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Evaluation of camphor derivatives in terpenoid synthesis Palme, Monica H. 1993

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EVALUATION OF CAMPHOR DERIVATIVES IN TERPENOID SYNTHESIS By MONICA H. PALME B.Sc., University of British Columbia, 1988  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF 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 UNIVERS Y OF BRITISH COLUMBIA April 1993 © Monica H. Palme  In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission.  (Signature)  Department of C)st---Q-Aev.4.4-7 The University of British Columbia Vancouver, Canada Date ^VG Vzlckti  DE-6 (2/88)  Abstract  New enantiospecific syntheses of 5,6-dehydrocamphor (36) and 5-methy1-5,6dehydrocamphor (178) are reported, and these two compounds were evaluated as intermediates in terpenoid synthesis. Addition of an alkenyl unit to (+)-5,6-dehydrocamphor (36) and subsequent anionic oxy-Cope rearrangement of the resulting 1,5-diene (64) provided hydrindenone 66. Ring expansion of 66 provided decalin intermediate 69  which contains the A/B ring system common to many terpenoids; however, the stereospecific introduction of an angular methyl group to provide a system such as 40 eluded us. Therefore, a similar synthetic strategy using (+5-methyl-5,6-dehydrocamphor (178) was investigated. Isopropenyl addition to 178 and subsequent anionic oxy-Cope rearrangement provided hydrindenone 190 which contained the desired angular methyl group. (-)-5-Methyl-5,6-dehydrocamphor (178) was also converted to enone 204, but stereoselective conjugate addition to this enone (204) was not satisfactory. Addition of a more complex alkenyl unit to (-)-5-methyl-5,6-dehydrocamphor (178) provided 1,5-diene 179, however, anionic oxy-Cope rearrangement to provide hydrindenone 180 did not  occur, presumably due to steric effects. The first enantioselective synthesis of (-)-4-methylcamphor (229) is also reported. It is expected that 229 will undergo reactions analogous to those reported for camphor (25) and therefore would provide a route to trans hydrindenone 232. The latter  compound is a potentially useful intermediate in the synthesis of the lanostane group of triterpenoids whereas its enantiomer (ent-232) derived from (+)-4-methylcamphor (ent178) could gain access to the euphane group of triterpenoids.  36  OH  69  180  40  ant-i 78  HO  232  HO  H 234, lanosterol  111  204  229  180  RO  66  25  ent-232  ^  Table of Contents Abstract^  ii  Table of Contents^  iv  List of Tables^  vi  List of Figures^  vii  Contents of Appendix^  vii  List of Abbreviations^  viii  Acknowledgements^  xiii  Dedication^  xiv  Chapter 1: The Evaluation of 5,6-Dehydrocamphor (36) and 5-Methyl5,6-dehydrocamphor (178) as Intermediates in Terpenoid Synthesis^  1  1.1: Introduction: The Anionic Oxy-Cope Rearrangement^2 1.2: Discussion^ 1.2.1: Introduction^  10 10  1.2.2: Synthesis of 5,6-Dehydrocamphor (36)^13 1.2.3: Synthesis of a Decalin System from 5,6-Dehydrocamphor (36) 1.2.4: Angular Functionalization Approaches  21 23  1.2.4.1: Hydroxyl-directed Cyclopropanation  23  1.2.4.2: Radical Cyclization and y-Alkylation  32  1.2.4.3: Anionic Oxy-Cope Rearrangement  41  1.2.5: Elaboration of A and B Rings  51  1.2.5.1: In Situ Methylation  52  1.2.5.2: C(1)-Oxygenation of Ring A  57  1.2.6: Evaluation of 5-Methyl-5,6-dehydrocamphor (178) as an Intermediate in Terpenoid Synthesis iv  59  1.2.6.1: Synthesis of 5-Methy1-5,6dehydrocamphor (178)^  61  1.2.6.2: Isopropenyl Addition to 5-Methyl -5,6dehydrocamphor (178) and Anionic OxyCope Rearrangement^  64  1.2.6.3: Allyl Addition to Hydrindenone 204 and Attempted Anionic Oxy-Cope Rearrangement^78 1.2.6.4: Allcynyl Addition to 5-Methy1-5,6dehydrocamphor (178) and Attempted Anionic Oxy-Cope Rearrangement ^82 1.3: Conclusion^  88  Chapter 2: A New Enantiospecific Synthesis of 4-Methylcamphor^91 2.1: Introduction^  92  2.2: Discussion^  96  2.3: Conclusion^  111  Experimental^  113  References and Notes^  214  Appendix^  222  V  List of Tables Table 1: Comparison of reaction rates of the oxy-Cope rearrangement and the corresponding anionic oxy-Cope rearrangement ^4 Table 2: Camphor derivatives in natural product synthesis ^11 Table 3: Conditions used in the attempted cyclopropanation of compound 87^  28  Table 4: Results of COSY experiment done on compound 138^47 Table 5: Results of NOE experiments done on compound 138^48 Table 6: Results of decoupling experiments done on major isomer of compound 210^  75  Table 7: Results of NOE experiments done on major isomer of compound 210^  77  Table 8: Results of NOE experiments done on compound 214^79 Table 9: Results of NOE experiments done on compound 255 ^101 Table 10: Specific rotation of (+)-4-methylisoborneol (267)^106 Table 11: Specific rotation of (-)-4-methylcamphor (229)^ 109  List of Figures  Figure 1: Chromatograms obtained for Samples A and B of ^ (+)-4-methylisoborneol (267)  108  Figure 2: 1H NMR (400 MHz) spectra after [Eu(hfc)3] addition to Sample C of (-)-4-methylcamphor (229)  ^  Figure 3: 1H NMR (400 MHz) spectra after [Eu(hfc)3] addition to Sample ^ D of (-)-4-methylcamphor (229)  110 112  Contents of AppendiN  1. X-ray crystal structure of alcohol 158^  222  2. X-ray crystal structure of ketone 171^  223  List of Abbreviation  Ac^acetyl Ac0-^acetate Ac20^acetic anhydride AIBN^azobis(isobutyronitrile) Anal.^microanalytically determined mass % aq^aqueous atm^atmosphere ax.^axial B-^base Bn^benzyl BnBr^benzyl bromide bp^boiling point br^broad Bu^primary butyl n-Bu^primary butyl t-Bu^tertiary butyl concentration (g/100 mL, specific rotation) Calc.^calculated mass % Calc. Mass^calculated exact mass conc^concentrated COSY^1H-1H correlation spectroscopy 18-cr-6^18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane) doublet dd^doublet of doublets ddd^doublet of doublets of doublets viii  ddm^doublet of doublets of multiplets DHP^dihydropyran DIBAL^diisobutylaluminum hydride diglyme^bis(2-methoxyethyl)ether dm^doublet of multiplets DMAP^4-dimethylaminopyridine DME^1,2-dimethoxyethane DMF^dimethyl formamide DMS^dimethylsulfide DMSO^dimethyl sulfoxide dq^doublet of quartets dt^doublet of triplets E+^electrophile e.e.^enantiomeric excess ent-^enantiomer (of) eq.^equatorial Et^ethyl Et20^diethyl ether Et0Ac^ethyl acetate Et3N^triethylamine Et0H^ethanol [Eu(hfc)3]^tris[3-(heptafluoropropylhydroxymethylene)-d-camphorato]europium(III) 3,2--Me 3,2-exo methyl shift GC^gas liquid chromatography h^hour 6,2-H^6,2-hydride shift HMDS^1,1,1,3,3,3-hexamethyldisilazane ix  HMPA^hexamethylphosphoramide HMPT^hexamethylphosphorous triamide HOAc^acetic acid HOB ut^tertiary butanol i.d.^inner diameter (capillary gas liquid chromatography column) IR^infrared J^coupling constant k^rate constant KOBut^potassium tertiary butoxide KHMDS^potassium hexamethyldisilazide LDA^lithium diisopropylamide lit^literature reference L-Selectride® lithium tri-secondary-butylborohydride m^multiplet M^metal or molarity (mol/L) M+^molecular ion (mass spectrometry) or metal cation Me^methyl m/e^mass to charge ratio Mel^methyl iodide Meas. Mass exact mass determined by high resolution mass spectrometry Me0H^methanol min^minute mmHg^millimeters of mercury MOM^methoxymethyl mp^melting point MS^mass spectrum n^normal (primary) x  Na0Me^sodium methoxide NMR^nuclear magnetic resonance NOE^nuclear Overhauser effect Nu-^nucleophile PCC^pyridinium chlorochromate PE^low boiling (30-60 0C) petroleum ether Ph^phenyl ppm^parts per million i-Pr^isopropyl i-Pr2NH^diisopropylamine py^pyridine quartet alkyl group R'^alkyl group different from R RBF^round bottomed flask rt^retention time RT^room temperature singlet Si02^silica gel SM^starting material triplet t-^tertiary temperature TBAF^tetrabutylammonium fluoride TBDMS^tertiary-butyldimethylsilyl TBDMSCI^tertiary-butyldimethylsilyl chloride td^triplet of doublets xi  Tf^trifluoromethanesulfonic (triflic) Tf20^trifluoromethanesulfonic anhydride THF^tetrahydrofuran THP^tetrahydropyranyl TLC^thin layer chromatography TMS^trimethylsilyl TMSCI^trimethylsilyl chloride p-Ts0H^para-toluenesulfonic acid Ts^para-toluenesulfonyl WM^Wagner Meerwein rearrangement wt^weight [a]TD specific rotation at 589 nm at T 0C 5^chemical shift v^absorption frequency 10^primary 20^secondary 30^tertiary  xi i  Acknowledgements  I would like to thank my research supervisor, Professor Thomas Money, for his guidance and support throughout the years I have studied under his direction. Even during those times when results came slowly, he could always inspire me to try another of his exciting ideas, which came from an apparently limitless supply. His enthusiasm and encouragement increased both my knowledge of chemistry and my confidence, and I will always consider Professor Money as my mentor who guided me at the critical beginning of my career in chemistry. I shall always strive to achieve his level of knowledge in so many diverse areas of chemistry, although this will no doubt be a difficult goal. I would like to thank Mike Wong and Scott Richardson, my co-workers, for their friendship, help and advice over the years. It was wonderful to share so much time with two undoubtedly diverse personalities who nevertheless complemented each other and each contributed to the lab atmosphere in a positive way. I would also like to thank the many friends, colleagues, and departmental staff members who made my graduate school years among the best of my life. Finally, I would like to thank my mother, Daisy Palme, for her consistent support and encouragement throughout my studies, for her genuine interest in what I do, and for listening to an amazing amount of technical information, especially considering that she thought I should have become a chartered accountant.  This thesis is dedicated to the memory of my father, Kurt Palme, from whom I inherited curiosity, patience and perseverance and to my mother, Daisy Palme, from whom I inherited drive, ambition and independence.  1  Chapter 1 The Evaluation of 5,6-Dehydrocamphor and 5-Methyl-5,6-dehydrocamphor As Intermediates In Telpenoid Synthesis  2 1.1 Introduction: The Anionic Oxy-Cope Rearrangement  The anionic oxy-Cope rearrangement is a versatile reaction that has been used extensively in the synthesis of natural products.1 The work described in Chapter 1 of this thesis utilizes the anionic oxy-Cope rearrangement as a key step in our route to a decalin system and relies on its stereospecificity to introduce three chiral centers. The anionic oxy-Cope rearrangement is a variation of the Cope2 rearrangement which is a thermal [3,3] sigmatropic rearrangement of 1,5-dienes. A sigmatropic process  A  involves a concerted reorganization of electrons during which a group attached by a a-bond migrates to a more distant terminus of an adjacent 7r-electron system; there is a simultaneous shift of the  it electrons.3  The [3,3] nomenclature comes from splitting the  molecule at the migrating sigma bond and numbering the carbon atoms in each resulting fragment from that end. The two digits reflect the numbers of the carbon atoms of each fragment which are joined as a new sigma bond is formed. The Cope rearrangement is reversible, giving an equilibrium mixture of two 1,5-dienes (starting material and product), with the ratio of the two reflecting their relative thermodynamic stabilities. Any 1,5-diene will rearrange, but will do so at lower temperature if there is a substituent on the C(3) or C(4) atom with which the new double bond that is formed can conjugate.4 If the group is hydroxyl (Z=OH), then the reaction is 2  4  C  A^  HO. '-'■1111r  3 called an oxy-Cope5 rearrangement and the product, an enol, tautomerizes to the ketone or aldehyde, causing the equilibrium to lie far to the right. In 1975, Evans and Golob6 reported that the oxy-Cope rearrangement is accelerated by factors of 1012-1017 if an allcoxide rather than an alcohol is used, and this variation became known as the anionic oxy-Cope rearrangement. The product is an enolate, which may be utilized in situ as will be discussed in Section 1.2.5.1 (p. 52), or may simply be protonated to provide an aldehyde or ketone. Evans and Golob studied the effects of various cations on the anionic oxy-Cope rearrangement of alkoxide 1 in THF (Scheme 1).  OM -  2  .  66°C  _  6 1  H+  Me0  Me0  2 Scheme 1 In all cases, the temperature was kept at 66 0C and the following results were obtained: If the cations were Li+ or +MgBr, then even after 24 hours, no reaction was observed. When Na or K were used, the half lives of the reactions were 1.2 hours and 1.4 minutes respectively, and upon protonation during work-up, the product was found to be ketone 2. Having established that potassium as the counterion resulted in the greatest rate increase, the effect of added ionophore 18-crown-6 was investigated. It was found that addition of up to 3 equivalents of 18-crown-6 resulted in a limiting 180-fold acceleration in rate of  4 reaction of lb (M=K) at 00C in THF. When HMPT was used as solvent and the reaction was run under similar conditions (except T=10 0C), the same results were obtained, suggesting that rate dependence on the dielectric constant of the solvent is negligible and that ion pair dissociation results in maximal rate acceleration. Another set of experiments probed the actual rate accelerations observed when the potassium alkoxides lb (M=K) and 3b (M=K) were used instead of the corresponding alcohols (Scheme 2). The effect of added ionophore 18-crown-6 was again investigated and the results are summarized in Table 1.  NI+  Me0 2  3  ^  4  Scheme 2 Table 1: Comparison of the reaction rates of the oxy-Cope rearrangement and the corresponding anionic oxy-Cope rearrangement Alcohol  Alkoxide  Temp (0C)  Equiv. 18-cr-6  Rate Accel. (kibilci a)  la, M=H  lb, M=K  25  1.1  1012  3a, M=H  3b, M=K  40  0  1012  3a, M=H  3b, M=K  0  1.1  1017  5 These experiments dramatically showed the exceptionally large increases in rate (k) which were observed when alkoxides lb (M=K) and 3b (M=K) were used instead of the corresponding alcohols (la, M=H and 3a, M=H). These results also confirmed the previously described reports of rate increases attainable when an ionophore is used as an additive. In 1984, Bartmess and co-workers7 suggested that a faster rate observed for tertiary alkoxides (as compared to secondary alkoxides) is due to steric hindrance around the anionic site, which results in decreased ion pairing and solvation at that location. This suggestion is consistent with the fact that an increase in rate is produced by the addition of 18-crown-6 which complexes potassium ions and hence reduces ion pairing. In order to explain the rate increases observed in the anionic oxy-Cope rearrangement, Evans and co-workers8 carried out ab initio C-H bond strength calculations for methanol, sodium methoxide, potassium methoxide and the methoxide anion and found that the bond strength decreased with increasing degree of ionization. The decrease calculated upon going from the alcohol to an alkoxide was attributed to increased charge transfer from the cation to the organic fragment and thus a tendency for the oxygen pit electrons to delocalize back onto the carbon, resulting in a weaker C-H bond. In the case of the bare, unsolvated methoxide anion, there is further oxygencentered electron delocalization and the C-H bond becomes even weaker. If this explanation is extended to a C-C bond where one carbon atom bears a hydroxyl substituent, then the C-C bond strength should be weaker in the alkoxide than in the parent alcohol, and cleavage of the bond should be more facile. This explanation accounts for the rate increases observed in the anionic oxy-Cope reaction; furthermore, it also supports the rate acceleration observed upon the addition of ionophore which should further weaken the C-C bond. In 1980, Evans and co-workers9 established that the anionic oxy-Cope rearrangement, as the Cope rearrangement itself, is a concerted process which usually proceeds through a chair-like transition state. Thus the stereochemical outcome of a  ^  6 reaction can usually be predicted in terms of a preference for the chair-like transition state which minimizes steric interactions. As shown in Scheme 3, for example, the Cope rearrangement of the meso isomer of 3,4-dimethy1-1,5-hexadiene can exist in one possible pseudo-chair conformation (5). Rearrangement of this isomer (5) via a concerted process leads to the formation of only one product, the cis, trans isomer 6, which was observed.10 Reaction of the meso isomer via either possible boat conformation 7 or 9 would lead to either the trans, vans product 8 or the c.is, cis product 10, neither of which were observed. 10  5  7  Me Me^  9  ^  Me Me 10  Scheme 3 The Cope rearrangement of systems such as 11 (Scheme 4) that can proceed via two possible chair-like transition states has also been examined.11 Rearrangement of 11 was found to give 12 as the major product, and only minor amounts of 13 were formed. This can be rationalized by the fact that the more sterically demanding phenyl substituent would favor the equatorial position in the transition state 11a, as opposed to the axial  7 H  ^  H  Ph^CH3^Ph ..1410,.............,  CH3 1 la  ^CH3 ...---CH3 12  Ph^  Ph  v. ,.  --ON.-^  CH3  11 Ph CH3  11  --4.-  Ph^  -ill■ CH3^CH3^CH3 \^CH3  H  1 lb^13  Scheme 4 position as in 11b, where it would experience greater 1,3-diaxial interaction than the methyl group. When enantiopure 11 was used, it was found that the major product 12 had an enantiomeric purity of at least 95%. Thus, not only can the stereochemistry of the newly formed double bonds be predicted, but also, when the starting 1,5-diene is optically active, the chirality of newly formed tetrahedral centers. A recent example of such a chirality transfer was reported by Nalcai and co-workers12 in their approach to (+)-faranal (18), an ant pheromone (Scheme 5).  H+  KH K+ - 0  HO  14  I •-'.. ./* \---j---)--0 18  Scheme 5  0 17  8 Diene 14 was prepared in >96% e.e. and upon treatment with KH and 18-crown-6 formed alkoxide 15 which rearranged via a chair-like transition state to give, upon protonation, enol 16 which tautomerized to aldehyde 17. The stereochemistry of 17 was determined to be as predicted, and the enantiomeric purity was 91%. In cases where the starting 1,5-diene is rigid, a chair-like transition state may not be possible; the anionic oxy-Cope rearrangement may then proceed via a boat-like transition state. An example of such a molecule is the bicyclo [2.2.1] heptenol intermediate 19 that Paquette and co-workers13 used in their synthesis of (+)-ikarugamycin (21) (Scheme 6). Although forced to proceed via a boat-like transition state, diene 19 rearranged in reasonable yield, and the stereochemistry of product 20 was as predicted.  KH, 18-cr-6 ^JoTHF, RT, 2.5 h 64%  20  Scheme 6 Although the anionic oxy-Cope rearrangement commonly is used to synthesize acyclic or 6-membered ring products, it can also be used to make medium ring products.  9 A striking example is Paquette and co-workers'14 synthesis of intermediate 23 (Scheme 7).  _  Mel  _  22^  23  _  ^  24  Scheme 7 Treatment of 22 with ICHMDS caused rearrangement to provide enolate 23. Instead of protonation of 23 by the addition of water, methyl iodide was added instead, which resulted in alkylation of the intermediate enolate 23 to provide 24. This in situ methylation of an enolate resulting from anionic oxy-Cope rearrangement will be discussed further in Section 1.2.5.1 (p. 52); however, reaction of 22 to provide 24 is an example of how the anionic oxy-Cope rearrangement can be utilized to provide a highly functionalized, medium ring product. The predictable stereospecificity of the anionic oxy-Cope rearrangement makes it a very useful reaction in organic synthesis. If the starting 1,5-diene is substituted, however, steric interactions may prevent the rearrangement from occurring, thus limiting the scope of the reaction. We have utilized the anionic oxy-Cope rearrangement in our efforts towards the enantiospecific synthesis of natural product intermediates. Our use of this versatile reaction, and also its limitations due to steric effects, is described in the discussion of Chapter 1 of this thesis.  10 1.2: Discussion 1.2.1: Introduction The use of (+)-camphor (25) or its enantiomer (ent-25) in natural product synthesis15 is due to the fact that camphor can be functionalized at the C(3), C(5), C(6), C(8), C(9) and C(10) positions In addition, cleavage of the C(1)-C(2), C(2)-C(3), and C(1)-C(7) bonds in camphor and camphor derivatives can be accomplished to provide synthetically useful intermediates (Scheme 8).  SO3H 27  26 (+)-camphor-10-sulfonic acid  28  (+)-9-bromocamphor  (+)-9,10-dibromocamphor  10  25  29 (+)-8-bromocamphor  Ac0  .41111  (+)-camphor  0  30  (-)-camphorquinone  AcOrt  31 5-ketoisobornyl acetate^(-)-isobornyl acetate  Scheme 8  OAc^OAc  32^ 34  0  (+)-bornyl acetate^5-ketobornyl acetate  11  Table 2 shows examples of camphor derivatives and some natural products or synthetic intermediates that have been synthesized using them as precursors. Each derivative can be synthesized in either enantiomeric form, and thus either enantiomer of the natural product is accessible.  Table 2: Camphor derivatives in natural product synthesis Camphor Derivative camphor-10-sulfonic acid (26) 9-bromocamphor (27)  natural Products or Intermediates khusimone,16 zizanoic acid,16 quadrone,17 epi-zizanoic acid16 a_santaiene,18,19,20 a-santalo1,21,22,23,24,25 13-santalo1,23,24 furodysinin,26 epi-3-santalene,19.27 furodysin,26  8-bromocamphor (29)  isoepicamphereno1,27 cannabidio1,28 cannabidiol dimethyl ether,28 hapalindole Q,29 helenanolide intermediate,30 vitamin B12 intermediate,31 steroid intermediates32,33.34 campherenone,27.35 a-santalene,27 sativene,27,36 copacamphene,27, 36 copaborneo1,27, 36 camphereno1,27 longiborneo1,35 longifolene,35 13-santalene27  9,10-dibromocamphor (28)  estrone,37,38 California red scale pheromone,39 ophiobolin C,40 helenanolide intermediate,41 steroid intermediates4143,44  5-ketoisobornyl acetate (33) 5-ketobornyl acetate (34) camphorquinone (30)  nojigiku alcohol45 epi43-necrodo146 patchouli alcoho1,47 taxusin,48 vitamin B12 intermediates49,50,51,52  12 Part of the continuing interest in our laboratory is to further investigate camphor (25) as a chiral starting material in natural product synthesis. The objective of the  research described in this thesis was to develop a general strategy towards the enantiospecific synthesis of sesquiterpenoids, diterpenoids, sesterterpenoids and triterpenoids that contain 4,4,10-trimethyl decalin (35) as a structural sub-unit (A/B ring system) in their carbon skeleton (Scheme 9).  •■■  -INN-  4110-  25  36 —  R2  A 40  39^  38  Scheme 9 It was envisioned that an alkoxide (37) derived by the formal addition of a transalkenyl unit to (+)-5,6-dehydrocamphor (36) or its enantiomer could undergo anionic  13 oxy-Cope rearrangement resulting in hydrindenone intermediate 38. The structure of the alkenyl unit would, of course, depend upon the class of terpenoid to be synthesized. For sesquiterpenoids, R1=H and R2=CH3, CH2OH or CHO. For the larger terpenoids, R1 represents an appropriate Cs, C10, or C15 unit. Due to the stereospecificity of the anionic oxy-Cope rearrangement, the ring junction in hydrindenone 38 is^and the C(9) substituent trans to the ring junction hydrogens. In addition, the absolute configurations of C(5), C(9) and C(10) are dependent upon which enantiomer of 5,6-dehydrocamphor (36) is used as starting ketone. Initially, the enolate of the hydrindenone (38) is formed, and therefore the stereochemistry of the R2 substituent is dependent upon which face of the enolate is protonated upon work-up; the C(8) center is, of course, epimerizable. Ring expansion of 38 should provide the decalin system and intermediate 39 contains most structural features inherent in the A/B ring system of many terpenoids: oxygen functionality at C(3) and C(7), the geminal dimethyl groups at C(4), and alkyl substitution at C(8) and C(9). Missing, however, is the angular methyl group at C(10). It was expected, however, that either the C(11) hydroxyl group or the A ring enone functionality in 39 could be used to introduce, stereoselectively, the angular methyl group.  1.2.2: Synthesis of 5,6-Dehydrocamphor (36)  Literature methods for the synthesis of (+)-5,6-dehydrocamphor (36) or its enantiomer (ent 36) involve laborious multi-step sequences. The first synthesis of -  (+)-5,6-dehydrocamphor (36) was Asahina's nine-step route outlined in Scheme 10.53 (+)-Camphor (25) is converted to (+)-bornyl acetate (32) in two steps. Oxidation of (+)-bornyl acetate (32) with Cr03/HOAc yields a mixture from which the desired product, 5-ketobornyl acetate (34) is obtained in only 24% yield. Further oxidation of 5-ketobornyl acetate (34) with Se02 in Ac20 gave 5,6-dioxobomyl acetate (42) in 56%  14  i  ii  (:6 i Ac0 32  25  1iii  tv  V  42  vii  44  OAc  45  i) Na, EtON ii) Ac20 iii) Cr03, HOAc iv) Se02, Ac20 v) NH2NH2 H20, EtON vi) Hg0, C6H6 vii) Cu viii) HBr, HOAc ix) Zn, HOAc Scheme 10  36  yield. (+)-5,6-Dehydrocamphor (36) was ultimately obtained after diazotization, reduction, bromination, and dehydrohalogenation steps. Hietaniemi and Malkonen's nine-step synthesis54 of (-)-5,6-dehydrocamphor (ent-36) also uses (+)-camphor (25) as a starting material (Scheme 11) and is dependent  15 on remote oxidation of (+)-bornyl acetate (32) to provide 5-ketobornyl acetate (34) as a key intermediate. Replacement of the acetyl protective group with the tetrahydropyranyl protective group, reduction, and treatment with CS2/CH3I yielded xanthate 50. After pyrolysis and oxidation (-)-5,6-dehydrocamphor (ent 36) was finally obtained. -  i  ii  Orf  1  OH  25  OAc  41  32  V  OH  THPO  vii  iv  OCS2Me  49  i) Na, Et0H ii) Ac20 iii) Cr03, AcOH iv) 10% KOH v) DHP, Fl+ vi) Li1JH4 vii) CS2, CH31 viii) heat i x) Al[OCH(CH3)03 ent-36  Scheme 11  The syntheses described above both involve remote oxidation of bornyl acetate (32) as a key step. Considerable experience in our laboratory has shown that this  16 produces 5-ketobornyl acetate (34) in variable yield.45 Separation of the desired isomer from the other major product, 6-ketobornyl acetate, is tedious. Recent investigations in our laboratory have resulted in the development of two alternative synthetic routes to 5,6-dehydrocamphor (36). The first route (Scheme 12) was based on the discovery that commercially available (+)-enclo-3-bromocamphor (52) undergoes acid-catalyzed rearrangement to provide (-)-endo-6-bromocamphor (53) in —40% yield.55 The mechanism proposed (Scheme 13) for the acid-catalyzed  II  Br  ^ ^ Br ^ ^ 52 53  HO2C ^ 36 54  i) CISO3H ii) KOH, DMSO/H20  Scheme 12  rearrangement of (+)-endo-3-bromocamphor (55, X=Br, Y=H) to (-)-endo-6-bromocamphor (56, X=Br, Y=H) is analogous to that reported for the acid-catalyzed racemization of camphor (55, X=Y=H)56 and is supported by the observation that (+)-endo-3-bromo-10-deuteriocamphor (55, X=Br, Y=D) rearranged to (-)-endo-6bromo-8-deuteriocamphor (56, X=Br, Y=D).57 A minor by-product in the rearrangement of 52 to 53 was 7-bromofenchone (57) and its formation can be rationalized by the mechanism outlined in Scheme 14 (p. 18).  