FarnesoI62 from Geranylacetone 86.

Il.6 - Metathesis of Model System Incorporating cis-FarnesoI62.

Olefin 92a was formed by Mitsunobu coupling of 0.5 equivalents of (2Z,6E)-

farnesol 62 to pentafluorobenzylester 60 using PPh3 and DIAD in anhydrous THF at

reflux (Scheme 25). 1. ".

<"l,

37

PPh3, DIAD + ~6 o-rrY

F 0 OH

~ HO -7 62

THF,Ci,10h

60 major

. ITO~ j PPh3, DIAD HO~ . THF, Ci, 10 h

61 30% over two steps

59

Scheme 25 - Alkylation using cis,trans-Farnesol 62 and Allylic Alcohol 61.

Once again, due to the presence of the two hydroxyl groups in ester 60, traces of

olefin 92b were observed by l H-NMR along with the desired olefin 92a in the first

Mitsunobu reaction step mentioiied above· (Scheme 25). Due to the difficulty in

separating the trace amount of dialkyl l92b by silica gel column purification, the crude

phenol 92 (a and b) was carried over to the next reaction sequence. As such, minor olefin

92b was never isdlated. Another Mitsunobu reaction was then performed to alkylate

olefin 92a with relay side chain 61. Olefin 59 was separated from the crude reaction

mixture by flash chromatography and obtained in 30% yield over two steps. With both

side chains in place, olefin 59 was subjected to metathesis conditions using 2nd generation

38

Grubbs catalyst 14 as well as 2nd generation Grubbs-Hoveyda catalyst 77 in attempts to

ob tain macrocyc1e 58 (Scheme 26).

~ ~MFFO \; '1 Catalyst

I/'F ~I DCM,L'.,18h

01

F,: ~ 58

'\.Jo

Scheme 26 - RRCM of Macrocycle 58.

1\ MesNyNMes

I ... ,CI Ru=..

Cl .... 1 Ph

PCY3

14

Grubbs Il (10 mol %) 7 - 10% with 5 eq. Ti(Oi-Pr)4 7 - 10%

1\ MesNyNMes

~Ub·~'CI Cl.... ,

6 r; ~

----<. 77 -

Grubbs-Hoveyda Il (10 mol %) with 5 eq. Ti(Oi-Pr)4 7 - 10%

Macrocyc1e 58 was obtained in 10% yield in anhydrous CH2Ch at reflux using

either of the above mentioned catalysts (Scheme 26). The use of Ti(Oi-Pr)4 was believed

to block the catalyst from coordinating to the carbonyl group of the ester and was

determined to be essential for successful macrocyclization.30 The next step was to

increase the macrocyc1ization yield by reducing the steric bulk of the terminal olefin of

cis-famesol to facilitate olefin metathesis at that position (Figure 12).

30 Pschirer, N. G.; Bunz, U. H. F. Tetrahedron Lell. 1999,40,2481-2484.

~o~1 +

r("0~ HO~ 61

F.~F FOH

I~ 1

O~F ~ 1

F 0 OH

60

r421 '~~;I~~~"''''''L. F~~~ F ~ M ~ DCM, 6, 18 h h F: 1 h 01

':; O~O: 'LlO

Figure 12 - Proposed Mode) Study using Disubstituted OIefin 93.

II.7 - Syntbesis of cis-Olefin 93.

39

The following procedure developed by Corey and co-workers has been modified

in an attempt to prepare the desired olefin 93 (Scheme 27),3\

r. TBDPSCI r. NBS ~ ... ~ . ~ Imid, DMF, 23·C, 30 min ~ THFHzO, O·C, 2h

OH 90% 1 OTBDPS 1 ~ ~ ~

~ Br OTBDPS

OH 96

! KZC03

MeOH, 23°C, 2h

r. EtPPh3Br, n-8uLi "": ..

THF, -78°C to 0 C, 2h

1 OTBDPS 58% yield in 4 steps

99

TBAF j

~ THF:H20,2~OC,30min ~~ ~ lOTBDPS OTBDPS

o 98 0 97

THF, 23°C, 5h

65%

·~OH ) 93 '-

Scheme 27 Preparation of OIefin 93 Following Modified Corey Procedure.

31 For the exact procedure see: Corey, E. l; Kania, R. S. J. Am. Chem. Soc. 1996, 118, 1229-1230.

40

Cis,trans-Famesol 62 was protected using TBDPSCI to afford silyl ether 95 in

90% yield. Without chromatographic purification over the next five reaction steps, silyl

ether 95 was taken up in THF and water and reacted with NBS to afford the bromohydrin

96. Epoxide 97 was prepared on treatment of bromohydrin 96 with potassium carbonate

in MeOH. Aldehyde 98 was formed by hydrolytic opening of epoxide 97 and subsequent

oxidative c1eavage of the resulting diol using sodium periodate and periodic acid.

Aldehyde 98 was converted to olefin 99 VIa Wittig reaction us mg

ethyltriphenylphosphonium bromide and n-BuLi. Alcohol 93 was formed by the

deprotection of silyl ether 99 using TBAF in anhydrous THF. The final olefin 93 was

isolated following silica gel flash chromatography in an overall reaction yield of 44%.

II.8 - Metathesis of Model System 94 using cis-Olefin 93.

Pentafluorobenzyl ester 60 was coupled with 0.5 equivalents of cis-olefin 93 via

the Mitsunobu alkylation using PPh3 and DIAD in anhydrous THF at reflux. With no

further purification, the relay side chain 61 was then coupled to crude phenol 100

(containing trace amounts of the dialkylated product) via the Mitsunobu reaction

affording olefin 94 in 30% yield over two steps following column purification (Scheme

28).

60

HO~ PPh3,D)AD .. THF, d, 10 h

y:,('o~

HO~ 61

100

J

i PPha. DIAD

THF, d. 10 h

30";1; over two steps

94

Scheme 28 - Alkylation using Si de Chain 93 and Allylic Alcohol 61.

41

Now with both si de chains in place, olefin 94 was subjected to metathesis

conditions in anhydrous CH2Cl2 at reflux (Scheme 29).

Scheme 29 - RRCM of Model System 94.

1\ MesNyNMes

I, .. ,CI Ru~

CI"'" 1 Ph

PCY3

14

Grubbs Il (10 mol %) 28%

1\ MesNyNMes

~u:o,~'CI Cl..... ,

6 f ~

----\ 77 -

Grubbs-Hoveyda Il (10 mol %) 20%

42

The macrocyc1e 58 was obtained in 33% yield using Grubbs catalyst 14 with 5.0

equivalents of titanium iso-propoxide. No improvement on reaction yields was observed

using the more reactive catalyst 77.

II.9 - Conclusion.

In the present chapter, the formation of a [14 ]paracyc1ophane was accomplished

by relay ring-c1osing metathesis of a famesylated cis-olefin prepared in our group. The

importance of these model studies suggest that the formation of highly hindered

macrocyc1ic structures such as [14]paracyc1ophanes can be accomplished using RCM. In

this manner, a macrocyclic ring structure containing three tri-substituted olefins was

obtained, resembling that of longithorone C.

43

Chapter III:

Attacking the Total . Synthesis of (±)-Longithorone C:

Attachment of Alkyl Chains via Coupling Reactions

In this chapter, the method of attaching the side chains on the central arene for

olefin metathesis will be described via coupling reactions (Figure 13).

'. '.1

x~ ln y HOW +

o x rf'o~ Y~

Figure 13 - Retrosynthetic Analysis of Longithorone C.

F0rF BrkF

F

The goal was to couple both chains, at'the desired para-position in order to obtain

an all carbon [12]paracyclophane with three stereodefined tri-substituted olefins, starting

from a 2,5-dihalobenzoic acid. Herein, we report the model studies used to detennine the

appropriate coupling reactions to obtain the desired target.

44

111.1 - Negishi Coupling Reactions.

Under the following Negishi conditions,32 our group attempted to couple the

organozincate of I-bromo-3-methyl-but-2-ene to methyl-2,5-dibromobenzoate.

Unfortunately, neither bromides 103 nor 104 were observed, and only bromide 101 was

obtained in full (Scheme 30).

Br (-BuU, ZnBr2' Pd(PPh314 /~/. ~ A + I~ / THF~~, 18h MeOyY ~'" M,a : 1 •

o Br Zn*/dibromoethane, Pd(PPh3)4 0 Br

101 102 THF, l'l, 18h 103

0%

Scheme 30 - Negishi Coupling using Prenylbromide 102.

M,a 6 ~

104

The organozincate was prepared through two different methods; allylic bromide

102 was either treated with t-BuLi and transmetallated with ZnBr2 or the zincate was

formed using zinc and dibromoethane/2 but neither case provided any product.

Coupling was also attempted on dibromide 101 with the organozincate of geranyl

iodide 80.32 Unfortunately, neither diene 105 nor 106 were observed (Scheme 31).

32 (a) Gomez-Reino, c.; Vitale, c.; Maestro, M.; Mourino, A. Org. Lett. 2005, 7, 5885-5887. (b) Palmgren, A; Thorarenson, A; Backvall, 1. E. J. Org. Chem. 1998,63,3764-3768. (c) Xie, M.; Wang, J.; Gu, x.; Sun, Y.; Wang, S. Org. Lett. 2006,8,431-434. (d) Rodriguez, A; Miller, D. D.; Jackson, R. F. W. Org. Biomol. Chem. 2003,1,973-977.

45

Br I-BuU, ZnBr2' PdCI2{PPh3h -..:::: Br

M~J t / THF,&,18h ~ +

~ 1 0% MeO + MeO

1 ~ Zn/12' PdCI2{PPh3h o Br o Br 7~4 101 80

DMF, <'>, 15h 105 106 0% " .

Scheme 31 - Negishi Coupling using Iodide 80.

1', J

In a third av.d final, attempt, alkyl bromide 107 was coupled to dibromide 101

affording olefin 108 in 20% yield, suggesting prenyl-derived organozincates may be the

source of the difficulties. Olefin 108 was preferably formed over olefin 109 likely due to

steric interactions (Scheme 32).

~ ~. ~Br _1_-B_uL-,i,_Z_nB_r",,2,_Pd-,{_PP_h..::::3}.::...4 •• W THF, 55·C, 18h

o Br 1 20%

101 107

MeO

o Br

20%

108

Scheme 32 - Negishi Coupling using Alkyl Bromide 107.

Br

4%

109

Negishi couplings of prenylated halides with dibromobenzoate 101 could not be

achieved, and as a result this chemistry had to be abandoned.

111.2 - Copper Catalyzed Grignard Reaction.

Knochel and co-workers have demonstrated that functionalized organomagnesium

reagents prepared through halogen-metal exchange could be used in cross-coupling ,',1.:

46

reactions. Allyl and prenyl electrophiles were coupled to aromatic Grignard reagents

containing ester functional groups (Figure 14).33

FG ~x i-prMgY. [FG 0 M9X •

VI THF,-40°C VI FG = F, CI, Br, CN, C02R, OMe

1. Copper Catalyst (JE • FG---'-- '-'::

2. Electrophile 1 ô

E = Allyl, prenyl

X = CI, Br, 1

y = CI, Br

Figure 14 - Copper Catalyzed Grignard Reactions.

As such, the following retrosynthetic analysis was devised in order to obtain both

the cis-olefin and relay piece at the correct para-position (Figure 15).

\' ~ o~

\ Coupling Reaction 110 r('O~

Y~ X =CI, Br,l

Figure 15 - Retrosynthetic Analysis using Copper Catalyzed Grignard Reactions.

Many reactions of organomagnesium compounds with electrophiles require room

temperature or heating for completion. Knochel and co-workers have demonstrated that

33 (a) Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Kom, T.; Sapountzis, 1.; Vu, V. A.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 4302-4320. (b) Rottlander, M.; Boyrnond, L.; Berillon, L.; Lepretre, A.; Varchi, G.; Avolio, S.; Laaziri, H.; Queguiner, G.; Ricci, A.; Cahiez, G.; Knochel, P. Chem. Eur. 1. 2000, 6, 767-770. (c) Jensen, A. E.; Dohle, W.; Sapountzis, 1.; Lindsay, D. M.; Vu, V. A.; Knochel, P. Synthesis 2002, 4, 565-569. (d) lIa, H.; Baron, O.; Wagner, A. J.; Knochel, P. Chem. Comm. 2006,6,583-593. (e) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 25, 3333-3336. (f) Krasovskiy, A.; Straub, B. F.; Knochel, P. Angew. Chem., Inter. Ed. 2006,1,159-162.

47

a low-temperature preparation of Grignard reagents could allow the synthesis of

polyfunctional magnesium organometallic reagents. In addition, at low enough

temperatures, organomagnesium species with highly sensitive functional groups could be

stable for several hours.

2,5-Dihalobenzoates such as 110 containing chelating groups at the ortho-position

rapidly undergo Mg-X exchange.33 The chelating group was believed to complex to the

Grignard prior to Mg-X exchange, which could facilitate this exchange. Dihalides such

as 110 were thus expected to undergo a chemoselective Mg-X exchange, leading

selectively to Grignard reagents such as 111, in which the magnesium was ortho to the

ester functionality (Figure 16).

ROJ o X

110 X=CI, Br, 1

i-PrMgCI or i-PrMgBr

THF, -40°C, Time

Figure 16 - Magnesium-Halogen Exchange.

.. X

RO~ O--MgX

111

Grignard reagents of type 111 may then react to allow the selective coupling of the relay

chain at the 2-position.

Knochel and co-workers used copper catalysts in the cross-coupling reactions of

aryl magnesates such as 112 in order to achieve successful coupling with allyl or

prenylhalides under fast reaction rates (Figure 17).34

34 Rottlander, M.; Boymond, L.; Berillon, L.; Lepretre, A.; Varchi, G.; Avolio, S.; Laaziri, H.; Queguiner, G.; Ricci, A.; Cahiez, G.; Knochel, P. Chem. Eur. J. 2000, 6, 767-770.

48

[ ]_. p~ (MgBr)

p~ Ph ",0, Ph 0

,-,::1 i-PrMgBr O:M'& CuCN*2LiCI O-C"CN Allyl Brom., '-':: ~ I

h • I

h • • I

h THF, -40·C

112 Figure 17 - Role of Copper Catalyst in Organomagnesium Cross-Coupling Reactions.

, l \.' .. :'

As such it was considered that a 2,5-dihalobenzoate such as 110 could be used, in

". conjunction with a copper catalyst, to accomplish the installation of the desired relay and

cis-olefins at the correct para-positions prior to macrocyc1ization.

The choice of the halogen precursor required evaluation, as weIl as the issue of

the stereochemistry retenti on of the side chains (Figure 18).

R~ o X

X=CI, Br,l

110

J:~

1 0 y

1. Grignard, THF, Temp., Time

Cu-Catalyst

2. Grignard, THF, Temp., Time . . Cu-Catalyst

~ Addition Method y

o~

Figure 18 - Proposed Synthetic Pathway for Copper Catalyzed Coupling of Grignard Reagents.

111.2.1 - Optiritizing Mg-X Exchange ..

Reaction conditions were exploi-ed to ob tain successful Mg-X exchange, ln a

reasonable amount oftime, without affecting the ester functional group (Table 1).

49

Table 1 - Effeet of Ester Group, Halide, and Grignard Reagent on Mg-X exehange.

R~ o X

1. Grignard .. THF, -4œC, Time

x -.

RDA o H

113 X = Br R=Me

116 X = Br R = iPr

119 X = 1 , , - l R = iPr

+

x X

R~ + ~ o X o X

114 X = Br 115 X=Br R=Me R=Me

117 X = Br 118 X=Br R=iPr R= iPr

120 X=I 121 X=I R=iPr R= iPr

Entry X' :R Grignard (eq:) Temp (OC) Tlme (h) Products Yleld Ratio (%)

Br Me i-PrMgCI(I.I) -40.0 3.0 113/114/115 16/58/25

2 Br i -Pr i -PrMgCI (1'.1) -20.0 3.0 116/117/118 83/17/0

3 i -Pr i -PrMgBr (1.2) -40.0 0.5 119/120/121 100/0/0

When methyl-2,5-dibromobenzoate (GC RI = 9.88 min, [M+Ht found 294) was

reacted with 1.1 equivalents of i-PrMgCI followed by an NH4CI quench, a 16/58/25

mixture was obtained ofbromide 113(GC RI = 8.30 min, [M+Ht found 216), dibromide . ,.

114, and ketone 115 (GC RI = 1 L60 min, [M+H]+ found 307) after 3 h ascertained by

GC analysis (Entry 1, Table 1)_

When the methyl ester of dibromide 114 was substituted for iso-propyl ester 117

(GC RI = Il.45 min, [M+Ht found 322), the Grignard reagent attack on the ester was

suppressed and the major product was bromide 116 (GC RI = 10.00 min, [M+Ht found

243) (Entry 2, Table 1)_ However, even after 3 h dibromide 117 was still observed by

GC. When dibromide H 7 was substituted by diiodide 120 (GC RI =11.87 min, [M+Ht

found 416), the ex change was completè in 0.5 h and only iodide 119 was obtained (GC RI

50

=9.70 min, [M+Ht found 291) (Entr)'.3" Table 1). Employment of 1.2 eq of i-PrMgBr

with respect to diiodide 120 resulted in a complete Mg-I exchange ortho to the iso-propyl

ester in 0.5 h at -40°C.· Although methyl 2,5-dibromobenzoate 114 was commercially

available, iso~propyl-2,5-diiodo.benzoate 120 was prepared via alkylation of 2,5-,

diiodobenzoic acid with i-propyl bromide in 87% yield under the presence of NaH in

DMF (Scheme 33).

• !:.:

H~ ---,--:--_i.p_rl __ 'r~ o 1

'121

Scheme 33 - Synthesis of i-Propyl-2,5-diiodobenzoate 120.

