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Polyolefin allylsilane cyclisations Armstrong, Rosemary Joyce 1983

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POLYOLEFIN ALLYLSILANE CYCLISATIONS By ROSEMARY JOYCE ARMSTRONG B.Sc., Monash University, 1979 A THESIS SUBMITTED IN PARTIAL FULFILLMENT THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Department of Chemistry) We accept this thesis as conforming to the required standard The University of British Columbia October 1983 ® Rosemary Joyce Armstrong, 1983 In presenting t h i s thesis i n p a r t i a l f u l f i l m e n t of the requirements for an advanced degree at the University of B r i t i s h Columbia, I agree that the Library s h a l l make i t f r e e l y available for reference and study. I further agree that permission for extensive copying of t h i s thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. I t i s understood that copying or publication of t h i s thesis for f i n a n c i a l gain s h a l l not be allowed without my written permission. Department of The University of B r i t i s h Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 Date DE-6 (3/81) ABSTRACT A series of Lewis acid-catalysed polyolefin cyclisations were performed, and the effect of the trimethylsilyl moiety and an ester group on the cyclisations were examined. It was found that an allylsilane not only directs formation of the resulting alkene to the less stable exocyclic position, but also activates an a,B-unsaturated ester in the cyclisation react! ons. The allylsilanes 138 and 172 were synthesised and were treated with a variety of Lewis acids to give the monocyclic gem-dime t hy1cy clohexane 140 and the drimane 173b, respectively. The a l l y l s i l y l acid 123 was also synthesised and converted to structure 125. Elaboration of 140 and 125 into the monocyclic terpenoid, trixagol (153), and of 173b Into several bicyclic terpenoids, albicanol (179b), albicanyl acetate (180), and isodrimenin (183), was achieved. The a l l y l s i l y l epoxides 191 and 226 were successfully synthesised and cyclised to the structures 189 and 229b, respectively. These are some of the f i r s t examples of an efficient cyclisation of an olefinic epoxide, and once again the trimethylsilyl group was found to be exceedingly useful in directing formation of the olefin to the exocyclic position. Karahana ether (193) was obtained in two steps from the cyclised product 189, and elaboration of 229b resulted in the f i r s t reported synthesis of 3-hydroxylabda-8(20),13-dien-15-oic acid (238). - i i i -'SiMe 3 ,COOMe 138 n = 1 172 n=2 -Tt 191 n = 0. R = C H 3 226 n=1 , R = CH(CMe 3) 2 SiMe 123 3 COOH 125 R=COOH, R'=H 140 R=COOMe . R'=H 189 R = COOMe , R'=OH 153 R'=H. R=H 2 C OH 173b R = COOMe.R=H 179b R=CH 2OH ,R' = H 180 R = CH 2OAc.R'=H 229b R = COOCH(CMe 3) 2 . R' 183 1 9 3 2 3 8 - iv -TABLE OF CONTENTS Page ABSTRACT i i TABLE OF CONTENTS i v LIST OF TABLES v i LIST OF SCHEMES v i i LIST OF GENERAL PROCEDURES v i i i LIST OF ABBREVIATIONS ix COMPOUND INDEX xi ACKNOWLEDGEMENTS xvi INTRODUCTION 1 A Synthetic Organic Chemistry 1 B Biomimetic Polyolefin Cyclisations 2 C Initiating Groups for Polyolefin Cyclisations 6 D Terminating Groups for Polyolefin Cyclisations 10 E 8-Keto Esters in Polyolefin Cyclisations 13 F Silicon in Organic Chemistry 18 G The Trimethylsilyl Group in Polyolefin Cyclisations.... 23 DISCUSSION 31 A Synthesis and Cyclisation of Acid Allylsilanes to Monocyclic Products . 31 B Synthesis and Cyclisation of Ester Allylsilanes to Monocyclic Products 36 C Synthesis of (±)-Trixagol (153) 43 D Synthesis and Cyclisation of Ester Allylsilanes to Bicyclic Products. Synthesis of (i)-Albicanol (179b), (t)-Albicanyl acetate (180), and (±)-Isodrimenin (183) 52 - v -Page E Synthesis and Cyclisation of Epoxy Ester Allylsilanes to Monocyclic Products. Synthesis of (t)-Karahana Ether (193) 63 F Synthesis and Cyclisation of Epoxy Ester Allylsilanes to Bicyclic Products 66 G Synthesis of (±)-3-Hydroxylabda-8(20),13-dien-15-oic Acid (238) 82 CONCLUSION 93 EXPERIMENTAL 94 A General 94 B Synthesis and Cyclisation of Allylsilanes to Monocyclic Products 98 C Synthesis of (i)-Trixagol (153) 110 D Synthesis and Cyclisation of Ester Allylsilanes to Bicyclic Products. Synthesis of (±)-Alblcanol (179b), (i)-Albicanyl Acetate (180), and (±)-Isodrimenin (183). 121 E Synthesis and Cyclisation of Epoxy Ester Allylsilanes to Monocyclic Products. Synthesis of (i)-Karahana Ether(193) 130 F Synthesis and Cyclisation of Epoxy Ester Allylsilanes to Bicyclic Products 135 G Synthesis of (±)-3-Hydroxylabda-8(20),13-Dien-15-oic Acid (238) 168 REFERENCES 192 SPECTRAL APPENDIX 200 - v i -LIST OF TABLES Table T i t l e Page I Bond energies of Si versus C(kJ raol-1) 19 II Cyclisation of a l l y l s i l y l acid J_23 34 III Cyclisation of s i l y l ester 138 41 IV Cyclisation of a l l y l s i l y l ester 172 55 V Cyclisation of epoxy allyls i l a n e 194 71 VI Cyclisation of epoxy allylsilanes 224-226 79 VII Purification of reagents 97 - v i i -LIST OF SCHEMES Scheme T i t l e Page 1 Synthesis of (±)-progesterone (20) 7 2 Skeletal structures formed by cyclisation of acyclic epoxide precursors 9 3 Synthesis of bicyclic ketal pheromones 15 4 Gem-dialkylation of ketones 22 5 Synthesis of an allylsilane precursor for polyolefin monocyclisation 32 6 Synthesis and cyclisation of the ester monocyclic precursor 138 39 7 Synthesis of subunit A 46 8 Synthesis of subunit B 49 9 Synthesis of (±)-trixagol (153) 50 10 Synthesis and cyclisation of the polyolefin bicyclic precursor 172 54 11 Synthesis of (±)-albicanol (179b) and (+)-albicanyl acetate (180) 61 12 Synthesis of (±)-isodrimenin (183) 62 13 Synthesis of (l)-karahana ether (193) 66 14 Synthesis and cyclisation of epoxy allyls i l a n e esters 224, 225, and 2__6 77 15 Synthesis of sulphone 249 85 16 Synthesis of (±)-3-hydroxylabda-8(20),13-dien-15-oic acid (238) 91 - v i i i -LIST OF GENERAL PROCEDURES Procedure T i t l e Page A Alkylation of the Dianion of 8-Keto Esters (21, 22).. 103 B Formation of (Z)-Enol Phosphates of B-Keto Esters (21) 104 C Formation of (Z)-Allylsilanes from (Z)-Enol Phosphates 105 D Synthesis of Alkyl Acetoacetates from Diketene (86).. 143 E Formation of Epoxides from Terminal Bromohydrins (69) 153 F Cyclisation of Epoxy Allylsilanes 159 G Formation of _t-Butyldimethylsilyl Ethers (92) 169 - ix -LIST OF ABBREVIATIONS acac acetylacetonate DIBAL diisobutylaluminium hydride DME dimethoxyethane E electrophile equiv. equivalent^ s) ether diethyl ether gc gas chromatography h hour(s) HMPA hexamethylphosphoramide LDA lithium diisopropylamide MCPBA m-chloroperoxybenzoic acid min minutes Ms methanesulphonyl NBS N-bromosuccinimide Nuc nucleophile py pyridine TBDMS t-butyldimethylsilyl Temp temperature THF tetrahydrofuran t i c thin-layer chromatography t r i f l a t e trifluoromethanesulphonate Ts toluenesulphonyl - x -Abbreviations for multiplicities of H nmr signals: s singlet d doublet t t r i p l e t q quartet dd doublet of doublets dt doublet of triplets m multiplet b broad - xi -COMPOUND INDEX The following is a l i s t of the compounds prepared and discussed in this thesis. The number and/or name of each compound i s followed by a set of 3 numbers. The f i r s t number refers to the page where the structure of the compound appears for the f i r s t time in the thesis, the second number refers to the page where the preparation of the compound i s discussed, and the last number refers to the page in the spectral appendix where the infrared and the nmr spectrum of the compound are provided. Compound name and/or number 50 (14, 121, 210) 52 (14, 103, 203) 122 (32, 98, 200) 123 (32, 99, 200) 125 (33, 100, 201) 126 (33, 101, 201) 128 (33, 102, 202) 129 (33, 109, 202) 137 (39, 104, 203) 138 (39, 106, 204) 140 (39, 107, 204) 141 (39, 108, 205 ) 0 153 trixagol (44, 120, 211) - x i i -Compound name and/or number 157 (46, 110, 205) 159 (46, 111, 206) 160 (46, 111, 206) 161 (46, 113, 207) geranyl benzoate (49, 114, 207) 165a (49, 115, 208) 165b (49, 115, 208) 166 (49, 116, 209) 167 (50, 117, 209) 168 (50, 119, 210) 171 (54, 122, 212) 172 (54, 123, 212) 173a (54, 124, 213) 173b (54, 124, 213) 179a (61 125, 213) 179b albicanol (61, 125, 214) 180 albicanyl acetate (61, 127, 215) 183 isodrimenin (62, 129, 217) 186 (62, 128, 216) 189 (66, 131, 218) 191 (66, 130, 218) 192 (66, 132, 219) 193 karahana ether (66, 134, 220) 194 (67, 153, 222) - x i i i -Compound name and/or number 195 (67, 140, 223) 196 (68, 137, 222) 197 (68, 139, - ) 200 (69, 135, 221) 201 (69, 136, 221) 202 (70, 153, - ) 203a (70, 159, 233) 203b (70, 159, 233) 206 (75, 165, 235) 207 (75, 167, - ) 208 (75, 142, - ) 209 (77, 143, 223) 210 (77, 143, 224) 211 (77, 144, 224) 212 (77, 144, 225) 213 (77, 145, 225) 214 (77, 146, 226) 215 (77, 147. 226) 216 (77, 148, 227) 217 (77, 149, 227) 218 (77, 150, 228) 219 (77, 151, 228) 220 (77, 152, 229) 221 (77, 154, 230) - xiv -Compound name and/or number 222 (77, 156, 231) 223 (77, 157, 232) 224 (77, 154, 230) 225 (77, 156, 231) 226 (77, 157, 232) 227a (77, 160, 234) 227b (77, 160, 234) 228a (77, 161, 234) 228b (77, 161, 234) 229a (77, 162, 235) 229b (77, 162, 235) 230 (82, 162, - ) 231 (82, 162, - ) 232 (82, 162, - ) 233 (82, 162, - ) 238 - 3-hydroxylabda-8(20), 13-dien-15-oic acid (83, 190, 245) 241a (85, 168, 236) 241b (85, 168, 236) 242a (85, 169, - ) 242b (85, 169, 236) 243a (85, 171, - ) 243b (85, 171, 237) 244a (85, 172, - ) - xv -Compound name and/or number 244b (85, 172, 237) 245a (85, 173, 238) 245b (85, 173, 238) 246 (85, 176, 239) 247 (85, 178, 239) 249 (85, 179, 240) 255 (85, 181, 240) 256a (89, 182, 241) 256b (89, 182, 241) 257 (89, 182, 242) 262 (89, 184, 242) 263 (91, 186, 243) 264 (91, 187, 243) 265 (91, 189, 244) - xvi -ACKNOWLEDGEMENTS My f i r s t thanks must go to Professor Larry Weiler who has helped me and laughed with me, and at me, through the course of this thesis. occupants Next, I want to thank the prisoners of lab. 344, both past and present, who have made my work here truly memorable. Finally, my thanks go to Margot, Ian, and especially to Mike; you three have made my stay in Canada a highlight of my l i f e - both in chemistry and out of chemistry. My gratitude is indescribable. - 1 -INTRODUCTION A„ Synthetic Organic Chemistry The f i e l d of synthetic organic chemistry is generally approached from one of two different perspectives. In the f i r s t , the chemist develops a synthetic method, which i s , in effect, a detailed study of a particular reaction or series of reactions in order to employ and opti-mise i t s u t i l i t y . The transformation is tested on a variety of sub-strates. Then the synthetic method is deemed successful i f i t can easily achieve a particular result which had previously been d i f f i c u l t or impossible to perform, as in the case of many of the protections, oxidations, reductions, and alkylations which chemists now use routinely. The second approach to synthetic organic chemistry is that of a total synthesis, or formal total synthesis, of a natural product. These syntheses have a target molecule which may consist of a complex carbon skeleton, with or without an array of functional groups, and often possessing a number of chiral centres. It rests with the ingenuity of the chemist to develop an efficient synthesis of the natural product, and an ideal synthesis w i l l be one which is short, has high yielding steps, and an elegant approach. The state of the art of synthetic organic chemistry is reflected in the increasing number of large and complex natural products which are synthesised each year. These two approaches are not merely complementary to each other, - 2 -but are synergistic, with the one building upon the other. A total synthesis could not be planned and executed without the background of synthetic methods for the chemist to resort to. On the other hand, many synthetic methods are developed with a particular synthesis in mind. B. Biomlmetic Polyolefin Cyclisations There i s a third approach to synthetic organic chemistry, namely, a biomlmetic type synthesis (1). This is basically a synthetic route designed to mimic the presumed biosynthetic pathway. The concept of biomlmetic polyolefin cyclisations, which is central to this thesis, is based upon the Stork-Eschenmoser hypothesis which was proposed in 1955 (2). The hypothesis is a postulate that cyclisation of a 1,5-diene should occur by anti-periplanar addition to the double bonds. Numerous chemical transformations have been shown to conform to this postulate, although there are also some exceptions (see below). The best known enzymic example is the conversion of squalene-2,3-epoxide (1) to a protosterol intermediate 2^  which then undergoes a series of methyl and hydrogen migrations to generate lanosterol (3_) (3). The folding of squalene-2,3-epoxide into a chair-boat-chair conformation, and the anti-periplanar olefin addition, determines the trans-syn-trans-anti-trans-fused ring system of carbonium ion 2. A number of excellent treatises have been written on biomlmetic polyolefin cyclisations (1,4). These articles refer to both enzymic transforma-tions and to purely chemical syntheses. - 3 -3 Cyclisation of polyolefins generally occurs via a chair-like transition state. However, when there is severe steric interaction in a chair-chair conformation, as shown in 4c, cyclisation can also occur via a chair-boat transition state (as shown in 4b)(5). Implicit in the Stork-Eschenmoser hypothesis is the fact that cyclisation of a trans-acyclic system w i l l give a trans-fused bicyclic product, whereas the corresponding cis-system w i l l result in a cis-fused bicyclic compound. One of the earliest studies of E- and _-isomers was performed by Johnson and Crandall (6a) on the j_-nitrobenzenesulphonates 7_ and 8. Solvolysis of each of these compounds under the same - 4 -conditions gave a mixture of acyclic, monocyclic, and bicyclic products. However, a l l identifiable products from the trans-sulphonate (e.g. _9 and 10) were shown to have a trans-stereochemistry. Similarly, compounds 11_ and 12, obtained from the cis-sulphonate, were shown to have a cis-geometry. The Stork-Eschenmoser hypothesis i s only valid for systems which cyclise in either a concerted manner, or which have a "frozen" conforma-tion of an intermediate. The presence of electron-withdrawing groups on an olefin may result in a crossover of stereochemistry with a cis-acyclic compound giving the more stable trans-fused product due to the decreased nucleophilicity of the olefin. Di- rather than trisubstituted double - 5 -8 bonds may also give a less stereoselective outcome (4h). Indeed, the lactone 1_ had such low nucleophilicity that only monocyclic products 1_ were observed upon treatment of __3 with stannic chloride (7). 13 14 - 6 -C. Initiating Groups for Polyolefin Cyclisations Since the introduction of the Stork-Eschenmoser hypothesis, chemists have been investigating not only the mechanistic and stereo-chemical aspects of polyolefin cyclisations, but they have also developed the concept of biomlmetic cyclisations into a useful synthetic route to natural products. The ingenious way in which Nature converts squalene epoxide j^, a compound with only one centre of asymmetry, into an intermediate containing four rings and eight asymmetric centres, is truly impressive. Much work has been performed on both the i n i t i a t i n g and terminat-ing groups for polyolefin cyclisations. Early work performed by Johnson et a l . (6), on arene sulphonates as in i t i a t i n g groups, was disappoint-ing. For example, the sulphonate 7_ gave the desired bicyclic alcohols 9_ in only 12% yield. Johnson then turned his attention to the acetal group and had considerable success. One example is the acetal 15_ which was converted in 30% yield to the tetracyclic ether 16_ (8). The product has an all-trans geometry and possesses six defined asymmetric centres. - 7 -An a l l y l i c alcohol functionality has proved to be one of the most effective i n i t i a t o r s . Johnson and coworkers achieved a 70% conversion of alcohol 17_ to alkene 18. Ozonolysis, followed by an aldol condensa-tion of the resulting trione 19, completed a synthesis of (±^proges-terone (20) (9) (Scheme 1). The a l l y l i c alcohol moiety has been incorporated into a five-membered ring (9), a six-membered ring (10), or an acyclic precursor (11). Scheme 1. Synthesis of (i)-progesterone (20). - 8 -Another extremely useful i n i t i a t i n g group Is the epoxide functionality. The inclusion of this group into the acyclic precursor is aesthetically pleasing because the system more nearly approaches that of many enzymic cyclisations (4e). Goldsmith (4g, 12) performed one of the f i r s t epoxide cyclisations using epoxide 2l_, which gave a mixture of three compounds, 23_ - 25. These products presumably arose from the carbonium ion intermediate 22. However, there can often be some di f f i c u l t y in the selective formation of terminal epoxides of polyolefins. Most oxidising agents show l i t t l e or no regioselectivity in the epoxidation of a polyene. This problem was solved by van Tamelen et a l . (13) with the use of N-bromosucciniraide (NBS) in a polar solvent. It appears that in a polar solvent, polyenes adopt a coiled, compact conformation, such that the - 9 -internal double bonds are not significantly exposed to the oxidising agent (1, 13). However, the terminal olefin i s attacked by bromonium ion to form a bromohydrin, which, upon treatment with base, i s converted to the terminal epoxide. Numerous carbon skeletons have been synthe-sised by van Tamelen and coworkers using a polyolefin epoxide. Some examples are the drimanes (26) (1,13a), pimaranes (27) (14), lanostanes (28) (15), and germanicanes (29) (16). Sharpless (17) converted squalene epoxide into yet another skeletal structure, malabaricane (30) (Scheme 2). Unfortunately, these cyclisations were frequently characterised by a low yield of the desired product - yields of 5-20% were not uncommon. 29 30 Scheme 2. Skeletal structures formed by cyclisation of acyclic epoxide precursors. - 10 -Some other i n i t i a t i n g groups which have been used are tertiary halides (18a), tertiary alcohols (18b), and epoxy cyclohexanones (4a). More detailed information on the use of ini t i a t o r s can be found in the review articles (1,4). D. Terminating Groups for Polyolefin Cydisations Early work on polyolefin cyclisations was mostly performed using terminal alkenes, conjugated esters, acetates, or enol acetates as terminators. These groups had the disadvantage that once cyclisation was complete, the resulting carbonium ion could lose a proton from a number of positions, and a mixture of products was frequently obtained. For example, with epoxide 21, not only was a mixture of double bond isomers obtained, but also ether formation occurred. In addition, a mixture of both five- and six-membered rings was often produced in these cyclisations. Johnson and coworkers (4b) found that the styryl terminating group in 3__ partially alleviated this problem by preferen-t i a l formation of products from the benzylic-stabilised cation 32_ rather than the homobenzylic cation 34. However, an efficient method of removal of the aromatic ring needs to be developed before the products of this cyclisation can be converted to natural products. The bicyclo[4.4.0] system was formed rather than the bicyclo[4.3.0] system when an allene such as 35_ was used (4b). However, in this case the resulting carbonium ion 37_ reacted with nucleophiles at both ends of the a l l y l i c system, and a mixture of alcohols 38_ and 39_ was obtained. - 12 -The introduction of an acetylene unit into the acyclic precursor has proved to be very versatile. Cyclisation of acetylenic alcohol 40 gave products arising from the carbonium ion _2_, rather than products from 41. For example, treatment of 4__ with stannic chloride in benzene gave compound _3, which could be ozonolysed to ketone 4_ (4b, 19). One other terminating group worthy of mention is the vinyl chloride moiety, which has been used by Lansbury (20). Cyclisation of - 13 -vinyl chloride 45 proceeded in better than 95% yield, but a mixture of cis- and trans-fused products 46_ and 4_7_ was obtained. 45 46 47 E. B-Keto Esters in Polyolefin Cyclisations 8-Keto esters are versatile compounds since they can be elabora-ted at either the ester or the ketone functionality. In addition, alkylation can occur at the a-position by formation of the raonoanion, or at the yp o s i t i o n via the dianion (e.g. 48). The B-keto ester can also be transformed into an isoprene unit 9^_, and reactions developed in this laboratory have greatly extended the use of B-keto esters (21, 22, 23). The incorporation of this functionality into a polyolefin cyclisation provides the possibility of further elaboration of the cyclised product. COOMe - 14 -In 1976 White and coworkers reported the acid-catalysed cyclisation of the polyolefin 8-keto ester 5C_ to give a 68% yield of bicyclic product __ (24). Similar conditions were used by Sum and Weiler (21, 25) in formation of the monocyclic product 53_ from 8-keto ester _2 (92% yield). Presumably these reactions occur through an enolic intermediate, probably with complexation of the Lewis acid (e.g. 54). These cyclisations were notable in that only C-cyclisation was COO Me COOMe 50 51 52 53 54 observed. Frequently 8-keto ester cyclisations occur to give O-cyclised compounds as major or even sole products. This tendency has been exploited by Sum and Weiler (26), culminating in syntheses of the insect - 15 -sex pheromones exo- and endo-brevicomln (58, 59), and frontalin (60). The c r i t i c a l step in these syntheses was cyclisation of 8-keto ester 5_5 to give the 6,8-dioxabicyclo[3.2.1]octane skeleton 57, presumably via intermediate 56_ (E = electrophile) (Scheme 3). Scheme 3. Synthesis of bicyclic ketal pheromones. A number of routes have been found to circumvent the tendency of 8-keto esters to undergo O-cyclisation. One method is the use of enol phosphate 61_ by Corey jet a l . (27). Treatment of 61_ with mercuric trifluoroacetate gave the organomercury compound 62^ , which was ultimately converted to aphidicolin (63). - 16 -Another useful derivative of the 8-keto ester i s the enol acetate, and a preliminary communication by van Tamelen and Hwu (28) reports i t s use in cyclisation of 6_ to give, after modification, the steroidal acid 65. A variety of protonic acids have been used to promote polyolefin cyclisations. These are generally strong acids, such as fluorosulphonic acid (29a), sulphuric acid (29a), picr i c acid (17), and both acetic acid and trifluoroacetic acid (4). Common Lewis acid catalysts which have - 17 -been employed are stannic chloride, titanium tetrachloride, boron trifluoride etherate, aluminium chloride, and alkylaluminium chlorides (4, 29b). Stannic chloride is generally the Lewis acid of choice for 8-keto ester cyclisations, but Jackson and Ley (30) have also used zinc iodide to produce the cis-bicyclic structure 67_ from the monocyclic acetylene 66. Phenylsulphenyl chloride and phenylselenenyl chloride have each been used in cyclisation of 8-keto ester 52_ to give the monocyclic compounds 68_ and 69_, respectively (31). The advantage of these electrophiles over protonic acids and many Lewis acids i s that the product has one extra functionality on the ring. Unfortunately, attempts at formation of more than one ring seems to give O-cyclisation when either sulphur or selenium reagents are used (32a, 32b). Other electrophiles which have been used to promote polyolefin cyclisations include bromonium ion, obtained from a number of sources (33a, 33b), the phenylselenium cation with a variety of counterions (32a), and mercury(II) salts (27, 32c). - 18 -F. Silicon In Organic Chemistry One of the major problems in polyolefin cyclisations, which was briefly alluded to earlier, is the lack of regioselectivity in quenching the carbonium ion produced during cyclisation. Terminal acetylenes are useful for directing formation of the carbonium ion to a specific carbon (4b). Another more recent terminator is the trimethylsilyl (TMS) group. This functionality not only stabilises carbonium ions beta to i t s e l f , but also appears to have an activating influence on an a l l y l i c double bond by increasing the nucleophilicity of the olefin. Silicon has a number of properties different from carbon which have made organosilicon chemistry one of the most rapidly expanding areas of synthetic organic chemistry In recent years. This growth is - 19 -reflected in the large number of reviews and books which have been written on the subject in recent years (34). The bond strengths of silicon bonded to other atoms give some clue to the unique position silicon holds in organic chemistry. It can be seen from Table I (34i) that relative to carbon, s i l i c o n forms weaker bonds to both hydrogen and carbon. However, both Si-F and Si-0 bonds are quite strong. This combination of bond strengths has lead to the development of many silicon based protecting groups. The Si-C and Si-0 bonds are strong enough to withstand many chemical manipulations and transformations; however, treatment of the compound with a source of fluoride ion w i l l generally result in cleavage of the Si-X bond (X = 0, C), and elimination of the protecting group. The electronegativity of sili c o n is 1.8 on the Pauling scale; this compares with a value of 2.5 for carbon. Thus, silicon is electropositive and has some degree of metallic character relative to carbon. In addition, silicon has vacant d-orbitals in the valence shell. Because of these two properties silicon stabilises carbonium ions beta to i t s e l f , and to a lesser extent can also stabilise carbanions in an a-position. Stabilisation occurs either by bridging of Table I. Bond energies of Si versus C(kJ mol" ). Si-F Si-0 Si-C Si-H 540-570 370-450 230-320 290-320 C-F C-O C-C C-H 440-465 350-360 347 414 - 20 -Si between the two carbons, or by hyperconjugation, or by a combination of these two. Many applications of these properties have been reported. In particular, vinyl trimethylsilyl groups are frequently used for regioselectively placing an electrophile on an olefin, the incoming electrophile invariably replacing the trimethylsilyl group. Depending on reaction conditions the replacement can also be stereoselective or stereospecific. Koenig and Weber (35a) showed complete stereospeci-f i c i t y in deuteration of _- and E-vinylsilanes __ and 12_ with deuterium chloride or deuterium bromide In acetonitrile. "Retention of configura-tion" about the double bond is always observed when the electrophile is a proton. However, inversion or retention can occur when halogens or W SiMe 3 70 71 SiMe 3 D 72 73 other electrophiles are used (35b). A proposed mechanism for this substitution, and a discussion on the origin of the stereoselectivity, can be found in a review by Chan and Fleming (34g). - 21 -Allylsilanes also react regioselectively with electrophiles, but at the y-position to give products resulting from the B-carbonium ion 75. Elimination of the s i l y l group in _75_ then occurs with formation of a new double bond. The stereoselectivity of the reaction can be controlled in certain cases (36). 