New the HMG-CoA Reductase Inhibitors (+)-Compactin Gregory · 2020. 4. 8. · Stereoselective Approaches to the Hexahydronaphthalene Portions of the HMG-CoA Reductase Inhibitors (+)-Compae

Stereoselective Approaches to the Hexahydronaphthalene Portions of the HMG-CoA Reductase Inhibitors (+)-Compactin and (+)-Mevinofin.

Gregory J. Hughes

A thesis subrnitted in conformity with the requirements

for the degree of Doctor of Philosophy,

Graduate Department of Chemistry,

University of Toronto.

O Copyright by Gregory J. Hughes 2001

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Stereoselective Approaches to the Hexahydronaphthalene Portions of the HMG-CoA

Reductase Inhibitors (+)-Compae tin and (+)-Mevinolin. Doctorate of Philosophy ,200 1,

Gregory J. Hughes, Chemistry Department, University of Toronto.

Abstract:

The first objective w a s to develop an efficient approach to the

hexahydronaphthalene portion o f (+)-compactin. The approach was to feature the use of

a catalytic enantioselective reductive ring opening o f a [2.2.l]oxabicycle, a

diastereoselective crotylation reaction, and a ring closing metathesis reaction of a

conjugated diene.

The second objective was to develop an approach to the hexahydronaphthalene

portion of (+)-mevinolin. This strate= would use a diastereoselective double ring

closing metathesis reaction follow by a sipatropic rearrangement.

The third objective was to use a palladium catalyzed formate reduction to allow

1,4-dichiorobutene to be used as a surrogate for 4-bromo- Lbutene. This strategy would

be employed for the butenylation sf a variety of different nucleophiles.

The fourth objective was to investigate the use of y-carboxy-a,P-unsaturated

aldehydes as replacements for B,y-unsaturated aldehydes. This strategy would also make

use of palladium catalyzed formate reductions, with paaicular interest being placed on

the development of a diastereoselective transformation.

Acknowledgernents

1 would fist and forernost like to thank Mark Lautens. He has been an

enthusiastic teacher and provided an excellent environment in which to acquire the

knowledge and skills necessary for the art and science of organic synthesis. 1 am

particularly grateful for the freedom that I was given to investigate some of my own

ideas, and for opportunities I was given to present our research at conferences within

Ontario, Quebec and British Columbia, as well as an international conference in Holland.

1 would like to acknowledge VaIentin Zunic and Jean-Franco is Paquin (graduate

students) and James Wu and Chuck Wen (undergraduate students) with whom 1 had the

pleasure of collaborating.

1 would like ta thank Professors Batey and Yudin, as well as the members of their

research groups who generously shared their expertise on the many occasions that 1

consulted with them- 1 am particularly indebted to Avinash Thadani and David Smil who

generously provided me with copious quantities of crotylating reagents which were used

in our efforts to synthesize compactin.

1 have had the privilege of having a number of t ruly excellent CO-workers in the

Lautens research group. In particular, 1 would like to acknowledge Tomislav Rovis who

was a senior graduate student, and Nick Smith who was a postdoc. They are both

excellent chemists who played instrumental roles in my development as a research

scientist. 1 am also deeply indebted to Keith Fagnou, with whom 1 shared a lab for the

last half of my Ph-D. He has been a great fî-iend and cornrade. I'm gratefuI to he and

Tim Stammers for their assistance in proof reading portions of this thesis. Thanks to al1

of the other members of the Lautens Iab group, both past and present, for their help and

Wendship that has been extended my way over the last four and a halfyean.

1 would like to thank Alan Lough for X-ray analysis, Alex Young for with mass

spectroscopy, and Tirnothy Burrow for NMR assistance.

The two scientists who have had the largest influence in rny life are my parents,

Dave and Lois Hughes. 1 could not have done this without their tremendous support and

encouragement. I would also like to thank rny mother and father-in-Iaw, Walter and

Audrey Wyand who have also been very supportive. My aunts and uncles Jan, Archie,

Marg and Ray should aiso be mentioned for their continued encouragement and interest

in my academic endeavors.

Finally, rny deepest appreciation is extended to my wife Shelly. Every good thing

1 accomplish is sweeter, and every difficulty is lessened, because 1 c m share them with

her .

to SheZZy,

you are the love of my Zfe-

Table of Contents

Abstrac t Acknowledgements Dedication Table of Contents List of Tabies

mures List of Schemes and Fi, List of Appendices

-- Il -.-

III

v vi ---

VI11

ix --. XlLI

1 Background. 1

1.1 Compactid Mevinolin Background. 1.1.1 BiologicaI reIevance of HMG CoA reductase inhibitors 1-1-2 Synthetic approaches to (+)-compactin and (+)-mevinolin. 1-13 Oxygen tethered analogues of (+)-compactin,

1.2 DiastereoseIective ring closing metathesis (DSRCM) reactions. 1.2.1 Bicycle formation via RCM. 1.2.2 DiastereoseIective ring closing me tathesis (DSRCM) reactions.

1.3 Novei applications of Pd catalyzed formate reductions. 26 1.3.1 1,4-Dicloro-2-butene and derivatives of cis- 1,4-but-2-endiol as but- 1-enyl eiectrophile equivalen ts- 27 1.3.2 a,y-Unsaturated aldehydes in organic synthesis. 29

1.4 References: 33

2 STUDIES TOWARDS THE TOTAL SYNTHESIS OF (+)-COMPACTIN. 39

2.1 Retrosynthetic analysis. 39

2.2 Optimization of reductive ring opening. 40

2.3 Hydroxyl differentiation. 2.3.1 First generation approach. 2.3 -2 Second generation approach,

2.4 Attempts to compfete of the synthesis of the HHN moiety. 47

2.5 Experimental. 55

2.6 References. 77

3 DIASTEREOSELECTIVE RING CLOSING METATHESIS. 78

3.1 Preparation of starting materials. 80

3.2 DSRCM to form bicyclic systems, 3 -2-1 Formation of [4.4.0] bicydic systems. 3.2.2 Formation of C3.3.01 bicyclic systems.

3.3 DSRCM reactions of triene systems to cyclohexenes and cyclopentenes. 85

Preparation of starting materials Formation of cyclohexenes and cyclopentenes.

Influence of p-stereocenters on DSRCM reactions. Preparation of starting materiais. Study of P chiral center infiuence in DSRCM reactions-

[2,3]-Sigmatropic rearrangements. Preparation of starting materiais. [2,3]-Wittig rearrangements-

Proposed pathway to bicyclic compounds having protected alcohoIs. Pr~posed pathway to bicyciic compounds of free dcohols. Rationakation of observed stereoselectivity. Effects of ethylene in DSRCM reactions. Acid sensitivity of cis and tram fused bicyclic matenals- [1,2]-Wittig rearrangement of a lithiomethyl ether-

Experimental.

References.

4 NOVEL APPLICATION OF PALLADIUM CATALYZED FORMATE REDUCTIONS IN THE PREPARATIONS OF TERMINAL OLEFINS. 126

4.1 Current methods for the preparation of terminal olefins. 126

4.2 Palladium catalyzed formate reductions of allyCic electrophites to form terminal olefins in problematic cases. 127

4.2.1 1.4-Dichlorobut-3-ene as a surrogate for conventional 1-buten-4-y1 electrophiles. 128 4.22 a$-Unsaturated aldehydes as sumogates for &y-unsaturated aldehydes, 133

4.3 Experimental. 138

4.4 References, 151

vii

List of Tables

Chapter 2.

Table 1. Effect of catalyst loadings. (Page 41)

Chapter 3.

Table 1. DSRCM fiom monocycloalkene formation. (Page 87)

Chapter 4.

Table 1. Diastereoselective formate reduction. (Page 137)

List of Schemes and Figures

Chapter 1.

Figure 1. Structures of (+)-compactin and (+)-mevinolin-Scheme 1. Role of HMG CoA reductase in the biosynthesis of cholesterol.

Figure 2. Weil defined Olefin Metathesis Catalysts.

Scheme 1. Role of KMG CoA reductase in the biosynthesis of cholesterol-

Scheme 2. Hagiwara's approach to (+)-compactin.

Scheme 3. Burke's approach to (+)-compactin.

Scheme 4. Kozikowski and Li's approach to (+)-compactin.

Scheme 5 . Sih and CO-workers' approach to (+)-compactin.

Scheme 6. Girota and Wendler's approach to (+)-compactin.

Scheme 7. Heathcock' s approach to (+)-compactin-

Scheme 8. Clive's approach to (+)-compactin.

Scheme 9. Hirama and CO-workers approach to (+)-compactin and (+)-mevinolin.

Scheme 10. Funk and ZelIer's approach to (+)-compactin.

Scheme 1 1. Deutsch and Snider's forma1 synthesis of (+)-compactin.

Scheme 12. Grieco and CO-workers approach to (+)-compactin.

Scheme 13. First example of RCM mediated füsed bicycle formation.

Scheme 14. RCM approaches to tethered oxygen hetereocycles.

Scheme 15. Spirocycle formation via double RCM reactions.

Scheme 16. Formation of polycyclic ethers via double RCM reactions.

Scheme 1 7. DSRCM as an approach to five membered nitrogen heterocycles.

Scheme 1 8. DSRCM as an approach to dihydropyrans.

Scheme 19. DSRCM reaction for the formation of a seven-membered ring in the

synthesis of Ciguatoxin.

Scheme 20. Palladium cataiyzed formate reduction of allylic electrophiles.

Scheme 2 1. Shunizu's approach to dimethyl butenyl malonate.

Scheme 22. Tsuj i' s Palladium cataly zed butenylation strategy .

Scheme 23. Isomerization of P,y-unsaturated aldehydes.

Scheme 24. Application of 4-tert-butyldiphenylsiloxybutanal as a synthetic equivalent to 3 -butenal.

Scheme 25. Crimmins' preparation of 3-butenal.

Scheme 26. The use of 3-butenal in an auxiliary controiled acetate aldol reaction.

Scheme 27. Alkoxy acetate aldol reactions involving 3-butenal.

Scheme 28. Aldol reactions involving 2-methyl-3 -butenal.

Scheme 29. Diastereoselective addition of organocopper and organozinc species to allylic chlorides.

Chapter 2.

Figure 1. Mechanism of acetal formation.

Figure 2. Homoallylic alcohol targets for the preparation of compactin and oxy- compactin-

Scheme 1. Retrosynthetic analysis of (+)-compactin.

Scheme 2. First Generation Differentiation Strategy .

Scheme 3. Burke's approach to (+)-compactin.

Scheme 4. Reductive Cleavage of Acetal.

Scheme 5. Differentiation between the oxygen atoms of 133.

Scheme 6. Preparation of Crotylation Precursor.

Scheme 7. Retrosynthetic approach to oxy-compactin.

Scheme 8. Preparation of cyclohexencarboxaldehydes for crotylation studies.

Scheme 9. Diastereoselective additions to cyclohexene carboxaldehydes having an sp2 hybridized carbon atom at the P-position.

Scheme 10. Diastereoselective additions to cyclohexene carboxaldehydes having an sp2 hybridized carbon atom at the y-position.

Scheme 1 1. Rat ionamg the stereoselectivity observed in the syn-crotyIation of 156b.

Scheme 12, Proof of sterecchernistry of 166.

Scheme 13. Proof of stereochemistry of si-168 and re-169.

Scheme 14. Activation and atternpted displacement of the secondary hornoallyiic alco hol.

Chapter 3.

Scheme 1. Approach to HMG Co-A reductase inhibitor (+)-mevinolin.

Scheme 2. DSRCM reaction of sirnplified tetraene substrates.

Scheme 3. Desyrnrnetrization of syrnmetrical bicyclic compounds.

Scheme 4. Pd catalyzed formate reduction approach to dibutenylated malonate.

Scheme 5. Preparation of substrates for DSRCM studies.

Scheme 6. DSRCM as an approach to cis- and trans- fused decalin systems.

Scheme 7. The use of aldehyde 223 in non-racemic aldol reactions.

Scheme 8. Synthesis of cycloheptene 184.

Scheme 9. DSRCM as an approach to diquinane systems.

Scheme 10. Synthesis of triene tertiary diallylic alcohols and ethers.

Scheme 1 1. Preparation of DSRCM substrates having a P-stereocenter.

Scheme 12. Influence of a stereocenter on diastereoselectivity of RCM.

Scheme 13. Preparation of the precursor for the Still variation of the [2,3]-Wittig rearrangement.

Scheme 14. Synthesis of propargyl ether starting material for [2,3] Wittig remangement.

Scheme 15. Still variation of the [2,3]-Wittig Rearrangement.

Scheme 16. [2,3]-Sigmatropic rearrangement of propargylic ethers.

Scheme t 7. Pathway to diastereomeric decalin systems.

Scheme 18. Pathway to diastereomeric free alcohol decalins.

Scheme 19- Transition state mode1 for DSRCM reactions under a stereocenter control.

Scheme 20. Transition state mode1 for DSRCM reactions under stereocenter control.

Scheme 2 1. Unprecedented [1,2]-Wittig Rearrangement o f a Lithiomethyl Ether.

Chapter 4-

Scheme 1. Approaches to temiinal olefins.

Scheme 2. Application of palladium catalyzed formate reductions for the preparation of terminal o leks .

Scheme 3. Butenylation of nitrogen nucleophiles.

Scheme 4. Butenylation of enolate nucleophiles.

Scheme 5. Palladium catalyzed rearrangement of vinylcyclopropanes

Scheme 6 . Alternatives to 3-butenal.

Scheme 7. The use of aldehyde 223 in non-racemic aldol reactions.

Scheme 8. Formation of Starting Material for Diastereoselective Formate Reduction.

Scheme 9. Diastereoselective Pd catalyzed formate reductions.

List of Appendices

AppendYc A. Abbreviations

Appendix B. Specta

1 Background. In this chapter, background information for the various projects covered in this

thesis will be presented. A brief discussion of the following topics is included:

1. Biologicd relevance of HMG CoA Reductase inhibitors.

2. An overview of various synthetic approaches to (+)-compactin 1 and (+)-mevinoh 2.

3. A discussion of some relevant ring closing metathesis @CM) transformations.

4- An overview of developments related to the application of Pd catalyzed formate

reductions.

1-1 Compactin/ Mevinolin Background.

1.1.1 Biological relevance of HMG CoA reductase inhibitors.

More than half of the cholesterol found in humans in synthesized de novo.' The

rate limiting step in the biosynthesis of cholesterol involves the reduction of 3-hydroxy-3-

methylglutaryl Co-enzyme A (HMG CoA) by a cytosolic reductase to produce

mevaionate (Scheme 1) which can be converted to isopentyl pyrophosphate, which is in

turn converted to squaiene, and then ultirnately to cholesterol.

HMG CoA .\\OH

"3- - - cholesterol reductase

OH

mevalonate H

HMG CGA

Scheme 1. Role of HMG CoA reductase in the biosynthesis of cholesterol.

In the mid 19703, two different research teams, Endo et al. at the Sankyo Co. and

Brown et al. at Beecham Pharmaceuticals, simultaneously reported the isolation of a

potent cornpetitive inhibitor of HMG CoA reductase fkom the metabolites of Penicillum

cirrinum and P. brevicompacturn respectively.'* ' Endo and CO-workers refered this

compound as ML236l3, whereas the Brown and CO-workers referred to it as compactin.

Alberts et al. working at Merck Sharp and Dohme reported the isolation of the

structurally related compound mevinolin from Aspergillus terrus in 1980, which was

shown to be three times more potent than compactin. The Merck group has also shown

that the hydroxy carboxylates, formed by ring opening hydrolysis of the lactone portions

of 1 and 2, are the biologically active forms of these s~bstances.'~." It was established

that this class of compound could be administered to patients suffering from

hypercholesterolemia in order to prevent coronary atherosclero~is,~ a major cause of

death in western civilizations.6

1 R=H (+)-Compactin 2 R=CH3 (+)-Mevinolin

Figure 1. Structures of (+)-compactin and (+)-mevinofin.

The inhibition of mevalonate synthesis has a number of repercussions.' The ce11

in which inhibition is taking place will begin producing more HMG CoA Reductase in

order that steroid production c m continue. Also, more LDL receptors are produced on

the ce11 surface and it is these receptors which are responsible for the reduction in plasma

LDL levels. In this manner, the plasma levels of LDL are lowered without impairing the

supply of cholesterol to the tell."*'

As a result of these intriguing biological properties, HMG CoA Reductase

inhibitors have proven to be highly effective pharmaceuticai agents, selling upwards of 5

billion dollars per year? There continues to be considerable interest in exploring the

structural activity relationships (SAR's) by varying the hexahydronaphthalene (HHN)

portion, while the S AR for the lactone moiety has been found to be highly infle~ible.~.'~

1.1 -2 Synthetic approaches to (+)-compactin and (+)-mevinolin.

Given the pharmaceutical importance of (+)-compactin and (+)-mevinolin and the

particular synthetic challenges they present, it is not surprishg that they have received

considerable attention fiom the synthetic organic cor~munity. Of particular interest are

the four contiguous stereocenters of the HHN subunit, as well as the sensitive P-hydroxy

6 Iactone, containing a masked syn 1,3 diol.

There have been no fewer than 11 total and fornial syntheses of (+)-compactin

and three of (+)-mevinoh reported in the literature to date, and an extensive review of

1 1-22 approaches descnbed prior to 1986 has appeared. The various synthetic strategies for

the formation of the HHN subunit can be divided into the four following general classes:

1: Non ~ ie l s -Alde r , ' ~*~~

II: Diels-Alder for ring A formation, l4

III Diels-Alder for ring B formation, 15-18

IV: Diels-Alder for the formation of rings A and B. '9-22

The approaches to the lactone moiety can also be divided into three categones:

1: Derivitkation of materials fkom the chiral-pool. 14* 16. 20* 21*

II: Chiral auxiiiary approach. l5

III: Catalytic asymmetric derivitization of prochiral compounds. l9

There have been a number of different strategies employed for coupling the

lactone and HHN entities which can be categorïzed as foilows:

1: Incorporation of lactone carbon backbone prior to formation of AB ruig

system. 13. 16, 19.22

II: SequentiaI addition of the carbon atoms of the lactone subunit after

formation of the AB ring ~ ~ s t e r n . ~ ~ * ' ~ * "

III: Convergent couphg of the AB and C ring systems. izrs

The chiral methylbutyryl side chain is incorporated in ail cases by acylation with

comrnercially available non-racemic anhydride, or by DCC coupling with the non-

racemic carboxylic acid.

1.1.2.1 Non-Diels Alder Approaches.

Hagiwara and CO-workers have described an approach to 1 which features a

double Michael addition protocol. Enone 3 was converted to alcohol 4, which was

resolved enzyrnatically and hydrolyzed to give enone S. The lithium enolate of the

methyl ketone in 5 was added conjugately to (E)-methyl crotonate. The resulting ester

enolate was then added to the remaining enone functionality in a 1,4 fashion to give

bicyclic ketone 6 as a single diastereomer. Twenty-one steps converted this material to

aldehyde 7, which was transformed into 1 following the procedure described by Sih and

CO-workers. 13, 18

3 OEt

3 steps - a-c -

a) Lipase Amano AK, vinyl acetate, hexane. b) K2COb MeOM. c) PTSA-H20,

acetone, d) TBSCI, D W , DMF. e) LDA, -7S°C, TMSCI, THF. f) i) MeLi, TW,

-78OC, ii) M ~ o ' N ~ ~ , MeOH, reflux. g) methyl crotonate, HMPA, -78OC-> -20°C. h)

MeONa, MeOH, reflux-

Scheme 2. Hagiwara's approach to (+)-compactin.

Burke and CO-workers have described a formal approach to 1 featuring a cationic

polyene cyclization of dienylacetal 8, formed in 14 steps fiom propargyl alcohol and F-

valerolactone. The absolute stereochemistry was set by the stoichiometric

enantioselective reduction of ketone 11 with (a-BMAL-H (90% ee). The cyclization

was induced by treating 8 with TiC4, giving bicycle 9 in 70% yield and modest (3.3:l)

diastereomeric ratio. Six M e r steps converted 9 to alcohol 10, which had also been

prepared by ~eathcock, '~ thus completing the formal synthesis of 1.12

14 steps ___.__t

a) TiC14, CH2C12, -78°C.

Scheme 3. Burke's approach to (+)-compactin.

1.1.2.2 Approaches using DielsAlder Reactions to Establish Ring A.

Kozikowski and Li have descrïbed a synthesis of 1 where the routes to both the

HKN and lactone moieties feature intramolecular nitrile oxide cycloaddition reactions.

The preparation of the lactone began with a [3+2] cycloaddition between nitro acetal 13

and olefm 14. The resulting isoxazoline 15 was converted to iodide 16 in 1 1 steps. The

AB ring system was derived from racemic lactone 17,~' which was converted to

orthoester 18. Stereosefective Johnson-Claisen rearrangement furnished terminal olefin

19 as a 5:1 mixture of diastereomers, with the major isomer being converted to sulfone 20

in six steps. Formation of the dianion of this racernic sulfone and coupling with optically

active iodide 16 fknished chromatographically separable diastereomers 21a and 2 1b.

The desired isomer, t l b , was converted in four steps to oxime 22, which undenvent a

dipolar cycloaddition to complete the formation o f the AB ring system. Nine M e r

steps were required to complete the synthesis of 1.''

6 steps

TBDPS .+O M e TBDPS .+OMe

S02Ph -O

d - D

TB& . 43% + 34%

TB^ 20

1 four steps

TBDPS ,,,O M e TBDPS

a) PhNCO, Et3N, b) E~,o%F<, NaOEt, c) E-crotyl alcohol, propionic acid (cat.), d) n-BuLi (2.0 eq.), HMPA, THF, 16, e) NaOCl, Et3N.

Scheme 4. Kozikowski and Li's approach to (+)-compactin.

1.1 2.3 Approaches using Diels-Alder Reactions to Establish Ring B.

The first synthesis of 1 was reported by Sih and co-workers. An enzymatic

resolution of racemic Cz-symmetrical dione 24 (formed by a Diels-Alder reaction

between butadiene and q ~ i n o n e ) ~ ~ was employed to give di01 25 in 3 3% yield and >98%

ee. This di01 was converted to enone 26 in five steps. Conjugate addition of cuprate 27,

followed by i>î situ alkylation with formaldehyde afforded 28 in 80% yield. Nine M e r

steps converted 28 to aldehyde 30. Addition of the dianion of aceto acetate, followed by

ketone reduction gave di01 31 as a mixture of four diastereomers, f?om which two were

separated and lactonized. Separation of the resulting mixture of diastereomerk lactones

afforded 1. lg

a) Aureo basidium pulZuZans, b) i) coupling of 26 and 27, ii) CH,O, iii) MsCl, Et,N, iv) DBU, c) H,, PdK, pyridine, benzene, d) Zn(BH&, e) separate, f) TsOH, g) separate.

Scheme 5. Sih and CO-workers' approach to (+)-compactin.

Girota and Wendler at Merck have described a linear racemic synthesis of (&)-1

whereby a 23 step process converts mes0 dione 32 (prepared via a Diels-Alder reaction

between butadiene and dihydroquinone) to diastereomeric aldehydes 39a and 39b. 39a

has aiso been prepared in enantiomerically enriched form by Sih and CO-workers. The

same methods of lactone incorporation (acetoacetate aldol react iod reduction and

separation of diastereomers) employed by Sih and CO-workers were also utilized by the

Merck group to complete the synthesis of racemic 1.''

2 steps -

C& 9 steps

a) NBS, wet DMSO, b) Jones oxidation, c) 3% HCV MeOH, d) TsNHNH2, THF, e) catachol borane; NaOAc-H20.

Scheme 6. Girota and Wendler's approach to (+)-compactin.

Heathcock and CO-workers have employed a convergent approach featuring a

Diels-Mder reaction of Danishefslq's diene with (2)-ethyl crotonate to give 40, as a

single diastereomer, containing the B ring. A conjugate addition/ aldol condensation

sequence gives 42, which contains al1 the carbon atoms of the AB ring system. Five

further steps convert 42 into racemic alcohol43. Estenfication with enantiomericaiiy

ennched methyl butyric anhydride, followed by deprotection of the primary alcohol

afforded an inseparable mixture of diastereomers which were esterified with (+)-O-

methyimandelic acid which allowed for separation. Selective deprotection of the primary

ester foliowed by oxidation gave non-racemic aldehyde 44, which was coupled using a

Wittig reaction with a stabilized enolate derived from 48. Keto-phosphonate 48 was

prepared in enantiomericdly enriched fonn from 47 in five steps. Non-racemic diester

47 was formed by opening anhydride 46 with (+)-phenylethyl alcohol.

Selective reduction of the acyclic double bond of 45, desilylation, sodium

borohydride reduction of the ketone (giving a 2:l mixture of diastereomeric dcohols),

followed by lactonization of the major isomer completes the synthesis 1."

5 steps d-i __C

4 steps -

46 k

+ - AO rh LTx 5 steps L OMe - Me

47 8:1 48 OMe

a) i SO°C, b) THF, HMPA, c) HCl (aq.), MeOH, d) (S)-methylbutyric anhydride, base, e) HF-CH,CN, f ) (+)-O-methylmandelic acid, DCC, DMAP, g) separate, h) 200 mol% KOH, MeOH, i) Swem [O], j) 48, LiCl, DBU, CH3CN, k) i) Et& DMAP, -30°C, ii) CH-,.

Scheme 7. Heathcock's approach to (+)-compactin.

Clive and CO-workers have described a novel approach to both 1 and 2 whereby

the B ring is formed by a diastereoselective Diels-Alder reaction using an Evans auxiliary

to establish the absolute stereochemistry in cyclohexene 49. Seven steps converted 49 to

Iactone 51. cc-Allcylation with iodide 50, prepared in ten steps from (S)-malic acid,

afforded coupled B and C ring precursors. Six further steps afforded keto aldehyde 53,

which was converted to 54 by a modified McMurry coupling protocol developed by

Clive and CO-workers, completing construction of the A ring. Eight further steps

completed the synthesis of 1. The synthesis of 2 was completed in the same way by

incorporating the appropriate side arm in the a-alkylation of ketone 55, which is also an

intermediate formed en route from 52 to 53.16

7 steps

TBDPS

a) LDA (2 eq. per SI), THF -78"C, 1.25 hr, 50 in THF/ HMPA, 12 hours, 54%, b) CsK, TiC13, DME, slow addition of 53 (9 hours), rt+reflwc, 85%.

Scheme 8. Che's approach to (+)-compactin.

1.1 -2.4 Approaches Using Diels-Alder Reactions to Establish Bath A and B rings.

Hirama and CO-worker s have emplo y ed an intrarnolecular Diels-Alder @MD A)

approach to both (+)-compactin and (+)-mevinoh whereby triene 56, prepared in a

convergent approach fiom chiral pool substrates, serves as starting material for both

targets. Refluxing 56 in benzene for 82 hours affords octahydronaphthalene 57 in 28%

yield, dong with other diastereomers. Nine steps converts 57 to 1,'" and twelve steps

converts it to 2.'9b

PhCH2

56 OTBS

Scheme 9. Hirama and CO-workers approach to (+)-compactin and (+)-mevinoh

Funk and Zeller have reported an approach to (2)-1, similar to the IMDA

approach described above, where both rings of the HHN system are forrned via an

intramolecular Diels-Alder reaction of triene 58, available in seven steps from readily

available starting rnaterials. Four M e r steps provide sulfone 60, which was subjected

to a brominatiod elimination protocol to funiish the desired conjugated diene 61, plus

two other isomers which were removed by preparative HPLC. Formation of the dianion

of 61 followed by allqiation with epoxide 62, gives 63 which was converted to 1 in a

TBSO TBSO

4 steps - b - -

58 59 60

1) n-BuLi (2 eq.)

61

a) EtAlCi= 25OC, 72 h, b) i. B r l Et3N, CHCl3, 0' C, ii, DBU, benzene, 35' C, 3 days.

Scheme 10. Funk and Zeller's approach to (+)-compactin.

Deutsch and Snider have descnbed a formal synthesis of 1 that features a unique

IMDA reaction of enone/ vinyl allene 64, prepared in six steps fiom readily available

starting materials. The Diels-Alder reaction gives racemic 65, as a single diastereomer,

whic h was reduced with L-Selectride and ac y lated with (3-2-methy lbutyric anhydride to

give a separable mixture of diastereomers. Hydrolysis of the rnixed acetal then gave

alcohol (+)-66a, which is a common intermediate in Sih's synthesis of 1. This approach

has also been applied to complete a formal synthesis of z . ~ '

66b

a) 150°C, 2 hours, b) L-Selectride, c) (S)-2-Methylbutyric anhydride, d) AcOH,

THF, H,O

Scheme 11. Deutsch and Snider's formai synthesis of (+)-compactin.

Grieco and CO-worker's approach to 1 features a Diels-Alder reaction between

oxabicycle 67 and 13-diene 68, which sets three of the four contiguous stereocenters in

the HHN. Non-racemic 67 was prepared in two steps fiom carboxylic acid 69, which

was separated fiom its enantiorner by a classical resolution with (-)-a-phenylglycinol.

Non-racernic 68 was derived from carbohydrate sources via Corey epoxide 70,~" which

was converted to 68 in 12 steps. Diels-Alder reaction between 67 and 68 (toluene,

125OC, 14 hours, 3eq. of 68 per 67) afforded bicyclic compound 71. Five fürther steps

converted this allylic sulfide to 72 having the C7 methyl group incorporated with the

correct orientation. Reduction of the methyl ester followed by a Grob-type hgmentation

of 73 gave 74 having the second double bond of the HHN and the necessary C l hydroxyl

functionality in the correct orientation. The synthesis was completed by a four step

procedure involving acylation of the alcohol, acid mediated hydmlysis to give a lactol,

oxidation to the lactone, and cleavage of the methyl ether protecting the B-hydroxy

lactone.=

M OMe 7 OMe

a - 5 steps 0' -

SPh

68

+ 71

q C O & l e 60% O

67

+ 30%of other isomers

4 steps - 1

73 74

a) Toluene, 125 OC, 14 hours. b) L M . c) KH, toluene, reflux.

Scherne 12. Grieco and CO-workers approach to (+)-compactin.

1.1 -3 Oxygen tethered analogues of (+)-compactin.

While the preparation of oxygen tethered analogues of 1 and 2 have not been

reported, two papers on the preparation and biological activities of related compounds A

and B have appeared and present codictiag re~ults . '~~" In an earlier report, Stokker et

al. reported that the oxymethylene bridge in A had a deleterious effect on its in vitro

potency relative to an ethenyl bridged However, in a later more detailed

study, Bartmann et al. report that the effectiveness of this type of linkage was highly

dependent on the nature of the planar aromatic portion of the inhibitors. 'OC Interestingly,

many of their inhibitors, such as B, displayed disproportionately high levels of activity in

whole ce11 and in vivo assays compared to their intrinsic potency, as measure in purified

enzyme studies. For instance, B was found to be slightly superior to 2 in p d e d enzyme

assays, but was LOO times more potent whole ce11 assays, and 4-6 times more efficacious

at reducing plasma choiesterol levels in rabbits.

,W0

1.2 Diastereoselective ring closing metathesis (DSRCM) reactions.

Olefin metathesis chemistry has enjoyed tremendous growth since its inception in

the mid 1960's and has become one of the most versatile methods of carbon-carbon bond

formation.26 While the strong Lewis acidity of the f i s t generation catalysts precluded

their use in manipulating functionalized organic molecules, the development of well

defmed transition metal allcylidene complexes such as Schrock's Mo catalyst 74,27 and

Grubbs' Ru catalysts 75a and 75b28 has lead to a myriad of studies involving more

densely functionalized sub~trates?~ More recently, fùrther modifications of Grubbs' Ru

catalyst by Herrmann et al. (76),30kb Nolan et al. (77a),'OC and Grubbs et d (77b))Od have

lead to highly active catalysts which retain functional group tolerability. An exhaustive

summary of recent developments in this field is certainly beyond the scope of this thesis,

but an overview of reports pertinent to the stereo-controlled formation bicyclic

compounds via RCM reactions will be presented.

Figure 2. Well defined Olefin Metathesis Catalysts.

1.2.1 Bicycle formation via RCM .

Shortly d e r Gnibbs et al. had developed Ru carbene 75a and identifïed it as an

efficient catalyst for RCM reactions, they reported its e s t application in the preparation

of fuçed bicyclic compounds." When dieneyne cornpounds, such as 78, were treated

with catalytic amounts of 75a, smooth conversion to the desired bicyclic conjugated

dienes, such as 79, was O bserved (Sc heme 1 3).

Scheme 13. First example of RCM mediated fused bicycle formation.

Since this initial report, there have been a number of exarnples involving the use

of double RCM to form bi- and polycyclic compounds. In 1996 Gmbbs et al. published a

ring openingl ring closing sequence to convert trienes 80 to tethered furans 8 1 . ~ ~ In a

related study, Mioskowski et al. have described the preparation of sunilar compounds 83

fkom tetraenes 82.33

Scheme 14. RCM approaches to tethered oxygen hetereocycles.

The preparation of spirocycles 85 via double RCM of tetraenes 84 has been

described by Harrïty et al.34 This method has been used to prepare both carbo- and

heterocycles in good to excellent yields (Scheme 15). The formation of butenolide 87 is

noteworthy, as it is one of the few examples of RCM reactions of a$-unsaturated esters

which proceeds without the assistance of a Lewis a ~ i d . ~ '

5 mol % 75b, CH2CI2, 6 hours - - q i5 ) "

85

84 X=O, CH2, n=1,2

>90%

8 mol% 75b, CH2CI2, 40°C, 48 hours -

87 86 68%

Scheme 15. Spirocycle formation via double RCM reactions.

Clark ef al. have described an approach to polycyclic ethers 89 via double RCM

reactions of advanced intermediate tetraenes 88. Generally, best results were obtained

using Gmbbs catalyst 75b (Scherne 16).'~

20-30 mol% 75b

0-

OPMB 1 OPMB

Scheme 16. Formation of polycyclic ethers via double RCM reactions.

1.2.2 Diastereoselective ring closing metathesis (DSRCM) reactions.

The fxst example of DSRCM was disclosed in 1996 by Blechert et al. who

treated triene 90 with both 74 and 75 b.'7 In their stuclies, dihydropyroles 9 1 a and 9 1 b

were formed diastereoselectivity. Interestingly, complementary selectivities were

observed with the ~ r y z - isomer 91a being favored by a ratio of 6:l when 90 was treated

with 74, and the anti- isomer 91b being favored by a ratio of 1 1.5: 1 when treated with

75b. Unfortunately, this strategy could not be extended to the formation of six-

membered rings where complete loss of stereoselectivity was observed.

Scheme 17. DSRCM as an approach to five membered nitrogen heterocycles.

In two recent communications, Schmidt et al. have described the use of DSRCM

to f o m dihydropyrans 93a and b (Scheme lQ3' Cyclization onto one of the two

diastereotopic olefms of a tertiary doubly allylic alcohol 92 or ether 94 were examined.

The position of the existing stereocenter relative to the prochiral carbon was essential for

the induction of stereoselectivity. The a positionhg (92)38a was more effective than a y

alternative (94)?b One particularly interesting exception to this trend is observed with

96. A synergistic combination of kinetic and thermodynarnic factors gives rise to the

selective formation of spirocycle 98a over 9%. Cyclization to give five-membered rings

97a and 97b is nonselective. These two compounds interconvert quickly, and 97a

cyclizes irreversibly to 98a faster than 97b closes to give 98b. As a result, 98a was

formed preferentidly in a ratio of 7: 1.