17  55  VVM  1  3,2 Me  6,2 H  OH^3,2 Me^OH X X^  VVM  - H*  x 56  Scheme 13  (-)-endo-6-Bromocamphor (53) was dehydrobrominated with KOH in DMSO/H20 to give (+)-5,6-dehydrocamphor (36, mp:145-148 0C, lit mp53:148 0C) in —40% yield. The poor yield in this reaction is due to the competing ring-cleavage reaction that produces campholenic acid (54) as a co-product (cf. Scheme 12).  18 IMIN•  H+  Scheme 14 A simple two-step synthesis of (+)-5,6-dehydrocamphor (36) is therefore available, and it is also possible to obtain (-)-5,6-dehydrocamphor (ent-36) by the same sequence, starting with commercially available (-)-endo-3-bromocamphor (ent-52). The development of a new six-step synthetic route to (-)-5,6-dehydrocamphor (ent-36) (or its enantiomer) was the starting point of the work described in this thesis. Although longer than the synthesis described above, each step of the new synthesis is easily carried out and occurs in good to high yield (Scheme 15). In the first step of the  88%  Br  ii  Br  78%^78%  Br  52  0^iii^0  59  58  60 iv  vi ent-36  92% ^  62  91% ^  61  i) Br2, CH3CO2H, reflux, 2.5 h ii) Et2Zn, benzene, reflux, 24 h iii) 48% HBr, Ac20, 65 °C, 3 h iv) TMSC1, ethylene glycol, RT, 2.5 h v) KOH, DMSO/H20, 100 °C, 2.5 h vi) 1 M HC1, acetone, RT, 1.5 h Scheme 15  19 synthesis addition of bromine to (+)-endo-3-bromocamphor (52) in refluxing glacial acetic acid58 provided (+)-3,3-dibromocamphor (58) in 88% yield. Subsequent treatment with Et2Zn in refluxing benzene59 gave cyclocamphanone (59) as a white solid in 78% yield. The spectral characteristics of cyclocamphanone (59) were identical to those reported in the literature and the melting point is 168-169 0C (lit mp: 168-170 oC).59 The mechanism proposed59 for this reaction is outlined in Scheme 16. The reaction was  heat  Et2Zn C6I-16  ZnBr  Br  1^[  H20 11  heat  OrY5 Br  52  59  Scheme 16 monitored by GC and an intermediate was seen whose retention time matched that of an authentic sample of endo-3-bromocamphor (52). Further heating showed disappearance of the intermediate as the tricyclic product (59) was formed, presumably via a carbene insertion reaction. Thus, the GC data is consistent with the proposed mechanism.59 Cyclocamphanone (59) was heated at 65 0C with 48% hydrobromic acid in acetic anhydride6o to provide ow-5-bromocamphor (60) in 78% yield as a white crystalline solid (mp: 109-111 0C, lit mp58: 110-111 0C). The position of the bromine is confirmed by the C(5) endo proton signal in the 1H NMR (400 MHz, CDC13) spectrum of 60. As expected, it is downfield at 4.06 ppm, due to the electron withdrawing properties of the  20 C(5) bromine. It appears as a doublet of doublets, showing no coupling with the C(4)H with which it forms an angle of approximately 90 0. The C(5) endo proton does show coupling of 8 Hz with the C(6) endo proton, and of 5 Hz with the C(6) rag proton. Thus, bromination occurred at the C(5) gm position as expected. With the C(5) position now functionalized, it was hoped that treatment with base would result in dehydrohalogenation to provide (-)-5,6-dehydrocamphor (ent 36). -  However, treatment with a variety of bases resulted in enolate formation and subsequent loss of bromide to provide cyclocamphanone (59). Thus protection of the carbonyl group was required. This was done using ethylene glycol and TMSC1 to form ketal 61 in 92% yield. The infrared spectrum (CHC13) of 61 showed the absence of the carbonyl stretch which was present at 1745 cm-1 in eLco-5-bromocamphor (60) and its 1H NMR (400 MHz, CDC13) spectrum also showed both C(3) protons to be more shielded (1.41 vs 1.84 ppm for C(3) endo H and 2.11-2.17 vs 2.46 ppm for C(3) ow H) than in the corresponding carbonyl compound (60). Treatment of ketal 61 with KOH in DMSO/H20 at 100 0C provided 5,6-dehydrocamphor ketal (62) in 92% yield and subsequent hydrolysis with 1 M HC1 in acetone gave (-)-5,6-dehydrocamphor (ent 36) as a white crystalline solid (92% yield): ^0 (c 2.10, 95% Et0H), lit [a]/%5 -735 0 (c 1.0,95% Et0H).53.54 This compound [a] -  was identical in all respects to (+)-5,6-dehydrocamphor (36) prepared via the two-step synthesis (cf. Scheme 12, p. 16) except for the sign of optical rotation.  21 1.2.3: Synthesis of a Decalin System from 5,6-Dehydrocamphor (36) With 5,6-dehydrocamphor (36) easily accessible in either enantiomeric form, the next goal was to add an allcenyl unit to the carbonyl group in this compound and to investigate the subsequent anionic oxy-Cope rearrangement of this product (Scheme 17).  OH  ii  36  6 4 /  OH  OH •■•  0-  66  MM.  i) L1C7---CCH2OLi , THE , -78° - AT, 76%^ii) LiAIH4 , THF , 40°, 1 h, 85% iii) KH , THF ,40° , 15 min, 85%  Scheme 17 The dianion of propargyl alcohol, formed by addition of n-BuLi at -78 0C in THF61 was added to (+)-5,6-dehydrocamphor (36) to give alkyne diol 63 as a white crystalline solid in 76% yield. Reduction of 63 using LiA1H4 in THF62 afforded transalkene diol 64 as a white solid in 85% yield. This compound was quite insoluble in common organic solvents such as Et20 and CHC13; however, its 1H NMR spectrum was obtained as a solution in CD3CN. The 1H NMR (400 MHz, CD3CN) spectrum of 64 supported the reduction of the alkyne to the allcene; however, the signals due to the vinyl protons of the newly formed alkene overlapped with the C(6) vinyl proton signal. That the reduction had occurred trans and not  cis could not be proven at this point. In later  22 experiments, however, alkene diol 64 was derivatized and X-ray crystallographic evidence supported the irans stereochemistry (see p. 54). Treatment of alkene diol 64 with excess KH in THF at 40 ciC resulted in facile anionic oxy-Cope rearrangement to give hydrindenone 66 in 85% yield. The relative stereochemistry of the product was confirmed by X-ray crystallographic analysis of a later derivative (see p. 54). It was predicted at this point, however, based on the presumed trans-geometry of the alkene diol and the stereospecificity of the concerted anionic oxy-Cope rearrangement. Therefore, the ring junction hydrogens were assumed to be  is and the C(9) hydroxymethylene substituent to be equatorial (trans to the ring  junction protons). Ring expansion of hydrindenone 66 to decalin intermediate 69 was accomplished by the reaction sequence shown in Scheme 18.  i) Ac20, Et3N, DMAP, CH2C12, 95% ii) 03, Me0H, CH2Cl2, -78 °C; Zn, HOAc, AT iii) p-Ts0H, C6H6, reflux  Scheme 18  Thus protection of the hydroxyl group in 66 to provide acetate 67, followed by ozonolysis and reductive work-up provided keto-aldehyde 68. Subsequent treatment with p-Ts0H•H20 in refluxing benzene resulted in acid-catalyzed aldol condensation to provide enone 69. The structure of 69 was confirmed by the presence of IR carbonyl absorptions for the ester (1740 cm-1), ketone (1720 cm-1) and enone (1680 cm-1) functionalities. The 1H NMR (400 MHz, CDC13) spectrum of 69 also showed the absence of the original vinyl proton (5.17 ppm in the acetate 67) and the appearance of  23 new vinyl protons: 6.16 (1H, dd, J=11, 3 Hz, C(2)H); 6.82 (1H, dt, J=11, 1 Hz, C(1)H) which were downfield, as expected for an a43-unsaturated ketone. Enone 69 is obviously related to the familiar A/B ring system of many terpenoids. It possesses the geminal dimethyl groups at C(4), oxygenation at C(3) and C(7) and the hydroxymethylene group at C(9). As a result we concluded that enone 69 could be a potentially useful intermediate in terpenoid synthesis. A missing structural feature, however, is the C(10) angular methyl group and our next objective was, therefore, to introduce, stereoselectively, a C(10) angular methyl group into enone 69.  1.2.4: Angular Functionalization Approaches  1.2.4.1: Hydroxyl-directed Cyclopropanation  Traditional approaches to introducing an angular methyl group in the synthesis of terpenoids have often included elaboration of the 10-methyldecalin system (cf. 72) by Robinson annulation63 or modifications thereof.64  0 71^  72  Other approaches have also been explored. One of these involves cyclopropanation reactions, and the subsequent opening of the cyclopropane ring provides a methyl group.65 For example, such a sequence was used in a reported synthesis of 10epi-testosterone (77)66 (Scheme 19). Classical Simmons-Smith conditions67 were used to cyclopropanate 73 and provide intermediate 74. The stereochemistry of the cyclopropane ring in 74 derives  24  77  ^  76  Scheme 19 from the established tendency for allylic and homoallylic hydroxyl groups to direct the methylene carbene attack on the double bond so that the cyclopropane ring is formed  cia  to the directing group.68 Not only can an allylic or homoallylic hydroxyl substituent act as a directing group, it also enhances the rate of the cyclopropanation,69 and often may be necessary for reaction to occur at 01.70 Oxidation of 74 followed by removal of the protective group produced intermediate 76. Treatment of 76 with base resulted in removal of a C(4) proton with subsequent opening of the cyclopropane ring and led to the formation of 10-epi-testosterone (77). A second example of a base-promoted cyclopropane ring opening to provide an angular methyl group is shown in Scheme 20.71 In this work, isomeric cyclopropyl alcohols 78 and 80 were both prepared. Treatment of 78 (which has the C(2) hydroxyl group cj to the cyclopropane ring) with KOBut in HOBut and DMSO gave 79 in high yield. However, under identical conditions, 80 (which has the C(2) hydroxyl group trans to the cyclopropane ring) failed to react at all. This result suggests that a ketone adjacent to the cyclopropane ring, in some cases, may not be enough for base-promoted ring  25  HO  KOBut  HO  HOB ut DMSO  KOBut  HO„, HOBut DMSO 81  Scheme 20 opening to occur. A hydroxyl group homoallylic to the double bond from which the cyclopropane ring was derived may also be required to assist in ring opening; furthermore, the stereochemistry of the alcohol can be crucial. Our first attempt to introduce, stereoselectively, a C(10) angular methyl group into enone 69 was based on this methodology (Scheme 21). Thus we considered that deconjugation of the C(1)-C(2) enone double bond in 69 to the C(1)-C(10) position followed by cyclopropanation directed by homoallylic oxygen substituents at C(3) or C(11) would provide intermediate 83. Subsequent cleavage of the cyclopropane ring in 83 could then provide the required angularly methylated intermediate 84. By analogy with the related studies in the steroid area (Scheme 20)71 we also assumed that the hydroxymethyl group at C(9) could assist in the base-promoted ring cleavage reaction. Evaluation of this general approach to angular methylation is outlined in Schemes 22 and 23.  26 OAc^  84  ^  HO  83  Scheme 21 21 Thus treatment of enone 69 with ethylene glycol and p-Ts0H-F120 in refluxing benzene for 45 minutes provided the monoketalized acetate 85 in 77% yield. Further treatment with ethylene glycol and p-Ts0H-1-120 in refluxing benzene overnight provided a mixture of diketal-acetate 86 and diketal-alcohol 87 in 37% and 48% yields respectively. The two compounds could easily be separated chromatographically and the acetate (86) converted to the alcohol (87) by treatment with KOH in aqueous Me0H. The alcohol 87 showed an absence of any C=0 absorptions in its infrared spectrum and the presence of a broad 0-H absorption as expected. The 1H NMR (400 MHz, CDC13) spectrum of 87 showed eight ethylene ketal proton signals. That deconjugation of the double bond had occurred was apparent by the presence of only one vinyl proton signal at 5.33 ppm due to the C(1)H. In addition, the C(10) proton signal in the 1H NMR (400 MHz, CDC13) spectrum of the starting enone (69) was a distinctive broad singlet at 3.06 ppm. This signal was absent in the spectrum of the deconjugated alcohol (87).  27  i  85  69 OH  +  86  87  iii i) P-Ts0H•120, ethylene glycol, C6H6, reflux, 45 min, 77% ii) p-Ts0H•1120, ethylene glycol, C6H6, reflux, -12 h, 37% of 86, 48% of 87 iii) KOH, Me0H, H20, 30 min, 95 c'/c.  Scheme 22 Several classical cyclopropanation reactions on 87 were attempted; unfortunately, none yielded any cyclopropyl-containing product as determined by 1H NMR and mass spectrometry. Table 3 summarizes the reagents used and products obtained. This complete lack of success was unexpected and we concluded that the reaction could be inhibited by steric effects. Examination of the structure of alcohol 87 led to the possibility that either the p C(3) ketal substituent or the 13 C(4) methyl group may be blocking the [3 face of the C(1)-C(10) double bond and preventing cyclopropanation from occurring.  28 Table 3: Conditions used in the attempted cyclopropanation of compound 87 Products  Entry  Reagents  172  CHC13, BuN+Et3C1-, 50% Na0F1(ao  complex mixture  273,74  Et2Zn, toluene, CH2I2, 02  39% recovered alcohol 87 and side-products  367  Zn-Cu, 12, CH212, Et20  17% recovered alcohol 87 and side-products  475  Zn, CuCI, Et20, CH2Br2, TiC14  complex mixture  87  87  Base -01/-  90  Scheme 23  29 We decided, therefore, to remove the C(3) ketal group and use a C(3)0 hydroxyl group to direct the cyclopropanation. For simplicity, and to check the feasibility of this approach, the hydroxymethyl group and the C(7) hydroxyl group obtained after reduction of the C(7) carbonyl group in 66 were protected as methyl ethers (Scheme 24). OCH3  OCH3^  H 91  66  OCH3 92  OCH3 vi OCH3  V 00 OCH3 H^ 94  (—  i) LiAIH4, THF, -78 °C - AT, lh ii) KH, THF, RT, 1h; Mel, RT, lh, 83% (2 steps) iii) 03, CH2Cl2, Me0H, -78 °C, 45 min; Zn, HOAc, AT, 1h; p-Ts0H•120, C6H6, reflux, 1 h, 52% iv) p-Ts0H+120, ethylene glycol, C6H6, reflux, 3 d, 53% v) 1 M HCI, acetone, 70 °C, 15 min, 95% vi)LiAIH4, THE, -78°C - RT, 2h, 89%  Scheme 24 For this purpose keto-alcohol 66 was treated with LiAlat in THF to give a crude diol that was converted directly to its dimethyl ether (91) using KH and MeI in an overall yield of 83%. The diastereomeric ratio resulting from the stereoselective reduction was determined by 1H NMR spectroscopy to be —4:1. Based on the following analysis, the major isomer (91) was predicted to be that with a 0 C(7) methoxy subtituent. There are two considerations when predicting which face of a carbonyl group will be attacked by a hydride reducing agent (or other nucleophile). The first is the presence  30 of substituents which may block the approach of the hydride reagent. In our cyclohexanone derivative 66 these are the C(5) and C(9) axial hydrogens. If the reducing  66  agent is bulky enough, these two substituents would hinder approach from the a face. Therefore, a large hydride reducing agent would approach from the 13 face to give an a-hydroxyl group (i.e. an axial hydroxyl group upon reaction with 66). However, the reducing agent used was LiA11-14 which is relatively small, and may not be subject to severe steric hindrance from the C(5) and C(9) axial hydrogens and therefore a second factor, torsional strain, must be considered. If one looks down the C(7)-C(8) bond of hydrindenone 66, one sees Newman projection A:  a  C  a attack  A  If the hydride approaches from the a face, then the new C-OH bond is formed without eclipsing the vicinal C-H bonds (cf. B). If, however, the hydride approaches from the 13 face, the new C-OH bond is formed with eclipsing of a vicinal C-H bond (cf. C) and this results in torsional strain. When a small reducing agent such as LiA1H4 is used, the torsional strain factor outweighs any other factors and in cyclohexanone derivatives this results, primarily, in the formation of an equatorial hydroxyl group. Thus, LiA1H4  31 reduction of ketone 66 was predicted to result in the p orientation (i.e. in the equatorial position) of the C(7) hydroxyl group. This stereochemistry was not established at this time since it was irrelevant to the cyclopropanation investigation. However, as the synthetic sequence progressed and each compound was purified, the mixture of diastereomers became more and more enriched in the major isomer as small amounts of the minor isomer were separated. The dimethyl ether (91) was treated with ozone and a reductive work-up using Zn and HOAc to give a keto-aldehyde intermediate which was immediately cyclized under acid-catalyzed aldol conditions to give enone 92 in 52% yield (Scheme 24, p. 29). The enone was deconjugated as before by prolonged treatment with p-Ts0H.H20 and ethylene glycol in refluxing benzene to give ketal 93 in 53% yield. The ketal could be removed without reconjugation of the double bond by short (15 min) acid treatment at 70°C to provide deconjugated enone 94 in 95% yield. Infrared spectroscopy showed the C=0 absorption to be at 1714 cm-1, which is significantly higher frequency than what one would expect if the enone were conjugated (cf. 1679 cm-1 in enone 92). The 1H NMR (300 MHz, CDC13) spectrum of 94 showed only one vinyl proton signal at 5.26 ppm due to the C(1)H and the distinctive broad singlet due to the C(10)H at 3.12 ppm in the 1H NMR (400 MHz, CDC13) spectrum of enone 92 was absent. Ketone 94 was reduced with LiA1H4 to give alcohol 95 in 89% yield. Based on the same  rationale described above for the reduction of the C(7) carbonyl group in compound 66, the C(3) hydroxyl group in 95 was predicted to be in the p (i.e. equatorial) orientation. Alcohol 95 was treated with Zn-Cu couple and CH2I2 under classical SimmonsSmith conditions.67 Two compounds were obtained and the 1H NMR (400 MHz, CDC13) spectrum showed these to be mainly unreacted starting alcohol (95) and a compound which was probably the cyclopropanation product (96) as shown by a proton signal at 0.45 ppm. As a satisfactory result could not be obtained under these reaction conditions, cyclopropanation of 95 was attempted using Et2Zn, CH2I2 and 02 (as a rate  32 accelerator).73,74 Under these conditions, cyclopropyl compound 96 was formed, although in an extremely poor yield of 4%! This low yield suggests that the  p C(4)  methyl group (as opposed to the 0 C(3) ketal substituent) may be the cause of the steric hindrance which makes the 13 face of 95 inaccessible. It is unlikely that cyclopropanation would occur from the a face as an alternative because that face is the hindered concave face of 95. Evidence that a small amount of cyclopropyl compound 96 was formed was given by the high resolution mass spectrum of 96 which showed a parent ion peak corresponding to compound 96 (C16H2803 Calc. Mass: 268.2038, Meas. Mass: 268.2029) and the 1H NMR (300 MHz, CDC13) spectrum of 96 showed two characteristic cyclopropyl proton signals at 0.45 and 0.67 ppm. OCH3  OCH 3^  Et2Zn, CH212  toluene, 50 °C OCH3^4%  OCH3  HO 96  Although the cyclopropyl compound 96 was finally obtained, this route to an angular methyl group was not pursued further, due to the unacceptable yields obtained in the cyclopropanation reactions. 1.2.4.2: Radical Cyclization and y-Alkylation Another approach to the stereoselective introduction of an angular methyl group at C(10) involved radical cyclization. It was envisioned that the hydroxymethyl group at C(9) could be used for this purpose. It was expected that a radical intermediate such as 97 (Scheme 25) could undergo radical cyclization to produce the synthetically useful  intermediate 98. Intermediate 97 would be designed such that Y=carbon or a heteroatom  33 such as silicon so that facile cleavage of cyclized product 98 would provide an angularly functionalized decalin (99). CH2—Y 0  0 87  97  99  98  Scheme 25 Literature reports indicate that exo ring closure of the hex-5-enyl radical and analogous systems is kinetically preferred over endo ring closure to give a 5-membered ring product.76,77,78 Bu3Sn'  Br  2% Bu3Sri  b b Bu3Sn'  98%  With radical intermediate 97 (Scheme 25), however, the possible cyclization products were either a 6-membered ring by exo closure or a 7-membered ring by endo closure and  34 it was hoped that in this case a 6-membered ring would form preferentially. It is experimentally observed in the formation of 5- and 6-membered bicyclic ring products that the newly formed ring junction is predominantly da.79,8° Therefore, if 6-membered ring cyclization of radical 97 could be induced, the new bond to C(10) would be expected to be cis to the C(9) group in bicyclic product 98, i.e. the C(10) substituent would be in the 13 orientation, as required. The carbon-centered radical is usually formed from a bromide, and the two-atom chain in intermediate 97 should be such that the Y-0 bond in 98 can ultimately be cleaved to give angularly functionalized decalin 99.  Stork and co-workers79,81 have used compounds such as 100 and 102 and have shown that 6-membered ring formation is possible using the acetal linkage in 102 (Scheme 26). 65%  OEt 90%  102 CO2Me^  103 C°2Me  Scheme 26 More recently, Koreeda and co-workers82 have reported successful 6-membered ring formation using the bromomethyldimethylsilyl chain tethered to an allylic hydroxyl group (Scheme 27).  ^  35  :  104  ^  105  Scheme 27  The silicon tether appealed to us because it is easily cleaved, either reductively with TBAF in DMF/THF to give Y'=H, or oxidatively using 30% H202 and 1CF in DMF to give Y1=0H in 99 (Scheme 25, p, 33).82,83,8485 Therefore, both the possibility for introducing an angular methyl group or an angular aldehyde existed. Although an angular methyl group is more common, some natural products exist in which this methyl group has been oxidized. Our route is outlined in Scheme 28. \•\S / i■ r^Si B^ \./ 0^/ 0 i  87  00  ii  0 ( E \,.-0 H 0 106  107  OH  r 0^0 (..0 H 0%) 108  109  i) BrCH2SiMe2CI, Et3N, DMAP, CH2Cl2, RT, 30 min, 76% ii) Bu3SnH, AIBN, C6H6, reflux, 7 h, 79%  Scheme 28  36 The diketalized alcohol (87), obtained as before (Scheme 22, P. 27) for use in the cyclopropanation work, was treated with bromomethyldimethylsilyl chloride, Et3N and DMAP in CH2C12 for 30 minutes to give the silylated alcohol 106 in 76% yield. Bromine abstraction and radical formation was induced by Bu3SnH in refluxing benzene using AIBN as initiator. Both concentrated conditions with rapid Bu3Stifl addition and highly dilute conditions with Bu3SnH addition over hours were tried. In all cases, no cyclization products were detected, and only the reduction product 107 was formed in 65-80% yield. The structure of the latter compound was confirmed by the presence of one vinyl proton signal at 5.18 ppm and a singlet due to the trimethylsilyl protons at 0.10 ppm in the 1H NMR (400 MHz, CDC13) spectrum of 107. A small sample of 107 was treated with TBAF in THF and the product from this reaction was identical to starting alcohol 87, further confirming the structure of 107. The fact that reduction rather than cyclization had occurred shows that hydrogen radical abstraction to quench the initially formed methylene radical is faster than interaction with the double bond. The usual source of the quenching hydrogen radical is Bu3SnH and a common solution to this type of problem is to use high dilution techniques.86 However, these reaction conditions also failed to induce cyclization and therefore another source of the quenching hydrogen had to be considered. Stork has reported that in homoallylic systems, [1,5] hydrogen atom transfer is common (Scheme 29).79 If compound 110, for example, is treated with Bu3SnH and AIBN, the major product is the cyclized compound 111; however, significant amounts of 112 are also produced. It is believed that 112 is formed by quenching of the radical that  is initially formed at position 1, not by hydrogen radical abstraction from the Bu3SnH, but from the hydrogen that is present in 110 at position 5.  37 OEt  Bu3SnH AIBN  110  111  112  ..7  1 rOEt  Bu3SnH  H  90% yield H^cyclization product  AIBN  114 c02me  Scheme 29 In our case, this hydrogen atom source is the C(9) hydrogen. A possible solution to the problem is to replace the C(9) hydrogen with an alkyl group; however, in view of our general synthetic objectives, this approach was not investigated. OH  Co  L)  CO  H 0■.)^  0R  0■)  Stork has also reported that conjugating the double bond with an ester or ketone functionality leads to increased yields of cyclization product and decreased yields of reduction product (Scheme 29).79 Thus, introducing an ester group at the C(1) position of our compound 87 may encourage cyclization. Again, however, this solution would involve too many steps to be practical.  38  A final solution would be to convert our homoallylic system to an allylic system  by conversion of the hydroxymethyl group at C(9) to a hydroxyl group. Thus, [1,5] hydrogen abstraction is no longer a problem, and it is expected that the 5-membered ring cyclization product would form in reasonable yield. This idea is unattractive, however, because it involves losing an important carbon atom of the terpenoid framework. Also, during either its removal or re-introduction at a later stage, the C(9) center would likely become trigonal with subsequent loss of the initially introduced stereochemistry. OH  Although the radical cyclization route was unsuccessful, we thought that the bromomethyldimethylsilyl group used in that approach might be useful as an intramolecular alkylating agent. An enone functionality in ring A of our decalin system was readily accessible to us as a result of the ring expansion sequence described previously (Scheme 18, p. 22). Extensive investigations by Fleming and Paterson have led to the recommended use of electrophiles such as 1,3-dithienium fluoroborate and chloroalkylphenyl sulfides for the y-alkylation of dienolates.87 However, even in cases where the yields of the y-alkylated products were reasonable, the alkylations have not  39 been stereoselective and few have been reported where the y position has been tertiary. Scheme 30 shows some representative examples.87  TMSO  OTMS  116, 8:1^6a: 63  PhSC1  ^V.-  30% 118  11 7  TMSO Pri2CHO  PhSCH2C1 91%  11 9  SPh  Pri2CHO  + Pri2CHO  120, E:Z^70:30^1 2 1  80  SPh 20  Scheme 30 In our work, y-alkylation at the C(10) position must be stereoselective for this route to be synthetically useful, as a C(10) methyl group or equivalent is tertiary and therefore not epimerizable.  OR  40 Thus we considered the possibility of achieving stereoselective y-allcylation by an intramolecular approach that involved the use of the bromomethyldimethylsilyl group in 122 (Scheme 31) as a potential alkylating agent. OAc^  OH  H 0 122  85  ii  III  124  ^  123  i) KOH, Me0H, H20, RT, 30 min, 86% ii) CISi(Me)2CH2Br, Et3N, DMAP, CH2C12, RT, 30 min, 100% iii) LDA, THF, -78°C to RI or KH, THF, AT  Scheme 31 The monoketalized acetate 85, obtained as before (Scheme 22, p. 27), was treated with KOH(aq) and Me0H for 30 min at room temperature to provide alcohol 122 in 86% yield. This was converted quantitatively to the silyl ether 123 using bromomethyldimethylsily1 chloride, Et3N and DMAP in CH2C12. Upon treatment with base, it was hoped that alkylation to compound 124 would occur. With compound 123, a-alkylation is hardly possible as the C(2) center is far from the bromomethyl terminus; however, the y, or C(10), position is in reasonable proximity for a 6-membered ring to be formed. As  41 in the radical cyclization approach, it was assumed that if this 6-membered ring could be formed, the C(10) stereochemistry of 124 would be dictated by the C(9) stereochemistry of 123 and therefore would be 13 as desired. As before, the silicon could be either oxidatively or reductively removed from compound 124 to give an angular C(10) aldehyde or methyl group. Unfortunately, however, treatment of 123 with either LDA or KB in THT gave a mixture of products. In both cases, some alcohol 122 was isolated (20-35% yield), a result of silyl ether cleavage. None of the other products isolated were identified, but they were not y-allcylation products, as determined by 1H NMR and mass spectrometry. As a result, this approach to the introduction of a C(10) angular methyl group was also abandoned. 