6 Nuc Fleming and Paterson (37) have used the allylsilane for conver-sion of a ketone into a quaternary carbon in a process known as gem-dialkylatioh. A Wittig reaction on the ketone 77^  gave the allylsilane 78, which was then treated with a variety of electrophiles, generally in the presence of titanium tetrachloride, to give the products 79_ - 83_ (Scheme 4). Yields were generally good to excellent. The a b i l i t y of a s i l y l group to stabilise a carbonium ion in a B-position has been used to obtain good regioselectivity in Diels-Alder reactions. Wilson et a l . (38a) and Hosomi et^ a l . (38b) obtained nearly pure para products from the reaction of allylsilane 84_ with electron-deficient alkenes 85. - 22 -- 23 -S i l y l enol ethers are now used routinely by chemists to obtain either the kinetic or the thermodynamic alkylation product. S i l y l enol ethers can react with tertiary halides and a,8-unsaturated ketones; they can also be employed in Diels-Alder reactions, in Claisen rearrange-ments, and in other sigmatropic reactions. Examples of these and other uses can be found in s i l y l enol ether reviews (39) and in general s i l i c o n reviews (34). The Peterson olefination reaction (40) i s a silicon analogue of the Wittig reaction. The properties of silicon have, however, resulted in a number of advantages of the Peterson olefination over the conven-tional Wittig reaction: (i) Sterically hindered carbonyls w i l l react more readily with the sili c o n reagents, ( i i ) better stereochemical control can often be obtained, and ( i i i ) the by-products of the reaction are more easily removed. Other common uses of organosilicon compounds in organic chemistry are as hindered, non-nucleophilic bases, in carbonium ion rearrange-ments, as reagents for Sjj2 hydrolysis reactions, and for the introduc-tion of a variety of functional groups. More applications of sil i c o n in both organic and organometallic chemistry can be found in the review articles (34, 39). G. The Trimethylsilyl Group i n Polyolefin Cyclisations The f i r s t published paper on the use of an allyls i l a n e in a cyclisation reaction was by Fleming et a l . (41a) in 1976. Treatment of the acetal 88^  with stannic chloride gave the olefin 90_ as the only - 24 -isolated product. This compares with the cyclisation of acetal 8_ by Johnson and coworkers (42), which gave a mixture of five different products. Presumably a l l products arose from the carbonium ion 89. A later publication by Fleming and Pearce (41b) stated that cyclisation of the allylsilane 88_ was essentially complete In carbon tetrachloride at room temperature within 3 min. In comparison, the h a l f - l i f e for the cyclisation of 87, was 8 min at room temperature. Hence not only did the trimethylsilyl group direct formation of the exocyclic olefin, but i t also appeared to have an activating influence in the cyclisation. Since this f i r s t communication on the allylsilane cyclisation, several groups have also achieved cyclisations of allylsilanes. The slx-membered carbocycles 92_ were formed when aldehyde 9l_ was treated with stannic chloride at -78°C for less than 15 min. Hydrolysis of the s i l y l ethers occurred during work-up to give _3_ (43). - 25 -91 92 93 The t r i c y c l i c compound 9_ was obtained from allyl s i l a n e 94_ by Lewis acid-catalysed cyclisation, probably via the intermediate _5_ (44). Further examples of intramolecular allylsilane cyclisation with carbonyls can be found in reference 45. Danheiser et a l . (46) achieved a cyclopentene annulation using enones of type 97_ and trimethylsilylallene 98. This "one-pot" synthesis is characterised by a 1,2 shift of the trimethylsilyl group as proposed in 99. - 26 -OTiCI 3 100 Heathcock and coworkers (47) were able to form preferentially a bicyclo[3.2.2] structure rather than a [2.2.2] system by directing formation of a carbonium ion beta to a trimethylsilyl group. Cyclisa-tion of acetylene 101 gave the formate ester 102 in 82-84% yield. However, treatment of silylacetylene 103 with formic acid gave, after hydrolysis, ketone 104 in 85% yield. Heterocyclic compounds have been prepared from both vinyl- and all y l s i l a n e s . The lactone 106 was obtained in 57% yield from the allylsilane 105 (48). Compound 106 is reported to rearrange very easily to the conjugated isomer 107; thus, this reaction highlights the mild conditions used for many allylsilane cyclisations. Cyclic ethers (49a, 49b) and cyclic amines (49c) have also been synthesised from s i l y l precursors. - 27 -OCHO \ S i M e 3 106 107 105 The use of organosilanes to achieve cyclisation of more than one ring has only been reported by two groups at this stage. Brinkmeyer found that the trimethylsilylacetylene 108 could be treated with 2,2,2-trifluoroethanol to effect conversion to the bicyclic ketone 110 in 76% yield (50). - 28 -Johnson's group has used both allylsilanes and silylacetylenes in formation of steroids. Formation of ketone 112 was achieved in only low yield from the silylacetylene 111 (51a). However, the homologous compound 113 was converted to 114 (C/D trans: C/D cis = 88:12) in 58% yield (51b). The allylsilane 115 also gave a 5-membered D ring compound Si Me 3 I - 29 -U_ (83% yield), but with a mixture of eplmers at the side chain (51c). 115 116 Cyclisation of 117 with trifluoroacetic acid and ethylene carbonate in 1,2-dichloroethane gave ketone 118 in 52% yield (51d). Finally the allylsilane 119 was converted to 120 in 66% yield (51c). SiMe - 30 -A l l the products obtained from cyclisations with a trimethylsilyl terminating unit can be rationalised on the basis of selective formation of a carbonium ion in the 8-position to the sili c o n atom. Other explanations based on steric control are also possible (51). However, there are many examples in the literature (34 and references therein) which give credence to the former rationalisation for the regioselecti-vity observed in these cyclisations. It can be seen that the trimethylsilyl group might have a profound effect on polyolefin cyclisations, and there is much scope for further investigations into the u t i l i t y of this moiety. The aim of this project was to study the effect of both an unsaturated ester and the trimethylsilyl group in polyolefin cyclisations. The use of epoxides in the cyclisation of allylsilanes was also to be investigated. A number of terpenoid natural products, such as the drimanes and the monocyclic gem-dimethylcyclohexanes, possess the carbon skeleton obtained in these reactions, and the cyclised products were to be elaborated into a variety of natural products. - 31 -DISCUSSION A. Synthesis and Cyclisation of Acid Allylsilanes to  Monocyclic Products An obvious prerequisite to a study of the cyclisation of silicon substituted conjugated esters or acids is the synthesis of the appropriate precursors. A number of methods are available for the preparation of allylsilanes (34g, 34h), but there are very few reported syntheses of allylsilanes conjugated to a carbonyl functionality. Our attention was directed to a preparation of the carboxylic acid 123 by Itoh, Fukui, and Kurachi (52). In this synthesis, diketene (121), which 3 acts as a synthetic equivalent of a 3-butenoic acid a synthon, reacts with trimethylsilylmethylmagnesium chloride to give the carboxylic acid 122 (Scheme 5). Nucleophilic attack on diketene generally occurs at the carbonyl carbon to give a 8-diketone, and the reaction of diketene with the s i l y l Grignard reagent in the presence of a nickel catalyst (53a) i s the f i r s t example of vinyl-oxygen bond cleavage of 121 by a carbanion (52, 54). In our hands, acid 122 was obtained in 85% yield by the method of Itoh et a l . (52, 54), with minor modifications. The biscopper dienolate of 122 was regioselectively alkylated in the Y-P°sition (52, 55) with l-bromo-3-methyl-2-butene to give the s i l y l acid 123 in 70% yield (E:Z. =7:3). No trace of a-alkylated product was observed. This regioselectivity i s known to occur with copper dienolates of conjugated acids, although the corresponding ester enolates generally undergo - 32 -O O A A Nuc 123 Scheme 5. Synthesis of an allylsilane precursor for polyolefin monocyclisation. a-alkylation (55). Some care had to be taken in the purification of allylsilane 123 as the trimethylsilyl group was lost upon heating. A later synthesis of 123 by Itoh and coworkers (56) was achieved with formation of the pure E_-isomer, but in this case 10% a-alkylation also occurred. Polyolefin cyclisations can be effected with a variety of reagents and reaction conditions; the results of the study on - 33 -cyclisation of allyls i l a n e 123 are shown in Table II. It was anticipated that cyclisation of allylsilane 123 would proceed via the carbonium ion 124, and the purpose of the trimethylsilyl group was to direct formation of the olefin to the less stable exocyclic position to give 125 rather than either of the two possible endocyclic products 126 or 127. SiMe, COOH 123 Me. COOH 124 C O O H 127 CX + ^ X ^ C O O H 125 C O O H 126 Li AIH/ OH OH 128 129 In the cyclisation of allylsilane 123 only a mixture of the two B,Y~unsaturated acids was obtained - the conjugated acid 127 was not detected in any of the cyclisations studied. The ratio of the regioisomers 125:126 was determined by 80 MHz *H nmr spectroscopy; the - 34 -Table II. Cyclisation of a l l y l s i l y l acid 123. Lewis (equlv.) Bronsted (equiv.) Solvent Temp. Time 125:126:123^'-Run Lewis acid (equiv.) 1 TiCU ( 1 ) 2 TiCli, ( 1 ) 3 SnCli, ( 1 ) 4 BF 3 'Et 2 0 ( 1 0 ) 5 BF 3 «Et20 (5) 6 SnCli, ( 1 ) 7 BF 3 «Et 20 ( 2 ) 8 BF 3 «Et 2O ( 1 0 ) 9 BF 3.Et 2 0 ( 1 0 ) 1 0 BF 3 «Et 2O ( 1 0 ) 11 BF 3 «Et 2 0 (8) 12 SnCli, (5) a,b acid (°C) (h) AcOH (1) AcOH (2) AcOH (5) AcOH (5) AcOH (5) AcOH (4) CH2Cl2 0 4 1 8 0 CH2C12 -50 14 0 1 CH2Cl2 -50 15 3 1 0 toluene 0-25 1.5 4 1 0 * toluene 0-25 2.5 4 1 OS. toluene -50 24 3 1 0 CH2C12 0 4 3 2 0 benzene 5 48 3 2 0 toluene 5 48 3 1 0 toluene -23 8 0 0 1 toluene -7 12 3 1 0 C H j C l ^ 25 2 1 4 0 3. 1. — Ratios were determined by H nmr spectroscopy; — Crude yields of a l l runs were nearly quantitative; — Some acyclic product with no trimethylsilyl residue was also obtained; ^ 40% purified yield of 125_ and 126; — 76% purified yield of 125 and 126 after conversion to alcohols 128 and 129; — Methylene chloride saturated with water. - 35 -olefinic protons of 125 resonate at 64.85 and 64.91, whereas the olefinic proton of 126 resonates at 65.65. It was found that titanium tetrachloride gave a very small amount of the exocyclic compound 125 regardless of the temperature employed (runs 1 and 2). Both stannic chloride and boron trifluoride etherate gave similar product ratios. The addition of acetic acid with boron trifluoride etherate had no effect on the ratio of 125:126, but the yield of products was improved (runs 4 and 5). Toluene was found to be the solvent of choice over both methylene chloride and benzene when boron trifluoride etherate was used as the Lewis acid (runs 7-9); however, when stannic chloride was employed the isomer ratio seemed to be solvent independent (runs 3 and 6). The optimum temperature for the formation of 125 appeared to be quite low (-50°C) when stannic chloride was used as the catalyst; however, higher temperatures were required for cyclisation to proceed when boron trifluoride etherate/acetic acid was used (runs 5, 10, and 11). Increasing the temperature above ambient temperature did not improve the isomer ratio. The optimum cyclisation conditions for the formation of exocyclic product 125 from s i l y l acid 123 are those shown in run 5 (125:126 = 4:1), but the carboxylic acids were not easily separated. Treatment of the mixture of acids with lithium aluminium hydride in ether gave alcohols 128 and 129 which were separable by flash chromatography. The overall yield of pure exocyclic alcohol 128 from acid 123 was 61%. Some loss of volatile alcohol 128 was observed when removing trace amounts of residual solvent. - 36 -The cyclisation of acid 123 was not affected by the lack of stereochemical homogeneity about the double bond since only one asymmetric centre is present in the monocyclic product 125. However, i t was envisioned that problems would occur with extension of this route to the bicyclic case, as cyclisation of the proposed precursor 130 could give a mixture of epimers at C-9 (which are now diastereomers), in addition to a mixture of olefinic products. Thus an investigation was undertaken in the hope of finding a more stereoselective route to the allylsilane precursors. B. Synthesis and Cyclisation of Ester Allylsilanes to  Monocyclic Products Much work has been carried out in this laboratory on p-keto esters and in particular on their conversion to conjugated esters 134 by reaction of a cuprate reagent with the enol phosphate 133 (21, 23). This method seemed an attractive possibility for formation of the - 37 -COOMe 132 133 134 desired allylsilane precursors, although at this stage only primary, unhindered alkyl groups had been coupled to the enol phosphate. Earlier attempts at coupling the necessary s i l y l cuprate reagent [R" = Me3SiCH2, prepared from trimethylsilylmethyllithium (57)] with enol phosphate 133, were unsuccessful in our laboratory. A more recent procedure for the preparation of trimethylsilylmethyllithium was also followed (57d), but again, the cuprate coupling could not be achieved. We were unsure whether this was due to inabi l i t y to form the desired lithium salt, or because the cuprate species would not react with the enol phosphate. We then turned to a study of the reaction of the Grignard reagent, trimethylsilylmethylmagnesium chloride, with enol phosphate 133. Either the enol phosphate or the starting 8-keto ester 132 was recovered when 133 was treated with the Grignard reagent in ether or in THF at a variety of temperatures. The addition of HMPA had no effect on the reaction. A variety of copper catalysts [Cul, Cu(OAc)2#H20, CuBr»Me2S] were investigated, using from 2% to one equivalent of the catalyst, but again only recovered enol phosphate or B-keto ester was obtained. The use of nickel acetylacetonate dihydrate [Ni(acac)2*2H20] (53b) was also unsuccessful. - 38 -Nickel catalysts have been used in coupling reactions of s i l y l enol ethers with Grignard reagents (53a). In our hands, treatment of the s i l y l enol ether 136 with trimethylsilylmethylmagnesium chloride in the presence of Ni(acac)2*2H20 gave none of the desired product 135. 136 Finally i t was discovered in our laboratory (58) that the anhydrous form of nickel acetylacetonate w i l l catalyse the coupling reaction of trimethylsilylmethylmagnesium chloride with enol phosphates to give conjugated s i l y l esters, and this method was subsequently used for the preparation of a l l a l l y l s i l y l esters. B-Keto ester _52_ was prepared from the dianion of methyl acetoacetate and l-bromo-3-methyl-2-butene (21, 22), and was then converted to the enol phosphate 137 (21). The s i l y l Grignard reagent was prepared in ether at room temperature, to suppress Wurtz coupling, - 39 -and then 0.025 - 0.05 equiv. of Ni(acac) 2 was added to the Grignard reagent. An exothermic reaction occurred upon the addition of enol phosphate 137 to the reaction mixture and a brown sludgy precipitate formed. This seemed to occlude the catalyst, and frequently more catalyst had to be added for the reaction to proceed to completion. A 142 Scheme 6. Synthesis and cyclisation of the ester monocyclic precursor 138. - 40 -75% yield of Z-allylsilane 138 was obtained and this product was found to contain none of the E-isomer. The coupling reaction did not occur in THF. Results of the cyclisation study of s i l y l ester 138 are shown in Table III. As with the acid cyclisations, the ratio of the regioisoraers 140:141 was determined by integration of the resonances due to the olefinic protons in the 1H nmr spectrum (140, 64.75, 64.86; and 141 , 65.60). F i r s t l y , i t can be seen that cyclisation i s only achieved in the presence of a Lewis acid (runs 1-3). Either stannic chloride . or boron trifluoride etherate w i l l effect cyclisation, but in the latter case at least one equivalent of acetic acid must be used in order to obtain 140 and 141 uncontaminated with by-products (runs 4-6). Interestingly, the presence of acetic acid reduces the amount of exocyclic isomer obtained when stannic chloride is used (runs 7-9); in fact, the endo-isomer was the sole product obtained (70% yield) with the reaction conditions listed in run 9. The effect of solvent was examined with both boron trifluoride etherate/acetic acid (runs 6 and 10) and with stannic chloride (runs 7, 11, and 12). There was no change in isomer ratio with either methylene chloride or toluene, but when the solvent was changed to methylene chloride which had been saturated with water (run 12) a significant improvement in the ratio of 140:141 was observed. Finally, a study was performed on the quantity of Lewis acid, the temperature, and the reaction time. At low temperature (run 13) a mixture of endocyclic product, exocyclic product, and also an acyclic chloride 145 was obtained; the yield of the latter product was 15%. A - 41 -Table III. Cyclisation of s i l y l ester 138. Run Lewis acid (equlv.) Bronsted (equlv.) acid Solvent Temp. (°C) Time (h) 140: 141 138^: Other Products 1 - - camphor- (1) sulphonlc acid CH 2C1 2 25 72 0 0 1 0 2 trlfluoro- (1) acetic acid CH2CI2 25 24 0 0 0 l£ 3 - AcOH (5) CH2CI2 25 3 0 0 1 0 4 BF 3 'Et 2O (10) toluene 25 24 0 0 1 0 5 BF 3 »Et 2O (5) AcOH (trace) CH 2C1 2 25 3 3 3 3 i i 6 BF 3 «Et 2O (4) AcOH (2) CH 2C1 2 0 48 3 1 0 0 7 SnCli, (2) CH 2C1 2 25 8 2 1 0 0 8 SnCl!, (5) AcOH (trace) CH 2C1 2 25 2 3 0 0 9 SnCli, (5) AcOH (1) CH 2C1 2 25 1 0 1 0 0 10 BF 3 .Et 2 0 (4) AcOH (2) toluene 0 60 3 1 0 0 11 SnClt, (1) toluene 0-25 24 2 1 0 0 12 SnCl,, (5) CH2Cl2^ 0 1 7 1 0' 0 13 SnCli, (5) CH 2 C12~ -23 2 4 1 0 i * 14 SnCl 4 (1 ) CH2CI2— 0 2 3 1 0 0 15 SnCli, (1 ) CH 2C12~ 25 1 3 1 0 0 16 SnCl^ (10) CH2CI2"— 0 0.5 5 1 0 0 17 SnCli, (0.05) - CH2Cl2— 25 4 0 0 1 0 a Ratios were determined by *H nmr spectroscopy j b Methylene chloride saturated with water > c Acyclic ester 143 was obtained; d Acyclic ester 144 was obtained; Acyclic chloro ester 145 was obtained. OCOCF. COOMe XOOMe 143 144 ci TMS COOMe 145 - 42 -similar ratio of 140:141 could be obtained by treatment of the allylsilane in wet methylene chloride at 0°C for 2 hours, or at room temperature for 1 hour (runs 14 and 15). Higher reaction temperatures gave increasing amounts of the endocyclic isomer and intractable material. The reaction time could be shortened to 30 min by increasing the amount of stannic chloride (run 16), but the optimum reaction condi-tions were found to be 5 equivalents of stannic chloride In wet methylene chloride at 0°C for 1 hour (run 12, 140:141 = 7:1, 70% yield). It should be noted that the reaction must be performed under dilute conditions (0.08 M) in order to obtain this regioselectivity. In addition, i t was found that the reaction gave a poorer regioselectivity when i t was scaled up to more than 10 mmole of al l y l s i l a n e . The crude yield In the cyclisation step was invariably quantitative, but the exocyclic product 140 was somewhat volatile and care had to be taken in handling the product. It i s interesting to speculate on the mechanism of the cyclisa-tion, but at this stage we merely note that at least one equivalent of Lewis acid is necessary to achieve reaction (run 17). The efficiency of both the ester and the acid cyclisation in the presence of a proton source, such as water or acetic acid, suggests that cyclisation i s initiated by proton attack on the terminal olefin to give the cyclic carbonium ion 124 or 139 which subsequently loses the trimethylsilyl group to give the exocyclic olefin. The endocyclic ester is presumably formed in a subsequent isomerisation. As with the acid cyclisation, none of the conjugated ester 142 was observed, presumably because of the - 43 -severe steric hindrance encountered in the tetrasubstituted olefin. The a b i l i t y of the trimethylsilyl group to control the regio-selectivity of the olefin i s seen very clearly when one compares the cyclisation of 138 with that of methyl geranoate (146). Kurbanov et a l . (29a) were able to cyclise 146 with either sulphuric acid or fluorosulphonic acid, both very strong proton sources. In each case the endocylic isomer 141 was the major product obtained, presumably via the cyclic carbonium ion 147. COOMe We were unsuccessful in isomerising the endocyclic isomer 141 to the exocyclic olefin 140. Because of the higher ratio of exocyclic product to endocyclic product in the cyclisation of ester 138, this was the preferred route over cyclisation of acid 123 in the synthesis of methylenecyclohexanes. C. Synthesis of (±)-Trixagol (153) A number of natural products possess the carbon skeleton 148 with an exocyclic methylene group on a cyclohexane ring. Among these are the - 44 -•y-damascones (149) (59a), onchidal (150) (59b) and related sesquiter-penoids isolated from marine sources 151(59c), diumycinol (152) (59d), and trixagol (153) (60). We elected to synthesise trixagol to to illustrate the usefulness of the monocyclic allylsilane cyclisation. B 153 - 45 -Trixagol is a hydroxy diterpene which has been recently isolated from the hemiparasite plant Bellardia trixago (60). We envisioned a synthesis of 153 via a convergent route which involved joining the two appropriately functionalised subunits A and B. The sulphide 155 was to be the synthetic equivalent of subunit B and this was to be alkylated with 154 (L = halide or sulphonate), which is a synthetic equivalent of subunit A. The mixture of esters 140 and 141 was readily converted to the corresponding alcohols using lithium aluminium hydride, and separation of the alcohols could be achieved by flash chromatography at this stage. However, numerous attempts at the formation of halide 154 (L = CI, Br, or I) were unsuccessful, and this is undoubtedly due to the severe steric crowding around the hydroxymethyl in 128 flanked by the quaternary carbon and the exocyclic double bond [A^» 3^ strain] (61). Consistent with this analysis was the observation that conversion of the cyclohexenyl alcohol 129 to the tosylate 158 could be performed in 24 hours, whereas the alcohol 128 required 72 hours for complete - 46 -COOMe 140 OH LiAIH 4 COOMe 141 OH 128 OTs 157 159 SPh MCPBA py.TsCI KH, PhSH, EtOH, A 129 OTs 158 SPh 160 SO aPh 161 Scheme 7. Synthesis of Subunit A. - 47 -conversion to the tosylate 157 (Scheme 7). In a less sterically hindered system Oppolzer and Snowden (62) were unable to convert alcohol 162 to halide 163. (L = Br, I), and they attributed this lack of reactivity to the steric congestion of the neopentyl-type system. We were not able to couple sulphide 155 with either the mesylate nucleophiles to 154. There are three possible conformations for such a nucleophilic substitution: 154a, 154b, and 154c. The conformation 154a has a serious 1,3-interactlon between a methyl group and the leaving group L - making this conformation rather inaccessible. In conforma-tions 154b and 154c the backside of the C-L bond is effectively blocked by the gem-dimethyl group, or by the exocyclic methylene, respectively. We feel that the inability of 154 to adopt a conformation suitable 162 163 or the tosylate 154. Nor were we able to add any other carbon L H H 154a 154b 154c - 48 -for backside displacement in an SN2 substitution may be responsible for the lack of reactivity of this compound. Kocienski has reported similar problems in his synthesis of diumycinol (152); the next higher analogue of 128, namely the alcohol 164, was used to overcome the problems associated with the lack of reactivity in 128 and i t s deriva-tives (59d). To overcome the lack of reactivity of 128 with carbon nucleophiles we chose to reverse the role of the electrophilic and nucleophilic components corresponding to subunits A and B. A synthesis of sulphone 161, also a synthetic equivalent of subunit A, is shown in Scheme 7. Treatment of a mixture of tosylates 157 and 158 with the highly nucleophilic thiophenolate anion in ethanol at room temperature (63) gave recovered starting materials only. However, sulphides 159 and 160 were obtained in 74% yield from their respective tosylates when the reaction mixture was heated at reflux for 16 hours. The mixture of isomers 159 and 160 was most easily separated by flash chromatography at this stage. Sulphone 161 was obtained from the sulphide 159 in 96% yield by oxidation using m-chloroperoxybenzoic acid. It was found that 164 152 - 49 -the optimum amount of MCPBA was from 2.4 to 2.5 equivalents: A mixture of sulphoxides and sulphone was obtained with only 2 equiv. of MCPBA, whereas the use of more than 2.5 equiv. resulted in epoxidation of the olefinic double bond. The protected hydroxy bromide 166 is a synthetic equivalent of subunit B, and a synthesis of 166 is shown in Scheme 8. Geraniol was protected as i t s benzoate ester in quantitative yield. Oxidation of the ester with selenium dioxide and 70% _-butyl hydroperoxide using a modification (21) of the method of Umbreit and Sharpless (64) gave the desired alcohol 165a in 50% yield. In addition, 40% recovered starting Scheme 8. Synthesis of subunit B. - 50 -material and 5% aldehyde 165b were isolated. It was found that i f the reaction temperature was allowed to warm above 10°C a higher proportion of the undesired aldehyde was obtained. Conversion of alcohol 165a to the bromide 166 was performed in 97% yield using phosphorus tribromide and pyridine. With subunits A and B in hand, the synthesis of trixagol was effected as shown in Scheme 9. Sulphone 161 was deprotonated using 1) nBuLi, THF. HMPA 2) 153 Scheme 9. Synthesis of (±)-trixagol (153). - 51 -n-butyllithium, and coupled to bromide 166 in the presence of HMPA, to give a mixture of diastereomers 167 in a nine to one ratio (as determined by *H nmr spectroscopy). The anion of the sulphone in THF-HMPA is a bright orange colour and i t was crucial that halide 166 be pre-dried by stirring as a solution in THF over calcium hydride. This solution was subsequently syringed into the reaction mixture, and i f no pre-drying had been carried out the colour of the solution immediately changed to yellow, indicating quenching of the anion. Sulphone 161 and i t s alkylated product 167 had nearly identical R_ values and i t was very d i f f i c u l t to separate a mixture of the two compounds at this stage. The alcohol functionality was deprotected by removal of the benzoate ester using DIBAL to give hydroxy sulphone 168 in 64% overall yield from sulphone 161. Unreacted sulphone 161 (36%) was also recovered during purification. In a similar reaction, Uneyama and T o r i i (65) have reported a yield of 76% of sulphone 170, along with 22% of the starting material 169, for their sterically hindered system. OH OH 169 COOMe 170 The final step in our synthesis was achieved by hydrogenolysis of the sulphone moiety with 6% sodium amalgam using a method analogous to - 52 -that of Trost et a l . (66). Once again some d i f f i c u l t i e s were encoun-tered in this reaction, presumably due to the steric hindrance of any functionality attached to the carbon alpha to the ring. Trost et a l . achieved cleavage of model sulphones with temperatures from -20°C to room temperature, and reaction times ranging from 7 min to 1 hour. However, i t was necessary to heat sulphone 168 in boiling ethanol for 16 hours before cleavage could be effected (68% yield). This reagent was developed because of the tendency of sulphones containing a l l y l i c functionalities to undergo rearrangements when treated with reagents such as Raney nickel. Indeed, i t was found that heating sulphone 168 for longer than 24 hours resulted in isomerisation of the double bonds; similarly, treatment of sulphone 167 with sodium amalgam at room temperature gave some loss of the benzoate ester and also gave a l l y l i -cally rearranged products, but no hydrogenolysis of the sulphone moiety occurred. The i r , *H nmr, and gas chromatographic data of the synthetic racemic trixagol were identical with those of the natural compound (60). This completes the f i r s t reported synthesis of racemic trixagol (67), and an overall yield of greater than 10% from methyl acetoacetate was achieved. D. Synthesis and Cyclisation of Ester Allylsilanes to Bicyclic Products. Synthesis of (±)-Albicanol (179b), (±)-Albicanyl Acetate (180) and (±)-Isodrimenin (183) The next step in this project was an extension of the monocyclic allylsi l a n e cyclisation to the bicyclic system. Synthesis of the - 53 -appropriate precursor 172, and cyclisation to the bicylic system, is shown in Scheme 10. The 8-keto ester 50_ and enol phosphate 171 had been prepared previously in this laboratory (21, 22). Conversion of the enol phosphate to the ester allylsilane 172 was achieved in a similar manner to that followed in the synthesis of the monocyclic precursor 138, using trimethylsilylmethylmagnesium chloride, enol phosphate 171, and a nickel(Il) catalyst in ether. It was found that the best yield for the reaction (72% for two steps from 50) could be obtained by vigorous st i r r i n g of the reaction medium using an overhead-stirrer, and by the addition of fresh catalyst 30 min and 1 hour after the enol phosphate had been added to the Grignard reagent. Results of the cyclisation study of s i l y l ester 172 are shown in Table IV. The ratio of the products was determined by a combination of % nmr spectroscopy and gas chromatography. Preparative gas chromato-graphy of some of the i n i t i a l cyclisation reactions gave moderately pure samples of the major products, 173a, 173b, 174a, and 174b, a l l of which possess drimane-type skeletons (68). The a-isomers 173a and 174a could be separated by gas chromatography, but the B-isomers 173b and 174b could not be separated from each other on a variety of columns. The olefinic protons of both the exocyclic isomers resonate at 64.63 and 54.81, whereas the olefinic proton of both isomers of 174 resonates in a broad multiplet centred at 65.40. An approximate ratio of the exocyclic olefins could be obtained from the high f i e l d region of the *H nmr spectrum: The quaternary methyls of 173b resonate at 60.80, 60.85, and 61.05, whereas those of 173a resonate at 60.80, 60.88, and - 54 -'COOMe + e e COOMe 173b COOMe COOMe SiMe 3 = COOMe COOMe 50 171 COOMe 1) NaH 2) (EtO)aPOCI OPO(OEt)_ COOMe Me 3 SiCH 2 M g CI Ni(acac)2 172 COOMe 175 Scheme 10. Synthesis and cyclisation of the polyolefin bicyclic precursor 172. - 55 -Table IV. Cyclisation of a l l y l s i l y l ester 172. Run 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Acid (equiv.) T i C l i , TiClt, SnCli, SnCli, SnCli, A 1 C 1 3 AICI3 (5) (1) (1) (5) (5) (5) (5) BF3«Et20 (5) BF 3.Et 20 (5) BF3«Et20 (5) SnCli, SnCli, SnCli, SnCli, SnClt, SnCli, SnCli, SnCl,, (5) (5) (5) (5) (5) (5) (5) (5) Solvent Temp. (°C) CK2C1^- -23 ether -18 toluene -18 CH3N02 -23 CH2C12 -56 0 CHjCljS- -56 0 CHjCl^ -23 CH2Cl2S- -40 0 0 Time 172:173b:173a:174b:174a: Other (h) Products CH2C125" CH2C122-CH2Cl2^ CH 201^ 2. 