. • ,'. ,l",

111.2.2 -'Optimizing SN2'/SN2-typ~ P~oduct Ratio.

o 1

120

In this section, the optimum reaction conditions will be discussed in order to

obtain the desired a-product 124 with high reaction yields. The outcome of these results

was dependant on choice of catalyst, electrophile, and addition method (Table 2) .

. l

Table 2 - Optimizing y / cr Product Ratio.

r~ O---MgBr

122

125 Y = Br 126 y = OAc

r("0~ Y~ Cu-Cat, THF, -4O'C, 1 h

Addition Method

Entry Aryl-I (eq) Catalyst (10 mol %)

1.0 CuCN+2LiCI

2 1.0 Li,Cul,

3 1.0 Li,Cul,

4 1.5 Li,Cul,

1.5 Li,Cul,

y-product

+ (-0 O~

123

Y (eq) Addition Method

Br (1.0) A"

Br (1.3) A

OAc (1.5) A

OAc (1.0) A

OAc (1.0) B"

8 Cu-catalyst added to Grignard reagent, followed by allylic electrophile

b Grignard reagent added to a solution of Cu-cat and allylic electrophile

C Based on l H-NMR yields

51

a-product

O~

124

y / a (% Yield)'

32/20

11/7

0/19

0/43

0/80

Two methods of addition were explored in order to prepare the desired a-product

124. Either the copper catalyst and side chain 125/126 were added to Grignard 122,

prepared from i-PrMgBr and iso-propyl-2,5-diiodobenzoate (Method A), or copper

catalyst and side chain 125/126 were mixed together prior to treatment with the Grignard

reagent 122 (Method B, inverse addition). The requisite allylic electrophiles 125 and 126

were prepared from allylic alcohol 61, treated with either PPh3 and CBr4 or AczO and

pyridine respectively (Scheme 34).

("o~ HO~

61

("o~ HO~

61

DCM, O°C, 1.5h, Dark

99%

23°C, 10 h

99%

Scheme 34 - Synthesis of Bromide 125 and Acetate 126.

•

•

("o~ Br~

125

("o~ ACO~

126

52

Using bromide 125 and addition method A, a 32/20 mixture of sNi/SN2-type

products was obtained based on the IH-NMR yield (Entry 1, Table 2). By employing

LhCuCl4 as catalyst, the formation of the SN2-type products, or a-products was

favored. 35 Employing LhCuCl4 as catalyst in this reaction with bromide 125 did not give

any improvement in the product ratio (Entry 2, Table 2). Switching to acetate 126 as

electrophile eliminated the SNi-type product, or the y-product and provided olefin 124

using LhCuCl4 as catalyst (Entry 3, Table 2). Fast addition of the freshly formed

Grignard reagent 122, to a premixed solution of LhCuCl4 (10 mol%) and acetate 126

(Method B), gave the desired a-product in 80% yield (Entry 5, Table 2).

Backvall and co-workers have conducted numerous studies in order to explain the

a/y product ratios in cuprate additions to allylic acetates, bromides, and chlorides.35, 36

They have demonstrated that in most cases, the more reactive allylic chlorides and

bromides showed a preference for y-substitution in copper catalyzed Grignard reactions,

where allylic acetates showed a preference for a-substitution.

35 Backvall, J.E.; Sellen, M.; Grant, B. 1. Am. Chem. Soc. 1990, 112, 6615-662l. 36 Schmid, M.; Gerber, F.; Hirth, G. He/v. Chim. Acta. 1982,65,684-702.

53

111.2.3 - Mechanism behind the a1rProduct Ratios.

The goal of the preceding study was to obtain the desired a·product, and maintain

the stereochemistry of the olefins in the side chain. Following the mechanism explained

by Backvall, the transmetallation step with the copper catalyst and the Grignard reagent

produces the monoarylcuprate species 127 (Figure 19).35

)-oA O---Mg

1 Br

122

THF, -40·C CuL, THF, -40·C II> Ail Transmetalation ro ~ Fast Grignard Add.

1 GE! O---Cu

1 MgBr L

monoarylcuprate 127

("O~ ACO~

126

y-product

("O~ ACO~

126

(l-product

Figure 19 - Regiocontrol in Copper Catalyzed Grignard Reactions.

Cuprate 127 can either react with the electrophile or a second equivalent of

organomagnesium 122, affording the dialkylcuprate species 128. It was known in the

literature that monoalkylcuprates tend to fonn y·products whereas dialkylcuprates tend to

fonn a-products.35 Fast addition of Grignard reagent 122, low catalyst loading, and low

54

concentration of the allylic acetate 126 are all expected to favour the fonnation of the

dialkylcuprate 128, which in tum should favour the fonnation of the a-product.35

It was believed that following oxidative addition of either mono- or diarylcuprates

onto acetate 126, the cuprate may add at the y-position to fonn o--allyl complex 129

(Figure 20),35

127

128 diarylcuprate L = Aryl a-arylcuprate 129

Figure 20 - Formation of ~Allyl Copper Species 129 with the Allylic Acetate 126.

Br /

Mg \ OAc

Following fonnation of the o--allyl complex 129, the cuprate can either undergo

reductive elimination to generate the y-product, or reversible isomerization to generate 7C-

allyl complex 130, which on reductive elimination would give the a-product (Figure 21).

1 .. ("'o~

A ACO~ JI L=Br,CI,CN

'1 126 Fast Reductive Elimination

rD l ,le e O,k!. Add. • . "(0 1 :

1 ,f' · O---yU Mg Br o"'CU~

L 1

L

monoarylcuprate 127 IJ-allyl complex 129

1

IL = R

Reversible Isomerization

fast

y-product

~Y"J ~ ,:Cu--i= ----.. ~ a-product

~~I' J o 'II ~

1

1t-allyl complex 130

Figure 21 - Formation of 7r-Allyl Copper Species 130 with Acetate 126.

55

Electron-withdrawing ligands such as Br, Cl, and CN on complex 129 have heen

suggested to accelerate reductive elimination leading to the y-product. 37 The latter may

result from using catalysts such as CuBr, CuCI, and CuCN, respectively. If the ligand L

on complex 129 is an alkyl or aryl group (resulting from the formation of the

diarylcuprate intermediate), then reductive elimination would he slow and o--allyl

complex 129 may undergo reversihle isomerization leading to tr-allyl complex 130, and

a-product 124 following reductive elimination (Figure 21).

37 Yamamoto, T.; Yamamoto, A.; Ikeda, S. 1. Am. Chem. Soc. 1971,93,3350-3360.

56

Catalysts such as LÏ2CuC14 lead to the fonnation of the diarylcuprate 130.

Delivery of the. aryl group to the less hindered position of lZ'-allylic complex 130 would

favor addition to the a-position. In addition, the aryl group delivery is believed to be

faster with LizCuC14 as catalyst such that complete retention of stereochemistry is

observed (Figure 21).38

To sum up thus far, starting from i-propyl-2,5-diiodobenzoate 120, 1.2

equivalents of i-PrMgBr was required with respect to 120 in order to have complete Mg-I

ex change in under 0.5 h at -40°C. The newly fonned Grignard reagent was then added to

a flask containing a premixed solution of allylic acetate 126 and Li2CuC14 as copper

catalyst over a 2-min period, affording iodide 124 in 80% yield (Scheme 35).

rOY~ o 1

(1.5eq)

120

Ero~ 126 AcO~

1. i-PrMgBr (1.8 eq), THF, -40°C, 30min

2. 126, Li2CuCI4 , THF, -40°C

2min inverse addition

3. THF, -40°C, 1.5h; 23°C, 1h

80% :7

(0 124 ~

Scheme 35 - Optimized Reaction Conditions in Forming Aryl Iodide 124.

111.2.4 - Attaching cis-Olefin 93 via the Copper Catalyzed Grignard Reaction.

In light of the previous coupling reaction, cis-olefin 93 was converted to allylic

acetate 131 in the presence of acetic anhydride and pyridine to afford acetate 131 in 96%

yield (Scheme 36).

38 Levisalles, J,; Rudler-Chauvin, M.; Rudler, H. 1. Organomet. Chem. 1977, 136, 103-110.

~. 93 , OH

23°C, 10 h

96% ~ 131 OAc

Sche~e 3~ Formation of the Allylic ~c~tat~ 131 perived from cis-Olefin 93.

57

When subjecting aryliodide 124 to the same reaction conditions, the absence of a • 1 ., ,

chelating group ortho to the iodine a~.om, was expected to slow Mg-l exchange. Two

equivalents of i-PrMgBr were require~~ to obtain complete Mg-I exchange with aryl

iodide 124 in 0.25 h at -40°C. The freshly formed Grignard reagent was then added to a L .'. ,t!U) \.'

p~emixed solution o~ cis~acet;ite 131 al1d the LhCuCl4 to afford the desired olefin 132 in

50% yield (Scheme 37).

é?' (1.5eq) 0

124 (' ,~

~131 . , ,!;' ".:,. OAc

1. i-PrMgBr(3.0eq);'fHF. ·40·C. 15min

2min inverse addition 3. THF, -40·C, 1.5h; 23°C, 1h

50%

..

Scheme 37 - Optimized Reaction Conditions in Forming Olefin 132.

132 é?' oJ

With reaction protocols for both allylic acetates 126 and 131 in hand, the next

step was to determine whether there .yvas retention of olefin stereochemistry in the

çoripling.reactions.

58

111.3 - Determining Stereochemistry of the Side Chains.

In the NOESY spectrum of trans-allylic acetate 126, nOe was observed between

the methyl signal at 1.66 ppm and the allylic methylene signal at 4.00 ppm. No nOe was

observed between the methyl signal (1.66 ppm) and vinyl proton (5.60 ppm) (Figure 22).

Hb '

ACO~O~ lH ~c

a....) nOe

126 '

_': :~ 1

Figure 22 - Stereochemistry of Relay Side Chain.

.. O~

124

'In the NOESY spectrum of iodide 124, the methyl signal exhibited nOe with the

methylene signal at 3.97 ppm and not with the vinyl proton (5.21 ppm) indicating

retenti on of stereochemistry in coupling of the allylic acetate 126 to iodide 120.

The NOESY spectrum of esfer 132 was complicated due to overlapping signaIs '. 'f .1 ......

for the alkenyl protons. As a mod~i system, ester 135 was formed following a similar

Cu-catalyzed Grignard reaction employing acetate 136 that was derived from cis-farnesol

62 (Scheme 38).

ACO~--Z

~ ~ .1 !

131

rOI, N'H. ,P,I rO',

HO ~ DMF, 23°C, 1;' ---(0 ~ 87% \

o 133 0 134

• , 1 ~ il , «

~131 - OAc

1. i-PrMgBr (3.0eq), THF, -40°C, 15min

2min inverse addition 3. THF, -40°C, 1.5h; 23°C, 1 h

80%

nOe f".

~ OH " ; 62

23°C, 10 h , 96% ~ 136 OAc

Scheme'38 - Synthesis of Acetate 136 and Stèieochemistry of Oleftn 153.

59

In the NOESY spectrum of ester 135, the vinyl proton at 5.33 ppm and methyl

signal at 1.76 ppm exhibited an pOe iI1dicative of a cis-olefin. Based on this result, a

similar retenti on of configuration has been assumed for ester 132. " - 1 •• _

111.4 - Conclusion.

In summary, copper-catalyzed cross coupling of aryl Grignard reactions to allylic

acetates 126 and 131 gave ester 132 with retention of stereochemistry. The stage was set

to explore the total synthesis oflongithorone C by formation of the macrocyc1e by RCM.

60

Chapter IV:

Improved Gearing Elements for Macrocyclic Olefin

Metathesis: A Model Study ' . ./

1/:1

IV.I - Improved Gearing Element used in Model Systems.

Our group has continued to invèstigate new and improved gearing elements for

oletin metathesis. During studies directed towards developing gearing elements that

function via non-covalent interactions, we investigated substituting the pentafluorobenzyl

ester with other fluorinated aromatics. One such attempt involved use of a 3,5-

bis(trifluoromethyl)benzylester (Schem~ ~9). This gearing element was tirst examined in

model systems before application to th~ total synthesis of longithorone C.

; "

94

139 , . •. ..... J.

137

Et3N DMF, 23°C, 24h

80% over two steps

Scheme 39 - Preparation of Bistrifluoromethyl Benzyl Ester 139 •

. \ ' ...

61

Ester 94 was hydrolyzed using NaOH in a mixture of toluene and methanol at

reflux for 24 h. The crude acid 137 was alkylated with 3,5-bistrifluoromethylbenzyl -

~ " ~

bromide and triethylamine in DMF to afford ester 139 in 80% yield over two steps.

Previously, ring c10singmetathesis using pentafluorobenzyl ester 94 gave 33% yield of

[12]paracyclophane 58. With bis(trifluoromethyl)benzyl ester 51 the same conditions

gave macrocyc1e 140 in 47% yield (Scheme 40).

~ F 0

~~'\ F 'II Grubbs Il (10 mol%) 14 b F ~ ..

Ti(Oi-Pr)4, DCM, 1'., 15h

o ~ 0 ) 33%

94 'Z ~o •

f;J o ~ 0 0

58

CF3

~~ o 0 140

Scheme 40 - Improved Bistrifluoromethyl Gearing Element on Model System.

62

Qualitatively, the results may be explained by electronic effects of the fluorine

substituents, Since the fluorine atoms of the pentafluorobenzyl ester are directly attached

to the arene in ester 141, the electron density is concentrated on the fluorine atoms and

the center of the arene is considered electropositive. The same effect can be caused by

the bistrifluoromethyl groups in ester 142. However, the fluorine atoms of the

pentafluorobenzyl ester may have both electron donating and electron withdrawing

abilities, where as the trifluoromethyl groups in the bistrifluoromethyl gearing element

are solely electron withdrawing.24 One may consider that the CF3 groups make the arene

more electropositive than that of the pentafluorobenzyl ester (Figure 23).

63

iF ;< OR iF

~ ~F OR

1,1 I~ F

;, CF;! F

0 0

0 141 o 142

Figure 23 - Quadrupolar Interactions using a CF3-Based Gearing Element.

IV.2 - Molecular Modeling using the Bistrifluoromethyl Auxiliary on Madel

Systems.

Molecular modeling was used in order to understand how the non-bonding

interactions affected the product distribution using high order DFT method calculations

(Figure 24).39

39 For a complete list ofmethods and results used in the molecular modeling studies see: Collins, S.; El­Azizi, Y.; Schmitzer, A. R. J. Org. Chem. 2007, 72,6397-6408.

"open" 143

"open" 146

Pentafluoro auxiliary t.H"'Ck - t.Hopon = -0.20 kcal/mol

3,5-Bis(trifluoromethyl) auxlllary t.H stack - t.Hopon = -1.28 kcal/mol

64

Oxygen - Arene

"stacked" 144

"stacked" 147 148

Figure 24 - Results of Higher Order DFT Calculations on Model System (Red color denotes areas of

increased electronic density due to fluorine atoms).

In the above model systems (that incorporate the oxygen atoms about the central

arene), the "stacked" conformer 144 of the pentafluorobenzyl ester was preferred over the

"open" conformer 143 by 0.20 kcal/mol. With the bistrifluoromethylbenzyl ester as

gearing element, the "stacked" conformer 147 was preferred over the "open" conformer

146 by 1.28 kcal/mol. These findings correlate with the increased yield for the

bistrifluoromethylbenzyl ester 140 relative to the pentafluorobenzyl ester 58 in the ReM

reaction. The "stacked" conformers above do not, however, engage in J[: J[ stacking

interactions, instead the benzyl group sits over an oxygen atom (145/148) and is believed

to engage in lone pair: J[ interactions between the electron deficient pendant arene and an

65

oxygen atom (Figure 24). These interactions, although rare, have been previously

documented for systems in solutions.4o

IV.3 - Molecular Modeling using the Bistrifluorometbyl Auxiliary on an Ali Carbon

System.

Molecular modeling was carried out in order to probe how the non-bonding

interactions between the electron deficient auxiliaries and electron rich arenes would

effect the product distribution in fonning an aU carbon [12]paracyclophane (Figure 25).

"open"149

"open" 152

Pentafluoro auxiliary "stacked" 150 ôE l1aCk - ôE_n = -0.55 kcal/mol

3,5-Bis(trifluoromethyl) auxiliary ôE.tack - ôE_n = -0.41 kcallmol

"stacked" 153

face-face

154

Figure 25 - Results of Higher Order DFT Calculations on Ail Carbon System (Red color denotes

area ofin

creased electron density due to the fluorine atoms).

40 Egli, M. ; Sarkhel, S. Ace. Chem. Res. 2007, 40, 197-205 .

66

The "stacked" confonner 150 of the pentafluorobenzyl ester was preferred over

the open confonner 149 by. 0.55 kcallmol. The "stacked" confonner 153 of the

bistrifluoromethyl auxiliary was preferred over the open confonner 152 by only 0.41

kcallmol. The lower energy difference calculated for the bistrifluoromethylbenzyl

gearing element may be due to steric repulsion between the trifluoromethyl groups and

the central arene. In the absence of oxygen atoms, the "stacked" confonners were

predicted to engage in quadrupolar n:n interactions (151/154) (Figure 25).

The pentafluorobenzyl ester was thus predicted to be more likely to fonn the all

carbon macrocyc1e. Consequently, RCM was examined on olefins 155 and 156

containing both auxiliaries to correlate the above findings with the paracyc10phane

product distribution (Figure 26).

Catalyst (10 mol %)

• Ti(Oi·Pr)4, DCM, L'., Time

o~

155 = Pentafluorobenzyl ester 157 = Pentafluorobenzyl ester

156 = Bis(trifluoromethyl)benzyl ester 158 = Bis(trifluoromethyl)benzyl ester

Figure 26 - Model System used in Determining the Ideal Gearing Element.