1.2.4.3: Anionic Oxy-Cope Rearrangement A final approach to introducing an angular methyl group into our A/B decalin system involved a second anionic oxy-Cope rearrangement. It was previously shown in connection with our C(3) hydroxyl-directed cyclopropanation approach (Scheme 24, p. 29) that the A ring enone in 92 could be deconjugated to give 94 and the ketone (94) was subsequently reduced. If, however, a vinyl group were added to the ketone of a similar deconjugated derivative (125, Scheme 32), a 1,5-diene (126) would be produced which could potentially undergo anionic oxy-Cope rearrangement to provide 127.  1 25  Scheme 32  42 It is expected that a small nucleophile such as vinylmagnesium bromide would attack as a small hydride reducing agent does, that is, to give a 13 hydroxyl group at C(3) as in structure 126. If anionic oxy-Cope rearrangement were successful, the C(2)-C(3) bond in 126 would be broken as the vinyl terminus forms a bond to C(10). As the vinyl group was originally added a to the C(3) ketone in 125, it must also attack the C(10) position from the a side, and becomes part of the new ring A in structure 127. The newly formed C(10) vinyl group actually originates from the A ring of 125 and therefore has 13 stereochemistry. There were two concerns with this approach. Firstly, the C(3) ketone in 125 is quite hindered due to the geminal dimethyl groups at C(4). Vinyl addition could be a problem, since the nucleophile can potentially act as a base and abstract a proton at C(2) instead of adding to the hindered carbonyl group of 125. Secondly, anionic oxy-Cope rearrangements are quite sensitive to steric hindrance, and thus in a fairly substituted compound such as 126, the rearrangement might not occur. However, upon examining molecular models, it was felt that the system was only moderately hindered and that this approach should be attempted. An advantage of this route is that, if created, the angular group in 127 is vinyl and therefore has the potential of being converted to either a methyl group, or an oxidized substituent (eg. -CHO or -CO2R). The synthetic route to the required deconjugated enone (135) is shown in Scheme 33. The trans alkene diol (64, obtained as before, Scheme 17, p. 21) was reacted with TBDMSC1 and imidazole in DMF to give primary silyl ether 128 in 97% yield. Anionic oxy-Cope rearrangement using n-BuLi in THF at 40 °C for 15 minutes gave hydrindenone 129 in 73% yield. L-Selectride® reduction of 129 at -78 °C in THF gave alcohol 130 in 78% yield. As this hydride reducing agent is bulky, approach from the a face of the carbonyl group would be hindered by the 1,3-diaxial hydrogen atoms and therefore addition from the 13 face would be preferred. Thus we assumed that the hydroxyl group in 130 is axial (a).  43  OH^ii  / OTBDMS 64  H 129  128  OTBDMS  OTBDMS iv  I  •0 li^'''" OC H3 H 131  132  H 130  "OH  vi OTBDMS  OTBDMS vii  00 17:i^gi'OCH 3 133  H 134^  A  "OC H3  135  i) TBDMSCI, DMF, imidazole, RT, 12 h, 97% ii) n-BuLi, THF, 40 °C, 15 min, 73% iii) L-Selectride, THE, -78 °C, 1.5 h; 30% H202, NaOH, H20, -78 °C to AT, 78% iv) KH, THF, RT, 1.5 h; Mel, RT, 12 h, 95% v) 03, CH2Cl2, Me0H, -78 °C, 30 min; Zn, HOAc, RT, 1.25 h; p-Ts01-1•1120, C6F16, reflux, 3 h, 28% yield vi) ethylene glycol, C6H6, reflux, 24 h, 25% vii) 1 M HCI, acetone, 70 °C, 30 min, 97% viii) TBDMSCI, imidazole, DMF, RT, 12 h, 95%  Scheme 33 Protection of this hydroxyl group as its methyl ether was accomplished using KH and Mel in THF at room temperature to give 131 in 95% yield. Ring expansion of compound  131 using ozonolysis, reductive work-up and acid-catalyzed aldol condensation provided enone 132 in only 28% yield. The low yield of 132 was believed to be due to the acid sensitivity of the TBDMS protective group, which was partially hydrolyzed under these conditions and caused by-products to be formed. The analogous reaction using acetate or  44 methyl ether as the protective groups proceeded in good yield. At this point, however, the sequence was continued with the TBDMS ether. Ketalization of 132 using ethylene glycol and p-Ts0H•H20 in refluxing benzene for 24 hours gave 133 in only 25% yield. Again, the low yield is attributed to the poor choice of protective group. When the ketal in 133 was removed using 1 M HC1 and acetone at 70°C, the keto-alcohol 134 was obtained in 97% yield. Under these acid conditions, the TBDMS group was hydrolyzed completely; however, in this reaction no side-products were obtained and the yield was not adversely affected. In the last step, the primary alcohol was re-protected to give the TBDMS ether 135. Both infrared and 1H NMR spectroscopy confirmed that the double bond was deconjugated to the C(1)-C(10) position in structure 135. The carbonyl absorption in the infrared spectrum was at 1715 cm-1, a significantly higher frequency than that of the carbonyl absorption at 1680 cm-1 in the spectrum of the conjugated enone 132. The 1H NMR (400 MHz, CDC13) spectrum of 135 showed only one vinyl proton signal at 5.23 ppm as compared to the two downfield signals (5.97 and 6.78 ppm) seen in the spectrum of the enone 132. Also, the characteristic broad singlet at 3.18 ppm due to the C(10)H of the enone 132 was absent in the spectrum of 135. Freshly prepared vinylmagnesium bromide was added to ketone 135 (Scheme 34) to give alcohol 136 in 57% yield. Because the C(3) carbonyl group in 135 is somewhat sterically hindered due to the geminal dimethyl groups at C(4), we were concerned that deprotonation at C(2) to form an enolate may compete with vinyl addition to the carbonyl group. Imamoto and co-workers88 have reported improved yields of addition products when the Grignard reagent is complexed with CeC13. The complexed reagent has increased nucleophilicity and decreased basicity and therefore there is a reduced tendency to form the enolate of the substrate ketone. Thus addition is favored, and fewer side reactions such as reduction or condensation reactions are observed. We therefore tried the conversion of 135 to 136 using vinylmagnesium bromide complexed to CeCI3, but found no improvement in yield. In fact, only 6% of alcohol 136 was isolated, in addition  45 to 6% of starting ketone 135. Although the CeC13 methodology is useful for reaction with highly enolizable ketones, it is also very sensitive in practice (rigorous drying of the initial CeC13•7H20 is essential) and, in fact, led to a decrease in yield in our conversion of 135 to 136.  135  ^  136  ^  137  138  i) CH2=CHMgBr, THF, reflux, 1h, 57% ii) KH, THF, 18-cr-6, reflux, 12 h, 16% ill) KHMDS, 18-cr-6, AT, 21 h, 98% iv) KH, THF, 0 °C, 30 min; Mel, 0 °C, 20 min,12% v) KH, 18-cr-6, xylenes, reflux, 2 days  Scheme 34 Anionic oxy-Cope rearrangement of 136 was attempted using the commonly used conditions of KH and 18-crown-6 in refluxing THF. After 12 h, the only isolated product was alcohol 137 in 16% yield. A similar reaction using KHMDS and 18-crown-6 in THF at room temperature also gave 137 in 98% yield. There was no evidence of any anionic oxy-Cope rearrangement product, as shown by the lack of a C=0 absorption in the infrared spectrum of any side-products. Once again, it was apparent that the TBDMS protective group was unstable and therefore attempts were made to convert the primary alcohol (137) to its methyl ether (138) using KH and Mel in TI-IF at 0 °C. Unfortunately this product (138) was obtained in only 12% yield, although enough was obtained to attempt the anionic oxy-Cope rearrangement under more rigorous conditions. The yield  46 of 138 was not optimized; in fact, in the C(3) hydroxyl-directed cyclopropanation work described on p. 29 it was found that protection of the C(11) and C(7) hydroxyl groups early in the synthetic sequence occurred in good yield and avoided the problems encountered here. However, it was established that the low yield of 138 was due to side reactions such as dimethylation, and was not due to anionic oxy-Cope rearrangement occurring during the protection. This was confirmed by the lack of a carbonyl absorption in the infrared spectrum of the crude reaction mixture before isolation of 138. While these investigations were proceeding, COSY and NOE 1H NMR experiments were done in an attempt to confirm the assumed stereochemistries at C(3) and C(7). Both experiments were performed on a CDC13 solution of compound 138 using a 400 MHz spectrometer and the following structure shows the numbering used to assign proton resonances in both analyses.  H13^  138  Table 4 shows the results of the COSY experiment. Chemical shift and proton assignments are listed in columns 1 and 2. Chemical shifts and assignments of protons coupled to the signal listed in column 1 are shown in columns 3 and 4. Signals which showed no coupling, such as the geminal dimethyl groups at C(4) are omitted for simplicity. In the case of the signal at 2.11 ppm, this was a multiplet due to three overlapping signals and therefore three protons are assigned to the one signal. The COSY experiment confirmed all proton assignments, although axial and equatorial C(8), C(6) and C(2) protons were not distinguished. The NOE experiment results are shown in Table 5. The chemical shift of the irradiated signal is shown in column 1 with the corresponding proton assignment in column 2. Any resonance which  47 was affected by the irradiation is shown in column 3, with the proton assignment of that signal in column 4.  Table 4: Results of COSY experiment done on compound 138 Signal (ppm)  Proton Assingment  Coupled Signal (Ppm) 2.11 2.51 3.67  Assignment of Coupled Proton  1.24  C(8)H  1.28  C(8)H  2.11 2.51  C(6)H C(9)H  1.58  C(5)H  2.11  C(6)H  2.11  2x C(6)H and C(2)H  1.24 1.28 1.58 3.67  C(8)H C(8)H C(5)H C(7)H  C(6)H C(9)H C(7)H  2.19  C(2)H  5.27  C(1)H  2.51  C(9)H  1.24 1.28 3.45 3.57  C(8)H C(8)H C(11)H C(11)H  3.45  C(1 1)H  2.51  C(9)H  3.57  C(11)H  2.51  C(9)H  3.67  C(7)H  1.24 1.28 2.11  C(8)H C(8)H C(6)H  5.11  H(13)  5.30 6.09  H(14) H(12)  5.27  C(1)H  2.19  C(2)H  5.30  H(14)  6.09  H(12)  6.09  H(12)  5.11  H(13) H(14)  5.30  48 Table 5: Results of NOE experiment done on compound 138 Irradiation (ppm)  Proton Assignment  1.24 1.28  C(8)H C(8)H  2.11  2x C(6)H and C(2)H  2.19  C(2)H  3.45  C(1 1)H  3.57  C(11)H  3.67  C(7)H  5.11  H(13)  6.09  H(12)  Enhanced Signal (ppm) 2.11 2.11 3.67 0.90 1.24 3.67 5.27 6.09 0.90 1.58 5.27 6.09 2.51 5.27 2.51 5.27 1.24 2.11 5.27 6.09 0.90 1.58 2.19 5.11 5.27  Assignment of Enhanced Signal C(6)H C(6)H C(7)H C(4)Me C(8)H C(7)H C(1)H H(12) C(4)Me C(5)H C(1)H H(12) C(9)H C(1)H C(9)H C(1)H C(8)H C(6)H C(1)H H(12) C(4)Me C(5)H C(2)H H(13) C(1)H  Overall, the NOE experiment re-confirmed the proton assignments obtained from both the COSY experiment and analysis of the simple one dimensional 1H NMR spectrum of compound 138. As the C(6) and C(8) axial and equatorial protons could not  49 be distinguished, there was no direct evidence that the C(7) proton was equatorial (p). However, the stereochemistry of the hydroxyl group formed at C(7) by L-Selectride® reduction of a similar derivative (157) was unambiguously established to be axial (a) by X-ray crystallographic analysis as discussed on p. 54 and one can therefore infer that the C(7) methyl ether group is also axial (a) in 138. The NOE experiment was useful in confirming the stereochemistry at C(3). When the signal due to the C(2)H was irradiated (2.19 ppm) there was an enhancement seen in the C(5)H signal at 1.58 ppm. The stereochemistry of the C(5)H was definitely a (axial). This was a result of the original anionic oxy-Cope rearrangement used to obtain the hydrindenone intermediate (129) from the 5,6-dehydrocamphor derivative (64) (Scheme 33, p. 43). Since the C(5)H and the C(2)H are near enough to experience an NOE effect, it can be deduced that the C(2)H at 2.19 ppm must be a (pseudo-axial). The H(12) proton on the vinyl group also experienced enhancement when the C(2) a H was irradiated. Therefore, the vinyl substituent at C(3) is assumed to be a also. Further confirmation of this C(3) stereochemistry is seen when the H(12) signal at 6.09 ppm is irradiated. The C(5)H signal showed enhancement, again suggesting that the vinyl group at C(3) is a. With the stereochemistry at C(3) established, compound 138 was treated with KH and 18-crown-6 in refluxing xylenes. This time, with methyl ethers as the protective groups, no side-products were formed. Yet even after 2 days under these rigorous conditions, no anionic oxy-Cope rearrangement occurred. Starting alcohol 138 was almost quantitatively recovered (98% yield). Although this result was disappointing, it is known that the anionic oxy-Cope rearrangement is sensitive to steric effects. A striking example of this sensitivity was reported by Koreeda and co-workers89 in their route to desmosterol. When the steroidal derivative 140 (Scheme 35) was treated with KR in refluxing dioxane for 1 h, ketone 141 was obtained in 94% yield. The stereospecific generation of the 20R stereochemistry was attributed to a chair-like transition state (144).  50  KH, dioxane reflux, lh 94% 141  140  KH, dioxane reflux, lh 143  144  147  Scheme 35 When the isomeric alcohol 142 was treated under the same reaction conditions, no anionic oxy-Cope rearrangement occurred; instead, a mixture of E and Z isomers of enone 143 was isolated. That absolutely no anionic oxy-Cope product was obtained when the Z isomer (142) was used was attributed to a quasi 1,3-diaxial interaction between the C(16)-alkoxide and the C(20)-methyl group in the chair-like transition state (146).  In our alcohol 138 one could envision a similar steric interaction in the transition state: as the vinyl terminus approached the a face to form a bond to C(10), it would  51 experience steric interaction with the substituents at C(5) and C(9), presumbably sufficient to prevent any rearrangement of 138 from occurring. The product (139) that would be obtained upon rearrangement has a 1,3-diaxial interaction between the newly formed vinyl group at C(10) and the 0 C(4) methyl group and the interaction in the transition state that leads to this steric arrangement may also prevent reaction of 138. --,, io^OCH3  _ .10.-  H  H 1 H OCH3 139  As this route, also, failed to provide any angularly functionalized product, we decided to re-direct our approach by introducing the C(10) methyl group at a much earlier stage in the synthetic sequence. This new approach will be discussed later in Section 1.2.6, p. 59.  1.2.5: Elaboration of A and B Rings  In the course of the angular methylation work, we also investigated the functionalization of positions other than the C(10) center of our decalin system.  52 Many natural products contain oxygen functionality at the C(1) position, as well as an alkyl substituent at C(8). Therefore, another objective was to use the existing oxygen substituents at C(3) and C(7) to introduce these functionalities. 1.2.5.1 In Situ Methylation There have been several reported examples where the enolate resulting from anionic oxy-Cope rearrangement has been utilized to introduce further functionality. In their approach to the ophiobolin ring system, for example, Paquette and co-workers reported90 in situ methylation of such an enolate (Scheme 36).  Li , THF, -78 °C  148  411■■  149  MEV  Mel  151  IMMI■  Scheme 36 Treatment of ketone 148 with the lithium anion generated from 1-bromocyclopentene at -78 0C in THF resulted in addition followed by anionic oxy-Cope rearrangement of the intermediate alkoxide 149. That this rearrangement occurred at such a low temperature is attributed to a low activation energy due to the decrease in  53 strain when the 4-membered ring is cleaved. The resulting enolate (150) was treated in situ with methyl iodide and the methylated ketone 151 was isolated in 96% overall yield. In an analogous fashion we expected that anionic oxy-Cope rearrangement of 152 (Scheme 37) followed by in situ methylation of the intermediate enolate (154) would provide bicyclic ketone 155 with the required methyl group at C(8). To evaluate this proposal the primary hydroxyl group in 64 was selectively protected using KH and Mel  _ i  OCH3 64  OCH3  152  153  VINO  1  IMIL  -  -41(^  154 —^  155  —  ONE,  iii  158  157  ANN  156  i) KH, THF, 0 °C, 15 min; Mel, 0 °C, 45 min, 63% ii) KH, THF, 40 °C, 20 min; Mel, -78 °C to AT, 12 h, 92% iii) L-Selectride, -78 °C, THF; H202, NaOH, 79%  Scheme 37  11•1••  54 in THF at 0 0C to give methyl ether 152 in 63% yield. Upon treatment with ICH in THF at 40 0C, anionic oxy-Cope rearrangement of 152 occurred and when the rearrangement was complete, (as indicated by TLC and GC), the reaction mixture was cooled to -78 °C and Mel was added. The product of this reaction was obtained in 92% yield and our initial assumption was that the expected product 155 had been formed. That methylation had occurred was established by the presence of a new methyl proton signal (1.19 ppm, 3H, d, J=8 Hz) in the 1H NMR (400 MHz, CDC13) spectrum. Overlapping signals made proof of the position of the new methyl group difficult via NMR techniques such as NOE and COSY experiments. Therefore, the methylated ketone was stereoselectively reduced to a crystalline alcohol using L-Selectride® in THF at -78 °C. Subsequent X-ray crystallographic analysis led to structure 158 being assigned to this compound and hence the original ketone was assigned structure 157. This evidence established the totally unexpected result that the newly introduced methyl group was in the 6a (equatorial) position and not at C(8) as originally predicted. This result will be discussed further, but first it is pertinent to point out that the structure of 158 confirmed assumptions previously made (cf. p. 22) about stereochemistry of the product in our anionic oxy-Cope rearrangements. Thus it was originally postulated that as a result of the anionic oxy-Cope rearrangement of 152 the ring junction in the product 157 would be g. Furthermore, if the alkene diol 64 was trans (as predicted from the LiA1H4 reduction of alkyne 63 shown in Scheme 17, p. 21) then the hydroxymethyl group at C(9) would be trans to the ring junction hydrogens. Finally, reduction of the carbonyl at C(7) in 157 was predicted to give a C(7) a (axial) hydroxyl group in 158 since L-Selectride® is a bulky hydride reducing agent. All of these assumptions were validated by the X-ray crystallographic analysis of 158. That the methylation occurred at the C(6) and not the C(8) position in 157 suggests that the enolate resulting from anionic oxy-Cope rearrangement (154) equilibrated to 156 before alkylation occurred (Scheme 37). Such an isomerization,  55 although unusual (and unknown to us at the time), is not unprecedented. In their approach to forskolin, for example, Paquette and co-workers have reported a similar result (Scheme 38).91  i Me0  160  ii  162  AIIIMMINNI  161  1=1■••  i) KH, THF, RT, 60 min; 18-cr-6, 70 °C, 20 min ii) PhSeCI, -78 °C, lh, 79% (from 159)  Scheme 38 Upon treatment with KH and 18-crown-6 in refluxing THF, alcohol 159 underwent anionic oxy-Cope rearrangement to provide intermediate 160. In situ treatment with PhSeC1 at -78 0C provided 162 in 79% yield. The position of the PhSesubstituent at C(6) in 162 rather than at C(8) shows that enolate 160 must have isomerized to enolate 161. Another example of enolate isomerization was reported by Evans and Golob.6 In this first report of anionic oxy-Cope rearrangement, the enolate resulting from rearrangement of 163 was trapped as its enol silyl ether using TMSC1 (Scheme 39).  56  OH  KH, TFIF RT, 20 h  163  OTMS Me0  TMSC1  Me0  A 165 + H  OTMS TMSC1  Me0  Me0  H 167  : H 166  Scheme 39 In this case, the enolate did not isomerize completely, but a 1:9 mixture of isomers 165:167 was obtained. The minor isomer (165) is the one actually derived from the initially formed enolate (164) of the anionic oxy-Cope rearrangement, and the major isomer (167) was derived from the isomerized enolate (166). It is generally assumed that for an enolate to isomerize, a proton source must be present so that the parent ketone is formed. Subsequent loss of a proton to form the thermodynamically more stable enolate can then occur. In all the reported examples, a possible proton source is the starting alcohol if the rearrangement is faster than initial deprotonation. To our knowledge, no examples of enolate isomerization have occurred without an alcohol as the starting material. For example, anionic oxy-Cope  57 rearrangement can occur after nucleophilic addition to a ketone, such as described on page 52. In cases such as this, where the starting material is a ketone and the source of the alkoxide is not deprotonation of an alcohol, no isomerization occurs. Our own work in the in situ rearrangement of an alkoxide derived from Grignard addition to 5-methyl5,6-dehydrocamphor (178) is discussed in Section 1.2.6.2 (p. 64). Trapping of the enolate in this case showed no evidence of isomerization and this supports the theory that a proton source such as an alcohol is necessary for enolate equilibration to occur. 1.2.5.2: C(1)-Oxygenation of Ring A In 1989 Ayer and Craw92 reported the isolation and structural elucidation of several natural products which lacked the angular methyl group usually present at C(10) in terpenoids (e.g. 175-177, Scheme 40). It was apparent that our decalin system (69) could be a key intermediate in the synthesis of these compounds if we were able to introduce oxygen functionality at C(1). This was accomplished by the following synthetic sequence. Enedione 69 was monoketalized and the acetate protective group removed as described previously (p. 27 and p. 40) to give 122. Protection of the C(11) hydroxyl group using TBDMSC1 and imidazole in DMF at room temperature for 12 h gave 168 in 99% yield. Epoxidation of the A ring enone was accomplished using alkaline H20293 in Me0H. Epoxide 169 was obtained in 80% yield and its structure was supported by the carbonyl absorption at 1705 cm-1 in its infrared spectrum which was at significantly higher frequency than that of the enone 168 (1675 cm-1). The 1H NMR (400 MHz, CDC13) spectrum of 169 showed characteristic signals for the C(1) and C(2) protons: 3.14 (1H, d, J=3 Hz, C(1)H) and 3.45 (1H, br s, C(2)H). These protons were significantly more upfield than in the 1H NMR (400 MHz, CDC13) spectrum of enone 168 (5.98 ppm, 1H, dd, J=10, 3 Hz, C(2)H and 6.78 ppm, 1H, dt, J=10, 2, Hz, C(1)H), as expected. Epoxide 169 was opened using NaSePh which was generated in situ from  58 ,  OTBDMS  11 OH^  1  168  69  iv OTBDMS  vi  170  171  #  ,  , ,,  OTBDMS  OTBDMS  HO  ,  MS0^9 H 0 173  174  2  176, R1 =OH, R =H, 3a-hydroxyoreadone 1 2 177, R =H, R =CHO, 0-formyloreadone  i) ethylene glycol, p-Ts0H•1-120, C6H6, reflux, 45 min, 77% ii) KOH, Me0H, 1120, RI, 30 min, 86% iii) TBDMSCI, imidazole, DMF, RI, 12 h, 99% iv) H202, NaOH, H20, Me0H, RI, 2h, 80% v) NaBH4, PhSeSePh, Et0H, RI, 12 h, 60% vi) TBDMSOTf, 2,6-lutidine, RI, 3 h, 50%  Scheme 40 PhSeSePh and NaBH4 according to the method of Sharpless and Lauer." The use of this reagent for the reduction of a,13-epoxyketones was first reported by Yoshikoshi and  59 co-workers in 1987,95 and gave the desired keto-alcohol 170 in 60% yield. The enone (168) resulting from dehydration was also isolated in 10% yield. Therefore the unstable  keto-alcohol (170) was immediately protected using TBDMSOTf and 2,6-lutidine in CH2C12 to give the silyl ether 171 as a crystalline compound in 50% yield. X-ray crystallographic analysis confirmed the structure of 171 and established the a C(1) protected hydroxyl group stereochemistry. Thus, it was established that the epoxidation of enone 168 occurred from the a face to give 169. Having successfully introduced oxygenation at C(1), this investigation was not carried further. However, structural similarities between intermediates 169 and 171 and target structures 175-177 are obvious and it seems reasonable to assume that appropriate functional group transformations could lead to advanced intermediates for the synthesis of these compounds. Reduction of the C(3) carbonyl group in 171 would lead to the A ring of 176, whereas deoxygenation using classical techniques such as thioketalization96 followed by Raney nickel desulfurization97 would lead to 177. The epoxide 169 could be converted to mesylate 173 for elimination and ring opening98 to 174. Alternatively, epoxide 169 could be directly converted to 174 using a Wharton99 reaction. In addition to these transformations, the cis ring junction of our intermediates must be converted to  trans, presumably via an epimerization of the C(10) proton as there exists a carbonyl group at the adjacent C(1) center in the natural products 175-177.  1.2.6: Evaluation of 5-Methyl-5,6-dehydrocamphor (178) as an Intermediate in Terpenoid Synthesis Since we were unable to angularly functionalize the decalin system obtained after our initial anionic oxy-Cope rearrangement, we decided to introduce the methyl group much earlier in our sequence. Our overall synthetic plan (Scheme 41) remained similar to our orignal route to a decalin system; however, the methyl group which would  60 ultimately become the C(10) methyl group in the decalin system (181) would originate from the camphor derivative (178) which would be the precursor to the 1,5-diene (179) used in the anionic oxy-Cope rearrangement.  178  25  RO  1 1 1  RO 182  ^  181  ^  180  Scheme 41  The simplest such camphor derivative is 5-methyl-5,6-dehydrocamphor (178). For the C(10) methyl group to have 13 stereochemistry, as in 180, the 5-methy1-5,6dehydrocamphor (178) must have the absolute configuration shown in Scheme 41. As before, formal addition of an appropriately substituted alkene to 178 would provide a 1,5-diene (179) which has the potential of undergoing anionic oxy-Cope rearrangement to provide a hydrindenone such as 180. Since the desired stereochemistry of a C(9) substituent in 180 is 0 (i.e. cis to the ring junction protons), the double bond of alkene 179 must be cis. It was proposed that if the anionic oxy-Cope rearrangement of 179 to 180 were successful under these steric requirements, the hydrindenone 180 would be expanded to a decalin such as 181 using the ozonolysis, reductive work-up and acidcatalyzed aldol condensation sequence described earlier. Finally, the ring junction would  61 be converted from gia to trans; the C(5) proton could presumably be epimerized via an enone derived from the ketone at C(7) and subsequent reduction.  1.2.6.1: Synthesis of 5-Methyl-5,6-dehydrocamphor (178)  Our first objective was the enantiospecific synthesis of (+5-methy1-5,6-dehydrocamphor (178) and this was accomplished by the reaction sequence shown in Scheme 42.  cf Scheme 15, p.18 C 0 61  II  59  vii  vi  i) AgBF4, DMSO, RI, 12 h; Et3N, RT 1h, 43% 183, 40% 184 ii) 1 M HCI, acetone, RT, 1 h, 100% iii) 48% HBr, Ac20, 65°C, 3 h, 78% iv) ethylene glycol, TMSCI, RI, 2.5 h, 92% v) Tf20, 2,6-di-t-butyl-4-methylpyridine, CH2Cl2, RI, 4 h, 95% vi) Me2CuLi, Et20, -20 °C, 2 h, 93% vii) 1 M HCI, acetone, RI, 15 min, 95%  Scheme 42  62 raQ-5-Bromocamphor ketal (61) was obtained from commercially available (+)-endo-3bromocamphor (52) in 4 steps as previously outlined in Scheme 15, p. 18. A modificationloo of the Komblum101 oxidation using AgBF4 and DMSO followed by Et3N gave the desired 5-ketocamphor ketal (183) in 43% yield and cyclocamphanone ketal (184) in 40% yield. If the mechanism of this reaction is similar to other DMSO oxidations such as the Swern102 oxidation, then one can assume that an intermediate ylide (187) is formed (Scheme 43).  