93a R=Me, frans (OH -> H):cis = 2.5:1,66% 93b R=P h, trans (OH -> H):cis = 4.0:1,74%

94 R=H, Bn, TBS di- = -1:1,80-84%

Scheme 18. DSRCM as an approach to dihydropyrans.

DSRCM has also been employed by Hirama et al. in theù approach to the AB-

ring fragment of Ciguatoxin. Treatrnent of triene 99 with 75b gave diene 100 in excellent

yield as a single diastereomer (Scheme 191.)' This is the sole example of a DSRCM

reaction producing a seven-membered ring.

OBn

6 ~ n 100

99 95%

Scheme 19. DSRCM reaction for the formation of a seven-membered ring in the synthesis of Ciguatoxin.

1.3 Novel applications of Pd catalyzed formate reductions.

In 1979 Tsuji and CO-workers published a report on the reduction of alIylic acetates

and phenyl ethers with ammonium formate under Pd ~ a t a l ~ s i s . " ~ The conditions

originally described ( P ~ ( O A C ) ~ (1 mol%)/ PPhi (1 0 mol%) or PdCL2PPh3 (1 mol%)/

HC02N& (2 eq.)/ refluxuig dioxane) gave 1-olefm: Zolefin ratios between 9223 and

94:6 with substrates 101 and 102 (Scheme 20). With less sterically hindered substrates

105 or 106, Iower levels of selectivity (-80:20) were observed upon conversion to olefms

107 and 108.

HC02-R3NH", Pd (O) 101 L

Ligand, Solvent 1 03 1 O 4

102

X= OAc, OPh, CI

R HCO$RjNH+. Pd (O)

1 05 R d Ligand, Solvent 1 07 108

-x

Scheme 20. Palladium catalyzed formate reduction of allylic electrophiles.

Tsuji and CO-workers later reporîed a series of optimizatïons including a switch in

ligand from Wh3 to n-Bu3P, formate source fiom H C O 2 W to HCOzEt3NH, and solvent

and temperature Eorn refluxing dioxane to THF at ambient temperature? Under these

modified conditions, it was possible to form the 1-olefins fiom 101, 102, 105, and 106 in

quantitative yields as single regioisomers within the detection limits of GC analysis.

1.3.1 1,4-Dicloro-2-butene and derivatives of cis-l,4-but-2-endiol as but-1 -enyl electrophile equivalents.

In a 1988 paper, Shimizu and CO-workers reported the Pd catalyzed formate

reduction of vinyl cyclopropanes, such as 109, having two gerninal electron withdrawing

groups attached to one of the carbons a to the vinyl substituted ~arbon ."~ These vuiyl

cyclopropanes could be conveniently prepared by treatrnent of a doubly activated

methylene group with two equivalents of a base and L=-am-1,4-dichlorobutene (Scheme

21).

NaOMe (2 eq.) Pd2(dba)s (0.25 moloh) 1

O O c-~' n-Bu3P (2 mol0h) MeOH O O NH4+HCQ2-, toluene /

O°C -> reflux, 90% 1 09 90% 1 OO°C, 1 6 hours 1% O O

110

Scheme 2 1. Shimizu's approach to dimethyl butenyl maionate.

This sequence afforded products that, in theory, could be obtained by treating

deprotonated doubly activated methylenes with butenyl electrophiles such 4-bromo-l-

butene, but Shimizu's two step protocol is superior for at least two reasons. Firstly, it is

difficult to selectively monoalkylate these soft nucleophiles and low yields due to double

allcylation are often problematic. Secondly, butenyl electrophiles such as 4-bromo-l-

butene and 3-buten-1 -01 derivatives (e-g. CH2=CHCH2CH20Ts, CH2=CHCH2CH20Tf,

28

CH2=CHCH2CH20Ms, etc.) are much more expensive than 13-dichlorobutene and tend

to undergo elimination reactions under basic conditions to give butadiene.

Tsuji has also shown that the acetate/ methylcarbonate of cis-1,4-butenediol(113,

prepared in two steps f?om cis-1,4-butendiol) can function as a surrogate for butenyl

e l e c t r ~ ~ h i l e s . ~ ~ Under Pd catalysis in the presence of a suitably activated pronudeophile

111, the allylic carbonate will be activated exclusively to give allylic acetate 114. Upon

addition of triethylammonium formate, the acetate is reduced to give exclusively the

terminal o l e k 115 (Scheme 22).

R 111 Pd(O), THF, 23%

+

Scheme 22. Tsuji7s Palladium catalyzed butenylation strategy.

W l e this procedure appears to be superior to that described by Shimizu in that it

replaces a two-pot procedure with a one-pot procedure, the potential for double

butenylation still exists when R=H. Additionally, two steps are required to prepare t h i s

particular butenyl electrophile equivalent, where as 1,4-dichloro-2-butene is

cornmercially available. Finally, to the best of my knowledge, neither of these

procedures has been successfully employed for the butenylation of harder nucleophiles

such as ketone enolates, ester enolates, or tosyl amides.

1 3.2 B,y-Unsaturated aldehydes in organic synthesis.

The use of P,y-unsaturated aldehydes in organic synthesis is often hampered by their

instability with respect to isomerization to the thermodynamically

unsaturated isomer (Scheme 23).

preferred a$-

Sc heme 23. Isomerization of P,y-unsaturated aldehydes.

As a result of these dificulties, rather elaborate alternatives are often employed

when a synthetic strategy calls for the use of these aldehydes. One such exarnple is

illustrated below in mode1 studies for the synthesis of the natural product (+)-Laurencin

conducted by Crimrnins et al. 4-tertButyldiphenylsiloxybutand (116) is subjected to

nucleophilic attack followed by protection of the resulting secondary dcohol to give 117.

Deprotection of the prirnary alco hol, fol10 wed by selenation, oxidation and elirnination

furnishes the desired product 118 (Scheme 24)."

Scheme 24. Application of 4-tert-butyldiphenylsiloxybutanal as a synthetic equivalent to 3-butenal.

1.3.2.1 Synthesis and applications of 3-butenal. The simplest exarnple of a P,y-unsaturated aldehyde, 3-butenal, has proven difficult

to prepare due to its instabitity and volatility. This might offer one explanation for its

limited use in organic synthesis. Crimrnins et al. have recently described an improved

two-step synthesis outlùied in Scheme 2 ~ . ~ ~ Double allylation of glyoxal with allyl

bromide and tin, followed by Nal04 cleavage of di01 119 in a buffered media gave good

yields of the desired aldehyde as a solution in CHz& which must either be used

immediately, or stored at low temperatures.

+Br Na104

+ Sn, H20, THF H CH2CI2, H20

ultrasound OH pH 4 Buffer

= L 119

H

Scheme 25. Crimmins' preparation of 3-butenal.

There have been a few exarnples of aldol reactions using 3-butenal. The first was

reported by Paquette et al. in 1997 in an acetate aldol reaction with the tin enolate of

thiazolidinethione 120 (Scheme 26).46 The yield and diastereoselectivity of 121 was high

(92%, dr=9:1), though the authors do not comment in this communication on how many

equivalents of the aldehyde were required to achieve these yields.

Scheme 26. The use of 3-butenal in an auxiliary controlled acetate aldol reaction,

Crimx-nins has also ernployed 3-butenal in auxiliary controlled aikoxy acetate aldol

reactions. In these examples, 5-fold excesses of 3-butenal were employed giving yields

of 27 and 65% for 123a and 123b respectively, with better yields being realized based on

recovered starting materials (Scheme ZQO4'

A ! ? 1) TiCk, iPqNEt 3 C r XC

OR CH2CI2, -78OC OR Bn 123a X=S 27% (90 % brsm)

2) 3-Butenal (5 eq.) 123b x=O 65%

Scheme 27. Alkoxy acetate aldol reactions involving 3-butenal.

1 -3.2.2 Aldol reactions involving âmethyf-3-butenal. In contrast to 3-butenal, 2-methyl-3-butenal has not been employed in

synthetically useful transformations, but has been studied to illustrate pnnciples in

stereocontrol. Roush has shown that moderate "Felkin selectivity" (3:l) is obtained in

the reaction of 2-methyl-3-butenal with lithium enolates of ethyl ketone 124 (Scheme

ZQ4* Bloch et al. have also obsenred similar results (4:l Fellcin selectivity) with the

lithium enolate of 126.~'

Scheme 28. Aldol reactions involving 2-methyl-3-butenal.

To the best of m y knowledge, there are no examples of aldol reactions using

enantiomerically enriched 2-methyl-3-butenal. Indeed, were it possible to prepare such

material, the fow levels of Felkin selectivity would limit the appeal of such a

transformation.

1.3.2.3 Acyclic diastereoselective x-allyl transition metal mediated react ions.

While there have been numerous examples of additions to carbonyls in acyclic

compounds where the facial selectivity of the addition is controlled by stereocenters

elsewhere in the molecule, usually at the a or P positions, analogous additions to C=C

double bonds are not nearly as prevalent. To the best of my knowledge, there are no

examples of facially selective additions to an q 3 - ~ ~ (TM=transition metal) being

controlled by a neighboring stereocenter in an acyclic compound, either under catalytic or

stoichiometric conditions. The set of transformations having the strongest relevance with

regard to the diastereoselective Pd catalyzed hydride delivery to allylic electrophiles is

probably described by Nakamura et al. in a series of papers published in the late 1980's

and early 1990's. These studies involved the stoichiometric and catalytic

diastereoselective addition of either organocopperSO or organozincS1 species to allylic

chlorides such as 128 and 130 to gave anti- addition products 129 and 131 (Scheme 29).

hexane/ THF, -70°C

= (y- / Bu

Bu2Zn-2LiC1, HMPA + 87%, ant isy~ = 89:ll

THF/ hexanes

Bu2CuLi/ZnC12 C

hexanel THF, -70°C Bu 130 131

98%, antksyn =>99:1 Scheme 29. Diastereoselective addition of organocopper and organozhc species to allylic chlorides.

In the copper mediated reactions, the addition of ZnClz was essential in order to

suppress the formation of products resulting from a SN2 rather than SN2' pathway.5'

Other similar additives such as Ti(OiPr)4 or BF3+Et20 also gave good SN2' selectivity.

Reactions using catalytic Cu also gave good regio- and diastereoselectivities, though with

lower yields. The use of allylic chlondes was also found to be important as brornides

give poor regioselectivity. With the R2Zd HMPA systems, phosphates were also shown

to be suitable leaving groups.

While this system probably does not involve a TI-allyl copper or ic-allyl zinc

intermediate, (for a discussion of the reaction mechanism, see reference 50b) the fact that

the same sense of facial attack is observed in our Pd catalyzed hydride delivery systems

(see Section 4.2.2) is noteworthy-

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2 Studies towards the total synthesis of (+)-compactin.

2.1 Retrasynthetic analysis. Our retrosynthetic analysis of 1 is outlined in Scheme 1. We intended to use a

convergent approach whereby the HHN and lactone fragments wouId be combined in the

late stages of the synthesis. Of the variety of possible coupling strategies that could be

employed, nucleophilic attack of an organometdlic compound A at the terminal carbon

of epoxide B seemed reasonable.

Scherne 1. Retrosynthetic analysis of (+)-compactin.

We hoped to displace the sulfate found in C with a nucleophile that could be

converted to a suitable anionic precursor. Ring closing metathesis of triene C would

furnish the second ring of the HHN moiety. Formation of a homoallylic alcohol would

be achieved by a stereoselective crotylation of aldehyde D, whose 1,3 diene fûnctionality

would be introduced by Wittig olefmation of an a$-unsaturated aldehyde. This

aldehyde could be produced by oxidation of homoallylic dcohol E under conditions that

would give nse to double bond isomerization.

A suitable precursor for these transformations could be arrived at by protecting

group manipulations of non-racemic cyclo hexenol 133. The catalytic enantioselective

reductive ring openhg of meso oxabicycle 132, developed by Lautens and Rovis, would

a o r d convenient access to 133 in enantiomerically enriched form.'

We hoped to prepare epoxide B by manipulation of the product of an aldol

reaction between an enolate and aidehyde F . ~

2.2 Optimization of reductive ring opening.

In previous investigations, the catalytic enantioselective preparation of

cyclohexenol 133 \vas described.' Though excellent yields and enantiomeric excesses

were realized, rather liberal catalyst loadings (14 mol% Ni(COD)2, and 21 mol% (R)-

BMAP) were employed. We were pleased to find that it was possible to lower the

catalyst loading to 2 mol% Ni(COD)2, and 3.5 mol% @)-BINAP without deleteriously

af5ecting the enantiomenc excess or chernical yields (Table 1, entries 14). Lowering the

catalyst Ioadings below 2 mol% did give rise to lower ee's (entries 5-8). This reaction

has been performed on scales as large as 20g of 132 using 2 mol% Ni(COD)î and 3.5

mol% R-BINAP (entry 4)-

DIBAL (1 .O5 eq.) (s€ow addn-) G"-'

Ni(COD)2, (RI-BINAP (1 -5 eql N i Toluene, 2S°C

133

2.3 Hydroxyl differen fia tion.

Table 1. Effect of catalyst loadings.

2.3.1 First generation approach.

The next synthetic challenge involved dserentiating between the three oxygen

Entry

1 2 3

atoms of 133. We initially hoped to form 134 having a six-rnembered acetal between 01

Rx Time

1 12 12

Mol % Ni 14 10 5

and 02, with 0 3 being available for conversion to a 1,3 diene by an oxidatiod

isomerizatiod Wittig olefination sequence. We then expected that a Lewis acidi hydride

Yield (%) 95 96 97

combination would selectively Liberate the Iess hindered oxygen of the acetal system in

135,~ allowing for distinction between oxygen atoms 01 and 0 2 (Scheme 2).

Ee (%)

97 96 96

[O], Base - Wittig

I

Lewis Acia/

Scheme 2. First Generation Differentiation Strategy.

2.3.1.1 Approaches to six-membered acetals.

We examined four different approaches to a suitable acetal (Scheme 3). We first

treated 133 with two equivaients of DDQ (Method A), hoping to form a dicationic

species 137 (Figure 1). The secondary alcohol would cyclize preferentially onto the

proximal oxocarbenium ion to give six membered acetal 138; and hydrolysis of the

remauiing oxocarbenium ion on workup would liberate the desired prirnary dcohol 139.

This transformation was cornplicated by the formation of significant quantities of

orthoester 140. The yields of 139 were highly variable, tending to decrease substantially

DDQ (2.1 eq.) 133 c

OH- -

Figure 1. Mechanism of acetal formation.

Complete hydrolysis of both of PMB ethers could be accomplished by DDQ

oxidation under acidic conditions (Scheme 3, Method 8). Although the isolation of the

resulting triol was prevented by its water solubility, two equivalents of p-anisaldehyde

are produced during hydrolysis, and azeotropic rernoval of water and acetic acid afforded

139, albeit in rnodest to good yieid.

Method A apMB PMB

Method B

DDQ (2.1 eq.) - anhydrous solvent

1) DDQ (2.1 eq.)

DlBAL - Ni(O), L*

DlBAL QH 1) NaH, PMBBr, 75%

Methad D kgp NiCo), L* - 139 P 2) -P(O-90%)

145 146

3) DDQ (1 -05 eq.) 85%

Scheme 3. Approaches to six-membered acetal.

A third strategy (Method C ) was exarnined involving reductive ring opening of

oxabicycles 142 having a seven-membered acetal or ketal. Acid catalyzed rearrangement

of the ring opened products 143, gave the six-membered acetai 144 when either R or R'

was a hydrogen. There is a strong thermodynamic preference for 143 vs. 144 when both

R and R' are alkyl substituents. This is presumably due to severe 1,3 diaxial interactions

present in the six-membered acetals of these systems, which are avoided in the seven-

membered ketals.' Unfortunately, the reductive ring opening reactions of both the acetals

and ketals gave significantly lower ee's (<go%) than their ethereal counterparts.

Our fourth strategy (Method D) involved reductive ring opening of oxabicycles

145, having protecting groups which could be removed in the presence of a PMI3 ether.

The secondary alcohol146 produced in the ring opening reaction could then be protected

as a PMI3 ether. Deprotection of the primary alcohols and treatrnent with 1 eq. of DDQ

then dlowed for a cleaner conversion to 139. Of d l the protecting groups examined

(P=MOM, Tr, TBS, t-Bu, TIPS), the TIPS ethers seemed most promising. The Tr and

TBS groups were partially cleaved during DIBAL ring opening, and the acidic conditions

required for cleaving t-Bu and MOM ethers also removed the secondary PME3 protecting

group. Ultimately, even the TIPS substrate would prove unsuitable as dropping the

catalyst loading below 10 mol% Ni resulted in ee's of <8S%.

2.3.1.2 Differentiation between acetal oxygens.

Oxidation of homoallylic alcohol 139 under Swern conditions, followed by Wittig

olefination proceeded smoothIy to give conjugated diene 147b. Attempts to distinguish

between the two oxygen atoms of the six-membered acetal in 147b proved to be very

difficult. Of a mynad of conditions available for the selective liberation of the prirnary

alcohol148, the use of TMSCl and NaCNBH3 was the most effective, giving a 99% yield

of a 2: 1 mixture of primary alcohol 148 and secondary alcohol 1 4 9 . ~ ~ In fact, the use of

SnCb and Et3 SX, which has also been reported to selectively liberate primary a lcoho~s ,~~

gave 149 preferentially (4:l) in 80% yield. A four step deprotection, protection,

protection, deprotection approach could also be employed, but the overall yield of 148

was approximately the same as that realized by the one step TMSCV NaCNBH3 approach

(Scheme 4).

NaCNBH3 CH3CN, -45%

PMP 3

95%, 148:149 = 2:1 SnCI4

- 1) Swem -> 147a +

139 Et3SiH 80%, 148:149 = 1 :4

90% 2) Witiig 85% CH2C12,-780C

- 148 62%, four steps 2) TBDPSCV Base 3) NaH, PMBBr 4) TBAF

Scheme 4. Reductive Cleavage of Acetd.

2.3.2 Second generation approach.

Through a serendipitous tum of events, we discovered that it is possible to

selectively remove either of the two primary p-methoxybenzyl ethers of 133 by treatment

with iodotrirnethylsilane (Scheme 5). When freshly distilled TMSI was added to an

anhydrous solution o f 133 and 2,6 lutidine (1.05 eq.) in CHzClz at O°C, di01 150 was

isolated in 62-80% yield as a separable 4-10:l mixture of regioisomers. This initial

discovery was surprising, considering that both ethers should exist in essentially the same

steric environment. Furthermore, when 3.6 eq. of TMSI was added to a -78°C solution of

133 in wet CH2Clr, the opposite regioisomer 151 was isolated in 90% yield as a single

isomer.

TMSl (2.5 eq.) TMSl (3.6 eq.) 133 b

63-80% 4 -1 0:1 mixture of regioisomers

- 151 triturate for 2 days

c 151 pyridine, DMAP, CH2CI2 -> 152a

94% ee in 30% etherl hexanes 88% 2) TBSOTf 99% ee 2,6 lutidine ->152b

3) DDQ , CH2C12, H20

IW ~ P M B 90% single regioisomer

152c AH 92% (3 steps)

Scheme 5. Dserentiation between the oxygen atoms of 133.

While it is tempting to attribute this switch in regioselectivity to Bronstead acid

(HI) mediated PMI3 cleavage versus a Lewis acid (TMSI) pathway,3b7d this explmation is

inconsistent with a nurnber of observations. When the cleavage is attempted simply by

adding aqueous HI to a solution of 133, the reaction is nonselective. In addition, lower

quality (partially hydrolyzed) TMSI also gives lower levels of selectivity in both reaction

protocols. The most important factor in determinhg the sense of regioselectivily appears

to be temperature. Even under anhydrous conditions in the presence of 2,6-lutidine, the

addition of TMSI to a -78°C CHzCl2 solution of 133 gives 151 preferentially, though in

lower yields than observed in the absence of base and presence of water.

While it should be possible to pefiorm the necessary transformations on either

diol, we elected to proceed with 151 for a number of reasons. Firstly, it is easier to

introduce water than it is to rigorously exclude it. The yield and level of regioselectivity

is higher in fomùng 151, and this di01 is a solid, whereas 150 is an oïl. It was possible to

enrich the enantiomeric excess of 151 simply by suspending it in a 50% (v/v) mixture of

ether/ hexanes and stimng vigorously for 3 days- Eighty-eight percent of the material

was recovered, having an ee of 99% versus 94% in the starting material. It was also

possible to enrich material of lower ee (70%) to 99% ee with prolonged stirrîng.

Selective protection of the primary dcohol as a pivalate 152a, followed by

silylation of the secondary alcohol and oxidative deprotection of the PMB ether 152b

gave primary alcohol 152c in 92% yield over three steps.

This approach dlows for differentiation between al1 three oxygen atoms in a

selective and efficient manner and we tumed o u attention to the completion of the HHnr

moiety .

2.4 Attempts to complete of the synthesis of the HtiN moiety.

Homo allylic alcohol 152c was subjected to Swem oxidation conditions, which

afforded a$-unsaturated aldehyde 153 in 77% yield. This product arises fkom

isomerization of P,y-unsaturated aldehyde 154 which was isolated in 4% yield along with

5% recovered starting material. Wittig olefination of this aldehyde furnished 1,3-diene

155 in 96% yield. Reductive cleavage of the pivalate followed by Dess-Martin

periodinane oxidation furnished the desired aldehyde 156b in 86% yield over two steps

(Scheme 6).6

1) (CICO);! (1 -2 eq.) T B J P i v T B 3 P i v 1 5 2 ~ -

DMSO (1 -7 eq.) qH + qH + 5% recavered SM CH2CI2, -78OC, 2 min.

2) iPr2NEt (5 eq.) 153 0 O

-78OC, 10 min., -60°C, 1 hr. 77% 4 O h

TBSg ?Pi, 1)DlBAL(2eq-) TBSQ M ~ P ~ ~ P * B ~ - (1 -2 eq.) f CH2CI2, -78OC

n-BuLi (1 -1 eq.), THF

O°C-> 23OC, 2 hr-

*

45rnin-,->156a

2) Dess-Marün 96% 86% (2 steps)

Periodinane ( 3 -7 eq.)

Scheme 6. Preparation of CrotyIation Precursor.

The next challenge to be addressed was the stereoselective crotylation of

cyclohexenyl carboxaldehyde 156b.' While our primary intention was the construction

of 1 v i a an intermediate resulting fiom syn- crotylatiorn of the re- face o f 156 b

(compound A, Figure 2), it occurred to us that a similar strategy might allow for

convenient preparation of oxy analogues of compactin. This secondary goal called for an

anti- crotylation of the si-face (compound B, Figure 2).

A R=OH, R'=H(re/syn) 6 R = HI R' = OH (su anti)

Figure 2. Homoallylic alcohol targets for the preparatiom of compactin and oxy- compac th.

A retrosynthetic approach to oxy-compactin 157 is outlined in Scheme 7. The

coupling of 158 and 159 would be affected by nucleophilic displacernent o f X' by

homoallylic aikoxide 159. The conjugated diene and homoallylic alkoxy portions of 159

could be formed in processes analogous to those described for the preparation of 1 in

Schemes 1,5, and 6 .

Scheme 7. Retrosynthetic approach to oxy-compactin.

In order to assess the viability of achieving both of the re-/ syn- and si-/ anti-

reaction pathways, aldehydes 161 and 165 were prepared, in addition to 156b, as outlined

h Scheme 8.

96%, 160 2) Dess Martin, 99%

1) TBDPSCI, Et3N

DMAP, CH2CI2, 162 2) MOMCI, iPr2NEt, 70%, 163 3) DDQ, H20/ CH2CI2, 94%, 164 4) Dess-Martin, 75%.

150 OH *

165 OTBDPS

Scheme 8. Preparation of cyclohexencarboxaldehydes for crotylation studies.

The aldehydes were treated with the (E)- and (2)- isomers of the potassium

crotyltrifluoroborate reagents recently developed in the Batey laboratories (Schemes 9

and 10).~ We were pleased to fmd that the first substrate/ crotylating agent combination

to be investigated, aldehyde 156b and (2)-crotylborate, afforded syn- crotylation

products, re-166 and si-166, with good levels of re selectivity (re : si = 11:l). This

satisfies the requirements of our strategy for the formation of 1. Reacting the same

substrate with (E)-crotylborate gave the anti- crotylation products re-167 and si-167 with

moderate re- selectivïiy (re : si = 2.7:l).

TBSO

-BF~K 156b -

TBAl (1 O mol%)

H20, CH2CI2, 23 OC

90% re: si= 11:1

-BF3K TBSg QH TBSQ

1566 c

/ TBAl (1 0 mol%) H20/ CH2CI2 re-167 si-1 67

81% re: si= 2.7 : 1

Scheme 9. Diastereoselective additions to cyclohexene carboxaldehydes having an sp2 hybndized carbon atom at the B-position.

Interestingly, when aldehyde 16 1 was treated with (2)-crotylborate, anti-

crotylation products si-168 and re-168 are now formed with selective addition to the si-

face (si : re = 11:l). When the same substrate was treated with (E)-crotylborate, a

reversal in facial selectivity was observed so that re-169 is now favored over si-169 by a

ratio of 2 1 . Attempts to reverse the sense of facial selectivity for anti- crotylation

processes by altering the size of the hydroxyl protecting groups, as in substrate 165,

failed. As such, our secondary goal of preparing an oxy analogue of compactin which

retains the correct relative stereochemistry remains illusive.

88% si: re= 1l:l

I re-168 OPMB

-BF3K MOMQ

165 TBAI (1 0 mol%) t MO* \ e - - \ \

Hfl, CH2CI2, -lO°C re-170 OTBDPS si-170 OTBDPS

Scheme 10. Diastereoselective additions to cyclohexene carboxaldehydes having an sp2 hybridized carbon atom at the y-position.

The observation of good re- facial selectivity in forming homoallylic alcohol 166

can be rationalized using models previously described by Roush to explain the facial

selectivity in the addition of boron enolates to aldehydes having an a-stere~center.~

Assuming that the crotylation proceeds through a six-membered cyclic transition state,

the vinylic methyl substituent of the reagent wil1 be oriented pseudo-axially (Scheme 11).

In order to minimize 1,3-diaxial interactions, the smallest a-substituent (H) is also

oriented pseudo-axially. Two diastereomeric transition States, TS-A and TS-B, are then

plausible. In TS-A, the a-substituent having an sp3 hybridized carbon center is presented

towards the vinylic proton of the crotylating reagent. It could be expected that this would

give rise to less severe steric interactions than are present in TS-B, where the a-

substituent having an sp2 hybridized carbon center is directed towards the crotylating

reagent. As a result, the vinyl group will interact with the vinylic hydrogen atom of the

crotylating reagent. At this point it is difficult to construct reasonable models to explain

the stereoselectivity observed with the other substrate/ reagent combinations and further

experiments may be necessary to resolve this issue.

TÇA TSB

fa voured dis fa voured

Scheme 1 1. RationdiMg the stereoselectivity observed in the syn-crotylation of 156 b .

The relative stereochemistry of re-166 and si-166 was established by treating re-

166 and 171 (formed by desilylation of si-166) with 77b to give HHN products 172 and

173 respectively (Scheme 12).1° Energy rninimization studies clearly show that the

hydrogen atom at C8 of 172 will be pseudo-equatorial and therefore shodd show small

coupling with the hydrogens at either Cl0 or C7. The 'H NMR spectra shows this proton

to be a broad singlet. By contrast, energy minirnization studies show that the hydrogen

atom on C8 of 173 is pseudo-axial, as are the hydrogen atoms on CIO and C7. As would

be expected, the 'H NMR spectnim shows this proton to be a triplet with a coupling

constant of 20 Hz.

77b (1 moi%) re-166

CH2CIL rt, 1 hour - TB& / / 172

Scheme 12. Proof of stereochemistry of 166.

The stereochemistry obtained when crotyIatïng 161 and 165 was established as

outlined in Scheme 13. Oxidative removal of the PME3 ether from si-168 gave di01 174,

which could also be obtained by reductive cleavage of the pivalate 175, a crystalline solid

whose structure was established by X-ray crystallography. The relative stereochemistry

of re-169 was established by Dess-Martin periodinane oxidation of this product and si-

168, which gave the sarne ketone 176- The relative stereochemistry of re-170 was

established by X-ray crystallography.

DDQ DI BAL si-168 - -

Scheme 13. Proof of stereochemistry of si-168 and re-169.

The next objective to be met was the activation of the secondary homoallylic

alcohol re-166 as a sulfate, followed by displacement with a suitable carbon nucteophile.

In order to activate the secondary alcohol for SN^ displacement, various conditions were

uivestigated to prepare a variety of sulfates. Attempts to form a rnesylate under

commonly employed conditions failed to produce more than 10% of the desired sulfate,

and more forcing conditions gave rise to decomposition of the starting material.

Deprotonation of re-166 with n-BuLi followed by the addition of fkeshiy re-crystallized

toluenesulfonyl chlonde gave 30% of the desire sulfate, atong with 50% recovered

starting material. The use of p-nitrophenylsulfonyl chloride aEorded much better yields

of sulfate 177 (72%, 92% based on recovered starting material), but treating this substrate

with cyanide only gave rise to unidentified byproducts, presumably arising from

nucleophilic aromatic substitution.

The most promising sulfate investigated was derived from chloromethanesuIfony1

chloride. l 1 As shown in Scheme 14, the formation of the chloromesylate 178 was facile

compared to the non-chlorinated analogue, going to completion in two hours under mild

conditions. Unfortunately, al1 attempts to install the requisite carbon atom by

displacement with cyanide gave rise to elimination products 179 and 180.

TBSQ QNs

THF, -78OC y ' 21 NsCI. 1 hr- 177

KCN, 18-crown-6 - 4

NMP, 70°C, 2 hr.

20% recovered r d 6 6

TBSQ QMcI CICH2S02CI Et4NCN

re-166 .) -

pyridine, O°C DMSO, 70°C

(10O0h, crude 'H NMR)

decomposition

TBSO -

TBSQ -

Scheme 14. Activation and attempted displacement of the secondary homodlylic dcohol,

In light of these dificulties, alternative strategies are under investigation by an

incorning researc her.

2.5 Experimental.

IR, SR, 6R-5,6-Bis-(4-metholry-benzyloxymethyl)-cycIohex-3-enoI (133)

A solution of Ni(C0D)z (0.282 g, 1.03 m o l ) in toluene (15 mL) was added to a 200 mL

flask containing (R)-BINAP (1 -12 g, 1.79 mmol) and stirred under a positive nitrogen

pressure for 2.5 hours to give a deep burgundy solution. A solution of oxabicycle 132

(20.0 g, 50.4 mmol) in toluene (50 mL) was added via cannda to give a brown/ green

solution. A 1.0 M solution of DIBAL (53 mL, 53 mrnol) in heptane was added via

syringe pump over 18 hours. The reaction was quenched by carefhl dropwise addition of

10% hydrochionc acid after cooling in an ice bath. The aqueous layer was extracted five

tirnes with ethyl acetate. The organic layers were cornbined, washed with brine, dried

over MgS04, filtered and concentrated to dryness. The residue was purified by flash

chromatography (30% ethyl acetate/ Hexanes) to yield the title compound as a colorless

oil(19.9 g, 99%)-

4aS,SR,SaS- [2-(4-~~ethoxy-phenyI)-4a,5,8,8a-tetrahydro-beol,3] dioxin-5-YI]-

methanoI(139).

DDQ (123 mg, 0.542 mmol) was added to a -5°C solution of 133 (100 mg, 0.252 m o l )

in acetonitrile (2.5 mL). After 30 minutes, the solution was warmed to 23OC for a M e r

90 minutes. The mixture was partitioned between 1N sodium hydroxide and ethyl

acetate. The aqueous layer was extracted three times with ethyl acetate, the organic

layers were combined, washed with brine, dned over MgSOa, fltered and concentrated to

m e s s . The residue was purified by flash chromatography (35 % ethyl acetate/ hexanes)

on triethylarnine washed silica gel to produce the title compound as a white solid as a 5: 1

mixture of diastereomers (50.4 mg, 73%) dong with orthoester 140 (7 mg, 10%).

Major Diastereomer: rnp=72-74°C (etherl hexanes); a ~ = -75.6 (10.2 mg/ mL CHC13, 10

cm); 'H NMR (400 MHz, CDC13) 6 1.87 (dt, J=6,3 Hz, lH), 2.32 (ABX, dd, J=19,

1.5Hz, IH), 2.52-2.60 (m, lH), 2.59 (ABX, dq, J=19, lH), 3.72 (dd, J=7, 7 Hz, lm, 3.79

(s, 3H), 3.83 (ABXy ddd J= 15, 6.5, 3.5 HZ, lH), 3.93 (ABX, ddd, J= 15, 7, 7 HZ, lH),

4.17 (ABX, dd, J= 12,3 Hz, lH), 4.31 (dd,J= 7,2 Hz, lm, 4.40 (AB, d, J= 12 k, 1H),

5.60 (s, lH), 5.68-5.77 (m, 2H), 6.88 (AB, d, J= 9 Hz, 2H), 7.41 (AB, d, J= 9 Hz, 2H);

I3c NMR (100 MHz, CDCb) 6 30.89, 33-96, 39-30? 55-23, 63-35? 70.22, 74-55, 102.43,

1 13.73, 124.75, 126.85, 127.32, 130.17, 160.05; IR (neat, cm-') 3460, 3055, 2987, 1615,

15 18, 1422, 1266, 738; HRMS: Calculated for C16~1s04+ (M-FI)+: 275-1283, Found:

275-1284.

l-(4-~ethox~-~hen~l)-2,11,12-triona-~c10[6.3.1.0(~~~~dodec-5-ene (140). 'H NMR

(400 MHz, CDCh) 8 2.33 (ABX, ddq, J= 17,9,3 Hz, lH), 2.46 (ABX, dt, J= 17, 5 Hz,

lK), 2.89-3.06 (m, 2H), 3.69 (ABX, dd,J= 8, 3 Hz, IH), 3.85 (s, 3H), 3.88 (dd,J=8, 6

H z , lH), 3-96 (quÏnt., J= 8 Hz, LH), 5.45 (dt, J = 8-5, 5.5 Hz, lH), 5.62 (AB, d, J=10 Hz,

lH), 5.71 (ABX, ddt, J=10, 5: 2.5 Hz, IH), 6.91 (AB, d,J= 9 Hz, 2H), 7.92 (AB, 8: J= 9

Hz, 2H); 13c NMR (1 00 MHz, CDC13) 6 26.09, 40.37,40.74, 55.39, 67.83,70.0 1, 73.06,

113.56, 122.59, 124.59, 124.24, 128.00, 131.53, 163.34, 165.65-

4aS,8aS-2-(4-Methoxy-phenyl)-4a,7,8,8a-tetrahydro-4H-benzo[1,3]dioxine-S-

carbaldehyde (147a).

DMSO (1.175 mL, 16.5 mmol) was added to a -78°C solution of oxdylchloride (0.834

mL, 9.55 mmol) in CHzC12 (50 mL). Afier 10 minutes, a solution of 139 (1.76 g, 6.37

mmol) in CH2C12 (12 mL) was added via cannula. After 45 minutes, triethylamine (8.87

mL, 63.7 mL) was added and the reaction mixture was warmed to 23°C for 72 hours.