IV.4 - Determining the Ideal Gearing Element in the Formation of an Ali-Carbon

[12]Paracyclophane.

The following retrosynthetic analysis was proposed to study the gearing element

for the fonnation of an all carbon macrocyc1e (Figure 27).

o~

159 "RRCM 124

67

(î .. ~ ,.~

+

Figure 27 - Retrosynthetic Analysis for the Model System used for Determining the Ideal Gearing

Element.

Aryl iodide 124 was made as described in chapter III. Bromide 161 was made

from commercially available olefin 162 (Scheme 41).

~OH

Î1 162

~Br ) 161

TBDPSCI

Imid, DMF, 23°C, 5h 99%

..

"'

DCM, DOC, 2h, Dark 99%

~OTBDPS Ozone ~OTBDPS

163 Py, DCM, -78°C, PPh3,"'1h') 11:.d o 164

~OH ) 166

1 EIPPh3Br, nBuLi

THF, -78°C

.. TBAF r-oTBDPS THF, 23°C, 5h

30% over three steps 1 165

Scheme 41 - Synthesis of Bromide 161.

Protection with TBDPSCI afforded silyl ether 163 in quantitative yield. Without

further purification silyl ether 163 was c1eaved by ozonolysis for 1 h at -78°C to afford

aldehyde 164 that was immediately converted to olefin 165 by a Wittig reaction using

ethyl triphenylphosphonium bromide and n-BuLi in anhydrous THF. Triphenylphosphine

oxide was precipitated out using hexanes and was filtered during workup, and the silyl

68

ether of olefin 165 was removed with TBAF to afford alcohol166 in 30% yield over four

steps. Finally, bromide 161 was prepared from alcohol166 in the dark using PPh3 and

CBr4 in CH2Clz for 1.5-2 h and was used without further purification in the next synthetic

step (Scheme 42).

124

+ ~Br

J 161

(-BuU, ZnCI2

PdCI2(dppf), THF, 55°C, 1~h r O~

155 = Pentafluorobenzyl ester

20%

.. DMF, 23°C, 10h HO

77% over two steps for both benzylbromides

156 = Bis(trifluoromethyl)benzyl ester

o

168

o O~

167

j NaOH PhMe:MeOH (1:1)

L'., 24 h

Scheme 42 - Synthesis of Pentafluorobenzyl ester 155 and Trifluoromethylbenzyl ester 156.

Triene 167 was formed by coupling the organozincate of bromide 161 to aryl

iodide 124 using PdClz(dppf) in anhydrous THF, albeit in 20% yield. Pentafluorobenzyl

ester 155 and trifluoromethylbenzyl estèr 156 were both made in 77% yield over two

steps by saponification of ester 167 with NaOH in al: 1 mixture of toluene and methanol,

and alkylation of acid 168 with the respective benzyl bromide (69 and 138).

69

Metathesis of esters 155 and 156 were conducted in anhydrous CH2Ch usmg

Grela catalyst 169 and the Blechert catalyst 170 in attempts to form [12]paracyclophanes

157 and 158 (Table 3).

Table 3 - RRCM of Model Compound [12]Paracyclophane 157 and 158.

Catalyst (10 mol %) •

Ti(Oi-Pr)4, DCM, 1'., Time

155 = Pentafluorobenzyl ester 157 = Pentafluorobenzyl ester

156 = Bis(trifluoromethyl)benzyl ester

Entry

2

4

~ MesNyNMes

CI,. 1

y~~N~ Grela 169

Aryl-CH, Catalyst (10 mol %)

3,S-bistrifluoromethylbenzyl ester Grela 169

penlafluorobenzyl ester Grela 169

penlafluorobenzyl ester Grela 169

pentafluorobenzyl ester Blechert 170

158 = Bis(trifluoromethyl)benzyl ester

~ MesNyNMes

CI,. 1

Y~9 Ph

Blechert 170

Solvent Addition Tlme (h) Reaction Time (h)

CH,Cl, 1.0 4.0

CH,Cl, 1.0 4.0

PhMe 1.0 4.0

CH,Cl, 1.0 4.0

Yield(%)

0

7-10

7-10

14

No trace of macrocycle 158 was observed after treatment of the

bistrifluoromethylbenzyl ester 156 with catalyst 169 for 4 h in CH2Ch (Entry 1, Table 3).

On the other hand, pentafluorobenzyl ester 155 reacted under the same reaction

conditions to fumish macrocycle 157 in 10% yield (Entry 2, Table 3). Using toluene and

increased reaction temperatures did not produce any improvement in the yield of 157

70

(Entry 3, Table 3). However, with the use of Blechert's catalyst 170, macrocyc1e 157

was obtained in a c1eaner reaction and in 14% yield (Entry 4, Table 3).

In the NOESY spectrum of macrocyc1e 157, the configuration about the newly

formed double bond was shown to be cis on observation of a nOe between the signaIs for

the methyl (1.73 ppm) and vinyl (4.36 ppm) proton signaIs (Scheme 43).

O~

Scheme 43 - NOESY of Macrocycle 157.

Blechert Catalyst 170 (10 mol%)

Ti(0i-Pr)4, DCM, il, Time

14%

•

nOe

In light of the cis-geometry of trisubstituted olefin 157 the ring strain involved in

forming [12]paracyc1ophanes was expected to lead to a cis-olefin in the ReM reaction to

form longithorone C.

IV.5 - Conclusion.

In this chapter, other fluorinated aromatics were demonstrated to serve as gearing

elements. Formation of aH carbon [12]paracyc1ophane 157 containing a tri-substituted

olefin was achieved by olefin metathesis albeit in low yield. As suggested by molecular

modeling calculations using the high order DFT method, the pentafluorobenzyl ester

proved superior to the bistrifluoromethylbenzyl ester for favoring a "stacked" conformer

as a result of the stronger non-bonding interactions between the pentafluorobenzyl ester

71

and the pendant arene that may be necessary for RCM.39 These suggestions correlated

with the fmmation of [12]paracyclophane 157 containing one tri-substituted olefin (Table

3). Although the yields in these macrocyclizations were low, the macrocyclization to

fmm 10ngithoroneC was expected to proceed more efficiently due to the presence of the

cis-olefin adjacent to the aromatic core ..

. :.

I! J

72

ChapterV:

Approach Towards the Total Synthesis of (±)-Longithorone C

The present ehapter will foeus on the approaeh towards the eompletion of the total

synthesis of longithorone C. The following retrosynthetie analysis eould be followed in

order to arrive to the desired target (Figure 28).

Oxidation :> :>

MeOH H

171

Il 1. Saponification il 2. Reduction! Oxidation

longithorone C

Coupling Metathesis /

132 174 173

Figure 28 - Retrosynthetic Analysis for Longithorone C.

73

Synthesis of ester 132 was described in chapter III. Following saponification of

the iso-propyl group of ester 132, and esterification with the gearing element of choice,

olefin 174 was expected to undergo RCM to form macrocycle 173. The remaining

synthetic steps would involve a series of oxidation/reduction reactions in order to form

the quinone core of longithorone C.

V.l- RRCM in Forming an Ali-Carbon [12]Paracyclopbane.

Saponification of the iso-propyl group of ester 132 was performed using an excess

ofNaOH in al: 1 mixture of toluene:methanol al reflux. Olefin 175 was obtained in 94%

yield, and without further purification, alkylated with either pentafluorobenzyl bromide

69 or bis-3,5-(trifluoromethyl)benzyl bromide 138 using K2C03 as base. The bromides

69 and 138 were passed through basic alumina twice prior to their use in alkylation of

olefin 175 in order to obtain 80% yield of olefins 174 and 176 respectively (Scheme 44).

:?' 0 Il 132 V

PhMe:MeOH 1:1, A, 10h HO

94%

1" j;F F

Br ;, F

F 69

175

K2C03

DMF, 23°C, 24h

80%

ArH 2CO

174 = Pentafluorobenzyl ester 176 = BistrifJuoromethyl ester

Scheme 44 - Synthesis of Macrocyclization Precursors 174 and 176.

74

A series of catalysts were next screened in the macrocyclization step in forming

macrocycles 173 and 177 (Table 4).

75

Table 4 - RRCM in forming Cyclophanes 173 and 177.

Ca,talyst (10 mol "la) .. Ti(Oi-Pr)4, Sol ven!, L\, Time

174 = Pentafluorobenzyl ester 173 = Pentafluorobenzyl ester 176 = Bistrifluoromethylbenzyl ester 177 = Bistrlfluoromethylbenzyl ester

Entr~ Substrate Catal~st (10 mol %~ Suivent Addition Tlme !hl' Reaction Tlme (hl Yleld (0/0)

174 G 1114 CH,Ci, 1.0 18.0 tracesb

2 174 G-H Il 77 CH2C12 1.0 18.0 traces

3 174 Grela 169 CH2Ci2 3.0 4.0 23

4 174 Grela 169 PhMe 3.0 4,0 20

5 176 Grela 169 CH2C12 1.0 4,0 la 6 176 Grela 169 PhMe 3,0 4,0 32

7 176 Blechert 170 CH2C1, 3.0 4,0 37

a Ali additions were conducted using a syringe pump

b Traces ofproduct were observed by 'H-NMR

From the macrocyclization of bistrifluoromethylbenzyl ester 176 in CH2Ch with

either 10 mol% of catalyst 14 or 77, after 18 h only traces of macrocycle 177 were

observed by IH-NMR (Entries 1 and 2, Table 4). Macrocycle 177 was isolated in 23 and

20% yields for 4 h using the Grela catalyst 169 in CH2Ch and PhMe respectively (Entry

3 and 4, Table 4).

Pentafluorobenzyl ester 174 with catalyst 169 in CH2Ch afforded macrocycle 173

in 10% yield (Entry 5, Table 4). An increased yield of 32% was obtained from reaction

of 174 in toluene (Entry 6, Table 4). In addition, using the Blechert catalyst 170 on

pentafluorobenzyl ester 174, afforded macrocycle 173 in 37% yield (Entry 7, Table 4).

The higher reaction yields observed using pentafluorobenzyl ester 174 relative to

76

bistrifluoromethylbenzyl ester 176 agreed with the findings of the molecular modeling

calculations that suggested superior stacking effects of the pentafluorobenzyl gearing

element would be preferred (Chapter IV).

V.2 - Future Work for Completing tbe Total Syntbesis of Longitborone C.

The best reaction conditions for RRCM was found using pentafluorobenzyl ester

69 as gearing element (olefin 174), in anhydrous CH2Ch, with 10 mol% of catalyst 170,

and 5.0 equivalents of Ti(Oi-Pr)4, affording macrocycle 173 in 37% yield (Table 4). Our

group is presently working on further optimizing the auxiliaries for macrocyclization of

the above aIl carbon system. The following synthetic steps would complete the total

synthesis oflongithorone C (Figure 29).

DIBAL-H . ------------------......

DCM. -7S·C H

: 31 % H20 2• KHS04

: MeOH ,

Oxidation ................... _ .. _--_ .....

longlthorone C 171

Figure 29 - Proposed Reaction Steps for the Completion of Longithorone C.

77

• 1 ~ ,

Following the fonnation of macrocyc1e 173 via RRCM, removal of the gearing

element may be achieved using DIBAL .. :H at low temperatures. An interesting procedure

developed by Backvall and co-workers may allow for the successful oxidation of

aldehyde 172 to phenol 171 resembling the Baeyer-Villiger reaction. The challenge with

the latter oxidation being unfavorable for substrates possessing functional groups labile to 1 :1

peracids, was overcome by the acid-catalyzed oxidation of benzaldehydes such as 172

with hydrogen peroxide in methanol, that proceed through peroxy hemiacetal " l'

i. l ,l," • 1 :1'1

intennediates such as 178b (Figure 30).41

- : ~ ~,

KHS04

H _._------_ .. _-----,..

MeOH. 23"C. 24h H

172 178a 178b

Ar Migra lion

Hydrolysis .---------------_.

171 179

Figure 30 - Proposed Mechanism for Oxidation of Benzaldehydes to Phenols.

The fonnation of hemiacetals of type 178b was made possible through dimethyl acetal

intennediates of such as 178a prepared by treating aryl aldehydes of type 172 in acidic

41 Matsumoto, M., Kobayashi, K., Hotta, Y. 1. Org. Chem. 1984,49,4740-4741.

78

methanol. Aryl migration of intennediate 178b would therefore provide ester 179, and

subsequent hydrolysis would afford phenol 171. In this manner, olefinic substituents in

benzaldehydes should be stable under the present reaction conditions and the oxidation

products should be phenols as opposeàto benzoic acids obtained via the Baeyer-Villiger

reaction (Figure 30). , "

In order to fonn ,the qüinone cdre'oflongithorone C from phenol 171, Sorokin and

co-workers developed a controlled oxidation for phenols bearing oxidizable olefinic

functional groups under mild conditions.using iron tetrasulfophthalocyanine supported on

silica as a heterogeneous catalyst and tert-butylhydroperoxide as the oxidant.42 Their

group observed that aromatic oxidation was the major pathway and the proposed

mechanism was based on an iron complex-based oxo species fonned when Iron

complexes in combination with hydropetoxides involved in 'oxidation reactions. ,,'

Following the completion of longithorone C, the asymmetric synthesis should be

attempted by employing either a chiral catalyst or a chiral auxiliary. For example Grubbs

has developed a chiral catalyst such as catalyst 180 that may be used in the asymmetric

synthesis of longithorone C, however bulky catalysts su ch as 180 have been known to

show low reactivity.43 Recently, Pierre-André Fournier within our group had developed a

reactive and less bulky catalyst, PAF-l 181, in order to have an increased level of

reactivity compared to existing chiral Ru-based catalysts (Figure 31 ).43

1 t!,

42 Sorokin, A.B.; Zalomaeva, a.v. NewJ. Chem. 2006, 30,1768-1773. 43 Seiders, T. J.; WardiD. W.;'Grubbs, R. H. Org. Lett, 2001, 3,3225-3228.

Grubbs 180

t-BU\_--(t-BU

Q:NyN_Me

I-Pr l,CI CI·Ru~

1 Ph PCY3

PAF-1 181

Figure 31 - Proposed Chiral Catalysts for the Asymmetric Synthesis of Longithorone c.43

79

The results found while cyc1i.~i~g the precursor 174 suggest that more reactive

catalysts are necessary in order to obtainhigh reaction yields. As such, catalyst PAF-1

181 would seem to be a promising choice (Figure 31).

Yet another method for per.forming the asymmetric synthesis would be to use

chiral gearing elements prepared fr0I? brql?ides such 182 and 183 (Figure 32).

~~ H Me F

182 . , 183

Figure 32 - Proposed Chiral AuxiIiaries for the Asymmetric Synthesis of Longithorone C.

Esterification with these auxiliaries may lead to chiral gearing elements, which in

tum may lead to the asymmetric synth,esis of longithorone C. ., ,

80

V.3 - Conclusion

Inspired by the independent work performed by Tadahiro and co-workers in

forming Longithorone B, and Shair and co-workers in forming Longithorone A, our , '

group had focused on optimi~ing macrocyclization reactions forming the , ". 1 ~, :. • 'l!

[12]paracyclophane longithorone C. Model studies revealed that ring-closing olefin

metathesis can be used in forming [12] and [14 ]paracyclophanes with macrocycles 1, j

resembling that of longithorone C. The formation of various macrocyclic cyclophanes

via ring-closing olefin metathesis was. possible through the use of a pendant fluorinated 1 • ,', • j~' 1

benzyl ester group. Bis(trifluoromethyl)benzyl ester proved best for model system 139

incorporating the oxygen atoms about the central aromatic core. Pentafluorobenzyl ester '.

was more effective in making the aIl carbon paracyclophane 157. Model studies revealed

that the use of relay side chain 126: was necessary in order to form highly substituted ,

double bonds by a novel techn.ique called relay ring-closing metathesis. In addition, our

group was able to stereoselectively form the [12]paracyclophane 173 using copper

catalyzed Grignard reactions optimized in our labs. The advanced precursor 173 has . '.

been prepared and may be converted to longithorone C by a sequence of reactions

featuring an ester re4uction and. aromatic ring oxidation.

81

Chapter VI:

Experimental , ,

li'"

VI.l - General Experimental Notès . l ,

Reagents

AU reagents were purchased from Aldrich, Sigma, or Alfa Aeser and were used without

further purification, unless otherw'ise noted.

Anhydrous Reaction Conditions

AIl anhydrous reactions were performed under an atmosphere of dry nitrogen. The glass

vessels, needles, stirring bars, and reflux condensers were either oyen dried at llO-140°C,

or flame dried, and cooled to room temperature under a flow of nitrogen. Solvents such

as tetrahydrofuran, dichloromethane;i diethyl ether, toluene, hexane, methanol, and

dimethylformamide were obtained· by filtration through the Seca Solvent System by

GlassContour, which filters the solvents over a column of alumina under an atmosphere

of argon. Acetonitrile and benzene were purchased from Aldrich and were dried using

molecular sieves (4-8 mesh, 0.125 inch, type 4 Â).

82

Temperature Control

The temperatures indicated in the reaction schemes and in the procedures are all external

temperatures. The following bath temperatures were obtained from the following

mixtures:

dry ice-acetone bath

dry ice-acetonitrile bath

ice water bath

ambient temperature

,( 1 •

Chromatography

, ..• .' 44 Silica gel flash chromatography was carried out according to the procedure of Still,

using silica gel obtained from Silicyc1e Chemical Division (40-63 nm; 230-240 mesh).

Thin layer chromatography (TLC) was performed usmg commercially available,

precoated glass backed Silica Gel 66' F254 plates with a thickness of 25 ).l.m.