b  =  Co  I ,) 1^SI : ....  H^H _ CH2  1  '■^ b  187  187  b  CO //' C1 Scheme 43 Subsequent removal of a C(5) proton via path a gives the desired ketone 183, whereas loss of a C(3) proton via path b gives the by-product 184. As these two compounds were formed in a 1:1 ratio, both protons must be equally accessible. The by-product 184 was easily recycled, however, to eILQ-5-bromocamphor ketal (61). Acid hydrolysis of the ketal in 184 provided cyclocamphanone (59) quantitatively. el_Q-5Bromocamphor ketal (61) was originally synthesized from cyclocamphanone (59) by hydrobromic acid ring opening to give 60 and ketalization to give 61 as shown previously in Scheme 15, p. 18.  63 The structure of ketone 183 was supported by the infrared spectrum which showed a strong carbonyl absorption at 1752 cm-1. The 1H NMR (400 MHz, CDC13) spectrum of 183 showed the absence of the C(5) endo proton signal which was a distinctive doublet of doublets (J=8, 5 Hz) at 4.05 ppm in the spectrum of bromide 61. Mass spectrometry also showed the absence of characteristic twin peaks due to brominecontaining fragments, and the high resolution spectrum showed the exact mass of the ketone 183 as expected (Calc. Mass: 210.1256, Meas. Mass: 210.1259). Ketone 183 was treated with trifluoromethanesulphonic (triflic) anhydride and 2,6-di-t-butyl-4-methylpyridine103 in CH2C12 to provide enol triflate 185 in 95% yield. The infrared spectrum of 185 showed the absence of the carbonyl absorption and the 1H NMR (400 MHz, CDC13) spectrum showed a characteristic vinyl proton singlet at 5.34 ppm due to the C(6) proton. Enol triflate104 185 was coupled with Me2CuLi (prepared in situ from CuBr•DMS and MeLilo) and 5-methyl-5,6-dehydrocamphor ketal (186) was obtained in 93% yield; the new vinyl methyl group at C(5) appeared at 1.62 ppm in the 1H NMR (400 MHz, C6D6) spectrum of 186. Unfortunately, ketal 186 obtained in this way was always contaminated with a small amount (-5%) of 5,6-dehydrocamphor ketal (62), resulting from protonation of the intermediate in the coupling reaction. We have no explanation for this result, but found that optimum conditions for the preparation of methylated product 186 occurred when 5 equivalents of cuprate in a 1 M Et20 solution at -20 0C were used. Simple acid hydrolysis of ketal 186 provided (-)-5-methy1-5,6dehydrocamphor (178) in 95% yield. Due to the presence of a small amount of (+5,6dehydrocamphor (ent-36) (not separable from 178), an accurate specific rotation for 178 could not be obtained. Specific rotations of samples of (-)-5-methyl-5,6-dehydrocamphor (178) which were taken ranged from [a]2D5-489 0 (c 1.98, 95% Et0H) to [a]D25-642 0  (c 2.09, 95% Et0H). There are no steps in this route to 178 where racemization could occur, and since the starting material (52) is enantiopure, one can assume that the  64 (-)-5-methyl-5,6-dehydrocamphor (178) has a similar enantiomeric purity. No experiments were done, however, to confirm this. It should be noted that the enantiomeric starting material, (-)-endo-3-bromocamphor (ent-52) is also commercially available and therefore a route to ent-178 also exists.  1.2.6.2: Isopropenyl Addition to 5-Methyl-5,6-dehydrocamphor (178) and Anionic Oxy-Cope Rearrangement  Our initial objective was to add a simple alkenyl unit to (-)-5-methyl-5,6-dehydrocamphor (178) and to determine whether anionic oxy-Cope rearrangement would occur. The Grignard reagent of 2-bromopropene was made and added to (-)-5-methyl-5,6dehydrocamphor (178) at room temperature (Scheme 44). The reaction was monitored •Ms  •=1,  —^188  OM  CH2=C(CH3)MgBr  ^7.-  THE, AT, 2 h  178  i reflux, 5.5 h  H30+  85% H 190  189 .-^  —  Scheme 44 by GC, and when addition was complete (after 2 h), the mixture was refluxed for an additional 5.5 h. This resulted in in situ anionic oxy-Cope rearrangement of alkoxide  65 188, and bicyclic ketone 190 was obtained in 85% yield. Since protonation of the initially formed enolate 189 could occur from either face, 190 was obtained as a mixture of diastereomers at the C(8) center. The 1H NMR (400 MHz, CDC13) spectrum of 190 showed the diastereomeric mixture to be 1:1. Evidence that rearrangement had occurred was a single vinyl proton signal for each diastereomer (5.18 and 4.95 ppm) as well as a doublet due to the newly introduced C(8) methyl group (1.01 and 1.03 ppm). The angular methyl group was also apparent (1.28 and 1.20 ppm) as well as the vinyl methyl group (1.60 and 1.50 ppm) and the geminal dimethyl groups (0.87, 1.00 and 0.83, 1.09 ppm). Having established that a simple hydrindenone (190) was accessible through this route, ring expansion to a decalin (191) was performed (Scheme 45). Hydrindenone 190 was subjected to ozonolysis, reductive work-up and acid-catalyzed aldol condensation to provide enone 191 (also a mixture of diastereomers) in 59% yield. Absorptions due to both saturated (1709 cm1) and a43-unsaturated (1673 cm-1) carbonyl groups were apparent in the infrared spectrum of 191, and the 1H NMR (400 MHz, CDC13) spectrum showed two vinyl proton signals downfield at 5.88 and 6.56 ppm as expected. An enone in ring B could potentially be used to introduce functionality at the C(9) position (cf. 197, Scheme 45), and therefore the enone functionality already present in ring A was first protected via the following sequence. Selective ketalization of the carbonyl group in ring B was accomplished using ethylene glycol and p-Ts0H•H20 in refluxing benzene for 1 h. The ketal 192 was isolated in 70% yield and infrared spectroscopy established that the a,13-unsaturated carbonyl group in ring A was still present (1671 cm-1) and that the carbonyl group in ring B was absent. Dissolving metal reduction106 of 192 using Li in NH3(l), Et20 and Et0H gave the alcohol 193 in 54% yield. The 1H NMR (400 MHz, CDC13) spectrum of 193 showed the absence of any vinyl proton signals, indicating that 1,4- and not 1,2-reduction had occurred. As the reduction was done in the presence of a proton source (Et0H) it was expected that the initially formed enolate would be protonated to give a ketone which would be subject to  66  II •■••■■■)11■■  190  191  iv Me0  HO  Me0 195  193  Me0  Me0 196  ^  197  i) 03, Me0H, CH2Cl2, -78 °C, 30 min; Zn, HOAc, RT, 1h; p-Ts0H•1120, C6H6, reflux, 1 h, 59% ii) ethylene glycol, p-Ts0H.H20, C6H6, reflux, 1h, 70% iii) Li, NH3, Et20, Et0H, -78 °C, 1h, 54% iv) KH, THF, AT, 25 min; Mel, 12 h, 94% v) 1 M HCI, acetone, RI, 1h, 91% vi) HMDS, Lil, TMSCI, CH2Cl2, 0 °C, 1h, 100% vii) PhSeCI, Et20, •  -78 °C, 1.25 h; H20, HOAc, H202, 0 °C to RT, 58%  Scheme 45 further reduction to provide the alcohol 193. A broad 0-H absorption (3615 cm-1) in the infrared spectrum of 193 and the lack of a carbonyl absorption confirmed that complete reduction had occurred. Protection of the hydroxyl group in 193 using KR and Me! in THF gave the methyl ether 194 in 94% yield. The 1H NMR (400 MHz, CDC13) spectrum of 194 clearly showed the presence of 4 signals due to the methyl ether protons, indicating that all 4 possible diastereomers were obtained and that the dissolving metal reduction had not occurred stereoselectively. However, no attempt was made to separate  67 the diastereomers since the C(8) center would later become trigonal in the synthetic sequence and the stereochernistry at C(3) was not relevant to subsequent functional group transformations. Hydrolysis of ketal 194 using 1 M HC1 and acetone at room temperature for 1 h provided ketone 195 in 91% yield. Compound 195 is a potentially useful decalin intermediate in terpenoid synthesis as it contains oxygenation at C(3) and C(7), an angular methyl group at C(10), gerninal dimethyl groups at C(4) and a methyl group at C(8). However, its potential could only be realized if it possessed a  13 C(9) substiutent which could be used in the elaboration of  sesquiterpenoids, diterpenoids or triterpenoids. We believed that such a group could be stereoselectively introduced via conjugate addition to an a,13 unsaturated ketone, and -  therefore enone 197 was prepared in the following way. The thermodynamic enolate of 195 was formed and trapped as its enol silyl ether  (196) using HMDS and TMSI107 generated in situ from TMSC1 and LiI108 in THF. This product (196) was not purified, but was used directly in the next reaction. However, the 1H NMR (400 MHz, CDC13) spectrum clearly showed the loss of the C(8) methyl doublet which was at 0.96 ppm in the spectrum of starting ketone 195 and showed a singlet at 1.53 ppm due to the C(8) methyl group which is vinyl in 196. A singlet due to the trimethylsilyl protons was also obvious at 0.18 ppm. Compound 196 was treated with PhSeC1 at -78 0C in THF for 1.25 h. The reaction was monitored by TLC and when all starting enol silyl ether was absent, the a-phenylseleno ketone intermediate was oxidized  in situ by treatment with H202, H20 and HOAc. Warming to room temperature caused elimination of the phenylselenoxide to provide enone 197 in 58% yield. The structure of  197 was confirmed by infrared and 1H NMR spectroscopy. The infrared spectrum of 197 showed a carbonyl absorption at 1671 cm-1 as expected for an a43-unsaturated ketone. The 1H NMR (400 MHz, CDC13) spectrum showed the C(8) methyl group to be vinyl (1.68 ppm) and showed one vinyl proton signal, downfield at 6.40 ppm as expected. Enone 197 was suitable for subsequent conjugate addition to introduce a substituent at  68 C(9). Such transformations have been extensively investigated on similar systems.1°9.110 For example, Kutney and co-workers109 have reported successful vinyl addition to 198 to provide 199 in 70% yield (Scheme 46).  198  199  202  i) CH2=CHMg13r, Cu!, DMS:THF (1:1), 70% ii) LDA, DME; Me!; KOH, Me0H, 60-70% iii) LDA, THF; PhSeCI; H202, py, 65% (based on 25% recovered SM) iv) Li, NH30), 90%  Scheme 46 The stereochemistry at C(9) in compound 199 was predicted to be 0 based on conformational analysis and 1H NMR spectroscopy confirmed that this was indeed the case. Subsequently, a C(8) methyl group was introduced by alkylation of the kinetic enolate generated with LDA to give 200. Initially a mixture of diastereomers, compound  200 was epimerized using KOH and Me0H to give the isomer shown in an overall yield of —65%. The cis ring junction in 200 was converted to trans by conversion to the enone  201 and subsequent dissolving metal reduction to give 202. As our own compound 197 was very similar to 198, it is expected that the reactions done by Kutney and co-workers would yield similar results on our system;  69 therefore, we did not pursue this route any further. However, having established that addition of propeny1-2-magnesium bromide to (-)-5-methyl-5,6-dehydrocamphor (178) and subsequent anionic oxy-Cope rearrangement occurred readily, we decided to use the enolate generated from the anionic oxy-Cope rearrangement (189) to introduce a ring B enone at this stage, and to investigate conjugate additions to this hydrindenone (203, Scheme 47).  i  178  .4111F.....+  204  ^  203  i) CH2=C(CH3)MgBr, THF, RI, 1h; 40 °C, 30 min; reflux, 8.5 h ii) PhSeCI, -78 °C to RI; H202, HOAc, H20, 0 °C to RI, 75% iii) 6 M HCI, acetone, 70°C, 30 min, 81%  Scheme 47 The Grignard reagent of 2-bromopropene was freshly prepared, added to (-)-5-methyl-5,6-dehydrocamphor (178), and subsequent heating resulted in anionic oxyCope rearrangement as before. Instead of quenching the resulting enolate (189) by the addition of water, the reaction mixture was cooled to -78 0C and PhSeC1 was added. After warming to room temperature to allow selenation to occur, the mixture was cooled to 0 °C and the intermediate oc-phenylseleno ketone was oxidized with H202, HOAc and H20. Warming to room temperature caused elimination to provide enone 203 as a mixture of exo-and endocyclic double bond isomers as determined by 1H NMR spectroscopy. The mixture was purified by column chromatography to give the mixture  70 of isomers (203) in 75% yield. Treatment with 6 M HC1 and acetone at 70 0C for 30 minutes caused isomerization to the thermodynamically more stable endocyclic isomer (204) which was isolated in 60% overall yield. Infrared spectroscopy showed a carbonyl  absorption at 1662 cm-1 as expected for an a40-unsaturated ketone. The 1H NMR (400 MHz, CDC13) spectrum of 204 showed two vinyl proton signals: 5.16 (1H, d, J=1 Hz, C(1)H) and 6.30 (1H, t, J=1 Hz, C(9)H) as expected. Signals due to two vinyl methyl groups (1.63 and 1.72 ppm) and three tertiary methyl groups (0.76, 1.00 and 1.24 ppm) were also observed. The cis hydrindenone 204 can exist in either conformation A or B. One might  10-  expect conformation B to be favored over A because in B the smallest of the 6-membered ring substituents, a hydrogen atom, is in the axial position and the largest, a tertiary alkyl substituent, is in the equatorial position. However, although the large tertiary alkyl substituent is in the axial position in A, there are no 1,3-diaxial interactions because the 3 positions with respect to that center are trigonal. The doublet due to the C(1) proton in the 1H NMR specturm of 204, however, showed a coupling constant of 1 Hz which is suggestive of W coupling with the proton at C(5). This W coupling is only possible in conformation B and therefore it is likely that conformation B is preferred. In both conformations A and B, however, the bottom (a) face is concave due to the cis ring junction and therefore it is assumed that the top (f1) face is more accessible. Thus it was predicted that conjugate addition to the enone (204) would occur from the top face to give stereochemistry at C(9).  71 Our first attempt at conjugate addition to 204 used lithium dimethylcuprate (Me2CuLi), generated in situ from CuBr•DMS and MeLi.105 This addition was done in the presence of TMSC1 which accelerates the rate of reaction and often improves yields." Treatment of enone 204 under these conditions (Scheme 48) resulted in conjugate addition and trapping of the intermediate enolate to provide enol silyl ether 205 in 89% yield.  204  205  III  207  ^  206  i) Me2CuL1, TMSCI, THF, -78 °C, 30 min, 89% ii) 1 M HCI, acetone, RT, 2 h, 70% iii) HOAc:HCI (cam) (9:1), 80°C, 1h, 52%  Scheme 48 The 1H NMR (300 MHz, CDC13) spectrum of 205 showed a singlet due to nine  trimethylsilyl proton signals (0.18 ppm) and two vinyl methyl proton signals at 1.51 ppm (3H, d, J=1.5 Hz) and 1.60 ppm (3H, d, J=1.5 Hz) as expected. A doublet (J=7 Hz) at 0.93 ppm due to the newly introduced C(9) methyl group was also diagnostic, although the stereochemistry of this methyl group was not determined at this stage. Treatment of  205 with 1 M HC1 and acetone at room temperature for 2 h gave the corresponding ketone (206) as a 2:1 mixture of diastereomers (as determined by GC) in 70% yield.  72 Isomerization of the mixture using a 9:1 mixture of HOAc:HC1(c0nc) at 80 0C for 1 h gave clean conversion to the single isomer 207 in 52% yield. Although we expected that the C(9) methyl group in 207 would be introduced from the convex (13) face of 204, analysis of the 1H NMR (300 MHz, CDC13) spectrum of  207 suggested that it had, in fact, approached from the concave face and was in the a (equatorial) position in 207. Analysis of 207 suggests that conformation B is favored over conformation A since in B the largest 6-membered ring substituent, a tertiary alkyl group at C(5) is in the equatorial position and the smallest, a hydrogen atom at C(5) is in  "!.  CH  A  the axial position. Thus the severe 1,3-diaxial interactions between the C(10) methyl group and the axial C(8) substituent and between the C(5) tertiary alkyl group and the axial C(9) group which occur in conformation A are avoided. Furthermore, upon epimerization of 206 to 207 the C(8) methyl group is assumed to be equatorial, as shown in conformation B. The stereochemistry of the C(9) methyl group was determined using conformation B and the coupling constant that was observed between the C(9) and C(8) protons. The C(9)H signal in the 1H NMR spectrum of 207 showed a coupling constant of 7 Hz with the C(9) methyl group and a coupling constant of 13 Hz with the C(8)H. Similarly, the C(8)H signal showed a coupling constant of 7 Hz with the C(8) methyl group and a coupling constant of 13 Hz with the C(9)H. This large J=13 Hz value is characteristic of a diaxial relationship between the adjacent C(8) and C(9) protons, whereas axial-equatorial or diequatorial coupling is commonly in the range of 2-4 Hz. A  73 diaxial relationship between the C(8) and C(9) protons establishes that the C(9) methyl group is in the equatorial (a) position and therefore conjugate addition to 204 must have occurred from the bottom (a) face. To be synthetically useful, we required the addition of a functionalized substituent at C(9) and therefore conjugate addition using both vinyl and cyanide nucleophiles was attempted (Scheme 49). Treatment of 204 with Et2A1CN112 in THF at room temperature  ii  209  208  ^  210  i) Et2AICN, THE, RT, 5.5 h, 68% ii) CH2=CHMgBr, CuBr•DMS, TMSCI, THF, -78 °C to RT, 24% (and 23% SM) iii) Na0Me, Me0H, RI, 3.5 h, 100%  Scheme 49 for 5.5 hours gave 208 in 68% yield. GC and 1H NMR spectroscopy showed that this was a complex mixture of diastereomers, due to conjugate addition to both faces of the enone and not just due to a mixture of epimers at the C(8) center. Evidence that conjugate addition had occurred, however, was the presence of a characteristic nitrile absorption (2236 cm-1) in the infrared spectrum of 208 as well as the carbonyl absorption at 1718 cm-1 as compared to the carbonyl absorption which was at 1662 cm-1 in  74 the a,3—unsaturated ketone 204. High resolution mass spectrometry also confirmed the presence of the parent mass (Calc. Mass: 231.1623, Meas. Mass: 231.1623). For this reaction to be synthetically useful, we required predominant, if not exclusive, attack to the 13 face of enone 204. We assumed that due to the small size of the cyanide nucleophile it did not experience much steric interaction in its attack from either side of the enone (204) and thus no stereoselectivity was observed. Therefore, we focussed our attention on the conjugate addition of a vinyl group; since this was a slightly more sterically demanding group, the addition would presumably be more stereoselective. The Grignard reagent of vinyl bromide was freshly prepared and added to enone 204 in the presence of both a Cu(I) species (to promote 1,4 addition)113 and TMSC1 (a  rate accelerator).i i i Ketone 209 was isolated in 24% yield, as well as 23% starting enone 204. That ketone 209 and not the corresponding enol silyl ether was isolated was  probably due to hydrolysis of the enol silyl ether which occurred either during the aqueous work-up or upon purification by column chromatography using silica gel. The diastereomeric mixture (209) was treated with Na0Me in Me0H to epimerize the C(8) center. Ketone 210 was isolated in quantitative yield and 1H NMR spectroscopy determined this to be a 2:1 mixture of diastereomers. A small amount of the major isomer was isolated and the following 111 NMR experiments were done to establish the stereochemistry at the C(9) center. It was possible, on the basis of chemical shift and coupling constant analyses, to assign all proton signals in the 1H NMR (300 MHz, CDC13) spectrum of 210. The geminal dimethyl groups at C(4) and the C(10) methyl group were not distinguished, however, nor were the C(6) axial and equatorial protons. Decoupling experiments verified several of these assignments, particularly the C(8) and C(9) protons of interest, and the results are shown in Table 6:  75 Table 6: Results of decoupling experiments done on major isomer of compound 210 Irradiation (ppm)  Proton Assignment  2.14  C(9)H  Affected Signal (PPIn) 5.60  4.94  2.24  0.95  C(8)H  C(8)Me  Proton Assignment  Change in Signal (Hz)  RCH=CH2  ddd (J=17, 10, 12) to dd (J=17, 10) dd (J=17, 2) to d (J=17) mtobrm  2.24  H trans to RCH=CH2 C(8)H  2.14  C(9)H  0.95  C(8)Me  dd (J=12, 9) to br m d (J=7) to s  2.24  C(8)H  m to d (J=12)  In addition to confirming proton assignments, irradiation at the frequency of the C(8) methyl group (0.95 ppm) gave valuable information about coupling constants. Originally a multiplet, the C(8) proton resonance collapsed to a doublet (J=12 Hz) when the C(8) methyl group frequency was irradiated. The coupling constant of 12 Hz must reflect the coupling of the C(8) proton with the C(9) proton, and not with the C(8) methyl protons, and as discussed in the analysis of methylated compound 207 (p. 72), a coupling constant as large as 12 Hz suggests coupling between two axial protons. Therefore, we concluded that the C(8) and C(9) protons were trans with respect to each other. Upon examining the two possible conformations of a QL hydrindenone such as 210, we again assumed that conformation B is favored over A and the rationale is analogous to that already discussed for compound 207 (p. 72). As we concluded from the coupling constant between the C(8) and C(9) protons, the C(9) proton is axial (f3), and therefore, conjugate addition of the vinyl group occurred predominantly from the a face of enone 204. Having some evidence for the stereochemistries at C(8) and C(9), the major isomer of compound 210  76  !  A is considered to have the conformation and configuration shown:  210  An NOE experiment was also performed on the major isomer of compound 210 and it confirmed the stereochemical deductions made. The results of the NOE experiment are shown in Table 7. Due to the stereospecificity of the anionic oxy-Cope rearrangement it was known that the stereochemistry of the C(5) proton must be 0 and cis to the C(10) angular methyl group. Irradiation at the frequency of the C(5) proton signal showed enhancement of the C(9) proton. Upon examination of possible conformations of 210 it is apparent that an NOE enhancement is only likely if the C(9) proton is gia to the  C(5) proton, i.e. also  0. Thus, this experiment also supported the assumption that the  conjugate addition of the vinyl group had occurred from the a face of the enone 204. Irradiation of the C(5) proton signal also caused enhancement of the signal at 2.35 ppm. This had previously been determined to be a C(6) proton signal; now it was assigned more specifically to the C(6) 13 proton and therefore the signal at 2.51 ppm was assumed to be the C(6) a proton resonance. Irradiation at the C(8) methyl group frequency  77 Table 7: Results of NOE experiments done on major isomer of compound 210 Irradiation (ppm)  Proton Assignment  0.95  C(8)Me  1.96  C(5)H  2.15  C(9)H  2.24  C(8)H  2.35 2.51  C(6)13H C(6)aH  Enhanced Signal (ppm) 2.24 2.35 2.35 2.15 5.60 4.94 1.07 0.95 2.51 2.35  Assignment of Enhanced Signal C(8)H C(6)13H C(6)13H C(9)H RCH=CH2 H trans to RCH=CH2 C(4)Me C(8)Me C(6)aH C(6)13H  appeared to cause enhancement of the C(6) 0 proton signal. It is more likely, however, that simultaneous irradiation of the C(4)13 methyl group had occurred and that this caused enhancement of the C(6)13 proton signal. As a result of these investigations, it was determined that conjugate addition of . both a methyl group and a vinyl group occurred from the bottom (concave) face of enone 204 resulting in a stereochemistry of that group at C(9). When the nucleophile was less sterically demanding, however, as in the case of cyanide, no selectivity was observed. These results were disappointing because we required 13 selectivity and had hoped to add even more sterically demanding groups to the C(9) center. However, a recent paper by Taguchi and coworkersllo shows similar results (Scheme 50). Conjugate addition of cyanide to enone 211 occurred from the 0 face to give 212. The 13 stereochemistry at C(9) was expected as the gia ring junction of decalin 211 results in a concave a face and a more accessible convex 13 face. However, vinyl addition to the same enone 211 resulted in a approach to give ketone 213 with the resulting a  78 stereochemistry at C(9). This was attributed to the steric interaction that would be felt between the angular trifluoromethyl substituent and the vinyl group if it approached from the same ([3) side. Thus, attack by a sterically demanding group such as vinyl was governed by the stereochemistry of the angular substituent whereas addition of a small nucleophile such as cyanide was governed by the folded shape of the gia decalin structure. Although our enone 204 was a hydrindenone with an angular methyl group as opposed to the angular trifluoromethyl containing decalin 211 shown in this example, the same arguments apply and the experimental results are similar. CN i  212  ii  211 i) KCN, NH4C1, DMF ii) CH2=CHMgBr, CuI  Scheme 50 1.2.6.3: Allyl Addition to Hydrindenone 204 and Attempted Anionic Oxy-Cope Rearrangement The previously described approach to C(9) functionalization involved conjugate addition to enone 204. Another route to C(9) functionalization would be 1,2-addition of an ally' group to the carbonyl at C(7), followed by anionic oxy-Cope rearrangement of the resulting 1,5-diene (214, Scheme 51). Addition of commercially available allylmagnesium bromide to enone 204 was complete after 30 minutes at room temperature, as indicated by GC and TLC. Heating of the intermediate alkoxide for 3 hours, however, gave no indication of any anionic oxy-Cope rearrangement occurring, therefore the reaction was quenched by the addition of water and alcohol 214 was isolated as a 9:1 mixture of isomers (as determined by GC and 1H NMR spectroscopy) in 78% yield. The  79  ii, iii, iv or v  i  204  215  i) CH2=CHCH2MgBr, THF, AT, 30 min; reflux, 3 h, 78% ii) KH, THF, reflux, 36 h iii) K2CO3,decalin, reflux, 3d iv) n-BuLi, THF, -78°C 1h; 0 °C, 1h; AT, 2.5 h; reflux, 9 h v) KH, 18-cr-6, diglyme, AT, 3d; reflux, 24 h  Scheme 51  structure of 214 was confirmed by the presence of an 0-H absorption (br, 3413 cm-1) in the infrared spectrum and the lack of a C=0 absorption. All proton signals in the 1H NMR (400 MHz, CDC13, major isomer) spectrum of 214 were identified and NOE experiments were done to confirm the stereochemistry at C(7). The NOE results are shown in Table 8.  