The mixture was diluted with CHzC12, and washed with saturated Na2CO3. The aqueous

layer was extracted three times with CH2Ch, the organic layers were combined, washed

with brine, filtered through Cotton and concentrated to dryness. The residue was purified

by flash chromatography (20% diethyl ether/ hexanes) on triethylamine washed silica gel

to yield the title compound as a white solid (1 -605 g, 92%). mp=102-103°C (ether /

hexanes); a ~ = +130.3 (10.6 mg/ mL CHCL, 10 cm); 'H NMR (400 MHz, CDC4) 6 1.58

(tdd, J= 13, 6, 1.5 H k , lH), 2.15 (df J= 13.5, 5 HZ, lH), 2.33 (dt, J=20, 6 Hz, lH), 2.4-

2.47 (m, lH), 2.65-2.78 (m, lH), 3.77 (s, 3H), 4.04 (dd, J= 12, 3 Hz, lH), 4.32-4.39 (m,

lH), 4.94 (d, J= 12 HZ, lH), 5.51 (s, lH), 6.85 (AB, d, J=9Hz, 2H), 7.03-7.08 (m, lH),

7.33 (AB, d, J=9 Hz, 219, 9.58 (s, 1H); 13c NMR (100 MHz, CDC13) 6 22.20, 26.93,

33.02, 55.28, 67.66, 71.98, 100.01, 100.65, 113.54, 127-34, 131.13, 139.13, 154.59,

159.88, 194.34; IR (neat, cm") 2931, 1683, 1578, 1516, 1394, 1303, 1250, 1 169, 1 118,

1028,909,830; HRMS: Calculated for c&I~o~+ (M-Q+: 273.1 128, Foud: 273.1 132.

4aS,8ali-2-(4-Metho~y-phenyl)-5-vinyl-4a,7,8,8a-te~ahydro4H-bemo [1,3] dioxine

(147b).

KHMDS (10.9 mL, 5.47 mmol) was added to a 0°C suspension of Ph3PCHsBr (2.12g,

5.92 mmol) in THF (18 mL). After 45 minutes, the mixture was cooled to -78°C and a

solution of 147a (1.25g, 4.56 mmol) in THF (4 mL) was added via cannula. The mixture

was warmed to 0°C and allowed to stir for 12 hours, wanning to 23°C. The mixture was

partitioned between diethylether and saturated NaHC03. The aqueous layer was

extracted thee times with ether, the organic layers were combined, washed with brine,

dried over MgS04, filtered and concentrated to dryness. The residue was purified by

flash chromatography (1 0% ethyl acetate/ hexanes) on eiethylamine washed silica gel to

give the title compound as a white solid (1.05 g, 85%). mp=88-90°C (ether / pentane);

a ~ = 72.9 (9.6 mg/ mL CHCL,, 10 cm); 'H NMR (400 MHz, CDCl,) 6 1.53-1.63(m7 lH),

1.99-2.11 (m, 2H), 2.39 (bs, IH), 2.46-2.58 (m, lH), 3.78 (s, 3H), 4.03 (ABX, dd, J=12,

4 Hz, lH), 4.37-4.41 (m, lH), 4.68 (AB, d, J= 12, lH), 5.01 (d, J= 12 HZ, lH), 5.01 (d,

J= 17 Hz, 1H), 5.53 (s, lH), 6.04 (d,J=6 Hz, 1H); 6.36 (dd, J= 17, 12 Hz, lH), 6.86 (AB,

d, J= 9 Hz, 2H), 7.37 (AB, d, J= 9Hz, 1H); "C NMR (1 00 MHz, CDC13) 6 2 1-04, 27.69,

34.20, 55.26, 68.30, 72.66, 100.47, 111.58, 123.54, 127.54, 130.67, 131.51, 134.23,

138.16, 159.90; IR (neat, cm") 3032, 2872, 1616, 1518, 1460, 1395, 1303, 1249, 1172,

1221, 1034, 905; HRMS: Calculated for ~ 1 7 ~ 2 0 0 3 ~ (M-H)~: 272-1412, Found: 272.1415.

Reductive Acetal cleavage to give alcohols 148 and 149.

NaCNBH3 (1.36 g, 2 1.6 mmol) and molecular sieves (500 mg) were added to a 23°C

solution of 147b (880 mg, 3.23 mmol) in CH3CN (1 0 ml;). The resulting mixture was

cooled to -50°C and TMSCI (2.74 mL, 21.6 mmol) was added. The mixture was stirred

for 30 minutes before methanol(5 mt) was added and the mixture \vas dlowed to wann

to 23°C. The mixture was diIuteci with CH2C12, filtered through celite and concentrated

to dryness. The residue was purified by flash chromatography (10+15% ethyl acetate/

hexanes) to yield the title compounds as colorless oils in a 2:l (148 : 149) ratio (842 mg,

95%)

148. R~0.25 (10% ethyl acetate hexanes); 'H N M R (400 ME3z, CDCl,) 6 1.79-1 -91 (m,

lH), 1.99-2.07 (m, lH), 2.1 1-2.24 (m, lH), 2.31 (ABX, dt, J= 10,6 Hz, LH), 3.49 (AB, d,

J= 1 lHz, lH), 3.66 (td, J= 11 Hz, 2 Hz, lH), 3.80 (s, 3H), 3.80-3.91 (m, 2H), 4.52 (AB,

d, J= 11 HZ, IH),4-62(AE3,d,J=ll HZ, IH),

149. R ~ 0 . 2 0 'H NMR (400 MHz, CDC13) 6 1.68-1 -78 (m, lH), 1.86-1 -94 (m, LH), 2.19-

2.30 (m, 2H), 3.62-3.71 (m, 2H), 3.81 (s, 3H), 3.90-3.98 (m, lH), 4.02 (AB, d, J=7 Hz,

lH), 4.43 (AB, d, J=11.4 Hz, ZH), 4.57 (AB, d, J 4 1 . 4 Hz, lH), 6.88 (AB, d, J= 9 Hz,

ZH), 7.24 (-AB, d, J=9 Hz, 2H)

IS, SR, 6R-5-Hydro~ymethyl-6-(4-methoxy-be~loethy1)-cyc1ohex-3-enol(150)~

Iodotrirnethyl silane (900 pL, 6.33 mmol) was added to a O°C solution of 133 (1.01g,

2.53 m o l ) and 2,6-lutidine (3 10 PL, 2.66 mmol). After five minutes, 10% hydrochlonc

acid was added. The aqueous layer was extracted three times with C&C12, dried over

Na2S04, filtered and concentrated to dryness. The residue was purified by flash

chromatography (40% -70% ethyl acetate/ hexanes) to yield the title compound as a

pale yeLlow oil(453 mg, 62%) dong with recovered 133 (228 mg, 23%). Rf = 0.40 (75%

ethyl acetate/ hexanes); 'H NMR (300 MHi, CDC4) 6 1 -97-2. 10 (m, 1 H), 2.24-2.44 (m,

2H), 2.55-2.66 (m, lH), 3.34-3.66 (m, 5H), 3.71 (ABXI dd, J=9, 3.5 Hz, lH), 3.80 (s,

3H), 4.00-4.07 (m, lH), 4.43 (AB, J=ll Hz, lH), 4.47 (AB, J= l l Hz, IH), 5.45 (ABX,

dq, J=10, 3 HZ, IH), 5-70 (dq, J=107 3 HZ, lH), 6.88 (AB, JZ9Hz7 2H), 7-35 (AB, J=

9Hz, 2H); 13c NMR (100 MHz, CDC1,) 6 32.78,39.97,40.44, 55.22,62.00, 66.63, 68.27,

73.22, 113.86, 126.09, 126.60, 129.43, 129.82, 159.29; IR (neat, cm-') 3282, 2885, 161 1,

151 6, 1360, 1246, 1 173, 1070, 1036; HRMS: Calcuiated for C1&ZZ04f OC: 278.15 18,

Found: 278.1524-

1 S , S R , 6 S - 6 - H y d r o x y m e t h y l - 5 - ( 4 - m e t h o x y - b e ~ n o I (151).

Water (20 mL) was added to a rapidly stirred -78°C solution of 133 (1 9.9 g, 49.9 mmol)

in CHzClz (200 mL). After 5 minutes, iodotrimethyl silane (25.6 rnL, 180 mrnol) was

added dropwise over 2 minutes. After 10 minutes, a saturated aqueous solution of

sodium chloride wîs added and the mixture allowed to wann to ambient temperature.

The aqueous layer was extracted five tirnes with CH2Cl2, the organic Iayers were dned

over Na2S04, filtered and concentrated to dryness. The residue was purified by flash

chromatography (40% ethyl acetatel hexanes+80% ethyl acetate/ hexanes) to yield the

title compound (1 1.1 1 g, 80%) as a pale yellow oil which solidified on standing. Starting

material (2.2 g, 1 1%) was also recovered, translating to a yield of 151 of 90% brsm. The

solidified product was ground in a mortar with a pestle and 10.53g was suspended in 50

mL of 50% (v/v) ether / hexanes and stùred for 24 hours. The solids were filtered off and

resuspended in a fiesh 50 mL potion of 50% ether / hexanes and stirred for 24 hours.

The solids were again filtered oE(10.00 g, 88% recovery). This material was found to

have an ee of 99%. Rr0.29 (75% ethyl acetate/ hexanes), mp=66-68% (ether / hexanes);

a ~ = -87.3 (1 1.0 mg/ mL CHCL3, 10 cm); 'H NMR (300 MHz, CDC13) 6 2.14-2.25 (rn,

2H), 2.28-2.37 (m, lH), 2.58-2.68 (m, ZH), 3.22 (bs, lH), 3.46-3.55 (m, 2H), 3.72-3.88

(m, 2W), 3.79 (s, lm, 4.02-4.23 (m, SH), 4.46 (s, 2H), 5.51 (ABX, ddt, J=10, 3, 2 Hz,

lm, 5.68 (ABX, dq, J=10, 3 Hz, lH), 6.87 (ABX, dt, J=8.5,2.5 Hg SH), 7.24 (ABX, dt,

J=8.5, 2.5 Hz, 2H); 13c NMR (100 MHz, CDCl3) 6 33.22, 37.52, 41.87, 55.20, 62.09,

67.42, 69.80, 73.02, 113.83, 125.60, 126.97, 129.32, 129.50, 159.34; IR (neat, cm")

3359, 2895, 1725, 1613, 1510, 1443, 1360, 1299, 1247, 1173, 1036, 905; Elemental

Anaiysis: Calculated: %C=69.04, %H=7.97, Found: %C=69.16, %H=8.19.

22-Dimethyl-propionic acid IR, 2R, 6S-6-hydroxy-2-(4-methoxy-beazyloxymethyl)-

cyclo hex-3-enylmethyl ester (152a).

Pyndine (732 pL, 9.05 rnmol) and trimethyIacety1 chloride (1 -03 n&, 8.35 mmol) were

added to a -10°C solution of 151 (2.00 g, 6.96 rnmol) and N,N-dimethyl-4-aminopyndine

(85 mg, 0.696 mrnol) in CH2Cl2 (20 m . ) . The mixture was allowed to warm slowly to

arnbient temperature and stirred for 18 hours. TLC analysis revealed residual 151 which

was consurned after adding a M e r portion (170 PL, 1.38 rnmol) of trimethylace~l

chloride and stimng for 3 hours. 10% HCl was added and the mixture extracted three

times with CHzC12. The organic layers were combined, washed with brine, filtered

through cotton and concentrated to dryness. The residue was purified by flash

chromatography (30% ethyl acetate/ hexanes) to yield the title compound as a colorless

oil, which solidified on prolonged standing (2.41 1 g, 96%). R ~ 0 . 3 9 (35% ethyl acetate/

hexanes); a*= -82.2 (1 1.3 mg/ mL CHCL,, 10 cm); mp=42-44OC; 'H NMR (CDCI,) 6;

1.18 (s, 9J3, 2.16-2.34 (m, 2H), 2.38 (qd, J=7.5, 2.5 Hz, lm, 2.50-2.60 (m, lH), 3.42-

3 -52 (m, 2H), 3 -80 (s, 3H), 3 -94 (bs, 1 H), 4.15 ( A B , dd, J=11, 8 Hz, 1 H), 4.1 7-4-23 (m,

lH), 4.27 (ABX, dd, J= 11,8 Hz, IH), 4.48 (s, 2H), 5.60 (ABX, dm, J=10 Hz, IH), 5.73

(ABX, dm, J=10 Hz, lH), 6.87 (ABXy dm, J=8.5 Hz, 2H), 7.23 (ABX, dm, J=8.5 Hz,

2H); 13c NMR (100 MHz, CDCl3) 6 27.16, 34.00, 36.40, 38.73, 39.85, 55.22, 63.83,

64.08, 68.29, 73.16, 113.87, 125.76, 127.18, 129.05, 229.56, 159.41, 178-33; IR (neat,

cm-') 3415,2930, 1722, 1610, 151 1, 1465, 1363, 1282, 1243, 1166, 1036, 818; Elemental

Analysis: Calculated: %C=69.59, %H=8.34, Found: %C=69.05, %H=8,81; HRMS:

Calculated for cz 1 ~ 3 0 0 5 + m: 3 62.2093, Found: 3 62.208 7.

2,2-Dimethyl-propionic acid IS, 2R , 6s-6-(tert-butyl-dimethyCsilany1oxy)-2-(4-

methoxy-benzyloxymethy1)-cyclo hex-3-enyhethyl ester (152 b).

Lutidine (1.01 mL, 8.65 mmol) and TBSOTf (1.83 mL, 7.98 mmol) were added to a

-15°C solution of secondary alcohol 152a (2.41 g, 6.65 mmol) in CHzC12 (25 mL). After

30 minutes, a saturated solution of NaHC03 was added and the mixture was extracted

four times with CH2Cl2. The organic layers were combined, washed with brhe, filtered

through cotton and concentrated to dryness. The residue was purified by flash

chromatography (3% ethyl acetatel hexanes) to yield the title compound as a colorless oil

(3.09 g, 99%). Rr0.57 (10% ethyl acetatej hexanes); a ~ = -54.0 (9.7 mg/ rnL CHCL3, 10

cm); 'H NMR (300 MHz, CDCl3) 6 0.04 (s, 6H), 0.86 (s, 9H), 1.16 (s, 9H), 1.96-2.06 (m,

lH), 2.11-2.27 (m, 2H), 2.61-2.70 (m, lH), 3.37 (ABX dd, J=9, 9Hz, lH), 3.58 (ABX,

dd, J=9, 5.5 Hz, lH), 3.80 (s, 3H), 4.02-4.07 (m, lH), 4.10 (ABX, dd, J=11, 7 Hz, lH),

4.22 (ABX, dd, J = l l y 5 H Z 1 H), 4.43 (AB, J=12 HZ, 2H), 5-60 (ABX, dqy J=1OY 3 HZ,

lH), 5.72 (ABX, dq, J=10,2.5 Hzy H), 6-87 (ABX, dm, J= 8.5 Hz, 2H), 7.25 (ABX, dm,

H3.5 Hz, 2H); "C NMR (1 00 MHz, CDCl3) 6 -4.94, 4.63, 17.95, 25.76, 27.15, 33 .29,

38.75, 40.88, 55.24, 62.09, 67.82, 71.87, 72.82, 113.76, 124.65, 127.53, 129.19, 130.55,

159.10, 178.38; IR (neat, cm-') 2951, 1729, 1610, 1511, 1462, 1394, 1363, 1279, 1251,

1 156, 1099, 1033, 934, 871, 839, 776; Elernental Analysis: Calculated: %C=68.03,

%H=9.30, Found: %C=67.64, %H=9.8 1 ; HRMS : Calculated for C27H4405~i+ (M)+:

476.2958, Found: 476.2994.

2,2-Dimethyl-propionic acid lS, 2R , 6s -6-(tert-butyl-dimethyl-silany1oxy)-2-

hydroxymethyl-cyclohex-3-enylmethyl ester (152~).

DDQ (1.05 g, 4.64 mmol) was added to a biphasic ambient temperature solution of 1526

(1.70, 3.57 m o l ) in CH2CL (26 rnL) and water (1.6 mL) to yie1d a green suspension.

M e r 30 minutes the m i m e was filtered through cehte and concentrated to dryness.

The residue was purified by flash chromatography (5% ethyl acetate/ toluene + 20%

ethyl acetatel Hexanes) to yield the title compound as a colorless oil (1.237 g, 97%).

RFO. 16 (10% ethyl acetate/ hexanes); ao= -28.4 (1 5.2 mg/ mL CHCL3, 10 cm); 'H NMR

(300 MHz, CDC13) 8 0.04 (s, BH), 0.86 (s , 9H), 1.16 (s, 9H), 1.94-2.03 (m, IH), 2.08-

2.27 (m, 2H), 2.60-2.70 (m, ZH), 3.37 (t, J=9 Hz, lH), 3.58 (dd, J=9, 5.5 Hz, lH), 3.80

(s, 9H), 4.05 (m, lH), 4.08 (ABX, dd, J=11, 7 Hz, IH), 4.23 (AE!X, dd, &l t , 5 Hz, lH),

4.43 (AB, J=11.5 Hz, IK), 5.61 (ABX, dq, J=10,2.5 Hz, l m , 5.72 (ABX, dm, J=10 Hz,

i), 6.87 (AB, J=8.5 Hz, 2H), 7.25 (AB, J=83 Hz, 2H) ; "C NMR (100 MHz, CDC13) 6 -

4.96, -4.69, 18.02, 25.69, 27.18, 33.31,38.73, 38.89, 40.25, 61.21, 63.24, 65.97, 124.92,

127.44, 178.23; IR (neat, cm-') 3427, 2947, 1722, 1467, 1284, 1253, 1 162, 1 1 OS, 1029,

872, 838, 773, 770; ; HRMS: Calculated for ~ ~ ~ ~ ~ ~ 0 & i ~ ( M - c ~ H ~ ) ~ : 299.1679, Found:

299-1682.

2,2-Dimethyl-propionic acid IS, 6S-6-(tert-butyCdimethyl-silanyIoq)-2-forrnyl-

cyclohex-2-enylmethyl ester (153).

DMSO (169 PL, 2.38 mmol) was added to a -78°C solution of oxdyl chloride (146 pL,

2.38mmoI) in CH2C12 (10 mL) over 30 seconds. After 10 minutes, a solution of alcohol

152c (500 mg, 1.40 m o l ) in CH2C12 (4 mL) was added via cannula over two minutes.

After ten minutes, iPr2NEt ( 2 -22 mL, 7.0 1 mmol) was added and the reaction mixture was

warmed to -60°C for 1 hour. The mixture was partitioned between saturated ammonium

chionde and dichforomethane and warmed to 23°C. The aqueous layer was extracted

three times with CH2CI2, the organic layers were washed with brine, filtered through

cotton and concentrated to dryness. The residue was purified by flash chromatography

(1 2% ethy 1 acetate/ hexanes) to yield the title compound as a coIorless oïl (3 8 1 mg, 77%)

dong with the P,y-unsaturated isomer 154 (22 mg, 4%) and starting material (26 mg,

5%). 153: RF 0.26 (10% ethyl acetatel hexanes); a ~ = -124.6 (9.3 mg/ mL CHCL3, 10

cm); 'H NMR (300 MHz, CDCL) 6 0.08 (s, 6H), 0.90 (s, 9H), 1.13 (s, 9H), 1.72-1.83,

(m, lH), 1.89-2.04 (m, tH), 2.33-2.62, (m, 2H), 2.94-3.04 (m, lH), 3.86-3.95 (m, lH),

4.3 1-4.4 1, (m, 2H), 6.83 (t, J=3 -7 Hz, 1 H), 9.44 (s, 1H); 13c NMR (1 00 MHz, CDCI,) G -

4.88, -4.69, 18-03,25-65,25.7-4, 37-12, 27.83, 37.08, 38.55, 61.42, 68.14,140.34, 151.55,

178.08, 192.77; IR (neat, cm-') 293 1, 1730, 1688, 1642, 1467, 1390, 1284, 1250, 1158,

1 101, 1067, 865, 834, 770; HRMS: Calculated for ClSHZO4~iL (M-c&J)+: 297-1522,

Found: 297.152 1.

154: RF 0.41 (10% ethyl acetatel hexanes); 'H NMR (CDC13) 6; 0.10 (s, 6H), 0.89 (s,

9H), 1.19 (s, 9H), 2.14 (ABX, ddt, J=19, 8, 2.7 Hz, lH), 2.43 ( A B X , dm, J=19Hz, ZH),

2.60-2.70 (m, IH), 4.07 (ABX, dd, J= l l , 8 Hz, lm, 4.38 (ABX, dd, J = l l , 5 Hz, lH),

4.47-4.55 (m, 1H) 5.88 (ABX, dt, M O , 1 Hz, l), 6-04 (ABX, dt, J 4 0 , 3-7 Hz, lH), 9.41

(s, w- 2,2-Dimethyl-pro pionie acid lS , 6S-6-(tert-butyl-dimethyl-siianyloxy)-2-vinyl-

cyclo hex-2-enylmethyl ester (155).

n-BuLi (2.46 mL, 3.44 m o l ) was added to a -10°C suspension of CH3PPh3Br (1.34 g,

3.76 mmol) in THF (25 mL). The resulting solution was warmed to 23OC for five

minutes, then cooled to -lO°C. A solution of aldehyde 153 (1.1 1 g, 3.13 mmol) in THF

(8 mL) was added via cannula and the resulting mixture was stirred for 4 hours. The

reaction was then partitioned behveen ether and water. The aqueous layer was extracted

three times with ether, the organic layers were washed with brine, dned over MgS04,

fittered and concentrated to dryness. The residue was purïfied by flash chromatography

(3% ethyl acetate/ hexanes) to yield the title compound as a coiorless oil (1.06 g, 96%).

RF 0.48 (5% ethyl acetate/ hexanes); a ~ = -145.1 (1 0.9 mg/ mL CHCL3, 10 cm); 'H

NMR (300 MHz, CDCI,) G 0.07 (s, 6H), 0.90 (s, 9H), 1.15 (s, 9H), 1-64-1.90 (m, 2H),

2.14-2.36 (m, 2H), 2.76, (d,5=4Hz7 1H),3.93 (ddd,J=11.7, 5.2,4.4Hz, lH), 4.16 (dd,

J= l l , 3.4 Hz, lH), 4.43 (dd, J= l l , 4.1 Hz, lH), 4.94 (d, J= l l Hz, lH), 5.16 (d, J=17.8

Hz, lH), 5.74 (t, J=3.8 Hz, lH), 6.27 (dd, J=17.6, 11 Hz, 1H) ; "C NMR (100 MHz,

CDCi3) G -4.73,-4.61, 18.10, 24.90, 25.85, 27.16, 27.84, 38.58, 39.46, 62.55, 69.44,

110.89, 129.93, 135.58, 138.20, 178.40; IR (neat, cm') 2957, 1725, 1461, 1399, 1280,

1155, 1093, 992, 891, 870, 832; HRMS: Calculated for c ~ ~ H ~ ~ ~ ~ s ~ + (M-C~H~)+:

295.1 729, Found: 295.1733.

1 S , 6 S - [ 6 - ( t e r t - B u t y l - d i m e t h y l - s i l a n y ~ y l ] - e t h a n o 1 ( 1 5 6 a ) .

DIBAL-H (4-41 mL, 4.41 m o l , 1-0 M solution in heptane) was added to a -78°C

solution of 155 (1 -00 g, 2.1 0 m o l ) in CH2C12 (10 mL). After 30 minutes a 1% aqueous

solution of HC1 was added and the mixture was warmed to ambient temperature- The

resulting mixture was extracted three times with CH2C12. The organic Iayers were

washed with brine, filtered through cotton and concentrated to dryness. The residue was

purified by flash chromatography (15% ethyl acetate/ hexanes) to yield the title

cornpound as a colorless oil (794 mg, 94%). R~0.12 (10% ether 1 hexanes); a ~ = -71 .O

(10.6 mg/ rnL CHCL3, 10 cm); 'H NMR (300 MHz, CDC13) 6 0.12 (s, 3H), 0.14 (s, JH),

0.92 (s, 9H), 1.66-1.82 (m, lm, 1-86-2.02 (m, lH), 2-12-2.35 (m, 2H), 2.90-2.99 (m,

1H), 3.61-3.72 (m, 2H), 3.82-3.95 (m, lH), 4.13 (dh J=12,4.5 Hz, lH), 4.98 (d, H l Hz,

lH), 5.29 (d, J= 17.5 Hz, lH), 5.66 (t, J= 3.7 Hz, lH), 6.22 (dd, J= 17.5, 11 H z , 1H); I3c

NMR (100 MHz, CDC13) -5.03, -4.03, 17.97, 25.L7, 25-80, 26.27, 41.55, 63.25: 73.12,

110.99, 129.93, 134.56, 137.79; LR (neat, cm-') 3526, 2956, 2856, 1466, 1409, 1256,

1072, 840; HRMS: Calculated for C 1 iHlgOz~iC (M-c~H~)~ : 2 1 1.1 154, Found: 2 1 1.1 160.

1S,6S-6-(tert-Butyl-dimethyl-silanyloxy)-2-vinyl-cyclohex-2-enecarbaIdehyde

(156b).

Dess-Martin periodinane (223 mg, 0-53 mrnol) was added to a 23OC solution of 156a (83

mg, 0.3 1 mrnol) in CH2C12 (1 rd). After 45 minutes, a satwated solution of NaHCO3

was added and the mixture was extracted three times with CH2Ck. The organic layers

were washed with brine, filtered through cotton and concentrated to dryness. The residue

was purified by flash chromatography (3% ether / hexanes) to yield the title compound as

a colorless oil (75 mg, 91%). Rr0.43 (10% ether / hexanes); a ~ = -341.6 (9.3 mg/ mL

CHCL3, 10 cm); 'H NMR (300 MHz, CDCb) 6 0.08 (s, 3H), 0.10 (s, 3H), 0.88 (s, 9H),

1.78-2.00 (m, 2H), 2.26 (ABX, dm, J=l9 Hz, lH), 2.44 (ABX, dm, J=19 Hz, IH), 3.46

(t, J= 5 Hz, IH), 4.1 1 (ddd, J= l l , 6 ,4S Hz, lm, 4.95 (d, J= 11 Hz, IH), 5.09 (d, J= 17.6

Hz, lH), 5.97 (t, J= 4 Hz, lH), 6.31 (dd, J= 17.6, 11 Hz, lH), 9.68 (d, J= 4 Hz); 13c

NMR (100 MHz, CDCl3) 4-97, -4-67, 18.01, 24.71, 25-69, 28-67, 53.90, 70.04, 1 12.44,

130.58, 132.21, 137.59,201.66; IR (neat, cm-') 2941,2865, 1726, 1469, 1258, 1091, 994,

856; HRMS: Calculated for c&~so~s~+ (M-H)+: 265.1624, Found: 265-1622.

[1S92R,6S-6-(tert-Bu~1-dimethy1-si1any1oxy)-2-(4-methoxy-benqlo~ethy1)-

cyclohex-3-enylj-methanol(160).

DIBAL (4.41 mL, 4-41 mmol) was added to a -78°C solution of 152b (1.00g, 2.1 0 m o l )

in CH2C12 (10 mL). Afier 30 minutes, 10% HC1 was added and the mixture was warmed

to 23°C. The aqueous layer was extracted three times with CH2C12, the organîc layers

were cornbined, filtered through cotton and concentrated to dryness. The residue was

purified by flash chromatography (15% ethyl acetate/ hexanes) to yield the title

compound as a colorless oil(794 mg, 96%). RF 0.2 1 (1 5% ethyl acetate/ hexanes); c c ~ = -

33.9 (87% ee) (1 1.2 mg/ mL CHCL3, 10 cm); 'H NMR (CDCl,) 6; 0.07 (s, 3H), 0.08 (s,

3H), 0.89 (s, 9H), 2.16 (m, 3H), 2.62-2.75 (m, IH), 3.37 (ABX, dd,J=9, 6 Hz,lH), 3-52

(ABX, dd, J=8.6, 8.6 Hz, lH), 3-66-3.61 (m, 2H), 3.79-3.85 (m, l m , 3.80 (s, 3H), 4.11

(ddd, J= 9, 6, 3Hz, lH), 4.43 (m, 2H), 5.42 (ABX, dd, J= 10, 2 Hz, lH), 5.59 (m, lH),

6.88 (AB, J= 8.6 Hz, 2H), 5.25 (AB, J= 8.6 Hz, 2H); I3c NMR (100 MHz, CDC13) 6 -

5.03, -4.75, 17.88, 25-74, 25.82, 32-80, 38.79, 42.20, 55-24, 60.15, 71.10, 71.50, 73.02,

1 13.83, 125.13, 126.62, 129.45, 129.90, 159.23; IR (neat, cm-') 3495, 2927, 1612, 1513,

1464, 1361, 1302, 125 1,1173, 1082,837,777; HRMS: Calculated for c ~ H ~ ~ ~ ~ s ~ ~ (MJf:

392.2383, Found: 392.2380.

lSJR,6S-6-(tert-ButyEdimethyl-silanylo~)-2-(4-metIioxy-ben~loxymethyi)-

cyclohex-3-enecarbaldehyde (161).

Dess Martin periodbane (144 mg, 0.34 mmol) was added to a 23°C solution of 160 (1 10

mg, 0.28 mmol) in CHzClz (1 mL)- After 45 minutes NaHC03 (saturated) was added.

After 10 minutes, the mixture was extracted three times with CH2Cl2. The organic layers

were combined, washed with brine, filtered through cotton and concentrated to dryness.

The residue was purified by flash chromatography (10% ethyl acetate/ hexanes) to yield

the title compound as a colorless oil (108 mg, 99%). Rr0.21 (10% ethyl acetate/

hexanes); a~=-74.8 (10.2 mg/ mL CHC4) (87% ee); 'H NMR (CDC13) 6; 0.06 (s, 3H),

0.08 (s, 3H), 0.87 (s, 9H), 2.27 (ABX, ddq, J=18, 9, 3.5 Hz, IH), 2.44 (ABX, dm, J=18

Hz, 1 H), 2-71 -2.82 (m, 2H), 3 -43 (dd, J= 9, 6 HZ, lH), 3 -56 (ABX, dd, J=9, 6 Hz, 1 H),

3.80 (s, 3H), 4.22 (ddd, J-9, 6, 4Hz, IH), 4.38 (s, 2H), 5.65 (AB,J= 10 Hz, lH), 5.71

(ABX, dm, J= 10 Hz, IH), 6.87 (AB,+ 8.6 HZ, 2H), 7.33, (AB, J=8.6 Hz, 2H), 9.81 (d,

J= 4 Hz, 1H); 13c NMR (100 MHz, CDCl,) 6 -4.91, -4.72, 17.93, 25.68, 33.32, 39.01,

54.69, 55.22, 68.88, 71.07, 72.88, 113.74, 125.10, 126.75, 129.37, 130.16, 159.16,

203.73; IR (neat, cm-') 2856, 1722, 1615, 1515, 1471, 1362, 1302, 1249, 1173, 1094,

1038, 837, 777; HRMS: Calculated for C ~ H ~ ~ N I O ~ S ~ + (MJ+ 390.2226: Found: 390.2251.

DMAP (38 mg, 0.313 mmol), Et3N (439 pL, 3.31 mmol), and TBDPSCl (856 pd, 3.29

mmol), were added to a 23OC solution of 150 (901 mg, 3.13 mmol) in CH2C12 (9 mL).

After 2.5 hours, 10% KCl was added, the aqueous layer was extracted three tirnes with

CH2C12, the organic layers were combined, washed with brine, filtered through cotton

and concentrated to dryness. The residue was dissolved in Z r m t (4.67 mL, 26-1 m o l )

and MOMCl(496 PL, 6.53 m o l ) was added. M e r 12 hours, 10% HCI was added, the

aqueous layer was extracted three times with CH2Cl2, the organic layer was washed with

brine, Ntered through cotton and concentrated to dryness. The residue was purified by

flash chromatography (10% ethyl acetatel hexanes) to yield the title compound as a

colorless oil (1.2628, 70%, 2 steps). 'H NMR (300 MHZ, CDC13) 6 1.05 (s, 9H), 1.98-

2.11 (m, lH),2.19-2.31 (m,2H),2.56-2.68 (m, 1H),3.31 (s,3H),3.40(dd,J=9, 7,5Hz,

1H), 3.58 (ABX dd, J= 9.5, 4.5 Hz, lH), 3.65 (t, J=9.5, lH), 3.77 (s, 3H), 3.84-3.98 (m,

2H), 4.22 (AB, d, J= 11.5 Hz, lH), 4.27 (AB, d, J= 11.5 Hz, lH), 4.61 (AB, d, J= 7 Hz,

lH), 4.63 (AB, d, J= 7 Hz, IH), 5.62 (ABX, dm,J= 10 Hz, lH), 5.85 (ABX, dd, J= 10,2

Hz, lH), 6.74 (AB, d, J= 8.5 Hz, 2H), 7.05 (AB, d, J=8.5 Hz, 2H), 7.31-7.42 (m, 6H),

7.62-7.69 (m, 4H); "C NMR (100 MHz, CDCk) 6 19.25, 26.90, 30.14, 39.68, 41.94,

55.24, 55.32, 65.72, 67.24, 72.7 1, 73.27, 95.16, 99.90, 1 13.63, 124.41, 127.56, 127.57,

128.03, 129.1 1, 129.47, 130.62, 134.03, 135.61, 135.63, 158.93; IR (neat, cm-') 3020,

293 7, 1694, 1593, 15 13, 1259, 1 107, 1040, 830; HRMS: Calculated for C30H3505Sit (M-

C4H9)+: 503 Z S 4 , Found: 503 -2243.

DDQ (993 mg, 4.37 mmol) was added to a 23°C solution of 163 (1-25g, 2-19 mmol) in a

9:l mixture of CHzC12 and water (10 mL). After 15 minutes, the m k t w e was filtered

through celite and concentrated to dryness. The residue was purified by flash

chromatography (1 0% ethyl acetatel toluene) to yield the title compound as a colorless oil

(1 -00 g, 99%). 'H NMR (300 MHz, CDC13) 6 1-07 (s, 9H), 2.1 0-2.24 (m, lH), 2.28-2.41

(m, lH), 2.42-3.52 (m, lH), 2.58-2.69 (m, lH), 3.32-3.40 (m, lH), 3.39 (s, 3H), 3.62-

3.90 (m, 4H), 3.98 (ddd, J=9, 5.7, 3.3 Hz, IH), 4.69 (AE!, J= 7 Hz, IH), 4.72 (AEi, J-7

Hz, II-f), 3.33 (dd, J=10, 2 Hz, lH), 5.60 (dm, J= 10 Hz, lH), 7.36-7-48 (m, 6H), 7.64-

7.71 (rn, 4H); 13c NMR (100 MHz, CDCI,) G 19.20, 26.83, 29.44, 40.88, 41 -05, 55.55,

9.55, 65.10, 75.32, 95.15, 225.33, 226.49, 127.77, 129.84, 133.03, 133.15, 135.54,

135.63; IR (neat, cm-') 3487, 3026,2934, 1467, 1425, 1140, 11 11, 1037, 908; HRMS:

Calculated for C u ~ 2 7 0 4 ~ i f (M-c~H~)~: 3 83.1678, Found: 3 83.168 1.

l S , 2 R , 6 S - 2 - ( t e r t - B u t y C d i p h e n y l - s ü a n y l o ~ -

enecarbaldehyde (165).