0 CH2C1^- 0 CH2Cl2^- -56 CH2C122- -56 CH2C120- -56 CHjClj 5- -78 3 2 14 1 2 0 0 0 0 0 2± 1^ 0 2 I 21 j£ yl i£ 0 3 1 0 0 0 1 0 2 2 0 4 0 3 2 0 1.5 0 1 1 0 4.5 0 1 1 0 4.5 1-S 0 0 0 10 min 0 73 27 0 20 min 0 68 32 0 0.5 <10 71 17 0 1 0 74 16 0 4 0 77 18 0 1 0 74 16 0 i i 1* i i 0 0 0 0 0 0 0 0 0 0 0 0 1.5 0 6C£ 10 60^ 20 10i 8 0 0 0 50 20 30^ 0 < i o i 0 i o i 0 si 0 i o i - 56 -Table IV continued... — Methylene chloride saturated with water; — An acyclic product with no trimethylsilyl residue was obtained; — 174b + 174a; — 173b + 173a; — Monocyclic product 176 was obtained; — An unknown product was obtained; A small amount of cyclisation had occurred; — 173b + 174b. COOMe 176 - 57 -60.92. The conjugated isomer 175 was not observed in any cyclisation reaction. If titanium tetrachloride was used as the Lewis acid catalyst (runs 1 and 2) the major products were acyclic or endocyclic compounds with none of the desired exocyclic products. Boron trifluoride etherate, aluminium chloride, and stannic chloride a l l effected the desired transformation, but the reactions were quite solvent dependent. Stannic chloride in toluene (run 3) gave a mixture of exo-, endo-, and monocyclic products, but in nitromethane (run 4) no endocyclic products were observed. The most dramatic effect occurred with the use of dry methylene chloride compared to methylene chloride which had been satura-ted with water. At -56°C, dry C H 2 C I 2 gave only recovered starting material, whereas the wet solvent gave nearly pure exocyclic product (173b: 173a » 4:1) (run 5 and 16-18). The use of aluminium chloride in wet methylene chloride resulted in exocyclic products and some other material, but no endocyclic product. Lowering the temperature below 0°C in an attempt to improve the epimer ratio of 173b: 173a was not very successful (runs 6 and 7). Boron trifluoride etherate in wet C H 2 C I 2 gave a 1:1 mixture of exocyclic products, and again lowering the temperature of the reaction did not lead to an improvement in the ratio of 173b:173a (runs 8-10). When allylsilane 172 was treated with 5 equivalents of stannic chloride in wet methylene chloride at 0°C, complete cyclisation occurred in less than 10 min (run 11). If the reaction was allowed to s t i r at 0°C for a longer period of time, the i n i t i a l product distribution - 58 -changed from pure exocyclic compounds (173b:173a = 2.5:1) to a mixture of exo- and endocyclic compounds 173 and 174, and fi n a l l y complete conversion to the endocyclic products occurred (runs 11-14). The ratio of epimers at C-9 remained approximately the same throughout the course of the reaction, although there was some loss of product over an extended period. These results indicate that the exocyclic compounds 173 are less stable than the endocyclic isomers 174. This i s consistent with many other studies on the isomerisation of methylenecyclohexanes to methyl cyclohexenes. Of interest here is the observation that the 8,y-unsaturated esters 174 appear to be preferred over the a,8-unsatura-ted ester 175. Again, this may reflect the serious steric crowding of the tetrasubstituted double bond of 175. The effect of temperature can be seen when one compares runs 11-14 with runs 15-18. At -56°C some starting material was s t i l l present after 30 min when allylsilane 172 was treated with stannic chloride in wet C H 2 C I 2 . After 1 hour only exocyclic products 173 (8:a » 4.5:1) were present in the reaction medium, and this product distribu-tion remained essentially constant at this temperature. No change in epimer ratio was observed at -78°C. The optimum cyclisation conditions for the s i l y l ester 172 are those shown in runs 16 and 17 (173b: 173a « 74:16) but we were unable to separate the two epimers at this stage, nor were we able to epimerise 173a to 173b. We were somewhat surprised to find that the cyclisation of the al l y l s i l a n e 172 gave an epimeric mixture of products 173b and 173a. In - 59 -accordance with the Stork-Eschenmoser hypothesis (2), folding of the allylsilane into a chair-chair conformation 172b would be expected to yield exclusively the S-isomer 173b. The a-isomer presumably arises via the chair-boat conformation 172a, and a possible mode of cyclisation i s shown below. It seems that small steric interactions in the transition state of the cyclisation may play an important role in determining the product distribution (see below). 173a In a similar system van Tamelen and coworkers (69a) have suggested that the stereochemical outcome of the cyclisation i s determined by the solvent-dependent conformation of the starting material. Treatment of epoxide 177 with boron trifluoride etherate in benzene gave a mixture of bicyclic products 178a and 178b in approximately 10% yield (178a;178b = 85:15). However when the reaction was performed with cold 85% phosphoric acid, the yield of bicyclic material was much the same, but the product ratio was reversed - 60 -(178a;178b = 15:85) (69a). Similar differences in product distributions were observed in the epoxidised methyl farnesoate series (69b,c). A l l of these results indicate that energy differences between the chair-chair transition state and the chair-boat transition state must be very small. 177 178b 178a Two marine natural products, albicanol (179b) and albicanyl acetate (180) were recently isolated from a nudibranch (70). Albicanol i s also found in terrestrial sources (71). Albicanyl acetate appears to have potent fish antifeedant activity, and because of the structural similarity of the albicanyl compounds to the cyclisation product 173b, i t was a relatively simple task to complete a synthesis of albicanol and albicanyl acetate (Scheme 11). A mixture of the esters 173 was treated with lithium aluminium hydride in ether to give albicanol (179b) and epi-albicanol (179a) (179b:179a = 83:17). The mixture of isomers was separated using flash chromatography to give albicanol in 75% yield from the trimethylsilyl ester 172. Albicanyl acetate (180) was prepared from the alcohol using acetic anhydride, pyridine, and a catalytic amount of 4-dimethylaminopyridine. The racemic compound 180 from this synthesis was found to have antifeedant activity comparable to that of natural albicanyl acetate, which is optically active (72). The spectral data - 61 -C1!! nmr, i r , ms) of the synthetic compounds 179b and 180 were in good agreement with that from authentic samples (70). 173a 179a Scheme 11. Synthesis of (±)-albicanol (179b) and (±)-albicanyl acetate (180). Cinnamodial (181) and warburganal (182) are two other members of the drimane class of natural products. These compounds have been shown to possess considerable insect antifeedant activity against the African army worms, Spodoptera l i t t o r a l i s and Spodoptera exempta (73). D i f f i c u l t i e s are often encountered in the synthesis of the drimanic sesquiterpenes due to the variations in functionality at the C-8 and C-9 positions. Syntheses of isodrimenin (183), an intermediate in a reported synthesis of warburganal (74), have frequently been character-ised by lack of regioselectivity to give both isodrimenin (183), and confertifolin (184), by double bond isomerisation to drimenin (185), or by low yields in the synthesis (75). A regioselective synthesis of isodrimenin from ester 173 i s shown in Scheme 12. - 62 -R O. CHO CHO ^ R 181 R= OAc 182 R=H 183 R=O . R'=CH 8 184 R =CH 8 ,R'=O 185 Olefins 173a and 173b were epoxidised in methylene chloride using m-chloroperoxybenzoic acid to give a mixture of a l l four possible isomers of 186 in 92% yield. The major isomer was thought to be the product obtained via equatorial attack of MCPBA on olefin 173b, since attack from the axial direction on 173 would be severely hindered by the bridgehead methyl group. The epoxy esters 186 were then treated with 5 equivalents of lithium diisopropylamide in THF at -78°C, and allowed to s t i r at room temperature for 3 hours (76). Isodrimenin (183) was isolated in 60% yield from 186; the spectral data ( 1H nmr, i r ) were in good agreement with that of an authentic sample (75a). COOMe COOMe M C P B A L D A 173 186 183 Scheme 12. Synthesis of (±)-isodrimenin (183). - 63 -E. Synthesis and Cyclisation of Epoxy Ester Allylsilanes to Monocyclic Products. Synthesis of (i)-Karahana Ether (193) Lewis acid-catalysed cyclisation of an allylsilane containing an ester group, such as compound 138, results in a product which has two different carbon atoms on the ring functionalised. It should be possible to derivatise C-5 through the olefin at C-6, but i t would be d i f f i c u l t to introduce functionality at C-3 and C-4 after cyclisation had occurred. One might be able to place additional alkyl groups in the SiMe 3 COOMe 138 R=H 187 R = alkyl allylsilane precursor, such as 187, but the cyclisation conditions would preclude the use of many functional groups in this compound. A number of natural products contain heteroatoms or double bonds at C-3 and/or C-4 of 140. Thus we turned our attention to the introduction of hetero-atoms at C-3 in cyclisations of our allylsilanes. Mercuric trifluoroacetate is a popular cyclisation catalyst (27, 32c) and cyclisation of allylsilane 138 with this electrophile gave a cyclised product with an organomercury residue at C-3 (77). The mercurial group can easily be cleaved in a reductive fashion to give the - 64 -hydrocarbon; however, replacement of mercury moieties by hydroxyl is a radical process and generally gives a mixture of diastereomers (78a). Replacement by bromine can occur stereoselectively with either retention or inversion of configuration (78b), but the stereoselective conversion of bromine to the more useful hydroxyl residue would involve at least one further reaction. C O O M e C O O M e 189 R = O H 190 R = h a l Cyclisation of an epoxy-olefin would yield an alcohol. This type of cyclisation i s frequently stereoselective and we decided to investigate such a process. Diene 138 was regioselectively epoxidised in 84% yield to the epoxy all y l s i l a n e 191 using MCPBA. This reagent i s known to preferentially attack electron-rich double bonds, thus i t appears that the electron-withdrawing effect of the methyl ester i s greater than the electron-donating effect of the trimethylsilyl group. Cyclisation of epoxy allyls i l a n e 191 proved to be extremely f a c i l e . Treatment of a solution of 191 in dry methylene chloride with - 65 -either stannic chloride or boron trifluoride etherate effected conver-sion to the hydroxy ester 189 in good yield, although boron trifluoride etherate was the Lewis acid of choice (Scheme 13). Gas chromatographic analysis indicated that the crude product contained approximately 80% of 189, 10% of 191, and 10% of two other unidentified products. Some loss of product was experienced in the column chromatographic purification of 189. However, when the crude cyclisation mixture was treated with lithium aluminium hydride, the diol 192 was isolated in 68% yield from 191. The spectral and chromatographic properties of 189 and 192 indica-ted that each was a single diastereomer. The spectral data of diol 192 was identical to that reported by Coates and Melvin (79) for a sample of 192 prepared by another unambiguous route. The structure and cis-stereochemistry of the diol 192 was further confirmed by i t s conver-sion to (±)-karahana ether (193) following the procedure of Coates and Melvin (79). Karahana ether is a volatile monoterpene, with a pleasant camphor-like odour, which has been isolated from Japanese hops (80). Two other syntheses of karahana ether have recently been reported (81). This i s one of the f i r s t examples of an efficient cyclisation of an olefinic epoxide. It illustrates the u t i l i t y of an allylsilane in electrophilic cyclisations of epoxyolefins. The stereochemistry of 189 can be interpreted as the outcome of a chair-like transition state for cyclisation (2). - 66 -192 193 Scheme 13. Synthesis of (i)-karahana ether (193). F. Synthesis and Cyclisation of Epoxy Ester  Allylsilanes To Bicyclic Products The extension of the monocyclic epoxy allyls i l a n e cyclisation to the bicyclic case was achieved with some d i f f i c u l t y . The f i r s t problem to be overcome involved the regioselective synthesis of the terminal epoxide 194. Oxidation of triene 172 with MCPBA in the presence of a phosphate buffer gave a mixture of regioisomers 194 and 195 in a 1:1 ratio, in addition to some unreacted starting material and some - 67 -unidentified non-silylated product. The two epoxides could only be separated with d i f f i c u l t y by column chromatography. The use of more than one equivalent of MCPBA resulted in over-oxidation of the triene 172 to give a di-epoxide. Lowering the temperature of the reaction mixture did not increase the regioselectivity of the reaction; nor did the use of jj-nitroperoxybenzolc acid lead to an improvement in the ratio of 194:195. 195 Some regioselectivity was observed in epoxidation of the enol phosphate 171. The optimum conditions were found to be 1.05 equivalents of MCPBA added to a cold (-50°C) solution of the enol phosphate in methylene chloride. The reaction was allowed to warm to 0°C over a period of one hour, and then stirred at this temperature for one hour. A mixture of starting material 171, terminal epoxide 196, and the isomeric epoxide 197 was obtained in a ratio of 1:4:1, and the material balance was excellent. The isomeric epoxy enol phosphates were not separable by flash chromatography. Conversion of the mixture of enol phosphates to the allylsilanes 172, 194, and 195 was inefficient, the desired product 194 being obtained in 33% yield from enol phosphate 171. A small amount of ketone 198 was also obtained from this reaction. - 68 -A third approach to the synthesis of allylsilane 194 proceeded via the epoxy halide 200. Geranyl bromide (199) was oxidised to the epoxide 200 with MCPBA. The crude epoxide was alkylated with the dianion of methyl acetoacetate to give epoxy 8-keto ester 201 in 69% yield from geranyl bromide. This constitutes one of the f i r s t examples of the facile y-al^ylation of a 8-keto ester with an epoxy halide, and - 69 -i t shows that, in this case, the a l l y l i c halide functionality is more reactive than the epoxide moiety. Conversion to the epoxy enol phos-phate 196 was readily achieved in near quantitative yield, but the Grignard coupling reaction gave only 40% yield of epoxy allylsilane 194. The fi n a l and most successful approach to the synthesis of the cyclisation precursor utilised the method of van Tamelen and coworkers (13, 69a). This involved conversion of triene 172 with N-bromosucc-inimide to the terminal bromohydrin 202. Closure of the epoxide was then performed with potassium carbonate in methanol to give the desired epoxy allylsilane 194. The NBS reaction could be performed in either - 70 -DME-H20(3:1) or in THF-H20(5:1). The resulting bromohydrin was unstable to heat and slowly decomposed upon standing at room temperature; hence the crude reaction mixture was generally treated immediately with base at 0°C. If the reaction was allowed to warm above 0°C the product decomposed with loss of both the trimethylsilyl moiety and the epoxide functionality. Lower yields were also obtained when the reaction was allowed to proceed for a long period of time, and hence i t was necessary to carefully monitor the reaction by t i c . The yield of terminal epoxide from this two-step procedure was generally from 45 to 55% after p u r i f i c -ation, and complete regioselectivity in epoxide formation was invariably obtained. Van Tamelen (1, 13) has attributed this regioselectivity to the conformation of the polyolefin in the polar solvent which only exposes terminal olefins to electrophilic attack (see Introduction). Results of the cyclisation study of epoxy allyls i l a n e 194 are shown in Table V. The ratio of the products was generally determined by gas chromatography, although some indication of the product distribution was obtained by inspection of the *H nmr spectra. Runs 1-11 show the - 71 -Table V. Cyclisation of epoxy allyls i l a n e VM_. Run Acid (equiv.) Solvent Temp. (°C) Time (h) 203a:203b: Other Products 1 CF 3C00H (2) CH2C12 0 2 0 0 l * 2 Me3SiOS02CF3 (1) CH2C12 0 2 0 0 1* 3 TiCli, (2) CH2C12 0-25 2 0 0 l i 4 ZnCl 2 (2) CH2C12 0-25 16 0 0 l l 5 FeCl 3 (2) CH2C12 0-25 2.5 37^ 63=- 0 6 C 7. 5FeCl3^ (2) CH2C12 25 2 5(£ 5(£ 0 7 AICI3 (2) CH2C12 0-25 20 35 37 28i 8 AICI3 (2) CH3N02 0-25 2 0 0 1* 9 AICI3 (2) CH3N02 -23 2 1^ 2^ 0 10 C9A1C1 3(C1 2) 0. 25^ O) CH2C12 0-25 24 0 0 lS. 11 EtAlCl 2 (3) CH2C12 0-25 6 0 0 l i 12 BF 3 »Et 20 (2) CH2C12 0 3 1 1 0 13 BF 3 »Et 20 (2) CH2C12 -56 4 1 1 i i 14 BF 3 »Et 20 (2) C H ^ l ^ 0-25 3 2 2 i i 15 SnCli, (1.2) CH2C12 0-25 3 1 2* 0 16 SnCli, (1.2) CH2C12 0-25 3 2 3 i 0 17 SnCli, (2) CH2CI2 -23 8 22 50 2&2. 18 SnCli, (2) CH2Cl2£ 0 2 0 50 50^ 19 SnCli, (2) toluene 0-25 2.5 0 0 l i 20 SnCli, (2) ether 0-25 2.5 0 0 1^ 21 SnCli, (2) CH3N02 0 3 0 0 i i 22 SnCli, (0.2) CH2C12 0-25 2 1 1 3s- : 3 i 23 SnCli, (5) CH2C12 0 2 1 1 0 24 SnCli«i (2) CH2C12 0-25 2 0 0 i i 25 S n C l ^ (2) CH2C12 0 2.5 2 3 0 - 72 -Table V continued... £ Monocyclic material; J l Unidentified material; £ Low yield of material; fL Kindly provided by Professor J.G. Hooley, University of British Columbia; JL Conjugated ester 204 was obtained; JL Monocyclic allylsilanes 205 were obtained; S. Methylene chloride saturated with water; h. Scale < 1 mmole; i. Scale 1-5 mmole; j_ Inverse addition of 194 and catalyst; i i 0.1 equiv. of AcOH added to the reaction. COOMe COOMe 204 205 - 73 -effect of various catalysts on the reaction and i t can be seen that a Bronsted acid, such as trifluoroacetic acid, is not an efficient catalyst. Ferric chloride gave a reasonable ratio of 203a:203b, but the yield of the products was very low. Aluminium trichloride was also an effective catalyst, but the products were either contaminated with a significant amount of an unknown by-product or were obtained in low yield. The product ratio changed when the catalyst was intercalated into graphite; however, there was no improvement in the product yield (runs 6 and 10). Boron trifluoride etherate (runs 12-14) gave a good yield of hydroxy esters 203a:203b in a ratio of approximately 1:1 at 0°C in dry C H 2 C I 2 . Cyclisation at -56°C gave both isomers of ester 203 and gave a monocyclic product 205. This by-product was also obtained upon cyclisation in wet methylene chloride. Stannic chloride in methylene chloride (runs 15 and 16) gave the best yield and ratio of hydroxy esters 203a:203b. When performing small scale reactions (< 1 mmole), the mixture of isomers could be consistently isolated in about 60% yield (203a:203b = 1:2). Larger scale reactions (1 to 5 mmole) gave about 55% yield of products, but the ratio of epimers decreased to 1:1.5. Cooling the reaction mixture to -23°C gave better stereoselectivity, but also gave some monocyclic product (run 17). At -56°C the majority of the product was monocyclic. Dry methylene chloride was the solvent of choice when using stannic chloride as the Lewis acid catalyst (runs 18-21). The last entries in the Table show the effect of different amounts of stannic chloride, of inverse addition, and of the addition of a small amount of acetic acid. None of these variations gave any - 74 -improvement in the product distribution, and the optimum conditions found for the cyclisation of allylsilane 194 were those shown in entries 15 and 16. The structures of the by-products are tentative assignments, based on the *H nmr spectra of the products. The structures of hydroxy esters 203 were confirmed by their transformation to the esters 173 which had been previously synthesised and converted into albicanol (179b) and epi-albicanol (179a). The mixture of alcohols 203 (a:6 = 1.00:1.44) was oxidised with pyridinium chlorochromate in the presence of sodium acetate and molecular sieves (82) to give the ketones 206 (a: 8 = 1.00:1.44), thus confirming that the isomers are epimeric at C-9. The mixture of ketones was converted to the tosylhydrazones 207 and then treated with catecholborane (83). Two products were obtained in a ratio of 1.00 to 1.42, and co-injection of this mixture with authentic samples of 173a and 173b gave a coincidence of peaks on the gas chromatogram. Removal of the tosylhydrazone was also effected with sodium cyanoborohydride under acidic conditions (84). However, under these conditions three products were obtained -the two esters 173a and 173b, and also the conjugated ester 175. Although the conversion of hydroxy esters 203 to the correspond-ing esters 173 gives no indication of the stereochemistry of the hydroxyl at C-3, i t does confirm the structure of the remaining carbon skeleton. The stereochemistry of the alcohol was deduced to be beta (equatorial) by inspection of the 400 MHz *H nmr spectrum of esters 203: The C-3 proton (63.25) is coupled to both the axial and equatorial protons of C-2 with values of 11 and 5 Hz. These splittings are consistent with an axial proton at C-3; thus the alcohol must be in - 75 -COOMe COOMe P C C , NaOAc, 4A molecular sieves COOMe 173 COB =100 =1-42 catechol borane CHCI 3 TsHN-N COOMe COOMe TsNHNH 2 i EtOH the equatorial, or beta position. This stereochemistry is also in accord with the Stork-Eschenmoser hypothesis for these cyclisations. If one assumes that cyclisation of the epoxy allylsilane 194 occurs via a chair-chair transition state to give ester 203b, or via a chair-boat transition state to give ester 203a, then the energy of the chair-chair transition state must be very similar to, but slightly lower than, the energy of the chair-boat transition state, to give the product distributions obtained in the reaction. The cyclisation step is an irreversible process and the cyclic esters 203 do not equilibrate under the reaction conditions. The a-ester would be the more stable product because of the A^»^) strain in 203b; thus we conclude that the ratio of the two products is kinetically controlled and depends on the - 76 -activation energy leading to the transition states from 194. It is not immediately apparent what the controlling factors are in the transition states but steric interaction of the ester with other groups might be expected to play an important role in determining the outcome of the reaction. To test this hypothesis we decided to alter the size of the ester moiety to see i f this had any effect on the product distribution. The A value of the t-butyl group is very large compared with that of the methyl group (85). However, the Jt-butyl ester was not stable to a variety of cyclisation reaction conditions. The A value of the isopropyl group i s also quite large, thus the isopropyl ester 224 became the target for synthesis. The preparation of this ester is shown in Scheme 14. H e C=<^>=0 + 121 ROH 20 8 3 OPO(OEt)_ COOR 2151, 2168, 217 3 2181,2192, 220 a 209 , 2102,211s CGOR 212 1, 213*, 214s SiMe HO i , , 221l,222a,223 3 COOR 3 Scheme 14. Synthesis and cyclisation of epoxy allyls i l a n e esters 224, 225, and 226. - 78 -Isopropyl acetoacetate (209) was prepared from diketene (121) and isopropanol via the method of Lawesson et a l . (86). This 8-keto ester was transformed smoothly to the allylsilane 218 in 70% overall yield by the general methods previously described. The monoanion of the 8-keto ester 212 precipitated as a viscous gel in THF and a large amount of solvent was required in the formation of this anion. Conversion to the epoxide 224 via the bromohydrin 221 was achieved in 56% yield. Small scale (< 1 mmole) cyclisation of isopropyl ester 224 gave an epimeric mixture of bicyclic products 227 in 51% yield (227a:227b = 1:3, Table VI, run 1). Large scale (1-10 mmole) reactions gave a similar yield of product, but the ratio of isomers was only 1:2 (run 2). Nevertheless, with this slight Improvement in stereoselectivity over the methyl ester cyclisation, we were encouraged to prepare other ester precursors. Syntheses of the epoxy neopentyl ester 225 and the epoxy di-t-butylmethyl ester 226 were achieved as outlined in Scheme 14, in similar yields to those obtained with both the methyl and the isopropyl series. The prerequisite di-t^butylcarbinol (208) was formed by reaction of 2 equivalents of tj-butyllithium with ethyl formate in cold (-78°C) ether (63% yield). No marked improvement was observed in the product ratio obtained in the cyclisation of neopentyl ester 225 with stannic chloride. There was only a small increase observed in the ratio of a: 8 isomers in the cyclisation of the di-t-butylmethyl ester 226 with stannic chloride (Table VI, run 4). Treatment of epoxy ester 226 with boron trifluoride etherate (run 19) afforded 229a:229b in a ratio of 1:2. Thus, i t seems - 79 -Table VI. Cyclisation of epoxy allyls Ilanes 224 -226 • Run Ester Acid (equiv.) Bronsted (equiv. ) acid Temp. (°C) Time (h) Product 1- I-Other Products^-1 224 SnCli, (1.2) 0-25 3 1 3* 0 2 224 SnCli, (1.2) 0-25 3 1 2-£ 0 3 225 SnCli, (1.2) 0-25 2.5 5 0 4 226 SnCli, (1.2) 0-25 3 1 3 0 5 224 SnCli, (1.1) AcOH (0.05) 0 2.5 1 2 0 6 224 SnCli, (1.1) AcOH (0.10) 0 2.5 1 2 0 7 224 SnCli, (1.1) AcOH (0.15) 0 2.5 1 2 0 8 225 SnCli, (1.1) AcOH (0.10) 0 2 1 3 0 9 226 SnCli* (1.1) AcOH (0.02) 0 2 1 2.1 0 10 226 SnCli, (1.1) AcOH (0.05) 0 2 1 3.4 0 11 226 SnCli, (1.1) AcOH (0.08) 0 2 1 3.5 0 12 226 SnCli, (1.1) AcOH (0.10) 0 2 1 5 0 13 226 SnCli, (1.1) AcOH (0.12) 0 2 1 5 0 14 226 SnCli, (1.1) AcOH (0.15) 0 2 1 4 0 15 226 SnCli, (1.1) AcOH (0.5) 0 2 1 3 0 16 226 SnCli, (1.1) AcOH (1.0) 0 2 2 i i 17 226 SnCl i, (1.1) AcOH (0.1) -10 3 1 3 1^  18 226 SnCli, (1.1) AcOH (0.1) -15 3 1 3 i£ 19 226 BF 3*Et 20 (1.2) 0 3.5 1 2 1^ 20 226 BF 3*Et 20 (1.2) AcOH (0.1) 0 3.5 1 1 1^ — A l l reactions were performed in C H 2 C I 2 ; £ Scale < 1 mmole; £. Scale 1-10 mmole; i . Unidentified material; 5. Monocyclic material. - 80 -that both Lewis acids give about the same stereoselectivity. A startling improvement in the product distribution was obtained with the di-t-butylmethyl ester by the addition of a small amount of acetic acid to the stannic chloride-catalysed reaction. It can be seen from Table VI that the maximum stereoselectivity is obtained by the addition of approximately 0.1 equivalents of acetic acid (229a:229b = 1:5). No improvement in product distribution was observed when acetic acid was added to the stannic chloride-catalysed cyclisation of either the methyl ester (Table V) or the isopropyl ester, and only a marginal improvement was noted for the neopentyl ester 225. Unfortunately, large scale (1-5 mmole) cyclisation of the epoxy di-_-butylmethyl ester 226 was not quite as stereoselective, and a consistent ratio of 229a:229b of approximately 1:3 was obtained in 55% yield. It would appear from these results that some c r i t i c a l size of the ester group must be reached for the addition of the acetic acid to have any observable effect. It Is somewhat obscure why the optimum amount of acetic acid should peak at 0.1 equivalents. It can be seen from Tables V and VI that the larger the size of the ester group, the greater the percentage of 6-isomer obtained relative to a-isomer, and hence the larger the difference in the activation energy of the chair-chair transition state relative to that of the chair-boat transition state (see above). This result can be rationalised by comparing the interaction of the ester group with the bridgehead methyl group and with the C-l methylene of the incipient A ring. In the chair-chair transition state there is a gauche interaction - 81 -between COOR and both CH3 and the C-l methylene (see Newman projec-tion). The ester group Is eclipsed with the C-l methylene in the chair-boat transition state. For small esters the effect of the eclips-ing in the chair-boat transition state may be small; however, this interaction w i l l increase as the size of the ester group increases. Hence, the chair-chair transition state is the preferred conformation for larger esters. In addition to the a- and 8-esters 229, which were the major products obtained from the cyclisation reaction, eleven other compounds were isolated by flash chromatography of the reaction mixture. The total yield of these by-products was 38%, but none of the compounds was present in more than 7% yield. Four of the compounds were very - 82 -non-polar and appeared to have acyclic structures, one of which was thought to be the ketone 230(5%). The remaining seven by-products were a l l intermediate in polarity. The spectral information of three of the compounds was consistent with the monocyclic hydroxy esters 231(7%), 232(4%), and 233(3%). However, these are tentative assignments only. 232 233 G. Synthesis of (±)-3^ydroxylabda-8(20) ,13-dien-15-oic Acid (238) A large number of natural products possessing the bicyclic carbon skeleton 234 have been isolated from various sources. The presence of the C-3 alcohol is somewhat less common in nature. Farnesiferol A (235) contains a C-9oc functionality (87a,b), but the majority of natural - 83 -products 236-239 have the beta-configuration at C-3 and at C-9 (87, 88, 89). 