Visualization of the UV active co~pounds on the TLC plates was do ne with the aid of a

J , ~ I} 4'.

UV254 lamp. The TLC plates were stained with either of the following stains:

• Cerium molybdate stain:4S Pn;pared by dissolving 12 g ammonium molybdate,

and 0.5 g ceric ammonium molybdate in 235 mL H20 and 15 mL

, . concentrated sulfuric acid.

44 Still, w. c.; Kahn, M.; Mitra, A. 1. Org. Chem. 1978,43,2923-2925. 45 El Khadem, H.; Hanessian, S. Anal. Chem. 1958,30, 1965-1965.

83

• Potassium permanganate stain: Prepared by dissolving 1.5 g potassium

permanganate, 1 (i) .g potassium; carbonate and 1.25 mL 10% NaOH in 200 mL

H20.

Instrumentation

Nuc1ear Magnetic Resonance Spectroscopy:

Routine nuc1ear magnetic resonance spectra were recorded on Bruker AMX 300 (lH 300

MHz, 13C 75 MHz), Bruker AV 300 (lH 300 MHz, 13C 75 MHz), Bruker ARX 400 (lH

400 MHz, 13C 100 MHz), and Bruker AV 400 eH 400 MHz, 13C 100 MHz) instruments.

Chemical shifts (0) and coupling constants (J) are expressed in parts per million (ppm)

and hertz (Hz) respectively. Abbreviations used describing the splitting of the peaks are

as follows:

s

d

t

q

dd

ddt

m

sept

\ .;. singlet

. ,) doublet

triplet

quartet

", ~.' doublet of doublets

doublet of doublet of triplets

multiplet

septet

84

Please note that' ail J3C signais for~,carbons bearing fluorine substituents are often

observed as .very weak signaIs.. These signaIs are often unobservable or barely

distinguishable from the baseline. As su ch, the signaIs are not reported.

Gas Chromatography:

Ge-MS data were measured using an Agilent Capillary Column model number 19091s-

433 HP-5MS, 30.0 m length, 250;0 -Ilm,diameter, and 0.25 Ilm thickness. Front inlet

Splitless, with an,initial temperature of250°C.· The run time was 0 - 27.5 min. The oven

temperature was 50°C 275°C, withJan' instrumental rate of 10°C/min. The flow rate

was established at 1.0 mL/min, using,helium gas and the Front detector IlECD was set at

250°C.

Mass spectra:

High resolution mass spectroscopy (HRMS) was done by the Centre régional de

spectrométrie de masse at the Department of Chemistry, Université de Montréal using an

LC-MSD-TOF instrument from Agitent Technologies in positive electrospray mode.

Either protonated molecular ions (M + Ht or sodium adducts (M + Nat were used for

empiricai formula confirmation. lodide 152 proved to be too unstable for HRMS by

FAB, API, El, and CI. As such, iodide 152 did not ionize and consequently did not

provide any valid mass spectral data.

85

VI.2 - Experimental Proced.ures and data

Preparation and Titration of i-PrMgBr

The preparation of i-PrMgBr has been described by Steglich and co-workers.46 The

titration ofi-PrMgBr-'has been described by Paquette and co-workers.47

\ :.' ~

Titration of n-BuLi, s-BuLi, and t-B,uLi

The titration of organolithium reagérits has been described by Bac1awski and co-

workers.48

Preparation of dilithium tetrachlorocuprate

LiCI and CuCh were independently dried for 10 h at 100°C under reduced pressure.

Both reagents were transferred to a glove box under a nitrogen atmosphere. To a round

bottom flask containing CuClz (0.67 g,5 mmol) and LiCI (0.42 g, 10 mmol) anhydrous

THF (10 mL) was added. The solution was allowed to stir at room temperature for 10

min affording a homogeneous dark-recl.colored solution. The concentration of Li2CuCl4

prepared in this manner was 05 M and was used immediately. This solution was never

stored for more than a couple ofhours.46

46 Steg1ich, W. Synthesis 2005, 6, 1019-1027. 47 Lin, H. S.; Paquette, L. Synth. Commun. 1994,24,2503-2506. 48 Kofron, W. G.; Bac1awski, L. M. J. Org. Chem. 1976, 4/, 1879-1880.

86

Pentafluorobenzyl-2,S-dihydroxybenzoate (60)

OH F

ttJ HoA t;: + HO 1: F

PPh3• DIAD • THF. 23"C. 10h h F ~

46% 01 o OH F F 0 OH _l .

66 67 60

In a round bottom flask, benzoic acid 66 (1.54 g, 9.99 mmol), PPh3 (4.20 g, 16.0 mmol),

and alcohol 67 (0.99 mg, 5.00 mmot) were dissolved in anhydrous THF (100 mL), cooled

to OCC, and treated over a 2 min period with DIAD (3.10 mL, 16.0 mmol). The reaction

was allowed to stir at room temperature for 10 h, and was monitored by TLC (diphenol

60: Rf = 0.2, 100% ethyl acetate, product appeared purple under UV irradiation).

Additional PPh3 (2.10 g, 8.00 mmol) was added to the mixture until the yellow color of

DIAD had disappeared. The volatiles were evaporated to a residue that was purified by

silica gel flash chromatography (10% ethyl acetatelhexanes). Evaporation of the

collected fractions gave ester 60 as' a white solid (1.52 g, 46%). Spectral data for 60 .7 !,

matched that reported in the literature.49

.1 "

Pen tafluorobenzyl 2,S-dihydroxybenzoate (60)

.1. OH F

M HoA 1;.' . ~ ElaN . 1 • + DMF, 23"C. 10h Br h F h F ~

80% 01 o OH F F 0 OH

66 69 60

In a round bottom flask, benzoic acid 66 (0.20 g, 1.30 mmol) and bromide 69 (0.18 mL,

1.30 mmol, previously passed through a short plug of basic alumina) were dissolved in

. . .

49 Collins, S. K.; EI-Azizi, y, Pure Appt. Chem. 2006, 78, 783-789.

87

anhydrous DMF (13 mL), cooled to Q?,C, treated dropwise with Et3N (0.20 mL, 1.42

mmol) and stirred at ODC for 10 min. The solution was allowed to warrn to room

temperature and stirred for 10 h ... 1h~ reaction was monitored by TLC (100% ethyl

acetate). The reaction was cooled to ODC and quenched with IN HCI (7.1 mL, 7.13

mmol). The mixture was extracted ~ith Et20 (3 x 15 mL). The combined organic :J ~ ~ 1

extracts were washed with brine (1 x 45 mL), and dried over Na2S04. The volatiles were 1

evapo~ated to a residue that w~s purifi~?,by silica gel flash chromatography (10% eth yi

acetate/hexanes). Collection of the fracti~ns gave ester 60 as a white solid (0.35 g, 80%). ,,1' ,'!

Spectral data for 60 matched that reported in the literature.49

(E)-4-(Allyloxy)-2-methylbut-2-en-l-01 (61) ,',

o ° EtO'P)0(OEt °

1 ~ o .~OTBDMS

OEt ____ ~----_.~ EtO 1

NaH, THF, ooe ~ 30min, 23°C - 10 h OTBDMS

71

~O~ ~O~BDMS 75

j TBAF

THF, 23°C, 5h

30% over 4 steps

~O~ " ~OH

61

.. NaH, Allyl bromide

THF, 23°C, 10h

~'. ",

72 cisltrans 13:87

j DIBAL-H

DCM, -78°C, 2h

HO"ll ~OTBDMS

73

88

In' ':l round bottom flask, under nitrogèn, NaH (15.2 g, 0.38 mol) was washed with

anhydrous hexane (3 x 100 mL), taken up in anhydrous THF (500 mL), cooled to O°C,

and treated dropwise with tris(triethyl)phosphonoacetate (70.0 mL, 0.35 mol) monitoring

closely the release ofhydrogen.gas. The solution was allowed to stÎr at O°C for 1 h. The

solution gradually changed appearance, becoming transparent. Silyl ether 71 (55.0 g,

0.29 mol) was added diopwise at O°C to the reaction mixture, that was stirred for 0.5 h

and allowed to warm to room temperature, with stirring for 10 h. The reaction was

monitored by TLC (16% ethyl acetate/hexanes). The solution was quenched with water

(100 :mL) at O°C. The mixture was extiacted with Et20 (3 x 100 mL). The combined

organic extracts were washed with brine (1 x 100 mL), and dried over Na2S04. The

volatiles were evaporated to a residueas Cis:trans isomers (13:87, determined by LCMS:

Gimini C-18, 5 Il, 50 x 4.6 mm Column, 0.5 mUmin, 70% ACNIH20). The pale yellow . CI" .

oil was immediately carried over to tHe next reaction. Spectral data for 72 matched that

reported in the literature.5o In a round bottom flask, a solution of ester 72 (75.0 g, 0.29

mol) in anhydrous CH2Cb (500 mL) was cooled to -78°C, treated dropwise over 2 h with

DIBAL-H (697 mL, 0.69 mol), stirred at -78°C for 2 h, and monitored by TLC (13% ..

ethyl acetatelhexanes). The reaction was~quenched at -78°C with a saturated solution of

RochelIe's salt, and stirred at room tempe rature until a successful partition between the

two phases had been achieved. At times, the separation was achieved by adding more

Rochelle's salt. The mixture was extracted with EhO (3 x 100 mL). The combined

organic extracts were washed with brine (1 x 100 mL), and dried over Na2S04, and

evaporated to give crude 73 as a pale-yellow oil used without further purification.

50 Baldwin, 1. R.; Whitby, R. J. Chem. Comm. 2003,22,2786-2787.

89

Spectral data for 73 matched that. reported in the literature.5o In a round bottom under

nitrogen, NaH (15.2 g, 0.38 mol)was :washed with anhydrous hexane (3 x 100 mL),

suspended in anhydrous DMF'(500 mL), cooled to O°C, and treated dropwise with

alcohol 73 (63.0 ,g, 0.29 mol) monitoring c10sely the release of hydrogen gas. After

stirring for 1 h at O°C, the mixture was treated dropwise with allyl bromide (27.0 mL,

0.32 mol, previously passed through a:~short plug of basic alumina), stirred for 0.5 h,

warmed to room temperature, stirred' for 10 h, monitored by TLC (10% ethyl

acetate/hexap.es), cooled to O°C, and quenched with water (100 mL). The mixture was

extracted with Et20 (3 x 100 mL), dried over Na2S04, and evaporated to give crude 75 as

a pale-yellow oil, that was used without; further purification. In a round bottom flask,

silyl ether 75 (36.7 g, 0.14 mol) was dissolved in anhydrous THF (500 mL), cooled to

O°C, treated dr()pwise with TBAF (430 mL, 0.43 mol), and allowed to warm to room

temperature. The reaction was monitored by TLC (20% ethyl acetate/hexanes). After

stirring for 12 h, the reaction :was quenched with NaHC03 (500 mL), and extracted with

Et20 (3 x 250 mL).' The combined organic extracts were washed with brine (1 x 250

mL), dried over Na2S04, and evaporatedto give a residue that was purified by silica gel

flash chromatography (10% ethyl acetate/hexanes) to afford alcohol 61 as a pale-yellow

oil (8.10 g, 30% over four steps). IH l~R (400 MHz, CDCh) 8 5.83 (ddt, J = 17.1,

1O.S, 5.7 Hz, 1H), 5,51 (t,J=6.7Hz, 1H),5.19(dd,J= 17.1,3.3 Hz, 1H),5.10(dd,J=

10.5, 3.3 Hz IH), 3.95 (d, J = 6.7 Hz, 2B), 3.89 (m, 4H), 3.29 (s, 1H), 1.59 (s, 3H); I3C

NMR (100 MHz, CDCh) 8 139.2;1134.4, 120.5, 116.9, 70.9, 67.2, 65.9, 13.5; HRMS

(ESI) calculated for C8H1502 [M + Ht, 143.1067, found 143.1064.

90

Pentafluorobenzyl· . 5-«2E,6E)-3, 7 ,11-trimethyldodeca-2,6,1 0-trienoxy)-2-( (E)-4-

(allyloxy)-2-methylbut-2-enoxy)benzoate (64)

FV,y~:<IH M~ 01 .

F 0 OH 60

HO~ 65

PPh3' DIAD, THF, 6,10 h

."

r("O~ HO~

61

PPh3, DIAD

THF, 6,10 h 30% over two steps

In a round bottom flask, ester 60 (0.17 g, 0.51 mmol), a1cohol 65 (0.06 g, 0.25 mmol),

and PPh3 (0.11 g, 0.41 mmol) were dissolved in anhydrous THF (50 mL), heated to a

reflux using an oil bath, treated dropwise with DIAD (0.08 mL, 0.41 mmol) such that the

yellow color disappeared before the ne~t drop, and stirred for 4 h. The reaction was

monitored by TLC (13% ethyl acetate/hexanes). The solution was allowed to cool to

room temperature, treated with PPh3 ~ (0.05 g, 0.21 mmol) until the yellow color

disappeared, and evaporated to give'a residue that was further purified by silica gel flash

chromatography (5% ethyl acetate/nexanes). Evaporation of the collected fractions gave

phenol 76 as a pale-yellow oil (0.08 g, 55%), contaminated with traces of dialkylated

byproduct as indicated by both IH~NMR and I3C-NMR spectroscopy. Without any

91

further purification, phenol 76 was treated with alcohol 61 (0.03 g, 0.23 mmol), and PPh3

(0.10 g, 0.36 mmol), disso1ved ih anhydrous THF (50 mL), heated to a reflux using an oil

bath and treated dropwise with DIAD (0.07 mL, 0.36 mmol) such that the yellow color

disappeared before the next drop. ,The solution was stirred for 4 h, and monitored by

TLC (l3% ethyl acetate/hexanes). the reaction was allowed to cool to room

temperature, treated with PPh3 (0.05 g, 0.18 mmol) until the yellow color disappeared,

and evaporated to a residue that was purified by silica gel flash chromatography (5%

ethyl acetate/hexanes). Ether 64 wa,s .obtained as a pale-yellow oil (0.05 g, 30% over two

steps). lH NMR (300 MHz, CDCh) ù 7.33 (d, J = 3.1 Hz, lH), 7.01 (dd, J = 9.1, 3.1 Hz,

1H), 6.87 (d, J = 9.1 Hz, IH), 5.92 (ddt, J 17.1, 10.4,5.7 Hz, IH), 5.73 (t, J = 6.5 Hz,

IH), 5.45 (t, J = 6.6 Hz, 1H), 5.40 (s, 2H), 5.27 (dd, J = 17.1,3.1 Hz, 1H), 5.19 (dd, J =

10.4, 3.1 Hz, 1H), 5.09 (d, J = 5.3 Hz, 2H), 4.49 (d, J = 6.6 Hz, 2H), 4.42 (s, 2H), 4.05

(d, J = 6,5 Hz, 2H), 3.97 (dt, J = 5.7., ~.~.Hz, 2H), 2.05-1.92 (m, 8H), 1.72 (s, 6H), 1.67

(s, 3H), 1.59 (s, 6H); ,I3C NMR (75 MHz, CDCh) ù 165.2, 152.7, 152.3, 141.6, l35.4,

l34.8, l34.7, 131.3, 124.5, 124.3, 123;6 (2C), 120.8, 119.7, 119.2, 117.1 (2C), 115.4,

74.6, 71.2, 66.0, 65.5, 53.6, 39.7,.,\39.5, 26.7, 26.2, 25.7, 17.6, 16.6, 16.0, 13.8; HRMS

(ESI) calculated for C37H43FsOsNa [M'+iNar, 685.2924, found 685.2926.

,f '

(E}-Ethyl 7,II-dimethyl-3-oxododeca-6,10-dienoate (81)

HO~ I~ 79 . Nal. ACN. 23"C. O.5h 80

62%

'j

j NaH. n-BuLi

Ethyl A:etoacet~te THF.O C. 10mm;

23"C.10h 43%

EtO~ ~

81

92

In a round bottom flask, geraniol 79 (5.00 mL, 28.8 mmol), NaI (4.30 g, 28.8 mmol) and

anhydrous ACN (200 mL) were added. In the dark, the reaction was cooled to O°c,

treated with Amberlyst 15 (29.0 g) in portions over 15 min, and monitored every 5 min

by TLC (25% ethyl acetatelhexanes). Once no more geraniol was observed by TLC, the

solution was filtered to remove the resin, and evaporated in the dark at room temperature

to yield crude 80 (4.71 g, 62%), which was used without further purification. To avoid

using excess resin, the reaction must be closely monitored following each addition of

Amberlyst 15, and filtered immediately after a11 the geraniol had been consumed.

Spectral data for 80 matched that reported in the literature.51 In a round bottom flask

under nitrogen, NaH (0.08 g, 1.92 mmol) was washed with anhydrous hexane (3 x 10

mL), suspended in anhydrous THF (10 mL), cooled to O°C, treated dropwise with

ethylacetoacetate (0.20 mL, 1.54 mmol) monitoring cIosely the release of hydrogen gas.

The reaction was stirred for 10 min. n-BuLi (0.81 mL, 1.92 mmol) was added, and the

51 (a) Tajbakhsh, M.; Hosseinzad~h, R.; Lasemi, Z.; Rostami, A. Synth. Commun. 2005,35,2905-2911. (b) Tajbakhsh, M.; Hosseinzadeh, R.; Lasemi, Z. Synlett 2004, 4, 635-638.