Dess-Martin periodinane (23 1 mg, 0.545 mmol) was added to a 23 OC soIution of 164

(1 20 mg, 0.272 mmol) in CHzC12 (3 mL). After 30 minutes, sodium thiosulfate (aqueous)

was added, the aqueous layers were exîracted three times with CH2C12, the organic layers

were combined, washed with brine, filtered through cotton and concentrated to dryness.

The residue was pur5ed by flash chromatography (15% ethyl acetatd hexanes) to yield

the title compound as a colorless oil(89 mg, 75%). 'H NMR (300 MHZ, CDCLs) 6 1-04

(s, 9H), 2.36 (ddm, J=18, 9 Hz, lH), 2.54 (dm, J=18 Hz, lm, 2.73-2.84 (m, lH), 2.98

(dd, J=9,4.5 Hz, lH), 3.38 (s, 3H), 3.68 (AB, dd, J= 10, 6 Hz, lH), 3.73 (AB, dd, J= 10,

6 Hz, lH), 4.10-4.18 (m, lH), 4.69 (AB, J= 7 Hz, lH), 4.75 (AB, J= 7Hz, IH), 5.65

(ABX, dd, J=10,2 Hz, IH), 5.76 (ABX, dm, J= 10 Hz, lH), 7.24-7.47 (m, 6H), 7-58-7.67

(m, 4H), 9.90 (d, J= ~Hz, 1H); "C NMR (100 MHz7 CDCl3) 6 19.20, 26.77, 30.50,

41.28, 52.10, 55.60,64.81, 73.58,95.32, 125-37, 126.72, 127.70, 129.69, 129.73, 133.21,

133.27, 135.56, 135.65, 203 -26; Hl&IS: Calculated for C2&30~~i+ (M-H)+: 437.2 148,

Found: 437.2 133.

1R,2S-1- [lS,6S-6-(tert-Buty 1 - d i m e t h y l m -2-

methyl-but-3-en-1-01 (re-166) and lS,2R-1-[1S,6S-6-(tert-Butyl-dimethyl-s~-

2-vinyl-cyclohex-2-eny1]-2-methyl-but-3-en-1-01 (si-166).

Potassium (2)-crotyltrifluoroborate (1.38 g, 8.54 rnmol), tetrabu~l ammonium iodide (90

mg, 0.244 m o l ) and water (2 mL) were added to a 23°C solution of 156b (650 mg, 2.44

mmol) in CH2Cl* (25 mL). After 12 hours, b ~ e was added and the mixture extracted

three times with CH2C12. The organic layers were filtered through Cotton and

concentrated to dryness. The residue was purïfied by flash chromatography (5%+8%

ether / hexanes) to yield re-166 as a colorless oil (643 mg, 82%) plus si-166 (58 mg,

7.4%) and recovered starting material (26 mg, 4%).

re-166: R ~ 0 . 1 7 (5% ethyl acetatel hexanes), RF 0.28 (100% toluene); ao= -147.2 (7.8

mg/ mL CHCL3, 10 cm); 'H NMR (CDCL) 6; 0.06 (s, 6H), 0.91 (s , 9H), 1.09 (d, J= 6.6

Hz, 3H), 1.61-1.72 (m, lH), 1.74-2.09 (m, lH), 2.14-2.39 (m, 2H), 2.24-2.47 (m, lH),

2.88 (d, P 4Hz, lH), 3.77-3.88 (m, 2H), 4.96-5.10 (m, 3H), 5.25 (d, J= 17.4 Hz, lH),

5.73 (ddd, J= 19.2, 10.3, 8.6 Hz, l m , 5.95 (t, J=4Hz7 lH), 6.34 (dd, J= 17.5, 11Hz, 1H);

NMR (100 MHz, CDCb) 6 -4.72, -4.70, 18.1 1, 18.48, 25.22, 25.88, 26.73, 42.66,

44.53, 70.54, 71.73, 112.28, 114.46, 132.12, 134.70, 139.42, 142.87; IR (neat, cm-')

3486,2941, 1464, 1252, 1086, 1005,903,839, 772; HRMS: Calculated for c ~ ~ H ~ ~ ~ s ~ +

(M+H)': 323.2406, Found: 323.2396.

si-166: RF 0.27 (5% ethyl acetate/ hexanes); 'H NMR (CDCL3) 6; 0.1 1 (s, 3H), 0.15 (s,

3H), 0.92 (s, 9H), 1.07 (d, J= 6.6 Hz, 3H), 1.70-1.86 (m, ZH), 2-02-2.50 (m, 4H), 2-70

(dd, J= 8.5,4 Hzt IH), 3.89 (dt, J= 8.5,2.9 Hz, lH), 4.15 (dt, J= 10.8,4.2 Hz, ZH), 4.76

(dd, J= 2.3, 1 Hz, lH), 4-92-5.04 (m, 3H), 5.19 (d, J= 17.4 Hz, lH), 5.73 (t, J= 4 Hz, lH),

5.71 (ddd, J= 17.3, 10.4, 7.3 Hz, lH), 6.28 (dd, J= 17.5, 11 Hz, 1H); 13c MUR (100

MHz, CDCL3) 6 -5.1 1, -4.58, 13-04, 17-95, 23.72, 25.76, 26.26, 40.07, 41.36, 73.00,

76.78, 111.17, 113-19, 128.64, 136.73, 138.82, 143.53.

1S,2R-1-[1S,2R-6S-6-(tert-Bu~-dimethyI-siIanylo~y)-2-(4-metho~-

benqloxymethyl)-cyclohex-3-enyl]-2-methy-but-3-en-l-o1(168) and 1 R , 2S-1-

[1S~R,6S-6-(tert-Bu~I-dimethyl-slanyloxy)-2-(4-methoxy-be~loxymethyl)-

cyclo hex-3-enyl] -2-methyl- but-3-en-1-01 (168).

Water (3 drops), potassium (2)-crotyl trifluoroborate (98 mg, 0.606 mmol) and

tetrabutylammoniurn iodide (6 mg, 0.017 rnmol) were added to a -1 O°C solution of 161

(69 mg, 0.173 mmol) in CH2Cl2 (3 mL). After 45 minutes, the mixture was filtered

through celite and concentrated to dryness. A crude 'H NMR reveaied an 1 1 : 1 mixture of

diastereomers favoring si-168. The residue was purified by flash chrornatography (7%

ethyl acetatel hexanes) to yield si-168 (60 mg, 78%) and re-168 (5 mg, 7%) as colorIess

oils.

si-168. Rfl.21 (10% ethyl acetate/ hexanes); a~=-49.5 (10.2 mg/ mL CHCL,) (96% ee);

L H NMR (CDC13) 6; 0.04 (s, 3H), 0.05 (s, 3H), 0.85 (s, 9H), 0.98 (d, J=7 Hz, 3H), 1.86

(ddd, J=9, 6, 2 Hz, lH), 2.09-2.32 (m, 3H), 2.38-2.50 (m, 2H), 3 -55-3.65 (m, 2H), 3-73

(ddd, J= 9, 4, 3 Hz, IH), 3.80 (s, 3H), 4.38-4.44 (m, 2H), 5.03 (dt, J=17, 1.5 Hz, ZH),

5.08 (dt, J= 10.5, 1.5 Hz, lH), 5.59 (ABX, dm, J=10 Hz, ZH), 3.83 (ddd, J=17, 10.5, 6

Hz, lH), 5.90 (ABX, dm, J=10 Hz, ZH), 6.87 (AB, d, J= 9Hz, 2H), 7.22 (AB, d, J= ~ H z ,

2H); "C NMR (100 MHz, CDCl3) 6 -5.00, -4.54, 10.78, 17.89, 25.8 1, 34.57, 36.85,

38.94, 42-62, 55.25, 66.46, 71.34, 72.37, 72.81, 113.74, 114.60, 123.53, 129.05, 129.27,

130.63, 142.50, 159.10; IR (neat, cm-') 3486,2915, 1609, 151 1, 1465, 1360, 1297, 1082,

836; HRMS: Calculated for c & L Q o ~ s ~ ~ (M)? 446.2852, Found: 446.2842.

1R,2R-l- f lS,2R-6S-6-(tert-Butyl-dimethyl-silanyloxy)-2-(J-methoxy-

be~loxymethyl)-cyclohes-3-enyl]-2-methyl-but-3-en-l-ol (si-169) and lS,2R-1-

[ l S , 2 R - 6 S - 6 - ( t e r t - B u t y I - d i m e t h y l - s i l a n y l o ~ -

cyclohex-3-enyl]-2-methyl-but-3-en-l-ol (re-169).

Water (3 drops), potassium (E)-crotyl trifluoroborate (92 mg, 0.572 mmol) and

tetrabutylammonium iodide (5 mg, 0.0 14 mmol) were added to a - 10°C solution of 161

(56 mg, 0.143 mmol) in CH2C12 (3 mL). After 45 minutes, the mixture was filtered

through a column of silica gel (10% ethyl acetate/ hexanes) to yield the title compounds

as an inseparable 5: 1 mixture of diastereomers favoring si-169 (3 1 mg, 86%). R ~ 0 . 2 3

(10% ethyl acetatel hexanes); a~=-44.0 (9.7 mg/ mL CHCb) (96% ee); 'H NMR (CDCI,)

6; 0.01 (s,

(dd, J= I O,

3H), 0.04 (s, 3H), 0.84 (s, 9H), 0.83-0.88 (m, l m , 1.19 (d, J=7 Hz, 3H), 1.84

5 Hz, lH), 2.06-2.22 (m, 2H), 2.46-2.58 (m, lH), 2.68-2.80 (m, lH), 3.37 (dd,

J= 9, 2.6 HZ, IH), 3.76-3.84 (m, 1H): 3.80 (s, 3H), 3.94 (d, J=4 Hz, lH), 4.18 (t, J=9Hz,

2H), 4.41 (AB, J=11.5 Hz, lm, 4.45 (AB, M 1 . 5 Hz, l m , 4.98 (dd, J=17, 2 Hz, lm,

5.04 (dd, J= 10.5, 2 Hz, lH), 5.54 (dm, J= 10 Hz, lH), 5.66 (dm, J= 10 Hz, lm, 5.89

(ddd, J=17, 10, 9 Hz, l m , 6.87 (AB, J= 9 Hz, 2H), 7.23 (AB, J= 9 Hz, 2H); 13c NMR

(100 MHz, CDCI,) G -4.84, -4.55, 17-91, 18.64,25.78, 34.64, 35.93, 39.49,43.91, 55.22,

66.30, 71.63, 72.58, 72.89, 113.89, 115.05, 123.46, 128.30, 129.46, 129.82, 139.75,

159.3 1; IR (neat, c d ) 3465, 2946, 1615, 1524, 1459, 1368, 1299, 1253, 1177, 1074,

1036,937; HRMS: Calculated for ~ ~ ~ & ~ 0 & + O+: 446.2852, Found: 446.285 1.

1RJR-l-[1S,2R,6S-2-(tert-Bu~1-dimethyl-s~anyIo~ethy1)-6-metho~metho~-

cyclohex-3-enyl]-2-methyl-but-3-en-l-ol (re-170) and lS, 2s -1 - [ lS , ZR, 6s-2-(tert-

B u t y l - d i m e t h y l - s i l a n y 1 o x y m e t h y l ) - 6 - m e t h o t

but-3-en-1-01 (si-170).

Potassium (@-crotyltrifluoroborate (65 1 mg, 4.02 mmol), TBAI (49 mg, 0.134 rnmol),

and water (10 drops) were added to a 0°C solution of 165 (586 mg, 1.34 mmol) in

CHzC12 (1 0 mL). After 45 minutes, the mixture was partitioned between bnne and

CH2C12. The aqueous phase was extracted three times with CH2C12, the organic phases

were filtered through cotton and concentrated to dryness. The residue was puïfied by

flash chromatography (10+40% ethyl acetatel hexanes) to yield the title compound as a

mixture of re- (485 mg, 73%) and si- (76 mg, 1 1%) isomers dong with recovered starting

material (60 mg, 10%).

re-170: mp= 72-74OC; 'H NMR (300 MHz, CDCls) 6 1.07 (s, 9H), 1.24 (d, J= 7Hz, 3H),

1.94-2.12 (m, 2H), 2.27 (ABX, dm, J=18 Hz, lH), 2.58-2.71 (m, lK), 2.81-2.92 (m, 1H),

3.30 (s, 3H), 3.53 (dd, 3 H z , 1H), 4.20 (AB, d, J= 3, lH), 4.06-4.15 (m, 2H), 4.28

(dd, J= 10,9 H z , lH), 4.42 (AB, d, J= 7 Hz, tH), 4.58 (AB, d, J= 7 Hz, lH), 5.02 (dd, J=

17,2 Hz, lm, 5-06 (dd, J= 8, 2 Hz, lH), 5.48-5.61 (m, 2H), 5.91 (ddd, J= 27, 8 Hz, lH),

7.34-7.47 (m, 6H), 7.67-7.73 (m, 4H); 13c NMR (300 MHz, CDC13) 6 18.73, 18.98,

26.71, 30.28, 37.85, 39.16, 43.44, 55.58, 65-86, 70.58, 72-64, 94.80, 115.32, 124.17,

127.68, 127.77, 128.03, 129.78, 132.62, 132.79, 135.58, 135.69, 139.55; IR (neat, cm-')

3469,29l8,1216, ll48,llO9,lO37,9O7+

si-170: 'H NMR (300 MHz, CDC13) G 0.91 (d, J= 7Hz, 3H), 1.06 (s, 9H), 1.70-1.78 (m,

lH), 2.06-2.24 (m, 2H), 2.28-2.47 (m, 2H), 2.52 (d, J= 5.5 Hz, lH), 3.26 (s, 3H), 3.42-

3.49 (m, lH), 3.73 (ABX, dd, J= 10,5 Hz, lH), 3.87 (ABX, dd,J= 10,lO Hz, lH), 4.15-

4.20 (m, lH), 4-52 (AB, d, J= 6.5 Hz, 1H)y 4.56 (AB, d, J= 6.5 Hz, lH), 5.60-5.70 (m,

1H), 5.71-5.84 (m, lH), 6.07-6.16 (m, IH), 7.33-7.45 (m, 6H), 7.64-7.72 (m, 4H); "C

NMR (300 MHz, CDCl3) 6 18.32, 19.22, 26.91,31.19, 37.78, 39.23,42.96, 53.41, 55.49,

65.14, 71.64, 71.87, 96.20, 115.91, 122.88, 127.58, 127.66, 129.50, 129.56, 129.65,

133.87, 135.61, 135.64, 138.70; W S : Calculated for C26H3304~i+ (M-C~H~)+:

437.21 48, Found: 437.2132.

1R,2S,8S,8aS-8-(tert-ButyI-dimethyl-silanyloxy)-2-methyl-l,2,6,7,8,8a-hexahydro-

naphthalen-1-01 (172).

77b (4 mg, 0.005 mmol) was added to a rt. solution of re-166 (50 mg, 0.155 mmol) in

CH2C12 (1.5 mL). After 1 hour the mixture was concentrated to dryness and the residue

was purified by flash chromatography (10% diethylether/ hexanes) to afford the title

compounds as a colorless oil (32 mg, 70%). RF 0.2 1 (1 0% diethylethed hexanes); L ~ ,

NMR (300 MHz, CDCl3) 6 0.16 (s, 3H), 0.20 (s, 3H), 0.92 (s, 9H), 1.01 (d, J=7 Hz, 3H),

1.61-1.76 (m, lH), 1.88 (ABX, dm, J=13 Hz, lH), 2.05 (ABX, dm, J= 18 Hz, IH), 2.33-

2.50 (m, 2H), 4.37-4.42 (m, l m , 4.43 (s, 31), 3.94 (bs, lH), 5.58 (ABX, dd, J= 10, 5 HZ,

l m , 5.72-5.78 (m, lH), 6.07 (AB, d, J=10 Hz, 1H); "C NMR (100 MHz, CDCl,) S -

5.12, -4.13, 17.89, 18.44,20.26, 25.78, 30.02,37.79, 38.32,71.60, 73-63, 126.12, 127.65,

129.08, 130.71.

lS,2R,8S,8aR-8-(tert-B~~1-dimethy1-siianyIo~)-2-methy1-l,2~6,7~8~8a-hexahydro-

naphthalen-1-01 (173).

A few small particles of 77b were added to a 23°C solution of 171 (prepared by

desiIylation of si-166) (3 mg) in CHKL (200 CIL). Afier two hours, the mixture was

concentrated to m e s s and the residue purified by flash chromatography (50% ethyl

acetate/ hexanes) to yield the title compound as a white solid. 'H NMR (300 MHz,

CDCls, D20 shake) 6 1.15 (d, J= 7 Hz, 3 H), 1.68 (tdd, J= 12, 7, 1 -5 H z , 1 H), 2.20 (dt, J=

15,4.5 Hz, IH), 2.1 1-2.43 (m, 4H), 3.45 (t, J= 10 Hz, l m , 4.44 (bs, lm, 5.37 ( B X , d,

J= 9.5 Hz, ZH), 5.59-5.68 (m, lm, 5.97 ( A B X , dd, J= 10,2 Hz, 1H).

4-Nitro-benzenesulfonic acid 1R JS-l-[tR,6S-6-(tert-butyl-dimethyl-silanyloxy)-2-

vinyl-cyclohex-2-enyl]-2-methyl-but-3-eny1 ester (177).

n-BuLi (60 PL, 0.17 mrnol) was added to a -78OC solution of re-166 (50 mg, 0.155

mrnol) in THF (2 mL). After 15 minutes, 4-NsCl (38 mg, 0.17 m o l ) was added. After

one h o u NaHC03 (saturated) was added and the mixture warrned to 23OC. The mixture

was extracted three times with ether, the organic layers were combined, washed with

brine, dried over MgS04, filtered and concentrated to dryness. The residue was purified

by one chromatographie purification (100% toluene) to separate unreacted starting

material fiom the desired product, folIowed by a second (7% ethyl acetate hexanes) to

removed another impurity yielding the title compound as a coIorless oil (57 mg, 72%)

dong with recovered starting material (10 mg, 20%). RF 0.59 (100% toluene); a ~ = -96.9

(6.7 mg/ mL CHCL3, 10 cm); 'H NMR (CDC13) 6; 0.06 (s, 3H), 0.07 (s, 3H), 0.90 (s,

9H), 1-15 (d,J= 6.8 Hz, 33, 1.65-1.77 (m, lH), 1.84-2.01 (m, lH), 2.05-2.27 (m, 2H),

2.82-3.05 (m, 2H), 3.89 (dt, J= 12,4.5 H z , lH), 4.82 (d, J= 11 H z , lH),4.94 (dt, J= 10.4,

1.2 Hz, IH), 5.02 (dt, J= 17.3, 1.4 Hz, lH), 5.05 (d,J= 17.4 H i , lH), 5.18 (dd, J= 7.5, 3.2

Hz, lH), 5.41 (t, J=3.7 Hz, lH), 5.77 (ddd, J= 17.3, 10.4, 7.1 Hz, IH), 5.93 (dd, J= 17.4,

1 1 Hz, 1 H), 7.97 (AB, d, J=8.9 Hz, 2H), 8.29 (AB, d, J=8.9 Hz, 2H); "C NMR (1 00

MHz, CDC13) S -4.81, -4.68, 13.07, 18.09, 24.78, 25.88, 41.30, 42.80, 70.77, 89.75,

11 1.26, f 15.20, 123.55, 128.87, 129.98, 134.99, 139.52, 140.75, 144.14, 150.18; IR

(neat, cm-') 3099, 2947, 1642, 161 1, 1528, 1463, 1352, 1314, 1257, 1189, 1090, 990,

914, 846, 773, 743; HRMS: Calculated for c ~ I H ~ ~ N ~ o & s ~ ' (M-c~H~)+: 450.1406,

Found: 450.1393.

2.6 Re ferences.

1. a) Lautens, M.; Chiu, P.; Ma, S.H.; Rovis, T. J. Am. Chem Soc., 1995, 11 7, 532; b)

Lautens, M.; Rovis, T. Teîruhedron, 1998,54, 1107.

2. Hughes, G.; Lautens, M.; Wen, C. Org. Lem, 2000,2, 107.

78

(a) Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, John Wiley

& Sons, New York, 1999,201 -245. (b) Johansson, R-; Sarnuelsson, B. J. Chem. Soc.

Perkin Tram. 11984,2372. (c) Ennolenko, M.S.; Shekharam, T.; Lukacs, G.; Potier,

P. Tetrahedron Lett. 1995, 36, 2461. (d) Garegg, P.J.; Hultberg, H.; Wallin, S.

Carbohyd~~ Res. 1982,108,97.

Oikawa, Y.; Yoshioka, T-; Yonemitsu, O. Teri-ahedron Lett. 1982,23,889,

Brewster, A-G.; Leach, A, Teni-ahedron Lett. 1986,27, 2539,

Dess, D.B.; Martin, J-C. J. Org. Chem. 1983, 48,4155.

Yamamoto, Y.; Asao, N. Chem. Rev. 1993,93,2207.

a) Batey, R. A.; Thadani, A. N.; Smil, D.V. Tetrahedron Lett. 1999,10, 4289. b)

Batey, R.A.; Thadani, A.N.; SmiI, D.V.; Lough, A.J. Synthesis, 2000,990.

a) Roush, W.R. J. Org. Chem. 1991,56,4151. b) Brinkmann, H.; Hoffinann, R.W.

Chern. Ber.1990, 123,2395. c) Roush, W.R.; Adam, M.A.; Walts, A.E.; Harris, D.J.

J. Am. Chem. Soc. 1986,108,3422.

10. Scholl, M.; Ding, S.; Less, C.W.; Grubbs, R.H. Org. Lett. 1999,1, 953.

11. For a related strategy involving displacement of hindered sulfates with carboxylate

nucleophiles see: Shimizu, T.; Hiranuma S.; Nakata, T. Tetrahedron Lett. 1996,37,

6145.

3 Diastereoselective ring closing metathesis.

The RCM reaction used to f o m the second ring of the HHN portion of 1 (si-158

-+ 160) inspired us to consider an alternative strategy for the preparation of these

important pharmaceuticals. This new approach would be particularly well suited for the

preparation of 2, which differs from 1 in that it has an additional allylic rnethyl

substituent at C3. We considered that this carbon atom could be introduced by either a

sigmatropic rearrangement or an S N 2 ' displacement of OR in 184. This bicyclic moiety

could in him be produced by double RCM reaction of tetraene 185 (Scheme L)-'

Sigmatropic P Rearrangement or & -,&, DSRCM

Allylic Displacement

OR 4

Scheme 1. Approach to HMG Co-A reductase inhibitor (+)-rnevinolin.

This cyclization event affords the possibility of forming either cis- o r trans- fused

bicyclic products. Our preliminary investigations examined the possibility of perforrning

these reactions on simplified tetraene substrates 187, which could be prepared in a

straightforward manner (Scheme 2). The tertiary doubly allylic alcoho 7 L 8 7 (R=H)

would be produced by the addition of two equivalents of a vinyl metallic species to ester

188, which is in turn obtained by the decarboxylation of a malonate formed by

dibutenylation of dimethyl malonate.

Scheme 2. DSRCM reaction of simplified tetraene substrates.

While these investigations are interesting in and of themselves, the simplified

bicyclic products 186 could serve as usefùl starting material for the synthesis of cornplex

natural products. These syrnmetrïcal systems contain enantiotopic olefins, which could

be differentiated by an enantioselective process to give advanced chiral intermediates.

Some possible strategies are outlined in Scheme 3-

R=CH 2CR'1=CR'"X, X=Br, II OTf

cyclo propanatiod Heck - 186

epoxidation/ aziridination

I sigrnatropic rearrangementd allylic displacements

Scheme 3. Desymmetrization of symrnetrical bicyclic compounds.

Enantioselective epoxidation, cyclopropanation, or aziridination would provide

[4.4.1 .O .O] -tricycles 1 9 1. Enantioselective sigmatropic rearrangements or SN2'

displacements would produce conjugated dienes t 92, which are reminiscent of the

decalin portion of the HMG CoA reductase inhibitors. Enantioselective Heck reactions

or hydrogenations would give 189 and 190, respectively.

3.1 Preparation of starting materials.

Due to the expense involved in the butenylation of malonyl anion with simple

butenyl electrophiles such as a Cbromo-1-butene (see Chapter 4), an alternative approach

was employed. Dimethyl butenylmalonate 110 was deprotonated and treated with 1,4-

dichlorobutene (mixture of cis- and tram- isomers) to yield allyl chlonde 193 in 57%

yield. Subsequent reduction with ammonium formate under Pd catalysis, followed by

Krapcho decarboxylation afforded the desired methyl ester 195 (Scheme 4). Al1 of the

intemediates to this point were isolated in good to excellent yieids by distillation, which

facilitated large scale synthesis (up to 30 g of 195).

M ~ O N ~ , Cw 110

CI

Me n-Bu3P

MeOH HC02NH4

DMSO, 180°C

Toluene, 1 OOOC

Scheme 4. Pd catalyzed formate reduction approach to dibutenylated malonate.

The addition of two equivaf ents of vinyllithium or viny lmagnesium bromide to

195 proved troublesome as the second equivalent strongly preferred to undergo conjugate

addition, affording less than 10% of the desired tertiary alcohol 1 9 % ~ 11 had been

reported that the addition of two equivalents of a vinyl c e n u reagent to esters could

generate tertiary diallylic alcohols in 35% yield.3 The literature conditions called for the

use of 3 eq. each of vinylmagnesium bromide and pre-dried CeC13 at 0°C. We found that

more extensive drying of the CeClp7 H20 (6-12 hours at 140°C, <O. 1 mm Hg), lower

reaction temperatures (-7g°C) and the use of 3.5 eq. of vinylmagnesium bromide and 4.0

eq. of CeC13 gave 197 in 86% yield. The alcohol was then converted to p-methoxybenzyl

ether 199 under standard conditions. Benzyl ether 200, which would serve as a precursor

to diquinanes, was synthesized by an analogous series of traasformations (Scheme 5).

a) 1974199: NaH (2.0 eq.), PMBBr (2.0 eq.), DMF, 23OC; 1984200: THF, 60°C,

KH (2.0 eq.), BnBr (2.0 eq.)

Scheme 5. Preparation of substrates for DSRCM studies.

3.2 DSRCM to form bicyclic systems.

3.2.1 Formation of 14.4.01 bicyclic systems.

With these substrates in hand, we began our DSRCM investigations. When PME3

ether 199 was treated with 3 mol% of 75b, cycloheptene 201 was isolated as the major

product dong with trace arnounts of bicyclic products 202 (Scheme 6). This result was

somewhat unexpected, as seven-membered rings generally form slower than six-

membered rings. In this case, however, stenc congestion hinders the formation of

c cl oh ex en es.^ We were pleased to fmd that subjecting either 199 or 201 to higher

catalyst loadings (12 and 15 mol% respectively), longer reaction tirnes, and an

atrnosphere of ethylene resulted in the smooth conversion to cis- and trans-202, with the

cis- isomer being favored by a ratio of 6.5: 1. Performing the reaction with Schrock's Mo

catalyst 74 gave slightly higher (8.0: 1) levels of diastereoselectivity, with the cis isomer

still predominating. Additionally, the reaction tirnes were much shorter with the

83

cycloheptene, still formed initially, rearranging much fater to cis- and h-ans-202 in 3 0

minutes.

199 70%

OPMB

b o r c

- OPMB

1 d (85%)

OPMB cis -202 tram -202

6.5:l for b (80%) 8: 1 for c (82%)

( 3 4 OMe

tram-203 cis-203 8476, trans : cjs = 2,7:1

a) (PCy)2Ci$tu=CHPh (3moI%), CH2C12 3 hours- b) pCy3)2C12Ru=CHPh (12 mol%), CH2C13

ethylene atm, 18 hours. c) ((CF3)2CHgO)2Mo(=NAr)(=CHC(CH3hPh) (Ar2,6 diisopropylphenyl)

(12 moi%), C6H6, 30 min. d) (ECy&X2Ru=CHl?h (10 moi%), CH2ClL ethylene atm, 18 hours. e)

(PCy3)fi12Ru=CHPh (10 mol%), CH2Clt closed system, 30 min. f ) CH2=CHMgBr (3.5 eq.), CeCI3

(4.0 eq., anhydrous), THF, -78OC- g) NaH (2.0 eq.), PMBBr (2.0 eq.), DMF, 23OC.

Scheme 6. DSRCM as an approach to cis- and trans- fûsed decalin systems.

The next system to be investigated was fiee alcohol 197, which is compatibIe with

75b, but not with 74. Treating 197 with 15 mol% of 75b gave cis- and trans-203 in 84%

yield. In contrast to the PMB ether analogues, the trans isomer is favored by a ratio of

2.7: 1. The cyclization proceeded much faster than the PMI3 ether analogues, going to

completion in less than two hours with no observed cycloheptene formation. This rate

enhancement is consistent with observations made by Hoye and Zhao, who have shown

that allylic alcohols cyclize at accelerated rates compared to their ether analogues.5

Interestingly, optimal conversions with this substrate were observed in sealed

systems where the liberated ethylene cannot escape. When conducted under a stream of

ethylene, or under a stream of nitrogen, the reactions failed to go to completion before

catdyst decomposition.

The fact that cycloheptene 201 can be used as starting material for the decalin

systems suggested an alternative approach to starting materiais, via methyl ester 204

(Scheme 6)? Reaction between the enamine 206 and acrolein gave [3.2.1] bicycle 207.

Treating 207 with methyliodide gave a tetraaikyIammonium iodide, which was treated

with potassium hydroxide, giving a cycloheptene carboxylic acid, wtiich was converted

to 204 (Scheme 8).

Scheme 8. Synthesis of cycloheptene 184.

3.2.2 F omation of 13.3.01 bicyclic systems.

1) Mel - 2)KOH 3) MeOH

We have also examined the synthesis of diquinane systems using our DSRCM

strategy. When benzyl ether 200 was treated with 75b (4 moi%, 20 hours), an excellent

yield of cis-fused diquinane 209 was realized, along with monocycle 210 (ratio of

209:210=6.5: 1), which cannot under go M e r cyclization as this wouid give rise to a

highly strained tram-fised [3.3.0] bicyclic compound. In this instance, cyclization

between the less hindered olefms to give cyclopentene 208 is again favored kinetically,

but prolonged reaction times again allowed for complete conversion to 209 and 210

(Scheme 9).

Scheme 9. DSRCM as an approach to diquinane systems.

3.3 DSRCM reactions of triene systems to cyclohexenes and cyclopentenes.

3.3.1 Preparation of starting materials.

In order to examine the diastereoselectivity of RCM events in the absence of

complications due to the formation of cycloheptene 201 or cyclopentene 208, a series of

trienes that would only be capable of undergoing diastereomeric transformations were

prepared (Scheme 10). Six-membered ring precursors were prepared by alkylation of

110 with TBDPS O(CH,),B r, followed by Krapcho decarboxylation and vinylcerium

addition to give 213. Protection of the free alcohol gave P M . ether 214. Five membered

ring precursors were prepared by alkylation of dimethylmalonate with TBSO(CH,J,Br,

foIlowed by allylation. Krapcho decarboxylation and vinykerium addition then gave

alcohol217 and subsequent protection of the free alcohol gave benzyl ether 218.

a) NaH (5.0 eq.), Br(CH2)@TEDPS (1.5 eq.), THF, 60°C, 48%. b) NaCl (2.4 eq.), H g , DMSO,

180°C, 4 hom, 58% (212), 440A (216). c) CH2=CHMgBr (3.5 eq.), CeC13 (4.0 eq., anhydrous),

THF, -78OC, 57% (213), 32% (217). d) NaH (2.0 eq.), PMBBr (2-0 eq.), DMF, 23"C, 65%. e) i)

NaH (1.0 eq.), Br(CH2)30TBS (0.3 eq.), THF, 60°C 3 1%. ii) NaH (2.0 eq.), alIyl bromide (1.5

eq.), THF, 60°C, 83%. f) KH (1.5 eq.), BnBr (1 -5 eq.), THF, 60°C, 89%.

Scheme 10. Synthesis of triene tertiary diallylic alcohols and ethers.

3.3.2 Formation of cyclohexenes and cyclopentenes.

Results fiom treating f iese trienes with 75b and 74 are sumrnarized in Table 1.

Treating 213 with 75b gave a 2.8: 1 mixture of diastereomers favoring ~ m s - 2 1 9

(CH2=CH e, (CH&OP) (entry 1 ), whereas treating 214 with 75b gave a 6.1 : 1 mixture of

diastereomers favoring the cis-220 (CHr=CHtt(CH2)30P) isomer (entry 2). Switching

to 74 gave slightly higher levels of stereoselectivity (7.8:1, entry 3). Cyclopentenol 221

was forrned as a 1 : 1 mixture o f diastereomers upon treatment of 217 with 7Sb (entry 4),

whereas the benzyl ether 218 gave rise to cyclopentene 222 as an 8.0:l mixture of

diastereomers, favoring cis-222 (entry 5). The use of 74 gave the same sense of

selectivity in forming 222, but with signincantly Lower levels of stereoselectivity (1 -7: 1,

6)-

cis- frans

Table 1. DSRCM fkom monocycloalkene formation-

a) For 219 and 220 P=l

Catalyst Mol%/

T h e (h)

9 TIBDPS, for 221 and 222 P=TBS.

These results parallel the observations made in bicycle formation suggesting that,

while RCM transformations are potentially reversible, these selectivities are the result of

kinetic control. In fact, submitting the minor isomers isolated fiom the reaction mixtures

to the original reaction conditions failed to show any equilibration.

3.4 Influence of p-stereocenters on DSRCM reactions.

In order to explore M e r the possibility of employing DSRCM methodologies in

an approach to 2, we wanted to examine the Muence of other stereocenters on the

diastereoselectivity of the RCM event.

3.4.1 Preparation of starting materials.

The preparation of RCM precursor 227 began with an aldol reaction between the

lithium enolate of ethyl acetate and aidehyde 223 that proceeded in 77% yield (Scheme

11). Protection of the secondary alcohol followed by Pd catalyzed formate reduction

furnished the terminai olefm 226 in 98% yield over two steps (see Chapter 4). Treatment

with vinyIcerium gave fiee alcohol227 in 84% yield.

226 98% (2 steps)

a) i) LDA (1.1 eq.), THF, -7S°C- ii) 223 -7S°C-> rt., 77% b) TBSOTf, 2,6 Lutidine. c )

HCO2'HNEt3+, Pdz(dba)3 (0.5 mol%), n-Bu3P (4 mol), THF, 23%. d) CH2=CHM@r (3.5 eq.),

CeCl3 (4.0 eq.), THF, -7S°C,

Scbeme 11. Preparation of DSRCM substrates having a P-stereocenter.

3.4.2 Study of P chirai center influence in DSRCM reactions.

Treating fiee alcohol227 with 75b gave cyclized materid 229 in 88% yield as a

2.7: 1 mixture of diastereomers with the tram-isomer predominating (Scheme 12).

Interestingly, this is the sarne level of selectively achieved under the infiuence of an a

stereocenter (Table 1, entry 1).

QTBS QTBS 75b (15 mol%)

CH2CI2 - & J OH p OH

tranç.229 cis- 229

88%, frans (OH<->OTBS): cis = 2.7:1

Scheme 12. Influence of a stereocenter on diastereoselectivity of RCM.