3-Acetoxylabda-8(20),13-dien-15-oic acid (237) was isolated in 1977 from the autumnal leaves of Metasequoia glyptostroboides (88). Its enantiomer was isolated from a Brazilian tree (popularly known as - 84 -"Copaiba") as the free hydroxy acid 238 (89). The acid 240 i s also a known natural product (90a). Acid 240 was synthesized in 1958 by Ohloff COOH (90b) but syntheses of the hydroxy labdadienes 237 and 238 have not been reported as yet. The remainder of this discussion describes a synthesis of the hydroxy acid 238. Our f i r s t approach to the synthesis of the labdadiene was patterned after the trixagol synthesis described earlier. A synthesis of the desired sulphone 249 is shown in Scheme 15. The C-3 alcohol was i n i t i a l l y protected as i t s _t-butyldimethylsilyl (TBDMS) ether by reaction of the alcohol with TBDMS-C1 and imidazole in DMF (91). However, due to the hindered nature of this alcohol, complete conversion to the ether took from 4 days (R = Me) to more than 10 days [R = CH ( C M e 3 ) 2 l . If the alcohol was treated with TBDMS t r i f l a t e and 2,6-dimethylpyridine in CH2CI2 (92), protection was complete within 15 min. The next step in the labdadiene synthesis was reduction of the ester group at C-9 to an alcohol. We had hoped to be able to selectively reduce the less hindered a-ester, and use this as a method - 85 -COOR HO' base. TBDMSX X= CI. OTf R=H 3 C R= H C ^ R= H aC—|— 229 R=HC X EtoN . MsCI 246 KH.PhSH EtOH . A SPh Ph 2 Se 2 , 30 7. H 2 0 2 247 COOR -Hio 241 242 243 244 245 a = c°oc 245b=c 9u SOxPh 248 x=i 249 x=2 Scheme 15. Synthesis of sulphone 249. to purify the two isomers. Various reducing agents were employed in an attempt to reduce the methyl ester 241 selectively. Lithium - 86 -tri-js-butylborohydride gave recovered starting material, whereas lithium aluminium hydride and diisobutylaluminium hydride (DIBAL) effected complete conversion to the a- and B-alcohols. Lithium triethoxy-aluminium hydride was inactive towards the esters, but some stereoselec-t i v i t y was obtained using lithium diethoxyaluminium hydride in ether. A mixture of esters 241 (a:8 = 1:1.5) was treated with LiAl(0Et) 2H2 and separated by flash chromatography to give a fraction enriched with the 8-ester (241a:241b = 1:5, 45%) and a mixture of alcohols (245a:245b = 1.7:1, 53%). The a- and 8-alcohols are just separable by flash chromatography. The remaining esters 241 were transformed smoothly to a mixture of alcohols enriched with the 8-isomer, by treatment with LiAlHi+. We then looked at the esters with bulkier R groups. The isopropyl esters 242 and the neopentyl esters 243 were reduced to the alcohols 245a and 245b with L1A1HI+ in ether; however, when the di-t^butylmethyl esters 244 were treated with LiAlHit in ether, no reaction occurred. If esters 244 were heated with LiAlH^ in THF at reflux, the compounds decomposed. Recovered starting material was obtained when reduction was attempted in THF at room temperature with DIBAL, but a small amount of product was obtained i f the reaction was heated to 95°C for 16 hours. However, treatment of esters 244 with DIBAL in toluene gave complete reduction at room temperature; lowering the temperature of the reaction did not result in any selectivity. Finally, i t was found that reduction of the esters 244 with a mixture of DIBAL and THF in toluene gave preferential reduction of the a-ester. - 87 -Thus, treatment of the mixture of esters 244 (a:8 = 3:7) with DIBAL and THF in a ratio of ester to DIBAL to THF = 1:3.5:1.75 resulted in a mixture of a- and 8-alcohols (1:1, 60%), and an ester fraction (a :B = 1:11, 40%). The amount of THF present in the reaction was quite c r i t i c a l - i f the ratio was increased to 1:3.5:2, no reduction occurred, and with less THF present, the stereoselectivity decreased. The amount of toluene was not c r i t i c a l . The nearly pure 8-ester was reduced with DIBAL in toluene to give alcohol 245b (> 90% purity). Although the alcohols 245a and 245b could be separated by flash chromatography, i t was often easier to perform t r i a l reactions on the mixture of epimers. Conversion of the alcohols to the mesylates 246 was achieved in quantitative yield, and the crude mixture was transformed to the sulphides 247, with, potassium hydride and thiophenol (63) in ethanol at reflux, as previously described (94% yield). We were unsuccessful in oxidising the sulphides 247 to the sulphones 249 with MCPBA. Attack of MCPBA on the exocyclic olefin occurred preferentially to give products containing an epoxide moiety and only a small amount of the desired sulphone. Potassium hydrogen persulphate ( K H S O 5 ) , the reagent developed by Trost and Curran (93) for the oxidation of sulphides to sulphones, was found to convert the sulphides 247 to the sulphoxides 248 quite readily; however, prolonged treatment of the sulphoxides with KHSO5 resulted in decomposition of the sulphoxides, and no sulphones were obtained. Finally, a mixture of diphenyl diselenide and hydrogen peroxide (94) was found to be a suitable oxidising agent, and the sulphones 249 were obtained in 85% yield from the sulphides 247 using this mixture. - 88 -The anion of sulphone 249 was generated in THF-HMPA with n-butyllithium, but we were unable to alkylate this anion with any of " the halides 250-253. Alkylation of sulphone 249 was achieved with methyl iodide, and we could also form the olefin 255 by alkylation with 3-bromopropene. But the latter reaction gave only 45% product with recovery of 49% starting material. Thus i t appears that the sulphone 249 i s too hindered to be alkylated with a l l but the smallest of electrophiles. Because of our previous i n a b i l i t y to transform the monocyclic alcohol 128 to a halide, we were somewhat pessimistic in our attempts to form a halide from the bicyclic alcohols 245. The majority of - 89 -halogenating reagents gave the diene 257, polymeric material, and/or recovered starting material. However, treatment of a mixture of - alcohols 245a and 245b with N-methyl-N.N'-dicyclohexylcarbodiimidium iodide in THF-HMPA (95) resulted in formation of the iodides 256_ (65%) and the diene 257 (32%). Unfortunately, we were unable to alkylate the dianion of methyl acetoacetate with iodides 256; diene 257 was the sole product obtained from the reaction. Other alkylating agents which we tried to couple with the dianion from methyl acetoacetate without + ? i O * H A / COOMe 256 L = I 258 L = OTs 259 L=OSO aPh 260 L = O S O 2 - N ^ J 261 L = O S 0 8 C F 3 COOMe 262 + 257 + 245b Me'' je 1 - 90 -success, were the tosylate 258, the benzenesulphonate 259, and the imidazylate 260 (96): The former two reactions yielded unreacted starting material, and the latter reaction resulted in a mixture of products, none of which was the desired 8-keto ester 262. Alkylation was fi n a l l y achieved, albeit in low yield, with the t r i f l a t e 261. The alcohol 245b was added to a cold (-40°C to -50°C) mixture of pyridine and t r i f l i c anhydride in the minimum amount of C H 2 C I 2 . Pyridinium t r i f l a t e precipitated out of the reaction and this salt had to be removed in order for the alkylation to occur. However, since pyridinium t r i f l a t e i s sparingly soluble in C H 2 C I 2 and since the t r i f l a t e 261 decomposes above 0°C, the solvent had to be removed from the reaction under high vacuum while keeping the temperature cold. The residue was then dissolved in hexane and the insoluble salts were removed by f i l t r a t i o n . The t r i f l a t e 261 was added to the dianion of methyl acetoacetate, and after appropriate work-up and purification of the products of the reaction by flash chromatography, a 28% yield of 8-keto ester 262 was obtained, in addition to diene 257 (22%) and alcohol 245b (14%). It was found that i f the crude reaction mixture was not purified on the same day as the reaction was performed, the product decomposed. This is the f i r s t example of a dianion alkylation of a B-keto ester with a t r i f l a t e , and the use of t r i f l a t e s should extend the scope of the dianion alkylation reaction. Sulphur dioxide is an effective solvent for many t r i f l a t e reactions (97), and the alkylation of the dianion of methyl acetoacetate with hexanyl t r i f l a t e , a model compound, in liquid SO2 was achieved in - 91 -good yield. However, the alkylation with 261 was unsuccessful in this solvent system. 238 Scheme 16. Synthesis of (±)-3-hydroxylabda-8(20),13-dien-15-oic acid (238). The synthesis of the hydroxy labdadienoic acid 238 from 8-keto ester 262 is shown in Scheme 16. Compound 262 was transformed into the - 92 -enol phosphate 263 In 90% yield, and a cuprate coupling reaction (23) gave the ester 264. This product was contaminated with approximately 2% of the Zj-isomer. Somewhat surprisingly, treatment of s i l y l ether 264 with tetra-n-butylammonium fluoride (91) did not effect removal of the t^-butyldimethylsilyl group. Instead, hydrolysis of the methyl ester occurred, presumably via an SJJ2 mechanism. Removal of the s i l y l protecting group was achieved with 4.8% hydrofluoric acid in aceto-n i t r i l e (98). The final step in this synthesis was hydrolysis of the methyl ester 265 with aqueous methanolic KOH (83%, 2 steps). The spectral data of the product 238 (*H nmr, i r , ms) is in good agreement with that of an authentic sample (89). CONCLUSION It can be seen from these results that the trimethylsilyl group is very effective in activating a terminal a,6-unsaturated ester in the electrophilic cyclisation of polyolefins and olefin epoxides, and in controlling the regiochemistry of the resulting alkene. This i s a particularly powerful technique for the synthesis of 8,y-unsaturated esters. Although the allylsilanes studied could a l l be cyclised with a variety of Lewis acid catalysts, i t i s apparent that there i s no general set of experimental conditions which can be applied to these cyclisa-tions; a study of temperature, solvent, catalyst, and other variables must be performed in order to optimise each reaction. Despite this limitation, cyclisation products are obtained in good yield with excellent control of stereochemistry. A number of natural products have been synthesised from the products of cyclisation. This methodology could presumably be extended to t r i c y c l i c and tetracyclic systems, with possible applications to steroid synthesis. EXPERIMENTAL A. General. Unless otherwise stated the following are implied. Melting points were determined on a Kofler micro heating stage and are uncorrected. Kugelrohr di s t i l l a t i o n s were performed by means of a Buchi Kugelrohr thermostat. Infrared spectra were recorded on a Perkin-Elmer model 710B spectrophotometer. Solution spectra were performed using a sodium chloride solution c e l l of 0.2 mm thickness. Absorption positions are given in cm - 1 and are calibrated by means of the 1601 cm-* band of polystyrene. The proton nuclear magnetic resonance spectra were taken in deuterochloroform solution and recorded on a Bruker WP-80 (80 MHz) instrument unless otherwise specified. The 400 MHz spectra were recorded on a Bruker WH-400 instrument, and the 270 MHz spectra were recorded on a home-built unit consisting of an Oxford instrument 63.4 KG superconducting magnet and a Nicolet 32K computer. Signal positions are given in parts per million downfield from tetramethylsilane using the 6 scale. The signal positions were determined relative to chloroform. Signal multiplicity, coupling constants, and integrated areas are indicated in parentheses. The coupling constants quoted for the ABX systems are measured from the appropriate peaks in the *H nmr spectra, although these observed splittings do not exactly correspond to J^x o r jiBX (99). Low resolution mass spectra were determined on either a Varian MAT model - 95 -CH4B or a Kratos-AEI model MS50 mass spectrometer. Spectra are quoted as m/e_ values. The major Ion fragmentations are reported as percentages of the base peak. High resolution mass measurements were determined using a Kratos-AEI model MS50 mass spectrometer. Gas-liquid chromatography was performed on either a Hewlett Packard model 5830A gas chromatograph using a 6 ft x 1/8 in. column of 3% OV-17 or 10% Carbowax 20M, or on a Hewlett Packard model 5880A gas chromatograph using a 12 m x 0.2 mm column of OV-101 or Carbowax 20M. The flow rate for the 5830A model was 30 mL/min and nitrogen was the carrier gas. The flow rate for the 5880A model was 1.0 mL/min or 2.4 mL/min and helium was used as the carrier gas. In a l l cases a flame ionisation detector was used. Microanalyses were performed by Mr. P. Borda, Microanalytical Laboratory, University of British Columbia, Vancouver. S i l i c a gel ^ 2 5 4 + 3 6 6 supplied by E. Merck Co. was used for preparative t i c . The plates were ca. 1 mm In thickness. Analytical t i c was performed on commercial, pre-coated s i l i c a gel plates ( s i l i c a gel 60 F 2 5 4 ) supplied by E. Merck Co. Visualisation was effected by a combination of UV fluorescence, iodine vapour, or a 3 M sulphuric acid spray. Flash chromatography (100) was performed using s i l i c a gel 60, 230-400 mesh ASTM, supplied by E. Merck Co. A l l reactions involving air or moisture sensitive reagents were performed under an atmosphere of dry nitrogen using either oven or flame-dried glassware. A l l reaction products were dried by allowing the solutions to stand over anhydrous magnesium sulphate. The petroleum ether used was of boiling range ca. 30-60°C. Wet CH2O I2 w a s obtained by - 96 -shaking with water and using the saturated CH2Cl2 layer. Sodium hydride was weighed as a 50% or 60% dispersion in mineral o i l and was washed with dry ether to remove the o i l prior to use. DIBAL, n-BuLi, _t-BuLi, and MeLi were obtained from Aldrich Chemical Company, Inc. The alkyllithium solutions were standardised either by titration against 1.0 M t-butyl alcohol in benzene using 1,10-phenanthroline as indicator (101a) or by tit r a t i o n against l,3-diphenyl-2-propanone tosylhydrazone in THF (101b). The methods that were used to dry or purify many of the reagents are shown in Table VII. - 97 -Table VII. Purification of Reagents Reagent Drying Agent Reference diisopropylamine CaH2 102d N,N-diraethylformamide CaH2 102c ethanol Mg(OEt)2 102e ethyl ether L1A1H4, Na/Ph2CO 102b hexamethylphosphoramide CaH2 102c hexane CaH2 102a methanol Mg(OMe)2 102e methylene chloride 102a pyridine CaH2 102d tetrahydrofuran LiAlH l +, Na/Ph2CO 102b triethylamine CaH2 102d toluene CaH2 102a a D i s t i l l e d under reduced pressure (20 Torr); k D i s t i l l e d under reduced pressure (0.5 Torr). - 98 -B. Synthesis and Cyclisation of Allylsilanes to Monocyclic Products. 3-[(Trimethylsilyl)nethyl]-3-butenoic acid (122) Me3SiN. J L ^COOH This compound was prepared using a method analogous to that of Itoh et a l . (52, 54). The Grignard reagent was prepared from 5.35 g (0.22 mole) of magnesium turnings and 27.8 mL (0.20 mole) of trimethylsilylmethyl chloride in dry THF, and to this stirred suspension was added 0.48 g (2.0 mmole) of nickel(II) chloride (253) at 0°C. The brown mixture was stirred for 10 min at room temperature, cooled to 0°C, and a solution of 15.6 mL (0.20 mole) of diketene (121) in THF was added. The resulting green reaction mixture was stirred for 5 h and allowed to warm to room temperature. The reaction mixture was quenched with 1 M HC1 and diluted with ether. The aqueous layer was separated, extracted twice with ether, and the combined organic layers were washed twice with saturated NaCl, dried, and concentrated. The crude material was diluted with 200 mL of hexane, stirred for 10 min, decanted from an insoluble gum, and the solvent was removed under reduced pressure to give 29.7 g of 122 (86%) as an orange o i l . Preparative t i c of a small amount of this material using petroleum ether-ethyl acetate-acetic acid (93:5:2) gave 122 as a colourless liquid; Rf 0.4; bp (Kugelrohr d i s t i l l a t i o n ) 53°C/0.01 Torr. The spectral data (*H nmr, i r ) i s in good - 99 -agreement with that of the literature (54); i r ( C H C I 3 ) : 2960, 1710, 1635, and 850 cm"1; lR nmr ( C D C I 3 ) 6: 0.10 (s, 9H), 1.69 (d, J = 1 Hz, 2H), 3.06 (d, J = 1 Hz, 2H), 4.78 (bs, IH), 4.82 (bs, IH), and 11.35 (bs, IH); mass spectrum, m/e: 172 (M+, 0.5), 157(5), 117(5), 82(5), 75(30), 74(10), 73(100), and 53(14). Anal, calcd. for C 8H 1 60 2Si: C 55.77, H 9.36; found: C 56.00, H 9.44. 7-Methyl-3-[(trimethylsilyl)methyl]-2,6-octadienoic acid (123) This compound was prepared using a method analogous to that of Itohjet e l . (52, 56) and Katzenellenbogen and Crumrine (55). To 9.23 mL (0.066 mole) of a solution of diisopropylamine in dry THF at 0°C was added 42.6 mL (0.066 mole) of a 1.55 M solution of n-butyllithium in hexane. The pale yellow solution was stirred for 30 min and a solution of 5.16 g (0.030 mole) of 122 in dry THF was added slowly. The mixture was stirred for 30 min at 0°C, forming an orange solution, and was then cooled to -78°C, and 5.72 g (0.030 mole) of freshly purified cuprous iodide (103) was added. The slurry was stirred for 1 h at -78°C, and 3.49 mL (0.030 mole) of freshly d i s t i l l e d l-bromo-3-methyl-2-butene was quickly added to the bright yellow slurry. The reaction was stirred overnight while allowing i t to warm to room temperature. The reaction SiMe - 100 -mixture was quenched with 1 M HC1, diluted with ether, and filtered through a Celite pad. The aqueous layer was extracted four times with ethyl acetate,and the combined organic layers were washed twice with saturated NaCl, dried, and concentrated. The crude material was diluted with hexane, stirred for 10 min, decanted from an insoluble gum, and the solvent was removed under reduced pressure to give 123 as a yellow o i l . Purification by flash chromatography using chloroform as eluant gave 5.05 g (70%) of 123 as a pale yellow o i l . Preparative t i c of a small amount of this material using petroleum ether-ethyl acetate-acetic acid (93:5:2) gave a mixture of E_- and 2>isomers of 123 as a colourless liquid (EzZ = 7:3); Rf 0.6; bp (Kugelrohr d i s t i l l a t i o n ) 105°C/0.20 Torr; i r (CHC13): 2960, 1680, 1608, and 850 cm-1; XH nmr (CDC13) 6: 0.05 (s, 9H), 1.64 (s, 3H), 1.7-1 (s, 3H), 1.80 (s, 1.4H), 2.05-2.75 (m, 4H), 2.45 (s, 0.6H), 4.90-5.30 (m, IH), 5.48 (s, 0.7H), 5.58 (s, 0.3H), and 12.85 (bs, IH); mass spectrum, m/e: 240(M+, 3), 225(7), 157(14), 156(11), 122(13), 107(17), 82(36), 75(40), 73(100), 69(59), and 45(20). Anal, calcd. for C ^ r ^ i ^ S i : C 64.95, H 10.06; found: C 65.23, H 10.17. 2,2-Dimethyl-6-methylenecyclohexanecarboxylic acid (125) To a solution of 4.80 g (0.020 mole) of the trimethylsilyl acid 123 in 150 mL of toluene was added 1.15 mL (0.020 mole) of acetic acid COOH - 101 -at 0°C. A solution of 12.3 mL (0.10 mole) of BF 3.Et 20 in 25 mL of toluene was added slowly, and the reaction mixture was stirred for 2.5 h while allowing i t to warm to room temperature. The solution was quenched with saturated NaCl, diluted with ether, and washed four times with saturated NaCl. The organic layer was dried and concentrated, to give 4.30 g of a mixture of 125 and the endo-isomer 126 (125:126 = 4:1, as determined by *H nmr spectroscopy). The crude mixture was used without further purification in the preparation of alcohol 128. Preparative t i c of 310 mg of acids 125 and 126 using petroleum ether-ethyl acetate-acetic acid (93:5:2) gave the following components: (a) carboxylic acid 125 (140 mg) as a colourless o i l (bp 75°C/0.20 Torr, Kugelrohr d i s t i l l a t i o n ) which crystallised on standing; Rf 0.3; mp 43-48°C; i r ( C H C 1 3 ) : 2950, 1705, 1645, and 900 cm-1; lR nmr ( C D C 1 3 ) 6: 0.96 (s, 3H), 1.07 (s, 3H), 1.10-2.70 (m, 6H), 2.90 (s, IH), 4.85 (bs, IH), 4.91 (bs, IH), and 10.50 (bs, IH); mass spectrum, m/e: 169(4), 168(M+, 38), 153(21), 125(19), 123(22), 111(19), 100(24), 82(18), 81(15), and 69(100). Anal, calcd. for CioHi 60 2: C 71.39, H 9.59; found: C 71.60, H 9.66. (b) 2,6,6-trimethylcyclohex-2-enecarboxylic acid (126) (40 mg) as a colourless o i l (bp 90°C/0.10 Torr, Kugelrohr d i s t i l l a t i o n ) which crystallised on standing; Rf 0.15; mp 101-103°C [ l i t . (104) mp 104°C]; i r ( C H C I 3 ) : 2950 and 1705 cm"1; XH nmr 6: 1.00 (s, 3H), 1.07 (s, 3H), 1.20-2.30 (m, 4H), 1.75 (bs, IH), 2.64 (bs, IH), 5.65 (bs, IH), and 9.50 (bs, IH). - 102 -2,2-Dimethyl-6-methylenecyclohexanemethanol (128) A mixture of 4.30 g of the crude acids 125 and 126 in dry ether was slowly added to a slurry of 0.76 g (0.02 mole) of LiAlH^ in dry ether at 0°C. The reaction mixture was heated at reflux for 2.5 h, then cooled to room temperature. The reaction mixture was quenched with 1 M HC1, diluted with ether, and the organic phase was washed once with 1 M HC1, twice with saturated NaCl, dried, and concentrated to give a mixture of alcohols 128 and 129. Purification by flash chromatography using petroleum ether-ethyl acetate (9:1) as eluant gave 2.34 g of 128 and 129_ (128:129 = 4:1; 76% from 123). Further purification by flash chromatography using the same solvent system gave 1281 as a colourless liquid; bp (Kugelrohr d i s t i l l a t i o n ) 80-86°C/2.0 Torr; i r (CHC13): 3600, 3400, 1245, and 850 cm"1; XH nmr ( C D C I 3 ) 6: 0.88 (s, 3H), 0.97 (s, 3H), 1.20-1.80 (m, 4H), 1.70 (bs, IH, exchangeable with D 20), 1.90-2.25 (m, 3H), 3.58-3.80 (m, 2H), 4.75 (bs, IH), and 4.95 (bs, IH). A H nmr spectrum of alcohol 128 was kindly provided by Professor Paul A. Grieco, Indiana University (105). - 103 -General Procedure A. Alkylation of the Dianion of  6-Keto Esters (21, 22) Sodium hydride (50% or 60% dispersion In oil) was washed under a nitrogen atmosphere with dry ether and the resulting pale grey solid was suspended in THF. To this slurry was slowly added a solution of the 8-keto ester (1.0 equiv.) in THF and the reaction was stirred for 10-20 min at 0°C to ensure complete formation of the insoluble monoanion. n-Butyllithium (1.0-1.2 equiv.) was added to the reaction mixture, and after 10 min a solution of the alkylating reagent in THF was added to the soluble dianion. The reaction was stirred for approximately 2 h, then allowed to warm to room temperature, and quenched by the careful addition of 1 M HC1 until the mixture was acidic to litmus paper. The organic layer was diluted with ether, washed twice with 1 M HC1, twice with saturated NaCl, dried, and the solvent was removed. Methyl 7-methyl-3-oxo-6-octenoate (52) (21) This compound was prepared according to general procedure A using 10.6 g (0.22 mole) of sodium hydride (50% dispersion in o i l ) , 21.6 mL (0.20 mole) of methyl acetoacetate, 142 mL (0.22 mole) of a 1.55 M solution of n-butyllithium in hexane, and 24.4 mL (0.21 mole) of freshly d i s t i l l e d l-bromo-3-methyl-2-butene. Work-up of the reaction mixture COOMe - 104 -gave 39.5 g of crude product which was used without further purification in the preparation of enol phosphate 137. D i s t i l l a t i o n of a small amount of B-keto ester 52_ gave a colourless o i l ; bp 80-82°C/0.2 Torr (CDC13) 6: 1.62 (s, 3H), 1.68 (s, 3H), 2.15-2.80 (m, 4H), 3.45 (s, 2H), 3.73 (s, 3H), and 4.95-5.20 (m, IH). General Procedure B. Formation of (Z)-Enol Phosphates of B-Keto Esters (21) Sodium hydride (50% or 60% dispersion in o i l ) was washed under a nitrogen atmosphere with dry ether and the resulting pale grey solid was suspended in ether. To this slurry was slowly added a solution of the B-keto ester (1.0 equiv.) in ether and the reaction was stirred for 10-20 min at 0°C to ensure complete formation of the insoluble monoanion. Diethyl chlorophosphate (1.0-1.2 equiv.) was added to the mixture and the reaction was stirred for 2 h while allowing i t to warm to room temperature. The reaction was quenched with 1 M HC1, and the organic phase was washed once with 1 M HC1, twice with saturated NaCl, dried, and the solvent was removed. Methyl (Z)-3-[(diethylphosphoryl)oxy]-7-methyl-2,6-octadienoate (137) [ l i t . (21) bp 67-68°C/0.1 Torr]; i r (CHC13): 1745 and 1715 cm _1 1. H nmr OPO(OEt)8 This compound was prepared according to general procedure B using - 105 -10.6 g (0.22 mole) of sodium hydride (50% dispersion in o i l ) , 39.5 g of crude B-keto ester 52_, and 31.7 mL (0.22 mole) of diethyl chlorophosphate. Work-up of the reaction mixture gave an orange o i l which was purified by d i s t i l l a t i o n to yield 52.7 g (82% from methyl acetoacetate) of enol phosphate 137 as a yellow o i l . Preparative t i c of a small amount of this material using petroleum ether-ethyl acetate (2:1) gave 13]_ as a colourless liquid; bp 144-148°C/0.25 Torr; i r ( C H C 1 3 ) : 1730, 1670, 1280, and 1030 cm-1; lYL nmr ( C D C I 3 ) 6: 1.35 (dt, icH 2CH 3 = 7 H z » ipoCH 2CH 3 = 1 H z » 6 H ) » 1 , 6 0 ( s» 3 H ) » 1 , 7 0 <s» 3 H ) ' 2.15-2.60 (m, 4H), 3.68 (s, 3H), 4.30 (dq, J(; H OT = 7 Hz, J p 0 C H 2 = 8 Hz, 4H), 5.00-5.20 (m, IH), and 5.35 (s, IH); mass spectrum, m/e: 320 (M+, 18), 289(11), 252(23), 220(31), 192(23), 176(17), 174(19), 155(100), 135(18), 134(63), 127(41), 107(26), 106(28), 98(57), 91(25), 81(18), and 69(31). Anal, calcd. for C 1 i 4H 2 50 6P: C 52.50, H 7.87; found: C 52.49, H 7.92. General Procedure C. Formation of (Z)-Allylsilanes from (Z)-Enol Phosphates The Grignard reagent was prepared from magnesium turnings (1.5-2.0 equiv.) and trimethylsilyl chloride (1.5-2.2 equiv.) in ether at room temperature under nitrogen, and to this stirred solution was added 0.025-0.05 equiv. of anhydrous nickel(II) acetylacetonate (53). The resulting dark-brown mixture was stirred for 5 min at room temperature and a solution of enol phosphate (1.0 equiv.) in ether was slowly added (exothermic reaction). The reaction mixture was stirred at - 106 -room temperature or at reflux for the desired time, and various amounts of catalyst were added during this time. The reaction was cooled to room temperature, quenched by the careful addition of 1 M HC1 (until the mixture was acidic to litmus paper), and diluted with ether. The organic layer was washed once with 1 M HC1, twice with saturated NaCl, dried, and the solvent was removed. Methyl (Z)-7-methyl-3-[(trimethylsilyl)methyl]-2,6-octadienoate (138) This compound was prepared according to general procedure C using 1.82 g (0.075 mole) of magnesium turnings, 11.8 mL (0.085 mole) of trimethylsilylmethyl chloride, 0.32-0.64 g (2.5-5.0 mmole) of anhydrous nickel(II) acetylacetonate, and 16.0 g (0.050 mole) of enol phosphate 137. The reaction mixture was heated at reflux for 16 h and further portions of 0.32-0.64 g (2.5-5.0 mmole) of catalyst were added after 0.5 h, 1.5 h, 2.5 h, and 4 h. Work-up of the reaction mixture gave 12.7 g of crude product which was purified by flash chromatography using petroleum ether-ethyl acetate (40:1) as eluant to yield 9.5 g (75%) of 138 as a yellow o i l . Preparative t i c of a small amount of this material using petroleum ether-ethyl acetate (20:1) gave 138 as a colourless liquid; bp (Kugelrohr d i s t i l l a t i o n ) 90°C/0.1 Torr; i r (CHC13): 1705, 1620, 1435, 1250, 1155, and 850 cm-1; XH nmr ( C D C I 3 ) 6: 0.05 (s, 9H), - 107 -1.60 (s, 3H), 1.70 (s, 3H), 2.05-2.20 (m, 4H), 2.43 (s, 2H), 3.65 (s, 3H), 4.95-5.25 (m, IH), and 5.55 (s, IH); mass spectrum, m/e_: 255(4), 254(M+, 18), 239(32), 223(12), 186(19), 150(30), 135(22), 107(63), 89(28), 82(60), 80(20), 73(100), 69(33), and 59(22). Anal, calcd. for C14 H2602 S 1 : C 66.07, H 10.32; found: C 65.89, H 10.24. Methyl 2,2-dimethyl-6-methylenecyclonexanecarboxylate (140) COOMe To a solution of 2.54 g (0.010 mole) of the trimethylsilyl ester 138 in 110 mL of CH2Cl2 saturated with water at 0°C was slowly added a solution of 5.85 mL (0.050 mole) of SnCl^ in 15 mL of wet CH2C12. The reaction mixture was stirred for 1 h at 0°C then quenched with an aqueous solution of KF at 0°C. The organic layer was diluted with ether, washed four times with aqueous KF, twice with saturated NaHC03, once with saturated NaCl, dried, and the solvent was removed to give 2.0 g of a mixture of 140 and the endo-isomer 141 [140:141 = 7:1, as determined by 1H nmr and gc (T = 100°C)]. Purification by flash chromatography using petroleum ether-ethyl acetate (40:1) as eluant gave 1.27 g (70%) of 140 and 141 (7:1), and this mixture was used without further purification in the preparation of alcohol 128. Preparative t i c of a small amount of this material using petroleum ether-ethyl acetate - 108 -(10:1) gave J40_ as a colourless liquid; bp 130°C/760 Torr; i r (CHC13): 1730, 1645, and 1155 cm-1; XH nmr (CDC13) 6: 0.95 (s, 3H), 1.00 (s, 3H), 1.10-2.55 (m, 6H), 2.90 (s, IH), 3.67 (s, 3H), 4.75 (bs, IH), and 4.86 (bs, IH); mass spectrum, m/e: 182(M+, 46), 167(29), 125(31), 123(65), 122(77), 114(42), 107(41), 83(22), 82(31), 81(31), 79(20), 59(100), and 57(21). Anal, calcd. for C i i H i 8 0 2 : C 72.49, H 9.95; found: C 72.36, H 10.05. The endo-isomer 141 was prepared as shown below. Methyl 2,6,6-trimethyl-2-cyclohexenecarboxylate (141) To a solution of 2.54 g (0.010 mole) of the trimethylsilyl ester 138 in 110 mL of CH2Cl2 saturated with water was added a solution of 0.58 mL (0.010 mole) of acetic acid at room temperature. A solution of 5.85 mL (0.050 mole) of SnCl^ in 20 mL of wet CH 2C1 2 was added slowly, and the reaction mixture was stirred at room temperature for 2 h. The solution was quenched with an aqueous solution of KF, diluted with ether, and the organic layer was washed four times with aqueous KF, and once with saturated NaCl. The solution was dried and the solvent was removed to give 1.64 g of crude ester 141. Purification by flash chromatography using petroleum ether-ethyl acetate (19:1) as eluant gave C O O M e - 109 -1.28 g (70%) of 1412 as a colourless liquid; bp (Kugelrohr d i s t i l l a t i o n ) 80°C/0.8 Torr; i r (CHC13): 1730, 1440, and 1160 cm-1; 1H nmr (CDC13) 6: 0.97 (s, 6H), 1.10-2.25 (m, 4H), 1.67 (bs, 3H), 2.64 (s, IH), 3.71 (s, 3H), and 5.60 (bs, IH). 