93

solution was allowed to warm to room temperature. After stirring for 1 h, geranyl iodide

80 (0.20 g, 0.77 mmol)'was added to t~~Jeaction mixture, which was stirred for 1 h, and

. '\'.

monitored by TLC (5% ethyl acetate/hexanes). The solution was cooled to O°C,

quenched with 10% AcOH (10 mL), and extracted with Et20 (3 x 25 mL). The combined

organic extracts were washed with brine (1 x 10 mL), dried over Na2S04, and evaporated

to give a residue that was purified by silica gel flash chromatography (5% ethyl

acetate/hexanes). Ester 81 was obtained as a pale-yellow oil (0.09 g, 43%) and exhibited

spectral data as reported in the literature.52

,\} ,

Geranyl bromide (87)

1 1 PPh3• CBr4 ~OH ..

. DCM. Q·C. 1.5h. Dark ~Br 79 l ''', 99% 87

In a' round bottom flask in the dark, geraniol 79 (3.00 mL, 17.1 mmol) and PPh3 (6.73 g,

l' .

25.6 mmol) were treated with anhydrous' CH2Clz (170 mL), cooled to O°C, and treated

with CBr4 (8.5 g, 25.6 mmol) over 0.2'5 h, stirred for 1.5 h, and monitored by TLC (13%

ethyl acetate/hexanes). The solution was treated with cold hexanes (100 mL), and

transferred to a separatory funnel. The bottom layer, a pale orange oil, was removed and

discarded. The top layer, a milky white solution, was evaporated to a white residue that

was treated with co Id hexanes (50 ml.) and filtered using high vacuum filtration. The

filtrate was evaporated to a pale-yellow oil that was treated with co Id hexanes (50 mL)

and filtered through a short plug of silica gel under high vacuum. The plug was washed

three times with cold heXanes (3 x 50 mL) and the filtrate was evaporated to a pale-. "

52 Xie, H.; Shao, Y.; Becker, J. M .. ; Naider, F.; Gibbs, R. A. J. Org. Chem. 2000, 65, 8552-8563.

94

yellow oil (3.70 g, 99%) that was used immediately in the next reaction step. Spectral

data for bromide 87 matched that.reported in the literature.53 The product was stored in

the freezer (-20°C) for several days.

.1 ~ ,

Pentafluorobenzyl 5-«2Z,6E}-3,7,11-trimethyldodeca·2,6,lO.trienoxy)-2-((E)-4-

(aUyloxy)-2-methylbut-2-enoxy.)benzoitte (59)

M F 0 OH

60

H~F~ PPh3• DIAD »~~ F ~

----------~. h: 1 THF. 6.10 h "

01 FO OH

92a

, 0 'J' ~ HO 61

PPh3• DIAD

THF, 6, 10 h

30% over two steps

\ l ( ll} •

Follow experirnental for pentafluorobenzyl 5-«2E,6E)-3,7,II-trirnethyldodeca-2,6,1O-t l'l,' , ....

trienoxy)-2-«E)-4-(allyloxy)-2-methylbut-2-enoxy)benzoate (64). lH NMR (400 MHz,

CDCb) Ù 7.33 (d, J = 3.1 Hz, IH), 7.01(dd, J = 9.1, 3.1 Hz, IH), 6.87 (d, J 9.1 Hz,

IH), 5.92 (ddt, J = 17.1, 10.4, 5.7, Hz, IH), 5.73 (t, J = 6.5 Hz, IH), 5.47 (t, J 6.6 Hz,

IH), 5.40 (s, 2H), 5.27 (dd, J = 17.1,),l,Hz, IH), 5.19 (dd, J= 10.4,3.1 Hz, IH), 5.11-: \ .

53 Durst, H. D.; Liebeskind, Li. Drg. Chem. 1974,39,3271-3.

95

5.05 (m, 2H), 4.49 (d, J = 6.6 Hz, 2H), 4.42 (s, 2H), 4.05 (d, J = 6.5 Hz, 2H), 3.97 (dt, J

= 5.7,1.2 Hz, 2H), 2.12-2.03 (m, 6H), 1.99-1.95 (m, 2H), 1.79 (s, 3H), 1.72 (s, 3H), 1.67

(s, 3H), 1.59 (s, 6H); l3C NMR (75 MHz, CDCh) 0 165.2, 152.6, 152.2, 141.9, 135.7,

134.7,134.6,131.2,124.3,124.1,124.1,123.2,120.6, 119.8, 119.6, 117.1, 117.1, 115.2,

74.4, 71.1, 65.9, 64.0, 53.5, 39.5, 32.2, 26.5, 26.0, 24.4, 17.5, 16.5, 15.8, 13.7; HRMS

(ESI) calculated for C37H44F505 [M + Ht, 663.3103, found 663.3101.

Cyclophane (58)

~ F 0 F 0 ~

~~'1 Grubbs Il (10mol %) .. ~ F.W" 1 b F ~ 1 Ti(Oi-Prl4. DCM, 6, 18 h 1 b F. 1 b 14 ~

7-10%

FO) FOO

59 '( 58

~O

To a flame dried three neck round bottom flask equipped with a reflux condenser under

nitrogen, 2nd Generation Grubbs Catalyst (0.002 g, 0.003 mmol) and anhydrous CH2Ch

(100 mL) were added. The solution was heated to a reflux and treated dropwise with a

solution of ester 59 (0.03 g, 0.05 mmol) and Ti(Oi-Pr)4 (0.07 mL, 0.25 mmol), dissolved

in CH2Ch (30 mL) over 1 h using a syringe pump. The reaction was allowed to stir at

reflux for 10 h and was monitored by TLC (10% ethyl acetate/hexanes). The reaction

was quenched with ethyl vinyl ether (5 mL), evaporated down to about 1 mL, and

purified by silica gel flash chromatography (5% ethyl acetate/hexanes). Macrocycle 58

was obtained as a pale-yellow oil (0.002 g, 7%). IH NMR (300 MHz, CDCh) 0 7.26 (d,

96

J= 3.1 Hz, 1H), 7.12 (dd, J= 9.1, 3.1 Hz, 1H), 6.83 (d, J= 9.1 Hz, 1H), 5.38 (s, 2H),

5.41-5.37 (m, 2H), 5.23 (t, J = 7.6 Hz, 1H), 4.54-4.50 (m, 4H), 2.10-2.05 (m, 2H), 1.98-

1.93 (m, 2H), 1.81-1.77 (m, 2H), 1.67 (s, 3H), 1.52 (s, 3H), 1.46 (s, 3H), 1.38-1.32 (m,

2H); 13C NMR (75 MHz, CDCh) cS 165.0, 152.9, 151.6, 144.5, 132.2, 130.6, 130.6,

128.3, 126.0, 123.9, 123.2, 119.8, 119.4, 116.0, 74.1, 68.0, 53.6, 38.9, 31.7, 27.0, 25.0,

23.6, 15.3, 13.2; HRMS (ESI) calculated for CZ9H30Fs04 [M + Ht, 537.2059, found

537.2047.

(2Z,6E)-1-t-Butyldiphenylsilyloxy-3, 7 ,11-trimethyl-2,6,1 O-dodecatriene (95)

r '<::::

1 OH

62

TSDPSCI

Imid, DMF, 23°C, 30 min

90% 0 -<:::

1 OTSDPS

95

In a round bottom flask, alcohol 62 (1.23 g, 5.53 mmol), imidazole (0.56 g, 8.30 mmol),

and TBDPSCI (1.70 mL, 6.64 mmol), were dissolved in anhydrous DMF (10 mL), and

stirred at room temperature for 0.5 h. The reaction was monitored by TLC (13% ethyl

acetate/hexanes). The reaction was partitioned between hexanes and water (83:17). The

mixture was extracted with EtzO (3 x 50 mL). The combined organic extracts were

washed with saturated NaHC03 (1 x 10 mL) and brine (1 x 10 mL), dried over NaZS04,

and evaporated to a residue that was further purified by silica gel flash chromatography

(100% hexanes, 1 column volume (cv), 2% ethyl acetate/hexanes, 1 cv, 5% ethyl

acetate/hexanes). Ether 95 was obtained as a pale-yellow oil (2.24 g, 90%). IH NMR

(400 MHz, CDCh) cS 7.68-7.66 (m, 4H), 7.38-7.37 (m, 6H), 5.39 (t, J = 6.2 Hz, 1H), 5.05

(t, J = 7.0 Hz, 1H), 4.99 (t, J = 5.8 Hz, IH), 4.19 (d, J = 6.2 Hz 2H), 1.95-1.85 (m, 8H),

97

1.70 (s, 3H), 1.66 (s, 3H), 1.57 (s~ 3H), 1.50 (s, 3H), 1.04 (s, 9H); 13C NMR (75 MHz,

CDCi))'ù 137.5, 135.6 (4C), 135A; .134.8, 134.0, 131.3 (2C), 129.5, 128.3 (4C), 124.8,

124.3, 123.7, 60.8, 39.6, 32.2, 26.8 (2C), 26.6, 25.7, 23.4, 19.2, 17.7, 15.9, -5.6 (2C);

HRMS (ESI) ealeulated for C31~40SiNa{M + Nat, 483.3054, found 483.3067.

(2Z,6E,10Z)-3,7-Dimethyldodeca,.2~6',10 .. trien-l-ol (93)

0 """ 1 OTBDPS

99

TBAF

THF. 23°C, 5h

65%

.. 0.""" 1 OH 93

A solution ofsilyl ether 99 (1.10 g, 2.46 mmol) in THF (50 mL) was treated with TBAF

(7.40 mL, 7.39 mmol, 1 M) ançl stirred àt room temperature for 5 h. The reaetion was

monitored by TLC (25% ethyl aeetate/hexanes). The solvent was evaporated and the

residue was partitioned between satutated NaHC03 (50 mL) and ethyl aeetate (50 mL).

The aqueous layer was extraeted with'ŒtOAe (3 x 50 mL). The eombined organies were

washtid with brine (1 x 50 mL), dried over Na2S04, evaporated to a residue that was

purified by si lie a gel flash ehromatography (10% ethyl aeetate/hexanes to 33% ethyl

aeetate/hexanes). A1cohol 93 was obtained as a pale-yellow oil (0.33 g, 65%). 1H NMR

(300 MHz; CDCi)) ù 5.40-5.29 (m; 3H);.5.12 (t, J= 4.7 Hz, 1H), 4.10 (d, J= 6.4 Hz,

'. 13 2H),-2.19-2.08 (m, 8H), 1.75 (s, 3H), 1.61 (s, 3H), 1.59 (s, 1H), 1.57 (s, 3H); C NMR

(75 MHz, CDCi)) ù 140.1, 135.7, 130.1, 124.3, 123.9, 123.7,59.0,39.3,31.9,26.5,25.4,

23.4, 15.9, 12.8; HRMS (ESI) ealèulated for C 14H250 [M + Ht, 209.1899, found

209.1900.

98

Pentafluorobenzyl .,··5-( (2Z,6E,1 OZ}:-3, 7 -dimethyldodeca-2,6,1 O-trienoxy)-2-«E)-4-

(allyloxy)-2-methylbut-2-enoxy)benzoate (94)

60

___ P_P----'h3"--, D_IA_D____ F, 1: F : 1 THF, 1'., 10 h 0 1

, . 1 •

F 0 OH

100

94

PPh3 , DIAD

THF,t., 10 h

30% over two steps

Follow experimenta1 for pentafluorobenzy1 5-«2E,6E)-3, 7, 11-trimethy1dodeca-2,6, 1 0-

. ' 1 tnenoxy)-2-«E)-4-(ally1oxy)-2-methy1but-2~enoxy)benzoate (64). H NMR (300 MHz,

CDCh) Ù 7.33 (d, J = 3.1 Hz, 1H),. 7.0T::(dd, J = 9.1, 3.1 Hz, 1H), 6.87 (d, J = 9.1 Hz,

1H), 5.92 (ddt, J = 17.1, 10.7, 5.7 Hz, 1H), 5.73 (t, J = 6.1 Hz, 1H), 5.47 (t, J = 6.2 Hz,

1H), 5.42-5.37 (m, 3H), 5.27 (dd, J = '17.1,3.3 Hz, 1H), 5.19 (dd, J = 10.7,3.3 Hz, 1H),

5.16-5,10 (m, 1H), 4.45 (d, J =6~6'Hz, 2H), 4.42 (8, 2H), 4.05 (d, J = 6.5 Hz, 2H), 3.97

(dt, J = 5.7, 1.2 Hz, 2H), 2.16-2.Ui J(m;l6H), 2.04-1.99 (m, 2H), 1.79 (8, 3H), 1.72 (8,

3H), 1.64-1.60 (m, 6H);. \3e NMR (75 MHz, CDCh) ù 165.2, 152.7, 152.3, 141.1, 135.6,

134.8, 130.2, 124.5, 123.8, 123.7, 123.5, 120.7, 120.0, 119.7, 117.1 (3C), 115.4, 74.6,

99

71.2, 66.0, 65.1, 53.6, 39.3, 32.4, 26.5, 25.4, 23.5, 15.9, l3.9, 12.7; HRMS (ESI)

calculated for C361:142F505 [M + H]+, 639.2947, found 649.2935.

1

Methyl 2-bromo-5-(9-methyldec-8-enyl)benzoate (l08) , . . .

M'O~ ',.

o Br

+ ~Br l-BuLi. ZnBr2. Pd(PPh3)4 ------=-...:.---::.;..:......... MeO 1 THF. WC. 18h

20% 0 Br

101 107 108

To a round bottom flask containing anhydrous THF (5 mL) -78°C, t-BuLi (0.70 mL, 0.90

mmol) was added dropwise followed by a solution ofbromide 107 (0.11 g, 0.38 mmol) in

THF (5 mL). The reaction was allowed to stir for 0.5 h at -78°C and the ex change was

monitored by TLC (100% hexanes). A solution of ZnBr2 (0.10 g, 0.45 mmol) in THF

(1.0 mL) was added to the -78°C solution which was stirred for 1 h, allowed to warm to

room temperature, and stirred for an add~tional 1 h. The reaction was monitored by TLC

(100% hexanes). The zincate solution transferred by syringe to a round bottom flask

containing a solution of ester 101 (0.11 g, 0.37 mmol) and

t,etr~~s(triphenylphosphine)pal1adium \~'e3 g, 0.03 mmol) in anhydrous THF (2 mL).

The reaction mixture was stirred for 12h at 55°C, and was monitored by TLC (20% ethyl

acetatelhexanes). The reaction was coole.d to 23°C, quenched with NaHC03 (50 mL) and

the mixture was extracted with EhO (3 x 20 mL). The combined organic extracts were , .

washed with brine (1 x 20 mL), dried.over Na2S04, and evaporated to give a residue that " \ l '

was purified by silica gel flash chromatography (10% ethyl acetatelhexanes). Bromide

108 was obtained as a pale-yellow oil (0.03 g, 20%). IH NMR (300 MHz, CDCb) ô 7.98

100

(d, J= 2.2 Hz, 1H), 7.52 (dd, J= 8.3;'2.2 Hz,lH), 7.12 (d, J= 8.3 Hz, 1H), 5.11 (t, J=

7.1 Hz, 1H), 3.89 (s, 3H), 2.92-2.88 (m, 2H), 2.00-1.94 (m, 2H), 1.68 (s, 3H), 1.59 (s,

3H), 1.40-1.31 (m, lOH); 13C NMR (75 MHz, CDCb) ô 167.7, 144.6, 135.5, 134.2,

133.4, 132.0, 132.0, 125.7, 119.9, 53.0, 34.7, 32.5, 30.7, 30.5, 30.2, 30.1, 28.9, 26.6,

18.5; HRMS (ESI) calculated for C19H28Br02 [M + Ht, 367.1267, found 367.1261.

ï ~ j- , :

Iso-propyl 2,5-diiodobenzoate (120)

HoA -D-M-i~_" :-o~_H:-:-2-P;-:C-, 1-0h-' '-0 6 87% / W

o 1

121 , .\'t. i'

o 1

120

In a round bottom flask, under nitrogeQ. atmosphere, NaH (0.08 g, 2.00 mmol) was

washed with hexane (3 x 50 mL), suspe!1.ded in anhydrous DMF (20 mL), cooled to O°C,

treated dropwise with a solution ~f 2,5-diiodobenzoic acid 121 (0.50 g, 1.34 mmol) in

DMF (5 mL), stirred for 0.5 h, treared ~ith iso-propyl iodide (0.15 mL, 1.47 mmol), . , ..

warrned to room temperature, and stirred for 12 h. The reaction was monitored by TLC

(25% ethyl acetate/hexanes). The solvent was evaporated and the residue was taken up in

Et20 (50 mL), and treated with sa,turat~d NFl4Cl solution (25 mL). The aqueous phase

was extracted with Et20 (3 x 50 mL).;, T~e combined organic extracts were washed with

brine (1 x 25 mL) dried over Na2S04, and evaporated to give a residue that was purified

by silica gel flash chromatography (10% ethyl acetate/hexanes). Ester 120 was obtained

as a pale-yellow oil (0.48 g, 87%)., IH NMR (300 MHz, CDCb) ô 8.01 (d, J = 2.2 Hz,

1H), 7.64 (d, J= 8.3 Hz, 1H), 7.40 (dd, J,F 8.3, 2.2 Hz, 1H), 5.25 (sept., J = 6.3 Hz, 1H), • 1 \ ~

101

1.39 (s, 3H), 1.37 (s;.3H); J3C NMR (75 MHz, CDCI) 3 164.6, 142.5, 141.1, 139.1,

137.5,93.2,93.1, 70.0,21.8,21.8; HRMS (ESI) calculated for CIOHIOIz02Na [M + Nat,

438.8662, found 438.8650.