Table 8: Results of NOE experiments done on compound 214 Irradiation (ppm) 1.90  1.76  1.15  Proton Assignment C(5)H  C(6)13H  C(10)C113  Enhanced Signal (ppm)  Assignment of Enhanced Signal  5.12-5.20  C(9)H and -CH=Cf_12  2.23, 2.40  -CH2-CH=CH2  5.90 1.90 1.36 0.92  -CH=CH2 C(5)H C(6)aH  1.90  C(5)H  C(4)CH3  80 Based on conformational analysis of the  cis fused hydrindenone system (cf. p. 70), it was  expected that nucleophilic attack would occur predominantly from the top (f3) face of enone 204, and the NOE experiment results were consistent with this prediction. Irradiation at the C(5) proton frequency resulted in enhancement of the multiplet at 5.125.20 ppm and of the signals at 2.23 and 2.40 ppm. The multiplet was due to overlapping signals due to the C(9)H and the terminal allyl methylene protons and therefore analysis of this enhancement is not valid as it cannot be distinguished with which of the 3 protons the C(5) proton is interacting. That enhancement was observed with the signals at 2.23 and 2.40 ppm, however, suggests that the allyl group is syn to the C(5)H, i.e. 13, because those signals are assigned to the methylene protons of the allyl group. Irradiation at the frequency of the C(6)13 H showed enhancement of the signals at 1.90, 1.36 and 0.92 ppm as could be expected. However, the most informative enhancement was seen in the signal at 5.90 ppm, which is due to the -CH=CH2 of the allyl group. This result further suggests that the allyl group must have been added to the  13 face of enone 204. Finally, irradiation  at the frequency of the C(10) methyl group showed enhancement of the signal due to the C(5)H. While this did not give information about the C(7) stereochemistry directly, it did support the proton assignments that were made based on coupling constant information from the one-dimensional 111 NMR (400 MHz, CDC13) spectrum of 214. All other NOE experiment results also supported these assignments. The anionic oxy-Cope rearrangement of 214 was first attempted using the commonly used conditions of KR in refluxing THF. The only product isolated from this reaction was enone 204 in 30% yield. There was no evidence of any rearrangement product as determined by the lack of a C=0 absorption in the infrared spectrum of the crude product. The formation of enone 204 can be explained by a retro-ene reaction which could occur if the alcohol (214) were not deprotonated before heating began. We are aware of at least one similar report in the literature. Koreeda and co-workers89 found  81  214  ^  204  that the E isomer 140 (Scheme 35, p. 50) rearranged smoothly to give ketone 141, but the Z isomer 142 gave a mixture of isomeric enones (143). No explanation was given regarding the mechanism of the enone formation, however, it was also the loss of an ally! group that occurred, presumably via a retro-ene reaction. The retro-ene reaction can only occur if alcohol, and not alkoxide, is the reacting species, and therefore we treated alcohol 214 with an excess of a strong, readily soluble base (n-BuLi) before anionic oxyCope rearrangement was attempted. Thus alcohol 214 was allowed to stand in contact with n-BuLi for 1 hour at -78 °C, for 1 hour at 0 °C and for 2.5 hours at room temperature. Subsequent heating at reflux did not result in anionic oxy-Cope rearrangement, and starting alcohol 214 was isolated in 74% yield. That no enone 204 was recovered, however, supported our assumptions that a retro-ene reaction of alcohol 214 had occurred previously. In a subsequent experiment alcohol 214 was treated with KR and 18-crown-6 in diglyme for 3 days at room temperature to ensure complete deprotonation, and then was refluxed for 24 hours. A complex mixture of products was isolated, as determined by GC and TLC. None was the desired rearrangement product 215, as indicated by the lack of a carbonyl absorption in the infrared spectrum of the crude mixture. A final reaction using oxy-Cope conditions was tried. Treatment of alcohol 214 with K2CO3 in refluxing decalin for 3 days resulted in the formation of 40% enone (204) and the recovery of 38% unreacted starting material (214). After these investigations it seemed evident that neither oxy-Cope nor anionic oxy-Cope rearrangement of alcohol 214 to ketone 215 was feasible.  82 1.2.6.4: Alkynyl Addition to 5-Methyl-5,6-dehydrocamphor (178) and Attempted Anionic Oxy-Cope Rearrangement  After the previously described initial investigations in which we determined that addition of propeny1-2-magnesium bromide to (-)-5-methyl-5,6-dehydrocamphor (178) followed by anionic oxy-Cope rearrangement was feasible, we returned to our initial objective of adding a more complex and therefore potentially more useful alkenyl unit to  178 (cf. Scheme 41, p. 60). In particular, the allcenyl unit would be designed so that upon anionic oxy-Cope rearrangement of the intermediate alcohol (179), the product hydrindenone (180) would possess the C(9) substituent which could not be successfully introduced in the previously described work.  RO  179  180  Propargyl alcohol was protected as its enol silyl ether and upon treatment with n-BuLi at -78 0C for 2.75 h the resulting anion61 was added to (-)-5-methy1-5,6-dehydrocamphor (178) to provide alkyne 216 in 96% yield (Scheme 52). Subsequent reduction with H2 using Lindlar's catalyst114 provided alkene 217 in 77% yield. The 1H NMR (400 MHz, CDC13) spectrum of 217 showed three vinyl proton signals: 5.16 (1H, br s, C(6)H), 5.43 (1H, m, -CH=CHCH2OTBDMS) and 5.52 (1H, dt, J=12, 1 Hz, -CH=CHCH2OTBDMS). The coupling constant of 12 Hz between the two adjacent vinyl proton signals suggests that the hydrogenation did occur cis as expected. Irradiation at the frequency of one of the -CH2OTBDMS protons simplified the vinyl proton signal which was a multiplet to a doublet of doublets with the coupling constant  83  HO i  II TBDMSO^216  iii, iv, v, vi or vii  HO  "4- -X- -  TBDMSO^  217  ix or x  220  219  HO i) LiC=CCH2OTBDMS,THF, -78 °C to AT, 96% ii) H2, Lindlar's catalyst, 2:1 hexane:Et0Ac, RT,30 min, 77% iii) KH, 18-cr-6, THF, reflux, 3h, 41% (diol) iv) KHMDS, THE, reflux, 17 h v) toluene,140 °C, sealed tube, 14 h vi) toluene, propylene oxide, reflux, 66 h vii) K2CO3, decalin, reflux, 2.75 h viii) TBAF, THE, AT, 15 min, 91% ix) KH, 18-cr-6, THF, reflux, 47 h x) K2CO3, decalin, reflux, 5h  Scheme 52 of 12 Hz between adjacent cis protons and the coupling constant of 5 Hz between the vinyl proton and the non-irradiated CH2OTBDMS proton. For the subsequent C(9) substituent of hydrindenone 218 to possess 13 stereochemistry, the alkene 217 must be cia; rearrangement of the corresponding trans alkene would result in a stereochemistry at the  84 subsequent C(9) center. The 1,5-diene 217 was subjected to various conditions in an attempt to effect anionic oxy-Cope rearrangement. Treatment of 217 with KH and 18-crown-6 in refluxing THF for 3 hours failed to induce anionic oxy-Cope rearrangement as determined by the lack of a carbonyl absorption in the infrared spectrum of the crude product mixture. The diol (219) resulting from enol silyl ether cleavage was isolated in 41% yield. Treatment of 217 with KHMDS in refluxing THF for 17 hours resulted in a complex mixture of products as indicated by TLC and GC. Again, infrared spectroscopy was used to determine that none of the products was the desired rearrangement product 218. These discouraging results led us to believe that the basic conditions were too harsh and caused decomposition of 217; thus we tried the rearrangement under oxy-Cope conditions using higher temperatures but no base. Heating of 217 in toluene in a sealed tube115 at 140 0C for 14 hours, however, also gave a complex mixture of products. Heating of 217 for 66 hours in refluxing toluene in the presence of propylene oxide which acts as a proton scavenger116 resulted in less decomposition but only starting material (35%) was isolated. Finally, 217 was heated in refluxing decalin for 2.75 hours in the presence of K2CO3.117 A new compound was isolated which could not be identified, but which was determined not to be the desired rearrangement product 218. The unknown compound had the same molecular weight as the starting alkene 217 as determined by mass spectrometry, and it contained two carbonyl absorptions (1718 and 1663 cm-1) in its infrared spectrum as well as an 0-H absorption (3571 cm-1); however, 1H NMR spectroscopy established that the compound was not ketone 218. The 1H NMR (400 MHz, CDC13) spectrum of the unknown compound showed three vinyl proton signals: 5.07 (1H, m), 5.13 (1H, br s) and 6.30 (1H, d, J=10 Hz) as compared to the one signal expected if compound 218 had been produced. In particular, the proton signals downfield at 5.13 and 6.30 ppm suggest that the product is an a,13—unsaturated ketone;  85 this was supported by a strong carbonyl absorption at 1663 cm-1 in addition to the carbonyl absorption at 1718 cm-1 in the infrared spectrum. To ensure that the large silyl protecting group in 217 was not interfering with rearrangement, it was removed by treatment of 217 with TBAF in THF for 15 minutes at room temperature and diol 219 was isolated in 91% yield. The diol (219) was then treated with KR and 18-crown-6 in refluxing THF for 47 hours; however the only product that could be isolated was recovered starting material (12%). Since anionic oxyCope rearrangement of 219 did not occur, the diol (219) was heated in refluxing decalin in the presence of K2CO3 under oxy-Cope conditions for 5 hours. This led to a complex mixture of products, none of which was the desired rearrangement product 220 as determined by infrared spectroscopy. Finally, we prepared the trans compound 222 (Scheme 53). Although rearrangement of the trans compound would give a and not  p C(9) stereochemistry in the  product (223), we felt it would be interesting to see if rearrangement would occur; if so, this would suggest that it was the cis stereochemistry which prevented rearrangement of  217. Alkyne 216 was treated with TBAF in THF at room temperature for 30 minutes to provide alkyne diol 221 in 91% yield. Treatment of 221 with LiA1H4 62 in THF at 40 °C for 2 hours gave trans alkene diol 222 in 31% yield. The trans stereochemistry was supported by coupling constant evidence in the^NMR (400 MHz, CDC13) spectrum of  222: the large coupling constant (J=16 Hz) of the doublet signal at 5.67 ppm due to one of the adjacent vinyl protons (-CH=CHCH2OH) is consistent with a trans relationship between these two protons. Subsequent treatment of 222 with ICHMDS and 18-crown-6 at room temperature for 3 days showed no sign of reaction as indicated by TLC and GC. Therefore, the reaction mixture was heated at reflux for 2 days, which resulted in a complex mixture of products. There was no evidence for the formation of the rearrangement product (223) as determined by infrared spectroscopy.  86  HO  TBDMSO  /  OH^ HO iii  223  ^  222  i) TBAF, THE, AT, 30 min, 91% ii) L1AIH4, THE, 40°C, 2h, 31% iii) KHMDS, THF, RT, 3 d; reflux, 2 d  Scheme 53 It was evident from these investigations that the anionic oxy-Cope rearrangement is very sensitive to steric effects. Paquette and co-workers118 have extensively investigated the anionic oxy-Cope rearrangement of 1,5-dienes (cf. Scheme 54) derived from bicyclo [2.2.2] octenones and these are comparable, to some extent, with the results described above for 1,5-dienes derived from bicyclo [2.2.1] heptenones. For example, compound 224 rearranged using KHMDS and 18-crown-6 in THF at room temperature while 225 required KH and 18-crown-6 in refluxing THF. As indicated previously, 5,6-dehydrocamphor derivatives 64, 128 and 152 rearranged using KH in THF at 40 °C. On the other hand, compound 188 which can be likened to structure 225 required refluxing TI-IF and longer reaction time when the corresponding alkoxide was generated  in situ from Grignard addition to (-)-5-methyl-5,6-dehydrocamphor (178). The longer  87 OR  HO  64, R=H 152, R=CH3 128, R=TBDMS HO  188 OR  HO  ^ 217, R=TBDMS ^ 219, R=H 226,R=TBDMS 227,R=MOM OMe  OH HO\,--/  222  Scheme 54 reaction time is attitributed to the steric effect of the 5-methyl substituent as well as to the  fact that magnesium was used as the cation, as opposed to potassium; nevertheless yields were excellent. Finally, it is interesting to note that compounds 226 228 completely -  failed to rearrange. Paquette and co-workers used KH and 18-crown-6 in both refluxing 11-1F and diglyme as well as KHMDS and 18-crown-6 under identical conditions and were only able to isolate starting material in all cases. Paquette's compounds 226 228 are -  88 similar to structures 217, 219 and 222, and as discussed previously, we had a complete lack of success in our attempts to effect rearrangement of these compounds using a variety of reaction conditions. It is apparent, therefore, that substitution at various positions of the 1,5-dienes can inhibit or completely prevent anionic oxy-Cope rearrangement, and these observations have been attributed to steric effects. 1.3: Conclusion 5,6-Dehydrocamphor (36) can be synthesized in either enantiomeric form using one of several enantiospecific routes. It has been used as a precursor to 1,5-diene systems (37) which can undergo anionic oxy-Cope rearrangement to provide hydrindenones (38) which have three fixed predictable chiral centers based on the stereospecificity of the concerted rearrangement reaction (Scheme 55).  1111=1■  AM,^  37  40  ^  Scheme 55  39  89 Hydrindenone 38 could be easily ring expanded to the familiar A/B decalin system of terpenoids (39), however, the stereospecific introduction of an angular methyl group to provide a system such as 40 eluded us. The introduction of the methyl group was tried using such diverse approaches as hydroxyl-directed cyclopropanation, radical cyclization, y-alkylation and anionic oxy-Cope rearrangement. All routes relied on a C(1)-C(10) double bond as a means toward C(10) functionalization and conformational analysis of such systems shows that the 13 face is rather sterically hindered. It was attempted to alleviate some of these steric interactions by removal of, for example, a  13 C(3) substituent; in the case of y-alkylation, the dienolate ion generated in ring A of an enone such as 39 flattens the A ring considerably. However, the  13 C(4) methyl group  may well have been the major contributor to steric hindrance at the C(10) center, and of course, removal of this substituent is not feasible. Future investigations in this area could involve the introduction of the angular methyl group utilizing a C(10)-C(9) double bond in ring B; however, this would involve losing the C(9) stereochemistry which was originally introduced stereospecifically, and therefore such a route did not appeal to us. We did, however, develop an enantiospecific route to (-)-5-methy1-5,6-dehydrocamphor (178) which via a similar synthetic strategy to that outlined for 5,6-dehydrocamphor (36) led to a hydrindenone (190) that contained the angular methyl group (Scheme 56). It was found that anionic oxy-Cope rearrangement of a simple 1,5-diene derivative (188) of (-)-5-methyl-5,6-dehydrocamphor (178) occurred readily to give hydrindenone (190) which was expanded to decalin 197. Conjugate addition to enone 197 and to the B ring enone derived from the enolate of 190 (189 to 204, Scheme 47, p. 69) was attempted to introduce a substituent at C(9) and varying degrees of success were achieved. Thus, the 1,5-dienes 217 and 219 were prepared. Anionic oxy-Cope rearrangement of 217 and 219 would provide hydrindenones 218 and 220 respectively which contain both the angular methyl group and a C(9) substituent; however,  90  178  U  188  OR  g  0^Me0 RO^217, R=TBDMS 219, R=H  H 218, R=TBDMS 220, R=H  197  Scheme 56 rearrangement could not be induced under a variety of conditions. This lack of success was attributed to steric interaction between the C(5) methyl group and the CH2OR substituent in dienes 217 and 219, and these results are consistent with reports by Paquette and co-workers118 who studied similar systems. Therefore, future work would probably focus on the simpler system which provided hydrindenone 190 and goals would include more diverse functionalization of 190 than was achieved in the work described in this thesis. There is no doubt that the work described in Chapter 1 of this thesis proved disappointing; although both 5,6-dehydrocamphor (36) and 5-methy1-5,6-dehydrocamphor (178) appeared to be potentially useful chiral starting materials, it became evident that their use in our synthetic strategy was limited due (to a great extent) to the steric sensitivity of the anionic oxy-Cope rearrangement which was the basis for many of our functional group transformations.  91  Chapter 2  A New Enantiospecific Synthesis of 4-Methylcamphor  92 2.1: Introduction As described in Chapter 1, (+)-camphor (25) or its enantiomer (ent-25) is a useful chiral starting material for the synthesis of natural products because it can be functionalized at many positions. For example, (-)-camphor (ent-25) is readily converted to (-)-9,10-dibromocamphor (ent-28) in 4 steps via a series of bromination and selective debromination reactions55,119 and it has been shown that ent-28 can be converted to a  0 ent-28, R=H 230, R=Me  ent-25, R=H 229, R=Me  15  HO 233  231, R=H 232, R=Me  Scheme 57 trans-hydrindenone intermediate 231 that has been used in an enantiospecific synthesis of (+)-estrone (233, Scheme 57).37,38.43 If (-)-4-methylcamphor (229) could be similarly transformed to the corresponding 9,10-dibromo derivative 230, a useful route to transhydrindenone 232 could be realized. The latter compound (232) is a potentially useful intermediate in the synthesis of the lanostane group of triterpenoids (cf. Scheme 58) while its enantiomer (ent-232) derived from (+)-4-methylcamphor (ent-229) could be used to gain access to the euphane group of triterpenoids. The successful outcome of this route  93 2)  18 12  12  11  10  6  1  15  15  232  ent-232  I i  1 1  :  HO^  CI^  HO  234, lanosterol^  1:1 235, euphol  Scheme 58 is, however, initially dependent on the availability of enantiopure 4-methylcamphor (229). Camphor (25) is commercially available in high enantiomeric purity in either enantiomeric form and as no racemization occurs in any of the steps leading to hydrindenone 231, this product is obtained in high enantiomeric purity as well. (-)-4-Methylcamphor (229), however, must be synthesized, and no enantiospecific synthesis has yet been reported. Literature methods120,121,122,123for the synthesis of (-)-4-methylcamphor (229) use commercially available, enantiopure (+)-camphor (25) or (+)-fenchone (237) as starting materials (Scheme 59). Acid-catalyzed rearrangement of derivatives 236 or 238 provide (+)-4-methylisobornyl acetate (239) which is easily converted to (-)-4-methylcamphor (229). The enantiomeric purity of the (-)-4-methylcamphor (229) obtained via these routes, however, was not determined. A shorter synthesis of (-)-4-methylcamphor (229) which utilizes an acid-catalyzed rearrangement similar to those shown in Scheme 59  94  0 237  25 HOAc 11-12SO4 HOAc  HO  OAc  H2SO4  238  ^  239  ^  229  Scheme 59 has been developed in our laboratory (Scheme 60)124 and the mechanism of the rearrangement has been thoroughly investigated.124 Conversion of (+)-camphor (25) to  HOAc  H2C=PPh3  OAc 1) LiAIH4  H2SO4  25  ^  240  ^  239  2) PCC ^  229  Scheme 60 (-)-2-methylenebornane (240) in excellent yield was easily accomplished using a Wittig reaction.125 Subsequent treatment of 240 with a 40:1 mixture of HOAc:H2SO4 at room temperature for 15 minutes gave (+)-4-methylisobornyl acetate (239) in —75% yield. Subsequent removal of the acetate protective group and oxidation provided (-)-4-methylcamphor (229) in an overall yield of —60%. The acid-catalyzed rearrangement of 240 to provide 239 is believed to occur via the mechanism outlined in Scheme 61, and deuterium labelling studies have supported this mechanism.124 Although intermediates are represented and referred to as carbocations, they are only used as a model to explain our results; in fact, there is evidence that exo-methylene intermediates (cf. 2421,, 243b) are involved in this rearrangement. Wagner Meerwein rearrangement of  95  .....47  Fl+^  4•A  WM  240^ 241^242a^* 42b ,13,2 gm Me  — OAc  Ac0 239  ^  244  243a  ^  243b  6,2 H  — OAc  OAc ent-239  Scheme 61 241 followed by a 3,2-exo methyl shift provides 243a. A second Wagner Meerwein  rearrangement occurs to give 244 and this carbocation reacts with acetate to provide (+)-4-methylisobornyl acetate (239). However, this intermediate (244) can undergo a 6,2-hydride shift to provide ent-244 and hence (-)-4-methylisobornyl acetate (ent-239) can also be formed. (+)-4-Methylisobornyl acetate (239) was isolated in —75% yield and since partial racemization could occur by the mechanism shown in Scheme 61, the enantiomeric purity of this compound was determined. The lanthanide shift reagent [Eu(hfc)3]126 and 1H NMR spectroscopy were used to determine that the enantiomeric purity of the (+)-4-methylisobornyl acetate (239) obtained in this reaction was —60%.124 Thus partial racemization had occured via a 6,2-hydride shift in intermediate 244 to provide an 80:20 ratio of 239:ent-239. The optical rotation of (+)-4-methylisobornyl  96 21.5 acetate (239) prepared via our route ([c]p +35.79,0 c 2.28, Et0H) was compared to the 20  rotations reported in the literature ([a]D +18.900 and +35.840)122,127,128 and confirmed that those methods of preparation also did not provide enantiopure 239. This was not surprising since these routes also relied on a similar acid-catalyzed rearrangement reaction where partial racemization could occur by the 6,2-hydride shift shown in Scheme 61. The results of these investigations confirmed that an enantiospecific route to (-)-4-methylcamphor (229) did not exist, since the precursor to 229, (+)-4-methylisobomyl acetate (239), had not been obtained as an enantiopure compound. 2.2: Discussion Since (-)-4-methylcamphor (229) and its enantiomer (ent-229) are potentially useful starting materials for the synthesis of triterpenoids (cf. Scheme 58, p. 93), our objective was to develop an enantiospecific route to these compounds. Our initial approach was to use a camphor derivative which would undergo acid-catalyzed rearrangement to lead to (-)-4-methylcamphor (229) or its enantiomer (ent-229), but where the 6,2-hydride shift (cf. 244 to ent-244, Scheme 61, p. 95) is prevented or restricted. Our first approach involved the synthesis of the thioketal derivative of 5-keto2-methylenebornane (245, Scheme 62).  H*  OAc  "OAc 247  246  229  Scheme 62 If the acid-catalyzed rearrangement occurred as it did for (-)-2-methylenebornane (240, Scheme 61, p. 95), then intermediate 246 is analogous to intermediate 244. The  97 thioketalized intermediate (246), however, does not have a hydrogen atom that can undergo 6,2-hydride shift. Trapping of 246 with acetate would then provide enantiopure 247 which could subsequently be converted to enantiopure (-)-4-methylcamphor (229).  Dithiane 245 was prepared by the reaction sequence outlined in Scheme 63.  i  i  59  i) HOAc: H2SO4 (40:1), 100 °C, 46 h, 50% (and 13% SM) ii) CH212, Zn, TiC14, THE, RT, 1.25 h, 89% iii) C1COCOCI, DMSO, CH2Cl2, -78 °C, 1h; Et3N, -78 ° to RT, 12 h, 62% iv) HSCH2CH2SH, BF3•0Et2, CH2Cl2, RT, 12 h, 42%  Scheme 63 Thus treatment of cyclocamphanone (59) with H2504 and HOAc at 100 °C for 46 hours resulted in cyclopropane ring opening to provide keto-acetate 248 in 50% yield (63% yield based on recovered starting material). Compound 248 was determined to be a 5:1 mixture of cm:end° isomers by GC analysis and 1H NMR spectroscopy. The 1H NMR (400 MHz, CDC13, gm isomer) spectrum of 248 clearly showed a singlet due to the acetate methyl protons at 2.03 ppm as well as the C(5) proton signal at 4.72 ppm (1H, dd, J=8, 4 Hz). The infrared spectrum of 248 showed a broad carbonyl absorption centered at 1747 cm-1 which was due to both the C(1) carbonyl group and that of the acetate. It was found that treatment of keto-acetate 248 with an excess of the modified "Super Wittig" reagent prepared from CH2I2, TiC14 and Zn in THF129 resulted in both methylenation, as  98 expected, and removal of the acetate group to give alcohol 249 in 89% yield. The infrared spectrum (CHC13 solution) of 249 showed the absence of any carbonyl peaks and the presence of 0-H absorptions at 3613 and 3445 cm-1. The 1H NMR (400 MHz, CDC13) spectrum of 249 showed the em methylene proton signals as broad singlets at 4.66 and 4.72 ppm. In addition, the C(5) proton had shifted from 4.72 ppm in acetate 248 to 3.85 ppm in alcohol 249. Swern oxidation102 of 249 provided 5-keto-2-methylenebornane (250) in 62% yield and thioketalization using ethanedithiol and BF3.0Et2 in CH2C1296 provided the target dithiane 245 in 42% yield. The 1H NMR (400 MHz, CDC13) spectrum of 245 showed that the exo double bond had remained intact during these transformations (4.81 and 4.95 ppm, vinyl proton signals), and also showed the expected multiplet due to the thioketal protons (3.10-3.35 ppm). The infrared spectrum of 245 showed the loss of the carbonyl absorption that had been present at 1742 cm4 in the spectrum of ketone 250. The yields of these reactions were not optimized as it was first essential to determine whether or not the acid-catalyzed rearrangement of 245 would occur. Dithiane 245 was treated with the identical reaction conditions that were used to prepare (+)-4-methylisobornyl acetate (239) from (-)-2-methylenebornane (240), i.e. with HOAc:H2SO4 (40:1) at room temperature. After 1.5 hours, no reaction had occurred and therefore the mixture was heated at 100 °C for 2 hours. One product was formed almost exclusively, but it could not be identified. The infrared spectrum of this product showed a very strong absorption at 1755 cm4; however, the 1H NMR (400 MHz, CDC13) spectrum showed the absence of a signal due to the methyl protons of an acetate group. The 1H NMR spectrum also showed the presence of four methyl groups (0.89, 1.07, 1.21 and 1.23 ppm) and the absence of any vinyl protons which suggested that the exo methylene group in 245 had been converted to a fourth methyl group, as desired. A distinctive set of signals were seen at 2.43 ppm (1H, d, J=18 Hz) and at 2.52 ppm (1H, dd, J=18, 1.5 Hz), and yet signals due to thioketal protons were missing, suggesting that  99 the harsh reaction conditions resulted in hydrolysis of the thioketal group. That rearrangement of 245 did not occur at room temperature suggested that the thioketal group was either too sterically demanding for rearrangement to occur, or else that electronic effects due to the sulfur atoms prevented the required Wagner Meerwein rearrangement. Reaction did occur at a higher temperature, but the product could not be identified. It was hoped that rearrangement of a modified derivative would occur at a lower temperature than was required for 245, or if a higher temperature was required, that the group at C(5) would be stable so that competing reactions due to the loss of that group would not occur. Thus ethers 251 and 252 were prepared as outlined in Scheme 64.  i or ii OR 249^OH^251, R=Bn 252, R.Me i) KH, THE, AT, 30 min; BnBr, 30 min, 84% ii) KH, THF, AT, 15 min; Mel, 15 min, 85%  Scheme 64 Alcohol 249 was prepared as previously described (Scheme 63, p. 97) and upon treatment with KR in TIM followed by addition of either benzyl bromide or methyl iodide, ethers 251 and 252 were respectively prepared. Alcohol 249 was an exo:endo (5:1) mixture of isomers, and after purification of the ethers 251 and 252 the ratio had become —9:1 exo:endo as the minor isomer was partially separated. Treatment of benzyl ether 251 with H2SO4 and HOAc at room temperature for 1 hour resulted in a complex mixture of products which were not separated or identified. Reaction of methyl ether 252 under the same conditions gave similar results. Thus, it was determined that the acid-catalyzed rearrangement of substituted 2-methylenebornanes is extremely sensitive to steric and/or electronic effects, resulting in complex mixtures of products which are not synthetically useful.  