2,2-Dimethyl-6-methylenecyclohexanemethanol (128) via reduction of ester 140 A slurry of 0.59 g (0.015 mole) of LiAlH^ in dry ether was stirred at 0°C, and 2.81 g (0.015 mole) of a mixture of esters 140 and 141 in dry ether was slowly added to the slurry. The reaction mixture was heated at reflux for 2 h, then cooled to room temperature and quenched with 1 M HC1. The ethereal layer was washed once with 1 M HC1, twice with saturated NaCl, dried, and concentrated to give 2.22 g (96%) of alcohol 128 and 2,6,6-trimethyl-2-cyclohexenemethanol (129) [128:129 = 7:1), as determined by 1H nmr and gc (T = 130°C)]. This material was used without further purification in the preparation of the tosylates 157 and 158. The spectral data of the mixture of alcohols i s in good agreement with that obtained previously. The endo-isomer 129 was prepared in a similar manner using 0.19 g 2 Spectral information on compound 141 was kindly provided by Professor Joseph Wolinsky, Purdue University (106). - 110 -(0.005 mole) of LiAlH^ and 0.91 g (0.005 mole) of ester 141. Work-up of the reaction mixture, as above, gave 0.76 g (99%) of crude 129 which was purified by flash chromatography using petroleum ether-ethyl acetate (9:1) as eluant to give 129 as a colourless liquid; bp (Kugelrohr d i s t i l l a t i o n ) 95°C/0.8 Torr. The spectral data nmr, i r ) i s in good agreement with the literature values (107); i r ( C H C I 3 ) : 3450, 1450, 1390, 1370, and 1025 cm-1; lE nmr (CDC13) 6: 0.92 (s, 3H), 1.06 (s, 3H), 1.25-2.10 (m, 5H), 1.40 (bs, IH, exchangeable with D 20), 1.78 (bs, 3H), 3.76 (d, 2H), and 5.62 (bs, IH). C. Synthesis of (±)-Trixagol (153) 2,2-Dime thyl-6—methylene—1-[ (jr-toluenesulphonyl)oxymethyl]cyclohexane (157) To a solution of 2.22 g (0.014 mole) of a mixture of alcohols 128 and _129_ in ether at 0°C was added 4.85 mL (0.060 mole) of pyridine. The reaction mixture was stirred at 0°C for 5 min, then 2.86 g (0.015 mole) of jj-toluenesulphonyl chloride (108) was added, and the mixture was refrigerated at 0°C for 72 h. The reaction was quenched with ice-water, - I l l -diluted with ether, and the organic phase was washed twice with 1 M H C 1 , twice with saturated NaHC03, once with saturated NaCl and dried. The solvent was removed to yield 4.30 g (97%) of a mixture of two tosylates which was used without purification in the preparation of sulphide 159. Flash chromatography of a small amount of this material using petroleum ether-ethyl acetate (15:1) gave pure exocyclic tosylate 157 as a colourless o i l ; i r ( C H C 1 3 ) : 1650, 1600, 1360, 1175, 1100, and 960 cm"1; *H nmr ( C D C I 3 ) 6: 0.81 (s, 3H), 0.95 (s, 3H), 1.2-1.7 (m, 4H) 1.9-2.3 (m, 3H), 2.45 (s, 3H), 4.10 (A part of an ABX system, = 10 Hz, J^x = 8 Hz, IH), 4.26 (B part of an ABX system, = 10 Hz, J g X = 5 Hz, IH), 4.55 (bs, IH), 4.79 (bs, IH), 7.33 (CC' part of a CC'YY' system, J C Y = ic'Y' = 9 H z ' 2 H^» a n d 7 , 8 0 ^ Y Y ' p a r t o f a CC'YY* system, J£ Y = ic'Y' = 9 1 1 2» 2 H^» 1 1 1 3 8 8 s P e c t r u m » m / e : 308(M+, 0.1), 173(2), 155(11), 137(17), 136(100), 122(54), 108(16), 107(30), 81(20), 80(16), 79(18), 69(22), 68(20), 57(17), 55(74), 53(46), and 41 (65). 2,2-Dimethyl-6-methylene-l-(phenylthioiiiethyl)cyclohexane (159) A slurry of 4.96 g (0.031 mole) of KH (25% in oil) in dry ethanol was stirred at room temperature and 3.14 mL (0.031 mole) of thiophenol - 112 -(63) was added to the slurry. After 10 min a solution of 4.71 g (0.015 mole) of the tosylates 157 and 158 in ethanol was added to the mixture, and the reaction was heated at reflux for 16 h. The ethanol was removed under reduced pressure and the residue was dissolved in ether and saturated NaCl. The two phases were acidified with 1 M HC1, and the organic layer was washed twice with saturated NaCl, dried, and concentrated. The crude product was purified by flash chromatography using petroleum ether as eluant, and by performing three successive chromatographic separations on the mixture of isomers. The following compounds were obtained in order of elution: (a) diphenyl disulphide; Rf 0.7; i r (CHC13): 3050, 2950, 1580, 1480, 1440, and 1025 cm-1; XH nmr (CDC13) 6: 7.25-7.60. (b) 2,6,6-trimethyl-l-(phenylthiomethyl)-2-cyclohexene (160) (0.35 g, 9%) as a colourless o i l ; Rf 0.6; bp (Kugelrohr d i s t i l l a t i o n ) llO°C/0.5 Torr; i r (CHC13): 1585, 1480, and 1440 cm-1; *H nmr ( C D C I 3 ) 6 : 0.88 (s, 6H), 1.20-2.40 (m, 5H), 1.70 (bs, 3H), 2.79-3.12 (m, 2H), 5.45 (bs, IH), and 7.15-7.40 (bm, 5H); mass spectrum, m/e_: 247(12), 246(M+, 62), 231(7), 137(32), 136(30), 123(100), 121(36), 109(13), 107(20), 95(27), 93(20), 91(12), 81(57), 79(20), 77(17), 69(14), 67(16), and 55(17). Exact Mass calcd. for Ci 6H 22S: 246.1443; found (ms): 246.1438. (c) thioether 15_9 (2.40.g, 65%) as a colourless o i l ; Rf 0.5; bp (Kugelrohr d i s t i l l a t i o n ) 100°C/0.5 Torr; i r ( C H C I 3 ) : 3080, 1640, 1580, 1480, 1440, 1390, 1370, 1095, 1025, and 900 cm-1; *H nmr ( C D C I 3 ) 6: 0.92 (s, 3H), 1.01 (s, 3H), 1.25-1.75 (m, 4H), 1.98-2.27 (m, 3H), 3.02 (A part of an ABX system, JAJJ - 12 Hz, = 10 Hz, IH), 3.18 - 113 -(B part of an ABX system, J ^ B = 12 Hz, J g X = 5 Hz, IH), 4.70 (bs, IH), 4.90 (bs, IH), and 7.15-7.42 (bm, 5H); mass spectrum, ra/e: 247(7), 246(M+, 29), 137(25), 136(61), 124(15), 123(100), 121(21), 107(16), 95(18), 93(30), 92(15), 81(47), 79(20), 77(16), 69(24), 67(22), 55(18), 45(16), 41(36), and 37(79). Anal, calcd. for C 1 6H 2 2S: C 77.99, H 9.00, S 13.01; found: C 77.83, H 8.94, S 12.80. 2,2-Dimetb.yl-6-methylene-l-(phenyl8ulphonylmethyl)cyclohexane (161) To a solution of 1.01 g (4.1 mmole) of thioether 159 in CH 2C1 2 at 0°C was slowly added 1.78 g (0.010 mole) of MCPBA (109). The ice-bath was removed from the reaction mixture, and the reaction was stirred for 3 h and allowed to warm to room temperature. The reaction was quenched with saturated NaHC03, and diluted with ether. The organic phase was washed three times with saturated NaHCOg, once with saturated NaCl, dried, and concentrated to give 1.2 g of crude 161. Purification by flash chromatography using petroleum ether-ethyl acetate (9:2) as eluant gave 1.09 g (96%) of sulphone 161 as a viscous o i l . Preparative t i c of a small amount of this material using petroleum ether-ethyl acetate (9:2) gave 161 as a colourless o i l ; bp (Kugelrohr d i s t i l l a t i o n ) 150°C/0.5 Torr; i r (CHC13): 1650, 1445, 1300, 1140, and 1080 cm"1; *H - 114 -nmr (CDC13) 6: 0.80 (s, 3H), 0.91 (s, 3H), 1.2-1.75 (m, 4H), 1.9-2.12 (m, 2H), 2.42 (dd, J^x = 3 Hz, Jg X = 8 Hz, 1H), 3.25 (A part of an ABX system, = 15 Hz, = 3 Hz, IH), 3.35 (B part of an ABX system, J^j • 15 Hz, - 8 Bz, IH), 4.57 (bs, IH), 4.74 (bs, IH), and 7.40-8.00 (m, 5H); mass spectrum, ra/e: 278(M+, 0.05), 143(17), 138(26), 137(81), 136(100), 121(36), 95(31), 94(30), 93(54), 82(22), 81(66), 79(23), 77(29), 69(70), 67(21), 55(25), and 41(58). Anal, calcd. for C 1 6 H 2 2 O 2 S : C 69.03, H 7.97, S 11.52; found: C 68.90, H 8.06, S 11.33. (E ) -3,4-Dimethyl -2,6-octadienyl benzoate OgPH A mixture of 17.3 mL (0.10 mole) of geraniol, 16.2 mL (0.20 mole) of pyridine, and a catalytic amount of 4-dimethylaminopyridine was stirred in dry ether at room temperature. A solution of 12.8 mL (0.11 mole) of benzoyl chloride in ether was added to the mixture, and the reaction was stirred for 2 h at room temperature. The reaction mixture was washed three times with saturated NaHCC>3, three times with 1 M HC1, twice with saturated NaCl, dried, and concentrated to give 27.4 g (quantitative yield) of the ester. This material was used without purification in the preparation of alcohol 165a; i r ( C H C I 3 ) : 1710, 1450, - 115 -1270, and 1010 cm-1; *H nmr (CDC13) 6: 1.64 (s, 3H), 1.71 (s, 3H), 1.80 (s, 3H), 2.07-2.25 (m, 4H), 4.86 (d, J - 7 Hz, 2H), 5.14 (bs, IH), 5.52 (t, J - 7 Hz, IH), 7.25-7.66 (m, 3H), and 8.00-8.20 (m, 2H). (F^E^-S-Hydroxy-S^-dimethyl^.e-octadienyl benzoate (165a) I 0 O H A suspension of 1.90 g (0.017 mole) of freshly sublimed selenium dioxide and 9.4 mL (0.069 mole) of 70% t-butyl hydroperoxide (Aldrich) in C H 2 C I 2 was stirred for 30 min at room temperature in the dark (21, 64). To the resulting solution was added 8.90 g (0.034 mole) of geranylbenzoate at 10°C, and the mixture was stirred for 5 h at 10°C, then quenched with saturated NaHC03. The organic phase was diluted with ether, washed three times with saturated NaHC03, once with saturated NaCl, dried, and concentrated. The crude material was purified by flash chromatography using petroleum ether-ethyl acetate (4:1) as eluant to give the following compounds in order of elution: (a) starting material (3.50 g, 40%); Rf 0.85. (b) (E,E)-3,7-dimethyl-8-oxo-2,6-octadienyl benzoate (165b) (0.46 g, 5%) as a colourless o i l ; Rf 0.6; bp (Kugelrohr d i s t i l l a t i o n ) 112°C/0.15 Torr; i r ( C H C I 3 ) : 1710, 1690, 1460, 1280, and 1110 cm-1; *H nmr ( C D C I 3 ) 6: 1.78 (s, 3H), 1.83 (s, 3H), 2.20-2.65 (m, 4H), 4.87 (d, J - 116 -= 7 Hz, ZH), 5.55 (t, J = 7 Hz, IH), 6.50 (t, J = 7 Hz, IH), 7.30-7.70 (m, 3H), 8.00-8.17 (m, 2H), and 9.42 (s, IH); mass spectrum, m/e: 272(M+, 0.1), 214(1), 150(25), 121(15), 106(11), 105(100), 96(12), 95(12), 94(12), 93(12), 84(20), 82(19), 81(10), 77(25), 68(13), 67(13), 55(23), 53(14), and 51(16). Anal, calcd. for C 1 7H 2 0O 3: C 74.97, H 7.40; found: C 75.05, H 7.41. (c) alcohol 165a (4.66 g, 50%) as a viscous o i l ; Rf 0.4; bp (Kugelrohr d i s t i l l a t i o n ) 140°C/0.15 Torr; i r (CHC13): 3600, 3450, 1715, 1455, 1280, and 1115 cm-1; LH nmr (CDC13) 6: 1.67 (s, 3H), 1.78 (s, 3H), 2.05-2.26 (m, 5H, IH exchangeable with D 20), 3.99 (s, 2H), 4.85 (d, J -6 Hz, 2H), 5.25-5.60 (m, 2H), 7.27-7.70 (m, 3H), and 7.98-8.19 (m, 2H); mass spectrum, m/e: 274(M+, 0.01), 257(0.1), 152(5), 134(24), 121(6), 119(7), 106(12), 105(100), 94(13), 93(8), 84(31), 77(32), and 68(22). Exact Mass calcd. for C 1 7H 220 3: 274.1569; found (ms): 274.1564. (E_,E)-8-Bromo-3,7-dimethyl-2,6-octadienyl benzoate (166) To a stirred solution of 1.10 g (4.0 mmole) of alcohol 165a and 0.016 mL (0.20 mmole) of pyridine in dry ether at 0°C was slowly added 0.15 mL (1.6 mmole) of phosphorus tribromide in ether. The reaction mixture was stirred at 0°C for 5 h then quenched with ice-water. The Br - 117 -organic phase was diluted with ether, washed 3 times with saturated NaHC03, once with saturated NaCl, dried, and concentrated to give 1.31 g (97%) of bromide 166 which was used without further purification in the preparation of compound 167. Preparative t i c of a small amount of this material using petroleum ether-ethyl acetate (10:1) gave 166 as a colourless o i l which decomposed upon d i s t i l l a t i o n ; i r ( C H C I 3 ) : 1710, 1455, 1275, and 1105 cm-1; lR nmr ( C D C I 3 ) 6: 1.79 (s, 6H), 2.12-2.40 (m, 4H), 3.97 (s, 2H), 4.86 (d, J = 7 Hz, 2H), 5.39-5.71 (m, 2H), 7.27-7.70 (m, 3H), and 8.00-8.20 (m, 2H); mass spectrum, m/e_: 257(M+, 8) 136(8), 135(62), 134(6), 107(24), 106(13), 105(100), 93(34), 91(10), 81(10), 79(13), 77(47), 68(39), 67(38), 55(13), 53(20), 51(14), and 41(29). Anal, calcd. for Ci7H2lBr02: C 60.54, H 6.28, Br 23.69; found: C 60.67, H 6.48, Br 23.50. (E_,E)-3,7-dimethyl-9-(2 *,2'-dimethyl-6'-methylenecyclohexanyl)-9-phenylsulphonyl—2,6-nonadienyl benzoate (167) To a stirred solution of 0.22 g (0.80 mmole) of sulphone 161 in 8 mL of THF and 0.8 mL of HMPA at 0°C was added 0.70 mL (1.2 mmole) of a 1.7 M solution of n-butyllithium in hexane. After 1 h a solution of 0.30 g (0.88 mmole) of halide _166 in 3 mL of THF (pre-dried by sti r r i n g S08Ph - 118 -over CaH2) was added to the mixture at 0°C, and the reaction was stirred overnight, while allowing i t to warm to room temperature. The reaction mixture was quenched with 1 M HC1, diluted with ether and petroleum ether, and the organic phase was washed once with 1 M HC1, and four times with saturated NaCl. It was dried and the solvent was removed to give 0.44 g of crude coupled product 167 which was used without further purification in the preparation of alcohol 168. Preparative t i c of a small amount of this material using petroleum ether-ethyl acetate (6:1) gave both diastereomers of 167 (« 9:1 as determined by nmr spectroscopy) as a viscous o i l which decomposed upon d i s t i l l a t i o n ; i r (CHC13): 1705, 1445, 1300, 1275, and 1145 cm-1; *H nmr (CDC13) 6: 0.76 (s, 0.3H), 0.87 (s, 0.3H), 0.96 (s, 2.7H), 1.10 (s, 2.7H), 1.30-2.75 (m, 13H), 1.76 (s, 6H), 3.40-3.70 (m, 1H), 4.79 (bs, IH), 4.82 (d, J = 6 Hz, 2H), 5.05 (bs, IH), 5.15-5.30 (m, IH), 5.47 (t, J = 6 Hz, IH), 7.40-7.66 (m, 6H), and 7.8-8.15 (m, 4H); mass spectrum, m/e: 534(M+, 0.5), 413(2), 412(5), 272(17), 271(65), 270(31), 255(12), 215(12), 203(21), 202(12), 201(14), 187(13), 177(17), 175(22), 163(11), 161(15), 159(16), 149(19), 148(18), 147(66), 146(23), 145(16), 135(25), 133(32), 123(38), 122(59), 121(40), 120(35), 119(38), 109(42), 107(42), 105(100), 95(39), 93(52), 91(30), 81(67), 79(33), 77(59), 69(48), 67(24), and 55(37). Exact Mass calcd. for C 3 3H l t 20 4S: 534.2804; found (ms): 534.2789. - 119 -(E,E)-3,7-dimethyl-9-(2*,2'-dimethyl-6 ,-methylenecyclonexanyl)-9-phenylsulphonyl-2,6-nonadien-l-ol (168) To a stirred solution of 0.44 g of crude benzoic ester 167 in dry ether at 0°C was added 2.4 mL (2.4 mmole) of a 1 M solution of DIBAL in hexane. The reaction was stirred for 2 h and allowed to warm to room temperature, then cooled to 0°C and quenched with 1 M HC1 until both layers were clear. The mixture was stirred for 15 min then diluted with ether, the organic phase was washed twice with saturated NaCl, dried, and the solvent was removed. The crude product was purified by flash chromatography using petroleum ether-ethyl acetate (7:2) as eluant to give the following compounds in order of elution: (a) sulphone 161 (0.083 g, 36% from coupling reaction); Rf 0.80. (b) both diastereomers of alcohol 168 ( M 9:1 as determined by nmr spectroscopy) (0.219 g, 64% from coupling reaction) as an extremely viscous o i l which rearranged upon d i s t i l l a t i o n ; Rf 0.40; i r (CHC13): 3600, 3500, 1450, 1305, 1150, and 1090 cm-1; XH nmr ( C D C I 3 ) 6: 0.98 (s, 2.7H), 1.10 (s, 2.7H), 1.19 (s, 0.3H), 1.24 (s, 0.3H), 1.30-2.80 (m, 13H), 1.65 (s, 6H), 1.90 (bs, IH, exchangeable with D 20), 3.45-3.90 (m, - 120 -IH), 4.12 (d, J = 7 Hz, 2H), 4.76 (bs, - 0.9H), 5.04 (bs, - 1.1H), 5.10-5.25 (m, IH), 5.40 (t, J = 7 Hz, IH), 7.40-7.68 (m, 3H), and 7.75-7.95(m, 2H); mass spectrum, m/e: 430(M+, 2), 289(14), 288(17), 272(12), 271(43), 270(21), 255(13), 203(34), 162(20), 149(25), 147(54), 135(30), 133(32), 123(55), 122(36), 121(45), 120(20), 119(33), 109(55), 107(52), 105(52), 95(52), 93(60), 91(38), 81(100), 80(20), 79(52), 77(34), 69(92), 67(39), 57(26), 55(78), and 53(22). Anal, calcd. for C 2 6 H 3 8 O 3 S : C 72.52, H 8.89, S 7.45; found: C 72.26, H 8.80, S 7.31. (E,E)-3,7-dimethyl-9-(2 *,2'-dimethyl-6*-methylenecyclobexanyl)-2,6-nonadien-l-ol (trixagol) (153) To a stirred solution of 0.151 g (0.35 mmole) of sulphone 168 in dry ethanol was added 0.20 g (1.4 mmole) of disodium hydrogen phosphate, then 0.54 g (1.4 mmole) of freshly ground 6% sodium amalgam (66, 110). The reaction mixture was heated at reflux for 16 h, then cooled to room temperature, quenched with 1 M HC1, diluted with ether, and decanted from the mercury residue. The organic phase was washed once with 1 M HC1, twice with saturated NaHC03, twice with saturated NaCl, dried, and the solvent was removed. The crude product was purified by flash chromatography using petroleum ether-ethyl acetate (5:1) as eluant to - 121 -3 give 0.069 g (68%) of alcohol 153 as a colourless o i l whose spectral data (^ nmr, i r ) is in good agreement with that of the literature (60); i r (CHC13): 3600, 3450, 1645, 1450, 1385, 990, and 800 cm"1; XH nmr (CDCI3) 6: 0.85 (s, 3H), 0.91 (s, 3H), 1.15-2.20 (m, 15H), 1.20 (bs, IH, exchangeable with D 20), 1.60 (s, 3H), 1.70 (s, 3H), 4.17 (d, J - 7 Hz, 2H), 4.54 (m, IH), 4.75 (m, IH), 4.95-5.20 (m, IH), and 5.45 (t, J = 7 Hz, IH); mass spectrum, m/e: 290(M+, 2), 288(3), 257(6), 204(7), 203(6), 177(20), 175(26), 137(28), 136(42), 135(23), 123(29), 121(36), 109(45), 107(36), 105(24), 95(45), 93(57), 81(100), 79(27), 69(71), 67(28), and 55(37). Exact Mass calcd. for 02(^31+0: 290.2610; found (ms): 290.2610. D. Synthesis and Cyclisation of Ester Allylsilanes to Bicyclic Products. Synthesis of (±)-Albicanol (179b), (±)-Albicanyl Acetate (180), and (±)-lsodrlmenin (183) Methyl (E_)-7,ll-dlmethyl-3-oxo-6,10-dodecadienoate (50) (21) This compound was prepared according to general procedure A using 8.70 g (0.18 mole) of sodium hydride (50% dispersion in o i l ) , 17.7 mL Spectral information and a sample of trixagol were kindly provided by Professor Joaquin de Pascual Teresa, Salamanca University, Spain (60). o 3 - 122.-(0.16 mole) of methyl acetoacetate, 113 mL (0.18 mole) of a 1.6 M solution of n-butylllthium in hexane, and 3 9 . 2 g (0.18 mole) of geranyl bromide. Work-up of the reaction mixture gave 44 g of crude product which was purified by Kugelrohr d i s t i l l a t i o n to give 30.3 g (73%) of the B-keto ester 50 as a yellow liquid; bp 130°C/0.1 Torr [ l i t . ( 21 ) bp 90-92°C /0.02 Torr]; i r ( C H C 1 3 ) : 1745, 1715, 1650, and 1630 cm-1; *H nmr (CDCI3 ) 6: 1.62 (s, 6 H ) , 1.70 (s, 3H), 2 . 0 0 (bs, 4 H ) , 2 . 0 - 2 . 7 (m, 4 H ) , 3.42 (s, 2 H ) , 3 .74 (s, 3H), and 5.08 (m, 2 H ) . Methyl (2^,6E)-3-[(diethylphosphoryl)oxy]-7,ll-dlmethyl-2,6,10-dodecatrienoate (171) (21) This compound was prepared according to general procedure B using 6.30 g (0.13 mole) of sodium hydride (50% dispersion in o i l ) , 30.3 g (0.12 mole) of 8-keto ester 50, and 17.3 mL (0.12 mole) of diethyl chlorophosphate. Work-up of the reaction mixture gave a quantitative yield of crude enol phosphate 171 which was used without further purification in the preparation of trimethylsilyl ester 172. The spectral data (*H nmr, i r , ms) is in good agreement with that of the literature (21); i r (CHC13):1730, 1670, 1270, and 1030 cm-1; *H nmr OPO(OEt) 2 COOMe (CDC 13) 6: 1.37 (dt, J C H 2 C H 3 = 7 Hz » iPOCH2CH3 = 1 Hz, 6 H), 1.59 (s, 6H), 1.65 (s, 3H), 1.85-2.45 - 123 -(m, 8H), 3.67 (s, 3H), 4.27 (dq, J CH 2CH 3 = 7 Hz, JpOCH2 = 8 Hz, 4H), 4.9-5.2 (m, 2H), and 5.35 (s, IH). Methyl (2£,6E)-7,1l-dimethyl-3-[(trlmethylsilyl)methyl]-2,6,10-dodecatrienoate (172) This compound was prepared according to general procedure C using 1.95 g (0.080 mole) of magnesium turnings, 12.2 mL (0.088 mole) of trimethylsilylmethyl chloride, 0.25-0.50 g (1.0-2.0 mmole) portions of anhydrous nickel(II) acetylacetonate, and 15.5 g (0.040 mole) of crude enol phosphate 171. The reaction mixture was heated at reflux for 4 h and further portions of 0.25-0.50 g (1.0-2.0 mmole) of catalyst were added after 0.5 and 1.5 h. Work-up of the reaction mixture gave 14.2 g of compound 172 as an orange o i l . The crude product was purified by flash chromatography using petroleum ether-ethyl acetate (40:1) as eluant to yield 9.3 g (72%) of trimethylsilyl ester 172. Preparative t i c of a small amount of this material using petroleum ether-ethyl acetate (20:1) gave 172 as a colourless liquid; bp (Kugelrohr d i s t i l l a t i o n ) 100°C/0.2 Torr; i r (CHC13): 1700, 1620, 1435, 1245, 1160, and 855 cm-1; *H nmr (CDC13) 6: 0.05 (s, 9H), 1.60 (s, 6H), 1.70 (s, 3H), 1.97-2.25 (m, 8H), 2.41 (s, 2H), 3.65 (s, 3H), 5.00-5.22 (m, 2H), and 5.55 (s, IH); mass spectrum, m/e: 322(M+, 15), 307(19), 253(18), - 124 -186(14), 150(12), 149(87), 121(19), 119(11), 117(36), 115(10), 95(12), 93(21), 89(25), 82(46), 81(25), 79(17), 75(10), 74(10), 73(100), 69(59), 59(19), 55(14), and 53(19). Anal, calcd. for C 1 9H 3 l t0 2Si: C 70.75, H 10.62; found: C 70.90, H 10.60. Methyl trans-decahydro-5,5,8aB-trlmethyl-2-aethylene-ll~ naphthalenecarboxylate (173) C O O M e 0^  To a solution of 1.60 g (5.0 mmole) of the trimethylsilyl ester 172 in 120 mL of wet CH2C12 at -56°C was slowly added a solution of 1.46 mL (12.5 mmole) of SnCl^ in 20 mL of wet CH2C12. The reaction mixture was stirred for 3 h at -56°C, then quenched with aqueous KF solution and diluted with ether. The organic phase was washed four times with aqueous KF, twice with saturated NaHC03, once with saturated NaCl, and dried. The solvent was removed to give 1.40 g of crude bicyclic esters 173a and 173b which were used without further purification in the preparation of alcohols 179. Purification of compounds 173 by flash chromatography using petroleum ether-ethyl acetate (40:1) gave 0.76 g (61%) of a mixture of a- and 8-isoraers of 173 as a colourless liquid [173a:173b = 17:83, as determined by gc (T = 160°C)]; bp (Kugelrohr d i s t i l l a t i o n ) 108°C/0.1 Torr; i r (CHC13): 1730, 1645, and 1165 cm-1; lR - 125 -nmr (CDC13) 6: 0.80 (s, 3H), 0.85 (s, 2.5H), 0.88 (s, 0.5H), 0.92 (s, 0.5H), 1.05 (s, 2.5H), 1.10-2.55 (m, 11H), 2.78 (bs, IH), 3.65 (s, 3H), 4.63 (bs, IH), and 4.81 (bs, IH); mass spectrum, m/e: 251(14), 250(M+, 66), 235(25), 191(12), 175(24), 137(100), 136(17), 125(16), 124(23), 123(48), 121(24), 114(45), 109(30), 107(25), 105(19), 95(36), 93(20), 91(20), 82(22), 81(43), 79(22), 77(17), 69(49), 67(19), and 55(36). Anal, calcd. for C 1 6H 2 60 2: C 76.75, H 10.47; found: C 76.58, H 10.41. trans—Decahydro-5,5, 8a8-trimethyl-2-methylene-lB-naphthalenemethanol (albicanol) (179b) This compound was prepared according to the procedure for alcohol 128 using 0.190 g (5.0 mmole) of LiAlH^ and 1.40 g of a mixture of esters 173a and 173b. Work-up of the reaction mixture gave 1.11 g of compound 179b and the a-isomer as a yellow o i l [179a: 179b = 17:83, as determined by gc (T = 170°C)]. The crude product was purified by flash chromatography using petroleum ether-ether (2.5:1) as eluant. After six successive chromatographic separations of the mixture of isomers, 0.90 g of crude product gave 0.15 g (17%) of the a-isomer 179a, and 0.67 g (75% from trimethylsilyl ester 172) of alcohol 179b. Each alcohol was further purified by preparative t i c using petroleum ether-ether (1.5:1) - 126 -as eluant, and the following spectral data was obtained: (a) alcohol 179a; i r ( C H C I 3 ) : 3600, 3450, 1650, 1465, 1025, 975, and 900 cm"1; % nmr (CDC13) 6: 0.86 (s, 3H), 0.92 (s, 3H), 1.00 (s, 3H), 1.1-2.4 (m, 13H), 3.45-3.85 (m, 2H), 4.76 (bs, IH), and 4.95 (bs, IH); mass spectrum, m/e_: 222 (M+, 7), 205(5), 203(13), 137(29), 136(19), 124(15), 123(29), 121(25), 109(32), 107(21), 95(31), 93(21), 81(39), 79(17), 69(42), 67(16), 55(28), 43(18), 41(48), and 40(100). Exact Mass calcd. for C 1 5 H 2 6 O : 222.1984; found (ms): 222.1982. (b) alcohol 179b as a colourless o i l [bp (Kugelrohr d i s t i l l a t i o n ) 130°C/0.1 Torr] which crystallised on standing. The spectral data (*H nmr, i r , ms) is in good agreement with that of the literature (70, 71); mp 49-51°C; i r ( C H C I 3 ) : 3600, 3400, 1650, 1470, 1025, 975, and 900 cm-1; XH nmr (270 MHz) (CDC13), 6: 0.71 (s, 3H), 0.80 (s, 3H), 0.88 (s, 3H), 1.10-1.81 (m, 9H), 1.6 (bs, IH, exchangeable with D 20), 1.97-2.11 (m, 2H), 2.45(ddd, = 10 Hz, Jp^ = 4 Hz, J = 2 Hz, IH), 3.77 (A part of an ABX system, J ^ B = 11 Hz, J^ x = 10 Hz, IH), 3.84 (B part of an ABX system, J^B = 11 Hz, Jjgx = 4 Hz, IH), 4.68 (d, J_ = 2 Hz, IH), and 4.98 (d, J = 2 Hz, IH); mass spectrum, ra/e: 223(12), 222(M+, 52), 207(25), 204(31), 189(23), 138(22), 137(96), 136(38), 135(20), 123(42), 121(33), 119(25), 109(50), 107(46), 105(36), 95(68), 93(67), 91(63), 82(24), 81(80), 79(65), 77(38), 69(70), 68(24), 67(58), 57(24), 56(37), 55(100), 53(39), 43(54), and 41(100). Anal, calcd. for C 1 5 H 2 6 O : C 81.02, H 11.79; found: C 80.80, H 11.93. Spectral information on albicanol (179b) was kindly provided by Professor Ray J. Andersen, University of British Columbia (70,71). - 127 -trans—Decahydro-5,5,8a6-trimethyl-2-methylene-1B-naphthalenemethyl acetate (albicanyl acetate) (180) A mixture of 0.16 mL (1.6 mmole) of acetic anhydride, 0.13 mL (1.6 mmole) of pyridine, and a catalytic amount of 4-dimethylamino-pyridine was stirred in dry ether at room temperature. A solution of 0.33 g (1.5 mmole) of alcohol 179b in dry ether was added to the mixture, and the reaction was stirred for 2 h at room temperature. The reaction mixture was diluted with ether, washed three times with saturated NaHC03, three times with 1 M HC1, twice with saturated NaCl, dried, and concentrated to give 0.38 g (95%) of acetate 140. Preparative t i c of this material using petroleum ether-ethyl acetate (10:1) gave 1805 as a colourless liquid whose spectral data ( 1H nmr, i r , ms) is in good agreement with that of the literature (70); bp (Kugelrohr d i s t i l l a t i o n ) 105°C/0.1 Torr; i r (CHC13): 1730, 1645, 1390, 1370, and 1260 cm-1; *H nmr (270 MHz) (CDCI3) 6: 0.72 (s, 3H), 0.78 (s, 3H), 0.84 (s, 3H), 1.08-1.78 (m, 9H), 1.97-2.07 (m, 2H), 1.99 (s, 3H), Spectral information on albicanyl acetate (180) was kindly provided by Professor Ray J. Andersen, University of British Columbia (70,71). - 128 -2.41 (ddd, JAX = 10 HZ, = 4 Hz, J = 4 Hz, IH), 4.20 (A part of an ABX system, = 12 Hz, = 10 Hz, Jg X = 4 Hz, IH), 4.33 (B part of an ABX system, Jj^ = 12 Hz, J g X = 4 Hz, IH), 4.50 (s, IH), and 4.84 (s, IH); mass spectrum, m/e: 204(M+ - AcOH, 29), 189(17), 137(35), 136(20), 133(15), 123(20), 121(16), 119(17), 109(21), 107(27), 105(19), 95(37), 93(39), 91(30), 81(48), 79(36), 77(20), 73(22), 69(41), 67(26), 55(42), 53(18), 43(100), and 41(60). Anal, calcd. for C17H2&O2: C 77.22, H 10.67; found: C 76.98, H 10.83. Methyl trans-decahydro-5,5,8aB-trimethyl-2-methylene-1£-naphthalenecarboxylate epoxide (186) C O O M e To a solution of 0.678 g (2.7 mmole) of alkenes 173a and 173b in dry CH2C12 at 0°C was slowly added a solution of 0.56 g (3.4 mmole) of MCPBA (109) in CH2C12. The reaction mixture was stirred for 2 h while allowing i t to warm to room temperature, and was then diluted with ether. The organic layer was washed three times with saturated NaHC0 3, once with saturated NaCl, and dried. The solvent was removed to give 0.658 g of a mixture of crude epoxides 186 which was used without further purification in the preparation of lactone 183. Preparative t i c of a small amount of this material using petroleum ether-ethyl acetate - 129 -(20:1) gave a mixture of the four isomers of 186 as a colourless liquid; bp (Kugelrohr d i s t i l l a t i o n ) 100°C/0.1 Torr; i r ( C H C I 3 ) : 1730 and 1175 cm"1; *H nmr ( C D C I 3 ) 6: 0.90 (s, » 2.4H), 0.95 (s, - 2.4H), 1.00 (s, - 0.6H), 1.05 (s, - 0.6H), 1.10 (s, - 0.6H), 1.15 (s, - 2.4H), 1.00-2.10 (m, 1 1 H ) , 2.43-2.72 (m, 2 H ) , 3.30-3.50 (bs, IH), 3.61 (s, - 2 . 