3.5 [2,3]-Sigmatropic rearrangements.

As mentioned above, desymmetrization of the bicyclic products is an attractive

objective in order to allow for the synthesis of complex materials fiom simple starting

materials. We have exarnined two variations of the [2,3]-Wittig rearrangement as a

method of desymmetrization of the [4.4.0] bicyclic compounds.

3.5.1 Preparation of starting materiais. Stannylmethyl ether 230 was prepared by deprotonation of 197 with KH,

followed by alkylation with tributylstannylmethyliodide in the presence of 18-crown-6 to

give the desired product in 93% yield. After treating 230 with 75b (15 mol%) in

refluxing CH,CIZ for 8 hours, RCM product 231 was isolated in 86% yield as a single

diastereomer (Scheme 13).

1 ) KH, THF, 23OC

- T 75b (1 5 mol%)

2) 18-crown-6 ethylene, CH2CI2 reflux, 8 hr.

= a ICH$3nBu3, reflux ' P' 230 SnBu3 231 SnBu3

93% 86% Scheme 13. Preparation of the precursor for the Still variation of the [2,3]-Wittig rearrangement.

We have also looked at a propargylic version of the [2,3]-Wittig rearrangement.

We aimed to prepare the necessary starting material by direct RCM reaction of propar=~l

ether 232, but only unreacted starting material was recovered. This problem was

overcome by performing the RCM reaction on TMS ether 233 with 74, which gave a 5: 1

mixture of diastereomers, favoring the cis-isomer. Desilylation, propargylation, and

methylation of the acetylenic carbon atom then afforded the requisite sigmatropic

rearrangement precursor 237 (Scheme 14).

[M]=CHR = X No Reaction

232 R=CH3 or TMS

1 ) KHI THF, 23OC 74 (10 mol%) 197

2) TMCl Cd6, 23OC, 30 min. OR OTMS

233

92%

a) TBAF (3.0 eq.), THF, Z°C, 86%- b) NaH (5.0 eq-), BrCH2G=CH (5.0 eq.), THF, 46%. c) n-BuLi (1.1 eq.),

Me1 (1 -5 eq.), THF, -78OC, 90%.

Scheme 14. Synthesis of propargyl ether starting material for [2,3] Wittig rearrangement.

3.5.2 [2,3]-Wittig rearrangements. With these substrates in hand, we tumed our attention to the s ipa t rop ic

rearrangements. Treating stannylmethyl ether 231 with MeLi at -78°C afforded a 74%

yield of the [2,3]-Wittig rearrangement product 238 (Scheme 15).' In addition to the

desired [2,3]-Wittig rearrangernent products, 15% of [1,2]-sigmatropic rearrangement

product 239 was also isolated."

74% 15%

Scheme 15. S till variation of the [2,3]- Wittig Rearrangement.

The formation of the [1,2]-Wittig rearrangement product 239 is noteworthy, as

previous attempts to achieve this type of reactivity have proven unsuccessful with

stannylmethyl ether~. '~

Treatrnent of propargyl ether 237 with t-BuLi at -78°C gave the [2,3]-Wittig

rearrangement product 242 in 63% yield as a 2:l mixture of diastereomeric alcohols

(Scheme 16). The possibility exists for this reaction to be rendered enantioselective upon

addition of chiral agents capable of complexing alkyl lithium reagents, a strategy which

has been successfidly employed in analogous acyciic reactions.*

t-BuLi (4.0 eq.) 237 -

THF, -78OC

Sc heme 16. [2,3] -Sigmatropic rearrangement of propargylic ethers.

3.6 Discussion.

3.6.1 Proposed pathway to bicyclic compounds having protected alcohols.

Based on our studies and previous work outlining the reactivity patterns of

various olefins, we propose the following reaction pathway for decalin formation from

199/ 200: Transakylidenation in 199 or 200 occurs at one of the two less hindered

olefins to give 243 or 244, respectively (Scheme 17). These intermediates then cyclize

initially to give cycloalkenes 201 or 208, respectively. The formation of both these

compounds is reversible, as demonstrated by the fact that 201 and 208 are aiternative

entries into the cataiytic cycle. A second slower but irreversible pathway involves

cyclization ont0 one of the two more stencally hindered diastereotopic olefins to give

either cis-2451246 or trans-2451246. RCM between the two remaining acyclic olefins

then affords bicyclic products 202 and 209, a process that should also be initiated by

transallcylidenation at the Iess hindered alkene. While both ris- and trans-245 will go on

to give the corresponding cis and t ram fused hexahydronaphthalenes, only cis-246 goes

ont0 to cis fuse diquinane as m e r cyclization of trans-246 would give rise to a highly

strained tram fused bicycIo[3 -3 -01 cornpound.

Scheme 17. Pathway to diastereomeric decalin systems.

3.6.2 Proposed pathway to bicyclic compounds of free alcohols.

Double cyclization of free alcohols display interesting differences in

diastereoselectivity compared to their ether analogues. As others have previously no ted,'

allylic alcohols appear to cyclize at accelerated rates relative to the analogous ethers. For

example, whereas the p-methoxybenzyl ether 199 reacts to give the cycloheptene 201

faster than to forrn a cyclohexene 245, we have been unable to observe the formation of

cycloheptene 205 when free alcohol 197 is used as starting material. I n fact, when 205 is

used as starting material, no conversion to decalin is observed, suggeçting that alkylidene

formation may be taking place at the more hindered olefin to give 247 (Scheme 18). The

implications of these observations with regard to stereoselectivity issues are intriguing

and warrant M e r study.

Scheme 18. Pathway to diastereomeric fiee alcohol decalins.

3.6.3 Rationalization of observed stereoselectivity.

The observed stereoselectivities obtained under a stereocenter control can be

explained by invoking chair transition states for six-membered ring formation, and

envelope transition states for five-mernbered transition states (Scheme 19). The alkyl

chah R will prefer to be oriented in a pseudo-equatonal position, and the plana vinyl

substituent may be considered smaller than the benzylic ether substituent. As such, the

vinyl substituent will preferentially occupy a pseudo-axial position and transition state A

would be favored in the cyclization events to afford cis-six-membered rings (OR-H)

with protected tertiary alcohols with an a-stereocenter. Conversely, if free alcohol

substituents are considered to be smaller than vinyl substituents, transition state B would

be favored to give rise to tram-six-rnembered rings. These explmations couid also be

invoked to account for the selectivities observed by Schmidt ef al. (see Chapter 1, ref.

kT Favored for R#H Favored for R=H Favored for R f H

Scheme 19. Transition state mode1 for DSRCM reactions under a stereocenter control.

in the case of five-membered ring formation, analogous arguments could be made

to account for the selective formation of protected tertiary dcohols. Envelope transitions

state C should be preferred as the bullcier R and OR' substituents assume pseudo-

equatorial orientations-

In the formation of six-rnembered rings selectively with p-stereocenter control,

the sense of selectivity can again be understood by invoking a chair transition state with

the buikïer vinyl and OTBS substituents occupying pseudo equatorial orientations.

Therefore, transition state E is preferred and trans-229 (OH-OTBS) is formed

preferentially (Scheme 20).

1 OTBS

ri? tranç-229

OTBS -

C~S-229

Scheme 20. Transition state mode1 for DSRCM reactions under P stereocenter control.

3.6.4 Effects of ethylene in DSRCM reactions.

The effect of added ethylene depends on the structure of the tetraene: enhancing

the conversion with some substrates and hinderïng the cycfization of others. For

exampIe, when cyclizing fiee alcohol 197, the use of an ethylene atmosphere resulted in

incomplete conversion (-50%) before the catalyst decomposed. If the reaction was

repeated but under a Stream of Ar, the reaction also failed to go to completion. However

when the reaction was conducted in a sealed system so that the ethylene produced upon

cyclization was retained, complete consumption of starting materiai was observed. These

observations c m be explained if a certain concentration of ethylene is necessary to

stabilize low-valent Ru intermediates, but too much ethylene cornpetes with bulkier

substrates for coordination sites and the propagation rates become slower than

decomposition pathways.

3.6.5 Acid sensitivity of cis and trans fused bicyclic materials.

The relative sensitivities of the cis- and tram-fùsed decdins also warrants M e r

mention. As one might expect, the tertiary diallylic alcohols and ethers are susceptible to

solvolysis under acidic conditions. M i l e most of the RCM precursors and the

monocyclic intermediates could be isolated without difficulty, bicyclic materials were

found to decompose upon chromatography unless the silica gel was neutralized with

triethylamine. The trans-fused decalins were found to be particularly acid sensitive,

decomposing during TLC development, while the cis-fused analogues did not. Geometry

optimization caIculations (3-2 1 G*) of cis-203 and trans-203 revealed that the dihedral

angles between the olefui planes and the allylic C-O bond are 130" and 97' for cis-203,

whereas both dihedral angles in trans-203 are 90°, leaving the C-O bond in an

antiperipIanar orientation with both double bonds. This wodd be expected to Iower the

energy barrier to carbenium ion formation.

3.6.6 [1,2]-Wittig rearrangement of a lithiomethyl ether.

In previous investigations of the [1,2]-Wittig rearrangement, al1 attempts to detect

products arising fiom rearrangement of lithiomethyl ethers 250 (G=H) have fai~ed.'~" It

fias been proposed that the reaction proceeds via radical intermediates 251 and 252

(Scheme 21)~ '~ This happens most readily when both R and G are able to effectively

stabilize the radical fragments. Presumably, attempts to conduct these rearrangements

when G=H have failed because none of the R groups employed to date have been

s ~ ~ c i e n t l y effective at stabilizing radical 251 to compensate for the hstability of 252

when G=H. To the best of my knowledge, the most effective R group examined to date

is R=benzyl. Apparently, the tertiary doubly allylic radical used in our systems is

suEciently stable to overcome the instability of 252 (R=H), allowing the [1,2]-Wittig

rearrangement to proceed and compete with the [2,3]-Wittig rearrangement.

Li [.- 0 Li ] - 4

OLi 251 252

250 253

Scheme 21. Unprecedented [1,2]-Wittig Remrangement of a Lithiomethyl Ether.

3.7 Experimen ta/.

ToIuene and THF were distilled fkom sodium/ benzophenone. DMF was dried by

prolonged standing over 4A molecular sieves. HMPA was distilled under reduced

pressure fiom C e 2 . CHzCh was distilled fiom CaH2. Grubbs' catalyst was prepared

according to a literature procedureIo and triturated for 12-1 8 hours in a 1 : 1 mixture of

acetone and methanol. The absence of fiee tricyclohexyl phosphine and tricyclohexyl

phosphine oxide was confirmed by ''P and was crucial in order for the double

metathesis reactions to proceed- Schrock7s catalyst was usrd as received fkom Strem

Chemicds Ltd. Computational work was done using MacSpartan PlusO, version 1.2 -7

(Wavefunction Int. Irvine CA, 1996-1997).

General Procedure for the Decarboxylation of Dirnethyl MaIonates.

NaCl (1.5 equivdents) and water (1 drop/ 1 mL DMSO) was added to a 23OC solution of

malonate in DMSO (1 .O M). The resulting mixture was heated to 180°C for 5- 10 hours.

The mixture was cooled to 23"C, diluted with ether and washed with water. The aqueous

layer was extracted 3 times with ether. The organic layers were combïned, washed with

brine, dried over magnesium sulfate and fiItered. The filtrate was concentrated to dryness

and purified by distillation or flash chromatography on silica gel.

General Procedure for the Formation of Diailylic Tertiary Alcohols:

CeC1,*7H2O (4.0 equivalents) was ground with a mortar and pestle, placed under vacuum

(<0.1 rnmHg) and warrned to L40°C for 2 hours. A stir bar was added and heating under

vacuum with stimng continued for a M e r 4-10 hours. The resulting powder was

cooled to 0°C and THF (3 mL/ mm01 of CeCl,) was added via cannula under vacuum.

The remaining vacuum was displaced with N, and the resulting suspension stirred for 24

hours, then cooled to -78°C. Vinylmagnesium bromide (-1 M in TKF, 3.5 equivalents)

was added via syringe at a rate such that the interna1 temperature was kept below -65°C.

After 1 hour a solution of ester (1 .O equivalent) in THF (-1 M) was added via cannula at

a rate such that the interna1 temperature did not exceed -6S°C. After 30 minutes, the

mixture was diluted with ethyl acetate and water was added. The organic layer was

decanted off and the aqueous slurry extracted 3 times with diethylether. The organic

Iayers were combined, washed with brine, dried over sodium sulfate, and filtered. The

filtrate was concentrated to dryness and purified by flash chrornatography on

triethylamine washed silica gel.

General Procedure for the p-Methoxy Benzylation of Tertiary Diallylic Aicohols:

NaK (60% suspension in oïl, 5.0 equivalents) was washed 3 times with pentane, dried

under a stream of N, and suspended in DMF (0.3 M). A solution of alcohol in DMF (1 .O

M) was added via cannula at a rate such the H, evolution is controlled. After 5 minutes,

PMBBr was added via syringe and the resdting mixture was stirred at 23°C for 16 hours.

The mixture was diluted with ether and the reaction carefully quenched by drop-wise

addition of saturated ammonium chloride. The aqueous layer was extracted 3 tirnes with

ether; the organic layers were combined, washed with brine, dried over sodium sulfate

and filtered. The filtrate was concentrated to dryness and the residue purified by flash

chromatography on triethylamine washed silica gel.

General Procedure for the Benzylation of Tertiary Diallylic Aicohols:

Potassium hydnde (35% suspension in oil, 1.5 equivalents) was washed three tirnes with

pentane, dried under a stream of argon, and suspended in THF (half of total reaction

volume). A solution of aicohol in THF (half of reaction volume, reaction concentration

of 0.2 M) was added via cannula. The resulting suspension was warmed to 60°C and

after 10 minutes benzyl bromide (1 -5 equivalents) was added via syringe and the resulting

mixture was stirred for an hou , cooled to 23"C, diluted with ether and quenched

carefully by drop-wise addition of water. The aqueous layer was extracted two tirnes

with ether, the organic layers were combined, washed with b ~ e , dried over sodium

sulfate, filtered and concentrated to dryness. The residue was purified by flash

chromatography on triethylarnine washed silica gel.

Methyl2-(but-3-enyl) hex-5-enoate (195):

2,2 Di-(2-but-3-enyl) malonic acid dimethyl ester 194 (6.70 g, 27.9 &) was reacted

according to the general procedure for decarboxylation. The crude product was purified

by flash chromatography (3% ether/ hexanes) to yield the title compound as a colorless

1 oil(3.62 g, 71 %). H NMR (400 MHz, CDC13) 6 1.48-1.57 (m, ZH), 1.64-1.76 (m, 2H),

1.94-2.08 (m, 4H), 2.35-2.43 (m, IH), 4.94 (dq, J= 9, 1 Hz, 2H), 4.98 (dm, J= 17 Hz,

2H), 5.69-5.79 (m, 2H); 13c NMR (100 MHz, CDC13), 6 31.52, 44.35, 51.36, 114.89,

137.70, 176-00.

2-But-3-enyi- 1-vinyl-octa-l,7-dien-3-oi (197) :

Methyl ester 195 (1.00 g, 5.49 rnmol) was reacted according to the general procedure for

the formation of tertiary diallylic alcohols. The cmde mixture was purified by flash

chromatography (3% ethed hexanes) on triethylarnine washed silica gel to yield the title

compound as a colorless oiI(1.03 g, 90 %). 'H NMR (400 MHz, CDCl3) 6 1.18-1 -28 (m,

2H), 1.41-1 -49 (m, 2H), 1.59-1.69 (m 2H), 1.97-2.08 (m, 2H), 2.09-2.20 (m, 2H), 4.92

(dm, J = l O Hz, 2H), 4.98 (dq, J= 17, 2 Hz, 2K), 5.14 (dd, J = l l , 1 Hz, 2H), 5.25 (dd,

J=17, 1 Hz, 2H), 5.71-5.82 (m, 2H), 5.94 (dd, J=17, 1 1 Hz, 2H); I3c NMR (100 MHz,

CDC13) 6 29.39, 32.99, 45.78, 79.05, 113.42, 114.41, 138.97, 142.07; IR (neat, cm-')

3478, 3078, 2934, 2978, 1640, 1456, 1414, 1300, 996, 912, 735; ERh4S calculated for

Ci4Hzi0 (M-H)': 205.1592, found: 205.1601.

4-Aliyl-3-vinyl-hepta-l,S-dien-3-0l(198):

Methyl2-propenylpent-4-enoate 196 (000 mg, 3.89 mmol) was reacted according to the

general procedure for the formation of a tertiary diallylic alcohol. Purification by flash

chromatography (5% ethed hexanes) on triethylamine washed silica gel yielded the title

compound as a colorless oïl (599 mg, 86%). Rï0.19 (5% ether); 'NMR (400 MHz,

CDC13) 6 1.70 (sept., J= 4 Hz, lH), 1.87 (s, lH), 2.07 (quint, J= 8 Hz, 2H), 2.28-2.36 (m,

2H), 5.00 (d, J= 9 Hz, 2H), 5.03 (d, J= 17 Hz, 2H), 5.79-5.91 (m, 2H), 5.95 (dd, J= 17

Hz, 1 1 Hz, 2H); 13c NMR (100 MHz, CDC13) 6 l9.20,23.65,26.85,3 l.60,32.38, 36.42,

45.32, 51.33, 63.60, 116.62, 127.57, 129.49, 134.05, 135.50, 135.54, 176.04; IR (neat,

cm-') 3072,2933,2859, 1738, 1642,1473, 1428, 1390, 1195, 1164, 11 12,998,917, 824,

741,703,614; HRMS calculated for (M-@+: 177. 1279, found: 177.1287.

[2-But-3-enyl-l,l-divinyl-hex-5-enylo~ymethy1]-4-methoxy-benzene (199):

Ncohol 197 (200 mg, 0.969 rnmol), was reacted according to the general procedure for

the p-rnethoxy benzylation of tertiary diallylic alcohols. The crude mixture was purified

by flash chromatography (5% ethed hexanes) on triethylamine washed silica gel to yield

the title compound as a pale green oil (244 mg, 78%). 'H NMR (400 MHz, CDCI,) 6

1.1 1-1.22 (m, SH), 1.60 (hept, J= 4 Hz, lH), 1.67-1.77 (m, 2H), 2.02-2.21 (m, 4H), 3.81

(s, 3 H), 4.3 1 (s , 2H), 4.94 (dm, J= 10 Hz, 2H), 5.0 1 (dq, J= 1 7, 2 Hz, 2H), 5.3 1 (dd, J=

18, 1.5 Hz, 2H), 5.37 (dd, J= 11, 2 Hz, 2H), 5.76-5.86 (m, 2H), 5.88 (dd, J= 18, 11 Hz,

2H), 6.88 (AB, J=9 HZ, 2H), 7.26 (AB, J= 9 Hz, 2H); 13c NMR (100 MHz, CDC13) 6

30.05, 33.37, 47.30, 55.24, 64.82, 83.96, 113.57, 114.18, 117.39; IR (neat, cm-') 3478,

3078,2934,2978, 1640, 1456, 1414, 1300,996,912,735; HRMS calculated for (M-H)':

326.2246, found: 326.2257.

[2-Allyl-1,l-divinyl-pent-4-enyloxymethyl] benzene (200):

Tertiary alcohol 198 (500 mg, 2.80 mmol) was reacted according to the general

procedure for the benzylation of tertiary diallylic dcohols- The cmde product was

purified by flash chromatography (100% hexanes + 2% ethed hexanes) on triethylamine

washed silica gel to yield the title compound as a colorless oil (749 mg, 99%). Rï0.29

(2% ethed hexanes); 'H NMR (400 MHz, CDCI,) 6 1-84 (sept., J= 4 Hz, lK), 1-96 (dt,

J= 14, 8 Hz, 2H), 2.44 (dm, J= 14.5 Hz, 2H), 4.38 (s, 2H), 4.94 (d, J= 11 Hz, 2H), 4.98

(d, J= 18 Hz, 2H), 5.79-5.90 (m, 2H), 5.90 (dd,J= 18, 11 Hz, 2H), 7.21-7.26 (rn, lH),

7.29-7.36 (m, 4H); "C NMR (100 MHz, CDC13) 6 34.41, 48.07, 65-15, 83.53, 1 15.12,

117.63, 126.79, 126.85, 128.15, 137.87, 138.73, 139.88; IR (neat, cm-') 3074, 2920,

1639, 1497, 1453, 1414, 1377, 1096, 1064, 1000, 910, 729; HRMS calculated for (M-

H)+: 267-1749, found: 267-1734.

4a-(4-Methoxy-beqloxy)-1~,4a,7,8,8a-hexahydronaphthaIee (202) (Ru Cat.):

To a solution of 199 (200 mg, 0.613 m o l ) in dichloromethane (12 mL) 2t 23OC was

added 75b (61 mg, 0.073 mmol) and the mixture was placed under an atrnosphere of

ethylene. After 18 hours, the mixture was concentrated to dryness. The residue was

purified by flash chromatography (3% ether/ hexanes) on triethylamine washed silica gel

to yield cis-202 (1 15, 70%) and hans-202 (20mg, 12%) as reddish oils. RF 0.15 (4%

ethed hexanes); 'H NMR (400 MHz, CDC13) 6 1.50- 1.6 1 (m, 2H), 1-85 (quintd, J= 6.5,

3.5 Hz, 2H), 1.98-2.14 (m, 4H), 2.19 (hept, J= 4 Hz, lH), 3.79 (s, 3H), 4.38 (s, 2H), 5.61

(dt, J= 10,2 Hz, 2H), 5.87 (dt, J= 10,4 Hz, 2H), 6.85 (AB, J= 9 Hz, 2H), 7.25 (AB, J= 9

Hz, 2H); 13c NMR (100 M.&, CDC13) 8 23.32,24.29,34.43, 55.25,64.10, 74.14, 113.70,

129.05, 129.64, 130.27, 132.18, 158.87; IR (neat) 3019, 2826, 1653, 1613, 1586, 1559,

1513, 1456, 1374, 1301, 1248, 1172, 1034, 947, 821; HRMS calculated form M?:

270.1620, found: 270.16 1 1.

Cycloheptene intermediate: 5-(penta-1,4-dien-3-01, p-methoxy benzyl ether)-

cyclohept-1-ene (201): RF 0-37 (4% ether/ hexanes); 'H NMR (400 MHz, CDC13) 6

1 -05 (9, J= 1 1 Hz, 2H) 1 -77 (tt, J= 1 1, 3 HZ, 1 H), 1 -92-2.06 (m, 4H), 2.2 1-2-33 (m, 2H),

3.79 (s, 3H), 4.29 (s, 2H), 5.28 (dd, J= 18, 6 Hz, 2H), 5.35 (dd, J= 11, 2 Hz, 2H), 5.72-

5.80 (m, 2H), 5.86 (dd, J= 18, 11 Hz, 2H), 6.87 (AB, J= 9 Hz, 2H), 7.26 (AB, J= 9 Hz,

2H); "C NMIX (100 MHz, CDC13) 6 27.98, 28.02, 52.62, 55.24, 64.72, 83.36, 117.25,

128.21, 131.87, 132.06, 138.16, 158.65; IR (neat, cm-') 2919, 1612, 1585, 1512, 1450,

1300,1247,1108,1037,927,820,737,697.

4a-(4-Methoxy-benqloxy)-l,2,4a,7,8,8a-hexahydronaphthalene (202) (Mo Cat.):

To a solution of 199 (47 mg, 0.142 m o l ) in C6H6 (0.5 rnL) at 23°C was added a

solution of 74 (12 mg, 0.016 mmol) in Cs& (1.5 mL). After 20 hours the mixture was

concentrated to dryness and the residue purified by flash chromatography (3 % ether/

hexanes) on triethylamine washed silica gel to yield cis-202 (28 mg, 73 %) and tram-202

(3.5 mg, 9%) as co1orIess oils.

cis and tram 2,7,8,8a-Tetrahydro-1H-naphthalen-4-ol(203):

To a solution of 197 (1 00 mg, 0.242 m o l ) in dichloromethane (4.5 mL) at 33OC was

added 75b (40 mg, 0.049 mmol). The system was sealed and equipped with neither an

inlet or outlet. After 1 hour PPh3 (17 mg, 0.065 m o l ) was added and the mixture was

concentrated to dryness. The residue was purified by flash chromatography (30% ether/

hexanes) on triethylamine washed silica gel to yield the title compounds as a white solid

and a colorless oil (frans-203, 45 mg, 62 % ), (cis-203, 16 mg, 22 % ). Due to the

sensitivity of the pans compound, it was immediately hydrogenated and characterized.

The structure of the resulting decahydronaphthalenol was confmed by comparison to

spectral data reported in the fiterature! ' tram-203: 'H NMR (400 MHz, CDC13) 6 1.35 (s, 1 H), 1.45-1 -53 (m, 2H), 1.60-1.77 (m,

3H), 2.1 1-2.18 (m, 4H), 4.76-5.85 (m, 2H).

cis-203: 'H NMR (400 MHz, CDC13) 6 1.49-1 -60 (m, 2H), 1.76- 1 -84 (m, 2H), 1 -87- 1 -94

(m, IH), 2.01-2.07 (m, 4H), 5.58 (dt,J=10,2 Hz,2H), 5.77(dt, J=lO, 3.7Hz,2H); I3c

NMR 8 23.1 1, 24.27, 39.70, 38.34, 128.19, 131.34; IR (neat) 3351, 3023, 2908, 1429,

1383, 1326, 1204, 1021, 960; HRMS calculated for C i o ~ 1 4 0 f 0: 150.1045, found:

lSO.1044.

Cycloheptene 205.

Methyl ester 204 (121 mg, 0.785 mmol) was reacted according to the general procedure

for the formation of a tertiary diallylic alcohol. Purification by flash chromatography

(8% ether/ hexanes) on triethylamine washed silica gel yielded the title compound as a

colorless oil(122 mg, 87%). 'H NMR (400 MHz, CDCI,) 6 1-09 (q, J=l 1 Hz, 2H), 1.56-

1.65 (m, 2H), 1.86-2.03 (m, 4H), 2.21-2.33 (m, 2H), 5.15 (d, J= l l Hz, 2H), 5.26 (d, J=

17 Hz, 2H), 5.71-5.80 (m, 2H), 5.95 (dd, J= 17, 11 Hz, 2H); "C NMR (100 MHz,

CDC13) 6 27.63,27.71, 5 1.54, 78.77, 1 13-60, 13 1-70, 141.95; IR (neat, c d L ) 3470, 2920,

1642, 1293,923.

cis 3a-Benzyloxy-1 Ja,6,6a-tetrahydro-pentale (209) (Ru Cat.):

To a solution of benzyl ether 200 (100 mg, 0.372 mmol) in dichloromethane (4 mL) at

23°C was added 75b (12 mg, 0.014 mmol). The resulting solution was stirred under an

ethylene atmosphere for 20 hours before PPh3 (14 mg, 0.053 m o l ) was added and the

mixture concentrated to dryness. The residue was purified by flash chromatography (2%

ether/ hexanes) on triethylamine washed silica gel to yield the title compound as a

colorless oil (63 mg, 80%) dong with cyclopentene 210 (12 mg, 13%). Rf 0.1 1 and

0.3 4 (2% ether/ hexanes) respectively; 'H NMR (400 MHz, CDCl,) 6 2-06-2.1 5 (m, 2H),

2.81-2.91 (m, 3H), 4.42 (s, 2H), 5.83 (dt, J= 6 ,2 Hz, ZH), 5.92 (dt, J= 6 , 2 Hz, 2H), 7.21-

7.26 (m, lH), 7.28-7.35 (m, 4H); "C NMR 6 40.72, 43.03, 65.58, 105.70, 127.16,

127.55, 128.25, 132.54, 134.27, 139.56; IR (neat) 3053,2919, 2848, 1497, 1448, 1378,

1349, 1216, 1139, 1099, 1028, 991, 733, 697; HRMS calculated for C15H160 m: 212.1201, found: 212-1 196.

Cyclopentene intermediate 210: 'H NMR (400 MHz, CDC13) 6 2.3 8 (d, J= 6 Hz, 4H),

2.74 (qUint7 J= 8Hz7 lH), 4.43 (s, 2H), 5-32 (AB, J= 1.5 HZ, 2H), 5.35 (q, J= 1.5 HZ, 2H),

5.62 (s, 2H), 5.90 (dd, J= 18, 10.5 Hz, 2H), 7.22-7.26 (m, 1H), 7.30-7.37 (m, 4H); 13c

NMR 6 34.27,45.33,65.089, 82.77, 117.1 1, 126.82, 126.87, 128.15, 129.74, 138.04.

2-But-3-enyI-2-(3-t-butyldiphenylsiloxy-propyl) malonic acid dimethyl ester (211):

Sodium hydride (1 -10 g, 32.2 m o l ) was washed three times with pentane, dried under a

stream of nitrogen, and suspended in DMF (40 mL). A solution of dimethylbut-3-enyl

malonate 110 (4.00 g, 21.5 mmol) in DMF (10 mL) was added via cannula at a rate such

that hydrogen evolution was controlled. After 30 minutes, a solution TBDPSO(CH2),Br

in DMF (10 mL) was added via cannula. Afier 20 hours, the mixture diluted with ether

and quenched by careful addition of water. The aqueous layer was extracted with ether,

the organic Iayers were combined, washed with brine, dried over magnesium sulfate,

filtered and concentrated to dryness. The residue was purified by flash chromatography

(5% ethed hexanes) to yieId the title compound as a colorless oil(5.00 g, 48%). 'H NMR

(400 MHz, CDCi3) 6 1.05 (s, 9H), 1.36-1.46 (m, 3H), 1.89-2.05 (m, 7H) 3.65 (t,J= 6 Hz,

2H), 3.70 (s, 6H), 4.97 (dd, J= 10, 1.5 Hz, IH), 5.03 (dd, J= 17, 1.5 Hz, lH), 5.72-5.83

(m, lm, 7.36-7.45 (m, 6H), 7.64-7.67 (m, 4H); 13c NMR (100 MHz, CDCl,) 6 19.17,

26.81, 27.28, 28.30, 28.90, 31.60, 52.29, 57.04, 63.57, 115.00, 127.60, 129.56, 133.79,

135.52, 137.46, 172.02; HRMS calcuiated for Cz&I2905Si (M-C4H9) 425.1784, found

425-1793.

2-(3-t-Butyldiphenylsilo~y-propyl)..hex-5-enoic acid methyl ester (212):

Malonate 211 (5.00 g, 10.4 rnmol) was reacted according to the general procedure for

decarboxylation. The crude mixture was purified by flash chromatography (5% ether/

hexanes) to yield title cornpound as a colorless oil (2.58 g, 58%). 'H NMR (CDC13) 6

1.05 (s, 9H), 1.49-1.79 (m, 6H), 2.00-2.08 (m, 2H), 2.35-2.44 (m, ZH), 3.63-3.68 (m,

5H), 4.97 (dm, J= 10 Hz, ZH), 5.02 (dq, J= 17, 2 Hz, lH), 5.72-5.83 (m, ZH), 7.36-7.46

(m, 6H), 7.65-7.69 (m, 4H); I 3 c NMR (100 MHz, CDCl3) S 19-20, 26.84, 28.59, 30.22,

31.47, 31.54, 44.62, 51.33, 63.51, 115.02, 127.59, 129.53, 133.94, 135.54, 137.85,

176.5 1 ; IR (neat) 2930, 1734, 1428,111 1; HRMS calculated for Cz2Hzs03Si (M-C4~9+):

367.1729, found: 367.1725.

4-(3-t-Butyldiphenylsiloxy-propyl)-3-~hepta-1,6-dien-3-01(213):

Methyi ester 212 (1.25 g, 2.94 m o l ) was reacted according to the general procedure for

the conversion of a methyl ester to a tertiary diallylic dcohol. The crude product was

purified by flash chromatography (8 % ether/ hexanes) on triethylamine washed silica

gel to yield the title compound as a colorless oil(754 mg, 57%). R~0.25 (10 % ethed

hexanes); 'H NMR (400 MHz, CDCb) 6 1-05 (s, 9H), 1.14- 1.26 (m, 2H), 1.3 8-1 -44 (m,

lH), 1.46-1 -69 (m, 5H), 1.94-2.06 (m, lH), 2.09-2.20 (m, 1 H), 3.63 (t, J= 6. Hz, 2H), 4.93

(dm, J= 10 Hz, lH), 4.98 (dq, J= 17, 2 Hz, IH), 5.14 (ddd, J= 11, 3.5, 1 Hz, 2H), 5.25

(ddd, J= 17,4, 1 Hz, 2H), 5.71-5.82 (m, lH), 5.94 (ddd, J= 17, 11, 2 Hz, 2H), 7.35-7.45

(m, 6H), 7.65-7.69 (m, 4H); "C NMR (100 MHz, CDC13) 6 19.19, 26.09, 26.87, 29.3 8,

31.86, 32.86, 46.18, 64.14, 79.10, 113.37, 114.39, 127.56, 129.50, 134.05, 135.57,

139.02, 142.06, 142.15; IR (neat) 3475,2930, 1636, 1472, 1427, 1 1 1 1; HRMS calculated

for C25H; i02Si ( M - C Q H ~ ~ 391 -2093, found 39 1.2098.

[2-(3-f-Butyldip h e n y l s i i o x y - p r o p y 1 ) - 1 , l - d

benzene (214):

Alcohol 213 (400 mg, 0.891 m o l ) was reacted according to the general procedure for

the p-rnethoxy benzylation of tertiary diallylic alcohols. The crude material was purified

by flash chromatography (2% ethed hexanes) on triethylamine washed silica gel to yield

the title compound as a colorless oil (325 mg, 65%). RF 0.22 (5 % ethed hexanes); 'H

NMR (400 MHz, CDC13) 6 1 -08 (s, 9H), 1.12-1.24 (m, 2H), 1.55-1.80 (m, SH), 2.02-2.23

(m, ZH), 3.66 (t, J= 6 Hz, 2H), 3.81 (s, 3H), 4.32 (s, 2?3, 4.95 (dm, J=10 Hz, 1H), 5.01

(dq, J= 17, 2 Hz, l m , 5.31 (dt, J= 18, 1.5 Hz, 2H), 5.37 (ddd, J= 11, 4, 1.5 Hz, 2H),

5.78-5.87 (m l m , 5.88 (ddd, J= 18, 11, 1 Hz, 2H), 6.87 (AB, J= 9 Hk, 2H), 7.27 (AB, J=

9 Hz, 2H), 7.37-7.47 (m, 6H), 7.68-7.72 (m, 4H); "C NMR (100 MHz, CDC13) F 19.20,

26.81, 26.88, 30.01, 32.29, 33.28, 47.70, 55.22, 64.37, 64.82, 84.01, 11 3.58, 114.13,

117.28, 127.54, 128.13, 129.45, 132.14, 134.16,. 135.57, 138.15, 138.23, 139.35, 158.54;

IR (neat) 2930, 161 5, 15 13, 1428, 1247, 11 1 1; HRMS calculated for C3,H3,0,Si (M-

~ 4 ~ ~ 3 : 5 1 1.2668, found: 51 1.2689.

2-Ailyl- (3-t-Butyldimethybiloxy-propy1)-malonic acid dimethyl ester (215).