100 We believed that a ketone instead of the thioketal or ether substituents at the C(5) position of (-)-2-methylenebornane (240) would probably inhibit the second Wagner Meerwein rearrangement due to the electron withdrawing effects of the carbonyl group. However, since we had prepared 5-keto-2-methylenebornane (250) as a precursor to thioketal 245 (Scheme 63, p. 97), we decided to test this hypothesis by subjecting 250 to the normal rearrangement conditions (HOAc/H2SO4).  Fl+  254^255 3,2Me gm  OAc  OAc  --40  258  Ac0  Ar-257  OAc  260^  259  Scheme 65 Treatment of 5-keto-2-methylenebornane (250) with H2SO4 and HOAc at room temperature for 4 days gave ketone 255 as the major product (55% yield, Scheme 65). Several possible intermediates and products are possible if 250 rearranges according to our proposed mechanism. The lack of signals due to acetate protons in the 1H NMR (400 MHz, CDC13) spectrum of the product and the presence of .exo methylene vinyl proton signals at 4.80 and 4.86 ppm led us to conclude that the product was either ketone  101 255 or 257. NOE experiments were done to confirm that the structure was 255, and the  results are summarized in Table 9.  Table 9: Results of NOE experiments done on compound 255 Irradiation (ppm)  Proton Assignment  1.07  C(9)Me  1.15 2.29 4.80 4.86  C(8)Me C(4)H HB HA  Enhanced Signal (ppm) 1.15 4.80 2.29 1.15 4.86 1.30 4.80  Assignment of Enhanced Signal C(8)Me HB  C(4)H C(8)Me HA  C(10)Me HB  That enhancement was seen in the C(8)Me signal when the C(4)H signal was irradiated suggests that the product is indeed 255 and not 257. Further evidence is provided from the enhancements seen when the vinyl protons HA and HB are irradiated. These results show that a carbonyl group at C(5) in the 2-methylenebornane system does not inhibit the first Wagner Meerwein rearrangement (cf. 253 to 254, Scheme 65, p. 100). It does, however, inhibit the 3,2-methyl shift that is expected to occur next, and thus by loss of a proton, ketone 255 is isolated. While the synthesis of 255 was not useful in providing a synthetic route to (-)-4-methylcamphor (229) or its enantiomer (ent-229), it did suggest that the first Wagner Meerwein rearrangement occurs readily.  102 At this stage we became intrigued by reports in the early literature (Houben and Pfankuch, 1931 and 1933)130,131 on the acid-catalyzed rearrangement of (-)-1-chlorocamphene (261, Scheme 66). These results dramatically illustrate the differences in  100% ee HBr/  262  HOAc  CI3CCO2H  69% ee  11- c t 3c o2  HCO2H  263  OHCO  0% ee 264  Scheme 66 enantiomeric purity obtained when different acids are used. Treatment of (-)-1-chlorocamphene (261) with 45% HBr/HOAc solution gave the brominated compound 262.130,131 Reconversion of 262 to (-)-1-chlorocamphene (261) showed no loss of optical activity; therefore, it was deduced that 262 had been formed as an enantiopure compound. When trichloroacetic acid was used instead, 263 was formed, and it too was reconverted to (-)-1-chlorocamphene (261), which only showed 69% of the optical activity of the starting materia1.130,131 Thus, it was concluded that 263 had been formed in 69% enantiomeric excess. A much later study by Warnhoff and co-workers132 showed that when formic acid was used, the product 264 was racemic.  103  (-)-1-Chlorocamphene (261) is structurally similar to the product (255) we obtained upon acid-catalyzed rearrangement of the 5-keto-2-methylenebornane (250). In addition, the carbocation intermediate 265 presumably involved in the rearrangement of 261 is very similar to the intermediate 243a proposed for the rearrangement of  (-)-2-methylenebornane (240, Scheme 67).  H+ -4--cf, Scheme 66  255  250  H+  + 265  243 a  240  Scheme 67 As indicated above, the enantiomeric purity of the product obtained by rearrangement of (-)-1-chlorocamphene (261) depends upon the acid used and two competing rearrange-  ment processes can be invoked to illustrate these results (Scheme 68). In pathway i, bromide ion adds after Wagner Meerwein rearrangement has occurred but before 6,2hydride shift to give 262; in pathway ii, bromide adds after 6,2-hydride shift occurs to give ent-262. In the presence of 45% HBrfflOAc, it was observed that only 262 was formed, and this can be explained by the exclusive operation of pathway i. When an acid other than HBr is used, (eg. formic acid or trichloroacetic acid), then pathway ii competes with pathway i: enantiomeric products result and enantiomeric purity is lost or decreased. Based on these results, we decided to investigate the rearrangement of (-)-2-methylenebornane (240) using 45% HBr/HOAc instead of H2SO4 and HOAc as we had used previously.  104  CI  ^  262  II  262  ^  II  ent-262  Scheme 68 (-)-2-methylenebomane (240) was prepared in 87% yield133 by reaction of (+)-camphor (25) with the Wittig125 reagent prepared from methyltriphenylphosphonium bromide (Scheme 69). Upon treatment of 240 with a 45% solution of HBr in HOAc for 5 minutes at room temperature,130.131 a single product was obtained in 87% yield, which was determined to be 4-methylisobomyl bromide (266). The 1H NMR (400 MHz, CDC13) spectrum of 266 showed four singlets due to four methyl groups at 0.72, 0.91, 1.00 and 1.05 ppm as well as a characteristic doublet of doublets (J=8, 5 Hz) at 4.15 ppm due to the C(2) endo proton. As this compound (266) was not reported in the literature  105  45, 25  ^  Br  II  240  ^  266  i) CH2=PPh3, THF, 24 h, 87% ii) 45% HBr/HOAc, RT, 5 min, 87%  Scheme 69 and no specific rotation was available for comparison, the enantiomeric purity was not determined at this stage, and it was converted to the known compound (+)-4-methylisoborneol (267) (Scheme 70). The bromide (266) was found to discolour upon storage  OH  266  i)  ^  II  ^ 267 (m OH) 268 (0112. 1 OH)  229  Mg, THF, RT, 30 min; 02, 1.5 h, 40% ii) Cr03, H2SO4, acetone, H20, RT, 1h, 97% Scheme 70  and therefore it was always freshly prepared, purified by column chromatography and immediately used in the next reaction to provide alcohols 267 and 268. Grignard reagent formation from the bromide 266 followed by reaction with oxygen provided a 1:1 mixture of exo and endo alcohols 267 and 268 in 40% yield. Although conversion of bromide 266 to the corresponding Grignard derivative is slow, satisfactory results (for the purpose of determining enantiomeric purity) were obtained when the Grignard reaction was performed under concentrated conditions (-1 M) with rapid addition of the bromide to freshly ground magnesium in dry THF. Attempts to increase the yield of the conversion of 266 to 267/268 are currently being investigated in our laboratory; other sources of oxygen such as Mo05•py-HMPA134 or (camphorylsulfonyl)oxaziridine135will  106 also be investigated. That a mixture of isomers was obtained in this reaction did not matter, since the mixture of epimeric alcohols was subsequently oxidized to (-)-4-methylcamphor (229). Careful column chromatography of the mixture of isomers, however, led to the separation of (+)-4-methylisoborneol (267) so that its enantiomeric purity could be determined. The spectral charateristics of 267 were identical to those obtained for (+)-4-methylisoborneol (267) previously prepared in our laboratory by hydrolysis of (+)-4-methylisobomyl acetate (239, cf. Scheme 60, p. 94). The specific rotation, however, was significantly higher than any previously reported values and suggested a very high enantiomeric purity. Table 10 compares literature specific rotations of (+)-4-methylisoborneol (267) with those obtained for the alcohol prepared by our new route. It should be noted that entries 1-3 are rotations that were taken for three different samples of 267 prepared by acid-catalyzed (45% HBr/HOAc) rearrangement of (-)-2-methylenebomane (240). These results indicate that the rotation is consistent regardless of slight variations in reaction time or temperature and thus the high specific rotations are a result of the acid catalyst used and are also reproducible. Table 10: Specific rotation of (+)-4-methylisoborneol (267) Entry 1 2 3 4 5 6 7  Specific Rotation [a]l) +32.9 0 (c 2.7, 95% EtOH) +32.9 0 (c 8.1, 95% Et0H) +33.0 ° (c 3.1, 95% EtOH) +25.200 (c 10.0, Et0H) +14.80 +22.69 0 (Et0H) +19.5 0 (c 10.00, Et0H)  T (0C) 25 26 25 20 20 20 30  Reference  121 127 122 124  Based on the high specific rotations obtained for alcohol 267, we believed that the alcohol synthesized via 45% HBr/HOAc catalyzed rearrangement of (-)-2-methylene-  107 bornane (240) was of very high enantiomeric purity, and we performed additional analyses to confirm this. It was found that a Chirasil-val III column (Alltech, 25 m x 0.25 mm i d) was able to separate (+)-4-methylisoborneol (267) and (+4-methylisoborneol (ent-267) when an oven temperature of 60 0C and a flow rate of 1.46 mL/min (carrier gas=He) were used. A sample of (+)-4-methyisoborneol (267) prepared via the H2SO4/HOAc route D +20.9 0, c 9.4, 95% Et0H, Sample A) was used as standard and it was found that (bocf4 two peaks with relative areas of 81.7 and 18.2% (rt=29.90 and 30.70 min) were obtained. Although complete baseline resolution could not be achieved, the integration ratio of the two peaks was consistent when different oven temperatures and injection volumes were used and the results are consistent with previous determinations.124 A sample of (+)-4methylisobonieol (267) prepared via our new route ([cc]D25 +33.0 0, c 3.1, 95% Et0H, Sample B) was analyzed under the same GC conditions and only one peak was detected.  The chromatograms obtained for both Sample A and Sample B are shown in Figure 1 (p. 108). Considering the resolution attainable and the GC detection limits, we believe that our new route provides (+)-4-methyl-isoborneol (267) that is at least 95% enantiomerically enriched. Future work may involve obtaining a chiral GC column that is capable of better resolution of the two enantiomers (267 and ent-267) and with ideal resolution the detection limits using this method should be at least 1%. The final step in this project was to oxidize the mixture of Ds_o and rndo alcohols 267 and 268 to the corresponding ketone, (-)-4-methylcamphor (229, Scheme 70, p. 105).  This was accomplished in 97% yield using Jones' reagent, Cr03 in H2SO4 and acetone.136 The (-)-4-methylcamphor (229) obtained through this route showed spectral characteristics identical to those reported in the literature; however, its specific rotation, as expected, was higher. Table 11 (p. 109) compares the specific rotation obtained for our compound with those reported in the literature. Entries 1 and 2 are rotations taken for two samples of 229, both prepared via our new route but in separate experiments.  ^ 108  ^ Oven Temp.=60 GC 0.76  2.18  30.70  29.90  RT^Area^Type^Area %^[a],%4 +20.9 0,  c 9.4,95% Et0H  ^2.18^1.93^BB^0.015 29.90^10676.10^BV^81.745^Sample A 38.70^2382.27^VB^18.241 Total Area= 13060.30  Oven Temp.=60 cC 0.75  29.93 RT^Area^Type^Area %^[a] +33.00,  c 3.1, 95% Et0H  29.93^12180.00^BH^100.00^Sample B Total Area=10180.00  Figure 1: Chromatograms obtained for Samples A and B of (+)-4-methylisoborneol (267)  109 Table 11: Specific rotation of (+4-methylcamphor (229) Entry 1 2 3 4  Specific Rotation [43 -27.0 0 (c 0.7,95% Et0H) -26.7 0 (c 3.4,95% Et0H) -14.5 0 (c 10.0, Et0H) -16.0 0 (c 2.00, Et0H)  T (0C)  Reference  24 25 20 21  121 124  As for the (+)-4-methylisoborneol (267), the high rotations obtained for (-)-4-methylcamphor (229) obtained via our new route suggested that it was of high enantiomeric purity, and further experiments were done to confirm this. Unfortunately, neither of the two chiral GC columns available to us (the previously described Chirasilval III or Cyclodex-30N, 30 m x 0.25 mm i.d., film thickness 0.25 m) were able to resolve the two enantiomers present in a test mixture of 4-methylcamphor (229) prepared by the H2SO4/HOAc catalyzed rearrangement of (+2-methylenebornane (246). Earlier studies, however, had been done using the chiral shift reagent [Eu(hfc)3] and 1H NMR spectroscopy. 127 To a 0.1 M solution of (-)-4-methylcamphor (229) prepared via the H2SO4/HOAc route (Sample C) was added successively 0.10, 0.20 and 0.30 mole equivalents of the chiral shift reagent and a 1H NMR (400 MHz, CDC13) spectrum was recorded after each addition. The spectra are shown in Figure 2 (p. 110) and after a total of 0.60 equivalents of reagent were added, a second signal due to the protons of a methyl group in a diastereomeric species was detected. Integration of the parent signal and of the minor new signal showed a ratio of —4.3:1, and this suggests that the (-)-4-methylcamphor (229) as prepared by the H2SO4/HOAc route has an enantiomeric purity of —60%. A sample of the (-)-4-methylcamphor (229, [45 -26.7 0, c 3.4, 95% Et0H, Sample D) prepared via our new route was treated under similar conditions as those used  for Sample C and 1H NMR (400 MHz, CDC13) spectra were recorded after the  110  0 equiv. [Eu(hfc)3]  0.1 equiv. [Eu(hfc)3] ,===zdZWglos  0.3 equiv. [Eu(hfc)3]  4.3:1 0.6 equiv. [Eu(hfc)3]  5^4^3  0 ppm  Figure 2: 1H NMR (400 MHz) spectra after [Eu(hfc)3] addition to Sample C of (-)-4-methylcamphor (229)  111 successive addition of 0.10, 0.30 and 0.30 mole equivalents of [Eu(hfc)3]. The spectra are shown in Figure 3 (p. 112) and comparison with those obtained for Sample C shows a similar trend in signal broadening and chemical shift change. However, Sample D shows no extra signals that would indicate the presence of a diastereomeric species, and thus, considering the NMR detection limits, our (-)-4-methylcamphor (229) can be considered to be enantiopure. 2.3: Conclusion A new short synthetic route to (-)-4-methylcamphor (229) has been developed which uses the acid-catalyzed (45% HBr/HOAc) rearrangement of (-)-2-methylenebomane (240) as a key step. As the starting material, (+)-camphor (25), is available in either enantiomeric form, a route to (+)-4-methylcamphor (ent-229) is also available. Comparison of the specific rotations obtained for (+)-4-methylisobomeol (267) and (-)-4-methylcamphor (229) obtained via our new route to those reported in the literature suggested that these compounds had been obtained enantiopure, and subsequent GC analyses and NMR experiments showed no evidence of the presence of enantiomers ent-267 or ent-229. The availability of enantiopure 4-methylcamphor (229) provides an  opportunity to evaluate its potential as an intermediate in the enantiospecific synthesis of triterpenoids.  112  0.1 equiv. [Eu(hfc)3]  Figure 3: 1H NMR (400 MHz) spectra after [Eu(hfc)3] addition to Sample D of (-)-4-methylcamphor (229)  113 Experimental  General Experimental: All reagents used were of commercial grade and were used as received unless otherwise specified. Reactions involving air- or moisture-sensitive reagents were performed in flame- or oven-dried glassware and performed under an Ar atmosphere. Dry solvents and reagents were obtained as follows: THF and Et20 were distilled from Na/benzophenone; CH2C12, C6H6, toluene, Me0H, i-Pr2NH, and diglyme were distilled from CaH2; pyridine and DMSO were distilled from KOH; TMSC1, xylenes and Et3N were distilled from LiA1H4; and DMF and quinoline were stored over 4 A molecular sieves. Absolute Et0H was obtained by refluxing 95% Et0H for 6 h over oven-dried CaO, followed by distillation. Low boiling petroleum ether (PE, bp. 30-60 0C) was distilled prior to use in chromatography. Aqueous solutions used in reaction work-ups were saturated unless otherwise specified and MgSO4 used as a drying agent was anhydrous. Column chromatography was performed on Merck Silica Gel 60 (230-400 mesh) and radial chromatography was performed on a Harrison Research Chromatotron® 7924T, using plates of Merck Silica Gel 60, PF254 containing gypsum, of 1, 2 or 4 mm thickness and 4.0-11.25 cm radius. Thin layer chromatography (TLC) was performed on Merck 5735 Precoated Silica Gel 60, PF254 on plastic sheets and visualization was accomplished using I2 vapour or an ammonium molybdate/H2SO4 spray. Gas liquid chromatography (GC) was performed on a Hewlett-Packard HP5830A instrument, using either a 0.2 mm x 11 m OV-101 column or a 0.25 mm x 25 m Chirasil-val III column (for the optical purity determination work) and He as the carrier gas. Melting points were determined on a Reichert heating stage and are uncorrected. Infrared spectra were recorded using either a Perkin-Elmer 710B scanning spectrophotometer (calibrated using the 1601 cm-1 band of polystyrene) or a Bomem Michelson 100 Fourier Transform Infrared spectrometer using internal calibration. Samples were  114 prepared as neat films between NaCl plates or as solutions in NaC1 cells of 0 1 mm path length. 1H NMR spectra were recorded at 300 MHz on a Varian XL-300 spectrometer and at 400 MHz on a Bruker VVH-400 spectrometer and signal positions are given in ppm and are referenced to tetramethylsilane. 31P NMR spectra were recorded at 121.4 MHz on a Varian XL-300 spectrometer and signal positions are given in ppm and are referenced to 85% H3PO4 in D20. Low resolution mass spectra were obtained using a Kratos MS-80 spectrometer and high resolution mass spectra were obtained using a Kratos MS-50 spectrometer. Specific rotations aap were recorded on a Jasco J-710 spectropolarimeter in a 0.1 dm cell using the sodium D line (589 nm). Elemental analyses were performed by Mr. P. Borda, Microanalytical Laboratory, Department of Chemistry, U.B.C. and X-ray crystallographic analyses were done by Dr. S. Rettig, Department of Chemistry, U.B.C. Conversion of (+)-endo-3-bromocamphor (52) to (+)-5,6-dehydrocamphor (36):  Br  52  36  Chlorosulphonic acid (240 mL) was cautiously added to (+)-endo-3-bromocamphor (52, 60.0 g, 0.26 mol).55 The solution was heated at 55 0C for 15 mm, then cooled in ice for 15 min. The reaction mixture was cautiously poured onto ice (— 500 g) and extracted with Et20 (3x). The combined extracts were washed with NaHCO3(aq) solution until the washings were basic, then with brine (6x), and dried over MgSO4. Removal of the solvent gave crude (-)-endo-6-bromocamphor (53) as a brown solid which was not purified. A solution of KOH (26.0 g, 0.46 mol) in water (100 mL) was added, followed by DMSO (600 rnL). The solution was heated at 120 0C overnight, then cooled and diluted with water (700 mL). The reaction mixture was extracted with Et20  115 (3x) and the combined extracts washed with brine (5x) and dried over MgSO4. Removal of the solvent gave a yellow solid which was purified by sublimation (20 mmHg, 50 °C) to afford (+)-5,6-dehydrocamphor (36, 4.83 g, 12% yield) as a white solid. mp: 145-148 °C (lit53 148 °C) C10li140^Calc. Mass: 150.1044 Meas. Mass: 150.1036 111 NMR (400 MHz, CDC13): 8=0.92 (3H, s, C(8)H); 1.02 (3H, s, C(10)H); 1.08 (3H, s, C(9)H); 1.94 (1H, d, J=16 Hz, C(3) endo H); 2.23 (1H, dd, J=16, 4 Hz, C(3) §LCQ H); 2.69 (1H, br s, C(4)H); 5.59 (1H, d, J=6 Hz, C(6)H); 6.45 (1H, dd, J=6, 4 Hz,C(5)H). IR (CHC13): D=2969 (C-H); 1740 (C=0) cm-1 MS: m/e (%)=150 (M+, 7.9); 108 (100); 107 (72); 93 (98); 91(66); 77 (30). [a]D25 +731° (c 1.3, 95% Et0H) (lit53 [o]r• -735 0 for enantiomer (c 1.0, Et0H)) Bromination of (+)-endo-3-bromocamphor (52) to give (+)-3,3-dibromocamphor (58):  Br Br 5 2  0 Br  58  Bromine (20 mL, 0.39 mol) was added dropwise over 1 h to a refluxing solution of (+)-rado-3-bromocamphor (52, 69.2 g, 0.299 mol) in HOAc (250 mL).58 After an additional 30 min, a second portion of bromine (10 mL, 0.19 mol) was added dropwise over 1 h. The reaction was cooled to RT and cautiously poured onto ice (-500 mL). Solid NaHS03 was added until the mixture turned from orange to pale yellow. Solid  116 NaHCO3 was cautiously added until the aqueous layer was saturated. The white precipitate was dissolved with Et20 and the mixture was diluted with water. The mixture was extracted with Et20 (3x) and the combined extracts were washed with saturated NaHCO3(ac) solution (5x, until basic) and brine (5x). After drying the extracts over MgSO4, removal of the solvent gave an orange oil which was diluted with PE. Upon cooling, (+)-3,3-dibromocamphor (58, 63.00 g, 68% yield) was obtained as white crystals. A second crop of crystals yielded an additional 18.86 g (20% yield) of product. mp: 59-60 0C (lit58 64 0C) C101114079Br79Br  Calc. Mass:  307.9411  Meas. Mass: 307.9417 CI 011 14079Br8 1 Br C10111 4 0 811301Br  Calc. Mass:  309.9401  Meas. Mass:  309.9385  Calc. Mass:  311.9381  Meas. Mass: 311.9379 ^ Calc.: C 38.74^H 4.55 Br 51.55% ^ Anal.: C 38.68^H 4.53 Br 51.80% 1H NMR (400 MHz, CDC13): 8=1.01 (3H, s, CH3); 1.10 (3H, s, CH3); 1.23(3H, s, CH3); 1.61-1.67 (2H, m, C(5) endo H and C(6) endo H); 2.07 (1H, m, C(6) v_s_o H); 2.33 (1H, m, C(5) exo H); 3.82 (1H, d, J=4 Hz, C(4)H). IR (CHC13): D=2962 (C-H); 1761 (C=0) cm-1  MS: m/e(%)=312, 310, 308 (M+, 3.4, 6.7, 3.1); 284, 282, 280 (7.2, 16, 7.7); 203 (54); 201 (55); 122 (84); 83 (100).  117 Debromination of (+)-3,3-dibromocamphor (58) to give cyclocamphanone (59): ^ Br 0 Br  58  ^  °Zs 59  To a solution of (+)-3,3-dibromocamphor (58, 5.89 g, 19.0 rnmol) in dry benzene (100 nil.) under an Ar atm was added Et2Zn (17.3 mL, 1.1 M/toluene, 19.0 mmol).59 The mixture was refluxed for 24 h, then was cautiously poured onto ice (-100 mL). 1 M HC1 was added to dissolve the white precipitate and the mixture was extracted with Et20 (3x). The combined extracts were washed with water (3x, until neutral), and dried over MgSO4. Removal of the solvent gave an orange solid which was purified by column chromatography using 24:1 PE:Et20 as eluant. Cyclocamphanone (59) was isolated as a white solid (2.21 g, 78% yield). mp: 168-169 0C (lit59 168-170 0C) C101-1140^Calc. Mass: 150.1044 Meas. Mass: 150.1044 Calc.: C 79.96^H 9.39 % Anal.: C 80.00^H 9.44 % 1H NMR (400 MHz, CDC13): 84.81 (3H, s, CH3); 0.91 (3H, s, Cf_13); 0.97 (3H, s, CH3); 1.44 (1H, t, J=5.5 Hz, C(3)H); 1.71 (1H, d, J=11 Hz, C(6) endo H); 1.93 (1H, dd, J=11, 1.5 Hz, C(6) exo H); 1.96 (1H, t, J=5.5 Hz, C(4)H); 2.01 (1H, t, J=5.5 Hz, C(5)H). IR (CH2C12): D=3065, 2964, 2874 (C-H); 1747 (C=0) cm-1 MS: m/e(%)=150 (M+, 27); 135 (44); 121 (12); 108 (22); 107 (100).  ^  118 Bromination of cyclocamphanone (59) to give em-5-bromocamphor (60):  59  ^  60  To a solution of cyclocamphanone (59, 23.10 g, 0.153 mol) in Ac20 (68 mL, 0.72 mol) was cautiously added dropwise hydrobromic acid (48%, 470 mL, 4.15 mol).60 The reaction was heated at 65 °C for 3 h, then cooled to RT and carefully poured onto ice (-500 mL). The yellow precipitate was collected by filtration, dissolved in Et20 and washed with water (2x), NaHCO3(aq) solution (2x), and brine (3x). After drying over MgSO4, removal of the solvent gave a yellow solid which was recrystallized from 4:1 PE:Et20 to give exo-5-bromocamphor (60) as a white crystalline solid (27.60 g, 78% yield). mp: 109-111 °C (lit60 110-111 °C) C101-115079Br^Calc. Mass: 230.0306 Meas. Mass: 230.0307 C101-115081Br^Calc. Mass: 232.0286 Meas. Mass: 232.0288 Calc.: C 51.97^H 6.54^Br 34.57 % Anal.: C 51.78^H 6.44^Br 34.43 % 1H NMR (400 MHz, CDC13): 8=0.89 (3H, s, CH3); 0.96 (3H, s, CH3); 1.37 (3H, s, CH3); 1.84 (1H, d, J=18 Hz, C(3) endo H); 2.15 (1H, dd, J=16, 8 Hz, C(6) endo H); 2.27 (1H, dd, J=16, 5 Hz, C(6) 02 H); 2.46 (1H, dd, J=18, 5 Hz, C(3) 2.52 (1H, d, J=5 Hz, C(4)H); 4.06 (1H, dd, J=8, 5 Hz, C(5)H).  tl_ CQ H);  119 IR (CH2C12): D=3058, 2969 (C-H); 1745 (C=0) cm-1 MS: m/e(%)=232, 230 (M+, 7.2, 7.4); 151 (34); 123 (80); 110 (18); 109 (100). Ketalization of exo-5-bromocamphor (60) to give 61:  60  ^  61  To a solution of gLco-5-bromocamphor (60, 18.93 g, 81.91 mmol) in ethylene glycol (70.0 mL, 1.23 mol) was added TMSC1 (32.0 mL, 0.246 mol) under an Ar atm. After stirring at RT for 2.5 h, brine was added and the mixture was extracted with Et20 (3x). The combined extracts were washed with NaHCO3(aq) solution (2x), brine (3x) and dried over MgSO4. Removal of the solvent gave a yellow solid which was recrystallized from 4:1 PE:Et20. The ketal 61 was isolated as a white crystalline compound (20.72 g, 92% yield). mp: 72-74 °C C12H190279Br^Calc. Mass: 274.0568 Meas. Mass: 274.0569 C12H 0281Br^Calc. Mass: 276.0548 Meas. Mass: 276.0553 Calc.: C 52.38^H 6.96^Br 29.04 % Anal.: C 52.49^H 7.00^Br 29.00 % 1H NMR (400 MHz, CDC13): 8=0.83 (3H, s, CH3); 1.05 (3H, s, CH3); 1.23 (3H, s, CH3); 1.41 (1H, d, J=13 Hz, C(3) endo H); 2.02 (1H, dd, J=14, 5 Hz, C(6) endo  120 H); 2.11-2.17 (2H, m, C(4)H and C(3) em2H); 2.61 (1H, dd, J=14, 8 Hz, C(6) Q_CQ H); 3.70-3.96 (4H, m, ketal H's); 4.05 (1H, dd, J=8, 5 Hz, C(5)H). IR (CHC13): u=3028, 2962, 2885 (C-H) cm-1 MS: m/e(%)=276, 274 (M+, 9.2, 9.2); 261, 259 (17, 18); 195 (55); 194 (15); 179 (38); 108 (100). Dehydrobromination of bromide 61 to give 5,6-dehydrocamphor ketal (62):  61  ^  62  A solution of bromoketal 61 (0.94 g, 3.4 mmol) and KOH (1.23 g, 21 9 mmol) in DMSO (34 mL) and water (4.5 mL) was heated at 100 °C for 2.5 h. After cooling to RT, water was added and the mixture was extracted with Et20 (3x). The combined extracts were washed with brine (3x) and dried over MgSO4. Removal of the solvent gave 5,6-dehydrocamphor ketal (62) as a pale yellow oil (0.60 g, —91% yield) which was not purified but which was used directly in the next reaction. A small sample was purified for elemental analysis by column chromatography using 9:1 PE:Et20 as eluant. The pure ketal 62 was isolated as a very volatile colourless liquid. C12H1802^Calc. Mass: 194.1307 Meas. Mass: 194.1315 Calc.: C74.19^H 9.34% Ana.: C74.13^H. 9.45 % 1H NMR (400 MHz, CDC13): 8=0.90 (3H, s, CH3); 0.92 (3H, s, CE3); 1.05 (3H, s, CH3); 1.45 (1H, d, J=12 Hz, C(3) endo H); 2.06 (1H, dd, J=12, 3 Hz, C(3) p_Lo H);  121 2.37 (1H, br t, J=3 Hz, C(4)H); 3.65-4.00 (4H, m, ketal H's); 5.79 (1H, d, J=6 Hz, C(6)H); 6.15 (1H, dd, J=6, 3 Hz, C(5)H). IR (CHC13): v=2954, 2873 (C-H) cm-1 MS: m/e(%)=194 (M+, 1.6); 179 (2.5); 108 (100); 93 (80); 86 (35). Hydroysis of ketal 62 to provide (-)-5,6-dehydrocamphor (ent-36):  62  ent-36  A solution of ketal (62, 0.50 g, 2.6 mmol) in acetone (13 mL) and 1 M HC1 (8.0 mL) was stirred at RT for 1.5 h. After dilution with water, the mixture was extracted with Et20 (3x). The combined extracts were washed with water (3x), dried over MgSO4 and the solvent removed to yield a white solid. Purification by column chromatography using first PE as eluant, then gradually increasing the polarity to 9:1 PE:Et20 gave (-)-5,6-dehydrocamphor (ent-36) as a white crystalline compound (0.33 g, 85% yield). mp: 145-148 0C (sealed tube) (lit53 148 0C) C101-1140^Calc. Mass: 150.1045 Meas. Mass: 150.1038 1H NMR (400 MHz, CDC13): 8.0.90 (3H, s, CH3); 1.00 (3H, s, C113); 1.06 (3H, s, C113); 1.93 (1H, d, J=16 Hz, C(3) g_Kk H); 2.21 (1H, dd, J=16, 3 Hz, C(3) exo H); 2.68 (1H, br s, C(4)H); 5.58 (1H, d, J=6 Hz, C(6)H); 6.45 (1H, dd, J=6, 4 Hz, C(5)H). IR (CHC13): v=2969 (C-H); 1734 (C=0) cm-1  122 MS: m/e (%)=150 (1v1+, 7.0); 109 (27); 108 (100); 107 (41); 93 (86); 83 (46). [a]t)5 -714 0 (c 2.10, 95% Et0H), (lit53 [a]r) -735 0 (c 1.0, Et0H)) Conversion of (+)-5,6-dehydrocamphor (36) to alkyne diol 63:  x...T5.  