(E)-4-(Allyloxy)-2-methylbutM 2-enyl acetate (126)

fi"o~ HO~

61 23·C.10h

96%

fi"o~ ACO~

126

In a round bottom flask were actded alcohol 61 (5.50 g, 38.7 mmol) and Ac20 (4.40 mL,

46.4 mmol), followed bydistilled pyridine (3.8 mL, 46.4 mmol) at O°C. The reaction

was stirred for 10 h at room temperature and was monitored by TLC (25% ethyl

acetate/hexanes). The reaction. mixture was purified as is by silica gel flash

chromatography (25% ethyl ace~ate/hexanes) to give acetate 126 as a pale-yellow oil

(6.83 g, 96%). l H NMR (400 MHz, CDCh) 3 5.88 (ddt, J = 17.1, 10.5,5.7 Hz, IH), 5.60

(t, J= 6.6 Hz, 1H), 5.24 (dd,J = 17.1,:3.0 Hz, 1H), 5.15 (dd, J 10.5,3.0 Hz, IH), 4.45

(s, 2H), 4.00 (d, J = 6.6 Hz, 2H), 3.9.4 (dt, J = 5.7, 1.2 Hz, 2H), 2.04 (s, 3H), 1.66 (s, 3H);

J3e NMR (lOI MHz, CDCb) 3 170.6, 134.6, 133.8, 124.5, 117.1, 71.2, 68.8, 65.9, 20.8,

14.1; HRMS (ESI) calculated for CIOHI603Na [M + Nat, 207.0992, found 207.0996.

Iso-propyI2-«E)-4-(allyloxy)'-2-methylbut-2-enyl)-5-iodobenzoate (124)

120

AcQ 1 Q, 126 S~

1, i-PrMgBr (1,8 eq), THF, -40·C, 30min

2,126. Li2CUCI4, THF, -40°C

2min inverse addition

3, THF, -40·C, 1,5h; 23·C, 1h

,80% '

124

102

In a round bottom flask, a solution of iso-'propyl ester 120 (6.87 g, 16.5 mmol) dissolved

in anhydrous THF (55 mL) was added. The solution was cooled to -40°C and treated ~j i

dropwise with i-PrMgBr (7.60 mL, 19.& ~mol) affording a color change from c1ear to

yellow. The solution was stirred for 0.5 h and the Mg-I exchange was monitored by GC ",1

analysis (exchange intennediate Rt = 12.85 min). The Grignard reagent solution was

transferred over 2 minutes via cannula to a second round bottom flask containing

LhCuCl4 (2.2 mL, 1.10 mmol) and acetate 126 (2.00 g, 11.0 mmoI) in anhydrous THF " ,

J '. ;

(55 mL) at -40°C affording a color change from dark red to clear and then to orange. The

reaction was stirred for 1 h at -40°C, warmed to room temperature, and stirred for 1 h.

The reaction was monitored by TLC (10% ethyl acetatelhexanes). The reaction was

quenched with saturated NH4CI solution (1 x 55 mL), diluted with water (1 x 55 mL), and ", .l

extracted with Et20 (3 x 55 mL). The combined organic ex tracts were washed with

NH40H (1 x 55 mL) and brine (1 x 55 mL), dried over Na2S04, and evaporated to a

residue that was purified by silica gel flash chromatography (5% ethyl acetatelhexanes).

Iodide 124 was obtained as a yellow oil (3.60 g, 80%). IH NMR (300 MHz, CDCh) 8

8.10 (d, J = 1.8 Hz, IH), 7.69 (dd, J = 8.1, 1.8 Hz, IH), 6.96 (d, J = 8.1 Hz, IH), 5.88

103

(ddt, J = 17.3, 10.5,5.7 Hz, 1H), 5.28~5.23 (m, 2H), 5.21-5.16 (m, 2H), 3.97 (d, J = 6.5

Hz, 2H), 3.91 (d, J = 5.7 Hz, 2H), 3.64 (s, 2H), 1.63 (s, 3H), 1.34 (s, 3H), 1.32 (s, 3H);

I3C NMR (75 MHz, CDCh) 8. 165.7, 140.2, 139.9, 138.9, 138.7, 134.8, 133.1, 133.0,

• 1

122.9, 117.0,90.8,71.0,68.8,66.4,42.3,. 21.8, 21.8, 16.9; HRMS (ESI) ca1cu1ated for

, + .),1,

ClsH23I03Na [M + Na] ,437.0582, found 437.0584.

(2Z,6E,1 OZ)-3, 7-Dimethyldodeca-2~6~tO::!trienyl acetate (131)

~ '93 OH

.. ~ 131 OAc

23 ~c, 10 h

. l;. . . Follow experimenta1 for (E)-4-(ally10xy)-2-methy1but-2-eny1 acetate (126). The reaction

w~s allowed to stir for 10 h at room terhperature and was monitored by TLC (25% ethy1

acetate/hexanes). The reaction miXt~re was purified as is by si1ica gel flash

chromatography (13% ethy1 acetate/hexànes) to give acetate 131 as a pa1e-yellow oi1

1 ,,!' . .' (96%). H NMR (300 MHz, CDCh) 85.50-5.39 (m, 3H), 5.12 (t, J = 6.1 Hz, 1H), 4.56

~ ... , \' ~]'

(d, J = 7.3 Hz, 2H), 2.18-2.07 (m, 8H), 2.05 (s, 3H), 1.77 (s, 3H), 1.61 (s, 3H), 1.59 (s,

3H); I3C NMR (75 MHz, CDCh) 8 171.1, 142.7, 135.6, 130.2, 123.8, 123.5, 119.1,61.1,

. . 39.4,32.1,26.5,25.4,23.5,21.1, 15.9, 12.8; HRMS (ESI) ca1cu1ated for C16H2602Na [M

+ Nat, 273.1825, found 273.1827. . ) l

104

Iso-propyl . 2-«E)-4-(allyloxy)-2-methylbut-2-eoyl)-S-«2Z,6E,10Z)-3,7-

dimethyldodecà-2,6,1 O-trieoyl)beozOtite (132)

Follow

CO ~24 ~

~131 , l" \ OAc

1, i-PrMgBr (3,Oeq). THF. -40·C. 15min

2min inverse addition

3, THF. -40·C. 1 ,5h; 23°C. 1 h

50%

'"

•

132 P' OJ

experimental ,for iso-prppyl , , 2-( (E)-4-( allyloxy)-2-m ethylbut -2-enyl)-5-

iodobenzoate (124): The Mg-I exchange reaction was allowed to stir for 0.25 h. The

crude residue was purified by silica gel''flà.sh chromatography (5% ethyl acetatelhexanes)

to afford olefin 132 as a pale yellôw oil'(0.24 g, 50%). lH NMR (400 MHz, CDCh) ù

, "l'

7.61 (s, 1H), 7.21 (d, J 7.9 Hi, IH),' 7.13 (d, J = 7.9 Hz, 1H), 5.90 (ddt, J = 17.3, 10.5,

5'.7 Hz, 1H), 5.48-5.30 (fi; 8H), 3.99 (cl; J 6.7 Hz, 2H), 3.93 (d, J = 5.7 Hz, 2H), 3.67

(s, 2H), 3.35 (d, J 7.2 Hz, 2H), 2.l3 (in, 6H), 2.01 (m, 2H), 1.76 (s, 3H), 1.65 (s, 3H),

1.62 (s, 6H), 1.35 (s, 3H), 1.33 (s, 3H); 13C NMR (101 MHz, CDCh) ù 167.6, l39.8

(2C), 137.4, l36.7, l35.2 (2C), 131.3'(2C), 130.3 (2C), 123.8, 123.5, 123.3, 122.3 (2C),

117.0, 70.9, 68.2, 66.5, 42.5; 39.4, 33.5, 32.0, 26.5, 25.4, 23.5, 21.9 (2C), 16.9, 16.0,

12.8; HRMS (ESI) calculated for C32R n03 [M+Ht, 479.3520, found 479.3522.

105

Iso-propyl 3-iodobenzoate (134)

HO~ o 133

NaH, i-Prl i ..

DMF, 23°C, 10h 87% ~O~

o 134

.(.\

Follow experimental for iso-propyl 2,5-diiodobenzoate (120). The crude residue was -

purified by silica gel flash chromato'~à.p~y (10% ethyl acetatelhexanes) to afford iodide

134 as a white solid {0.45 g, 87%). IH NMR (300 MHz, CDCb) Ô 8.35 (s, IH), 7.99 (d, J

= 1.6 Hz, IH), 7.85 (d, J = 1.6 Hz, IH), 7.16 (t, J = 8.0 Hz, IH), 5.23 (sept., J = 6.3 Hz,

IH), 1.37 (s, 3H), 1.35 (s, 3H); 13C NMR (75 MHz, CDCb) Ô 164.5, 141.4, 138.3, 132.7,

129.9, 128.6, 93.7, 68.~, 21.9 (2C). lodide 134 proved too unstable for HRMS by FAB,

API, El, CI; product could not be ionized.

(2Z,6E)-3, 7 ,11-Trimethyldodeca-2,6,1 O-triene acetate (136) \ . .:

A~O, Py •

HO 23 oc, 10 h AcO

96%

62 136

To a round bottom flask, AC20 (0.46 mL, 4.88 mmol) and pyridine (0.39 mL, 4.88 mmol)

followed by a1cohol 62 (0.90 g, 4.07 mmol) were added. The solution was stirred at

room temperature for 10 h, and the reaction was monitored by TLC (25% ethyl

acetate/hexanes). Once complete, the reaction mixture was purified by silica gel flash

chromatography (10% ethyl acetate/hexanes). Acetate 136 was obtained as a pale-yellow

oil (1.03 g, 96%). IH NMR (400 MHz, CDCb) Ô 5.30 (t, J = 7.3 Hz, IH), 5.08-5.03 (m,

106

2H), 4.50 (d, J = 7.3 Hz, 2H), 2.05 (t, J 4.9 Hz, 4H), 2.03-2.00 (m, 2H), 1.96 (s, 3H),

1.95-1.92 (m, 2H), 1.70 (s, 3H), 1.61 (s, 3H), 1.54 (s, 6H); 13C NMR (101 MHz,

CDCh) cS 170.6, 142.2, 135.5, 131.0, 1174.1, 123.2, 119.0,60.8,39.5,31.9,26.4,26.3,

25.4, 23.2, 20.7, 17.4, 15.7; HRMS (ES!) calculated for C17H2802Na [M + Nat,

287.1982, found 287.11981.

Iso-propyl 3-( (2Z,6E,1 OZ)-3, 7-dimethyldodeca-2,6,1 O-trienyl)benzoate (135)

~o~ o 134

~131 OAc

1. i-PrMgBr (3.0eq), THF, -40·C, 15min

2.

2min inverse addition 3. THF. -40·C, ~ .5h; 23°C, 1 h

, 80% '"

Follow experimental for iso-propyl 2-«E)-4-(allyloxy)-2-methylbut-2-enyl)-5-

iodobenzoate (124). The residue was purified by silica gel flash chromatography (5%

ethyl acetate/hexanes) to afford olefin 135 as a yellow oil (0.53 g, 80%). lH NMR (300

MHz, CDCb) cS 7.85 (s, 2H), 7.35 (s, 2H)," 5.33 (t, J 6.7 Hz, 1H), 5.24 (apparent septet,

J = 6.3 Hz, IH), 5.16 (t, J = 6.4, Hz, 1H), 5.09 (t, J 6.7, Hz, IH), 3.40 (d, J = 7.3 Hz,

2H), 2.19-2.15 (m, 4H), 2.10-2.06 (m, 2H), 2.02-1.90 (m, 2H), 1.76 (s, 3H), 1.68 (s, 3H),

/'! . 13 1.61 (s, 3H), 1.60 (s, 3H), 1.37 (s, 3H), 1.35 (s, 3H); C NMR (75 MHz, CDCb) cS

,

166.3,142.1,136.9,135.4,132.7,131.3,130.9,129.4,128.2, 127.0, 124.3, 123.9, 123.1,

68.2, 39.7, 33.9, 32.0, 26.7, 26.5, 25:7, 23.5, 21.9 (2C), 17.7, 16.0; HRMS (ESI) , .

calculated for C25H3702 [M + Ht, 369.2788, found 369.2790.

107

3,5,:,Bis(trifluoromethyl)benzyl. ' 5-( (2Z,6Z,1 0Z)-3, 7-dimethyldodeca-2,6,1 0-

trienyloxy)-2-((E)-4-(allyloxy)-2-methylbut-2-enyloxy)benzoate (139)

,', .

. ) l.

~' Br#CF

3

138

139

137

Et3N

DMF, 23°C, 24h

80%

In a round bottoIn flask equipped with"a reflux condenser, ester 94 (0.05 g, 0.10 mmol),

" . was dissolved in a 1:1 mixture of toluene:methanol (10 mL), heated to a reflux, treated

with NaOH pellets (0.05 g, 1.32 mmol); and stirred for 24 h. The reaction was monitored

by TLC (13% eth yi acetate/hexanes). The solvent was removed by evaporation under

reduced pressure, dissolved in ethyl acetate, quenched with 1 N HCI (6.50 mL, 6.50

mmol), extracted with Et20 (3 x 20' mL), washed with brine, dried over Na2S04, and

evaporated to afford olefin 137 (0:11 "g,0.22 mmol) that was dissolved in anhydrous

DMF (22 mL), cooled to O°C, treated dropwise with Et3N (0.04 mL, 0.25 mmol), stirred

for 0.5 h, treated with bromide 138 (0.04 mL, 0.22 mmo1, which prior to addition was

108

passed through a short plug of basic alumina), and stirred for 10 h at room temperature.

The reaction was monitored by TLC, ,(50% ethyl acetate/hexanes). The solvent was

removed by evaporation, and the residue was taken up in Et20 (20 mL). The solution

was quenched with IN HCI (5 mL), extracted with Et20 (3 x 20 mL), washed with a 10%

aqueous CUS04 solution (3 x 20 mL), brine (1 x 20 mL), dried over Na2S04, and

evaporated to a residue that was purified by silica gel flash chromatography (10% ethyl

acetate/hexanes) to afford es~er 139 as a pale-yellow solid (0.13 g, 80%). I H NMR (300

MHz, CDCh) ô 7.92 (s, 2H), 7.84 (s, 1H), 7.38 (d, J = 3.1 Hz, 1H), 7.03 (dd, J = 9.1, 3.1

Hz, 1H), 6.91 (d, J = 9.1 Hz, 1H), 5.89 (ddt, J = 17.1, 10.4,5.7 Hz, 1H), 5.74 (t, J = 5.9

Hz, 1H), 5.49 (t, J = 5.6 Hz, 1H), 5.45 (s, 2H), 5.36 (m, 2H), 5.25 (dd, J = 17.3, 3.3 Hz,

1H), 5.17 (dd, J = 10.4, 3.3 Hz, 1H), 5.11-5.01 (m, 1H), 4.48-4.45 (m, 4H), 4.03 (d, J =

6.4 Hz, 2H), 3.94 (dt, J= 5.7, 1.3 Hz, 2H), 2.14-2.12 (m, 6H), 2.01-2.00 (m, 2H), 1.79 (s,

3H), 1.69 (s, 3H), 1.63-1.59 (m, 6H); 13C NMR (75 MHz, CDCh) Ô 165.8, 152.6, 152.4,

142.1, 138.8, 135.6, 134.7, 134.5, 131.0, 128.0, 125.3, 125.1, 124.9 (2C), 124.7, 124.6, . . " !"

123.8,123.4,121.9,120.2,117.1,116.9,115.4,74.3,71.2, 66.0, 65.1, 64.9, 39.3, 32.3,

26.5, 25.4, 23.5; 15.9, 13.8, 12.7; HRMS (ESI) calculated for C38H4sF60s [M + Ht, ), '.;

695.3166, found 695.3161.

,. .f

" 1

109

Cyclophane (140)

Follow experimental procedure cyclophane (58) for the preparation of cyclophane 140.

The crude reaction mixture was purified by silica gel flash chromatography (5% ethyl

acetate/hexanes) to afford cyclophane 140 as a pale-yellow oil (l3.6 mg, 47%). 'H NMR

(400 MHz, CDCh) 8 ppm 7.91 (d, J = 3.0 Hz, 1H), 7.71 (s, 1H), 7.58 (s, 2H), 7.02 (dd, J

9.0,3.0 Hz, 1H), 6.67 (d, J = 9.1 Hz, 1H), 5.47 (t, J 8.1 Hz, 1H), 5.25 (t, J 7.0 Hz,

1H), 4.88 (s, 2H), 4.67 (t, J = 6.3 Hz, 1H), 4.54-4.49 (m, 4H), 2.09-2.05 (m, 2H), 2.05-

1.97 (m, 2H), 1.91-1.88 (m, 2H), 1.61 (s,3H), 1.54 (s, 3H), 1.45 (s, 3H), 1.52-1.49 (m,

2H); I3C NMR (lOI MHz, CDCh) 8 165.7, 152.8, 151.6, 144.5, 139.0, 132.2, 132.0,

131.7, 130.4, 128.0, 127.6, 126.0, 124.1, 123.4, 121.8, 119.8, 119.4, 115.8, 73.6, 68.1,

64.7,39.0,31.7,27.1,25.0,23.6,15.4,13.2; HRMS (ESI) calculated for C3,H33F604 [M

+ Ht, 583.2278, found 583.2289.