Sodium hydride (4.16 g, 104.1 mmol) and potassium hydride (cat.) were washed 3 times

with pentane, suspended in DMF (75 mL) and cooled to O°C. A solution of dïmethyl

malonate (1 1 -9 mL, 104.1 mmol) in DMF (50 mL) was added via addition funne1 at a rate

such that the evolution of H2 was controlled. The mixture was warmed to 23OC. After 30

minutes, a solution of TBDPSO(CH,),Br (8.80 g, 34.7 mmol) in DMF (10 mL) was

added via cannula. M e r 14 hours, the mixture was diluted with ether and quenched

carefully with water. The aqueous layer was washed 3 times with ether; the organic

Iayers were combined, washed with brine, dried over magnesium sulfate and filtered.

The filtrate was concentrated to m e s s and the residue purified by fiactional distillation.

Collection of the fiaction boiling between 100-1 10°C (0.1 mm Hg) yielded the

monoallqlated malonate as a colorless liquid (3 -26 g, 3 1%). Rf= 0.23 (1 5% ether/

hexanes); 'H NMR (400 MHz, CDCb) 6 0.03 (s, 6H), 0.88 (s, 9H), 1.49- 1.57 (rn, 2H),

1.91-2.00 (m, 2H), 3.41 (t, J=8 Hz, lH), 3.62 (t, J=6 Hz, 2H), 3.73 (s , 6H); 13c

(100 MHz, CDC13) G -5.41, 18-26, 25.47, 25.87, 30.27, 51.35, 52.39, 62.40, 169.86; IR

(neat) 2955, 2858, 1768, 1436, 1389, 1255, 1155, 1099, 1009, 837, 777; HRMS

calculated for (M-CH3)+: 289.147 1, found: 289.1474.

Sodium hydride (0.509 g, 21.2 m o l ) was washed three times with pentane and

suspended in THF (20 mL). A solution of the monoal&lated malonate prepared as

described above (3.00 g, 9.85 mmol) in THF (20 mL) was added via cannula at a rate

such tbat Hz evolution is controlled. Afier 15 minutes, allyl bromide (1 -86 mL, 2 1.2

mmol) was added via syrkge. Afier 1 hour the mixture was diluted with ether, quenched

carefully with water, and the aqueous Iayer was extracted 2 times with ether. The organic

layers were combined, washed with brine, dried over magnesiurn sulfate and filtered.

The filtrate was concentrated to dryness and purïiïed by flash chromatography (10%

ether/ hexanes) on silica gel to yield the title compound as a colorless oil (2.80 g, 83%).

R/= 0.32 (15 % ether/ hexanes); 'H NMR (400 MHz, CDC13) 6 0.03 (s, 6H), 0.87 (s, 9H),

1.35-1.44 (m, 2H), 1.87-1.95 (m, 2H), 2.64 (d, J= 7 Hz, 2H), 3.58 (t, J=6 Hz, 2H), 3.70

(s, 6H), 5.05-5.13 (m, 2H), 5.57-5.69 (m, 1H); 13c NMR (100 MHz, CDC13) 6 5.36,

18.26, 25.89, 27.45, 28.84, 37.09, 52.29, 57.38, 62.86, 118.92, 132.38, 171.68; IR (neat)

2954, 2858, 1737, 1435, 1388, 1361, 1256, 1210, 1099, 1034, 921, 837, 776; IHIRMS

calculated for (M- CH^)+: 329.1 784, found: 329.1 80 1.

2-(3-t-Butyldimethybiloxy-propy1)-pentenoic acid methyl ester (216):

Malonate 215 (2.61 g, 7.58 m o l ) was reacted according to the general decarboxyIation

procedure. The crude mixture was punfied by flash chromatography (7% ether/ hexanes)

to yield the title compound as a colorless oil (960 mg, 44%). RF 0.20 (5 % ethed

hexanes); 'H NMR (400 MHz, CDCl3) 6 0.02 (s, 6H), 0.87 (s, 9H), 1.44-1.66 (m, 4H),

2.18-2.26 (m, lH), 2.30-2.40 (m, lH), 2.41-2.49 (m, lH), 3.58 (td, J=6, 2 Hz, 2H), 3.65

(s, 3H), 4.97-5.08 (m, 2K), 5.66-5.78 (m, 1H); 13c NMR (100 MHz, CDCh) 6 5.36,

18.27, 25.89, 28.07, 30.40, 36.45, 44.97, 51.34, 62.72, 116.68, 135.41, 175.97; IR (neat)

2952,2858, 1740, 1361, 1256, 1167, 1102, 1006, 915, 837, 776; HRMS calculated for

(M- CH^)': 27 1.1729, found: 27 1.1742.

4-(3-t-Bu tyldimethylsiloxy-propy1)-3-vinyl-hepta- 1,6-dien-3- (2 17):

Methyl ester 216 (0.900 g, 3.13 mmol) was reacted under standard conditions for the

conversion of methyl esters to didylic teaiary alcohols. The crude product was purified

by flash chromatography (7 % ether/ hexanes) on triethylamine washed silica gel to yield

the title compound as colorless oil (3 14 mg, 32%). R/= 0.25 (10 % ether/ hexanes); 'H

NMR (400 MHz, CDC4) 6 0.04 (s, 6H), 0.88 (s, 9H), 1.16-1.26 (m, lH), 1.42-1.52 (rn,

lH), 1.53-1.70 (m, 3H), 1.83 (s, l m , 2.02 (quint, JI 7 Hz, IH), 2.30-2.38 (m, lH), 3.56

(t, J=6 Hz, 2H), 4.98 (dquint, J=10, 0.5 Hz, l m , 5.02 (dq H 7 , 0.5 Hz, 1H), 5.16 (dd,

J= l l , 1 Hz, 2H), 5.28 (dt, J= 17, 1 Hz, 2H), 5.81-6.00 (m, 3H); " C NMR (100 MHz,

CDC13) 6 5.29, 18.31, 25.32, 25.94, 31.75, 34.34, 46.51, 63.31, 79.23, 113.48, 115.80,

138.37, 141.79, 142.20; IR (neat) 3475,3079,2929,2858, 2639, 1472,4109, 1361, 1256,

1100, 999, 921, 836, 775, 735 ; HRMS calcdated for C,,H3,0,Si (M-CH3+) 295.2091,

found 295.209 1.

2-(3-t-Butyldimethylsiloxy-propyl)-l,l-divinyl-pent-4-enylomethyl)-beene (218):

Alcohol 217 (288 mg, 0.927 mmol) was reacted according to the general benzylation

procedure. The crude product was purified by flash chromatography (5% diethylethed

hexanes) to yield the title compound as a colorless oil (329 mg, 89%). RF 0.21 (2%

ethed hexanes); 'H NMR (400 MHz, CDCI,) 6 0.03 (s, 6H), 0.88 (s, 9H), 1.10-1.20 (m,

lH), 1.46-1.57 (m, lH), 1.58-1.74 (m, 3H), 1.82-1.94 (m, lH), 2.46-2.54 (m, lH), 3.55 (t,

J=6 HZ, 2H), 4-37 (s, 2H), 4-93 (d, HZ, 1 H), 4.99 (dq J=17, 1 Ek, lH), 5.30 (dd,

J=17, 1.5 Hz, 2l3, 5.36 (dd, J= 11, 1.5 HZ, 2H), 5.80-5.90 (m, lH), 5.89 (dd, J=18, 11

Hz, 2H), 7.21-7.26 (m, 1 H), 7.29-7.36 (m, 4H); "C NMFL (100 MHz, CDCb) 6 5.26,

18.33, 25.97, 26.36, 32.30, 35.13, 48.00, 63.56, 65.12, 83.79, 114.92, 117.48, 117.55,

126.75, 126.8 1, 128.14, 137.81, 138.16, 139.06, 139.98; IR (neat) 3086, 2929, 2858,

1639, 1497, 1472, 1408, 1380, 1255, 1099, 1027, 1004, 929, 836, 775, 728, 695, 661;

HRMS calculated for (M- CH^)': 3 85.2563, f o u d 385.258 1.

cis- and h.ims-6-(3-t-Butyldip henyIsiloxy-propyI)-l-vinyl-cyclohex-2-eno1(219):

75b (44 mg, 0.053 m o l ) was added to a 23OC solution of triene 213 (200 mg, 0.446

rnmol) in dichloromethane (4.5 mL). After 5 hours PPh3 (28 mg, 0.107 mmol) was added

and the mixture concentrated to dryness. A crude 'H NMR showed a 2.8:l mixture of

diastereomers in favor of the product fiaving the methine proton and OH substituent pans

to one another. The diastereomeric ratio was deterrnined by comparing the integration of

the peaks at 6 5.41 (cis) and 6 5.52 (tram). The residue was purified by flash

chromatography (15 % ethed hexanes) on triethylarnine washed silica gel to yield the

title product as a coIorless oïl (1 5 1 mg, 80 %)-

cis-219: 'H NMR (400 MHz, CDC13) 6 0.94-1 -08 (m, lH), 1.05 (s, 9H), 1.20-1 -33 (m,

lH), 1.47-1.59 (m, 2H), 1.62-1-78 (m, 3H), 2.01-2.07 (m, 2H), 3.62-3.71 (m, 2H), 5.14

(dd, J= 11,2 Hz, l m , 5.18 (dd, J= 17,2 Hz, lH), 5.41 (dt, J= 10,Z Hz, lH), 5.87 (dt, J=

10, 4 Hz, lH), 5.87 (dd, J= 17, 11 Hz, lH), 7.35-7.45 (m, 6H), 7.65-7.69 (m, 4H); 13c

NMR (100 MHz, CDCI3) 8 19.22, 24.78,25.21, 25.92, 26.91, 30.79, 45.21, 64.30, 75.31,

114.38, 127.58, 128.44, 129.50, 232.63, 134.15, 135.60, 140.37; IR (neat) 3441, 3071,

2931,1651, 1590, 1472, 1428,1390,1361,1175, I l l 1,998,822.

pans-219: 'H NMR (400 MHz, CDC13) F 1-07 (s, 9H), 1.10-1.21 (m, lH), 1.34-1 -54 (m,

4l3, 1.60-1.78 (m, 3J3, 1.92-2.04 (m, lH), 2.07-2.16 (m, lH), 3.68 (t, J= 6 Hz, 2H), 5.14

(dd, J= 11, 1.5 HZ, lH), 5.32 (dd, J= 17, 1.5 HZ, lH), 5.52 (dt, J= 10, 2 HZ, lH), 5.83

(dd, J= 17, 11 Hz, 1H)y 5.87 (dq, J= 10, 2.5 Hz, lH), 7.36-7.46 (m, 6H), 7.66-7.71 (m,

4H); I3c NMR (100 MHz, CDCls) 8 19.19, 22.85, 24.67, 25.43, 26.89, 30.75, 42.84,

64.18, 72.71, 113.14, 127.54, 229.47, 130.35, 13 1.78, 134.15, 135.58, 144.45; IR (neat)

3471,3071, 3020,2931,1649, 1589,1472,1428,1390,1361, 1304, 1111,997,954,921,

823, 937,701, 614; HRMS calculated for ( M - ~ 4 ~ 9 ) ~ : 363.1780, found: 363-1887.

c i s - and fians - [6 - (3 -t-Butyldiphenylsiloxy-propyl)-l-vinyl-cyclohex-2-

enyloxymethyl]-4-methoxy-benzene (220) (Mo Cat.):

74 (4 mg, 0.006 mmol) was added to a 23 OC solution of triene 214 (5 1 mg, 0.089 mmol)

in C6H6 (0.5 mL) as a solution in C6H6 (0.5 mL). The resulting mixture was stirred for 90

minutes before being concentrated to dryness. A cmde 'H NMR spectrum showed a

7.8: 1 mixture favoring the cis- diastereomer. The ratio was determined by comparuig the

integration of the doublets of triplets appearing at 6 5.61 (cis-) and 6 5.75 (trans-) in the

cmde 'H NMR. The residue was purified by flash chromatography (2% ether/ hexanes)

on tnethylamine washed silica gel to yield the title compounds as colorless oils (42 mg,

86%). R~(cis-220)= 0.20, R~(trans-220)= 0.29 (5% ether/ hexanes); cis-220: 'H NMR

(400 MHz, CDCI3) 6 0.92-1.10 (m, lH), 1.05 (s, 9H), 1.26-1.38 (m, lH), 1.44-1.55 (m,

lH), 1.63-1.89 (m, 4H), 2.03-2.09 (m, 2H), 3.66 (td,J= 6, 1.5 Hz, 2H), 3.79 (s, 3H), 4.38

(s, 2H), 5.18 (dd, J= 17,2 Hz, lH), 5.22 (dd, J= 11,2 Hz, lH), 5.61 (dt, J= 10,2 Hz, lH),

5.88 (dd, J= 17, 11 HZ, IH), 5-99 (dt, JE 10, 3-5 HZ, 1H) 6.84 (ABy J= 9 Hz, 2H), 7.24

(AB, J= 9 Hz, 2H), 7.35-7.45 (m, 6H), 7.66-7.70 (m, 4H); 13c NME2 (100 MHz, CD&) 6

19.00,23.86,25.03,25.19,26.68, 30.58,40.43, 55.06,65.93, 64.27, 76.48,, 30.58,40.43,

55.06, 65.93, 64.27, 76.48, 80.56, 113.44, 116.25, 127.35, 128.469, 129.22, 129.26,

13 1.08, 132.87, 134.96, 135.37, 140.89, 158.53; IR (neat) 293 1, 1613, 1513, 1472, 1428,

1301, 1247, 1171, 11 11, 998, 822, 702; HRMS calculated for C3iH;503Si (M-c~H~C):

483.2355, found: 483.2363.

ms-220: 'H MvfR (400 MHz, CDCb) 6 1-04 (s, 9H), 1.26-1 -50 (m, 3H), 1.56-1.76 (m,

3H), 1-76-1.86 (m, IH), 1-92-2.04 (m, lm, 2.07-2.17 (m, lH), 3.64 (t, J= 6.5 Hz, ZH),

3-78 (s, 3H), 4.39 (AB, J= I l Hz, lH), 4.42 (AB, J= 11 Hz, l m , 5.18 (dd, J= 6, 1.5 Hz,

lH), 5.22 (s, lH), 5.75 (dt, J= IO, 2 Hz, lH), 5.88-5.96 (m, lH), 6.01 (dq, J= 10,S Hz,

lm, 6.84 (AB, J= 9 Hz, 2H), 7.24 (AB, J= 9 Hz, 2H), 7.34-7.44 (m, 6H), 7.65-7.70 (m,

4H); "C NMR (100 MHz, CDCL) 6 19.21, 22.73, 24.08, 25.30, 26.88, 31.03, 43.83,

55.26, 64.36, 64.58, 110.39, 113.56, 115.25, 127.53, 128.16, 128.49, 129.42, 132.05,

132.49, 134.21, 135.58, 143.14, 258.50.

c i s - and tram - [ 6 - (3 -t-Bu~ldiphenylsiloxy-propyl)-l-vinyI-cyclohex-2-

eny loxymethyl] -4-methoq- benzene (220) (Ru Cat.) :

To a solution of triene 214 (200 mg, 0.351 m o l ) in dichioromethane (3.5 mL) at 23°C

was added 75b (1 2 mg, 0.0 14 mmol). M e r 3 hours PPh3 (7 mg, 0.029 mmol) was added

and the mixture was concentrated to dryness. A crude 'H NMR spectnim showed a 6.1 : 1

mixture favoring the cis- diastereomer. The ratio was determined by comparïng the

integration of the doublets of triplets appearing at 6 5.61 (cis-) and 6 5.75 ( m s - ) ui the

crude 'H NMR. The residue was p e e d by flash chromatography (5% ethed hexanes)

on triethylamine washed silica gel to yield the title compounds as colorless oils (1 81 mg,

96 %).

cis- and Pans 5 - ( 3 - I - B u t y l d i m e t h y l s i l o x y - p r o p y 1 ) - 1 - v i n y 1 (221):

TO a solution of triene 217 (29 mg, 0.093 rnmol) in C6H6 (1.0 rd,) at 23OC was added

75b (4.6 mg, 0.0056 mrnol). The resulting solution was stirred for 90 minutes before

PPh3 (6 mg, 0.0075 mmol) was added and the mixture concentrated to dryness. A cnide

'H NMR showed a 1:l mixture of diastereomers. The ratio was detemined by

comparing the integration of the doublets of quartets appearing at 6 5.59 and 6 5.69 in

the crude 'H NMR. The mumire was purified by flash chromatography (10% ethed

hexanes) on triethylanùne wasbed silica gel to yield the title compounds as a colorless oil

(1 7 mg, 65%).

cis-221 and ans-221: mixture: 'H NMR (400 MHz, CDC13) 6 0.04 (s, 6H), 0.88 (s, 9H),

1.20-1.32 (m, lH), 1.34-1.44 (m, 1H), 1.50-1.64 (m, SH), 1-87 (s, lH), 1.86-2-18 (m, 2

H), 2.54 (tdq, J= 16.5, 7.5, 1.5 Hz, IH), 3.62 (m, 2H3, 5.06-5.31 (series of doublets, 2H),

5.59, (dq, J= 6, 1 Hz, 0.5 H), 5.69 (dq, J= 6, 1 Hz, OSH), 5.82 (dd, J= 17, 1 L Hz, 0.5 H),

5.98 (dd, J= 17, 11 HZ, 0.5 H), 5.91 (quint., J= 2 Hz, OSH), 5.99-6.03 (m, 033); "NMR

(100 MHz, CDC1,) G -5.26, 18.37,25.99, 26.70, 31.65, 37.59,37.64, 47.66, 51.96, 63.39,

63.48, 84.77, 87.21, 112.3 1, 113.05, 132.32, 134.19, 136.12, 136.79, 143.43; IR (neat)

3418,2929,1472, 1255, L 097,995,922,836,775,663.

cis- and tram- 5-(3-t-Butyldimethylsiloxy-propy1)- 1 - v i n benzy 1

ether (222) (Mo Cat.):

To a solution of triene 2 1 8 (20 mg, 0.050 mmol) in C6H6 (0.5 II&) at 23 OC was added a

solution of 74 (2.5 mg, 0.003 mm01) in C6& (OS mL). n i e resuking solution was stirred

for 30 minutes before PPh3 (10 mg, 0.038 mrnol) was added and the mixture concentrated

to dryness. A cmde 'H NMR showed a 1.7: 1 mixture favoring the (R*, S*) diastereorner.

The ratio was determined by comparing the integration of the doublets of triplets

appearing at 6 5.8 1 (cis-) and 6 6.1 7 (pans-) in the crude H NMR. The mixture was

purified by flash chromatography (1% ether/ hexanes) on triethylamine washed silica gel

to yield the title compounds as colorless oils (35 mg, 94%). RA&)= 0.15, RAtrans)=

0.1 0 (2% ether/ hexanes).

cis-222 : 'H NMR (400 MHz, CDC13) 6 0.04 (s, 6H), 0.89 (s, 9H), 1.17-1 -28 (m, IHJ,

1.50-1.66 (m, 3K), 1.87 (qt, J= 8,2 Hz, lH), 2.31-2.41 (m, l m , 2.56 (qq, J=8, 1.5, lm,

3.55-3.64 (m, 2H), 4.49, 4.53 (AB, 12 Hz, 2H), 5.12 (dd, J=18, 2 Hz, lH), 5.19 (dd

J=l l , 2 Hz, ZH), 5.81 (dt,J=6, 2 Hz, IH), 5.89 (dd, J=18, 11 Hz, lH), 6.05 (dt,J=6, 1.5

Hz, lm, 7.21-7.26 (in, lH), 7.28-7.36 (m, 4H); I3c NMR (100 MHz, CDC13) 6 5.27,

18-33, 25.97, 26.81, 31.78, 37.06, 47.79, 63.44, 65.64, 93.08, 115.19, 127.01, 127.11,

128.19, 132.74, 134.44, 138.85, 139.90; IR (neat) 3062, 2929, 2856, 1497, 1472, 1406,

1381, 1360, 1255, 1096, 1064, 1028, 1005, 924, 836, 775, 733, 696, 667; HRMS

calculated for C23&602Si 0: 3 72.2453, found 372.2469

tram-222: 'H NMR (400 M l 3 q CDCl,) 6 0.05 (s, 6H), 0.90 (s, 9H), 1.51-1.68 (m, 3H),

1.68-1.80 (m, lH), 2.22 (ddt, J= 16.5, 8, 2 Hz, lH), 2.52 (dddd, J= 16.5, 9, 3, 1.5 Hg

lH), 3.59-3.68 (m, ZH), 4.36,4.48 (AB, 12 Hz, 2H), 5.14 (dd, J=l 1, 2 Hz, lH), 5.24 (dd

J=18, 2 Hz, lH), 5.81 (dq, J=6, 1.5 Hz, lH), 6.04 (dd, J=18, 11 Hz, l m , 6.17 (dt, J= 6

Hz, 2 Hz, lH), 7.20-7.26 (m, lH), 7.28-7.36 (m, 4H); "C NMR (100 MHz, CDC13)

6-5-25, 18.37,24.36,25.99, 31.96,38.32,50.08,63.59, 65.26,77.31, 89.21, 113.84, 126

-65, 126.76, 128.06, 132.63, 137.06, 140.30, 142.IB; (neat) 3056, 2929, 2857, 1741,

1608, 1472, 1434, 1380,1255, 1094,996,924,835,775,742,695; HRMS calculated for

CL9H2702Si (M-C&g) 315.1780, found 315.1781.

cis- and Pans- 5 - ( 3 - t - B u t y l d i m e t h y l s i l o x y - p r o p y 1 ) - 1 - v i n benzyl

ether (222) (Ru Cat.):

To a solution of triene 218 (39 mg, 0.097 mrnol) in dichloromethane (1.0 mL) at 23OC

was added 75b (2.4 mg, 0.003 rnmol). The resulting solution was stirred for 1 hour

before PPh3 (3 mg, 0.0 14 mrnol) was added and the mixture concentrated to dryness. A

crude 'H NMR showed an 8:1 mixture favorùlg the (cis-). The ratio was determined by

comparing the integration of the doubler of triplets appearhg at 6 5.8 1 (cis-) and 6 6.17

(trans-) in the crude 'H NMR. The mixture was purified by flash chromatography (1 %

ether/ hexanes) on triethylamine washed silica gel to yield the title compounds as

colorless oils (36 mg, 99%).

Benzoic acid 5-ethoxycarbonyl-4-hydroxy-pent-2-enyl ester (224).

n-BuLi (2.02 mL, 5.26 mmol) was added to a -78°C solution of iPr2NH (737 PL, 5.26

m o l ) in THF (20 mL). After 10 minutes, ethyl acetate (514 jL, 5.26 m o l ) was added.

M e r 10 minutes, a solution of 223 (1.00g, 5.26 mmol) in THF (5 mL) was added via

cannula. After 10 minutes, a saturated solution of ammonium chloride was added and the

mixture was warmed to 23OC. The mixture was extracted three tirnes with ethyl acetate,

the organic layers were combined, washed with brine, dned over MgSO4, filtered and

concentrated to dryness. The residue was p d e d by flash chromatography (50% ethyl

acetate/ hexanes) to yield the title compound as a colorless oil(1.12g, 77%).

Mixture of E- and 2- isomers R ~ 0 . 3 0 (35% ethyl acetate/ hexanes), 'H NMR (400 MHz,

CDC13) 6 1.27 (t, J=7 Hz, 3H (E-)), 1.28 (t, 5=7 Hz, 3H (2-)), 2.50-2.66 (m, 2H (E-/Z-)),

3 -07 (d, J=4S HZ, 1 H (E-)), 3 -23 (d, J=3.5 HZ, 1 H (2-)), 4.1 8 (q, J=7Hz, 2H (E-/ 2-)),

4.61 (sextet, J=4 Hz, 1H (E-)), 4.82-5.08 (m, 3H (E-), 4H (2-)), 5.69-5.79 (m, 2H (2-)),

5.89 (ABX, dd, J=15.5, 5.5 HZ, 1H (E-)), 6.05 (ABX, dt, J=15.5, 6 Hz, 1H (2-)), 7.44 (t,

J=7S H, 2H (E-/ 2-)), 7.54 (t, J=7.5 HZ, 1 H (E-/ 2-)), 8.05 (t, J=7.5 Hz, 2H ((E-/ 2-));

13c NMR (100 MHz, CDC13) 6 14-09, 41-10, 41-25? 60-77, 60.80, 64.35, 64-42, 67.89,

125.19, 125.84, 128.30, 128.32, 129.56, 129.91, 130.00, 132.96, 133.03, 134.63, 134.90;

IR (Neat) 3481,2985,l714, 1459,1371, 1272,1177,1104,1029,712.

Benzoic acid 4-(tert-bu~l-dimethyl-siIanyloxy)-5-ethoxycarbonyl-pent-2-enyl ester

(225)-

TBSOTf (681 PL, 2.96 mmol) was added to a -10°C solution of 224 (750 mg, 2.69

m o l ) and 2,6 Iutidine (372 jL, 3.23 mmol) in CH2C12 (10 mL). After 45 minutes, the

reaction mixture was partitioned between CH2Cl2 and NaHC03. The aqueous layer was

extracted three times with CH2Cl2, the organic layers were combined, washed with brine,

filtered through cotton and concentrated to dryness. The residue was purified by flash

chromatography (10% ethyl acetatel hexanes) to yield the titie compound as a colorless

oil(1.05 g, 99%).

Mixture of E- and 2- isomers: R ~ 0 . 4 0 and 0.33 (10% ethyl acetate/ hexanes); 'H NMR

(400 MHz, CDCI.3) G 0-04 (s, 3H ( E - ) ) y 0.06 (s, 3H (E-/ Z-)), 0-08 (s, 3H (Z-)), 0.85 (s, 9H

(2-)), 0.87 (s, 9H (E-)), 1.23-1 -38 (m, 3H (E-/ 2-)), 2.41-2.63 (m, 2H ((E-/ 2-)), 4.06-4.19

(m, 2H ((E-/ 2-)), 4.65 (dt, J=8, 5 HZ, 1 H (E-)), 4.80 (d, J=4S HZ, (E-)), 4.86-4.92 (m,

1H (2-)), 4.92-5.03 (m, 2H (2-)), 5-66-5.69 (m, 2H (2-)), 5.83-5.95 (m, 2H (E-)), 7.44 (t,

J=7.5, 2H ((E-/ 2-)), 7.56 (t, J=7.5 Hz, 1 H ((E-/ 2-)), 8.04 (d, J=7.5 H, 2H ((E-/ Z-)); 13c

NMR (100 MHz, CDCI,) G -5- 12, -4.50, -4.37, 14- 16, 17-96, 18.04, 25-63, 25.69, 43.60,

43.62, 60.43, 60.48, 60.68, 34.49, 65.84,69.72, 123.78, 124.40, 128.33, 129.56, 129.60,

130.15, 132.94, 132.98, 136.52, 136.70; IR (Neat) 2961, 2847, 1722, 1451, 1368, 1265,

1177; Elemental Analysis: Calculated: %C=64.25, %H=8.22, Found: %C=64.38,

%H=8.50.

3-(tert-Butyl-dimethyl-silany1oxy)-hex-5eoc acid ethyl ester (226).

Triethylamine (643 PL, 4.59 mmol), formic acid (210 PL, 4.59 mmol) and n-Bu3P (46

pL, 0.183 m o l ) were added to a 23OC solution of Pd~(dba)~ (42 mg, 0.056 mmol) in

THF (5 mL). M e r 15 minutes, a solution of 225 (600 mg, 1.53 m o l ) in THF (3 mL)

was added via cannda. M e r 12 hours the mixture was partitioned between CHzCIz and

W C 1 (sat.)- The aqueous layer was extracted three times with CH2CIz, washed with

brine, filtered through cotton and concentrated to dryness. The residue was purified by

flash chromatography (5% ethyl acetate/ hexanes) to yield the title compound as a

colorless oil(414 mg, 99%). Rï0.67 (10% ethyl acetatel hexanes), 'H NMR (400 MHz,

CDC13) S 0.04 (s, 3H), 0.07 (s, 3H), 1.26 (t, J=7 Hz, 3H), 2.27 (t, J=6.5 HZ, 2H), 2.42 (d,

J=2.5, lH), 2.43 (d, J=1 Hz, lH), 4.12 (qd, J=7, 2.5 Hz, 2H), 4.20 (quint, J=6 Hz, lm,

5.03-5.10 (m, 2H), 5.74-5.86 (m, 1H); 13C NMR (100 MHz, CDC13) 6 -4.93, -4.5 1,

14.18, 17.98, 25.70,25.73,42.14,42.22,60.29, 68-00, 117.70, 134.18, 171.81; IR (Neat)

2943,2842, 1736, 1466,1368,1309,1253, ll73,lO89,lO27,998,9l7,834.

5 - ( t e r t - B u t y l - d i m e t h y l - s i l a n y 1 o x y ) - 3 - w o l ( 2 2 7 ) .

Methyl ester 226 (290 mg, 1.06 mmol) was reacted according to the general procedure

for the formation of tertiary diallylic alcohols. The crude mixture was purified by flash

chromatography (5% ether/ hexanes) to yield the title compound as a colorless oil (251

mg, 84 %).

RI= 0.21 (5% ether / hexanes), 'H NMR (400 MHz, CDCb) 6 0.12 (s, 3H), 0.13 (s, 3H),

0.92 (s, 9H), 1 -74 (d, &3.5 Hz, 1 H), 1 -73 (s, 1 El), 2.23-2.34 (m, 2H), 4.05-4.12 (m, 1 H),

4.3 (s, lH), 5.02 (dd, J=10.5, 1.5 Hz, l m , 5.04-5.10 (m, 2H), 5.18 (dd, J=10.5, 1.5 Hz,

lH), 5.26 (dd, 5=18.5 1.5 Hz, lH), 5.39 (dd, J=17 H Z 1.5 Hz, lH), 5.67-5.78 (m, lH),

5.84 (dd, J=17, 10.5 Hz, 2H); "C NMR (100 MHz, CDCI,) 6 -4.39, -3.41, 17.88, 25.89,

42.73, 44.29, 70.94, 75-87, 112.00, 113.61, 117.89, 133.58, 142.09, 143.44; IR (Neat)

3486, 3070, 2947, 1638, 1463, 1408, 1357, 1257, 1176, 1141, 1057, 1141, 1057, 992,

924, 834, 770; HRMS calculated for (M-H)+: 28 1.193 7, found: 28 1.1930.

lS*,5S*-5-(tert-BuS.L-dimet hy I-silanylo-1-y-cycloex-2eo (O-ans-229) and

l S * , 5 R * - 5 - ( t e r t - B u t y 1 - d i m e t h y l - s i I a n y l o ~ - e n o I (cis-229).

75b (7.3 mg, 0.009 mmol) was added to a 23°C solution of 227 (50 mg, 0.177 mmol) in

CH2C.L2 (2 mL). M e r 20 hours, a M e r 13 mg of 75b was added. M e r 90 minutes,

Ph3P (30 mg) was added and the reaction mixture concentrated to dryness. The residue

w s purified by flash chromatography (5 + 15% diethyl ether/ hexanes) to yield the title

compounds as an inseparable mixture (40 mg, 88%).

Mixture of @ans- (OHttOTBS) and cis- (2.51) R ~ 0 . 0 8 (10% ether / hexanes), 'H NMR

(400 MHz, CDCL) 8 0.09 (s, 3H), 0.90 (s, 9H), 1-67 (dd, J= 13, 12 Hz, 1 H (tram)), 1-82

(ABX, dd, J= 13.4, 2 Hz, 1H (cis)), 1.92-2.06 (m, 2H (pans)), 2.22-2.28 (m, 2H (cis)),

2.36 (ABX, dt, J=17.6, 5.5 Hz, 1H (fians)), 3.91 (bs, 1H (cis)), 4.06-4.18 (m, 1H,

(trans)), 4.24-4.29 (m, 1 H (cis)),, 5 -07 (d, J= 10 -5 Hz, 1 H (trans)), 5 -09 (d, J= 1 1 Hz, 1 H

(cis)), 5.26 (d, J=17.4 Hz, 1K (cis)), 5.28 (d, J=17.2 Hz, 1H (trans)), 5.54 (ABX, dm,

J=lO Hz, 1H (tram)), 5.66 (m, 2H (cis)), 5.77 (ABX, ddd, J= 10, 6, 2 Hz, 1H (trans)),

5.88 (dd, J= 17.4, 1 1 Hz, 1H (cis)), 5.94 (dd, &17.2, 10.5 Hz, 1H (trans)); I3c NMR

(100 MHz, CDC13) 6 -5.08, -4.97, -4.67, -4.64, 17.96, 18.13, 25.75, 25.85, 33.64, 35.38,

41.91,45.42, 65.31,66.72,70.09,72.90, 112.09, 112.84, 124.14, 128.35, 130.31, 132.08,

143.63, 144.31; IR (Neat) 3423, 2930, 2852, 1377, 1251, 1107, 1001, 917, 839, 779;

HRMS catcdated for (M-H)+: 253-1624, found: 253.163 3.