1 H ) , 3.63 (s, « 0.35H), 3.67 (s, « 0.35H), and 3.68 (s, * 0 . 2 H ) ; mass spectrum, m/e:266(M+, 4), 251(12), 248(39), 236(37), 235(31), 143(28), 141(100), 137(50), 130(76), 129(43), 128(33), 123(40), 121(26), 112(25), 109(51), 107(26), 95(56), 93(30), 91(28), 82(34), 81(61), 79(33), 69(74), 67(38), 59(26), and 55(76). Exact Mass calcd. for C 1 6H 260 3: 266.1882; found (ms): 266.1881. (4,5,5aa,6,7,8,9,9aB)-Octahydro-6,6 ,9a-trlmethyl-naphtho-[1,2-c]furan-l(3H)-one (isodrimenin) (183) To a solution of 0.70 mL (5.0 mmole) of diisopropylamine in dry THF at 0°C was added 2.94 mL (5.0 mmole) of a 1.70 M solution of n-butyllithium in hexane. The pale yellow solution was stirred for 15 min at 0°C, cooled to -78°C, and a solution of 0.266 g (1.0 mmole) of epoxy esters 186 was added (76). The reaction was allowed to warm to - 130 -room temperature over a period of 1 h, stirred at room temperature for 3 h, then quenched with 1 M HC1 and diluted with ether. The organic phase was washed once with 1 M H C 1 , twice with saturated NaCl, dried, and concentrated to give 0.266 g of crude product. Purification by flash chromatography using petroleum ether-ethyl acetate (5:1) as eluant gave 0.141 g (60% from esters 173) of 183 as a white solid. Preparative t i c of a small amount of this material using petroleum ether-ethyl acetate 6 1 (6:1) gave 183 as a crystalline solid whose spectral data ( H nmr, i r , ms) is in good agreement with that of the literature (75a, 75f); mp 88.5-90.0°C [ l i t . (75f) mp 89-90°C]; i r (CHC13): 1740, 1670, 1340, 1145, 1030, and 1010 cm-1; lH nmr ( C D C I 3 ) 6: 0.87 (s, 3H), 0.91 (s, 3H), 1.13 (s, 3H), 1.05-2.75 (m, 11H), and 4.57 (s, 2H); mass spectrum, m/e: 234(M+, 82), 219(100), 163(21), 152(22), 151(60), 123(28), 110(25), 109(24), 105(21), 91(31), 81(21), 75(22), 69(31), 55(33), and 53(22). Anal, calcd. for C 1 5 H 2 2 O 2 : C 76.88, H 9.46; found: C 76.62, H 9.62. E. Synthesis and Cyclisation of Epoxy Ester Allylsilanes to Monocyclic Products. Synthesis of (±)-Karahana Ether (193) Methyl (Z)-6,7-epoxy-7-methyl-3-[(trimethylsilyl)methyl}-2-octenoate (191) SiMe 6Spectral data of isodrimenin (183) was kindly provided by Professor James D. White, Oregon State University (75a). - 131 -To 7.J63 g (0.030 mole) of diene 138_ in dry CH2Cl2 at 0°C was slowly added a solution of 5.70 g (0.033 mole) of MCPBA (109) in CH 2C1 2. The reaction mixture was stirred for 2 h at 0°C, then warmed to room temperature, and diluted with ether. The organic layer was washed three times with saturated NaHC03, once with saturated NaCl, dried, and concentrated to give 8.1 g of crude 191. Purification by flash chromatography using petroleum ether-ethyl acetate (12:1) as eluant gave 6.83 g (84%) of epoxide 191 as a colourless o i l . Preparative tic of a small amount of this material using petroleum ether-ethyl acetate (7:1) gave 191 as a colourless liquid; bp (Kugelrohr d i s t i l l a t i o n ) 80°C/0.1 Torr; i r (CHC13): 1700, 1615, 1250, 1160, and 850 cm-1; XH nmr ( C D C I 3 ) 6: 0.10 (s, 9H), 1.30 (s, 3H), 1.35 (s, 3H), 1.60-1.90 (m, 2H), 2.15-2.50 (m, 4H), 2.75 (bt, J = 6 Hz, IH), 3.68 (s, 3H), and 5.58 (s, IH); mass spectrum, m/e: 271(3), 270(M+, 11), 255(8), 123(12), 121(20), 96(17), 95(42), 91(11), 89(41), 85(16), 82(31), 80(10), 75(20), 74(12), 73(100), 71(10), 69(10), 67(14), and 59(38). Exact Mass calcd. for C l t tH 2 60 3Si: 270.1650; found (ms): 270.1650. Methyl cis—3-hydroxy-2,2—dimethyl—6—methylenecyclohexane-carboxylate (189) To a solution of 4.05 g (0.015 mole) of the trimethylsilyl epoxide 191 in 130 mL of CH2C12 at -56°C was slowly added a solution of - 132 -3.69 mL (0.030 mole) of BF 3.Et 20 in 20 mL of CH2C12. The reaction mixture was stirred for 4 h at -56°C, then quenched with saturated NaCl at -56°C. The organic layer was diluted with ether, washed four times with saturated NaCl, dried, and concentrated to give 3.41 g of crude product which was used without further purification in the preparation of diol 192. Purification of a small amount of this material by flash chromatography using petroleum ether-ethyl acetate (8:1) gave 189 as a colourless liquid; bp (Kugelrohr d i s t i l l a t i o n ) 95°C/0.1 Torr; i r (CHC13): 3420, 1710, 1650, 1155, and 1075 cm-1; XH nmr (CDC13) 6: 0.93 (s, 3H), 1.04 (s, 3H), 1.70-2.80 (bm, 4H), 3.00 (s, IH), 3.30-3.50 (m, IH), 3.70 (s, 3H), 4.35 (bd, J - 10 Hz, IH, exchangeable with D 20), 4.85 (bs, IH), and 4.95 (bs, IH); mass spectrum, m/e_: 198(M+, 13), 180(20), 167(9), 139(12), 138(11), 123(14), 122(13), 121(100), 120(15), 109(10), 105(14), 97(14), 96(18), 95(80), 93(12), 83(16), 82(10), 81(13), 79(16), 69(13), 67(20), 59(14), and 55(25). Anal, calcd. for C 1 1H 1 80 3: C 66.64, H 9.15; found: C 66.37, H 8.92. cis-3-Hydroxy-2,2-dimethyl-6-mettaylenecylohexanemethanol (192) A slurry of 0.850 g (0.022 mole) of LiAlHi* in dry ether was stirred at 0°C, and 3.41 g of the crude hydroxy ester 189 in dry ether - 133 -was slowly added to the slurry. The reaction mixture was heated at reflux for 2 h, then cooled to room temperature and quenched with 1 M HC1. The organic layer was washed once with 1 M HC1, twice with saturated NaCl, dried, and concentrated to give 1.95 g of crude 192. Purification by flash chromatography using petroleum ether-ethyl acetate (1:1) as eluant gave 1.73 g (68% from trimethylsilyl epoxide 138) of cis-d i o l 192 as a colourless o i l . Preparative t i c of a small amount of this material using petroleum ether-ethyl acetate (1:1.5) gave 1927 as a colourless liquid; bp (Kugelrohr d i s t i l l a t i o n ) 105°C/0.1 Torr; i r (CHC13): 3600, 3400, 1640, 1080, and 1010 cm-1; XH nmr ( C D C I 3 ) 6: 0.94 (s, 3H), 1.00 (s, 3H), 1.30-2.50 (m, 5H), 2.36 (bs, 2H, exchangeable with D 20), 3.44 (dd, = 4 Hz, J^Y = 4 Hz, IH), 3.69 (A part of an ABX system, Jj^ = 11 Hz, = 4 Hz, IH), 3.91 (B part of an ABX system, ^ = 11 Hz, J B X = 7 Hz, IH), 4.73 (bs, IH), and 4.93 (bs, IH); mass spectrum, m/e: 170(M+, 0.5), 152(21), 138(8), 122(100), 121(55), 109(22), 108(20), 107(90), 96(26), 95(21), 93(30), 91(18), 81(37), 79(30), 71(21), 69(17), 67(31), 55(34), and 53(18). Anal, calcd. for C 1 0 H 1 8 O 2 : C 70.55, H 10.66; found: C 70.40, H 10.70. Spectral information on diol 192 was kindly provided by Professor Robert M. Coates, University of I l l i n o i s (79). - 134 -8,8-Dimethyl-2-methylene-6-oxablcyclo[3.2.1]octane (karahana ether)(193) A solution of 0.850 g (5.0 mmole) of diol 192^  in 7 mL of dry pyridine was stirred at 0°C, and 0.950 g (5.0 mmole) of £-toluenesulphonyl chloride (108) was added to the solution. The reaction was stirred for 5 h while allowing i t to warm to room temperature. The reaction mixture was diluted with ether, washed five times with 1 M HC1, once with saturated NaHC03, once with saturated NaCl, dried, and the solvent was removed to give 1.04 g of crude 193. Purification by flash chromatography using petroleum ether-ether (9:1) as eluant gave 0.62 g (81%) of bicyclic ether 1938 as a colourless liquid with a pleasant, camphor-like odour whose spectral data ( *H nmr, i r , ms) is in good agreement with that of the literature (79-81); bp (Kugelrohr d i s t i l l a t i o n ) 120°C/90 Torr; i r (CHC13): 1645, 1060, 1035, 980, 910, 890, and 875 cm-1; h nmr (CDC13) 6: 0.95 (s, 3H), 1.05 (s, 3H), 1.55-1.80 (m, 2H), 2.10-2.60 (m, 2H), 2.30 (X part of an ABX system, JAX = 0 Hz, J$x = 4 Hz, IH), 3.75 (bs, IH), 3.80 (A part of Spectral information on karahana ether (193) was kindly provided by Professor Yasuji Yamada, Tokyo College of Pharmacy (81a) and by Professor Robert M. Coates, University of I l l i n o i s (79). - 135 -an ABX system, J^g = 8 Hz, J j ^ = 0 Hz, IH), 4.01 (B part of an ABX system, J^g = 8 Hz, Jp,y = 4 Hz, IH), and 4.50-4.65 (m, 2H); mass spectrum, m/e: 152(M+, 18), 123(9), 122(55), 121(55), 120(18), 119(8), 109(11), 108(10), 107(100), 95(17), 94(14), 93(27), 91(21), 81(25), 79(35), 67(25), 55(14), and 53(17). Exact Mass calcd. for C 1 0Hi 60: 152:1201; found (ms): 152.1200. F. Synthesis and Cyclisation of Epoxy Ester Allylsilanes to Bicyclic  Products (E)-6,7-Epoxy-3,7-dimethyl-2-octenyl bromide (200) To 17.2 g (0.079 mole) of geranyl bromide in dry CH2C12 at 0°C was slowly added a solution of 15.0 g (0.087 mole) of MCPBA (109) in CH2C12. The reaction mixture was stirred for 2 h at 0°C, then was allowed to warm to room temperature overnight. The reaction was cautiously quenched with saturated NaHC03 and diluted with ether. The organic phase was washed three times with saturated NaHC03, once with saturated NaCl, and dried. The solvent was removed to give 17.1 g (93%) of crude 200 as a colourless liquid which was used without purification in the preparation of B-keto ester 201. The spectral data (^ H nmr, i r ) is in good agreement with that of the literature (111); i r (CHC13): - 136 -1660, 1460, 1390, 1125, and 880 cm"1; XH nmr (CDC13) 6: 1.27 (s, 3H), 1.32 (s, 3H), 1.76 (d, J = 1 Hz, 3H), 1.55-1.85 (m, 2H), 2.10-2.40 (m, 2H), 2.73 (t, J = 6 Hz, 1 Hz), 4.00 (d, J « 8 Hz, 2H), and 5.60 (dt, J = 8 Hz, 1 Hz, IH); mass spectrum, m/e: 219(M+ - CH3,4), 217(M+ - CH3,4), 153(42), 111(64), 109(25), 101(26), 95(40), 93(43), 85(62), 83(25), 82(25), 81(100), 79(39), 71(82), 69(38), 68(48), 67(73), 59(75), and 55(100). Exact Mass calcd. for C 9H l 4 8 1Br0 (M+ - CH3): 219.0209; found (ms): 219.0215; calcd. for C 9H 1 1 + 7 9BrO (M+ - CH3): 217.0228; found (ms): 217.0230. Methyl (E)-l0,1l-epoxy-7,1l-dimethyl-3-oxo-6-dodecenoate (201) This compound was prepared according to general procedure A using 3.52 g (0.088 mole) of sodium hydride (60% dispersion in o i l ) , 7.91 mL (0.073 mole) of methyl acetoacetate, 52.7 mL (0.084 mole) of a 1.6 M solution of n-butyllithium in hexane, and 17.1 g (0.073 mole) of the epoxy bromide 200. Work-up of the reaction mixture gave 18 g of crude product which was purified by flash chromatography using petroleum ether-ethyl acetate (4:1) as eluant to yield 13.5 g (69%) of 201 as a yellow o i l . Preparative t i c of a small amount of this material using the same solvent mixture gave 201 as a colourless liquid; bp (Kugelrohr d i s t i l l a t i o n ) 135°C/0.1 Torr; i r (CHC13): 1750 and 1720 cm"1; lU nmr o C O O M e - 137 -(CDC13) 6: 1.24 (s, 3H), 1.28 (s, 3H), 1.62 (s, 3H), 1.40-1.85 (m, 2H), 2.00-2.60 (m, 6H), 2.65 (t, J = 6 Hz, IH), 3.42 (s, 2H), 3.70 (s, 3H) , and 5.10 (bt, J = 7 Hz, IH); mass spectrum, m/e: 268(M+, 5), 183(17), 151(18), 123(24), 119(20), 109(43), 108(23), 105(21), 101(49), 95(43), 94(32), 93(25), 85(100), 82(23), 81(74), 79(30), 74(22), 72(25), 71(70), 69(39), 67(33), 59(81), 57(35), 55(38), and 53(24). Anal, calcd. for Ci 5H 2H0i t: C 67.14, H 9.02; found: C 67.14, H 9.02. Methyl (2£,6E)-10,ll-epoxy-3-[(diethylphosphoryl)oxy]-7,11-dimethyl-2,6-dodecadienoate (196) OPO(OEt)2 J ^ ? ^ J ^ / ^ / C O O M e This compound was prepared via general procedure B using 2.69 g (0.067 mole) of sodium hydride (60% dispersion in o i l ) , 15.7 g (0.059 mole) of B-keto ester 201, and 8.86 mL (0.062 mole) of diethyl chlorophosphate. Work-up of the reaction mixture gave 23.6 g (99%) of enol phosphate 196 which was used without further purification in the preparation of s i l y l ester 194. Preparative t i c of a small amount of this compound using petroleum ether-ethyl acetate (1:1) gave 196 as a colourless o i l which decomposed upon d i s t i l l a t i o n ; i r ( C H C I 3 ) : 1730, 1670, 1275, and 1030 cm-1; *H nmr (CDC13) 6: 1.26 (s, 3H), 1.30 (s, 3H), 1.37 (dt, JCH 2CH 3 = 7 H z ' iP0CH 2CH 3 = 1 H z » 6H>> 1 > 6 5 ( s> 3 H ) » 1.50-1.80 (m, 2H), 2.00-2.52 (m, 6H), 2.70 (t, J = 6 Hz, IH), 3.71 (s, - 138 -3 H ) , 4.29 (dq, J C H 2 C H3 = 7 Hz, J p 0 C H 2 - 7 Hz, 4 H ) , 5.05-5.27 (bt, IH), and 5.37 (s, IH); mass spectrum, m/e: 404(M+, 3), 363(18), 287(17), 252(23), 220(27), 192(15), 164(20), 155(100), 135(17), 133(17), 127(33), 119(17), 105(19), 99 (45) , 85(17), 81(27), 79(16), 71(18), and 59 (35) . Exact Mass calcd. for C19H33O7P: 404.1964; found (ms): 404.1978. Methyl (2Z,6E)-10,11-epoxy-7,11-dimethyl-3-[(trlmethylsllyl)methyll-2,6-dodecadienoate (194) -SiMe. X O O M e This compound was prepared via general procedure C using 1.09 g (0.045 mole) of magnesium turnings, 6.87 mL (0.0495 mole) of triraethylsilylmethyl chloride, 0.096-0.19 g (0.38-0.75 mmole) of anhydrous nickel(II) acetylacetonate, and 6.06 g of epoxy enol phosphate 196. The reaction mixture was stirred at room temperature for 2 h with no further addition of catalyst. Work-up of the reaction mixture gave 5.8 g of crude product which was purified by flash chromatography using petroleum ether-ethyl acetate (15:1) to yield 2.04 g of 194 (40% from 8-keto ester 201) as a pale yellow liquid. Preparative t i c of a small amount of this material using petroleum ether-ethyl acetate (7:1) gave 194 as a colourless o i l ; bp (Kugelrohr d i s t i l l a t i o n ) 130°C/0.2 Torr; i r (CHC13): 1705, 1625, 1165, and 850 cm-1; XH nmr ( C D C I 3 ) 6: 0.04 (s, 9H), - 139 -1.25 (s, 3H), 1.29 (s, 3H), 1.61 (s, 3H), 1.45-1.76 (m, 2H), 1.95-2.26 (m, 6H), 2.39 (s, 2H), 2.69 (t, J = 6 Hz, IH), 3.65 (s, 3H), 5.00-5.28 (m, IH), and 5.55 (s, IH); mass spectrum, m/e: 338(M+, 3), 323(14), 253(13), 211(14), 186(18), 149(41), 107(36), 89(23), 85(21), 82(40), 81(22), 73(100), and 59(37). Anal, calcd. for CigH^C-aSi: C 67.41, H 10.12; found: C 67.33, H 10.22. Methyl (2Z,6E )-l0,1l-epoxy-3-[(diethylphosphoryl)oxy]-7,11-dimethyl-2,6-dodecadienoate (196) via epoxidation of triene 171 To 17.9 g (0.046 mole) of enol phosphate 171_ in CH2C12 at -50°C was slowly added a solution of 8.37 g (0.048 mole) of MCPBA in CH2C12. The reaction was allowed to warm to 0°C over a period of 1 h, then was stirred for 1 h at 0°C. (Crystals of m-chlorobenzoic acid were observed to appear at approximately -15°C). The reaction was cautiously quenched with saturated NaHC03, diluted with ether, and the organic phase was washed three times with saturated NaHC03, once with saturated NaCl, and dried. The solvent was removed to give 18.3 g of a mixture of 196, starting material 171, and the isomeric epoxide 197 [196:171:197 » 4:1:1, as determined by gc (OV-101: 150°C, 0 min; 10°C/min; 250°C, 5 min; Carbowax 20M: T = 215°C)]. The two epoxides 196 and 197 were inseparable by flash chromatography, and the crude reaction mixture was OPO(OEt)( - 140 -used without purification in the preparation of s i l y l epoxides 194 and 195. Methyl (Z)-6,7-epoxy-7,1l-dimethyl-3-[(trimethylsilyl)methyl]-2,10-dodecadienoate (195) This compound was prepared according to general procedure C using 2.43 g (0.10 mole) of magnesium turnings, 13.9 mL (0.10 mole) of trimethylsilylmethyl chloride, 0.30-0.60 g (1.3-2.5 mmole) of anhydrous nickel(II) acetylacetonate, and 18.3 g of a mixture of compounds 196, 171, and 197. Further portions of 0.30-0.60 g (1.3-2.5 mmole) of catalyst were added after 0.5 h, 1 h, and 2 h, and the mixture was stirred at room temperature for 4 h. Work-up of the reaction mixture gave 19.3 g of crude product which was purified by flash chromatography using petroleum ether-ethyl acetate (20:1) as eluant to give the following compounds in order of elution: (a) triene 172 (2.84 g, 19%) as a pale yellow liquid whose spectral data is in good agreement with that obtained previously; Rf 0.85. (b) epoxy silane 195 (1.09 g, 7% from enol phosphate 171) as a yellow o i l ; Rf 0.62. Preparative t i c of a small amount of this material using petroleum ether-ethyl acetate (7:1) as eluant gave 195 as - 141 -a colourless o i l ; bp (Kugelrohr d i s t i l l a t i o n ) 125°C/0.1 Torr; i r (s, 9H), 1.28 (s, 6H), 1.40-1.88 (m, 4H), 1.63 (bs, 3H), 1.9-2.35 (m, 4H), 2.42 (bs, 2H), 2.72 (t, J = 6 Hz, IH), 3.68 (s, 3H), 4.95-5.20 (ra, IH), and 5.56 (s, IH); mass spectrum, ra/e: 338(M+, 12), 125(16), 109(19), 107(18), 95(28), 82(34), 81(18), 75(15), 73(100), 69(44), 67(15), 59(19), and 55(17). Anal, calcd. for CigH^i^Si: C 67.41, H 10.12; found: C 67.60, H 10.09. (c) epoxy silane 194 (5.19 g, 33% from enol phosphate 171). The spectral data of the epoxide is in good agreement with that obtained previously; Rf 0.57. Methyl (2Z,6E)-10,11-epoxy-7,1l-dimethyl-3-[(trimethylsllyl)methyl]-2,6-dodecadienoate (194) via epoxidation of triene 172 To 0.672 g (2.1 mmole) of s i l y l alkene J72 in dry CH2C12 at 0°C was slowly added a solution of 0.362 g (2.1 mmole) of MCPBA (109) in CH2C12. The reaction was stirred at 0°C for 2.5 h, then was quenched with saturated NaHC03, and diluted with ether. The organic layer was washed three times with saturated NaHC03, once with saturated NaCX, dried, and the solvent was removed to give 0.676 g of crude epoxide. Purification by flash chromatography using petroleum ether-ethyl acetate (CHC13): 1705, 1630, 1250, 1160, and 855 cm -1 1. H nmr (CDC13) 6: 0.09 - 142 -(20:1) as eluant gave the following compounds in order of elution: (a) starting material 172^  (0.094 g, 14%); Rf 0.85. (b) internal epoxide 195_ (0.138 g, 20%); Rf 0.62. (c) terminal epoxide Jj?4_ (0.158 g, 22%); Rf 0.57. (d) an unidentified product (0.073 g) which contained an epoxide functionality, but no trimethylsilyl functionality; R^ 0.43. 2,2,4,4-Tetramethyl-3-pentanol (208) A solution of 200 mL (0.33 mole) of _t-butyllithium in pentane was cannulated under nitrogen into a pressure equalising addition funnel which lead to a 500 mL round-bottomed flask containing 200 mL of ether and 12.0 mL (0.15 mole) of ethyl formate at -78°C. The t-butyllithium was added to the stirred reaction mixture over a period of 2 h and the temperature was maintained at -78°C. The reaction was stirred for a further 30 min at -78°C, warmed to 0°C, cautiously quenched with H20, and acidified with 1 M HC1 until the mixture was acidic to litmus paper. The organic phase was washed with saturated NaCl and dried. The solvent was removed by d i s t i l l a t i o n at atmospheric pressure, and the product was d i s t i l l e d to give 13.7 g (63%) of a colourless solid; bp 161-163°C [ l i t . ( 112) bp 163°C]; h nmr ( C D C I 3 ) 6: 1.00 (s, 18H), 1.86 (s, IH, exchangeable with D 20), and 2.98 (s, IH). OH - 143 -General Procedure D. Synthesis of Alkyl Acetoacetates from Diketene (86) A mixture of anhydrous sodium acetate (0.005 equiv.) and the alcohol (1.0 equiv.) was heated with stirring to 80-85°C, or to the boiling point of the alcohol. Diketene (121) (1.05 equiv.) was added dropwise to the reaction mixture while maintaining the temperature below 115°C. The reaction was stirred for 2.5 h from the time of i n i t i a l addition of diketene, and the product was d i s t i l l e d directly from the reaction mixture. 2-Propyl 3-oxobutanoate (209) This compound was prepared according to general procedure D using 8.2 mL ( 0 . 1 1 mole) of 2-propanol, 0.040 g (0.5 mmole) of anhydrous sodium acetate, and 8.8 mL ( 0 . 1 1 mole) of diketene ( 1 2 1). The product was d i s t i l l e d to give 13.3 g (86%) of 209 as a colourless liquid; bp 90-100°C/45 Torr [ l i t . (113) bp 79-80°C/17 Torr]; i r ( C H C 1 3 ) : 1740, 1715, and 1105 cm-1; *H nmr ( C D C I 3 ) 6: 1.26 (d, J = 6 Hz, 6H), 2.26 (s, 3H), 3.42 (s, 2 H ) , and 5.05 (septet, J = 6 Hz, IH). 2,2-Dimethylpropyl 3-oxobutanoate (210) O C O O C O O , \ - 144 -This compound was prepared according to general procedure D using 5.28 g (0.060 mole) of 2,2-dimethylpropyl alcohol, 0.025 g (0.30 mmole) of anhydrous sodium acetate, and 4.90 mL (0.063 mole) of diketene (121). The product was d i s t i l l e d to give 7.69 g (75%) of 2\0_ as a colourless liquid; bp 100-116°C/45 Torr [ l i t . (114) bp 60°C/3 Torr]; i r (CHC13): 1740, 1705, and 1370, cm"1; XH nmr (CDC13) 6: 0.93 (s, 9H) , 2.25 (s, 3H), 3.46 (s, 2H), and 3.80 (s, 2H). 2,2,4,4-Tetramethyl-3-pentyl 3-oxobutanoate (211) This compound was prepared according to general procedure D using 13.2 g (0.092 mole) of alcohol 208, 0.038 g (0.5 mmole) of anhydrous sodium acetate, and 7.84 mL (0.10 mole) of diketene (121). The product was d i s t i l l e d to give 18.2 g (87%) of 211 as a colourless liquid; bp 120°C/5 Torr; i r (CHC13): 1730, 1715, and 1380 cm-1; lU nmr (CDC13) 6: 1.01 (s, 18H), 2.32 (s, 3H), 3.51 (s, 2H), and 4.65 (s, IH); mass spectrum, ra/e: 228(M+, 0.1), 171(11), 103(17), 87(42), 85(100), 69(17), 58(20), 57(85), 43(83), and 41(40). Anal, calcd. for Ci3H2k03: C 68.39, H 10.59; found: C 68.57, H 10.80. 2-Propyl (E)-7,ll-dimethyl-3-oxo-6,10-dodecadienoate (212) O - 145 -This compound was prepared according to general procedure A using 3.08 g (0.077 mole) of sodium hydride (60% dispersion in o i l ) , 10.1 g (0.070 mole) of 8-keto ester 209, 29.6 mL (0.077 mole) of a 2.6 M solution of n-butyllithium in hexane, and 16.3 g (0.070 mole) of geranyl bromide. Work-up of the reaction mixture gave 20.9 g of crude product which was used without further purification in the preparation of enol phosphate 215. Preparative t i c of a small amount of this compound using petroleum ether-ethyl acetate (8:1) gave 212 as a colourless liquid; bp (Kugelrohr di s t i l l a t i o n ) 150°C/0.25 Torr; i r (CHC13): 1735, 1705, and 1100 cm-1; lB. nmr (CDC13) 6: 1.31 (d, J_ = 6 Hz, 6H), 1.63 (s, 6H), 1.73 (s, 3H), 1.9-2.25 (bs, 4H), 2.25-2.75 (m, 4H), 3.45 (s, 2H), 5.09 (septet, J_ = 6 Hz, IH), and 5.0-5.3 (m, 2H); mass spectrum, m/e_: 280(M+, 5), 219(10), 169(17), 151(14), 136(33), 123(10), 109(81), 109(81), 105(17), 93(15), 87(11), 81(26), 69(100), 68(14), 67(15), and 55(18). Anal, calcd. for C 1 7H 2 80 3: C 72.82, H 10.07; found: C 72.94, H 10.03. 2,2-Dimethylpropyl (E)-7,1l-dimethyl-3-oxo-6,10-dodecadienoate (213) This compound was prepared according to general procedure A using 1.63 g (0.041 mole) of sodium hydride (60% dispersion in o i l ) , 6.35 g (0.037 mole) of B-keto ester 210, 25.4 mL (0.041 mole) of a 1.6 M solution of n-butyllithium in hexane, and 9.04 g (0.039 mole) of geranyl bromide. Work-up of the reaction mixture gave 12.2 g of crude product - 146 -which was purified by d i s t i l l a t i o n to yield 5.63 g (50%) of 213 as a yellow o i l . Preparative t i c of a small amount of this compound using petroleum ether-ethyl acetate ( 5 : 1 ) gave 213 as a colourless liquid; bp 155°C/0.15 Torr; i r ( C H C 1 3 ) : 1745 and 1720 cm"1; XH nmr ( C D C 1 3 ) 6: 0.98 (s, 9H), 1.64 (s, 6 H ) , 1.74 (s, 3H), 1.98-2.14 (m, 4 H ) , 2 . 2 0 - 2 . 7 5 (m, 4 H ) , 3.49 (s, 2 H ) , 3.87 (s, 2 H ) , and 4.95-5.25 (m, 2H) ; mass spectrum, m/e: 308(M+, 1 2 ) , 290(10), 247(12), 169(22), 136(36), 109(55), 93(20) 81(26), 71 (68) , 69 , ( 100 ) , 57(24), 55(24), 43(87), and 41 (74) . Anal, calcd. for C19H32O3: C 73.98, H 10.46; found: C 74.05, H 10.40. 2,2,4,4-Tetramethyl-3-pentyl (E)-7,1l-dimethyl-3-oxo-6,10-dodecadienoate (214) O This compound was prepared via general procedure A using 3.30 g (0.083 mole) of sodium hydride (60% dispersion in o i l ) , 17.1 g (0.075 mole) of B-keto ester 211, 53.2 mL (0.083 mole) of a 1.55 M solution of n-butyllithium in hexane, and 19.2 g (0.083 mole) of geranyl bromide. Work-up of the reaction mixture gave 30.5 g of crude product which was used without further purification in the preparation of enol phosphate 217. Preparative t i c of a small amount of this compound using petroleum ether-ethyl acetate (8:1) as eluant gave 214 as a colourless liquid; bp - 147 -(Kugelrohr di s t i l l a t i o n ) 120°C/0.1 Torr; i r ( C H C 1 3 ) : 1735, 1710, and 1370 cm-1; *H nmr ( C D C 1 3 ) 6: 1 .00 (s, 18H), 1.61 (s, 6H), 1.69 (s, 3H), 1.90-2.12 (m, 4H), 2.20-2.75 (m, 4H), 3.49 (s, 2 H ) , 4.65 (s, IH), and 4.96-5.23 (bt, 2 H ) ; mass spectrum, m/e: 364(M+, 0 . 1 ) , 238(11), 195(10), 136(10) , 109(27), 81(16), 71(26), 69(62), 57 ( 1 0 0 ) , and 41(48). Anal, calcd. for C23H40O3: C 75.78, H 11.06; found: C 75.73, H 10.96. 2-Propyl (2Z^6E)-3-[(diethylphosphoryl)oxy]-7,ll-dimethyl-2,6,10-dodecatrienoate (215) OPO(OEt) s C O O This compound was prepared according to general procedure B using 3.08 g (0.077 mole) of sodium hydride (60% dispersion in o i l ) , 20.9 g of crude B-keto ester 212, and 11.1 mL (0.077 mole) of diethyl chlorophosphate. Work-up of the reaction mixture gave a quantitative yield of an orange o i l which was used without further purification in the preparation of s i l y l ester 218. Preparative t i c of a small amount of this material using petroleum ether-ethyl acetate (2:1) gave 215 as a viscous liquid; bp (Kugelrohr d i s t i l l a t i o n ) 190°C/0.2 Torr; i r ( C H C I 3 ) : 1720, 1670, 1270, 1105, and 1020 cm-1; *H nmr (CDC13) 6: 1.28 (d, J = 6 Hz, 6H), 1.40 (dt, J CH 2CH 3 = 7 Hz, Jp 0CH 2CH 3 = 1 » 6H), 1.63 (s, 6H), 1.71 (s, 3H), 1.95-2.15 (m, 4H), 2.23-2.53 (m, 4H), 4.28 (dq, iCH 2CH 3 = 7 Hz. ipQCH 2 = 7 H z ' 4 H)» 4*87-5.25 (m, 3H), and 5.35 (s, - 148 -IH); mass spectrum, m/e: 416(M+, 5), 357(12), 287(32), 220(48), 192(19), 165(19), 155(100), 133(19), 127(37), 105(20), 99(38), and 69(31). Anal, calcd. for C 2 1H 3 70 6P: C 60.56, H 8.95; found: C 60.36, H 8.90. 2,2-Dimethylpropyl (2£,6E)-3-[(diethylphosphoryl)oxy]-7,11-dimethyl-2,6,10-dodecatrienoate (216) OPO(OEt) a c o o ^ X This compound was prepared according to general procedure B using 0.80 g (0.020 mole) of sodium hydride (60% dispersion in o i l ) , 5.63 g (0.018 mole) of B-keto ester 2L3> and 2.76 mL (0.019 mole) of diethyl chlorophosphate. Work-up of the reaction mixture gave 5.44 g (67%) of an orange o i l which was used without further purification in the preparation of s i l y l ester 219. Preparative t i c of a small amount of this material using petroleum ether-ethyl acetate (2:1) gave 216 as a viscous o i l ; bp (Kugelrohr d i s t i l l a t i o n ) 180°C/0.1 Torr; i r (CHC13): 1720, 1670, and 1030 cm-1; XH nmr ( C D C I 3 ) 6: 0.96 (s, 9H), 1.37 (dt, iCH 2CH 3 - 1 Hz, iP0CH 2CH 3 = 1 Hz, 6H), 1.67 (bs, 6H), 1.74 (bs, 3H), 1.90-2.17 (m, 4H), 2.26-2.64 (m, 4H), 3.82 (s, 2H), 4.27 (dq, J C H 2 C H 3 = 7 Hz, JpoCH2CH3 " 1 Hz, 4H), 5.0-5.26 (m, 2H), and 5.39 (s, IH); mass spectrum, m/e: 444(M+, 11), 308(17), 220(30), 155(100), 136(35), 127(39), 121(22), 109(49), 105(20), 99(45), 93(28), 85(27), 81(41), 71(60), 69(91), 67(24), 57(31), 55(34), 43(88), and 41(77). Exact Mass - 149 -calcd. for C 2 3H H 10 6P: 444.2641; found (ms): 444.2634. 2,2,4,4-Tetramethyl-3-pentyl (2Z,6E)-3-[(diethylphosphoryl)oxy]-7,11-This compound was prepared via general procedure B using 3.30 g (0.083 mole) of sodium hydride (60% dispersion in o i l ) , 30.5 g of crude B-keto ester 214, and 11.5 mL (0.08 mole) of diethyl chlorophosphate. Work-up of the reaction mixture gave a quantitative yield of a yellow o i l which was used without further purification in the preparation of s i l y l ester 220. Preparative t i c of a small amount of this material using petroleum ether-ethyl acetate (1:1) gave 217 as a colourless o i l ; bp (Kugelrohr di s t i l l a t i o n ) 140°C/0.1 Torr; i r (CHC13): 1715, 1670, and 4H), 4.63 (s, IH), 4.95-5.25 (bt, 2H), and 5.40 (s, IH); mass spectrum, m/e: 500(M+, 2), 357(22), 238(17), 220(38), 155(61), 136(16), 127(20), 109(30), 99(19), 81(22), 70(75), 69(25), 57(100), 55(18), 43(23), and 41(47). Anal, calcd. for C 2 7 H 4 9 O 6 P : C 64.78, H 9.87; found: C 64.57, H 9.90. dimethyl-2,6,10-dodecatrienoate (217) 1030 cm"1; *H nmr (CDC13) 6: 1.01 (s, 18H), 1.36 (dt, J C H 2 C H 3 = 7 H Z ' iP0CH 2CH 3 = 1 H z ' 6H>> !