110

Iso-propyl 2-( (E)-4-(but-3-enyloxy )-2-methylbu t-2-eny 1)-5-( (Z}-dodec-1 O-enyl)

benzoate (167)

~OH ) 166 DCM. QOC. 2h. Dark

99%

.. ~sr ) 161

I-SuU. ZnCI2• 161

PdCl2dppf. 124

THF. 55°C. 18h

20% 124

o :7 O~

167

o~

Follow experimental for geranyl bromide (87) for the preparation of bromide 161 that

was obtained as a pale-yellow oil (4.17 g, 99%) and was used without further

purification. Follow experimental for methyl 2-bromo-5-(9-methyldec-8-enyl)benzoate

(108) for the preparation of olefin 167. The zincate was added to a solution ofiodide 124

(0.11 g, 0.37 mmol) and PdCh(dppf) catalyst (0.03 g, 0.03 mmol), dissolved in

anhydrous THF (2 mL). The solvent was evaporated to give a residue that was purified

by silica gel flash chromatography (10% ethyl acetate/hexanes) to afford olefin 167 as a

pale-yellow oil (35.6 mg, 20%). I H NMR (400 MHz, CDCh) 0 7.61 (s, IH), 7.19 (d, J=

7.7 Hz, IH), 7.11 (d, J= 7.7 Hz, lH), 5.88 (ddt, J = 17.1,10.4,5.7 Hz, IH), 5.47-5.39

(apparent dt, IH), 5.27-5.19 (m, 4H), 3.97 (d, J = 6.5 Hz, 2H), 3.91 (d, J = 5.2 Hz, 2H),

3.66 (s, 2H), 2.58 (t, J= 7.6 Hz, 2H), 2.01-1.98 (m, 2H), 1.64 (s, 3H), 1.63-1.58 (m, 2H),

1.37-1.28 (m, 2lH); l3C NMR (75 MHz, CDCh) 0167.6, 140.7, 139.7, 137.1, 134.9,

111

131.4, 131.1, 131.0, 130.7, 130.0, 124:4, 123.5, 122.2, 116.8, 70.8,68.1,66.4,42.5,35.3,

32.5,31.3; 29.5 (2C), 29.2 (2C), 26.7, 21.8 (2C), 16.8, 12.7; HRMS (ESI) calculated for

C30&603Na [M + Na]+, 477.3363, found 477.3353.

Pentafluorobenzyl 2-( (E)-4-( allyloxy)-2-methylb u t -2-enyl)-5-( (Z)-dodec-l O-en yi)

benzoate (155)

PhMe:MeOH (1:1) HO 6,24h

O~ O~

168

F

~F K2C03

Br :-.1 F DMF, 23"C, 10h

77% over two steps F

: 1 ! 69

, J. 11

O~ 155

Fo llow experimental procedure for 3';5-Bis( trifluoromethyl)benzyl 5 -( (2Z, 6Z, 1 OZ)-3,7-

dimethyldodeca-2,6,1 O-trienyloxy)-2-( (Ë)-4-( allyloxy)-2-methylbut-2-enyloxy)benzoate . .

(139) for the preparation of olefin 155~ 'Olefin 168 (0.10 g, 0.23 mmol) was treated with

K2C03 (0.06 g, 0.46 mmol) and bromide 69 (0.04 mL, 0.25 mmol, which prior to

addition was passed through a short plug of basic alumina) in DMF (22 mL) at room

temperature, stirred for 10 h, filte~ed,' evaporated in vacuo to give a residue that was

, J '1

purified by silica gel flash chromatograpny (10% ethyl acetate/hexanes) to afford olefin

112

155 as a pale-ye11ow solid (0.10 g, 77%). IH NMR (400 MHz, CDCh) cS 7.67 (s, IH),

7.30 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.6 Hz, IH), 5.95 (ddt, J = 17.1, 10.9, 5.7 Hz, 1H),

5.52-5.47 (m, IH), 5.42 (s, 2H), 5.30-5.18 (m, 4H), 4.02 (d, J= 6.7 Hz, 2H), 3.98 (d, J=

5.7 Hz, 2H), 3.71 (s, 2H), 2.63 (t, J = 7.6 Hz, 2H), 2.11-2.04 (m, 2H), 1.67 (s, 3H), 1.63-

1.58 (m, 2H), 1.3.7:·1.28 (m,..I5H); De NMR (101 MHz, CDCh) cS 167.0, 141.1, 139.5,

138.1,134.9,133.1,132.4,131.5,130.8,130.5,129.0,124.5, 123.6, 122.4, 116.9,71.0,

66.5, 53.5, 44.6, 42.6, 35.3, 32.6, 31.3, 30.0, 29.4 (4C), 26.8, 22.2, 17.9, 16.8 (2C), 12.7; 1

HRMS (ESI) calculated for C34H41F503Na [M + Nat, 615.2868, found 615.2863.

3,5-Bis(trifluoromethyl)benzyl 2-«E)-4-(allyloxy)-2-methylbut-2-enyl)-5-«Z)-dodec-

10-enyl)benzoate (156)

o~

NaOH • PhMe:MeOH (1:1)

d, 24 h

., J ~ J ~ ! '~

138

156

168

K2C03

DMF, 23°C, 10h

77% over two steps

O~

Fo11ow experimental procedure for 3,5-Bis(trifluoromethyl)benzyl 5-((2Z,6Z,10Z)-3,7-

dimethyldodeca-2,6,1 O-trienyloxy }..,2-( (e)-4-( a11 yloxy)-2-meth ylbut -2-en yloxy)benzoate

113

(139) for the preparation of olefin 156. Olefin 168 (0.1 0 g, 0.23 mmol) was treated with

K2C03 (0.06 g, 0.46 mmol) and bromide 138 (0.05 mL, 0.25 mmol, which prior to

addition was passed through a short plug of basic alumina) in DMF (22 mL) at room

temperature, stirred for 10 h, filtered, evaporated in vacua to give a residue that was

purified by silica gel flash chromatography (10% ethyl acetate/hexanes) to afford olefin

156 as a pale-yellow oil (0.11 g,77%). l H NMR (300 MHz, CDCI3) cS 7.89 (s, 2H), 7.86

(s, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.29 (d, J = 1.9 Hz, lH), 7.17 (d, J = 7.9 Hz, lH), 5.88

(ddt, J = 17.0, 10.4, 5.7 Hz, 1H), 5.47-5.39 (m, 2H), 5.39 (s, 2H), 5.23 (dd, J = 17.4,3.3,

Hz, 1H), 5.15 (dd, J = 9.2, 3.3 Hz, 1H), 5.14-5.12 (m, 1H), 3.96-3.91 (m, 4H), 3.67 (s,

2H), 2.64-2.61 (m, 2H), 2.06-1.98 (m, 2H), 1.60 (s, 6H), 1.66-1.59 (m, 2H), 1.26 (s,

12H); 13C NMR (101 MHz, CDCh) cS 167.0, 141.1, 139.5, 138.7, 138.1, 134.9, 132.4,

131.6, 130.9, 130.4, 129.0, 124.5, 123.6, 122.4, 116.9, 71.0, 66.5, 64.8, 44.6, 42.6, 35.3,

32.6, 31.3, 30.0, 29.6, 29.5, 29.4, 29.4, 29.3, 26.8, 22.2, 17.9, 16.8, 12.7; HRMS (ESI)

calculated for C36H44F603Na [M + Nat, 661.3087, found 661.3094.

Cyclophane (157)

F~F '1 &F~ 0,

F 0

155 O~

81echert catalyst 170

Ti(Oi-Pr)4. DCM, 1'.. 4h

14%

157

Follow experimental procedure cyc10phane (58) for the preparation of cyc10phane 157.

The reaction was quenched with ethyl vinyl ether (5 mL) and the solvent was evaporated

to give a residue that was purified by silica gel flash chromatography (50%

114

toluene/hexanes) to afford cyc10phane 157 as a pale-yellow oil (0.07 g, 14%). IH NMR

(300 MHz, CDCh) Ô 7.93 (d, J = 1.6 Hz, lH), 6.98 (dd, J 7.8, 1.8 Hz, lH), 6.91 (d, J =

7.8 Hz, 1H), 4.95 (d, J = 1.6 Hz, 2H), 4.49 (d, J = 15.3 Hz, 1H), 4.36 (t, J = 6.8 Hz, lH),

3.05 (d, J = 15.5 Hz, lH), 2.44 (t, J = 6.2 Hz, 2H), 1.99-1.92 (m, 2H), 1.73 (s, 3H), 1.60-

1.15 (m, l4H); 13C NMR (75 MHz, CDCh) Ô 166.5, 141.0, 140.7, 136.7, 133.0 (2C),

131.6 (2C), 129.5, 124.9, 53.2,42.1, 35.2, 30.3, 28.9, 28.8, 28.5, 27.8, 26.9, 26.1, 25.8,

18.3; HRMS (ESI) calculated for C27H30Fj02 [M + Hr, 481.2160, found 481.2166.

Pen tafluorobenzyl 2-«E)-4-(allyloxy)-2-methylbut-2-enyl)-5-«2Z,6E,10Z)-3,7-

dimethyldodeca-2,6,10-trienyl)benzoate (174)

PhMe:MeOH 1:1, tl,10h HO

~Jr, F

69

K2COa DMF, 23°C, 24h

80%

O~

174

Follow experimental procedure for 3,5-Bis(trifluoromethyl)benzyl 5-«2Z,6Z, 1 0Z)-3, 7-

dimethyldodeca-2,6,10-tri enyloxy)-2-( (E)-4-( aIl yloxy)-2-methylbut-2-enyloxy)benzoate

115

(139) for the preparation of p4. Olefin 175 (0.10 g, 0.23 mmol) was treated with K2C03

(0.06 g, 0.46 mmol) and bromide 69 (0.05 mL, 0.25 mmol, which prior to addition was

passed through a short plug of b~~~c alumina) in DMF (22 mL) at room temperature,

stirred for 10 h, filtered, evaporated in(vJ},cuo to give a residue that was purified by silica

gel flash chromatography. (1.0% ethyl. ac.etate/hexanes) to afford olefin 174 as a pale-

yellow oil (0.11 g, 80ro). IH NMR (30.0 MHz, C6D6) 8 7.90 (d, J = 1.6 Hz, 1H), 7.10

(dd, J = 7.9,1.6 Hz, 1H), 7.04 (d,):~.7.9 Hz,'lH), 5.85 (ddt, J = 17.1, 10.5,5.7 Hz, 1H),

5.55-5.48 (m, 2H), 5.38 (t, J = 6.6 Hz, 1H), 5.31-5.23 (m, 3H), 5.06-5.03 (m, 3H), 3.90

(d, J = 6.6, 2H), 3,83-3.80 (m, 4H), 3.23 (d, J = 7.3 Hz, 2H), 2.21-2.15 (m, 2H), 2.15-

2.10 (m, 6H), 1.65 (s, 3H), 1.58 (s, 3H), 1.54 (s, 6H); I3C NMR (75 MHz, C6D6) 8 166.8,

140.3,139.1,138.9,137.0,135.8,135.2,132.6,132.1,130.9, 130.5, 129.9, 124.5, 124.0,

123.7, 123.6, 116.0, 71.0, 66.8, 53.4,_4~;9, 39.8, 33.7, 32.2, 26.8, 25.8, 23.5, 16.9, 15.9, , ."

15.8, 12.9; HRMS (EST) calculated for C36H42Fs03 [M + Ht, 617.3049, found 617.3069.

~, '- . ,

116

3,5-Bis(trifluoromethyl)benzyl '.' J,', 2-((E)-4-(allyloxy)-2-methylbut-2-enyl)-5-

((2:Z,6E,1 OZ)-3, 7-dimethyldodeca-2,6~1 O-trienyl)benzoate (176)

NaOH .. rO PhMe:MeOH 1:1, ~,10h HO

132

,/,

.. J.

j.

, ~

~' Br»CF

3

138

K2C03

DMF, 23°C, 24h

80%

O~

176

Follow experimental procedure for" 3;5-Bis(trifluoromethyl)benzyl 5-((22,62,1 0Z)-3, 7-

dimethyldodeca-2,6,1 O-trienyloxy)-2-( (E)-4-( aIl yloxy)-2-meth ylbut -2-enyloxy)benzoate

(139) for the preparation of 176. Olefin 175 (0.10 g, 0.23 mmol) was treated with K2C03

(0.06 g, 0.46 mmol) and bromide 138 (0.05 mL, 0.25 mmol, which prior to addition was

passed through a short plug of basic alumina) in DMF (22 mL) at room temperature,

stirred for 10 h, filtered, evaporated in vacua to give a residue that was purified by silica

gel flash chromatography (10% ethyl acetate/hexanes) to afford olefin 176 as a pale-

yeIlow oil (0.12 g, 80%). lH NMR (300 MHz, C6D6) Ù 7.88 (d, J = 1.5 Hz, lH), 7.63 (s,

IH), 7.46 (s, 2H), 7.11 (dd, J = 7.8,1.5 Hz, IH), 7.05 (d, J = 7.8 Hz, lH), 5.81 (ddt, J =

17.1, 10.6,5.3 Hz, IH), 5.54-5.45 (m, 2H), 5.38 (t, J = 7.2 Hz, lH), 5.30 (t, J = 6.8 Hz,

117

1H), 5.25-5.20.(m, 2H), 5.00 (ddd, J = 10.4, 3.3, 1.4 Hz, 1H), 4.81 (s, 2H), 3.87 (d, J =

6.6 Hz, 2H), 3.&0-3.78 (m, 4H), 3.2-5 (d,J = 7.3 Hz, 2H), 2.21-2.10 (m, 8H), 1.67 (s, 3H),

1.55 (s, 9H); 13C NMR (75 MHz, C6D6) cS 167.1, 140.4, 139.3, 139.0, 138.9, 137.0,

135.8,135.2,132.6,132.1, 132.1, 131.~, ,130.7, 130.5, 130.1, 124.5, 124.0, 123.6, 123.5,

121.9, 116.0, 71.0, 66.8, 64.8, 42.9, 39.8, 33.8, 32.2, 26.8, 25.8, 23.5, 16.9, 16.0, 12.9;

HRMS (ESI) calculated for C38RtsF603 [M + Ht, 663.3267, found 663.3295.

Cyclophane (173)

o~

174

Blechert Catalyst 170

Ti(Oi-Pr)4' DCM, t., 4h 37%

F-gFI

F, ~ F ~ 1

OE 0

173

Follow experimental procedure cyclophane (58) for the preparation of cyclophane 173. , ..

The reaction was quenched with ethyl vinyl ether (5 mL) and the solvent was evaporated

down to about 1 mL to give a residue that was further purified by silica gel flash \ !~ ,.

chromatography (50% ~oluene/hexanes) to afford cyclophane 173 as a pale-yellow oil

(18.7 mg, 37%). IH-NMR was carried out in C6D6 since running the sample in CD Ch , " •• 11.

caused decomposition. In addition, running the sample in C6D6 prevents overlapping of

the three alkenyl proton signaIs. IH NMR (400 MHz, C6C6) cS 7.98 (d, J = 1.6 Hz, 1H),

7.04 (dd, J = 7.9, 1.9 Hz, 1H), 6.89 (d, J = 7.7 Hz, 1H), 5.47 (t, J = 7.0 Hz, 1H), 4.94 (d,

J = 5.3 Hz, 2H), 4.50 (t, J = 5.8 Hz, l.H), 4.47-4.42 (m, 2H), 3.14 (d, J = 4.9 Hz, 1H), "\ "

3.03 (d, J = 15.8 Hz, 1H), 2.03-1:97 (m, 2H), 1.87 (t, J = 5.6 z, 2H), 1.80-1.79 (m, 4H),

118

1.73 (s, 3H), 1.58 (s, 3H), 1.29 (s,3H); lic NMR (101 MHz, C6D6) Ô 166.5, 141.2, 140.6,

140.4, 136.4, 133.2, 133.0, 131.3, 130.8,124.0, 121.6,42.1,38.8,33.4,31.9,30.8,29.3,

25.6,23.7,22.5, 18.7, 15.0, 14.3, 11.2CHRMS (ESI) calculated for C29H30Fs02 [M + Ht,

505.2160, found 505.2167.