5-(l-Tributylstannylmethoxy-l-vinyI-a~yl)-nona-1,8-diene (230):

Potassium hydride (729 mg, 7.27 m o l ) was washed three times with pentane, dried

under a stream of argon and suspended in THF (5 mL). A solution of alcohol 197 (500

mg, 2.42 mmol) in THF (3 mL) was added via cannula- After 5 minutes, a solution of

ICHzSnBus in THF (2 mL) was added via cannula followed by a small crystal of dry 18-

crown-6. The resulting mixture was heated to reflux for 1 hou, cooled to 23"C, diluted

with ether, and quenched carefully by drop-wise addition of water. The aqueous layer

was extracted 2 times with ether, the organic Iayers were combined, washed with b ~ e ,

dried over sodium sulfate, filtered and concentrated to dryness. The residue was pursied

by flash chromatography (100% hexanes) on triethylarnine washed silica gel to yield the

title compound as a colorless oil(1.15 g, 93 %). RF 0.55 (100 % hexanes) 'H NMR (400

MHz, CDCI3) G 0.89 (t, J= 7 HZ, 9H), 0-89 (fiy &-~n)= 25 HZ, AH-H)= 8 HZ, 6I3, 1 -04- 1.14

(m, 2H), 1.30 @ex., J= 7 HZ, 6H), 1.40-1.82 (m, 1 lH), 1.86-2.18 (III, 5H), 3.40 (t, 4&Sn)=

10 Hz, 2H),4.92 (dm,J=10 Hz, 2H), -4.97 (dq,J= 17,2 Hz, 2H), 5.17 (dd,J= 18, 2 Hz,

2H), 5.34 (dd, 1 1,2 Hz, 2H), 5.74 (dd, J= 18, 1 1 Hz, 2H), 5.72-5.86 (m, 2H); 13c NlVIR

(100 MHz, CDCU) G 8-84 (t, Ac-sn)= 61 HZ), 13-73> 27-36 6, 26 HZ), 29.21 (t,

4c-sn>= 10 HZ), 30.12, 33-46, 47-02, 52-46, 85.45, 114.03, 117.42, 137.92, 139.40; IR

(neat, c d ) 3079, 2926, 1640, 1456, 1416, 10 17, 909; HRMS calculated for CuJ&OSn

( M - ~ 4 ~ 9 ) ~ : 453 -2 179, fo~nd: 453.2 18 1.

cis 4a-T~butyIstannylmethoxy-l,2,4a,7,8,8a-hexahydrohaphthalene (231):

To a solution of 230 (1.00 g, 1.96 m o l ) in dichlorometinane (20 mL) at 23OC was added

75b (194 mg, 0.240 mmol). The reaction mixture was. placed under an atmosphere of

ethylene and heated to reflux. After 7 hours the reaction was concentrated to dryness and

the residue pded by flash chromatography (100% hexanes + 0.5 % -t 1 % +2 %

etherl hexanes) on triethylamùie washed silica gel to yield the title compound as a

colorless oil(760 mg, 86 %). RF 0.19 (1 % ether/ hexames) 'H NMR (400 M J h , CDC13)

6 0.88 (t, J= 7 HZ, 9H), 0.88 (tt, &-Sn)= 25 HZ, J[H-H)= 8 HZ, 6H), 1.25-1.34 (m, 6H),

1.43-1.54 (m, 6H), 1.70-1.79 (m, 2H), 1.98-2.05 (m, 4HI), 2.13 (hept., J= 3.5 Hz, ZH),

2-71-2234 (m, 3H), 3.53 (t, 10 Hz, 2H), 5.51 (dt, J=10,2 Hz, 2H), 5.80 (dt, J= 10,

4 Hz, 2H); 13c NMR (100 MHz, CDC13) 6 8.93 (t, J(C-Snl= 61 Hz), 13-74,23.41, 24.30, (t,

26 Hz), 29.17 (t, 4c-snI= 10 Hz), 32.99, 50.86, 74.69, 129.02, 130.49; IR (neat)

3051, 2924, 1464, 1348, 1040, 758; HRMS calculated for CisH3pOSn (M-C~H~)+:

397.1553, found: 397.1549.

cis (2,3,4,4a,5,6-Hexahydronaphthalen-2-yl)-rnethanoR (238):

MeLi (1.08 M, 214 PL) was added to a solution of sta?nnyLmethyl ether 231 (100 mg,

0.221 rnrnol) and HMPA (154 PL, 0.882 mmol). After 15 minutes the reaction was

quenched by adding MeOH (2 drops). The mixture w*as purified by adding the crude

reaction directly to column of triethylamine washed sllicca gel and eluting with 30% ether/

hexanes to yield the title compound as a colorless oil C28 mg, 74%). Rf= 0.17 (30%

ether/ hexanes); 'H NMR (400 MHz, CDC13) 6 1.21 -1. 36 (m, 3H), 1.36-1 -47 (m, 1 H),

1.77-1.94 (m, 3H), 2.08-2.26 (m, 3H), 2.39-2.49 (bs, 1 H), 3.50-3.61 (m, 2H), 5.37 (s,

lH), 5.72-5.78 (m, 1H). 6.02 (dm, J= 10 Hz, 1H); ')c NIMR (100 MHz, CDCb) 6 25.97,

26.07,30.10,30.21,35.76, 39.71,67.50, 123.77, 128.62, 129.12, 139.59.

Dienol239.

Ry0.25 (30% ether/ hexanes); 'H NMR (400 MHz, CDC13) 6 1.32 (t, J=6Hz, 1 H), 1.54

(ABX, sex., J=6.5 Hz, 2H), 1.68 (ABX, sex.d, P6.5, 3.5 Hz, 2H), 1.93-2.10 (m, 5H),

3.42 (d, J= 6.4 Hz, 2H), 5.33 (ABX, dt, H O , 2 Hz, 2H), 5.82 (ABX, dt, J=10, 5.8 Hz,

2H); I3c NMR (1 00 MHz, CDC13) S 23.22,24.57,32.05,43.l9,68.73, 128.77, 130.09.

5-(l-TrimethylsiIoxy-I-vinyl-aiiyI)-nona-l,&diene (233).

A 23°C suspension of KH (161 mg, 1.27 rnmol, 35% suspension in oil, washed 3 times

with pentane) in THF (5 mL) was added to neat 197 (250 mg, 1.21 mmol). After 15

minutes, TMSCl (1 61 pL, 1.27 mmol) was added via syringe. After 30 minutes, water

was added, and the mixture extracted three times with ether. The organic layers were

washed with brine, dried over NazS04, filtered and concentrated to dryness. The residue

was purified by flash chromatography (100 % hexanes) on trïethylamine washed silica

gel to yield the title compound as a colorless oil (3 10 mg, 92%). 'H NMR (400 MHz,

CDCl,) 6 0.88 (s, 9H), 1.05 (m, 2H), 1.39 (septet, J=3.5, lH), 1.58-1.65 (rn, 2H), 1.99-

2.19 (m, 4H), 4.92 (dm, J=10 Hz, 2H), 4.99 (dq, J=17, 1.7 Hz, 2H), 5.21 (ddJ=10.5, 2

Hz, 2H), 5.25 (dd, J=17.5, 2 Hz, 2H), 5.73-5.84 (rn, 2H), 5.92 (dd, J=17.5, 10.5 Hz, 2HJ;

13c NMR (100 MHz, CDCl3) G 2.59, 30.09, 33.50,48.05, 81.60, 114.14, 115.81, 139.38,

141 -03; HRMS calculated for CisHz70Si (M-c~H,)+: 25 1.183 1, found: 251.1824.

cis-4a-Trimethylsiloxy-l,2,4a, 7,8, Sa-hexahydronaphthalene (234).

A solution of 74 (174 mg, 0.23 mmol) in C6H6 (5 rnL) was added to a flask containing

233 (603 mg, 2.30 mmol). Afier 30 minutes 600 mg of P P b was added and the mixture

concentrated to dryness. The residue was purified by flash chrornatography (2% ether on

triethylamine washed silica gel) to yield to title compound as a colodess oil consisting of

a 5: 1 mixture of diastereomers favoring the cis- isomer (64 mg, 99%). 'H NMR (400

MHz, CDC13) 8 0.12 (s, 9H), 1.44-1.53 (m, 2H), 1.76-1.84 (m, 2H), 1.91-1.98 (m, lH),

1.99-2.12 (rn, 4H), 5.57 (dt, J=IO, 2Hz, 2H), 5-71 (dt, J 4 0 , 3.7 Hz, 2H); 13c (100

MHz, CDC13) 6 2.66, 23.23, 24.24, 39.85, 71.25, 127.38, 132.35; IR (neat, cm-') 2924,

1448,1428,1246, 1067,1029,907.

cis 2,7,8,8a-Tetrahydro-1H-naphthalen-4-ol(203).

TBM (355 mg, 1.28 mmol) was added to a 23°C solution of 234 (100 mg, 0-427 mmol)

in THF (2 d)- M e r 1 hour, the mixture was diluted with CH2C12, washed with Na2C03

(satutated) and brine, filtered through Cotton, concentrated to dryness and purified by

flash chromatography (30% diethylethed hexanes) on triethylamine washed silica gel to

yield the title compound as a colorless oil (55mg7 86%).

cis-4a-(Prop-2-ynyloxy)-l,2,4a, 7,8,8a-hexahydronaphthalene (236).

A THF (1 mL) solution of 203 (IO0 mg, 0.67 mrnol) was added to a 23°C suspension of

sodium hydride (133 mg, 3.33 mmol, 60% suspension in oil) which had been washed

three times with pentane. After five minutes, propargyl bromide (375 PL, 3.33 mmol,

70% solution in toluene) was added via syringe. After 26 hours, the reaction was

quenched by the careful addition of water. The mixture was extracted three times with

ether, the organic layers were combined, washed with brine, dried over Na2S04, filtered

and concentrated to dryness. The residue was purified by flash chromatography (5%

ether / hexanes) on triethylamine washed silica gel to yield the title compound as a

colorless liquid (58 mg, 46%). 'H NMR (400 MH5, CDCl,) G 1.46-1 -56 (m, 2H), 1.78-

1.87 (m, 2H), 1.96-2.15 (m, 5H), 2.36 (t, J=2.5 Hz, lH), 4.07 (d, J=2.5 Hz, 2H), 5.54 (dt,

&IO, ~ H z , 2H), 5.88 (dt, J=10, 3.7 HZ, 2H); I3c NMR 6 23.26, 24.17, 34.25, 50.53,

72.90, 75.24, 8 1-89, 129.35, 130.53; IR (neat, cm-') 3298, 3025, 2919, 1436, 1052;

HRMS calcdated for M?: 1 87.1 123, found: 1 87.1 126.

ch-4a-(But-2-ynyloxy), 1,2,4a, 7,8,8a, hexahydro-naphthalene (237).

A solution of n-BuLi (90 PL, 0.233 rruriol, 2.5 M solution in hexanes) was added via

syringe to a -78°C solution of 236 (40 mg, 0.212 mmol) in THF (2 r d ) . After fifieen

minutes, methyl iodide (20 pl,, 0-3 18 mmol) was added via syringe and the mixture wâs

ailowed to warm to 23OC. After two hours, water was added and the mixture was

extracted three times with ether, the organic layers were combined, washed with brine,

dried over Na2S04, filtered and concentrated to dryness. The residue was purified by

flash chromatography (5% ether / hexanes) on triethylamine washed silica gel to yield the

title compound as a colorless liquid (54 mg, 90%). 'H NMR (400 MHz, CDC13) 6 1.49

(sextet, J=7 Hz, 2H), 1.75-1.88 (m, 4H), 1.94-2.12 (m, SH), 3.98-4.05 (m 2H), 5.56 (d,

J = i O Hz, 2H), 5.87 (dt, .HO, 3.7 Hz, 2H); 13c NMR 6 3.70, 23.23, 24.18, 34.07, 50.89,

74.67, 76.86, 80.97, 129.54, 130.13;

lS*/R*,laS*, 4aS*-1-(2, 3,4,4a, 5,6-hexahydro-naphthalen-2-yl)-but-2yn-l-o1(242).

t BuLi (233 yL, 0.396 mrnol, 1.7 M solution in pentane) was added to a -78OC solution of

237 (20 mg, 0.099 mmol) in THF (1 mL). After 30 minutes, water was added and the

mixture extracted three times with ether. The organic layers were combined, washed

with brine, dned over MgS04, filtered and concentrated to dryness. The residue was

purified by flash chromatography (10% ether / hexanes) to yield the title compound as a

2: 1 mixture of colorless liquid diastereomers (12 mg, 63%). 'H NMR (400 MHz, CDC13)

6 1.20-2.24 (m, 10H), 2-50 (bs, lH), 4.15 @s, 1H (minor isomer), 4.24 (bs, 1H (major

isomer), 5.44 (s, 1H (major isomer)), 5.58 (s, 1H (minor isomer), 5.72-5.80 (m, lH),

6.00-6.10 (m, 1H); 13c NMR (1 00 MHz, CDC13) 6 -0.03, 3.61, 14.1 1, 22.67, 24.46,

24.86,25.41,25.97, 26.90, 29.69,30.04, 30.08, 30.23, 35-72, 43.91, 66.32, 66-58, 79.05,

8 1-83, 123.12, 123.02, 128.69, 128.76, 129.23, 140.08; IR (neat) 3400,6064,2922,2858,

1716, 1668, 1448, 1377, 1261, 1052; HRMS calculated for M?: 202.1358, found:

202,1351.

3.8 References.

1. (a) Lautens, M.; Hughes, G. Angew. Chem., Inf. Ed. Engl. 1999, 37, 129. (b)

Lautens, M.; Hughes, G.; Zunic, V. Cam J Chem. 2000, 78,868.

2. For other examples of this problem see: Watanbe, S.; Suga, K.; Fujita, T.; Saito, N.

Aust. J: Chem. 1977, 30,427.

3. Imamoto, T.; Takiyama, N.; Nakamura, K.; Habjima, T.; Kamiya, Y. J: Am. Chern.

Soc. 1989,111,4392.

4. For earlier examples showing the influence of a substitution on olefin reactivï~, see:

(a) P. Schwab, R.H. Grubbs, J.W. Ziller, J. Am. Chern. Soc. 1996, 118, 100. (b) A.

Fürstner, K. Langemann, J. Org. Chern. 1996,61,3942-3943.

5. Hoye, T.R.; Zhao, H. Org. Lett. 1999,1, 1 123.

6 Murry, D.F.; Baum, M. W.; Jones, M. J. Org. Chern. 1985,51, 1.

7. (a) Priepke, H.; Brückner, R. Chem. Ber. 1990,123, 153. (b) Still, W.C. J. Am.

Chern. Soc. 1978,100, 1481. (c) StiU, W.C.; Mitra, A. J. Am. Chem. Soc. 1978,100,

1927. (d) Tomooka, K.; Yamamoto, H.; Nakai, T . Liebigs Ann/RecueiZ 1997, 1275.

8. Tomooka, K.; Koinine, N.; Nakai, T. Tetrahedron Lett. 1998,39,55 13.

9 - a) Hamty, J.P.A.; Visser, M X ; Gleason, J-D.; Hoveyda, A-H. J. Am. Chem. Soc.

1997, 119, 1488- b) Weatherhead, G.S.; Ford, J-G.; Alexanïan, E.J-; Schrock, R.R.;

Hoveyda, A.H. J- Am. Chem. Soc. 2000,122, 1828, and references therein.

10. See Chapter 1, reference 28c.

11. a) Ayer, W.A.; Browne, L.M.; Fung, S.; Stothers, J.B. Org. Mag. Res.1978, 11, 73.

b) Brown, L-M.; Klinck, R-E.; Stothers, J.B. ibid, 1979,12,561,

4 Novel application of palladium catalyzed formate reductions in the preparations of terminal olefins.

Terminal olefms are fiequently employed in organic synthesis. With the growing

importance of RCM reactions, demand for their use will continue to grow. The ease with

which these materiais are prepared varies fiom substrate to substrate.

4.7 Current methods for the preparation of terminal olefins.

Wittig olefmation of aldehydes is a commonly employed approach to terminal

olefins, but this is unappealing on large scale due to the quantities of triphenylphosphine

oxide which are produced. Elimination reactions may also be employed, however these

pathways can be tedious. They often suffer fkom poor regioselectivity and usually

require the use of selenium reagents which are toxic and expensive (Scheme 1). Another

method for introducing terminal olefins is the alkylation of nucleophiles with

electrophiles containing a terminal olefin, such as allyl halides.

o - N ~ ~ C ~ H ~ S ~ C N / \ / O H

_ -SeAr [O]_ R

d BusP, THF. heat

Allcyation:

NuH Base ___t NU- - w

Nu n Scheme 1. Approaches to terminal o lehs .

4.2 Palladium catalyzed formate reductions of allylic electrophiles fo form terminal olefins in probletnatic cases.

While these approaches often function adequately, we have identified two

instances where the use of partïcularly useful unsaturated electrophiles was precluded

either because of their inaccessibility or incompatibility with the conditions associated

with nucleophilic attack. Specifically, these electrophiles are Qbromo- 1-butene and P,y-

unsaturated aldehydes. 4-Bromo- l -butene is expensive1 and prone to elimination, and

P,y-unsaturated aldehydes can be difficult to prepare and handle without bringing the

double bond into conjugation.

One approach to the preparation of terminal o l e h s which caught our attention as

a possible solution to both of these difficulties is the palladium catalyzed formate

reduction of allylic electrophiles (e-g. allylic chlorides, acetates, carbonates, etc.)

developed by Tsuji and CO-workers in the late 1970's and 1980's (see Chapter 1). As

outlined below, we felt that this transformation would allow for the use of surrogates for

both butenyl electrophiles and p,y-unsaturated aldehydes. The substitutes would contain

an allylic functionality that could be converted to terminal olefh (Scheme 2).

-1,6dichlorobutene as a surrogate for butenyl electrophiles:

- cx,f&unsaturated aldehydes as surrogates for B,y-unsaturated aldehydes:

Scheme 2. Application of palladium catalyzed formate reductions for the preparation of terminal olefins.

4.2.1 1,4-Dichlorobut-2-ene as a surrogate for conventional 1 -buten-4-yl electrophiles.

Dichloride 254 is much less expensive than more conventional butenyl

ele~tro~hiles,' and should display a stronger preference for allqlation versus elimination

to give allylic chlorides 255 andi or vinyl three-membered rings 256. Formate reduction

of these species in the presence of a suitable palladium catalyst would then fûmish the

desired butenylated nucleophiles 257 (Scheme 2). Ln some cases this approach merely

circumvents issues of economics, but in reactions involving harder nucleophiles this

strategy may function adequately where more traditional butenylation methods fail?

129

4.2.1 -1 Butenylation of nitrogen nucleophiles.

To test our proposal, a number of nitrogen-based nucleophiles were examined

(Scheme 3). Butenyl phthalimide 263 was formed in good yieId by attack of

commercially available potassium phthalimide on 254, followed by Pd catalyzed formate

reduction. While this product has previously been prepared, the literature procedure

required the use of the 4-bromo- 1 -butene, or 3-buten-l -ol under Mitsunobu conditions,

which can be problematic particularly with regards to scale up.'

a) CICH$X=CHCH2CI (4.0 eq.), THFI DMF, -7S°C -> 23%, 2 hr., b) HC02NH4(22

eq.), Pdz(dba)3 (0.03 eq.), n-Bup (0.24 eq.), toluene, 1009C, c) Cs2C03 (3 eq.), CICH2CH=CHCH2Cl(4.0 eq.), CH-jCN, reflux, 18 hr., d) Kg03 (1.5 eq.),

C1CH2CH=CHCH2C1 (4.0 eq.), DMF, 23OC, 45 hr., e) HC02NH4 (22 eq.), Pd2(dba)3

(0.0 1 eq.), n-Bup (0-08 eq.), toluene, 1 OO°C, 90min-

Scheme 3. Butenylation of nitrogen nucleophiles.

Tosyl protected secondary amine 266 was also prepared using the two step

process. This substrate is particularly interesting as literature reports regarding the

synthesis of similar substrates using standard 1-buten-4-y1 electrophiles have proven to be

problematic, r e q u i ~ g extensive optimization of the reaction conditions."

The use of constrained polypeptides as p-turn minietics is an important endeavor

in medicinal cherni~try.~ One strategy recently disclosed by Liskamp involves

butenylation of the nitrogen atoms of two amino acids within the peptide back bone,

followed by ruig closing metathesis? In a combinatorid approach, Liskamp used a

Mitsunobu strategy to introduce the butenyl substituent. In light of this report, we

decided to prepare an N-butenylated amino acid using o u two step approach (Scheme 4).

The m -nitrophenyl sulphonyl protected methyI ester of phenylalanine (2 6 7) was

converted to allyl chloride 268 under standard conditions in good yield.6 Pd/ HC02-

reduction again proceeded in excellent yield to give the desired N-butenylated amino acid

269.

4.2.1.2 Butenylation of enolate nucleophiles.

We required a number of butenylated carbon nucleophiles for a diastereoseIective

ring closing metathesis project (Chapter 3) and we found the two step protocol to be most

beneficial. Treatment of monosubstituted malonate 1108 with methoxide in the presence

of excess 254 in methanol af5orded a 57% yield of allyl chlonde 193, whîch upon Pd

catalyzed formate reduction afforded the desired dibutenylated malonate 194 in 90%

yield (Scheme 4).

~ L & L + 40% of 273 91%

274

$-cl

272

a) NaOMe (12 eq.), CICH2CH=CHCH2CI (4.0 eq-), MeOH, 23 OC, 2.5 hr., b) HC02NH4 (2.2

eq.), Pd2(dba)3 (0.25 mot %), n-Bu3P (2 mol%), toIuene, LOOOC, 16hr., c) LDA (12 eq.),

CICH2CH=CHCH2Ci (4.0 eq.), HMPA (4 eq.), THF, -78'C-> 23OC, 16 hr., d) HC02N& (2.2

eq-), Pd2(dba)3 (3 moI%), n-Bu3P (24 mol%), toluene, 100 OC, e) LDA (1.0 eq.),

CICH2CH=CHCH2Cl (4.0 eq.), HMPA (1.1 eq.), THF, -78OC -> 23OC, 16 hr., f ) HC02NH4

(22 eq.), Pd2(dba)3 (3 mol%), n-Bu3P (24 mol%), toluene, &O, IO0 OC.

Scheme 4. Butenylation of enolate nucleophiles.

We also examined the use of "barder", more basic nucleophiles such as the

lithium enolates of a lactone and cyclic ketone. Alkylation of the lithium enolate of y-

butyrolactone with 254 gave allyl chloride 271 in moderate yield. Palladium catalyzed

formate reduction provided 272 in 99% yield (Scheme 4).

Subjecting the lithium enolate of cyclohexanone to the same sequence of reactions

afforded two unexpected results. Firstly, in addition to allylic chionde 272, the alkylation

reaction produced significant quantities of vinyl cyclopropane 273- Fortunately, both 272

and 273 undergo the reduction process to give the desired butenylated cyclohexanone.

While Shimizu has previously shown that vinyl cyclopropanes having two

electron withdrawing groups are suitable substrates for palladium catalyzed reductive

ring opening,' to the best of our knowledge, this is the f rs t example of an opening

o c c h g with a vinyl cyclopropane having only one electron withdrawing substituent.

For the sake of simpliciîy and economy, 254 was used as a lirniting reagent (treating with

2.2 eq. of the lithium enolate of cyclohexanone) resulting in a 40% yield of 273 as an

irrelevent separable 4: 1 mixture of dia~tereorners~

The palladium catalyzed formate reduction of vinyl cyclopropane 273 was most

effective using moist ammonium formate. When the formate source was dry, a

significant arnount (10-50%) of a side product, dihyrdrohan 275, was isolated. This

material presumably arises fiom intramolecular attack of the ketone enolate onto the

intenial carbon of the x-allyl Pd cornplex. Protonation of the enolate by water would

negate this pathway.

Pd2(dba)3 (2 mol%)

273 275 BlNAP (8 mol%), THF

60°C, 85%, %ee=??

Scheme 5. Palladium catalyzed remangement of vinylcyclopropanes

In the absence of water or a formate source, vinyl dihydrofûran 275 is the only

product obsenred (Scheme 5). We were intrigued by the possibility of rendering this

transformation enantioselective by the addition of a chiral ligand. While we were pleased

to £ïnd that this transformation can be effectively catalyzed by a Pd-BINAP complex to

afford 275 in good yieid, we have been unable to determine the level of enatiomeric

excessm8

4.2.2 a$-Unsaturated aldehydes as surrogates for P,y-unsaturated aldehydes.

In contrast to B,y-unsaturated aldehydes, whose instability with regard to double

bond isomerization complicates their preparation and application, a$-unsaturated

analogues are easy to prepare and manipulate. Incorporation of an allylic leaving group,

as in 258, allows for Pd catalyzed formate reduction to follow nucleophilic attack of the

aldehyde to give the desired tenilinal olefin 260 (Scheme 2)-

A particularly intriguing possibility arises when R#H, in which case the P,y-

unsaturated aldehydes usually exhibit low Cram facial selectivity (-3 -4: 1 ) in nucleop hilic

additionsm9 When using intermediates 259 derived fiom 258 where R#H, hydnde is

delivered to one of the two diastereotopic faces of the allylic system, generating a new

stereocenter. We felt that controlling the selectivity of such a transformation would

afford a convenient method for the synthesis of homoallylic alcohols 260.

4.2.2.1 Surrogates for but-3-enal.

4.2.2.1.1 Formation of racemic aldol products.

We began our investigation of the hvo step approach using 3-pentanone and 223

as aldol coupling partners. After examining a nurnber of aldol conditions, we found the

titaniurn enolate of the ketone to be most convenient. As might be expected, addition of

this enolate to 223 furnished the syn-aldol product 276, l 1 which was silylated to give 277

in 92% yield over two steps. We were pleased to find that subjecting 277 to typical

formate reduction conditions gave the terminal olefin 278 in 95% yield as a single

regioisomer within the detection limits of 'H NMR (Scheme 6).

a) TiCI4 (2.0 eq.), CH2C12, -7g°C, 10 min; iPr2NEt (1-1 eq,), 20 min-; 223 (0.5 eq.), 90 min. b)

TBSCl(2.0 eq.), DMAP (O. 1 eq.), D m , 90 min. c) HCO~W+ (2.2 eq.), Pd2(dba)3 (3 mol%),

n-Bu$ (24 mol%), toluene, IOOOC, 3 hours.

Scheme 6. Alternatives to 3-butenal.

It is important to note that 276 and 277 were quite stable and no special

precautions were necessary in the isolation of these compounds, which could have been

prone to elimination reactions to f o m conjugated dienones.

4.2.2.1.2 Formation of non-racemic aldol products.

In good agreement with the findings of ~rirnnins," treating oxazolidinethione

279 with 2.0 eq. of TiCl4, 1.1 eq. of iPrzEtN, and 1.1 eq. of 223 afEorded an 86% yield of

the syn-aldol product 280 (99% yield brsm). Silyl ether formation gave the reduction

precursor 281 in 86% yield. We were initially concerned that the presence of a sulfür

atom might interfere with the Pd catalyzed formate reduction, but these fears proved

unfounded as subjecting 281 to essentially the same conditions used for the reduction of

277 gave a good yield of the desired temiinal o l e h 282 (scheme 7). The progress of the

reaction had to be monitored carefully as extended reaction times gave nse to hydrolysis

of the chiral auxiliary.

a) TiC14 (2.0 eq.), CH~CIL O°C, IO min.; iPr2NEt (1.1 eq-), 20 min; 223 (1.1 eq.), - 7 8 ' ~ ~ 90 min.

b) TBSOTf (1 .O eq.), 2,6-Iutidine (1-7 eq.), CHzCIa -10 OC, 13 hours . c) H C 0 2 w f (2.2 eq.),

P ~ i ~ ( d b a ) ~ (3 mol%), II-Bu3P (24 mol%), toIuene, IOOY, 5 min.

Scheme 7. The use of aldehyde 223 in non-racernic aldol reactions.

4.2.2.2 Diastereoselective formate reductions.

With these encouraging results in hand, we turned to the formate reduction of

aldol products derived fiom aldehyde 283. A simple three step literature procedure

provided 283 in 50% yield fiom chl~roacetone.'~ An aldol reaction was again perfomed

using the addition of the titanium enolate of 3-pentanone to 283 (86%) followed by

silylation of the secondary alcohol to give triethylsilyl ether 284 in good yield (91%)

(Scheme 8).

a 1) TiCI, (1 -1 eq.), iPr,NEt

CH2CI2, -78'~

I f 2) 283 (1 .O eq). 85% 1 1 1 3) TESOTf, 2.6-Lutidin@, 91% 284

283

Scheme 8. Formation of Starting Matenai for Diastereoselective Formate Reduction.

The formate reduction of 284 proved more challenging than previous substrates.

Application of the same conditions utilized to reduce 277 gave low conversion (Table 1,

entry 1). A number of different conditions were investigated in an effort to improve

conversion of 284 to 285 (Scheme 9). While the use of lower phosphine:Pd ratios did

increase the conversion (Table 1, entries 2,3), very little of the desired terminal olefin was

produced and diene 287 was found to be the major product.L3 While the use of a lower

boiling solvent (THF) in conjunction with a more soluble formate sourceL4 improved the

ratio of formate reduction to B-hydride elimination, the percent conversion was somewhat

lower (35%, entry 4). We were encouraged to find that the use of DMF as solvent gave

rise to a significant rate acceleration and complete consumption of 284 was now observed

after 18 hours at 60 OC (entry 5). Furthermore, none of the undesired diene product 287

was observed by 'H NMR spectroscopy and a moderate level of diastereoselectivity

(2.7:l) was observed, with the syn- reduction product dominating." The ratio of texminal

to interna1 olefin (285 : 286) was 4: 1. Under these conditions, however, significant

amounts of silyl ether hydrolysis (50%) was observed? This is particularly problematic

as the free alcohol undergoes nonselective reduction to give a 1 :l mixture of

diastereomers (288).

HCO~-NH~+, Solvent d$JyL +Jii+ syn-285 286 288

P hosp hine

Pd2(dba)3 (5 mol%)

Temperature

Scheme 9. Diastereoselective Pd cataiyzed formate reductions.

Table 1. Diastereoselective formate reduction.

nin Solvent Temp- / Time P:Pd ratio Ratiosa (%) d? (OC/ hr.)

284 285 286 287 288 (syn-285: anti-285)

1 Toluene LOO/ 16 4: 1 99 - - - -

2 Toluene 1 IO/ 16 2: 1 O 19 4 77 O

3 Dioxane 100/ 16 2: 1 O O O 1 O0 O -

5 DMF 60/ 18 2: 1 10 32 8 O 50 2.7: 1

6 DMF 60/ 18 I:1 5 60 15 O 20 4.9: 1

7 DMF 50/ 18 1 :2 5 89 (75)C 10 O 4 5.7: 1

8 DMF 60/ 18 1 :4 90 ( 5 <5 <5 ( 5

9 DMF 60/18 O: 1 90 O O O O

a) Ratios were determined by 'H NMR of crude reaction mixtures. b) HCO<Et3NH+ \vas used as a formate source. c) isolated yieid of qm-285.

The desilylation was found to be dependent upon the phosphine:Pd ratio, so that

l o w e ~ g the ratio to 1: 1, (entry 6 ) resulted in only 20% desilation. A rnoderate increase

in diastereoselectivity (dr4.9: 1) was also observed. Decreasing the phosphine:Pd ratio

even M e r to 1:2 (entry 7) afforded the optimal conditions for this transformation,

giving complete consumption of 284, no diene formation, a terminal 01efi:interna.l olefm

ratio of 8-9:1, and a dr of 5-7:1. Syn-285 was isolated in 75% yieId, with (5% of the

deçilylated byproducts being detected by 'H NMR spectroscopy. Further lowering of the

phosphine:Pd ratio (entries, 8,9) resulttd in low conversion.

4.3 Experimental.

Toluene was distilled for sodium/ benzophenone. ElMPA was distilled under vacuum

(-0.5 mmHg) fiom calcium hydride. DMF was dried by prolonged standing over

molecular sieves and degassed by purging with a flow o f Ar. Dichlormethane, iPr;>NEt

and 3-pentanone were distilled fiom Ca& at atmosphenc pressure. Ammonium formate

was recrystallized fiom MeOH and stored in a desicator. Al1 other solvents and reagents

were used as purchased fiom commercial sources.

Standard Conditions for the Pd catalyzed Formate Reduction of Allyl Chlorides:

Pd2(dba)3 (0.03 nimol), and n-Bu3P (0.24 m o l ) were added to a 23 OC suspension of

H C O m (2.2 mmol) in toluene (1 d). The dark purple solution tumed orange over

the course of 10 minutes at which point a solution of aIIyl chloride (1.0 m o l ) in toluene

(1 rnL) was added via cannrila. The resulting lime green suspension was placed in a 105

OC oil bath until TLC analysis revealed consumption of d l y l chloride. In the event that

the product and starting materials have the same RJvalue, consumption of allyl chloride

is also indicated by a color change of the reaction mixture fiom green back to orange.

CO2 evolution is also nonnally observed as the reaction miixture ~ t r a r ~ ~ s .

Standard Conditions for the Pd Catalyzed Formate Reduction of Allyl Benzoates of

Disubstituted Double Bonds:

Pd2(dba)3 (0.03 mmol) and n-Bu3P (0.24 mmol) were added to a 23 OC suspension of

ECO2= (2.2 mmol) in toluene (1 mL). The dark purple solution turned orange over

the course of 10 minutes at which point a solution of d y l benzoate (1 .O mmoI) in toluene

(1 mL) was added via cannula. The resulting suspension was placed in a 105 OC oïl bath

until TLC analysis revealed consumption of allyl acetate. The mixture was then diluted

with water, extracted three times with ethyl acetate, washed with brine, dried over

Na2S04, filtered and concentrated to dryness- The residue was purified by flash

chromatography.

N-(4-chlorobut-2-enyl) phthalimide (262).

A suspension of 261 (1.00 g, 5.40 mmol) in DMF (10 mL) was added to a -78 OC solution

of 254 (2.27 mL, 21 -6 mrnol) in THF (15 mL). The mixture was then allowed to warm to

23 OC. After two hours, the mixture was diluted with water and extracted three times

with 10% CH2Cl2/ hexanes. The organic Iayers were washed wiîh brine, dried over

MgS04, filtered and concentrated to dryness. The residue was purified by flash

chromatography (5% ethyl acetate/ hexanes- 15% ethyl acetate/ hexanes) to yield the

1 title compound as a white solid (905 mg, 71%). H NMR revealed a 6: 1 mixture of

double bond isomers. RF 0.44, (20% ethyl acetate/ hexanes); mp= 77-79 O C (15% ethyI

acetate/ hexanes); 'H NMR (400 MHz, CDCl,) 6 4.02-4.04 (m, 1/6H), 4.30-4.40 (m, 4

1/6H), 5.67-5.75 (m, 1H)y 5.81-5.89 (m, l 1/3 H), 7.71-7.75 (m, 2 1/3 H), 7.83-7.88 (m, 2

1/3 H); 13c NMR (100 MHk, CDCU) G 34.02, 38.58, 123.344, 127.14, 129.89, 132.06,

134.05, 167.73; FTIR (neat, cm-') 3053, 2956, 1767, 1709, 1538, 1428, 1386; Elemental

Analysis: Calculated: %C=6 1.16, %H=4.27, %N=5.94, Found: %C=6 1.12, %H=4.15,

YoN=5 - 8 7.

N-(but-3-enyl), phthalimide (263).

Aliyl chloride 262 (904 mg, 3 -84 mmol) was subjected to standard Pd catalyzed formate

reduction conditions to give the title compound as a white solid after flash column

chromatography (10 % ethyl acetatel hexanes) as a colorless oil after fash chromatogrphy

which solidified to a white solid upon standing (792 mg, 92%). Matched spectral data

fiom literature. l6

N-(4-chlorobut-2-enyl), N-cyclohexyE, N-p-toluenesulfonamide (265).

254 (328 PL, 3.1 1 m o l ) was added via syringe to a 23 OC mixture of 264 (0.200 g,

0.777 mmol) and Cs2C03 (760 mg, 2.34 mmol) in acetonitrile (5 mL)- The mixture was

heated to reflux for 18 hours. The m i m e was then cooled to 23OC, treated with water

and extracted three time with diethyl ether. The organic layers were combined, washed

with brine, dried over MgS04, filtered and concentrated to dryness. The residue was

purified by flash chromatography (10% ethyl acetatel hexanes) to yield the title

compound as a colorless oil (215 mg, 81%). RJ= 0.22 (10% ethyl acetatel hexanes); 'H

NMR (400 MHz, CDC13) 6 0.96- 1.18 (m, II*), 1.18- 1.42 (m, 4H), 1.54-1 -65 (m, 3H),

1.70-1.78 (m, 2H), 2.42 (s, 3H), 3.69 (tt, J=3.5, 12 Hz, lH), 3.83 (d, J= 4 Hz, 113 H), 3.93

(d, J=6 Hz, 2/3H), 4.02 (d, J= 5 Hz, 1/3H), 4.23 (d, J= 7 Hz, 2/3H), 5.58-5.73 (m, 1

1/3H), 5.74-5.79 (m, 213 H), 7.28 (AB, J= 8 Hz, 2H), 7.69 (AB, J= 8 Hz, 2H); "C NMR

(100 MHz, CDC13) 6 21.447, 25.23, 25.26, 26.01, 31.74, 31.77, 38.67, 39.86, 44.22,

44.46, 57.87, 57.96, 126-19, 126.92, 127.94, 129.54, 129.58, 133.09, 133.24, 138.53,

142.96, FTIR (neat, cm-'), 2934, 1329, 1610, 1475, 1159, 1094, 1039. HRMS:

Calculated for C I ~ H ~ ~ O ~ N C I S + (M3=341.1204, Found: 341.12 16

N-(but-3-enyl), N-cyclohexyl, N-p-toluenesulfonamide (266).