OH  0 ^  36^  63  II OH  n-BuLi (58 mL, 1.6 M/hexanes, 93 mmol) was added dropwise to a solution of propargyl alcohol (2.7 mL, 47 mmol) in dry THF (150 mL) at -78 0C under an Ar atm and stirred at -78 0C for 1 h.61 A solution of (+)-5,6-dehydrocamphor (36, 4.68 g, 31 mmol) in dry TI-IF (40 mL) was also cooled to -78 0C and cannulated into the reaction mixture which was stirred for another hour before being allowed to warm to RT overnight. The reaction was quenched by the addition of water, diluted with NH4C1(aq) solution and extracted with Et20 (3x). The combined extracts were washed with brine (2x), and dried over MgSO4. Removal of the solvent gave a crude pale yellow solid which was recrystallized from CH2C12 to afford pure alkyne diol 63 (4.84 g, 76% yield) as a white solid. mp: 1181200C C13H1802^Calc. Mass: 206.1307 Meas. Mass: 206.1300 ^ Calc.: C 75.69 H 8.79% ^ Anal.: C 75.77 H 8.59%  123 1H NMR (400 MHz, CDC13): 8=0.94 (3H, s, CH3); 1.10 (3H, s, CLI3); 1.11 (3H, s, CH3); 1.45 (1H, t, J=6 Hz, exchanges with D20, -CH2OL-1); 1.89 (1H, d, J=12 Hz, C(3) endo H); 1.97 (1H, s, exchanges with D20, 30 OM; 2.27 (1H, dd, J=12, 4 Hz, C(3) exo H); 2.42 (1H, br t, J=4 Hz, C(4)H); 4.26 (2H, d, J=6 Hz, Cli2OH); 5.74 (1H, d, J=6 Hz, C(6)H); 6.11 (1H, dd, J=6, 4 Hz, C(5)H). IR (Nujol mull): D=3300 (br, 0-H); 2950, 2900 (C-H) cm-1 MS: ix* (%)=206 (M+, 0.3); 176 (17); 145 (40); 108 (100); 107 (55); 105 (40); 93 (98); 91(77); 77 (46). Reduction of alkyne diol 63 to give alkene diol 64:  OH  63 I I  OH OH  A solution of alkyne diol 63 (6.04 g, 29.2 mmol) in dry THF (50 mL) was cautiously cannulated into a slurry of LiA1H4 (2.80 g, 73.0 mmol) in dry THF (100 mL) under an Ar atm.62 After heating at 40 °C for 1 h, the reaction was cooled to RT and cautiously quenched by the addition of water. 1 M HC1 was added to dissolve the resulting grey precipitate. The solution was extracted with Et20 (4x) and the combined extracts washed with brine (3x, until neutral). Removal of the solvent gave a pale yellow solid which was recrystallized from Et20 to afford the alkene diol 64 (5.16 g, 85% yield) as white crystals. mp: 158-161 °C  124 C13H2002^Calc. Mass: 208.1463 Meas. Mass: 208.1459 1H NMR (400 MHz, CD3CN): 8=0.90 (3H, s, CH3); 0.92 (3H, s, CH3); 1.17 (3H, s, CH3); 1.56 (1H, d, J=12 Hz, C(3) endo H); 2.10 (1H, dd, J=12, 4 Hz, C(3)  C,2{Q  H); 2.38 (1H, br t, J=4 Hz, C(4)H); 3.98 (2H, d, J=6 Hz, CH2OH); 5.65 (3H, m, C(6)H and trans vinyl H's); 6.00 (1H, dd, J=6, 4 Hz, C(5)H). IR (Nujol mull): D=3350 (br, 0-H); 2900 (C-H) cm-1 MS: m/e (%)=208 (M+, 3.1); 177 (18); 119 (24); 108 (100); 93 (61); 91(32). Anionic oxy-Cope rearrangement of alkene diol 64 to give keto-alcohol 66:  66  A solution of alkene diol 64 (3.51 g, 16.8 mmol) in dry THF (70 mL) was cannulated into a slurry of KR (2.03 g, 50.6 mmol) in dry THF (100 mL) under an Ar atm. After 15 min at 40 0C the reaction was cooled to RT, cautiously quenched by addition of n-propanol and diluted with water. The reaction was extracted with Et20 (3x) and the combined extracts washed successively with 1 M HC1 and brine (3x). Drying over MgSO4 followed by removal of the solvent gave a red oil which was purified by column chromatography using 2:1 PE:Et20 as eluant. The keto-alcohol 66 was isolated as a yellow liquid (2.98 g, 85% yield). C13H2002^Calc. Mass: 208.1463 Meas. Mass: 208.1466  125 1H NMR (400 MHz, CDC13): 8=0.94 (3H, s, CH3); 1.04 (3H, s, CH3); 1.45 (1H, br s, exchanges with D20, Off); 1.62 (3H, d, J=4 Hz, vinyl CI_13); 2.03 (1H, dd, J=16, 13 Hz); 2.20-2.40 (4H, m); 2.48 (1H, m); 3.26 (1H, br s, C(10)H); 3.65 (1H, dd, J=11, 7 Hz, -CHHOH); 3.73 (1H, dd, J=11, 7 Hz, -CHHOH); 5.20(1H, s, vinyl H). IR (neat): v=3400 (br, 0-H); 2950, 2900 (C-H); 1710 (C=0) cm-1 MS: m/e (%)=208 (M+, 36); 193 (49); 190 (28); 175 (43); 147 (48); 133 (48); 121 (75); 107 (100); 91(67). Protection of keto-alcohol 66 to give keto-acetate 67: OAc  OH^  66^  67  To a solution of keto-alcohol 66 (3.66 g, 17.6 mmol) in dry CH2C12 (-100 mL) under an Ar atm were added successively Ac20 (2.0 mL, 21 mmol), Et3N (4.9 mL, 35 mmol) and a catalytic amount of DMAP. After stirring at RT overnight the reaction mixture was diluted with water and extracted with CH2C12 (3x). The combined extracts were washed successively with water, 1 M HC1, brine (2x) and dried over MgSO4. Removal of the solvent gave a pale yellow liquid which was purified by column chromatography using 4:1 PE:Et20 as eluant. The keto-acetate 67 was isolated as a colourless oil (4.17 g, 95% yield). Ci3H2002^Calc. Mass: 250.1569 Meas. Mass: 250.1572  126 Calc: C71.97^H 8.86 % Anal.: C 71.68^H 8.90 % 1H NMR (400 MHz, CDC13): 8=0.94 (3H, s, CH3); 1.04 (3H, s, CH3); 1.62 (3H, br s, vinyl CH); 2.09 (3H, s, -02CCH3); 2.20-2.55 (6H, m); 3.20 (1H, br s, C(10)H); 4.03 (1H, dd J=11, 7 Hz, -CHHOAc); 4.17 (1H, dd, J=11, 7 Hz, -CHLHOAc); 5.17 (1H, s, vinyl H). IR (neat): D=2950, 2900 (C-H); 1730, 1710 (C=0) cm-1. MS: m/e (%)=250 (M+, 0.2); 190 (99); 175 (100); 148 (67); 107 (34); 91(33); 43 (53). Ring expansion of keto-acetate 67 to enone 69: OAc^ 0 IH  67  ^  68  OAc^  OAc  Si. ^  69  A solution of keto-acetate 67 (3.66 g, 14.6 mmol) in CH2C12 (60 mL) and Me0H (60 mL) was cooled to -78 0C and 03 was bubbled through the solution until a blue colour persisted (-1 h). Excess 03 was removed by bubbling 02 through the solution until it became colourless. The reaction mixture was poured onto Zn (7.75 g, 118 mmol), HOAc (15 mL, 266 mmol) was added, and the reaction was stirred at RT for 1 h. The mixture was filtered, washed successively with water, 5% Na0H0q) solution, water (4x, until neutral) and dried over MgSO4. Removal of the solvent yielded the crude ketoaldehyde 68 as a yellow oil which was not purified but which was used directly in the next reaction. The IR and 1H NMR spectra were consistent with those expected for the aldehyde 68.  127 IR (neat): u=2970 (C-H); 1735, 1715, 1705 (C=0) cm-I 1H NMR (400 MHz, CDC13): 8=1.15 (3H, s, CH3); 1.16 (3H, s, CH3); 2.05 (3H, s, -02CC113); 2.16 (3H, s, -00C1_13); 2.30-2.50 (6H, m); 2.65-2.82 (2H, m); 3.05 (1H, d, J=3 Hz, C(10)H); 4.03 (2H, d, J=7 Hz, -CH20Ac); 9.10 (1H, d, J=3 Hz, -CHO). A catalytic amount of p-Ts0H-H20 was added to a solution of crude ketoaldehyde 68 in dry benzene (-100 mL). The reaction was refluxed in a Dean-Stark apparatus under an Ar atm for 1 h. After cooling to RT, brine was added. The mixture was extracted with Et20 (3x), and the combined extracts were washed with NaHCO3(aq) solution and brine (2x). After drying over MgSO4 and removal of the solvent, a yellow liquid was obtained. The crude product was purified by column chromatography using 1:1 PE:Et20 as eluant to yield the enone 69 as a pale yellow liquid (3.23 g, 83% yield). A small amount was distilled (bp —150 0C at 0.1 mmHg) to yield a colourless oil for microanalysis. C15H2004^Calc. Mass: 264.1361 Meas. Mass: 264.1357 Calc. C68.16  H 7.63 %  Anal. C 67.97  H 7.63 %  1H NMR (400 MHz, CDC13): 8=1.09 (3H, s, CH3); 1.28 (3H, s, C1_13); 2.12 (3H, s, -02CC113); 2.14-2.40 (4H, m); 2.48 (2H, dd, J=14, 4 Hz); 3.22 (1H, br s, C(10)H); 4.18 (1H, dd, J=11, 6 Hz, -CHHOAc); 4.32 (1H, dd, J=12, 7 Hz, -CHHOAc); 6.16 (1H, dd, J=11, 3 Hz, C(2)H); 6.82 (1H, dt, J=11, 1 Hz, C(1)H). IR (neat): u=3050, 2980, 2900 (C-H); 1740, 1720, 1680 (C=0) cm-I  128 MS: mie (%)=264 (M+, 0.4); 204 (63); 153 (12); 135 (16); 108 (100); 107 (40); 69 (35). Monoketalization of enone 69 to give ketal 85: OAc^  69  OAc  85  To a solution of enone 69 (3.23 g, 12.2 mmol) in dry benzene (-100 mL) were added a catalytic amount of p-Ts0H•H20 and ethylene glycol (8.25 mL, 148 mmol), and the mixture was refluxed under an Ar atm for 45 min in a Dean-Stark apparatus. After cooling to RT, the mixture was poured onto brine and extracted with Et20 (3x). The combined extracts were washed with NaHCO3(aq) solution, brine (2x) and dried over MgSO4. Removal of the solvent gave a yellow oil which was purified by column chromatography using 2:1 PE:Et20 as eluant. The ketal 85 was isolated as a colourless oil (2.91 g, 77% yield). Cl7H2405  ^  Calc. Mass: 308.1623  Meas. Mass: 308.1623 1H NMR (400 MHz, CDC13): 8=1.09 (3H, s, CH3); 1.21 (3H, s, CH3); 1.22-1.45 (2H, m); 1.62 (1H, d, J=12 Hz); 1.73 (1H, dt, 1=12, 4 Hz); 2.05 (1H, m); 2.10 (3H, s, -02CC113); 2.32 (1H, br s); 3.06 (1H, br s, C(10)H); 3.93 (4H, s, ketal H's); 4.12 (1H, dd, J=11, 6 Hz, -CHHOAc); 4.22 (1H, dd, J=11, 8 Hz, -CHHOAc); 6.02 (1H, dd, J=11, 3 Hz, C(2)H); 6.67 (1H, dt, J=11, 1 Hz, C(1)H). IR (neat): D=2980, 2900 (C-H); 1740, 1680 (C=0) cm-1  129 MS: mie (%)=308 (M+, 32); 248 (13); 178 (42); 171 (100); 140 (67); 129 (43); 111 (48); 87 (68); 43 (84). Ketalization of enone 85 to give diketalized acetate 86 and diketalized alcohol 87: OAc^ OAc 0 CO H 0 86  87  Ethylene glycol (3.9 mL, 70 trump and a catalytic amount of p-Ts0H.H20 were added to a solution of acetate 85 (1.08 g, 3.5 mmol) in dry benzene (-50 mL). After refluxing under an Ar atm in a Dean-Stark apparatus overnight, the reaction was cooled to RT and poured onto brine. The mixture was extracted with Et20 (3x) and the combined extracts were washed with NaHCO3(ac) solution and brine (2x). After drying over MgSO4 the solvent was removed to yield a yellow oil which was purified by radial chromatography (4 mm plate) using 1:1 PE:Et20 as eluant. Two compounds were isolated: the dilcetalized acetate 86 as a colourless oil (0.46 g, 37% yield) and the diketalized alcohol 87 also as a colourless oil (0.52 g, 48% yield). Data for diketalized acetate 86: C19H2806^Calc. Mass: 352.1886 Meas. Mass: 352.1885 1H NMR (300 MHz, CDC13): 8=0.89 (3H, s, CH3); 0.99 (3H, s, CLI3); 1.40 (1H, t, J=12 Hz); 1.79-1.96 (3H, m); 2.06 (3H, s, -02CCH3); 2.21 (3H, br s); 2.55 (1H, br s); 3.84-4.03 (8H, m, ketal H's); 4.10 (1H, dd, J=11, 7 Hz, -CHHOAc); 4.33 (1H, dd, J=11, 5 Hz, -CHHOAc); 5.22 (1H, br s, C(1)H). IR (neat): D=2960, 2880 (C-H); 1740 (C=0) cm-1  130 MS: m/e (%)=352 (M+, 2.0); 309 (30); 223 (32); 171 (81); 114(100); 86(66). Data for diketalizetl alcohol 87: Ci7H2605^Calc. Mass: 310.1780 Meas. Mass: 310.1786 1H NMR (400 MHz, CDC13): 8=0.89 (3H, s, CLI3); 0.98 (3H, s, CE3); 1.24 (1H, t, J=6 Hz); 1.37 (1H, br, s, exchanges with D20, -OW; 1.43 (1H, t, J=12 Hz); 2.74 (1H, br d, J=9 Hz); 2.84 (1H, dt, J=12, 4 Hz); 2.91 (1H, dt, J=12, 4 Hz); 2.15-2.30 (2H, br m); 2.45 (1H, br s); 3.69-3.77 (2H, br m, -CH2OH); 3.80-4.02 (8H, m, ketal H's); 5.33 (1H, br s, C(1)H). IR (neat): D=3400 (br, 0-H); 2950, 2860 (C-H) cm-1 MS: m/e (%)=310 (M+, 5.3);267 (36); 181 (28); 129 (36); 114 (100); 99 (48); 86 (34). Deprotection of diketalized acetate 86 to give diketalized alcohol 87: OAc 0 < OS ) ■,.0 H 0,/ 86  To a solution of dike talized acetate 86 (0.429 g, 1.18 mmol) in Me0H (10 mL) was added a solution of KOH (0.20 g, 3.5 mmol) in water (10 mL). After stirring at RT for 30 min, the mixture was diluted with water and extracted with Et20 (3x). The combined extracts were washed with brine (3x), dried over MgSO4 and the solvent removed to provide a pale yellow oil. Purification by column chromatography using 1:1 PE:Et20 as eluant gave the diketalized alcohol 87 as a colourless oil (0.34 g, 95% yield). Spectral characteristics were identical to those of the alcohol 87 described previously.  131 Attempted cyclopropanation of diketalized alcohol 87:  -ON-  87  ^  88  Cyclopropanation attempt A72: To a solution of diketalized alcohol 87 (0.115 g, 0.40 mmol) in CHC13 (2 mL) at 0 °C were added BuN+Et3C1- (0.002 g, 0.008 mmol), then NaOH (0.5 mL, 50%/H20) dropwise. The mixture was stirred at 0 °C for 2.5 h, then at RT for 3 days. Water was added and the mixture extracted with Et20 (3x). Drying over MgSO4 and removal of the solvent gave a yellow oil which was purified by column chromatography using 1:1 PE:Et20 as eluant. None of the products obtained showed evidence of being a cyclopropanation product by either 1H NMR or mass spectrometry. Cyclopropanation attempt  B73,74:  To a solution of diketalized alcohol 87 (0.268 g, 0.860 mmol) in dry toluene (10 mL) under an Ar atm was added Et2Zn (1.9 mL, 1.1 M/toluene, 2.1 mmol) followed by CH2I2 (0.21 mL, 2.6 mmol). The system was flushed with 02 and the reaction stirred at RT 1.5 h. The reaction was then heated at 45 °C for 1 h, then at 95 °C overnight. After cooling to RT, NH4C1(aci) solution was added and the mixture extracted with Et20 (3x). The combined extracts were dried over MgSO4 and the solvent removed to yield a yellow oil which was a complex mixture by TLC and GC. The mixture was purified by column chromatography using 1:1 PE:Et20 as eluant to give starting material (0.105 g, 39% yield). There was no evidence of a cyclopropanation product as determined by 1H NMR and mass spectrometry.  132 Cyclopropanation attempt C67: To a slurry of Zn-Cu (0.37 g, 5.0 mmol) and  12 (0.37  g, 1.4 mmol) in dry Et20  (5 mL) under an Ar atm was added a solution of dilcetalized alcohol 87 (0.19 g, 0.62 mmol) in dry Et20 (5 mL). CH2I2 (0.15 mL, 1 8 mmol) was added and the reaction was stirred at RT for 30 min, then refluxed for 1 h. Additional CH2I2 (0.15 mL, 1.8 mmol) was added dropwise and the mixture was refluxed for a further 8 h. A final portion of CH2I2 (0.15 mL, 1.8 mmol) was added and the reaction was refluxed overnight. After cooling to RT, NH4C1(aq) solution was added and the mixture was filtered through Celite. The organic layer was separated and washed with NaHCO3(ac) solution, brine (3x), dried over MgSO4, and the solvent removed to give a yellow oil. Purification by column chromatography using 2:1 PE:Et20 as eluant gave recovered starting material as the major product (0.033 g, 17% recovery). Minor products showed no evidence of being cyclopropanation products as determined by 1H NMR or mass spectrometry. Cyclopropanation attempt D75: To a slurry of Zn (0.20 g, 3.1 mmol) and CuCl (0.03 g, 0.31 mmol) in dry Et20 (1 mL) under an Ar atm were added CH2Br2 (0.16 mL, 2.3 mmol) and a solution of diketalized alcohol 87 (0.24 g, 0.77 mmol) in dry Et20 (3 nE). TiC14 (5.0 IlL, 0.046 mmol) was cautiously added and the mixture diluted with dry Et20 (3 mL). After refluxing for 2 h, the reaction was cooled to RT and NII4C1(aco solution was added. After filtration and extraction with pentane (3x) the combined extracts were washed with 10% Na0H(aco solution (3x) and brine. Drying over MgSO4 and removal of the solvent gave a yellow liquid which was purified by column chromatography using 4:1 PE:Et20 as eluant. Many products were obtained, none of which appeared to be cyclopropanation products as determined by 1H NMR and mass spectrometry.  133 Reduction and protection of keto-alcohol 66 to give dimethyl ether 91: OH^  OC H3  OCH 3 66  To a slurry of LiA1H4 (0.12 g, 3.2 mmol) in dry THF (15 mL) at -78 0C under an Ar atm was added a solution of keto-alcohol 66 (0.554 g, 2.60 mmol) in dry THF (30 mL). The reaction mixture was allowed to warm to RT over —1 h. Water was cautiously added, then the mixture was diluted with 1 M HC1 and extracted with Et20 (3x). The combined extracts were washed with brine (3x) and dried over MgSO4. Removal of the solvent gave a yellow gum (0.606 g) which was not purified but which showed the following spectral characteristics, suggesting that the diol was formed: C13H2202^Calc. Mass: 210.1619 Meas. Mass: 210.1613 1H NMR (300 MHz, CDC13, major diastereomer) 8=0.95 (3H, s, CH3); 1.00 (3H, s, CH3); 1.10-1.30 (2H, m); 1.60 (3H, m, vinyl CLI3); 1.75-2.00 (4H, m); 2.95 (1H, br s, C(7)H); 3.50-3.80 (5H, m); 5.15 (1H, s, vinyl H). IR (neat): D=3350 (br, 0-H); 2900 (C-H) cm-1 MS: m/e (%)=210 (M+, 23); 192 (34); 177 (100); 174 (28); 159 (91). The crude diol was dissolved in dry TI-IF (15 mL) and cannulated into a slurry of KH (0.26 g, 6.5 mmol) in dry THE (10 mL) under an Ar atm. The reaction was stirred at RT for 45 min and then Mel (0.40 mL, 6.5 mmol) was added. After stirring for an additional 60 min, water was cautiously added, and the reaction was extracted with Et20  134 (3x). The combined extracts were washed with brine (3x) and dried over MgSO4. Removal of the solvent gave a yellow liquid which was purified by column chromatography using 15:1 PE:Et20 as eluant. The dimethyl ether 91 was isolated as a colourless liquid (0.515 g, 83% yield from keto-alcohol 66). 1H NMR spectroscopy showed the diastereomeric mixture to be —4:1. Ci5H2602^Calc. Mass: 238.1932 Meas. Mass: 238.1927 1H NMR (400 MHz, CDC13, major diastereomer) 8=0.94 (3H, s, CH3); 0.99 (3H, s, Cli3); 1.58 (3H, m, vinyl CH3); 1.70-1.80 (1H, m); 1.80-1.95 (3H, m); 2.94 (1H, br s, C(7)H); 3.80 (1H, m); 3.30-3.50 (10H, m); 5.14 (1H, s, vinyl H). IR (neat): D=2900 (C-H) cm-1 MS: m/e(%)=238 (M+, 4.5); 223 (1.1); 207 (4.2); 206 (27); 191 (20); 159 (100). Ring expansion of dimethyl ether 91 to give enone 92: OCH3  OCH3^  OCH3  OCH3 91^  92  A solution of dimethyl ether 91 (0.91 g, 3.8 mmol) in CH2C12 (10 mL) and Me0H (10 rnL) was cooled to -78 0C and 03 was bubbled through the solution until a blue colour persisted (-45 min). Excess 03 was removed by bubbling 02 through the solution until it became colourless. The reaction mixture was poured onto Zn (2.49 g, 38.1 mmol), HOAc (4.5 mL, 76 mmol) was added, and the reaction was stirred at RT for 1 h. The mixture was filtered, washed successively with water (2x), 5% Na0H(aq)  135 solution (2x), water (4x, until neutral) and dried over MgSO4. Removal of the solvent gave the crude keto-aldehyde as a yellow oil which was not purified. To the ketoaldehyde in dry C6H6 (-50 mL) was added a few crystals of p-Ts0H.H20 and the mixture was refluxed in a Dean-Stark apparatus under an Ar atm for 1 h. After cooling to RT brine was added and the mixture was extracted with Et20 (3x). The combined extracts were washed with NaHCO3(ac) solution, brine (3x) and dried over MgSO4. Removal of the solvent gave a yellow liquid which was purified by column chromatography using 4:1 PE:Et20 as eluant. The enone 92 was isolated as a colourless oil (0.502 g, 52 % yield). C15H2403^Calc. Mass: 252.1725 Meas. Mass: 252.1719 1H NMR (400 MHz, CDC13): 8=1.00-1.25 (2H,m); 1.09 (3H, s, CH3); 1.21 (3H, s, CH3); 1.77 (1H, br d, J=14 Hz); 1.93 (1H, br d, J=14 Hz); 2.06 (1H, br d, J=14 Hz); 2.33 (1H, br m); 3.12 (1H, br s, C(10)H); 3.30 (3H, s, -CHRR'OCH3); 3.38 (3H, s, -CH2OCLI3); 3.40-3.55 (3H, m, -Q120CH3 and C(7)H); 5.98 (1H, dd, J=10, 3 Hz, C(2)H); 6.75 (1H, dt, J=10, 2 Hz, C(1)H). IR (neat): D=2924, 2357, 2331 (C-H); 1679 (C=0) cm-1 MS: m/e(%)=252 (Mt, 11); 221 (4.9); 220 (30); 205 (3.1); 189 (5.0); 188 (22); 45 (100). Conversion of enone 92 to ketal 93: OCH 3^  OCH 3 92  OCH 3  O CH 3  136 A solution of enone 92 (0.50 g, 1.9 mmol), ethylene glycol (1.1 mL, 19 mmol), and a catalytic amount of p-T50H•H20 in dry C6H6 (-50 mL) was refluxed under an Ar atm in a Dean-Stark apparatus for 3 days. After cooling to RT, brine was added and the mixture was extracted with Et20 (3x). The combined extracts were washed with NaHCO3(4 solution, brine (3x) and dried over MgSO4. Removal of the solvent gave a pale yellow oil which was purified by column chromatography using 15:1 PE:Et20 as eluant. The ketal 93 was isolated as a colourless liquid (0.301 g, 53% yield). C17H2804^Calc. Mass: 296.1987 Meas. Mass: 296.1990 1H NMR (300 MHz, CDC13): 5=0.88 (3H, s, CH3); 0.99 (3H, s, CLI3); 1.12-1.30 (2H, m); 2.00-2.40 (5H, m); 2.55 (1H, br s); 3.33 (3H, s, -CHRR'OCLI3); 3.34 (3H, s, -CH2OCL13); 3.43 (1H, m, C(7)H); 3.54 (1H, m, -CHHOCH3); 3.65 (1H, m, -CHHOCH3); 3.85-4.00 (4H, m, ketal H's); 5.19 (1H, br s, C(1)H). IR (neat): u=2900 (C-H) cm-1 MS: m/e(%)=296 (M+, 2.9); 251 (7.1); 221 (13); 114 (100). Conversion of ketal 93 to deconjugated enone 94: OCH3  OCH3^  OC H3 93  ^  OCH3 94  A solution of ketal 93 (0.38 g, 1.3 mmol) in acetone (5 mL) and 1 M HC1 (5 mL) was heated at 70 °C for 15 min. After cooling to RT, the reaction was extracted with Et20 (3x) and the combined extracts were washed with brine (3x) and dried over MgSO4.  137 Removal of the solvent gave the deconjugated enone 94 as a colourless liquid (0.31 g, 95% yield) which was not purified but which was used directly in the next reaction. Ci5H2403^Calc. Mass: 252.1725 Meas. Mass: 252.1733 1H NMR (300 MHz, CDC13): 8=1.03 (3H, s, CH3); 1.07-1.22 (2H, m); 1.29 (3H, s, CH3); 2.11 (1H, br d, J=4 Hz); 2.17 (1H, br d, J=4 Hz); 2.52 (1H, dd, J=14, 4 Hz); -CHRR'OCL13); 3.39 (3H, s, -CH20C113); 3.39-3.41 (1H, m, C(7)H); 3.50-3.63 (2H, m, -CH2OCH3); 5.26 (1H, br s, C(1)H). IR (neat): D=2974, 2925, 2870, 2822 (C-H); 1714 (C=0) cm-1 MS: m/e(%)=252 (M+, 6.8); 221 (1.9); 220 (21); 189 (3.3); 188 (13); 45 (100). Reduction of deconjugated enone 94 to give alcohol 95: OCH3^  HO  OCH3  OCH3  A solution of deconjugated enone 94 (0.31 g, 1.2 mmol) in dry THF (5.0 mL) was cooled to -78 0C and was cannulated into a slurry of LiA1H4 (0.053 g, 1.4 mmol) in dry THE (5.0 mL), also at -78 0C and under an Ar atm. The mixture was allowed to warm to RT over 2 h, then was cautiously quenched by the addition of water. After dilution with 1 M HC1, the mixture was extracted with Et20 (3x) and the combined extracts were washed with water and brine (2x). Drying over MgSO4 and removal of the solvent gave the alcohol 95 as a colourless liquid (0.275 g, 89% yield).  138 C15H2603^Calc. Mass: 254.1881 Meas. Mass: 254.1881 1H NMR (300 MHz, CDC13): 8=0.80 (3H, s, CH3); 0.98 (3H, s, CLI3); 1.15-1.40 (2H, m); 2.00-2.12 (4H, m); 2.20-2.31 (1H, m); 2.50 (1H, br s); 3.34 (3H, s, CHRR'OCE3); 3.35 (3H, s, -CH20CH3); 3.36-3.58 (3H, m, -CH2OCH3 and C(7)H); 3.65 (1H, br t, J=4 Hz, C(3)H); 5.26 (1H, br s, C(1)H). IR (neat): v=3436 (br, 0-H); 2865 (C-H) cm-1 MS: m/e(%)=254 (M+, 0.1); 236 (1.3); 222 (5.4); 204 (8.6); 159 (100); 105 (35); 91(54). Conversion of alcohol 95 to cyclopropane 96: OCH3  HO  HO 4:51 = OCH3 I; 96 "  Cyclopropanation attempt E67: A slurry of Zn-Cu (0.032 g, 0.50 mmol) and CH2C12 (0.040 mL, 0.50 mmol) in dry Et20 (1.0 mL) was refluxed under an Ar atm for 20 min. A solution of alcohol 95 (0.061 g, 0.24 mmol) and CH2I2 (0.040 mL, 0.50 mmol) in dry Et20 (2.0 mL) was added dropwise. The mixture was refluxed for 5 h, then an additional portion of CH2I2 (0.040 mL, 0.50 mmol) was added. After 30 min at reflux, the reaction mixture was cooled to RT and stirred under an Ar atm overnight. It was then warmed to 50 0C and another portion of CH2I2 (0.040 mL, 0.50 mmol) was added. After 30 min, the reaction was cooled to RT, another portion of Zn-Cu (0.032 g, 0.50 mmol) was added and the mixture was refluxed for 45 min. One last portion of CH2I2 (0.040 mL, 0.50 mol) was added and reflux was continued 5 h. After cooling to RT, 0.5 M HCI was added and the  139 mixture was extracted with Et20 (3x). The combined extracts were washed with brine, dried over MgSO4 and the solvent removed to give a yellow oil. Purification by column chromatography using 9:1 PE:Et20 as eluant gave a colourless liquid (0.028 g) which was a mixture of 2 compounds as determined by GC. 11 1 NMR (400 MHz, CDC13) -  determined this to be a mixture of recovered starting material 95 and a cyclopropyl compound (tentatively assigned structure 96), as indicated by an NMR signal at 0.45 ppm. It was not possible to obtain a pure sample of the cyclopropyl compound. Cyclopropanation attempt 513,74: To a solution of alcohol 95 (0.127 g, 0.499 mmol) in dry toluene (2.0 mL) and Et2Zn (2.3 mL, 1.1 M/toluene, 2.5 mmol) at 50°C under an Ar atm was added dropwise CH2I2 (0.20 mL, 2.5 mmol) in dry toluene (2.0 mL). After heating for 30 min, the system was flushed with 02 and heated for a further 1 h. After cooling to RT, 0.5 M HC1 was added, and the mixture was extracted with Et20 (3x). The combined extracts were washed with brine (3x) and dried over MgSO4. Removal of the solvent gave a brown oil which was subjected twice more to the above cyclopropanation conditions. After the final work-up, the oil was purified by column chromatography using 9:1 PE:Et20 as eluant. The cyclopropyl compound 96 was isolated as a colourless oil (0.006 g, 4% yield). CI6H2803^Calc. Mass: 268.2038 Meas. Mass: 268.2029 1H NMR (300 MHz, CDC13): 8=0.45 (1H, dd, J=4, 11 Hz, cyclopropyl H); 0.67 (1H, m, cyclopropyl H); 0.80 (3H, s, CH.3); 0.81-0.82 (1H, m); 0.92 (3H, s, CH3); 0.950.99 (1H, m); 1.55 (2H, br m); 1.70-1.80 (1H, m); 1.88 (1H, d, J=14 Hz); 2.01 (1H, dd, J=11, 6 Hz); 2.10-2.20 (1H, m);3.30 (3H, s, -CHRR'OCH3); 3.32 (3H, s, -CH2OCH3); 3.33-3.42 (3H, m, -CLI2OCH3 and C(7)H); 3.76 (1H, m, C(3)H).  140 MS: m/e(%)=268 (M+, 0.7); 250 (2.4); 235 (11); 218 (15); 173 (66); 171 (40); 159 (35); 131 (45); 119 (45); 45 (100). Conversion of alcohol 87 to silyl ether 106:  OH^  e0  Br\> /c)  Ole^0 o N....0^ (...0 87  H 0  106  To a solution of diketalized alcohol 87 (0.408 g, 1.39 mmol), Et3N (0.24 mL, 1.7 mmol) and a catalytic amount of DMAP in dry CH2C12 (20 mL) was added bromomethyldimethylsilyl chloride (0.24 mL, 1.7 mmol) and the mixture was stirred at RT under an Ar atm for 30 min. Water was added and the mixture was extracted with CH2C12 (3x). The combined extracts were washed with brine (3x) and dried over MgSO4. Removal of the solvent gave an orange liquid which was purified by column chromatography using 4:1 PE:Et20 as eluant. The silyl ether 106 was isolated as a colourless liquid (0.46 g, 76% yield). C201-13305Si79Br^Calc. Mass: 460.1280 Meas. Mass: 460.1288 C20113305Si81Br^Calc. Mass: 462.1260 Meas. Mass: 462.1270 1H NMR (400 MHz, CDC13): 8=0.26 (3H, s, -SiCH3); 0.30 (3H, s, -SiCH3); 0.88 (3H, s, CH3); 0.98 (3H, s, CH3); 1.29 (1H, t, J=13 Hz); 1.70-1.78 (1H, br m); 1.83 (1H, dt, J=12, 4 Hz); 1.99-2.05 (1H, m); 2.17-2.30 (3H, br m); 2.39 (1H, br s); 2.48 (1H, s, -SiCHHBr); 2.50 (1H, s, -SiCHHBr); 3.65 (1H, dd, J=10, 8 Hz, -CHHOSi(CH3)2CH2Br); 3.86-4.20 (9H, m, 8 ketal H's and  141 -CHHOSi(CH3)2CH2Br); 5.18 (1H, br s, C(1)H). IR (neat): u=2970, 2890 (C-H) cm-1 MS: m/e(%)=462, 460 (M+, 0.8, 0.7); 419, 417 (6.2, 5.9); 333, 331 (1.6, 1.4); 279 (5.2); 193 (6.9); 165 (8.5); 114 (100); 99(12). Reduction of bromosilyl ether 106 to give silyl ether 107: 1 \S'/ \S'/ Br^ I.,^ 0^ / 0  0 (..0 H 0 106  107  Radical cyclization attempt A (concentrated conditions): A solution of bromosilyl ether 106 (0.42 g, 0.91 mmol), Bu3SnH (0.37 mL, 1.4 mmol) and a catalytic amount of AIBN in dry benzene (10 mL) was refluxed under an Ar atm for 45 min. The solvent was removed and the residue was purified by column chromatography using first PE as eluant, then gradually increasing the polarity until the eluant was 4:1 PE:Et20. A colourless liquid was isolated, which was not the desired cyclization product, but which was determined to be the trimethylsilyl ether 107 (0.235 g, 67% yield) resulting from radical reduction of the bromide 106. 