- 6 2 <bs> 6 H>» ! « 6 9 < b s» 3 H)» 1.90-2.16 (m, 4H), 2.25-2.55 (m, 4H), 4.26 (dq, J C H 2 C H 3 = 7 Hz, Jp 0 CH 2 = 7 Hz, - 150 -2-Propyl (2Z,6E)-7,1l-dlmethyl-3-[(trlmethylsilyl)methyl]-2,6,10-dodecatrienoate (218) This compound was prepared according to general procedure C using 3.40 g (0.14 mole) of magnesium turnings, 21.4 mL (0.154 mole) of trimethylsilylmethyl chloride, 0.45-0.90 g (1.8-3.5 mmole) of anhydrous nickel(II) acetylacetonate, and 31 g of crude enol phosphate 215. A further portion of 0.45-0.90 g (1.8-3.5 mmole) of catalyst was added immediately after addition of the enol phosphate, and the reaction was stirred at room temperature for one hour. Work-up of the reaction mixture gave 27 g of crude product which was purified by flash chromatography using petroleum ether-ethyl acetate (30:1) as eluant to yield 17.0 g (70% from isopropyl acetoacetate) of 218 as a yellow o i l . Preparative t i c of a small amount of this material using petroleum ether-ethyl acetate (20:1) gave 218 as a colourless o i l ; bp (Kugelrohr d i s t i l l a t i o n ) 130°C/0.1 Torr; i r ( C H C 1 3 ) : 1700, 1630, 1220 , 1170, 1115, and 850 cm-1; 1n nmr (CDCI3 ) 6: 0.08 (s, 9 H ) , 1.27 (d, J - 6 Hz, 6 H ) , 1.64 (s, 6 H ) , 1.71 (s, 3H), 1.97-2.30 (m, 8 H ) , 2 . 4 5 (s, 2 H ) , 4.85-5.25 (m, 3H), and 5 .54 (s, IH); mass spectrum, m/e: 350(M+, 5 ) , 281(7), 239(15), 223(10), 156(7), 149(29), 81(14), 75(26), 73 (100) , 69(50), 43(17), and 41 (49) . Anal, calcd. for C 2 i H 3 8 0 2 S i : C 71 .94, H 10.92; found: C 72 .20, H 1 0 . 9 9 . - 151 -2,2-Dimethylpropyl (2Z,6E)-7,ll-dimettayl-3-[(trimethylsilyl)methyl]-2,6,10-dodecatrienoate (219) This compound was prepared via general procedure C using 0.377 g (16 mmole) of magnesium turnings, 2.63 mL (17 mmole) of trimethylsilyl-methyl chloride, 0.050-0.10 g (0.19-0.33 mmole) of anhydrous nickel(II) acetylacetonate, and 3.44 g of crude enol phosphate 216. A further portion of 0.050-0.10 g (0.19-0.33 mmole) of catalyst was added immediately after addition of the enol phosphate, and the reaction was stirred at room temperature for one hour. Work-up of the reaction mixture gave 2.7 g of crude product which was purified by flash chromatography using petroleum ether-ethyl acetate (40:1) as eluant to give 1.92 g (66% from 8-keto ester 213) of 219 as an orange o i l . Preparative t i c of a small amount of this material using petroleum ether-ethyl acetate (30:1) gave 219 as a viscous liquid; bp (Kugelrohr d i s t i l l a t i o n ) 120°C/0.1 Torr; i r (CHC13): 1690, 1620, 1240, 1150, and 850 cm-1; XH nmr (CDC13) 6: 0.10 (s, 9H), 0.98 (s, 9H), 1.64 (s, 6H), 1.73 (s, 3H), 1.92-2.30 (m, 8H), 2.47 (s, 2H), 3.80 (s, 2H), 4.98-5.25 (m, 2H), and 5.62 (s, IH); mass spectrum, m/e_: 378(M+, 22), 309(20), 239(35), 223(17), 149(38), 82(15), 81(19), 75(32), 73(100), 71(25), 69(51), 55(15), 43(45), and 41(27). Anal, calcd. for C 23Hi t 202Si: C - 152 72.95, H 11.18; found: C 73.13, H 11.15. 2,2,4,4-Tetramethyl-3-pentyl (2£,6E)-7,ll-dimethyl-3-[(trimethylsilyl) methyl1-2,6,10-dodecatrienoate (220) This compound was prepared according to general procedure C using 1.94 g (0.080 mole) of magnesium turnings, 12.2 mL (0.088 mole) of trimethylsilylmethyl chloride, 0.25-0.50 g (1.0-2.0 mmole) of anhydrous nickel(II) acetylacetonate, and 20 g of crude enol phosphate 217. The reaction mixture was stirred at room temperature for 2 h with no further addition of catalyst. Work-up of the reaction mixture, and purification by flash chromatography using petroleum ether-ethyl acetate (40:1) gave 12.20 g of 220 as a yellow liquid (70% for 3 steps from 8-keto ester 211). Preparative t i c of a small amount of this material using the above solvent mixture gave 220 as a colourless o i l ; bp (Kugelrohr d i s t i l l a t i o n ) 120°C/0.1 Torr; i r (CHC13): 1690, 1620, 1155, and 850 cm-1; XH nmr (CDC13) 6: 0.08 (s, 9H), 1.03 (s, 18H), 1.64 (s, 6H), 1.72 (s, 3H), 1.97-2.28 (m, 8H), 2.51 (s, 2H), 4.59 (s, IH), 4.98-5.26 (m, 2H), and 5.62 (s, IH); mass spectrum, m/e: 434(M+, 0.1), 308(26), 293(18), 292(14), 291(40), 239(18), 109(20), 73(85), 71(16), 69(45), 57(100), and 41(30). Anal, calcd. for C27H 5o0 2Si: C 74.59, H 11.59; found: C 74.28, H 11.75. - 153 -General Procedure E. Formation of Epoxides from Terminal  Bromohydrlns (69) A solution of 1.0 equiv. of the olefin in THF-H20 (5 :1 ) (6 mL/mmole of olefin) was stirred at 10°C in the dark. To this solution was added NBS ( 1 0 2 ) ( 1 .1 equiv.) in small portions, and the reaction was stirred for 16 h while allowing i t to warm to room temperature. The reaction was diluted with ether, washed three times with saturated NaCl, dried, and the solvent was removed. The crude bromohydrin was dissolved in anhydrous methanol and cooled to 0°C. Anhydrous potassium carbonate ( K 2 C O 3 ) (2.5 equiv.) was added to the reaction and the mixture was stirred for 15-30 min at 0°C, while monitoring the reaction by t i c . The reaction was diluted with ether, acidified with 1 M H C 1 , and the organic phase was washed once with 1 M HC1 and three times with saturated NaCl. The aqueous washings were extracted three times with ether, the combined organic layers were dried, and the solvent was removed. Frequently the residue contained water, and was dissolved in ether, dried a second time, and the solvent was removed. Methyl (2£,6E)-10,11-epoxy-7,1l-dimethyl-3-[(trimethylsllyl)methyl]-2,6-dodecadienoate (194) This compound was prepared according to general procedure E using - 154 -3.50 g (0.011 mole) of diene 172 and 2.13 g (0.012 mole) of NBS in 70 mL of a 5:1 solution of THF-H20. The crude bromohydrin 202 obtained was moderately unstable, and was converted to epoxide 194 using 3.80 g (0.028 mole) of K2CO3 In anhydrous methanol. Work-up of the reaction mixture and purification of the crude product by flash chromatography using petroleum ether-ethyl acetate (15:1) as eluant gave 1.70 g (46%) of epoxide 194. The spectral data of the compound i s in good agreement with that obtained previously. 2-Propyl (2£,6E)-10,ll-epoxy-7,ll-dimethyl-3-l(trimethylsilyl)methyl]-2,6-dodecadienoate (224) This compound was prepared according to general procedure E using 10.3 g (0.029 mole) of diene 218_ and 5.76 g (0.032 mole) of NBS in 175 mL of a 5:1 solution of THF-H2O. Work-up of the reaction gave 13.3 g of crude bromohydrin 221 which was used without further purification in the formation of epoxide 224. Partial purification of a small amount of compound 221 by flash chromatography using petroleum ether-ethyl acetate (4:1) as eluant gave bromohydrin 221 as a viscous pale yellow o i l which decomposed upon d i s t i l l a t i o n ; i r ( C H C I 3 ) : 3600, 1700, 1630, 1255, 1215, 1170, 1115, and 855 cm-1; XH nmr ( C D C I 3 ) 6: 0.11 (s, 9 H ) , 1.30 (d, J = 6 - 155 -Hz, 6 H ) , 1.35 (s, 6 H ) , 1.67 (bs, 3 H ) , 1.90-2.35 (m, 8 H ) , 2.24 (bs, IH, exchangeable with D 20), 2.48 (s, 2H), 3.70-3.92 (m, IH), 4.85 -5 .35 (m, 2H), and 5 . 5 4 (s, IH); mass spectrum, m/e: 448(M+, 2), 446(M+, 2), 402(8), 239(13), 214(16), 135(23), 107(31), 93(22), 82(23), 81(56), 75(28), 73(100), 71(23), 69(21), 59(20), 55(23), 43(67), and 41 (37) . Exact Mass calcd. for C 2 i H 3 9 7 9 B r 0 3 S i : 446.1852; found (ms): 446.1835. The crude bromohydrin 221 was converted to epoxide 224 using 10.1 g (0.074 mole) of K2CO3 in anhydrous methanol. Work-up of the reaction mixture and purification of the crude product by flash chromatography using petroleum ether-ethyl acetate (15:1) as eluant gave 6.0 g (56%) of epoxide 224. Preparative t i c of a small amount of this material using petroleum ether-ethyl acetate (8:1) as eluant gave 224 as a colourless liquid; bp (Kugelrohr d i s t i l l a t i o n ) 160°C/0.15 Torr; i r ( C H C I 3 ) : 1700, 1625, 1255, 1210, 1170, 1110, and 850 cm-1; XH nmr (CDCI3) 6: 0.08 (s, 9 H ) , 1.29 (d, J = 6 Hz, 6 H ) , 1.30 (s, 3 H ) , 1.34 (s, 3 H ) , 1.65 (s, 3 H ) , 1.55-1.80 (m, 2H), 2.00-2.30 (m, 6 H ) , 2.44 (s, 2H), 2 .73 (t, J = 6 Hz, IH), 5.00 (septet, J = 6 Hz, IH), 5.00-5.27 (m, IH), and 5.51 (s, IH); mass spectrum, m/e: 366(M+, 5 ) , 239(11), 149(16), 107(18), 81(18), 75(26), 73(100), 71(18), 59(17), 4 3 ( 3 9 ) , and 41(16). Anal, calcd. for c 2 1 H 3 8 ° 3 S i : c 68.80, H 10 .45; found: C 68.92, H 10 .39. - 156 -2,2H)imethylpropyl (2£,6E)-l0,1l-epoxy-7,11-dimethy1-3-[(trimethylsilyl)i»ethyl]-2,6-dodecadienoate (225) ^ S i M e 3 This compound was prepared according to general procedure E using 1.13 g (3.0 mmole) of diene 219_ and 0.590 g (3.3 mmole) of NBS in 20 mL of a 5:1 solution of THF-H2O. Work-up of the reaction gave a quantitative yield of crude bromohydrln 222 which was used without further purification in the preparation of epoxide 225. Purification of a small amount of the bromohydrln by flash chromatography using petroleum ether-ethyl acetate (6:1) as eluant gave 222 as a viscous pale yellow liquid; i r ( C H C 1 3 ) : 3580, 1700, 1625, 1250, 1210, 1160, and 860 cm-1; *H nmr (CDCI3) 6: 0.09 (s, 9H ) , 0.99 (s, 9 H ) , 1.38 (s, 6H), 1.65 (s, 3H), 1.85-2.35 (m, 8H), 2.21 (bs, IH, exchangeable with D 20), 2.47 (s, 2H), 3.80 (s, 2H), 3.97 (dd, J = 9 Hz, 3 Hz, IH), 5.08-5.30 (m, IH), and 5.58 (s, IH); mass spectrum, m/e: 476(M+, 5), 474(M+, 4), 307(11), 242(13), 172(17), 135(20), 81(23), 75(22), 73(100), 71(26), 59(22), 43(66), and 41(15). Exact Mass calcd. for C ^ H ^ ^ B ^ S i : 476.2144; found (ms): 476.2151; calcd. for C 23H l t 3 7 9Br0 3Si: 474.2165; found (ms): 474.2160. The crude bromohydrin 222 was converted into epoxide 225 using - 157 -1.04 g (7.5 mmole) of K2CO3 in anhydrous methanol. Work-up of the reaction mixture and purification of the crude product by flash chromatography using petroleum ether-ethyl acetate (20:1) as eluant gave 0.64 g (54%) of epoxide 225. Preparative t i c of a small amount of this material using the same solvent system gave 225 as a colourless liquid; bp (Kugelrohr d i s t i l l a t i o n 130°C/0.1 Torr; i r ( C H C 1 3 ) : 1700, 1625, 1260, 1220 , 1160, and 860 cm-1; *H nmr ( C D C 1 3 ) 6: 0.09 (s, 9 H ) , 0 . 9 9 (s, 9 H ) , 1.31 (s, 3 H ) , 1 .35 (s, 3H ) , 1.69 (bs, 3H ) , 1.59-1.81 (m, 2 H ) , 2.04-2.31 (m, 6 H ) , 2 . 4 7 (s, 2 H ) , 2 . 74 (t, J = 6 Hz, 1 H ) , 3.80 (s, 2 H ) , 5.09-5.30 (m, IH), and 5 .59 (s, IH); mass spectrum, m/e: 394(M +, 7 ) , 3 7 9 ( 1 0 ) , 239(14), 149(20), 135(17), 121(16), 107(23), 85(17), 82(16), 81(24), 75(26), 7 3 ( 1 0 0 ) , 71 (43), 69(17), 67(17), 55(17), 43(89), and 41(23). Anal, calcd. for 0 2 3 ^ 2 0 3 8 1 : C 70 .00, H 1 0 . 7 3 ; found: C 69.83, H 10.80. 2,2,4,4-Tetramethyl-3-pentyl (2Z^6E)-l0,1l-epoxy-7,1l-dimethyl-3-[(trimethylsilyl)methyl]-2,6-dodecadienoate (226) / S i M e 3 This compound was prepared via general procedure E using 13.5 g (0.031 mole) of diene 220_ and 6.07 g (0.034 mole) of NBS in 180 mL of a 5:1 solution of THF-H20. Work-up of the reaction mixture gave bromohydrln 223 which was converted, without purification, into epoxide - 158 -226. Purification of a small amount of the bromohydrin by flash chromatography using petroleum ether-ethyl acetate (4:1) as eluant gave 223 as a viscous yellow o i l ; i r (CHC13): 3600, 3450, 1700, 1630, 1380, 1255, 1160, and 860 cm"1; ^ nmr (CDC13) 6: 0.07 (s, 9H), 1.01 (s, 18H), 1.36 (s, 6H), 1.64 (bs, 3H), 1.75-2.30 (m, 8H), 2.20 (bs, IH, exchangeable with D 20), 2.50 (s, 2H), 3.97 (dd, J = 9 Hz, 3 Hz, IH), 4.57 (s, IH), 5.07-5.30 (m, IH), and 5.59 (s, IH); mass spectrum, m/e: 532(M+, 0.1), 530(M+, 0.1), 435(5), 371(13), 309(25), 308(27), 307(100), 239(59), 197(35), 189(38), 172(31), 149(32), 147(27), 135(60), 127(35), 125(34), 121(36), 119(32), 107(46), 82(35), 81(53), 75(52), 73(74), 71(84), 69(40), and 57(68). Exact Mass calcd. for C 27H 5 1 8 1Br03Si: 532.2770; found (ms): 532.2756; calcd. for C 2 7H 5 1 7 9Br03Si: 530.2791; found (ms): 530.2742. The crude bromohydrin 223 was converted to epoxide 226 using 10.7 g (0.078 mole) of K2C03 in anhydrous methanol. Work-up of the reaction mixture and purification by flash chromatography using petroleum ether-ethyl acetate (30:1) as eluant gave 7.9 g (57%) of epoxide 226. Preparative t i c of a small amount of this material using the same solvent system gave 226 as a colourless liquid; bp (Kugelrohr d i s t i l l a t i o n 130°C/0.1 Torr; i r (CHCI3): 1700, 1625, 1160, and 860 cm"1; ln nmr (CDC13) 6: 0.07 (s, 9H), 1.03 (s, 18H), 1.28 (s, 3H), 1.32 (s, 3H), 1.67 (bs, 3H), 1.55-1.80 (m, 2H), 2.05-2.22 (m, 6H), 2.51 (s, 2H), 2.73 (t, J - 6 Hz, IH), 4.58 (s, IH), 5.15-5.30 (bt, IH), and 5.59 (s, IH); mass spectrum, m/e: 450(M+, 1), 307(9), 239(10), 197(14), 135(12), 125(13), 109(14), 107(13), 75(16), 73(89), 71(27), 57(100), 43(30), and - 159 -41(19). Anal, calcd. for C27H 5 0O 3Si: C 71.94, H 11.18; found: C 71.66, H 11.33. General Procedure F. Cyclisation of Epoxy Allylsilanes A solution of the epoxy allyls i l a n e (1.0 equiv.) in dry CH 2C1 2 (30 mL per mmole of allylsilane) was cooled to 0°C and to this solution was added the desired amount of acetic acid while stirring under nitrogen. The Lewis acid was slowly added as a solution in CH2CI2 and the reaction was either stirred for 1-4 h at 0°C, or was allowed to warm to room temperature. The mixture was quenched with aqueous KF, diluted with ether, and the organic layer was washed three times with aqueous KF, once with saturated NaCl, dried, and the solvent was removed. Methyl trans-decahydro—6B-hydroxy-5,5,8ap-trlmethyl-2-methylene—1£-naphthalenecarboxylate (203a), (203b) COOMe These compounds were prepared according to general procedure F using 1.35 g (4.0 mmole) of compound 194 and 0.56 mL (4.8 mmole) of stannic chloride. The reaction was stirred for 3 h while allowing i t to warm to room temperature. Work-up of the reaction mixture gave 1.14 g of crude product which was purified by flash chromatography using - 160 -petroleum ether-ethyl acetate (6:1) as eluant to yield 0.579 g (54%) of 203 [203a:203b = 1:1.5, as determined by *H nmr spectroscopy and gc (T = 180°C)]. Preparative t i c of a small amount of this mixture using the same solvent system gave 203 as a viscous o i l ; bp (Kugelrohr d i s t i l l a t i o n ) 150°C/0.1 Torr; i r (CHC13): 3630, 3460, 1730, 1650, and 1160 cm-1; XH nmr (400 MHz) (CDCA3) 6: 0.77 (s, 1.2H), 0.80 (s, 1.8H), 0.92 (s, 1.2H), 1.00 (s, 1.8H), 1.04 (s, 1.2H), 1.06 (s, 1.8H), 1.25-1.76 (m, 7H), 1.95-2.16 (m, IH), 2.28 (bd, J = 10 Hz, IH, exchangeable with D 20), 2.39-2.46 (m, 0.6H), 2.53-2.63 (m, 0.4H), 2.74 (s, 0.6H), 2.76 (s, 0.4H), 3.25 (dd, J = 11 Hz, 5 Hz, IH), 3.62 (s, 1.2H), 3.64 (s, 1.8H), 4.66 (s, 0.6H), 4.73 (s, 0.4H), and 5.03 (s, IH); mass spectrum, m/e: 266(M+, 46), 248(27), 139(27), 135(100), 134(22), 121(28), 119(31), 114(28), 107(38), 105(24), 97(21), 95(29), 93(28), 91(24), 79(22), 69(26), 67(22), 55(34), 43(52), and 41(56). Exact Mass calcd. for C 1 6H 2603: 266.1882; found (ms): 266.1881. 2-Propyl trans—decahydro-66-hydroxy-5,5,8aB-trimethyl-2-nethylene—1£-naphthalenecarboxylate (227a), (227b) These compounds were prepared via general procedure F using 2.67 g (7.4 mmole) of compound 224 and 1.04 mL (8.9 mmole) of stannic - 161 -chloride. The reaction was stirred for 3 h while allowing i t to warm to room temperature. Work-up of the reaction mixture and purification by flash chromatography using petroleum ether-ethyl acetate (6:1) as eluant gave 1.11 g (51%) of 227_ [227a:227b = 1:2, as determined by *H nmr spectroscopy and gc (T = 200°C)]. Preparative t i c of a small amount of this mixture using petroleum ether-ethyl acetate (8:1) gave 227 as a very viscous o i l ; bp (Kugelrohr d i s t i l l a t i o n ) 145°C/0.1 Torr; i r (CHC13): 3630, 3500, 1730, 1655, 1180, and 1010 cm-1; XH nmr (CDC13) 6: 0.82 (s, IH), 0.85 (s, 2H), 0.96 (s, IH), 1.04 (s, 2H), 1.08 (s, IH), 1.11 (s, 2H), 1.27 (d, J = 6 Hz, 6H), 1.3-2.58 (m, 9H), 2.75 (bs, IH), 3.29 (bs, IH, exchangeable with D 20), 3.32 (dd, J = 10 Hz, 6 Hz, IH), 4.69-4.80 (m, IH), 4.85 (bs, IH), and 5.04 (septet, J = 6 Hz, IH); mass spectrum, m/e: 295(14), 294(M+, 59), 234(30), 189(27), 135(75), 133(28), 121(28), 119(36), 107(38), 105(26), 100(33), 95(31), 93(29), 91(26), 81(25), 79(26), 69(39), 55(36), 43(100), and 41(70). Anal, calcd. for C18H30O3: C 73.43, H 10.27; found: C 73.28, H 10.18. 2,2-Dimethylpropyl trans-decahydro-6B-bydroxy-5,5,8aB-triraethyl-2-methylene-lS-naphthalenecarboxylate (228a), (228b) These compounds were prepared according to general procedure F COOv^X - 162 -using 0.099 g (0.25 mmole) of 225_, 1.4 uL (0.025 mmole) of acetic acid, and 0.032 mL (0.275 mmole) of stannic chloride. The reaction was stirred at 0°C for 2 h. Work-up of the reaction and purification by flash chromatography using petroleum ether-ethyl acetate (8:1) gave 0.040 g (50%) of 228 [228a:228b = 1:3, as determined by XH nmr spectroscopy and gc (T = 230°C)]. Preparative t i c of a small sample of this mixture using petroleum ether-ethyl acetate (6:1) gave 228 as an extremely viscous o i l ; bp (Kugelrohr d i s t i l l a t i o n ) 140°C/0.1 Torr; i r (CHC13): 3620, 3450, 1730, 1655, and 1160 cm-1; 2H nmr (CDC13) 6: 0.81 (s, 0.75H), 0.84 (s, 2.25H), 0.96 (s, 0.75H), 0.98 (s, 9H), 1.04 (s, 2.25H), 1.07 (s, 0.75H),1.10 (s, 2.25H), 1.1-2.45 (m, 9H), 1.57 (s, IH, exchangeable with D 20), 2.80 (bs, IH), 3.15-3.40 (m, IH), 3.72 (s, 0.50 H), 3.78 (s, 1.50H), 4.68-4.75 (m, 0.75H), 4.75-4.79 (m, 0.25H), and 4.82-4.89 (m, IH); mass spectrum, m/e: 322(M+, 10), 234(15), 189(17), 135(42), 119(23), 107(26), 93(20), 91(21), 71(37), 55(28), 44(100), 43(60), and 41(51). Anal, calcd. for C20H34O3: C 74.49, H 10.63; found: C 74.47, H 10.78. 2,2,4,4-Tetramethyl-3-pentyl trans-decahydro-6 B-hydroxy-5,5,8aB-trimethyl-2-methylene—l£-naphthalenecarboxylate (229a), (229b) These compounds were prepared via general procedure F using 0.62 - 163 -g (1.4 mmole) of compound 226, 7.8 uL (0.14 mmole) of acetic acid, and 0.18 mL (1.5 mmole) of stannic chloride. The reaction was stirred at 0°C for 2 h. Work-up of the reaction mixture and purification by flash chromatography using petroleum ether-ethyl acetate (8:1) as eluant gave the following compounds in order of elution: (a) a mixture (0.118 g, 19%) of at least four acyclic compounds whose structures were not assigned unambiguously; Rf 0.85-1.00. The mixture of compounds was further purified by flash chromatography using petroleum ether-ethyl acetate (50:1) as eluant. One compound was isolated in 5% yield (31 mg) and was tentatively assigned the structure 230; Rf 0.50; i r (CHC13): 1710, 1700, 1630, and 1160 cm-1; *H nmr (CDC13) 6: 0.00 (s, 9H), 0.96 (s, 18H), 1.06 (d, J = 6 Hz, 6H), 1.59 (s, 3H), 1.2-2.7 (m, 9H), 2.46 (s, 2H), 4.54 (s, IH), 5.00-5.25 (m, IH), and 5.56 (s, IH); mass spectrum, m/e: 450(M+, 1), 435(2), 309(10), 307(20), 239(37), 127(22), 125(19), 121(14), 81(11), 75(16), 73(77), 71(33), 69(15), 57(100), 55(15), 43(42), and 41(21). Exact Mass calcd. for C27H50O3S1: 450.3529; found (ms): 450.3506. (b) a mixture (0.118 g, 19%) of at least seven compounds whose structures were not assigned. Rf 0.42-0.55. The mixture of compounds was further purified by flash chromatography using petroleum ether-ethyl acetate (15:1) as eluant. Three compounds were isolated and tentatively assigned the following structures: - 164 -(i) monocyclic hydroxy ester 231 (0.043 g, 7%); Rf 0.4; i r ( C H C 1 3 ) : 3630, 3480, 1700, 1630, and 1160 cm-1; XH nmr (CDCI3): 0.05 (s, 9H), 0.89 (s, 3H), 1.00 (s, 21H), 1.37(s IH, exchangeable with D 20), 1.76 (s, 3H), 1.2-2.7 (m, 7H), 2.49 (s, 2H), 3.48 (m, IH), 4.57 (s, IH), 5.18-5.37 (m, IH), and 5.59 (s, IH); mass spectrum, m/e: 450(M+, 0.5), 307(11), . 235(12), 234(11), 199(13), 172(19), 135(15), 73(52), 71(20), 57(100), and 55(12). Exact Mass calcd. for C 27H 5 0O 3Si: 450.3529; found (ms): 450.3540. ( i i ) monocyclic hydroxy ester 232 (0.025 g, 4%); Rf 0.3; i r (CHCI3): 3630, 3470, 1700, 1630, 1380, and 1160 cm-1; XH nmr (CDCI3) 6 : 0.06 (s, 9H), 1.01 (s, 21H), 1.11 (s, 3H), 1.66 (s, 3H), 1.3-2.3 (m, 9H, IH exchangeable with D 20), 2.53 (s, 2H), 3.40-3.60 (m, IH), 4.60 (s, IH), and 5.60 (s, IH); mass spectrum, m/e: 450(M+, 1), 252(26), 235(31), 234(21), 189(24), 135(23), 127(11), 119(15), 107(13), 95(12), 84(10), 81(11), 73(17), 71(25), 69(14), 57(100), and 55(13). Exact Mass calcd. for C27H5o03Si: 450.3529; found (ms): 450.3528. ( i i i ) monocyclic hydroxy ester 233_ (0.016 g, 3%); Rf 0.25; i r (CHCI3): 3640, 3460, 1725, 1660, 1380, and 1165 cm-1; XH nmr (CDCI3) 6: 0.84 (s, 3H), 1.02 (s, 18H), 1.12 (s, 3H), 1.2-2.6 (m, 10H, IH exchangeable with D 20), 2.83 (bs, 2H), 3.18-3.48 (m, IH), 4.61 (s, IH), 4.77 (bs, 2H), and 4.89 (bs, 2H); mass spectrum, m/e: 378(M+, 1), 363(5), 252(11), - 165 -235(53), 234(25), 189(32), 139(12), 135(30), 133(11), 129(17), 121(10), 119(18), 107(12), 95(12), 81(11), 71(31), 69(14), 57(100), and 55(13). Exact Mass calcd. for C 2 4 H 4 2 ° 3 : 378.3134; found (ms): 378.3131. (c) alcohols 229 (0.287 g, 55%) [229a:229b - 1:3, as determined by 1H nmr spectroscopy and gc (T - 250°C)]; Rf 0.29. Preparative t i c of a small sample of this mixture using petroleum ether-ethyl acetate (6:1) gave 229_ as a white foam; bp (Kugelrohr d i s t i l l a t i o n ) 145°C/0.1 Torr; i r (CHC13): 3630, 3460, 1720, 1660, 1375, and 1165 cm-1; XH nmr (CDCI3) 6: 0.79 (s, 0.75H), 0.82 (s, 2.25H), 0.93 (s, 0.75H), 0.95 (s, 2.25H), 0.98 (s, 6.75H), 1.00 (s, 4.5H), 1.03 (s, 6.75H), 1.05 (s, 0.75H), 1.11 (s, 2.25H), 1.17-2.55 (m, 10H, IH exchangeable with D 20), 2.82 (bs, IH), 3.07-3.44 (m, IH), 4.54 (s, 0.25H), 4.59 (s, 0.75H), 4.75 (bs, IH), and 4.86(bs, IH); mass spectrum, m/e: 378 (M+, 4), 252(38), 234(27), 233(22), 189(31), 135(21), 127(18), 119(18), 71(31), 57(100), and 41(21). Anal, calcd. for C ^ i t H i ^ s : C 76.14, H 11.18; found: C 76.30, H 11.30. Methyl trans—decahydro—5,5,8a8-trlmethy1-2-methylene—6-oxo-1\— naphthalenecarboxylate (206) COOMe A suspension of 0.310 g (1.5 mmole) of pyridinium chlorochromate, -166 -0.040 g (0.48 mmole) of anhydrous sodium acetate, and 0.250 g (1% w/v of solvent) of 4 A molecular sieves (dried and crushed) was stirred rapidly in 25 mL of CH2CI2 at room temperature (82). To this suspension was added 0.258 g (0.97 mmole) of alcohols 203_ [203a:203b = 1:1.44, as determined by gc (T = 180°C)] and the reaction was stirred for 2 h at room temperature. The reaction mixture was diluted with ether, stirred for 5 min, and the supernatant was passed through a F l o r i s i l column (2.5 g F l o r i s i l ) which had a layer of MgSO^ on the top. The dark brown residue was washed with ether, the ethereal extracts were passed through the column, eluted with ether, and the combined eluate was concentrated to give 0.250 g of 206 [206a:206b = 1:1.44, as determined by gc (T = 170°C)]. Further purification by flash chromatography using petroleum ether-ethyl acetate (15:1) as eluant gave 0.228 g (89%) of 206 as an o i l ; bp (Kugelrohr d i s t i l l a t i o n ) 120°C/0.1 Torr; i r (CHCI3): 1735, 1705, 1650, and 1160 cm-1; lU nmr (CDC13) 6: 1.05 (s, 1.2H), 1.08 (s, 1.8H), 1.12 (s, 1.8H), 1.15 (s, 2.4H), 1.30 (s, 1.8H), 1.45-1.95 (m, 5H), 2.15-2.96 (m, 5H), 3.64 (s, 1.2H), 3.69 (s, 1.8H), 4.72 (bs, 0.6H), 4.81 (bs, 0.4H), and 4.92 (bs, IH); mass spectrum, m/e_: 264 (M+, 86), 249(55), 246(35), 232(68), 217(33), 199(42), 161(49), 148(39), 147(54), 135(32), 133(100), 125(37), 123(49), 121(41), 120(41), 119(52), 114(36), 109(51), 107(73), 105(53), 95(65), 93(45), 91(67), 81(57), 79(55), 77(39), 69(61), 68(56), 59(35), 55(82), and 53(38). Exact Mass calcd. for C 1 6H 2i t0 3: 264.1725; found (ms): 264.1727. - 167 -Methyl trans-decahydro-5,5,8aB-trlmethyl-2-raethylene-lt~-naphthalenecarboxylate (173) via removal of the carbonyl at C-6 To a solution of 0.053 g (0.20 mmole) of ketones 206 in 2 mL of dry ethanol was added 0.041 g (0.22 mmole) of jr-toluenesulphonyl-hydrazine. The reaction mixture was heated at reflux for 4 h, cooled, and the solvent was removed (84) to yield p-toluenesulphonylhydrazones 207 as a crystalline solid which was used without purification in the formation of compounds 173; i r (CHC13): 1730, 1600, and 1160 cm-1. To a solution of tosylhydrazones 207 in chloroform (dried and d i s t i l l e d from CaCl2) was added 0.026 g (0.22 mmole) of catecholborane at 0°C (83). The reaction was stirred for 1.5 h at 0°C; 0.082 g (0.60 mmole) of sodium acetate trihydrate was added, and the mixture was stirred at room temperature overnight. The reaction was diluted with ether, washed twice with saturated NaCl, dried, and the solvent was removed. Purification by flash chromatography using petroleum ether-ethyl acetate (10:1) gave 0.035 g (71%) of compounds 173 [173a:173b = 1.00:1.42, as determined by gc (T = 130°C)]. The gc retention times were identical with those of an authentic sample of epimeric esters 173. - 168 -G. Synthesis of (±)-3-flydroxylabda-8(20),13-dien-15-oic Acid (238) Methyl trans—decahydro-6B-[ (jt-butyldimethylsilyl)oxy]-5,5,8aB-trimethyl-2-methylene-lJ;-naphthalenecarboxylate (241a), (241b) To a solution of 0.709 g (10 mmole) of imidazole and 0.751 g (5.0 mmole) of freshly sublimed t-butyldimethylsilyl chloride (70°C/H20 aspirator) in the minimum volume of DMF was added 1.11 g (4.2 mmole) of alcohols 203 (203a:203b = 1:1.5). The reaction was stirred at room temperature for 4 days, then diluted with ether, washed four times with saturated NaCl, and dried. The solvent was removed to give 1.48 g (93%) of s i l y l ethers 241 which were used without further purification in the preparation of alcohols 245a and 245b. Purification of a small amount of these compounds by preparative t i c using petroleum ether-ethyl acetate (40:1) as eluant gave 241 (241a:241b = 1:1.5, as determined by Hi nmr spectroscopy) as a colourless liquid; bp (Kugelrohr d i s t i l l a t i o n ) 135°C/0.1 Torr; i r ( C H C 1 3 ) : 1730, 1650, 1160, 1100 , and 835 cm-1; *H nmr (CDCI3 ) 6: 0.07 (s, 6 H ) , 0.78 (s, 1 . 2 H ) , 0.82 (s, 1 . 8 H ) , 0.92 (s, 9 H ) , 0 . 9 5 (s, 3H), 1 .00 (s, 1 . 8 H ) , 1.09 (s, 1 . 2 H ) , 1.18 -2.44 (m, 9 H ) , 2 . 7 9 (bs, IH), 3.26 (dd, J = 9 Hz, 5 Hz, IH), 3.66 (s, 3H), 4.65-4.80 (m, C O O M e - 169 -IH), and 4.85 (bs, IH); mass spectrum, m/e: 380 (M+, 6), 324(31), 323(100), 247(14), 189(35), 147(13), 133(15), 119(14), 107(14), 95(17), 81(12), 75(68), and 73(35). Anal, calcd. for C2 Hi+o03Si: C 69.42, H 10.59; found: C 69.33, H 10.78. General Procedure G. Formation of t-Butyldiraethylsilyl Ethers (92) To a solution of the alcohol in CH2CI2 (1 mL solvent per mmole of alcohol) was added 2,6-dimethylpyridine (2.0-2.5 equiv.) at 0°C under nitrogen. After 5 min, 1.5 equiv. of ^-butyldimethylsilyl trifluoro-methanesulphonate (TBDMS t r i f l a t e ) (92) was added, and the reaction was stirred for 15 min while allowing i t to warm to room temperature. The reaction was diluted with ether, washed three times with 1 M HC1, three times with saturated NaHC03, once with saturated NaCl, dried, and the solvent was removed. 