Allyl chloride 265 (21 1 mg, 0.617mmol) was subjected to standard palladium catalyzed

formate reduction conditions. Purification by flash chromatography (10 % ethy1 acetate/

hexanes) yielded the title compound as a colorless oi1 (152 mg, 80 %). 'H NMR (400

MHz, CDC13) 6 0.96-1.08 (m, lm, 1.18-1-38 (m, 4H), 1.52-1.67 (m, 3H), 1.69-1.82 (m,

2H), 2.41 (s, 3H3, 3.12-3.19 (a, 2H), 3.62 (tt, J= 11, 3.5 Hz, lH), 5.03 (d,J=ll Hz, lH),

5.07 (d, H 8 Hz, lH), 5.69-5.81 (m, lH), 7.27 (AB, J= 8 Hz, 2H), 7.71 (AB, J= 8 Hz,

2H); "C NMR (100 MHz, CDC4) 6 21.41, 25.28, 26.01, 31.67, 36.41, 43.14, 57.87,

1 16.60, 126.82, 129.49, 135.05, 138.66, 142.73; IR (neat, cm-') 2924, 1636, 1595, 1493,

1442, 1333, 1 159; Elemental Analysis: Calculated: %C=66.4 1, %H=8.20, %N=4.56,

Found: %C=66.46, %H=8 -43, %N=4.54.

N-(4-chlorobut-2-enyl), N-(3-nitrophenylsulfonyl)-l-phenylalanine, methyl ester

(268).

DMF (2 mL) and 254 (812 pL, 770 m o l ) were added via syringes to a 23 OC mixture of

267 (700 mg, 1.92 mmol) and &CO3 (398 mg, 2.88 m o l ) and the resulting suspension

was stirred for 48 hours. The mixture was then diluted with water and extracted three

times with diethyl ether. The organic layers were combined, washed with brïne, dried

over MgS04, filtered and concentrated to dryness. The residue was purified by flash

chromatography (20+30% ethyl acetate/ hexanes) to give the title compound as a thick

pale green gum (652 mg, 75 %, 2:l mixture of cis and tram isomers). Rf= 0.20 (20%

ethyl acetatel hexanes); 'H NMR (400 MHz, CDC13) 6 2.99 (ABX, dd, J= 14.5, 9 Hz,

lH), 3.37, (ABX, dd, J= 14.5, 6.5 Hz, lH), 3.61 (s, 2H), 3.63 (s, lH), 3.88-4.15 (m, 4H),

4.87-4.94 (m, lH), 4.45 (dt, J=, 113H), 5.59 (dt, J=, 2/3H), 5.66-5.73 (m, 1/3H), 5.79 (dt,

J=, 213 H), 7.17-7.30 (m, 5H), 7.57-7.63 (m, IH), 7.88-7.95, (m, 1H),-8.33-8.38 (m, lH),

8.48-8.52 (m, 1H); I3c NMR (100 MHz, CDC13) 6; Neat FTIR (cm-'): 3098, 3039, 2954,

1745,1605, 1530,1435,1530,1436, 1344,1276,1171,

N-(but-3-enyl), N-(3-nitrophenylsulfony1)-L-phenyIalanine, methyl ester (269).

AllyI chloride 268 (400 mg, 0.883 mmol) was subjected to the standard conditions for the

palladium catalyzed formate reduction of allyl chlorides with the exception that catalyst

loadings of 1 mol % Pd~(dba)~ and 8 mol % n-Bu3P were used. The reaction was allowed

to run for 90 minutes in an oil bath of 105 OC. The title compound was isolated by flash

chromatography (20 % ethyl acetate/ hexanes+30 % ethyl acetate/ hexanes) to yield a

colorless oil (3 14 mg, 85%). Rf= 0.30 (20 % ethyl acetate/ hexanes); 'H Nh4R (400

MHz, CDCI,) 8 2.25-2.45 (m, 2H), 3.01 (ABX, dd, 5 4 4 , 8 Hz, lH), 3.24-3.42 (m, 3H),

3.55 (s, 3H), 4.85 (t, Jz7.5 Hz, lH), 5.05 (d, J=10 Hz, lH), 5.06 (d, J=18 Hz, lH), 5.63-

5.76 (m, 1H) 7.16-7.32 (m, 5H), 7.63 (t, J= 8 Hz, lH), 7.97-8.03 (m, IH), 8.34-8.40 (m,

lH), 8.54-8.60 (m, 1H); NMR (100 MHz CDC13) 6 34.42, 36.66, 45.56, 52.27,

61.51, 117.43, 122.48, 126.88, 127.04, 128.63, 128.95, 130.02, 132.79, 134.06, 136.06,

141.97, 148.06, 170.45; Neat FTIR (cm-'): 3192, 2947, 1739, 1601, 1535, 1349, 1271,

1236, 1 120, 1069, 10 10, 925; Elemental Analysis: Calculated: %C=57.40, %H=5.30,

%N=6.69, Found: %C=57.35, %H=5.53, %N=6.75,

2-(4-chlorobut-2-eny1)-2-@ut-3-enyl) dimethyl malonate (193).

A solution of 110 (500 mg, 2.69 rnrnol) in MeOH (2 mL) was added via cannuia to a

solution of sodium metal (74 mg, 3.23 m o l ) that was dissolved in MeOH (10 mL).

M e r 10 minutes, 254 (1.14 mL, 10.76 mmol) was added via syringe. After 2.5 hours,

the mixture was treated with water and extracted three times with diethyl ether. The

organic layers were washed with brine, dried over MgS04, filtered and concentrated to

dryness. The residue was purined by flash chromatography (5% etber/ hexanes) to yield

the title compound as a colorless liquid (421 mg, 57% yield, 6:l mixture of double bond

isomers). 'H NMR (400 MHz, CDC13) 61 -90-2.00 (m, 4H), 2.66 (d, J=6.5 Hz, 2H, major

isomer), 2.73 (dd, J= 7-8, 1.6 Hz, 2H, minor isomer), 3-70-3-74 (m, OH), 3.99, (d, J=6.2

Hz, 2H, major isomer), 4.08 (d, J= 7-9 Hz, 2H, rninor isorner), 4.97 (d, J= 10.3 Hz, ZH),

5.03 (d, J=17.8 Hz, lH), 5.43-5.51 (m, lH, minor isomer), 5.58-5.8 1 (m, 3H fiom major

and one fiom minor isomers).

2,2-(di-3-buteny1)-dimethyl malonate (194).

Allyl chloride 193 (7.69 g, 28.0 mrnol) was subjected to standard Pd catalyzed formate

reduction condition except that 0.25 mol% of P~ l~ (dba )~ and 2 mol % n-Bu3P were used

and the reactio proceeded for 26 hours. The cmde reaction mixture was punfied by

Kugelerhor distillation (80°C, 0.5 mm Hg) to yield the title compound as a colorless

liquid whose spectral data were in agreement with literature data (6.07 g, 90%).17

2-(4-chlorobut-2-eny1)-y-butyrolactone (271).

n-BuLi (3 -8 mL, 2.3 M solution in hexanes) was added to a -78 O C solution of i P r m

(1.4 rnL) in THF (25 mL). Afier IO minutes, y-butyrolactone (550 PL, 7A8mmol) was

added via syringe. After 2 hours, this mixture was added via cannula to a -78 OC mixture

of HMPA (5.0 r d , 28.7 mmol), THF (5 r d ) , and 254 (3.04 d, 28.7 m o l ) to give a

deep red solution. After lhour, the color had faded to orange and the mimue was

allowed to wann slowly to 23 "C over 16 hours at which point the reaction color had

returned to a deep red. The mixture was diluted with 50% saturated ammonium chloride

solution and extracted three times with 10% CH2C12/ hexanes. The organic layers were

combined, washed with brine, dned over MgS04, filtered and concentrated to dryness.

The residue was purified by flash chromatography (10% -1 5%+20% ethyl acetate/

hexanes) to give the title compound as a pale green liquid (615 mg, 52%). 'H NMR (400

MHz, CDCb) 6 1.94-2-07 (m, l m , 2.26-2.46 (m, 2H), 2.58-2.73 (m, 2H), 4.04 (d, J= 5.5

H z 2/3H), 4.21 (d, J= 12Hz, 1 1/3 H), 4.18-4.25 (m, lH), 4-32-4.39 (m, lH), 5.59-5.67

(m, 2/3H), 5.70-5.85 (m, 1 1/3); I3c NMR (100 MHz, CDC13) 6 27.32, 27.74, 27.81,

32.46, 38.73,38.82,44.53,66.47, 128.03, 129.10, 130.38, 13 1-04, 178.34; IR (neat, cm-')

2920, 1 77 1, 1445, 13 80, 1256, 12 10, 1 170; Elemental AnaIysis: Calculated: %C=55.02,

%H=6.35, Found: %C=55.26, %H=6.59.

2-(but-3-enyl) y-tiutyrolactone (272).

Aliyl chloride 271 (400 mg, 2.29 m o l ) was subjected to standard Pd catalyzed formate

reduction condition. Purification by flash chrornatography (1 2 % ethyl acetate/ hexanes)

yielded the title compound as a colorless liquid (315 mg, 98%). Spectral data matched

literature reports.

1-Vinyl-spiro [2.5]octan-4-one (273).

n-BSi (14.9 mL, 2.30 M solution in hexanes, 38.3 mmol) was added to a -78 OC solution

of iPrzNH (5.65 mL, 40.3 mrnol) in THF (50 mL). Afier 5 niinutes, cyclohexanone (4.0

mL, 38.6 mmol) was added via syringe. After 20 minutes, 254 (1.85 mL, 2.19 mrnol)

and HMPA (7.63 mL, 43.9 m o l ) were added via syringe and the mixture was allowed to

warm to 23 OC for 16 hours. Water was added to the mixture and it was extracted three

times with ether. The organic layers were combined, washed with brine, dried over

MgS04, filtered and concentrated to dryness. The residue was purified by flash

chromatography (3% +5% ethyl acetatel hexanes) to give the title compound as a

colorless liquid (1.05 g, 40 % based on 254) of the desired vinyl cyclopropane as a

colorless Iiquid. R/= 0.13 (5% ether / hexanes), 'H NMR (400 MHz, CDC13) 6 0.69 (AB,

d, J= 4.1 Hz, lH), 1.56-1.82 (m, 5H), 1.82-1.99 (m, 2H), 2.02 (q, J= 6.4 Hz, lH), 2.40

(AB, d, J= 6.8Hz, 2H), 5.14 (dm, J= 10.2 Hz, lH), 5.19 (dq, J= 17, 0.9 Hz, 1H), 5.60

(ddd, J= 17, 10.2, 8.2 Hz, 1H); "C NMR (1 00 MHz, CDClp) 6 21.90, 23.28, 23.87,

28.45, 32.03, 34.85, 69.64, 117.30, 134.99, 2E0.22; IR ( c d ) 2936, 2861, 1686, 1450,

1132,986,902.

2-But-3-enyl-cyclohexanone (274).

Vinyl cyclopropane 273 (200 mg, 1.33 mrnol) was subjected to the standard conditions

for the palladium catalyzed formate reduction of allyl chlorides with the exception that

100 pL of water were added to the reaction mixture. After 90 minutes, a TLC indicated

complete consurnption of the starting materiai. The mixture was concentrated to dryness

and purified by flash chromatography (5% ethyl acetate/ hexanes) to yield the title

compound as a coIorless liquid whose spectral data were found to be in agreement with

literature reports (245 mg, 9 1 %). l9

Benzoic acid 4R*-hydroxy-SR*methy1-6-oxo-i,ct-2-enyl ester (276).

TiCL (920 PL, 8.40mmol) was added to a -78 *C solution of 3-pentanone (490 pL, 4.64

m o l ) in CH2Cl2 (5 mL) to give a bright yellow suspension. After two minutes, iPr2EtN

(800 PL, 4.64 mrnol) was added to give a deep red solution. After 20 minutes, a solution

of 223 (400 mg, mmol) in CH2C12 (6 mL) was added via cannula. After 2 hours the

reaction was quenched by careful addition O f saturated NaHC03 at -78 OC. After

warming to 23 OC, the mixture was extracted three times with CK2C12. The organic

layers were washed with brine, fiitered through cotton and concentrated to dryness. The

majority of the material was converted to silyl ether 277 without M e r purification and

a small sample was purified for characterization by flash chromatography (30% ethyl

acetate/ hexanes) to yield the title compound as a colorless liquid. Rf = 0.24 (30 % ethyl

acetate/ hexanes); 'H NMR (CDC13) 6 1.05 (t, J= 7 Hz, 3H), 1.15 (d, J= 7 Hz, 3H), 2.43-

2.64 (m, 2H), 2.65-2.73 (m, lH), 2.90 (d, J= 3 Hz, 1 H), 4.50-4.55 (m, lH), 4.84 (dt, J= 6,

1 Hz, 2H), 5.80 (ABX ddt, J= 16, 5, 1 Hz, lH), 5.98 (ABX, dtd,J=19, 6, 1.5 Hz, 7.44 (t,

J=7S Hz, 2H), 7.57 (tt, J=7.5, 1.5 Hz, lH), 8.03-8.07 (m, 2H); IR (neat, cm-') 3475,

2968,2932, 1722,1278, 1 1 1 1.

Benzoic acid 4R*-t-Butyldimethylsiloxy-5R*-methyl-6-oxo-oct-2-enyl ester (277).

Imidizole (289 mg, 4.24 mrnol) and DMF (2 mL) were added to unpurified 276.

TBDMSCl(639 mg, 4.24 mmol) was added and the resulting solution was stirred at 23OC

for 16 hours. The mixture was treated with water and extracted three times with ether.

The organic layers were washed with brine, dried over Na2S04, filtered and concentrated

to dryness. The residue was purified by flash chromatography (20% ethyl acetate/

hexanes) to yield the titIe compound as a coIorIess fiquid (759 mg, 92% over two steps),

Rf= 0.47 (20 % ethyl acetatel hexanes); 'H M (CDClj) 6; 0.02 (s, 3H), 0.05 (s, 3l3,

0.88 (s, 9H), 0.98 (t, J= 7 HZ, 3H), 1.10 (d, J= 7 Hz, 3H), 2.40-2.55 (m, 2H), 2.69

(quintet, J= 7 Hz, l m , 4.33 (t, J= 3 Hz, lH), 4.78 (d, J=3 Hz, 2H), 5.78-5.83 (m, 2H),

7.41 (t, J=7.5 Hz, 2H), 7.54 (tt, J=7.5, 1.3 Hz, lm, 7.99-8.04 (m, 2H); 13c N M R (100

MHz, CDCl3) 8 -5.03, -4-24, 7-33, 12-65, 18.07, 25-74, 36-60, 52.57, 64-49, 74-34,

125.27, 128.35, 129.57, 132.94, 135.78, 166.2, 213.39; IR (neat, cm-') 2944,2862, 1724,

1457, 13 72, 1265, 1 1 15, 1 O7 2 , 980, 836; Elernental Analysis: Calculated: %C= 67.65,

%H= 8.77, Found: %C= 68.05, %H= 9.06.

5S*-t-ButyldimethyIsiloxy-4R*-methyl-oct-7-en-3-one (278).

Mlyl bentoate 277 (200 mg, 0.51 m o l ) was subjected to the standard conditions for Pd

catalyzed formate reduction. The residue was purified by flash chromatography (5%

ethyl acetate/ hexanes + 10% ethyl acetate/ hexanes) to yield the title compound as a

colorless liquid (135 mg, 98%). Rf = 0.61 (10 % ethyl acetate/ hexanes); 'H NMR

(CDCl3) 6 0.03 (s, 3H), 0.05 (s, 3H), 0.85 (t, J= 8 HG 3H), 0.87 (s, 9H), 1-01 (t, J= 7 Hz,

3H), 1-07 (d, J= 7 Hz, 3H), 2.09-2.18 (m, lH), 2.20-2.30 (m, 1H), 2.40-2.56 (m, 2H),

2.65 (di, J= 13,6 Hz, lH), 3-99 (q, J= 5.5 Hz, lH), 4-98-5.06 (m, 2H), 5.72-5.84 (m, 1H);

13c NMR (100 MHz CDC13) G -4.68, -4.27, 7.52, 12.45, 18.03, 25.81, 35.76, 39.84,

50.72, 72.88, 117.32, 134.63, 214.03; IR (neat, cm-') 2935, 1734, 1454, 1375, 1235,

1064.

Benzoic acid 6-(4S-be~zvl-2-thioxo-oxazolidin-3-yl)-4-hydro~y-5R-methyE6-oxo-

hex-2-enyl ester (280).

TiCb (210 PL, 1.91 mmol) was added to a O OC solution of 279 (238 mg, 0.956 mmol) in

CHzClz (4 mL) to give a yellow solid mass sticking to the stir bar. After 10 minutes,

iPr2EtN (1 83 PL, 1 .O5 mmol) was added to give a deep red solution. Afier 30 minutes,

this solution was cooled to -78OC and a solution of 223 (200 mg, 1.05 mmol) in CH2Clz

(1 mL). After 90 minutes the reaction was quenched by addition of saturated NaHC03 at

-78°C. After warmîng to 23 OC, the mixture was extracted three times with CH2C12. The

organic layers were washed with brine, filtered through Cotton and concentrated to

dryness. The residue was purified by flash chromatography (15% ethyl acetatd

hexanes+20% ethyl acetate/ hexanes+30% ethyl acetate/ hexanes) to yield the title

compound as a colorless liquid (373 mg, 84%) plus 279 (36 mg, 15%) and 223 (50 mg,

25%). 'H NMR (CDC13) 6 1.23, (d, J= 7 Hz, 3H), 2.76 (dd, J=13, 10 Hz, lH), 2.89 (bs,

lH), 3.27 (dd, J=13, 3.5 H z , lH), 4.24-4.35 (m, 2H), 4.72 (bs, IH), 4.87 (d, J = 16 Hz,

2H), 4.92-5.00 (m, 2H), 5.94 (ABX, dd, J= 16, 5 Hz, lH), 6.06 (ABX, dt, J= 16, 5.5 Hz,

lH), 7.20 (AB, J= 7 Hz, 2H), 7.26-7.36 (m, 3H), 7.40 (t, J= 7.5 Hz, 2H), 7.54, (t, J= 7.5

Hz, lH), 8.04 (AB, J= 7 Hz, 2K); 13c NMR (100 MHZ, CDC4) 6 11.01, 37.68, 42.12,

60.06, 64.57, 70.20, 71.84, 123.20, 127.41, 128.29, 128.97, 129.32, 229.56, 130.02,

132.91, 133.26, 135.04, 166.2, 176.81, 185.27; IR (neat, cm-') 3458, 2974, 1715, 1671,

1603, 1447, 13 1 1, 1 179, 972; HRMS Calculated for C~&SO~NS' (M+H)+: 439.1456,

Found: 439.1453.

Benzoic acid 6-(4S-beqI-2-thioxo-oxazolidin-3-yI)-4R-l-Butyldimethylsilo~y-5R-

methyl-6-0x0-hex-2-enyl ester (281).

To a -1 0 OC solution of 280 (710 mg, 1.62 mmol) in C&C12 (9 ml) was added 2,6-

Iutidine (207 jL, 1.78 mmol) was added TBSOTf (371 PL, 1.62 rnmol). The resulting

solution was warmed to 23 OC and after 13 hours, was treated with saturated NaHC03.

The mixture was extracted three times with CH2C12, washed with brine, filtered through

Cotton and concentrated to dryness. The residue was purif~ed by flash chromatography

(1 5 % ethyl acetate/ hexanes) to yield the title compound as a coIortess liquid (767 mg,

86%). Rf= 0.15 (10% ethyl acetatel hexanes); 'H NMR (CDC13) 6 0.05 (ç, 3H), 0.081 (s ,

3H), 0.91 (s, 9l3, 1.25 (d, J= 7 Hz, 3H), 2.60 (ABX, dd, J= 13, 11 Hz, lH), 3.28 (ABX,

dd, J= 13, 3 Hz, lH), 4.18-4.30 (m, 2H), 4.58 (t, J= 7 HZ, lH), 4.81 (qd, J= 13, 6 Hz,

2H), 4.88-5.00 (m, 2H), 5.92 (ABX, dt, J= 10, 6 Hz, lH), 6.03 (ABX, dd, J= 17, 7 Hz,

lH), 7.16, (d, J= 7 Hz, 2H), 7.24-7.37 (m, 5H), 7.50 (t, J=8 Hz, lH), 7.98 (d, J= 8 Hz,

2H); "C NMR (100 MHz, CDCI3) 6 -4.79, -4.00, 13.32, 18.16, 25.81, 37.83, 43.88,

60.07, 64.55, 70.01, 74.55, 126.02, 127.37, 128.31, 129.03, 129.29, 130.07, 132.90,

135.43, 135.57, 166.22, 175.79, 185.30; IR (neat, cm-'): 2959, 1718, 1456, 1369, 1314,

1266,1185,1146,1113,1068,1023,951,839.

l-(4S-benyl-2-thioxo-oxazo l i d i n - 3 - y l ) b

5-en-1-one (282).

Allyl benzoate 281 (77 mg, 0.13 mmol) was subjected to the standard conditions for

palladium catalyzed formate reduction. A TLC after 5 minutes in the 105°C oil bath

revealed cornplete consumption of 28 1. The residue was purified by flash

chromatography (8% ethyl acetate/ hexanes + 10% ethyl acetate/ hexanes) to yield the

title cornpound as a color less liquid (52 mg, 86%). 'H N M R (CDCI,) 6 0.09 (s, 3H),

0.10 (s, 3H), 0.92 (s, 9H), 1.23 (d, J= 6.8 Hz, 3H), 2.39 (t, J=58 Hz, 2H), 2.65 (ABX, dd,

J=13.1, 10.7 Hz, lH), 3.35 (ABX, dd, J=13.2, 3.3 Hz, IH), 4.20-4.30 (m, 3H), 4.81

(quint., J=7 Hz, lH), 4.88-4.95 (m, lH), 5.03-5- 1 1 (m, 2H), 5.84-5.96 (m, IH), 7.21-7.3 1

(m, 3H), 7.31-7.37 (m, 2H) ; 13c NMR (100 MHz, CDCI,) 6 -4.49, -3.94, 14.01, 18.14,

25.89, 37.82, 40.71,42.74, 60.09, 69.88, 72.81, 117.53, 127.39, 129.04, 129.30, 134.61,

135.44, 176.58, 184.89; IR (neat, cm-') 2942, 1704, 1686, 1466, 135 1, 1309, 1 194, 1 152;

Elemental Analysis: calculated %C= 65.03, % H= 5.73, %N= 3.19, found %C= 64.60,

%H= 5.72, %N= 3.04.

Acetic acid (E)-4R*-triethylsiloxy-3,5R*-dimethyl-6-oxo-oct-2-enyl ester (284).

TiCb (1 -77 mL, 16.2 mmol) was added to a -78 O C solution of 3-pentanone (940 PL, 8.90

m o l ) in CH2Cl2 (17 mL) to give a bright yellow suspension* After five minutes,

iPr2NEt (1 -55 mL, 8.90 mmol) was added to give a deep red solution. m e r 20 minutes, a

solution of 283 (575 mg, 4.05 rnmol) in CH2C12 (3 rnL) was added via cannula. After 90

minutes the reaction was quenched by addition of saturated NaHC03 at -78°C. M e r

warming to 23OC, the mixture was extracted five times with CH2C12. The organic layers

were washed with brine, aItered tbrough cotton and concentrated to dryness. The residue

was purified by flash chromatography (30% ethyi acetate/ hexanes) to yield the title

compound as a colorless liquid (795 mg, 86%). Rf = 0. 14 (20 % ethyl acetate/ hexanes);

1 H NMR (400 MHz, CDCl3) 6 1.05 (t, J= 3.5 Hz, 3H), 1.07 (t, J= 3.5 Hz, 3H), 1.67 (s,

3H), 2.05 (s, 3H), 2.44-2.64 (m, lH), 2.54 (qd, J= 17, 7.1 HZ, lH), 2.74 (qd, J= 7.3, 3.5

Hz, lH), 2.95 (d, J= 2.5 Hz, lH), 4.37, (s, IH), 4.65 (d, J= 7 Hz, 2H), 5.69 (tt, J= 7, 1.3

Hz, 1H); "C NMR (100 MHz, CDCl3) 6 7.50, 9.87, 13.62, 20.88, 34.96, 47.61, 60.83,

74.46, 120.13, 139.41, 171.02, 215.88; IR (neat, cm-') 3483, 2974, 2929, 1737, 1718,

146 1, 13 72, 1236, 102 1 ; HRMS calculated for C I Z H ~ I O ~ + (M+wc: 229.1440, found:

229.1444.

2,6-lutidine (347 PL, 2.41 mmol), and TESOTf (495 PL, 2.19 mmol) were added to a -

10°C solution of the aldol product (500 mg, 2.19 mmol) in CH2C12 (10 mL). m e r 45

minutes, the mixture was treated with sahirated NaHCO3. The mixture was extracted

three times with CH2C12, washed with b ~ e , filtered through cotton and concentrated to

dryness. The residue was purified by flash chromatography (5% ethyl acetate/ hexanes

+ 15% ethyl acetate/ hexanes) to yield the title compound as a colorless liquid (680 mg,

91%). Rj= 0.54 (20 % ethyl acetate/ hexanes); 'H NMR (400 MHz, CDCI,) 6 0.56 (q, J=

8 Hz, 6H), 0.92 (t, J= 8 Hz, 9H), 0.98 (t, J= 7.2 Hz, 3H), 1.09 (d,J= 6.8 Hz, 3H), 1.67 (s,

3H), 2.03 (s, 3H), 2.40 (dq, J= 7.2, 2.2 Hz, 2H), 2.72 (quint, J= 7.1 Hz, IH), 4.19 (d, J=

7.3 Hz, lH), 4.56 (d, J= 7.0 Hz, 2H), 5.47 (tt, J= 7, 1.1 Hz, 1H); 13c NMR (100 MHz,

CDC13) 6 4.74, 6.77, 7.35, 12.09, 12.75, 20.84, 35.89, 50.79, 60.60, 78.69, 121.04,

141.70, 170.87,213.52; IR (neat): 2968, 1741, 1456, 1372, 1230, 1068, 1016; Elemental

Analysis: Calculated: %C=63.11, %H=10.00, Found: %C=63.l9, %H=9.80.

5S*-triethyIsiloxy-4R*,6R*-dimethyl-oct-7-en-3-one (285).

A solution of n-Bu3P (3.6 pL, 0.022mmol) in toluene (36 yL) was added via syringe to a

mixture of 284 (1 OOmg, 0.303 mmol), HCO* (42 mg, 0.667 mmol) and Pd~(dba)~

(13.9 mg, mmol) in DMF (500 PL)- The resulting mixture was warmed to 50 OC. After

16 hours, water was added and the mixture extracted three times with ether, The organic

layers were combined, washed with brine, dried over MgS04, filtered and concentrated to

dryness. The residue was purified by flash chromatography (2% ether / hexanes) to yield

the aldol product as a colorless oil(65 mg, 75%). 'H NMR (400 MHz, CDC13) 6 0.60 (q,

J= 8 Hz, 6H), 0.95 (t, J= 8 Hz, 9H), 0.97 (d, J=6.8 Hz, 3H), 1.03 (t, J= 7.3 Hz, 3H), 1.09

(d, J= 7.1 Hz, 3H), 2.22 (sextet, J- 6.8 Hz, 1 H), 2.47 (q, J= 7.3 Hz, 2H), 2.66 (quint, J=

7.1 Hz, IH), 3.96 (t, J= 5.7 Hz, lH), 5.00 (d, J= 9.1 Hz, lH), 5.02 (d, J= 17.2 Hz, lH),

5.77 (ddd, J= 17.2, 10, 7.5 Hz, 1H); I3c N-MR (100 MHz, CDC13) 6 5.30, 6.98, 7.65,

12.34, 15.43,35.06,43.00,49.93, 76.29, 114.50, 141.57,214.02.

4.4 References.

1. Aldrich's 1999 catalogue quotes pnces for 4-bromo-1-butene, 3-buten-1-01 and 254

as $1,088.9 1/ mol, $432.44/ mol and $20.7/ mol respectively. Theses were the pices

at the time ehis approach was first developed and published. In a more recent

catalogue, Aldrich has lowered dramatically the price of 3-buten- 1-01, and

discontinued the tech grade 254, which was adequate for this application and by far

the most economical option. All prices listed are in Canadian dollars for the largest

available denornination. It shodd be noted that 254 does pose a health risk and

shodd be handled with caution.

2. Literature results reporting difficulties with Wlation with conventional butenylation

electrophiles: a) Tanner, D.; Hagberg, L.; Poulsen, A. Tetrahedron 1999,55, 1427.

b) Uenishi, J.; Tatsumi, Y.; Kobayashi, N.; Yonemitsu, O. Tetrahedron Lett. 1995,

36, 5909. c) Fry, A.J.; Little, R.D.; Leonetti, J. J. Org. Ckern. 1994,59,50 17. In

addition, there are no reports describing the butenylation mf y-butyrolactone, and

atternpts by us to perform this transformation under a number of conditions proved

futile, giving less than 10% yield of the desired product.

3. a) Harding, K. E.; Nam, D. Teb-uhedi-on Lett. 1988,29, 3793-3 796. b) Tamani, Y.;

Hojo, M.; Higashimura, H.; Yoshida, 2. J. Am. Chern, Soc. 1988,110, 3994.

4. a) Tetrahedron Symposia-in-Print No. 50 1993,49, (17), 3433. b) Miller, S.J.;

Grubbs, RH. J: Am. Chem. Soc., 1995,117,5855.

5. Reichwein, J.F.; Versluis, C.; Liskamp, R.M.J. J. Org. Chem. 2000, 65,0000.

6. Fukuyama, T.; Jow, C.-K.; Cheung, M, Tetrahedron Lett. 1995,36,6373.

7. Shimizu, 1.; Aida, F. Chem. Lett, 1988,60 1.

8. Compound 275 is somewhat volatile and was not isolate free fiom residual solvents

(hexanes). The sûmctural assignment was based on 'H and 13c NMR spectra. The 'H

NMR spectra showed peaks at 6 4.90 (ABX, dd, J= 9, 8Hz, IH), fiom

ROCmCHCH2, at 6 5-13 (d, J= 1 OHz, 1H) and 6 5.26 (d, J= 17Hz, 1H) fiom the

temiinal vinyiic hydrogens, and at 8 5.96 (ddd, J= 17, 10, 7Hz, IH) from the intemal

vinylic proton. The I3c NMR spectra shows peaks fiom the four olefinic carbons at 6

104.69, 115.22, 138.73, and 150.34. There is also a peak at 80.81, which would

correspond to ROCHR'CHCH2. For the formation of similar compounds by a related

process see: (a) Hayashi T.; Ohno, A-; Lu, S.; Maisumoto, Y.; Fukuyo, E.; Yanagi,

K. J. Am. Chern, Soc, 1994, 116,422 1 . (b) Hayashi, T.; Yamane, M.; Ohno, A, J.

Org. Chem. 1997, 62 , 204. Hayashi's enantioselective process suffers fiom

reversibility, Ieading to appreciable racemization of the product as the reaction

proceeds, a difficulty that should be of less concem in our system.

9. Aldol reaction with Sb: a) ROUS^, W.R. J. Org. Chern. 1991,56,4151, b) Ahmar, M.;

Bloch, R.; Mandville, G-; Romain, 1. Tetruhedron Lett. 1992,33,250 1,

10. Evans, D.A.; Rieger, D.L.; Bilodeau, M.T.; Urpi, F. J. Am. Chern. Soc. 1991,113,

1047.

1 1. Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am- Chern. Soc. 1997,119,7883.

12. Tietze, L. F. ; Eicher, T. Syntheses and Transformations of Functional Groups. In

Reactions and Syntheses; University Science Books: Mill Valley, CA, 1989, Chapter

13. Tsuji, J.; Yamakawa, T.; Kaito, M.; Mandai, T. Tetrahedron Lett. 1978,24,2075.

14. The stereochemistry of the reduction products was confirmed by conversion to known

compounds syn-289 and anti-289. Paterson, 1.; Hulme, A. J. Org. Chern. 1995, 60,

15. Similar reactivity has been previously observed: Sato, Y.; Watanabe, S.; Shibasaki,

M. Tetrahedron Lett. 1992,33,2589.

16. Takamizawa,A.; Matsumoto,S. Chern. Pharm.BulZ. 26; 1978; 790-797.

17. Gillon, A.; Ovadia, D.; Kapon, M.; Bien, S. Teh-ahedron, 1982,38, 1477-1484.

18- Bachi, M.D., Bosch, E.J- Org. Chem. 1993,57,4696.

19. Molander, G.A.; Cameron, K-O. J. Org. Chem. 1993,58,593 1.

Appendix A

Abbreviations

Ac BINAL BINAP Bn brsm Bz COD dba DCC DDQ DIBAL DMAP DME DMF DMSO DSRCM EA GC HHN HMG HMPA HPLC H R M S IMDA LAH LDA Mc1 MOM Ms NBS NMP NMR Ns Nu- Piv PMB PMI? RCM S A . SM TBAF TBAI TBDPS

2,2'-Bis(dipheny1phosphino)binaphtyl Benzyl based on recovered starting material Benzoyl 1,s-Dicyclooctadiene Dibenzylideneacetone Dicyclohexylcarbodiimide 2,3 -Dichloro-5 $5-dicyano- l,4-quinone Diiso butylalrIminum hy dride Na-Dirnethylarninopyridine 1,2-dimethoxyethane Na-Dimethylformarnide Dimethy lsulfoxide Diastereoselective ring closing methathesis Elemental Analysis Gas chromatograp hy Hexahydronaphtalene 3-Hydroxy-3 -methylglutary 1 Hexarnethy Iphosphorarnidate High pressure liquid chromatography High resolution m a s spectrometry IntramoIecular Diels-Alder Lithium aluminurn hy ciride Lithium N&-diisopropylamide ChloromethanesdfonyI Methoxymethyl Methanesulfonyl N-Bromosuccinimide N-Methylp yrrolidinone Nuclear Magnetic Resonance 4-Nitropheny lsulfonyl Nudeophile Trimethy lac ety 1 paraMethoxybenzy1 puraMethoxypheny I Ring closhg metathesis Structure activity relationship Starting material Tetrabutylammonium fluoride Te~abutylammoniurn iodide tertButyldiphenylsily1

TBS TES Tf THF m s n c TM TMS Tr Ts TS

tertButyldimethylsily1 Triethylsilyl Trifluoromethanesulfony l Te trahydro f i i ra Triisopropy lsilyl Thin Iayer chromatography Transition metal Trimethylsilyl Triphenylmethyl ToluenesuIfonyl Transition state

PPM 142.864 139. JI'? 134.693 132.110 114.459 113.979 77.426 77.000 76.574 71.739 70.542 41.529 41.654 26.727 25.876 25.217 18.475 18.110 -4.699 -4.730

TBSO OH

PPM 141.527 Al4 .a78 77 .al9 77.000 76.681 75.951 49.850 43.027 35.091 26.089 P6.044 15.497 12.442 7.655 -4wOS4