", '

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11006.603 Hz 0.346004 HZ

1.445!iSB sec 16384

29.400 usee 37.93 usee

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25.50 dB 2B.00 aB

300.0310500 MHz

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16566.30 Hz -5.839 DPIIi

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~~~omorooo~o~ru~-ru--~~-~~rom ~~o~m-o~ ~m~mq~o~ro~~~~qmww-~~~om~o ruoro~romru~ ~~~oro~~~o~_IDIDM~mmmMmmmom~ qo~ru-m-ro . . . . . . . . . . ~ . . . . . ~rurururo~ •• ru-O~q~MM---omm~ill~ ~~~~_~~. W~~.~M~~M~Mrururururururururu-- __ ~ ~~~~~mmw ~~~~~~~~~~~~~~~~~~~~~~~-~

~~~~~ ~I·I \/J

.1 1 l J~I J U

. .......... . cncnru-~~~f'-~~~ru (T)(T')M('t)ruC\J(\J ............ ..,...~--'

.

.1 l Il . l

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. ,' r-160

., .. T ·'1 -·T·---' .... ··r· _·'- .. ··T ·T·--r·--·r-· , ... _,.- "r' ··_-I-.. ··-r~-· 1--"--'- -'--"-.'- , .... , . , "'1' .. _, .. ""-1 . ·'1'·· ." .. - r .... ,- ",-

140 120 100 BO 60 . 40 20 0

: ~i=r,t Golb Pâf"bmeters I~E j:-2- 185

:,P!lü ~A\XIIO

~~ - LC:jl=ltlon P5rameté~s ),;t" _ 2é1lF0523 Il~lè "2.1)6 il6iF.l'f.1 av4ûO 'P08n[l '5 mm Pt.8S0 BEl-)Ut,..Pt1üG 2g30 fC, .t9152 ;Ot.I-EflT cocu IS 28 )5 2 ;1!1l 5995.20-1 HZ 1û~ES [;.121973 Hz

'D 4.0993266 sec ,-,L' 2-56 lU 83.400 USiC "E 6.00 usee ·t 294.4 K 11 J . LiÜOOOOOO 51'(

IUlES T e, . OOû(l(oOOO se: K~"Jt=:t\ [- • (1 150000{l se..:

1lIo:- j lii '1 IO.Ol! usee -u - 3. \){! Ils FOi ~OO . 132f:.OOO j,.1l

~ Pr .:;;ess )/19 pariimetêrs 65536

F <1(10.130004.1 11Hz D!~ E.' SB 0 El 0.30 H~ B 0 (: 1.(10

D ill,II:, clot p~f'ômetl?rs 2~.OO cm

(1.(1(1 (fT!

IP W.OOO Pflll> 1 -10':.! ,30 Hz 2P 0.000 ppm 2 0.00 Hz ~IC!~ Cl. 4166~ ppm, CRI

~CI-I If,e, i20B3 H:!, cm

t:.J 0- ru O"~ iTt en -.::r en v co fV1 Il''") r-.. 01 If) en 01 ûl Oî ru "q" ~ r--... mUJl'''-C\JU-JC""\J0 o -.c-t i'. tD ;r, ("\$ "l"""! 0. co 1.0 cr> r- l!' ru 0 0 0 0 \.Cl 1.0 . . . ~ ~ . . . . r-.r-I'-r--.r--.. ...... r--..r-tolO

Il.\\{V f/

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) ~ }~ J\ ) \

(~I 'n' I!' o uJ ~

l~ ~~ "t""i 'I;"""'t -"

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1 6 5 4 3 2 t

:;.tr"r ê'r"t [!:rt A Pôr 1I1'flCters

·.,.cHE ,:-2-1115 " .. f·"o} ?

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:tlH 25062 il5ê 114 ~liJK::S J .. 1â'j5ô5 H: -'ù J .ii?I~SOO sec -'0:; 32768 :11 19.95l> osee ~f 6w usee T~ 295.(' ~ JI .5,iJOOOOOO set :lI! ~.()Y.,\)OOOO sec ~'ELi , 1.3999999S sec !CP.E~ï ;:, 00&0000'; sec

'..J.:r.Rt. ,j.~15ôOûOù sec

.. '== .... ,.,"';::0 (:-1':'1 Il teL il a ....... =.;;;

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(11':'U.Jf.l 12 =1;-\:";;:15:_

;P(lPh(,:i! .. ~ h! 16 41.":2 IH

. :'Cfil2 96 00. USI<C

'1.2 -3.00 GB 'U2 16.0\1 \lB 'U:; 19.00 oll ,Fü2 ~O·) 1315006 11Hz

'2 PI"OCesslng CaîôUJelers H C;5536 ;F 100.6121714 MIiZ lÛ~~ riO

;SB 0 a 0.o,) Hz

;1.< 0

'i: !.-li)

f· f/W" ~ î N p"r;;m" t ers 25.;)0 Ci!>

d •

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HJ·J2.5i1;';23 H;. (11\ .

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00 (\1 ~ lD"'fOOOOlD rr, O-OJlDlDOI.OCDM 'q' (\.1 ID ~OI.D""'I'-""l" N OOlOlONfI')lO- .... m "'- rotO 100-01D"'1 0 UJOIO .... vCOCO"'f"'-••• + •• ••• •

~ru~..."mruN~oro"lD~"'1M_mml.O 101f)1f)"<il'1l'1l'1l'1l'1rururururururu ""' ..... 'If:"""t-«l""1l"C""f"o:""'i't"i~""I"1I"fW'f~"""">C""f ...... ~ ...... V"I .... "'""'''It"'''f .......

1 l ~~~\~.

r "1'

160 r-' . .,.- ''1"'._,_., .. ,--,.--,-.," .. ,. - 1 .. ,

t40 120 100

"'-MO N tt.I " ...... ~OO co MN"'f MNO lD lD _ "

"'- "'- "'- tO ('f) m-.:r " ...... " "" 1.01.0

/ , 1

, ..... 'T -'r-", .. T -'1" , 80 60

C\J ID' m

co (Tl

1

1 40

...... ...... tt.I CD M " mo "'- 0 mlD ~,,-.:rl"")

(Tl ru ru ru

\ \ II

1 20

fi') rrl "1' ..... ('f) N If) fi') .....

\ 1

1 o

':tiffef,t Gôta PafëO,eterS .• àlE 1 z -3- 12:' :"PN,' 1 "ROWO 1

Jate_ 2(1(170219 i Ime 19.06 1115 TF"_'j1 a',"lOO :'ROS.,[o 5 Jhm p"BBO BB-:'ULPROG 2930 iG -19152 ;Ol'iEliT COCJ3 IS 16 )S ;: ;I"IH 59~5.20~ Hz ;WRES 0.121973 H' \û 4.0993266 SE:C

~G 16 ;,i fG.AGO us.ee )E 6.00 u::.ec f[ 294.1i K ) 1 1 . ÛL'U(iOOOù SEC IC~E5i Ü .O\:IOOOOOC. SEC ICuR~. ':'.01500000 sec

CH;'lIl1EL i j .;====== ~Cl IH ') 10.00 USEe 'LI -3.00 aB .F li 1 -1(.0 . 1 326000 1·lHz

'2 - PrGCES510g parameters ;r 65536 ,F -"CIO. 1300090 1·IHz

no o

1i.00 tlz o

l.ü,:,

D N~IR plüt Pélrômeters 24.00 cm 0.00 cm

lP 10.000 ppm 1 4001.30 Hz ~p. 0.000 pplT, .;> Cl .00 tir

!)~~I-I 0.4166ï ppfiJ!cm =-~,·I le,E .. 72083 Hz/cm

'1 f)

! 8

.:0 f'.. cu U) '" o "'''''"cou:;; o 0 ~ 0

CUO"fCU 1O ('\J ru 'C""t ~

r-- "- r-.... "- "-

1 \1/) . Il(

Jt~ )g~ 1.'~j~·1 ':1 5:~R o me c> U)f"'l . .. . . _1 0........ ~ .....::r

-- T 6

.. --1'-.----... -7 5

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4 3 1 2

1_

1 -

1

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1 !t 1.>.' .....

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137.138 134.917 l32.730 1

'137.233

f:~n:~ ~-i31.070 ~"'-131.01B

130.923 130.747 130.659 130.001 128.791 12..:1.410 123.479 122.201 116.823

177 . ..:125 77.000 75.576

.jI~ 70.820 -.I;C 68. 050 J/ 66.443 ::/ r 44.669

42.474 35.273 32.518 31.267 29.992 29.511 29.459 29.387-29.236 29.183

~ 29.085

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,

22.242 21.819 21.282 17.8..:11 15.840 12.654

:ffffer.l OaÙlo Püramftf'fS ~~~ 1:-3-131 ::"PN[I 1 :>J::ûC,,"i

=2 - Àcqul~ltlon "èiôfheu:rs;

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"15 13 )5 <: ::l'IH 5995.20-1 Hz =lOHE5 0.121973 HZ .!û .J.0993266 St;C

~b .J0.3 )li 83.400 usee :'E 6.00 usee iE 294.6 i; :.) 1 .OilO(l(lOOO sec KHEST Ü . ü(oOÛ\lO(IO Si'(

·lCl'ih'l il. \) 15000û(j SeC

,=""'="' CH~UJEL 1 J '"===="" ~l IH )1 10.(1Û U5E:C

:U -3.00 oB ,FOl .100. j 326000 I·1H1

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,56 0 13 0.00 Hz i8 'C

Ü

1.00

IJ HI·IA l,lüt parameters .... 2-1.00 Cil!

0.00 Lili

IP 10.000 ppm ,,(l(. J .30 tlZ

~p i) . QO!) ppn, ;g v 00 lil

~IW il, .11667 prllP'cm ~UI J€,i'i '208J HZ/cm

ipa: , 9

, 8

lU tQ ru C\J 'q' nJ co f'J ..0 en o~tnruru f'-. --, cr, -- 01 ...0 ,'"1"} ru ("'ù ''l'''''l

~ ...... ,.....r-",

1 ~~l)

10 0 ru 1"- 1"- co I.D '<f 1"- ru."<f I.D 0 r-.. 0 Ol""ltOCI)MCOMCOCOO tniDMOM MIOOMOor-..01MI"- ro~lOru ..... tD 101""1 ru nJ COl"-ruo ro C\J~ror-..­''l''''l'''tMMC\JrunJru ..... oocnenl"-

• • • • ~ ~ & • ~ •• •

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o~

f 1 '---------',,_,h

J \ ) ~"

~ll~l~î , ï

o~~~t~o~~ ~I'OO'101M Of1'l"'l" 0 ru CO ...... _ "I:!""'lru_"I""'iO

... -.. __ .. - . -~. ·'-1- ...

5

If~~ -", -

4

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Wî!V

(~I ru (~-M CI) '" (l) "" 0 10

MM _ ......

1 .. _., . - ... ,

2 1

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:un'Ent û"tô P,;ralll~ter5 !li.li: J:-3-JjI :';'U0 :P.!jOi:'

. , - "':(jll1:;) t Jon P61"ômeters J5tè_ 2ùü ... ü223 la.e 22.55

:IlSTAUJ.l spect 1l1OBH[o 5 '~1Ii OIlP IH 'ULPriü6 :gpg '0 3276B ;OL '.'E:tï COCU IS J6oo0 's " ;l'I!I 22i2;,273 Hz Ie-RfS 0.69358J Hi'

,0 (o."I209~60 ~e(

li:. 22800 .1'1 22,000 u~e( -E .:sJ ,43 usee E 296.0 f; IJ'=' 0,Oü\)0200 S"C -liS l-I,(/C' dB

" 2.00000000 se, POF'P.G I1/iJU16 '31 85.00 lIsee JI 0.030000Q sec l5 12.00 oB J .:l.00 usee FOI WO.6244502 Nil! UClfus ne

2 - PrOCêsSlng parameters 1 l2ï68 F lûû.6!3SSS7 MI1z 01'1 Et<! SB 0 B B

2.\10 Hz o

1.00

o 1/l1A r.jot N,ramNers 25.00 cm 0.00 cm

,'.1 O'I~"m<:r ..... I.OIOUJ"lD" '-'<l'lOlO ID f"" MI...,I'\J~f")~cn~O('\Ja:;O aJI.OV~ (\J IL iJl M m CD ('\J /'i'j 1.0 fI'l 0'1 V 0J CO -COIOID f'"l . . ~ ~ ~.'.'"

lD ccn",,~(\J-OOaJfI'l(\J<D 1"'1.01.00 lD LO "l'f'I')f'I')('IJf'I')f'I')(1')(1')(\J(\JI'\J .... ''''l'-I'- ID ~"t-1~""t-t"t"'1~'V""'~"Ç""1~..:-t~

~\~k/I1) ~'I 1

~ O~

1 IP 217.000 ppm TJ---------2~j~e~3~r,~~1~H.~'----------~--------~~ l l 1 :

2P ·7.000 Iljlln 2 -~~4.30 Hz PI-li:J.1 1 ! il. 96000 ppill.' e m/ ;uRl 2·3li) l. 500-'19 H2." "Œû

1 160

,-' -,-'-T- -Y' ,--'-- -,-.,_. , - r---' ,.--", .. ,-,,-- ,- '--,.........·r-l-140 120 100 BO 60

~101O(r,tOC ..... I"'''mlO .... IO''O

p;~~~~~p;~~~g~~~lfl ... ~" . fI'l N tri (\J ..,., 01 en en en en en 1.0 (\J \.Q fIJ IlÎ'<I'{'f)f'I')f'I')Nrururururururu_ ...

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:J: '0 ~ o::'l ::::r: ~ "1 'C 1·" 't:' ,,,' '0 S ... S a;I S n '.~ il ,..,

!I

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.• OUl;! o·, o w mwwcP 00 .... "_ QOoos:cnr.:n; OCI '::'7

I~ ~ ~ ~~~ N HI ro ...

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'~ ln ~ ~e ~ t 1;-

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ggg?o~~~~~ o-~~~~~~~ ... '"' l '" ..,

... '" 0' 0 0 0 '=' C> •• J CIl (Ji t::,~ h.1 i:;t \,I..t CD ~ - ,.... Ch '\,t ~ ~~~~~~ _:: ro t'tt .,..~. tn u~ 1'lt'..I:., """i

"" ro. n ~ 8.50599

8.28005 8.10247

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o~ 0 ~-;;J1 ~

7.88509 ,69205 ,68584 .28905 .28271 .26003 ,18181 ,15560

15.87235

15.42458 5.40597 5.39200 5.26360 5.25811 !i-~.~~~~

~. 5.~6960

5.15418 5.13567

13.94369 3.91889 3.90373

...-3.89938 3.89501

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_-1.35j43

~\"-1. 33096 ''-1.31272

11.28306 1.25967 1 .25946

·0.9t928 0.89447 0.88204

turl'ent Data Parilllli HAME Îl.-.

2 1

2 - ACQUl5ltHlII Para.etf~rs 20010515

0.14 .. peu

5 Il''' ONP IH %009

32769 CIlCl3 12000

4 22727.213 Hz 0.693581 Hz

0.7209460 sec 22800

22.000 usee 31.43 usee 298.0 K

0.0000200 sec 14.00 dB

2.00000000 sec waltU6

65.0D usee 0.0300000 sile

12.00 dB ;1.00 usee

100. 6244502 HH~ 13e

2 • Process109 pal'a.eters 1 32768 F 100.6139007 11Hz

"DII EH :;SB 0 .8 2.00 Hz 39 0 ~C LOO

11) NMR plot para .. eters :i 25.00 C!lI

:V 0.00 CM

'IP 211.913 PPM 'j 2l925.12 Hz '2P -7.973 pp!!. '2 -B02.l6 HZ ~H 9.03544 Will'. iZCH 909.09088 Hz/c.

r--IXIOCOruIOOr-.r-._cnCO"'l" cn .... fYlONlOOlOlO ..... cnruru -anr-.-cn'<7!.DoJfYlC\lIO"ItO . , . . . ~ . . ~ . ...... Ola:lOO'<l'ru .... oO!JlfYlru" ';r (Tl (Tl 1"1 M fYl (11 m (11 (\1 ru ru ",...

~~\IP;ZP

~3 NeF o

o~

1 200

....,.··,··-,-·_·.---.---1 180 160

1 100

'<7 1001' fYlcn C\to 0,,", 010 '<7C\.tOIOO'<7 . . .. . """ta ..... ta """""10

1 80

1 1

1 60

C\loJlOC\I"!.D .... C\llDO C\I!.DfYl-fYllDlO .... "1'1 l''1C\1IOIO'<I'ruC\tOOOO'' . . ...... . r.n .... Cil 0". Cl en Cl lO lO ru mm(\Jf\lf\lrururu~-

.. __ ._------~-----------.-

E 0-c.

Current NA~IE

ExPNO PROCNO

Data Parameters IZ-3-151

1

1

F2 - ACQUISItIon Parameters Oate_ 20070524 lime O.IB 1 NSTRUM spe[t PROBHO 5 IlIm QHP lH PIA.PROG zg TO 32768 SOlVENT COCl3 NS 19 05 4 SWH 4504.504 Hz flORES 0.137467 Hz AG 3.6372981 sec RG 1024 01'/ OE TE 01 Pl SFOJ NUCLEUS

111. 000 usee 158.57 usee 29B.0 K

1.00000000 sec B.OO usee

400. 1364000 MHz lH

F2 - Processlng oarallleters SI 32766 SF 400.1344169 MHz 1'101'1 S5B lB 66 PC

10 NHR plot ex cv 'F1P FI F2P F2 PPr·leM HleM

no o

0,00 Hz o

1.00

parallleters 26.00 CIII

0.00 [III

10.000 PPITI 4001.34 Hz -0,000 ppm

-0.00 Hz 0.38462 ppm/cm

153.89786 Hz/cm

......

1

-ruq-tnfT) 000 ..... 00001/") OaJq"OlI/")ID lI'loor--IDruO ~OlC1lc:nOlOl . . . . . .

\~?

ru lO .... 0 01 ~ 0'1 "<r 0 0 ID 0.0 lO CI 01 Cl "<r 0 If. -.> lD ru 0.0 0 MlOaJOI/")-~M~_l/")o.oI/")M~ClaJOMOI/")OllOlI'l OM~.ID-MO"<rrul/").COII'l-~MOlMo.oM~lOOl ~MlO.ruM~-lO-O~lOOlCOo.o-Olo.o.Mru_ro 00 •• "<r 0'1 ...... I/")MruC\J 0 00'1 0l0l0l coCOaJCOaJ co ru ...... , .............. .

~rPV?

Il) ID

lD ID • C\J

r---­ppm

l' . ---- --·--"r-··· --··-···--'-r----·-·--·-·--l-·---·--,--· .. -'-··----.I -. ,---.-.--. -- .. '.---.--.-9 B 7 fi 5 LI 3

:uffaf,t C.::n5 Po.r;'IMtti-rs 'I~IIE )Z-)·151 ~'PHil 2 ~I~ 1

:2 - .lcOtJ15Hlcn Par(tmetet"s :lt;t~_ 2*~\}eI9 hm~ til,55 INsr<;l!î,1 s.,ect ~P.!l&.ir. :) mr., DJI~ Iri.' 1 "U!.PROG zlll1030 ru -19152 5ôL ~Elll CiiIl6 '15 12i);)i) )5 2' 511t1 t10iiii.a.>3 II.'! =IIJAES ij.3~iiu4 HZ ~O L 4~511a8 Sile '«; 16:l66 :'t1 i:'!:l.~QO usee :E )7,93 us"c TE 00 t. )) l ,(/i)ilû&J.:>CI sec III C ,\) .ùüOûùil seç i<LT.l ~. B99!l991iB sec ,!CRES; li ÏlùilOOC!\I() set -1\:1111. ,j,IlIS;;'O('O() sec

... 1114.;;',. .. (~lëIHlEl

l'Xl

J l •• _'*_s_=-13C

'J 'LI ;fûl

:.'I:lI'hG~

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