2-Propyl trans-decahydro-6B-[(jt-butyldimethylsilyl)oxy]-5,5,8aB-trimethyl-2-methylene-lC-naphthalenecarboxylate (242a), (242b) These compounds were prepared according to general procedure G using 1.56 g (5.3 mmole) of alcohol 227_ (227a:227b = 1:2, as determined by % nmr spectroscopy), 1.30 mL (11 mmole) of 2,6-dimethylpyridine, and - 170 -1.83 mL (8.0 mmole) of TBDMS t r i f l a t e in 5 mL of CH2C12. Work-up of the reaction mixture gave 2.11 g (98%) of compounds 242 (242a:242b = 1:2, by *H nmr) which were used without further purification in the preparation of alcohols 245a and 245b. Purification of a small amount of this material by preparative t i c using petroleum ether-ethyl acetate (40:1) as eluant gave 242 (242a:242b = 3:1, by nmr spectroscopy) as a colourless o i l ; bp (Kugelrohr d i s t i l l a t i o n ) 140°C/0.15 Torr; i r (CHCI3): 1730, 1655, 1180, 1110, and 840 cm-1; XH nmr (CDCI3) 6: 0.09 (s, 6H), 0.79 (s, 2.25H), 0.82 (s, 0.75H), 0.93 (s, 9H), 0.96 (s, 3H), 1.00 (s, 2.25H), 1.12 (s, 0.75H), 1.26 (d, J = 6 Hz, 3H), 1.29 (d, J = 6 Hz, 3H), 1.2-2.45 (m, 9H), 2.73 (bs, IH), 3.26 (dd, J = 9 Hz, 6 Hz, IH), 4.68-4.80 (m, IH), 4.80-4.89 (m, IH) , and 4.85-5.15 (m, IH); mass spectrum, m/e: 408 (M+, 9), 352(24), 351(64), 291(22), 189(45), 135(15), 133(12), 119(15), 107(13), 95(14), 75(100), 73(50), 69(14), 43(38), and 41(20). Anal, calcd. for C^H^OgSi: C 70.53, H 10.85; found: C 70.77, H 11.01. A small amount of pure 242b was also obtained as a crystalline solid; mp 68-72°C; *H nmr (CDCI3) 6: 0.09 (s, 6H), 0.82 (s, 3H), 0.93 (s, 9H), 0.96 (s, 3H), 1.12 (s, 3H), 1.26 (d, J = 6 Hz, 3H), 1.29 (d, J = 6 Hz, 3H), 1.3-2.4 (m, 9H), 2.73 (bs, IH), 3.27 (dd, J = 9 Hz, 6 Hz, IH), 4.73 (bs, IH), 4.85 (bs, IH), and 5.07 (septet, J = 6 Hz, IH). - 171 -2,2-Dimethylpropyl trans— decabydro-6ft-[(t-butyldimetbylsllyl)oxy]-5,5,8a8-trimethyl-2-inethylene-l£-naphthalenecarboxylate (243a), (243b) These compounds were prepared via general procedure G using 0.280 g (0.87 mmole) of alcohols 228, 0.25 mL (2.2 mmole) of 2,6-dimethyl-pyridine, and 0.30 mL (1.3 mmole) of TBDMS t r i f late in 2 mL of CH2Cl2. Work-up of the reaction mixture gave 0.360 g (95%) of compounds 243 which were used without further purification in the preparation of alcohols 245a and 245b. Purification of a small amount of this material by preparative t i c using petroleum ether-ethyl acetate (20:1) as eluant gave pure 243b as a colourless o i l ; bp (Kugelrohr d i s t i l l a t i o n ) 130°C/0.1 Torr; i r (CHC13): 1730, 1650, 1170, 1100, and 840 cm-1; XH nmr (CDCI3) 6: 0.08 (s, 6H), 0.82 (s, 3H), 0.92 (s, 9H), 0.95 (s, 3H), 0.98 (s, 9H), 1.09 (s, 3H), 1.2-2.5 (m, 9H), 2.79 (bs, IH), 3.27 (dd, J = 9 Hz, 6 Hz, IH), 3.79 (s, 2H), 4.70 (bs, IH), and 4.84 (bs, IH); mass spectrum, m/e_: 436(M+, 9), 381(27), 380(65), 362(23), 291(60), 217(31), 189(97), 175(41), 147(38), 135(41), 133(36), 119(51), 117(30), 107(37), 105(38), 95(35), 75(100), 73(95), 71(60), 55(42), 44(95), and 43(90). Anal, calcd. for C^H^gOsSi: C 71.50, H 11.08; found: C 71.69, H 11.00. - 172 -2,2,4,4-Tetramethyl-3-pentyl trans-decahydro-6B-[(t-butyldimethylsilyl) oxy]-5,5,8aB-trimethy1-2-methylene-1£-naphthalenecarboxylate These compounds were prepared according to general procedure G using 0.80 g (2.1 mmole) of alcohols 229, 0.60 mL (5.1 mmole) of 2,6-dimethylpyridine, and 0.73 mL (3.2 mmole) of TBDMS t r i f l a t e in 3 mL of CH2Cl2. Work-up of the reaction mixture gave 1.0 g (99%) of compounds 244 which were used without further purification in the preparation of alcohols 245a and 245b. Purification of a small amount of this material by preparative t i c using petroleum ether-ethyl acetate (60:1) as eluant gave pure 244b as a colourless glass; bp (Kugelrohr d i s t i l l a t i o n ) 140°C/0.1 Torr; mp 116-118°C; i r (CHC13): 1720, 1660, 1160, 1100, and 835 cm-1; XH nmr (CDCI3) 6: 0.08 (s, 6H), 0.80 (s, 3H), 0.92 (s, 9H), 0.94 (s, 3H), 1.01 (s, 9H), 1.06 (s, 9H), 1.12 (s, 3H) , I. 25-2.60 (m, 9H), 2.81 (bs, IH), 3.27 (dd, J - 9 Hz, 6 Hz, IH), 4.60 (s, IH), 4.75 (bs, IH), and 4.86 (bs, IH); mass spectrum, m/e: 492(M+, 0.1), 309(6), 189(14), 91(17), 75(80), 73(41), 71(41), 69(21), 57(100), 55(44), 43(16), and 41(55). Anal, calcd. for C 3 0H56O 3Si: C 73.11, H II. 45; found: C 73.07, H 11.40. (244a), (244b) - 173 -trans-Decahydro-6B-[(t-butyldlmethylsllyl)oxy]-5,5,8aB-trlaethyl-2-methylene-15-naphthalenemethanol (245a), (245b) (i) From methyl esters 241. A standard solution of 0.20 M lithium diethoxyaluminium hydride [LiAlH2(OEt)2l was prepared by adding 0.35 mL (6.0 mmole) of anhydrous ethanol to a slurry of 0.114 g (3.0 mmole) of lithium aluminium hydride (LiAlHO in 15.0 mL of ether slowly, with s t i r r i n g , at 0°C (115). The reagent was stirred for 15 min at 0°C, then 6.0 mL (1.2 mmole) of the reducing agent was transferred by syringe into a flask, and a solution of 0.224 g (0.59 mmole) of methyl esters 241_ (241a;241b = 1:1.5) in ether was added at 0°C. The reaction was stirred for 1 h and was followed by t i c and gc (T = 250°C) to monitor the disappearance of the a-ester. .Two further 1 mL portions of the LiAlH2(0Et)2 solution were added to the reaction at 0°C, after which period most of the a-ester 241a had been reduced. The reaction was diluted with ether, quenched with 1 M HC1, the organic phase was washed twice with 1 M HC1, once with saturated NaCl, dried, and the solvent was removed. Purification by flash chromatography using petroleum ether-ethyl acetate (8:1) as eluant gave 100 mg (45%) of esters 241_ (241a:241b) = 1:5), 37 mg (18%) of - 174 -alcohol 245a, 50 mg (24%) of a 1:1 mixture of alcohols 245a and 245b, and 23 mg (11%) of alcohol 245b. The recovered ester 241 was reduced using 10 mg (2.6 mmole) of LiAlH^ in ether via a procedure similar to that used for ester 189. Work-up of the reaction and purification by flash chromatography using petroleum ether-ethyl acetate (5:1) as eluant gave 17 mg (16%) of alcohol 245a and 77 mg (83%) of alcohol 245b. Each alcohol was further purified by preparative t i c using petroleum ether-ethyl acetate (8:1) as eluant and the following spectral data was obtained: (a) alcohol 245a; Rf 0.46; bp (Kugelrohr d i s t i l l a t i o n ) 138°C/0.1 Torr; mp 83-84°C; i r (CHC13): 3560, 3480, 1650, 1100, and 840 cm-1; XH nmr (CDCI3) 6: 0.07 (s, 6H), 0.79 (s, 3H), 0.92 (s, 9H), 0.95 (s, 3H), 0.99 (s, 3H), 1.24-2.33 (m, 10H), 3.20 (dd, J = 9 Hz, 6 Hz, IH), 3.40-3.85 (m, 2H), 3.78 (bs, IH, exchangeable with D 20), 4.78 (bs, IH), and 4.95 (bs, IH). (b) alcohol 245b; Rf 0.37; bp (Kugelrohr d i s t i l l a t i o n ) 138°C/0.1 Torr; mp 65-67°C; i r (CHC13): 3620, 3450, 1650, 1100, and 840 cm-1; XH nmr (CDCI3) 6: 0.07 (s, 6H), 0.76 (s, 3H), 0.77 (s, 3H), 0.91 (s, 9H), 0.94 (s, 3H), 1.12-2.62 (m, 10H), 1.37 (bs, IH, exchangeable with D 20), 3.15-3.37 (m, IH), 3.65-3.90 (m, 2H), 4.66 (bs, IH), and 4.95 (bs, IH); mass spectrum, m/e: 352(M+, 1), 295(21), 147(13), 107(18), 105(24), 95(20), 81(15), 75(100), 73(34), and 69(15). Anal, calcd. for C ^ H ^ O ^ i : C 71.53, H 11.43; found: C 71.28, H 11.52. - 175 -( i i ) From isopropyl esters 242. Alcohols 245a and 245b were prepared according to the procedure for diol ^92 using 0.197 g (5.2 mmole) of LiAlH^ and 2.11 g of crude esters 242 (242a:242b = 1:2). Work-up of the reaction mixture and repeated separations of the crude product by flash chromatography using petroleum ether-ethyl acetate (8:1) as eluant gave 0.598 g (33% from cyclised isopropyl esters 227) of alcohol 245a and 1.04 g (57% from esters 227) of alcohol 245b. The spectral data for the alcohols i s in good agreement with that obtained earlier. ( i i i ) From neopentyl ester 243b. Alcohol 245b was prepared according to the procedure for diol 192 using 4 mg (0.1 mmole) of LiAlHit and 44 mg (0.1 mmole) of pure ester 243b. Work-up of the reaction mixture and purification of the crude product by flash chromatography using petroleum ether-ethyl acetate (6:1) as eluant gave 33 mg (94%) of alcohol 245b. The spectral data for this compound is in good agreement with that obtained earlier. (iv) From di-t-butylmethyl esters 244. To a solution of 0.984 g (2.0 mmole) of esters 244_ [244a:244b = 3:7, as determined by gc (T = 250°C)] in 50 mL of toluene was added 0.28 mL (3.5 mmole) of THF. The reaction was cooled to 0°C, 7.0 mL (7.0 mmole) of a 1 M solution of DIBAL in hexane was added, and the reaction was stirred at 0°C for 1 h. The reaction was quenched with 1 M HC1 and diluted with ether. The organic phase was washed three times with 1 M HC1, once with saturated NaCl, dried, and the solvent was removed. Purification of the crude product by flash chromatography using - 176 -petroleum ether-ethyl acetate (40:1) as eluant gave 0.400 g (40% from cyclised esters 229) of esters 244 [244a:244b = 1:11, as determined by gc (T = 250°C)]. The column was then eluted with petroleum ether-ethyl acetate (8:1) to give alcohols 245a and 245b. After repeated chromatographic separations 0.212 g (30%) of alcohol 245a and 0.211 g (30%) of alcohol 245b were obtained. The spectral data of the alcohols is in good agreement with that obtained previously. The remaining B-ester 245b was dissolved in toluene and 3.52 ml (3.5 mmole) of a 1 M solution of DIBAL in hexane was added to the solution. The reaction was stirred at room temperature for 2 h, then diluted with ether, and quenched with 1 M HC1. The organic layer was washed three times with 1 M HC1, once with saturated NaCl, dried, and the solvent was removed. Purification of the product by flash chromatography using petroleum ether-ethyl acetate (8:1) as eluant gave 0.271 g (95%) of alcohol 245b. trans—Decahydro-6B-[(t-butyldimethylsilyl)oxy]-l£-(methanesulphonyloxy-methyl)-5,5,8aB-trimethyl-2-methylenenaphthalene (246). To a solution of 0.67 mL (4.8 mmole) of triethylamine in ether at 0°C was added a solution of alcohols 245a and 245b (245a:245b = 1:2, as determined by ^"R nmr spectroscopy) in ether at 0°C with stirring. After - 177 -5 min, 0.27 mL (3.5 mmole) of methanesulphonyl chloride was added to the reaction, and the mixture was stirred at 0°C for 2 h, then at room temperature for 2 h. The reaction was quenched with 1 M HC1, and the organic phase was washed three times with 1 M HC1, three times with saturated NaHC03, once with saturated NaCl, and dried. The solvent was removed to give 1.39 g (quantitative yield) of mesylate 246 which was used without further purification in the preparation of sulphide 247. Preparative t i c of a small amount of this material using petroleum ether-ethyl acetate (6:1) gave 246 (C-la:C-lB = 1:2, as determined by ^ nmr spectroscopy) as an o i l which slowly crystallised; mp 72-77°C; i r (CHC13): 1360, 1175, 945, and 840 cm-1; lB. nmr (CDC13) 6: 0.06 (s, 6H), 0.78 (s, 3H), 0.86 (s, 1.2H), 0.91 (s, 10.8H), 0.94 (s, 1.8H), 0.99 (s, 1.2H), 1.15-2.58 (m, 10H), 3.00 (s, 1.2H), 3.02 (s, 1.8H), 3.05-3.35 (m, IH), 4.20-4.50 (m, 2H), 4.61 (bs, 0.6H), 4.72 (bs, 0.4H), 4.85 (bs, 0.4H), and 4.92 (bs, 0.6H); mass spectrum, m/e: 430(M+, 3), 203(100), 153(32), 147(28), 135(22), 133(23), 119(24), 109(25), 107(39), 95(31), 93(23), 81(21), 75(61), and 73(35). Exact Mass calcd. for C^H^O^SSi: 430.2573; found (ms): 430.2572. - 178 -trans-Decahydro-68-[(t-butyldimethylsilyl)oxyl-5,5,8aB-trimethyl-2-methylene-l£-(phenyltUomethyl)naphthalene (247) A slurry of 1.02 g (6.4 mmole) of KH (25% in oil) in dry ethanol was stirred at room temperature and 0.66 mL (6.4 mmole) of thiophenol (63) was added to the slurry. After 10 min a solution of 1.39 g of mesylate 246 (C-l<x:C-18 = 1:1.5, as determined by 1H nmr spectroscopy) in ethanol was added to the mixture, and the reaction was heated at reflux for 16 h. The ethanol was removed under reduced pressure and the residue waspartitioned between ether and saturated NaCl. The two phases were acidified with 1 M HC1, and the organic phase was washed twice with saturated NaCl, dried, and concentrated. The crude product was purified by flash chromatography using petroleum ether as eluant to remove the mineral o i l and diphenyl disulphide. The column was then eluted with petroleum ether-ethyl acetate (40:1) to give 1.33 g (94% from alcohols 245) of sulphide 247 as a pale yellow solid. Preparative t i c of a small amount of this material using the above solvent system gave 247 (C-la :C-18 = 1:1.5, as determined by *H nmr spectroscopy) as a colourless crystalline solid; bp (Kugelrohr d i s t i l l a t i o n ) 180°/0.1 Torr; mp 73-89°C; i r (CHC13): 1100 and 840 cm-1; XH nmr (CDC13) 6: 0.07 (s, 6H), - 179 -0.79 (s, 3H), 0.93 (bs, 15H), 1.15-2.50 (m, 10H), 2.81-3.30 (m, 3H), 4.70 (bs, IH), 4.84 (bs, 0.4H), 4.99 (bs, 0.6H), and 7.15-7.48 (bs, 5H); mass spectrum, m/e: 445(13), 444(M+, 27), 387(26), 203(28), 133(15), 123(27), 119(15), 117(15), 109(16), 107(17), 95(17), 93(15), 81(16), 75(100), 73(56), 69(18), 57(19), and 55(51). Exact Mass calcd. for C27HititOSSi: 444.2882; found (ms): 444.2876. t r a i i 8 - D e c a h y d r o - 6 6 - [ ( t - b u t y l d i a e t h y l 8 l l y l ) o x y l - 5 , 5 , 8 a B - t r l m e t h y l - 2 -nethylene-1£-(phenylsulphonylmethyl)naphthalene (249) To a solution of 0.504 g (1.6 mmole) of diphenyl diselenide in a 5:1 mixture of ether-CH 2Cl 2 at 0°C was added 0.92 mL (8.1 mmole) of a 30% (w/v) solution of hydrogen peroxide in water (94). To this oxidising mixture was added 0.717 g (1.6 mmole) of sulphide 247 (C-la: C-18 = 1:1.5, by ^H. nmr spectroscopy) and the reaction was refrigerated at 5°C for 16 h, during which time colourless crystals were observed to form. The reaction mixture was diluted with ether and ethyl acetate, and fi l t e r e d to remove the insoluble crystals. The f i l t r a t e was washed three times with saturated NaCl, dried, and the solvent was removed to give 0.90 g of 249 as an o i l which was insoluble in petroleum ether. S02Ph - 180 -The crude product was dissolved in ethyl acetate and adsorbed onto s i l i c a gel. Purification by flash chromatography using petroleum ether-ethyl acetate (6:1) as eluant gave 0.65 g (85%) of 249 (C-la:C-18 = 1:1.5, as determined by *H nmr). Preparative tic of a small amount of this material using the same solvent system gave 249 as a colourless glass; bp (Kugelrohr d i s t i l l a t i o n ) 195°C/0.1 Torr; i r (CHC1 3): 1660, 1315, 1150, 1105, and 840 cm-1; XH nmr (CDC13) 6: 0.06 (s, 6H), 0.63 (s, 1.8H), 0.73 (s, 3H), 0.91 (s, 10.2H), 0.93 (s, 3H), 1.12-2.48 (m, 10H), 3.00-3.40 (m, 3H), 4.43 (bs, IH), 4.60 (bs, 0.4H), 4.74 (bs, 0.6H), and 7.49-7.98 (m, 5H); mass spectrum, m/e: 476(M+, 0.2), 420(29), 419(92), 217(61), 203(78), 201(34), 199(100), 147(23), 135(33), 109(20), 107(21), 95(24), 75(57), and 73(38). Anal, calcd. for C 2 7 H i ^ 0 3 S S i : C 68.02, H 9.30; found: C 67.85, H 9.18. A small portion of sulphone 249 (C-la:C-18 = 1:1.5, as determined by *H nmr spectroscopy) was crystallised from ether to give moderately pure 8-isomer; mp 156-159°C; lE nmr (CDCI3) 6: 0.06 (s, 6H), 0.63 (s, 3H), 0.73 (s, 3H), 0.91 (s, 9H), 0.93 (s, 3H), 1.15-2.50 (m, 10H), 3.04-3.58 (m, 3H), 4.43 (bs, IH), 4.74 (bs, IH), 7.49-7.68 (m, 3H), and 7.80-7.98 (m, 2H). - 181 -trans-Decataydro-l£-(l*-phenylsulphonyl-3*-butenyl)-6p-[(t-butyldimethyl-silyl)oxy]-5,5,8ap-triiaethyl-2-methylenenaphthalene (255) To a stirred solution of 0.19 g (0.40 mmole) of sulphone 249 (C-lct:C-lB = 1:1.5, as determined by *H nmr spectroscopy) in 4 mL of THF and 0.4 mL of HMPA at 0°C, was added 0.61 mL (1.6 mmole) of a 2.6 M solution of n-butyllithium in hexane. After 1 h, 61 uL (0.8 mmole) of 3-bromopropene (freshly purified by passage through basic alumina) was added to the mixture at 0°C. The reaction was stirred overnight, while allowing i t to warm to room temperature, then was quenched with 1 M HC1, and diluted with ether and petroleum ether. The organic phase was washed twice with a saturated solution of cupric sulphate to remove the HMPA, then washed three times with saturated NaCl, and dried. The solvent was removed to give a mixture of starting material and alkylated product. The mixture was purified by flash chromatography using petroleum ether-ethyl acetate (6:1) as eluant, and performing two successive chromatographic separations on the mixture of compounds. The following components were obtained in order of elution: (a) alkylated product 255 (0.092 g, 45%) as a pale yellow o i l . Preparative t i c of this material using the same solvent system gave 255 S02Ph - 182 -as a colourless o i l which slowly so l i d i f i e d ; bp (Kugelrohr d i s t i l l a t i o n ) 200°C/0.05 Torr; mp 35-38°C; i r (CHCI3): 1650, 1305, 1145, 1100, and 840 cm-1; :H nmr (CDC13) 6: 0.10 (bs, 6H), 0.77 (s, 1.8H), 0.81 (s, 1.2H), 0.92 (s, 12H), 1.01 (s, 3H), 1.15-2.86 (m, 12H), 3.02-3.25 (m, IH), 3.33-3.60 (m, IH), 4.73 (bs, IH), 4.84-5.07 (m, 3H), 5.1-6.0 (m, IH), and 7.50-8.00 (m, 5H); mass spectrum, m/e: 516(M+, 0.2), 375(13), 317(15), 243(100), 217(74), 201(27), 199(83), 147(23), 135(50), 133(22), 121(22), 119(22), 107(22), 105(20), 95(25), 93(22), 81(20), 75(92), 73(71),and 69(21). Anal, calcd. for C 3 0H 1 + 8O 3SSi: C 69.71, H 9.36; found: C 69.49, H 9.37. (b) sulphone 249_ (0.093 g, 49%). trans—Decahydro-66-[ t-butyldlmethylsilyl)oxy]-1£-iodomethyl-5,5,8aB-trimethyl-2-methylenenaphthalene (256a), (256b) N-Methyl-N,N'-dicyclohexylcarbodiimidium iodide was prepared from dicyclohexylcarbodiimide and iodomethane via the method of Scheffold and Saladin (95). To a solution of 0.96 g (2.8 mmole) of the above salt in 10 mL of THF and 1 mL of HMPA was added 0.39 g (1.1 mmole) of alcohols 245a and 245b (95). The reaction was stirred at 95°C for 48 h, then was cooled to room temperature, diluted with ether, washed three times with - 183 -saturated NaCl, and dried. The solvent was removed and the crude product was purified by flash chromatography using petroleum ether as eluant. The following compounds were obtained in order of elution: (a) trans-decahydro-5,5,8aB-trimethyl-l,2-bis(methylene)-6 8-(t-butyldimethylsilyl)oxynaphthalene (257) (0.12 g, 32%) as a colourless liquid; Rf 0.90; bp (Kugelrohr d i s t i l l a t i o n ) 125°C/0.05 Torr; i r ( C H C 1 3 ) : 1640, 1260, 1100, 1070, 910, 895, 870, and 840 cm-1; *H nmr (CDCI3) 6: 0.06 (bs, 6H), 0.82 (s, 3H), 0.92 (s, 12H), 0.97 (s, 3H), 1.15-2.63 (m, 9H), 3.09-3.35 (m, IH), 4.54 (d, J = 2 Hz, IH), 4.67 (dd, J = 2 Hz, 2 Hz, IH), and 4.74-4.86 (m, 2H); mass spectrum, m/e_: 334(M+, 4), 278(13), 277(43), 201(11), 117(13), 76(10), 75(100), 73(25), and 41(16). Exact Mass calcd. for C 2iH 3 8OSi: 334.2692; found (ms): 334.2696. (b) a mixture of iodides 256a and 256b (0.33 g, 65%). Preparative t i c of a small amount of this material using petroleum ether as eluant gave pure isomers of the iodides as colourless oils which slowly s o l i d i f i e d : 256a: Rf = 0.67; bp (Kugelrohr d i s t i l l a t i o n ) 130°C/0.05 Torr; mp 53-56°C; i r (CHC1 3): 1650, 1255, 1100, 1075, 885, and 835 cm-1; XH nmr (CDCI3) : 0.07 (s, 6H), 0.78 (s, 3H), 0.92 (s, 12H), 1.00 (s, 3H), 1.19-2.40 (m, 10H), 3.06-3.35 (m, IH), 3.35 (A part of an ABX system, = 10 Hz, IH), 3.70 (B part of an ABX system, J^g = 10 Hz, JjjX = 4 Hz, IH), 4.65 (bs, IH), and 4.89 (bs, IH); mass spectrum, m/e: 462(M+, 3), 406(11), 405(40), 277(24), 203(21), 147(12), 117(14), 109(12), 107(14), 95(15), 93(11), 81(12), 75(100), 73(32), 69(12), - 184 -55(11), and 41(16). Exact Mass calcd. for C2iH 3 9IOSi: 462.1815; found (ms): 462.1823. 256b: Rf = 0.58; bp (Kugelrohr d i s t i l l a t i o n ) 125°C/0.05 Torr; mp 45-47°C; i r (CHC13): 1660, 1260, 1100, 1065, 890, and 835 cm-1; XH nmr (CDC13) 6: 0.05 (s, 6H), 0.71 (s, 3H), 0.75 (s, 3H), 0.89 (s, 9H), 0.92 (s, 3H), 1.11-2.52 (m, 10H), 2.92-3.35 (m, 2H), 3.62 (B part of an ABX system, Jj^ = 10 Hz, J g X = 2 Hz, IH), 4.65 (bs, IH), and 5.01 (bs, IH); mass spectrum, m/e: 462(M+, 1), 406(13), 405(45), 203(24), 147(12), 133(12), 117(13), 109(12), 107(14), 95(13), 93(11), 81(12), 75(100), 73(33), 69(13), 55(11), and 41(15). Exact Mass calcd. for C2iH 3 9I0Si: 462.1815; found (ms): 462.1831. Methyl 5-[trans-decahydro-6'8-[(t-butyldlmethylsllyl)oxy]-5',5',8a 'B-trimethyl-2'-methylene-1* B-naphthalenyl]-3-oxopentanoate (262) To a solution of 73 uL (0.91 mmole) of pyridine in 1 mL of CH 2C1 2 at -40 to -50°C was added 139 uL (0.82 mmole) of freshly purified trifluoromethanesulphonic anhydride ( t r i f l i e anhydride) (116) with s t i r r i n g . A white precipitate formed immediately and after 5 min a solution of 0.290 g (0.82 mmole) of alcohol 245b in 2 mL of CH2CI2 was added to the mixture. The reaction was stirred at -40 to -50°C for 1 h - 185 -during which time the original precipitate disappeared and a new precipitate formed. The reaction was filtered through a glass sinter and the crystalline pyridinium t r i f l a t e was washed with hexane which had been cooled to approximately -20°C. The f i l t r a t e s were combined and the solvent was removed under high vacuum while maintaining the temperature below 0°C. The residue was dissolved in cold hexane (-20°C), and the insoluble matter was filtered through a glass sinter and washed with cold hexane. The fil t r a t e s were again combined and the solvent was removed under high vacuum while maintaining the temperature below 0°C. The resulting colourless to pink o i l was dissolved in cold (-40°C) THF, and added to a preformed solution of the dianion of methyl acetoacetate in THF which was cooled to -40°C. [The dianion was prepared via general procedure A, for B-keto ester alkylation, from 0.056 g (1.4 mmole) of sodium hydride (60% dispersion in o i l ) , 133 \£L (1.2 mmole) of methyl acetoacetate, and 0.93 mL (1.4 mmole) of a 1.5 M solution of n-butyllithium in hexane.] The reaction mixture was allowed to warm to 0°C over a period of 1 h, then stirred at 0°C for a further 2 h. The mixture was quenched with 1 M HC1, diluted with ether, the organic phase was washed once with 1 M HC1, once with saturated NaCl, and dried. The solvent was removed while maintaining the temperature below 50°C to yield an orange o i l . Purification was performed, on the same day, by flash chromatography using petroleum ether as eluant to give 0.060 g (22%) of diene 257 (spectral data in good agreement with that obtained earlie r ) . The column was then eluted with petroleum ether-ethyl acetate (25:1) to remove any remaining non-polar material. Elution with - 186 -petroleum ether-ethyl acetate (10:1) gave the following compounds in order of elution: (a) B-keto ester 262_ (0.104 g, 28%) as a pale yellow o i l . Preparative t i c of a small amount of this material using petroleum ether-ethyl acetate (6:1) gave 262 as a colourless o i l ; bp (Kugelrohr d i s t i l l a t i o n ) 170°C/0.1 Torr; i r (CHC13): 1750, 1720, 1255, 1100, and 840 cm-1; :H nmr (CDC13) 6: 0.06 (s, 6H), 0.71 (s, 3H), 0.76 (s, 3H), 0.91 (s, 12H), 1.08-2.73 (m, 14H), 3.24 (bt, J = 7 Hz, IH), 3.42 (s, 2H), 3.74 (s, 3H), 4.43 (bs, IH), and 4.84 (bs, IH); mass spectrum, m/e: 450(M+, 5), 394(32), 393(90), 149(19), 135(20), 121(17), 119(16), 107(17), 95(15), 81(15), 75(100), 73(50), 69(22), 55(20), 43(19), and 41(20). Exact Mass calcd. for C 26Hi+60i+Si: 450.3165; found (ms): 450.3168. (b) alcohol 245b (0.040 g, 14%). Methyl (Z)-5-[trans-decahydro-6'B-[(fr-butyldiniethylsllyl)oxy]-5',5*, 8a'B-trimethyl-2 *-methylene-1'B-naphthalenyl]-3-[(diethylphosphoryl) oxyl-2-pentenoate (263) This compound was prepared according to general procedure B, for 0J)-enol phosphate formation, using 11 mg (0.27 mmole) of sodium hydride OPO(OEt)2 C O O M e - 187 -(60% dispersion in o i l ) , 80 mg (0.18 mmole) of B-keto ester 262, and 31 uL (0.21 mmole) of diethyl chlorophosphate. Work-up of the reaction mixture gave a yellow o i l which was purified by flash chromatography using petroleum ether-ethyl acetate (2:1) as eluant to give 94 mg (90%) of 263_ as a viscous liquid; i r (CHC13): 1730, 1670, and 1035 cm-1; *H nmr (CDC13) 6: 0.06 (s, 6H), 0.70 (s, 3H), 0.75 (s, 3H), 0.91 (s, 12H), 1.05-2.55 (m, 14H), 1.38 (dt, J ^ c ^ = 7 Hz, Jp 0CH 2CH 3 = 1 Hz, 6H), 3.23 (bt, J = 7 Hz, IH), 3.71 (s, 3H), 4.27 (dq, i c ^ c ^ = 7 Hz, JpocH2CH3 = 8 B z ' 4 H ) » 4 , 4 9 ( b s> 1 H )» 4 , 8 5 ( b s ' 1 H ) ' a n d 5 , 3 5 ( s» IH); mass spectrum, m/e: 586(M+, 0.6), 530(29), 529(86), 432(16), 375(17), 300(14), 253(19), 252(82), 230(13), 229(100), 220(24), 211(26), 201(18), 183(20), 155(57), 135(16), 127(18), 119(16), 99(23), 81(15), 75(56), and 73(41). Exact Mass calcd. for CsoHssOyPSi: 586.3455; found (ms): 586.3435. Methyl (E)-3-nethyl-5-[trans-decahydro-6•B-[(t-butyldimethylsilyl)oxy1 5 *,5',8a*B-trimethyl-2 *-methylene-1'8-naphthalenyl]-2-pentenoate (264) COOMe A suspension of 67 mg (0.33 mmole) of cuprous bromide-dimethyl sulphide complex (CuBr»Me2S) (117) in 2 mL of ether was stirred at 0°C, and 0.39 mL (0.66 mmole) of a 1.7 M solution of methyllithium-lithium - 188 -bromide complex in ether was slowly added to the suspension. The resulting light tan solution was cooled to -78°C and a solution of 64 mg (0.11 mmole) of enol phosphate 263 in 1.5 mL of ether was added to the reaction (23). The reaction mixture was warmed to -50°C and stirred for 1 h while maintaining the temperature between -40 and -50°C. During this time the colour of the reaction mixture changed from bright yellow to a reddish-purple colour. The reaction was quenched at -40°C by the addition of a mixture of 50% aqueous ammonium chloride and concentrated ammonium hydroxide (ca. 5:1), and diluted with ether. The organic phase was washed three times with this ammoniacal solution to remove a l l copper salts, was washed once with saturated NaCl, dried, and the solvent was removed. The crude product was purified by flash chromatography using petroleum ether-ethyl acetate (40:1) as eluant to give 40 mg (82%) of 264 as a pale yellow o i l . Preparative t i c of this material using the same solvent system gave 264 as a colourless liquid; bp (Kugelrohr d i s t i l l a t i o n ) 130°C/0.1 Torr; i r (CHC13): 1720, 1650, 1155, 1105, and 840 cm-1; XH nmr (CDC13) 6: 0.08 (s, 6H), 0.72 (s, 3H), 0.77 (s, 3H), 0.92 (s, 12H), 1.06-2.55 (m, 14H), 2.18 (d, J = 1.5 Hz, 3H), 3.25 (bt, J = 7 Hz, IH), 3.71 (s, 3H), 4.51 (bs, IH), 4.88 (bs, IH), and 5.65 (bs, IH); mass spectrum, m/e_: 448 (M+, 2), 392(39), 391(100), 316(12), 285(11), 241(14), 171(12), 147(12), 135(23), 121(22), 119(16), 109(13), 107(17), 105(11), 95(29), 93(13), 81(13), 75(65), 73(34), and 69(12). Anal, calcd. for CjyH^gOgSi: C 72.27, H 10.78; found: C 72.32, H 10.85. - 189 -Methyl (E)-3-methyl-5-(trans-decahydro-5',5'.Sa'p-trimethyl^'-methylene-6'B—hydroxy-1 * p-naphthalenyl)-2—pentenoate (265) COOH A standard solution of 48% aqueous hydrofluoric acid and 10 volumes of acetonitrile was prepared (4.8% HF in CH3CN), and 3 mL of this standard solution was added to 9.5 mg (0.02 mmole) of s i l y l ether 264 (98). The reaction was stirred at 0°C for 2 h while allowing i t to warm to room temperature, then was diluted with ether. The organic phase was washed four times with water, dried, and the solvent was 9 removed to give 7 mg (99%) of crude alcohol 265 which was used unpurified in the preparation of 238. [98% pure by gc (T = 250°C)]. The spectral data ( 1H nmr, i r , ms) is in good agreement with that found in the literature (88,89); i r (CHCI3): 3620, 3470, 1720, 1650, 1210, and 1155 cm-1; lK nmr (CDCI3) 6: 0.72 (s, 3H), 0.80 (s, 3H), 1.01 (s, 3H), 1.1-2.55 (m, 15H, IH exchangeable with D 20), 2.18 (d, J = 1.5 Hz, 3H), 3.15-3.40 (m, IH), 3.70 (s, 3H), 4.53 (bs, IH), 4.88 (bs, IH), and 5.65 (bs, IH); mass spectrum, m/e: 334(M+, 6), 319(19), 316(16), 301(25), 260(19), 203(23), 175(21), 135(100), 134(25), 123(26), 121(38), 119(29), q Spectral information on compound 265 was kindly provided by Professor J.R. Mahajan, University of Brasilia (89). - 190 -114(55), 109(29), 107(53), 95(38), 93(35), 83(26), 82(26), 81(38), and 55(27). Exact Mass calcd. for 02^31*03: 334.2508; found (ms): 334.2512. (E)-3-Me thyl-5-(trans-decahydro-5',5*,8a*B-trlmethyl^'-nethylene-6' B-hydroxy-I 'B-naphthalenyD^-pentenolc acid (3-hydroxylabda-8(20), 13-dlen-15-oic acid) (238) C O O M e To a solution of 10 mg (0.03 mmole) of methyl ester 265 in 3 mL of methanol was added 1 mL of a 10% (w/v) solution of aqueous KOH at 0°C. The reaction was stirred at room temperature for 30 h, then diluted with ether, washed three times with 1 M HC1, and once with saturated NaCl. The aqueous washings were extracted three times with ether, the combined organic layers were dried, and the solvent was removed. The crude product was purified by flash chromatography using petroleum ether-ethyl acetate (1:1.5) as eluant to give 8 mg (83%, 2 steps) of 238^° as a crystalline solid whose spectral data (*H nmr, i r , ms) is in good agreement with that found in the literature (88, 89); mp 173-174.5°C; i r (CHC13): 3000, 1700, and 1640 cm-1; : H nmr (CDCI3) 6: 0.72 (s, 3H), 0.81 (s, 3H), 1.03 (s, 3H), 1.0-2.6 (m, 16H, 2H *°Spectral information on compound 238 was kindly provided by Professor J.R. Mahajan, University of Brasilia (89). - 191 -exchangeable with D 20), 2.19 (d, J = 1.5 Hz, 3H), 3.10-3.37 (m, IH), 4.52 (bs, IH), 4.89 (bs, IH), and 5.68 (bs, IH); mass spectrum, m/e: 320(M+, 7), 302(22), 152(25), 149(52), 136(27), 135(100), 134(26), 133(24), 123(31), 122(36), 121(48), 119(31), 109(40), 107(61), 105(28), 97(33), 96(31), 95(57), 93(48), and 91(39). Exact Mass calcd. for C20H32O3: 320.2351; found (ms): 320.2354. - 192 -REFERENCES 1. E.E. van Tamelen. Acc. Chem. Res. J^, 111 (1968). 2. (a) G. 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F R E Q U t N C ' I C M ) 4000 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 F R E Q U E N C Y (CM') F R E Q U E N C Y ( C M ' l - 206 -- 207 -- 209 -COOMe FREQUENCY I C M ' ' | N J FREQUENCY <CM~') - — - . - - — -1 ' / r \\\ / HI \( \ r 4 r r A f • X 1 I i. i f v V L II j • 1 >yti i j i I 1 i 1 ! !! 1 • i i 1 •• l li ' r~ I 1 1 1 1 - 4 — -1-4— •—r — 4000 3000 2000 1500 ^ 1000 900 800 700 FREQUENCY (CM1) - 221 -FREQUENCY (CM'') - 224 -- 225 -FREQUENCY (CM*1) - 227 -- 228 -- 2 2 9 -- 230 -- 231 -- 232 -- 234 -- 235 -- 236 -FREQUENCY iCWi) - 238 -- 239 -- 240 -FREQUENCY (CM') 4000 3600 J 200 MOO 3400 1000 ItOO l«00 1400 1300 1000 100 600 FREQUENCY (CH''I 

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