1H NMR (400 MHz, CDCI3): 8=0.10 (9H, s, -Si(CLI3)3); 0.88 (3H, s, CH.3); 0.98 (3H, s, CH3); 1.19-1.30 (2H, m); 1.83 (1H, dt, J=12, 4 Hz); 2.03 (1H, dt, J=12, 4 Hz); 2.17-2.28 (3H, br m); 2.37 (1H, br s); 3.55 (1H, dd, J=10, 8 Hz, -CHHOTMS); 3.86-4.00 (9H, m, 8 ketal H's and -CHEOTMS); 5.18 (1H, br s, C(1)H). IR (neat): D=2950, 2890 (C-H) cm-1  142 A small sample of 107 was treated with TBAF in THF. The product, as expected, was the diketalizetl alcohol 87, showing spectral characteristics identical to the previously prepared product. Radical cyclization attempt B (dilute conditions): A solution of Bu3SnH (0.27 mL, 0.99 mmol) and a catalytic amount AIBN in dry benzene (10 mL) was added dropwise over 7 h to a refluxing solution of silyl ether 106 (0.46 g, 0.99 mmol) in dry benzene (20 mL) under an Ar atm. The solvent was removed and the residue was purified by column chromatography using 9:1 PE:Et20 as eluant. As before, no cyclization product was obtained, only the trimethylsilyl ether reduction product 107 as a colourless liquid (0.30 g, 79% yield). Deprotection of acetate 85 to give alcohol 122: OAc  85  ^  122  To a solution of acetate 85 (2.90 g, 9.4 mmol) in Me0H (40 mL) was added a solution of KOH (1.58 g, 28 mmol) in water (40 mL). After stirring at RT for 30 min, the reaction was diluted with water and extracted with Et20 (3x). The combined extracts were washed with brine (2x) and dried over MgSO4. Removal of the solvent yielded the alcohol 122 as a pale yellow oil (2.16 g, 86% yield). A small amount could be crystallized from Et20 for microanalysis. mp: 149-151 °C C15H2204^Calc. Mass: 266.1518 Meas. Mass: 266.1524  143 Calc. C 67.64  H 8.32 %  Anal. C 67.70  H 8.25 %  1H NMR (400 MHz, CDC13): 8=1.08 (3H, s, CH3); 1.12-1.30 (4H, m); 1.40 (1H, t, J=12 Hz); 1.60 (1H, d, J=12 Hz); 1.72 (1H, d, J=12 Hz); 2.02 (1H, d, J=12 Hz); 2.15 (1H, br s); 3.15 (1H, br s, C(10)H); 3.68-3.82 (2H, m, -CLI2OH); 3.93 (4H, s, ketal H's); 6.00 (1H, dd, J=11, 3 Hz, C(2)H); 6.23 (1H, d, J=11 Hz, C(1)H). IR (neat): D=3400 (br, 0-H); 2980, 2900 (C-H); 1670 C=0) cm4 MS: m/e(%)=266 (M+, 15); 140 (24); 129 (100); 86 (25). Conversion of alcohol 122 to silyl ether 123:  122  ^  123  A solution of alcohol 122 (0.617 g, 2.32 mmol), Et3N (0.50 mL, 3.5 mmol), bromomethyldimethylsilyl chloride (0.40 mL, 2.5 mmol) and a catalytic amount DMAP in dry CH2C12 (20 mL) was stirred under an Ar atm for 30 min. Water was added and the mixture was extracted with CH2C12 (3x). The combined extracts were washed with brine (3x) and dried over MgSO4. Removal of the solvent gave a yellow liquid which was purified by column chromatography using 1:1 PE:Et20 as eluant. The silyl ether 123 was isolated as a colourless liquid (0.96 g, 100% yield). C18112904Si79Br ^Calc. Mass: 416.1018 Meas. Mass: 416.1018  144 C18H2904Si81Br^Calc. Mass: 418.0998 Meas. Mass: 418.0995 1H NMR (400 MHz, CDC13): 8=0.29 (6H, s, -Si(CH3)2); 1.08 (3H, s, CE.3); 1.22 (3H, s, CH3); 1.39 (1H, t, J=13 Hz); 1.45 (1H, br m); 1.55-1.70 (2H, m); 2.00-2.05 (1H, m); 2.16 (1H, br m); 2.50 (2H, m, -CH20SiMe2CL12Br); 3.16 (1H, br s, C(10)H); 3.71-3.80 (2H, m, -CH20SiMe2CH2Br); 3.92-3.98 (4H, m, ketal H's); 6.00 (1H, dd, J=11, 3 Hz, C(2)H); 6.75 (1H, br d, J=11 Hz, C(1)H). IR (neat): v=2960, 2890 (C-H); 1675 (C=0) cm-1 MS: ni/e(%)=418, 416 (Mt, 8.4, 7.6); 281, 279 (100, 99); 235 (70); 165 (65); 140 (81); 99 (64); 86 (72). Conversion of silyl ether 123 to alcohol 122:  123  ^  122  y-Alkylation attempt A: A solution of LDA was prepared by adding n-BuLi (1.7 mL, 1.6 M/hexane, 2.5 mmol) to a solution of diisopropylamine (0.35 mL, 2.5 mmol) in dry THF (10 mL) at -78 °C under an Ar atm. After 15 min, the solution was stirred at 0 °C for 15 min and then re-cooled to -78 °C. A solution of silyl ether 123 (0.96 g, 2.3 mmol) in dry THF (20 mL) was added. The yellow mixture was stirred at -78 °C for 4 h, allowed to warm gradually to RT and stirred overnight. Water was added and the mixture was extracted with Et20 (3x). The combined extracts were washed with brine (3x) and dried over MgSO4. Removal of the solvent gave a red liquid which was purified by column  145 chromatography using 2:1 Et20:PE as eluant. A colourless liquid (0.207 g, 34% yield) was isolated and was determined to be the alcohol 122 resulting from silyl ether cleavage. Spectral characteristics were identical to those of the alcohol 122 prepared previously. None of the other side-products isolated were the desired y-alkylation product, as determined by 1H NMR, IR, and MS. y-Alkylation attempt B: To a solution of silyl ether 123 (0.15 g, 0.36 mmol) in dry THF (20 mL) under an Ar atm was added ICH (0.022 g, 0.55 mmol). The mixture was stirred at RT overnight. Water was added and the mixture was extracted with Et20 (3x). The combined extracts were washed with 1 M HC1 and brine (3x) and dried over MgSO4. Removal of the solvent gave a yellow liquid which was a complex mixture by GC and TLC. Purification by column chromatography using 2:1 PE:Et20 as eluant gave the alcohol 122 resulting from silyl ether cleavage as a colourless liquid (0.021 g, 22% yield). Spectral characteristics were identical to the alcohol 122 prepared previously. None of the other sideproducts isolated were the desired y-alkylation product as determined by 1H N1VIR and MS. Protection of alkene diol 64 to give silyl alcohol 128: OH^  64^  OH^128  OH  OTBDMS  To a solution of alkene diol 64 (4.47 g, 21.4 mmol) in dry DMF (-100 mL) under an Ar atm were added successively TBDMSC1 (3.85 g, 25.6 mmol) and imidazole (2.18 g, 32.1 mmol). After stirring at RT overnight, the reaction was diluted with water, extracted with Et20 (3x) and the combined extracts washed with brine (3x). After drying  146 over MgSO4 and removal of the solvent, a yellow oil was isolated which was purified by column chromatography using 4:1 PE:Et20 as eluant. The silyl alcohol 128 was isolated as a white solid (6.66 g, 97% yield). mp (sealed tube): 108-110 'DC C19H3402Si Calc. Mass: 322.2328 Meas. Mass: 322. 2334 Calc. C 70.75  H 10.62 %  Anal. C 70.36  H 10.55 %  1H NMR (400 MHz, CDC13): 8=0.04 (6H, s, -Si(CF13)2); 0.89 (9H, s, t-Bu); 0.92 (6H, s, 2x CH3); 1.16 (3H, s, CH3); 1.60 (1H, d, J=12 Hz, C(3) endo H); 2.13 (1H, dd, J=12, 3 Hz, C(3) exo H); 2.40 (1H, br t, J=3 Hz, C(4)H); 4.16 (2H, d, J=3 Hz, -CH2OTBDMS); 5.55-5.70 (3H, m, C(6)H and trans vinyl H's); 5.98 (1H, dd, J=6, 3 Hz, C(5)H). IR (CHC13): p=3610 (0-H); 3010, 2950, 2930, 2870 (C-H) cm-1 MS: rn/e (%)=265 (M+-t-Bu, 5.9); 177 (17); 108 (100); 93 (29); 75 (26). Anionic oxy-Cope rearrangement of silyl alcohol 128 to give ketone 129: OTBDMS  1 29  To a solution of silyl alcohol 128 in dry THF (5.0 naL) under an Ar atm was added dropwise n-BuLi (0.16 mL, 1.6 M/hexanes, 0.26 mmol). The resulting yellow  147 solution was warmed to 40 0C for 15 min then water was added. The mixture was extracted with Et20 (3x) and the combined extracts were washed with brine (3x), dried over MgSO4, and the solvent removed to give a yellow liquid. Purification by column chromatography using 9:1 PE:Et20 as eluant gave ketone 129 as a pale yellow liquid (0.040 g, 73% yield). CoH3402Si Calc. Mass: 322.2328 Meas. Mass: 322.2325 1H NMR (400 MHz, CDC13): 8=0.05 (6H, s, Si(CU_3)2); 0.90 (9H, s, t-Bu); 0.92 (3H, s, C113); 1.02 (3H, s, CE3); 1.61 (3H, br s, vinyl CE3); 2.01 (1H, dd, J=16, 12 Hz); 2.22-2.40 (4H, m); 2.47 (1H, m); 3.22 (1H, hr s, C(5)H); 3.59 (1H, dd, J=10, 6 Hz, -CEHOTBDMS); 3.67 (1H, dd, J=10, 7 Hz, -CHHOTBDMS); 5.19 (1H, br s, vinyl H). IR (neat): v=2940, 2910, 2890, 2840 (C-H); 1715 (C=0) cm-1  MS: m/e(%)=265 (M-F-t-Bu, 59); 173 (30); 157 (25); 143 (41); 131 (40); 105 (42); 75 (100); 59 (35); 41(53). Reduction of ketone 129 to give alcohol 130: OTBDMS^ OTBDMS  129  il  s"OH  130  To a solution of ketone 129 (3.51 g, 10.8 mmol) in dry THF (70 mL) at -78 0C under an Ar atm was added dropwise L-Selectride® (21.6 mL, 1 WTHF, 21.6 mmol). After stirring at -78 0C for 1.5 h, NaOH (5.4 mL, 3 M, 16.2 mmol) was cautiously added, followed by H202 (27 mL, 30%). The mixture was allowed to warm to RI and was  148 diluted with water. After saturation with K2CO3, the mixture was extracted with Et20 (4x) and the combined extracts were dried over MgSO4. Removal of the solvent gave a pale yellow oil which was purified by column chromatography using 15:1 PE:Et20 as eluant. Some starting material 129 (0.26 g, 7% yield) was recovered along with the alcohol 130 (2.73 g, 78% yield) as a colourless oil. C19H3602Si Calc. Mass: 324.2484 Meas. Mass: 324.2486 Calc.: C70.31^H 11.18% Anal.: C70.25^H 11.31% 1H NMR (400 MHz, CDC13): 8=0.06 (6H, s, -Si(CH3)2); 0.90 (9H, s, t-Bu); 0.94 (3H, s, CH3); 0.98 (3H, S. CH3); 1.03-1.18 (2H, m); 1.30-1.42 (1H, m); 1.58 (3H, dd, J=3, 1.5 Hz, vinyl CH3); 1.67 (1H, br d, J=13 Hz); 2.02-2.10 (1H, m); 2.11-2.21 (1H, m); 3.01 (1H, br s, C(10)H); 3.56 (1H, dd, J=10, 7 Hz, -CHHOTBDMS); 3.63 (1H, dd, J=10, 6 Hz, -CHHOTBDMS); 4.12 (1H, br s, C(7)H); 5.19 (1H, s, vinyl H). IR (neat): D=3380 (br, 0-H); 3040, 2930, 2740 (C-H) cm-1 MS: m/e(%)=267 (M-4--t-Bu, 22); 249 (20); 192 (100); 175 (74); 159 (75); 135 (61); 105 (66); 75 (90); 73 (73). Protection of alcohol 130 to give methyl ether 131: OTBDMS  OTBDMS  s'OCH3 130^  131  149 A solution of alcohol 130 (1.62 g, 5.0 mmol) in dry THF (40 mL) was cannulated into a slurry of ICH (0.30 g, 7.5 mmol) in dry THF (20 mL) under an Ar atm. After stirring at RT for 1.5 h, Mel (0.50 rnL, 7.5 rnmol) was passed through basic alumina directly into the reaction mixture. After stirring overnight, NH4C1(aq) solution was cautiously added and the reaction was extracted with Et20 (3x). The combined organic extracts were washed with brine (3x) and dried over MgSO4. Removal of the solvent gave a yellow liquid which was purified by column chromatography using 24:1 PE:Et20 as eluant. The methyl ether 131 was obtained as a colourless liquid (1.60 g, 95% yield). C201-13802Si Calc. Mass: 338.2641 Meas. Mass: 338.2644 1H NMR (400 MHz, CDC13): 8=0.05 (6H, s, -Si(CH3)2); 0.90 (9H, s, t-Bu); 0.91 (3H, s, CH3); 0.98 (3H, s, CH3); 1.20-1.30 (2H, m); 1.57 (3H, br s, vinyl CH3); 1.69 (1H, br d, J=12 Hz); 1.86 (1H, br d, J=12 Hz); 1.98-2.10 (2H, m); 2.97 (1H, br s, C(10)H); 3.29 (3H, s, -OCH3); 3.50-3.63 (3H, m, -CH2OTBDMS and C(7)H); 5.19, (1H, br s, vinyl H). IR (neat): u=2960, 2940, 2860 (C-H) cm-1 MS: m/e(%)=338 (M+, 17); 281 (52); 249 (64); 206 (100); 193 (79); 175 (87); 159 (87); 148 (69); 134 (73); 122 (68); 119 (75); 89 (93). Ring expansion of alkene 131 to give enone 132: OTBDMS^ OTBDMS  is'OCH3 132  150 A solution of alkene 131 (0.836 g, 2.46 mmol) in CH2C12 (20 mL) and Me0H (20 mL) was cooled to -78 0C and 03 was bubbled through until a blue colour persisted (-30 min). Excess 03 was removed by bubbling 02 through the solution until it became colourless. The mixture was poured onto Zn (4.84 g, 74.0 mmol), HOAc (7.0 mL, 0.12 mol) was added and the reaction mixture was stirred at RT for 1.25 h. The mixture was filtered, washed successively with water (2x), 5% Na0H(aq) solution (2x), water (4x, until neutral) and dried over MgSO4. Removal of the solvent gave the crude ketoaldehyde as a yellow oil which was not purified but which was immediately dissolved in dry benzene (-50 mL). A catalytic amount of p-Ts011•1120 was added, and the solution was refluxed under an Ar atm in a Dean-Stark apparatus for 3 h. After cooling to RT, the mixture was poured onto brine and extracted with Et20 (3x). The combined extracts were washed with NaHCO3(aq) solution, brine (3x) and dried over MgSO4. Removal of the solvent gave a yellow oil which was purified by column chromatography using 9:1 PE:Et20 as eluant. The enone 132 was obtained as a colourless liquid (0.244 g, 28% yield). 1H NMR (400 Mhz, CDC13): 8=0.08 (6H, s, Si(CH3)2); 0.90 (9H, s, t-Bu); 0.96-1.08 (2H, m); 1.10 (3H, s, CLI3); 1.21 (3H, s, Cf_13); 1.76 (1H, br d, J=12 Hz); 1.92 (1H, br d, J=14 Hz); 2.04 (1H, br d, J=12 Hz); 2.20 (1H, br m); 3.18 (1H, br s, C(10)H); 3.29 (3H, s, -0C1i3); 3.53 (1H, t, J=3 Hz, C(7)H); 3.66 (2H, d, J=8 Hz, -CH2OTBDMS); 5.97 (1H, dd, J=3, 10 Hz, C(2)H); 6.78 (1H, dt, J=10, 1.5 Hz, C(1)H). IR (neat): u=2950, 2870 (C-H); 1680 (C=0) cm-1 MS: m/e(%)=295 (M+-t-Bu, 31); 265 (28); 189 (61); 161 (30); 147 (30); 119 (71); 105 (27); 91(36); 89 (100).  151 Protection of enone 132 to give ketal 133: OTBDMS^ OTBDMS  "OCH3 132  A solution of enone 132 (0.244 g, 0.69 mmol), ethylene glycol (0.38 mL, 6.9 mmol) and a catalytic amount of p-Ts0H•H20 in dry benzene (-50 mL) was refluxed under an Ar atm in a Dean-Stark apparatus for 24 h. After cooling to RT, the mixture was poured onto brine and extracted with Et20 (3x). The combined extracts were washed with NaHCO3(ao solution and brine (3x). Drying over MgSO4 and removal of the solvent gave a yellow oil which was purified by column chromatography using 15:1 PE:Et20 as eluant. The ketal 133 was isolated as a colourless liquid (0.068 g, 25% yield). C22H4004Si Calc. Mass: 396.2695 Meas. Mass: 396.2701 1H NMR (400 MHz CDC13): &0.05 (6H, s, Si(C113)2); 0.88 (9H, s, t-Bu); 0.89-0.91 (4H, m); 0.98 (3H, s, CH3); 1.12 (1H, td, J=12, 4 Hz); 1.20-1.30 (1H, m); 2.06 (1H, br d, J=12 Hz); 2.17 (1H, br s); 2.27 (1H, br d, J=12 Hz); 2.40 (1H, br s); 3.23 (3H, s, -OCH3); 3.56 (1H, t, J=8 Hz); 3.66 (1H, br s, C(7)H); 3.83-3.96 (6H, m, -0-120TBDMS and ketal H's); 5.10 (1H, br s, C(1)H). IR (neat): u=2950, 2900 (C-H) cm-1 MS: m/e(%)=396 (M+, 8.0); 353 (27); 339 (52); 251 (37); 171 (43); 119 (28); 115 (33); 114 (100); 99 (48).  152 Hydrolysis of ketal 133 to give deconjugated enone 134: OTBDMS^ OH  s'OCH3  H  s'OCH3  134  A solution of ketal 133 (0.062 g, 0.156 mmol) in 1 M HC1 (2.0 mL) and acetone (2.0 mL) was heated to 70°C for 30 min. After cooling to RT, water was added and the mixture was extracted with Et20 (3x). The combined extracts were washed with brine (3x) and dried over MgSO4. Removal of the solvent gave the keto-alcohol 134 as a colourless liquid (0.036 g, 97% yield) which was not purified but was used directly in the next reaction. C14H2203^Calc. Mass: 238.1568 Meas. Mass: 238.1567 1H NMR (400 MHz, CDC13): 8=0.93 (3H, s, CH3); 1.05 (3H, s, CLI3); 1.13 (2H, m); 2.17 (2H, br d, J=12 Hz); 2.53 (1H, dd, J=16, 4 Hz); 2.56 (1H, br s); 2.77 (1H, dd, J=20, 4 Hz, C(2)H); 3.12 (1H, dt, J=20, 2 Hz, C(2)H); 3.34 (3H, s, -0Ca3); 3.68 (1H, dd, J=11, 4 Hz, -CHHOH); 3.84 (1H, dd, J=11, 7 Hz, -CHEOH); 5.32 (1H, br s, C(1)H). IR (neat): u=3400 (br, 0-H); 2970, 2940, 2890 (C-H); 1715 (C=0) cm-1 MS: m/e(%)=238 (M+, 14); 220 (48); 206 (50); 175 (88); 145 (65); 119 (91); 117 (48); 107 (50); 105 (93); 91 (100).  153 Protection of alcohol 134 to give silyl ether 135:  134  ^  135  To a solution of alcohol 134 (0.036 g, 0.15 mmol) in dry DMF (1.0 mL) was added imidazole (0.021 g, 0.31 mmol) and TBDMSC1 (0.035 g, 0.23 mmol) and the mixture was stirred under an Ar atm at RT overnight. Water was added, the mixture was extracted with Et20 (3x) and the combined extracts were washed with NH4Cloco solution and brine (3x). Drying over MgSO4 and removal of the solvent gave the silyl ether 135 as a pale yellow oil (0.050 g, 95% yield) which was not purified but which was used directly in the next reaction. C20H3603Si Calc. Mass: 352.2433 Meas. Mass: 352.2428 1H NMR (400 MHz, CDC13): 8=0.02 (3H, s, SiCLI3); 0.06 (3H, s, SiCH3); 0.90 (9H, s, t-Bu); 0.93 (3H, s, CH3); 1.04 (3H, s, CH3); 1.06-1.18 (2H, m); 2.13 (1H, dq, J=13, 3 Hz); 2.26 (1H, dq, J=13, 3 Hz); 2.43 (1H, br s); 2.51 (1H, dd, J=13, 4 Hz); 2.73 (1H, dd, J=20, 4 Hz, C(2)H); 3.07 (1H, dt, J=20, 3 Hz, C(2)H); 3.33 (3H, s, -OCH3); 3.56-3.63 (2H, m, C(7)H and -CHHOTBDMS); 3.81 (1H, dd, J=11, 6 Hz, -CHHOTBDMS); 5.23 (1H, br s, C(1)H). IR (neat): u=2950, 2850 (C-H); 1715 (C=0) cm-1 MS: m/e(%)=295 (M+- t-Bu, 33); 263 (54); 237 (42); 171 (71); 89 (100); 75 (97); 73 (94).  154 Vinyl addition to ketone 135 to give alcohol 136: OTBDMS^ OTBDMS  lSg  135  ^  s'OCH3  HO 136  Preparation A: To flame-dried Mg (0.055 g, 2 3 mmol) in a 3-necked, 25 mL round bottomed flask equipped with an addition funnel and condenser and kept under an Ar atm was added dry THF (5.0 mL) and a crystal of 12. A solution of vinyl bromide (0.13 triL, 1.9 mmol) in dry THF (1.0 mL) was added dropwise via the addition funnel to initiate the Grignard reaction, then at a rate to maintain reflux. After refluxing for a further 5 min after the addition was complete, the reaction mixture was cooled to RT and a solution of ketone 135 (0.135 g, 3.83 mmol) was added. The mixture was refluxed for 1 h, cooled to RT and NH4C1(aq) solution was cautiously added. The mixture was extracted with Et20 (3x) and the combined extracts were washed with brine (3x) and dried over MgSO4. Removal of the solvent gave a yellow oil which was purified by column chromatography using 4:1 PE:Et20 as eluant. The alcohol 136 was isolated as a white solid (0.082 g, 57% yield). C221-14003Si Calc. Mass: 380.2746 Meas. Mass: 380.2750 1H NMR (400 MHz, CDC13): 8=0.05 (6H, s, Si(CL13)2); 0.90 (16 H, br s, t-Bu and 2x CH.3); 1.08-1.17 (2H, m); 2.10 (21-1, br d, J=12 Hz); 2.15 (1H, br s); 2.25 (1H, br d, J=12 Hz); 2.66 (1H, br s, C(9)H); 3.33 (3H, s, -OCE3); 3.57 (1H, dd, J=10,  155 8 Hz, -CHHOTBDMS); 3.68 (1H, t, J=3 Hz, C(7)H); 3.88 (1H, dd, J=10, 6 Hz, -CHHOTBDMS); 5.11 (1H, dd, J=11, 1.5 Hz, vinyl H di to -Q-I=CH2); 5.20 (1H, br s, C(1)H); 5.30 (1H, dd, J=17, 1.5 Hz, vinyl H, trans to -CH=CH2); 6.09 (1H, dd, J=17, 11 Hz, -CLI=CH2). IR (CHC13): u=3630 (br, 0-H); 3030; 2950; 2870 (C-H) cm-1 MS: m/e(%)=380 (M+, 0.6); 323 (61); 291 (26); 273 (31); 231 (34); 199 (71); 185 (47); 157 (57); 143 (53); 119 (50); 105 (63); 91(48); 89(99); 75 (100); 73 (98). Preparation B91: To CeC13•7H20 (0.87 g, 2.34 mmol) which was dried at 140 0C under vacuum for 2 h was added dry THF (20 mL) and the slurry was kept under an Ar atm and cooled to 0 °C. A solution of vinylmagnesium bromide, prepared as described above by the addition of vinyl bromide (0.16 mL, 2.34 mmol) in dry TI-IF (5.0 mL) to flame-dried Mg (0.057 g, 2.34 mmol) and a crystal of 12 in dry THF (15 mL), was added dropwise to the slurry. A solution of ketone 135 (0.552 g, 1.56 mmol) in dry THF (10 mL) was added and the mixture was allowed to warm to RT overnight. Water (20 mL) and HOAc (1.0 mL) were added and the mixture was extracted with Et20 (3x). The combined extracts were washed successively with brine, NaHCO3(aco solution and brine. After drying over MgSO4, removal of the solvent gave a yellow oil which was purified by column chromatography using 15:1 PE:Et20 as eluant. Starting material 135 (0.032 g, 6% yield) and the desired alcohol 136 (6% yield) were isolated and showed spectral characteristics as described previously.  156 Conversion of alcohol 136 to diol 137: OTBDMS^  OH  11„ 40CH3  HO 136  137  Anionic oxy-Cope rearrangement attempt A: To a slurry of KH (0.0032 g, 0.079 mmol) in dry THF (1.0 mL) under an Ar atm was added alcohol 136 (0.0060 g, 0.016 mmol) in dry THF (1.0 mL). The mixture was stirred at RT for 1 h, then 18-cr-6 (0.028 g, 0.079 mmol) was added. After refluxing for 12 h, the mixture was cooled to RT and water was cautiously added. The mixture was extracted with Et20 (3x) and the combined extracts were washed with brine (3x). After drying over MgSO4, removal of the solvent gave a brown-yellow solid which was purified by column chromatography using 1:1 PE:Et20 as eluant. A colourless liquid (0.004 g, 16% yield) was isolated which was not the desired anionic oxy-Cope rearrangement product, but which was identified as the diol 137 resulting from silyl ether cleavage. C16H2603^Calc. Mass: 266.1881 Meas. Mass: 266.1887 1H NMR (400 MHz, CDC13): 8=0.86 (3H, s, C1j3); 0.87 (3H, s, CL-13); 1.20-1.40 (3H, m); 1.50 (1H, br t, J=10 Hz); 2.06 (4H, m); 2.16 (1H, br s); 2.40 (1H, br s, C(5)H); 3.30 (3H, s, -OCH3); 3.65 (1H, t, J=3 Hz, C(7)H); 3.71 (1H, dd, J=12, 7 Hz, -CJHOH); 3.79 (1H, dd, J=12, 7 Hz, -CHHOH); 5.08 (1H, dd, J=11, 1.5 Hz, vinyl H cis to -CLI=CH2); 5.26 (1H, dd, J=17, 1.5 Hz, vinyl H Irans to -CH=CH2); 5.30 (1H, br s, C(1)H); 6.04 (1H, dd, J=17, 11 Hz, -CH=CF12). IR (CHC13): v=3620 (br, 0-H); 2940 (C-H) cm-1  157 MS: m/e(%)=266 (M+, 1.0); 234 (23); 216 (23); 191 (26); 185 (38); 133 (31); 105 (35); 98 (100); 91(38); 55 (31). Anionic oxy-Cope rearrangement attempt B: To a solution of 18-cr-6 (0.034 g, 0.13 mmol) in dry THF (0.50 mL) under an Ar atm was added KHMDS (0.33 mL, 0.39 WITIF, 0.13 mmol). A solution of alcohol 136 (0.044 g, 0.11 mmol) in dry THF (1.0 mL) was added, and the solution was stirred at RT for 21 h. NH4C1(aq) solution was added and the mixture was extracted with Et20 (3x). The combined extracts were washed with 1 M HC1 and brine (3x). Drying over MgSO4 and removal of the solvent gave a yellow gum. Purification by column chromatography using 2:1 PE:Et20 as eluant gave a pale yellow liquid (0.030 g, 98% yield) which was not the desired anionic oxy-Cope product, but which was identified as the diol 137 resulting from silyl ether cleavage as before. Spectral characteristics of the diol 137 were identical to those described above. Protection of alcohol 137 to give methyl ether 138: OH^  440CH3  HO  OCH3  H  "OCH3  138  To a slurry of ICH (0.012 g, 0.30 mmol) in dry THF (1.0 mL) under an Ar atm and at 0 0C was added a solution of diol 137 (0.040 g, 0.15 mmol) in dry THF (2.0 mL). After 30 min, Mel (0.010 inL, 0.15 mmol) was added. After a further 20 min at 0 0C, NH4C100 solution was added and the mixture was extracted with Et20 (3x). The combined extracts were washed with brine (3x) and dried over MgSO4. Removal of the solvent gave an orange oil which was purified by column chromatography using 9:1  158 PE:Et20 as eluant. The dimethyl ether 138 was isolated as a white solid (0.0050 g, 12% yield). C17H2803^Caic. Mass: 280.2038 Meas. Mass: 280.2034 1H NMR (400 MHz, CDC13): 8=0.90 (6H, br s, 2x CLI3); 1.24 (1H, d, J=2 Hz, C(8)H);  1.28 (1H, d, J=3 Hz, C(8)H); 1.58 (1H, m, C(5)H); 2.11 (3H, m, 2x C(6)H and C(2)H); 2.19 (1H, br s, C(2)H); 2.51 (1H, br s, C(9)H); 3.34 (3H, s, -OCJj); 3.35 (3H, s, -OCR3); 3.45 (1H, dd, J=10, 6 Hz, -CffHOCH3); 3.57 (1H, dd, J=10, 6 Hz, -CHHOCH3); 3.67 (1H, t, J=3 Hz, C(7)H); 5.11 (1H, dd, J=11, 1.5 Hz, vinyl H da to -CE=CH2); 5.27 (1H, br s, C(1)H); 5.30 (1H, dd, J=17, 1.5 Hz, vinyl H trans to -Cff=CH2); 6.09 (1H, dd, J=17, 11 Hz, -CH=CH2). IR (CHCI3): v=3620 (br, 0-H); 2940, 2890 (C-H) cm-1 MS: m/e(%)=280 (M+, 1.4); 230 (13); 185 (89); 183 (35); 143 (35); 133 (41); 119 (31); 105 (61); 98 (100); 91(69); 45 (71). Anionic oxy-Cope rearrangement attempt of alcohol 138: OCH 3^  OCR3  410-  s'O CH 3  s'O CH3 138  ^  139  To a slurry of KH (0.0014 g, 0.036 mmol) in dry xylenes (0.5 rnL) was added a solution of alcohol 138 (0.0050 g, 0.018 mmol) and 18-cr-6 (0.0094 g, 0.036 nunol). The mixture was refluxed under an Ar atm for 23 h, then another portion of KH (0.0014 g, 0.036 mmol) and 18-cr-6 (0.0094 g, 0.036 mmol) was added. After another 5 h at reflux,  159 third portion of ICH (0.0014 g, 0.036 mmol) and 18-cr-6 (0.0094 g, 0.036 mmol) was added and reflux was continued for another 21 h. The mixture was cooled to RT, water was cautiously added, and the mixture was extracted with Et20 (3x). The combined extracts were washed with brine (3x), dried over MgSO4 and the solvent removed to yield a yellow solid. Purification by column chromatography using 9:1 PE:Et20 as eluant gave a white solid (0.0049 g, 98% recovery) which was determined to be starting material 138. Protection of alcohol 64 to give methyl ether 152:  To a slurry of KH (0.96 g, 24 mmol) in dry THF (30 mL) at 0 0C under an Ar atm was added a solution of diol 64 (2.53 g, 12.1 mmol) in dry THF (30 mL) also cooled to 0 °C. After 15 min, Mel (0.76 mL, 12 mmol) was passed through basic alumina directly into the reaction mixture. After another 45 min at 0 °C, NH4C100 solution was cautiously added and the mixture was extracted with Et20 (3x). The combined extracts were washed with brine (3x) and dried over MgSO4. Removal of the solvent gave a yellow liquid which was purified by column chromatography using 4:1 PE:Et20 as eluant. The methyl ether 152 was isolated as pale yellow liquid (1.67 g, 63% yield). C14H2202^Calc. Mass: 222.1619 Meas. Mass: 222.1629 1H NMR (400 MHz, CDC13): 8=0.94 (6H, s, 2x C.H_3); 1.20 (3H, s, Cji3); 1.58 (1H, s, exchanges with D20, —OLD; 1.63 (1H, d, J=13 Hz, C(3) endo H); 2.17 (1H, dd, J=13, 3.5 Hz, C(3) gi_cg H); 2.43 (1H, t, J=3 Hz, C(4)H); 3.32 (3H, s, -OCH3); 3.91  160 (2H, d, J=4 Hz, -Cf_120CH3); 5.64 (1H, d, J=6 Hz, C(6)H); 5.71 (2H, m, trans vinyl H's); 6.03 (1H, dd, J=6, 3 Hz, C(5)H). IR (neat): u=3450 (0-H); 2950, 2870 (C-H) cm-1 MS: m/e(%)=222 (M+, 1.2); 204 (20); 186 (31); 171 (34); 161 (100); 145 (35); 129 (79); 108 (91); 91(77). Anionic oxy-Cope rearrangement of methyl ether 152 to give ketone 157:  Ac:i 152  OCH3  157  A solution of alcohol 152 (0.24 g, 1.1 mmol) in dry THF (6.0 rriL) was cannulated into a slurry of KH (0.051 g, 1.3 mmol) in dry THF (10 mL) under an Ar atm. The mixture was warmed to 40 0C for 20 min (at which point rearrangement had occurred, as indicated by TLC and GC), then cooled to -78 °C. Mel (0.66 mL, 11 mmol) was passed through basic alumina, dissolved in dry TI-IF (1.0 mL), cooled to -78 c•C and the solution was added to the reaction mixture. After warming to RT overnight, NH4C1(aco solution was cautiously added and the mixture was extracted with Et20 (3x). The combined extracts were washed with brine (3x) and dried over MgSO4. Removal of the solvent gave a yellow oil which was purified by radial chromatography (1 mm plate) using 2:1 PE:Et20 as eluant. The ketone 157 was isolated as a pale yellow oil (0.23 g, 92% yield). C15H2402^Calc. Mass: 236.1776 Meas. Mass: 236.1770  161 1H NMR (400 MHz, CDC13): 8=0.97 (3H, s, CH3); 1.06 (3H, s, CH3); 1.19 (3H, d, J=8 Hz, C(6)CI-_13); 1.64 (3H, m, vinyl CH3); 2.09-2.18 (2H, m); 2.37 (1H, ddd, J=16, 4, 1 Hz, C(8)H); 2.33-2.48 (2H, m); 3.18 (1H, br s, C(10)H); 3.29 (1H, dd, J=9,7 Hz, -CHHOCH3); 3.26 (3H, s, -0033); 3.41 (1H, dd, J=9, 7 Hz, -CHHOCH3); 5.20 (1H, br s, vinyl H). IR (neat): v=2950 (C-H); 1705 (C=0) cm-1 MS: m/e(%)=236 (M+, 0.7); 204 (40); 189 (23); 161 (19); 148 (22); 133 (20); 121 (27); 108 (19); 45 (23). Reduction of ketone 157 to give alcohol 158: OCH3  OCH3^  "OH 157  158  To a solution of ketone 157 (1.88 g, 7.98 mmol) in dry THF (40 mL) at -78 0C under an Ar atm was added dropwise L-Selectride® (16 mL, 1 MfTHF, 16 mmol). The solution was stirred at -78 0C for 1 h, then 3 M Na0H(ac) solution (4.2 mL) was cautiously added followed by H202 (21 mL, 30%). After warming to RT, water (40 mL) was added and the aqueous layer was saturated with K2CO3. After extraction with Et20 (4x) the combined extracts were dried over MgSO4 and the solvent removed to give a yellow liquid. Purification by column chromatography using 4:1 PE:Et20 as eluant gave recovered starting material (0.187 g, 9% yield) and the desired alcohol 158 (1.49 g, 79% yield) as a white crystalline solid. mp (sealed tube): 109-110 0C  162 Ci5H2502^Calc. Mass: 238.1933 Meas. Mass: 238.1937 Calc.: C75.58^H 10.99% Anal.: C 75.56^H 10.97 % 1H NMR (400 MHz, CDC13): 8=1.00 (3H, s, CH3); 1.05 (3H, s, C.1-13); 1.09 (3H, d, J=7 Hz, C(6)CE.3); 1.28 (1H, td, J=13, 2 Hz, C(8)H); 1.58 (3H, m, vinyl C113); 1.66 (1H, dtd, J=13, 3, 1.5 Hz, C(8)H); 1.77 (1H, dd, J=9, 7 Hz); 2.33 (1H, m); 3.01 (1H, br s, C(10)H); 3.32 (1H, dd, J=9, 7 Hz, -CLIHOCH3); 3.36 (3H, s, -OCH3); 3.41 (1H, dd, J=9, 7 Hz, -CHEOCH3); 3.77 (1H, br s, C(7)H); 5.19 (1H, br s, vinyl H). IR (neat): v=3630 (0-H); 2940 (C-H) cm-1 MS: m/e(%)=238 (Mt, 52); 206 (25); 193 (95); 175 (49); 173 (100); 135 (46); 121 (36). Protection of alcohol 122 to give silyl ether 168: OH^  I:1^ 122^  OTBDMS  00  1:1^•-..? 168  A solution of alcohol 122 (0.128 g, 0.481 mmol), imidazole (0.049 g, 0.72 mmol) and TBDMSC1 (0.0865 g, 0.576 mmol) in dry DMF (10 mL) was stirred at RT under an Ar atm overnight. Water was added and the mixture was extracted with Et20 (3x). The combined extracts were washed with NH4C1(aco solution and brine (3x) and dried over MgSO4. Removal of the solvent gave a yellow liquid which was purified by column  163 chromatography using 2:1 PE:Et20 as eluant. The silyl ether 168 was isolated as a colourless liquid (0.18 g, 99% yield). C211-13604Si Calc. Mass: 380.2383 Meas. Mass: 380.2382 1H NMR (400 MHz, CDC13): 8=0.07 (3H, s, -SiCLI3); 0.08 (3H, s, -SiCLI3); 0.90 (9H, s, t-Bu); 1.09 (3H, s, CH.3); 1.19-1.25 (1H, m); 1.22 (3H, s, Ca); 1.40 (1H, t, J=13 Hz); 1.54 (1H, br d, J=13 Hz); 1.72 (1H, dm, J=13 Hz); 2.02 (1H, dm, J=13 Hz); 2.34 (1H, br m); 3.17 (1H, br s, C(10)H); 3.70 (2H, d, J=6 Hz, -CH2OTBDMS); 3.93 (4H, br s, ketal H's); 5.98 (1H, dd, J=10, 3 Hz, C(2)H; 6.78 (1H, dt, J=10, 2 Hz, C(1)H). IR (neat): v=2950, 2890 (C-H); 1675 (C=0) cm-1  MS: m/e(%)=323 (M1--t-Bu, 39); 279 (22); 243 (20); 159 (24); 119 (24); 108 (100); 105 (26); 93 (79); 91(35); 86 (37); 84 (39); 75 (84); 73 (51); 49 (53). Conversion of enone 168 to epoxide 169: OTBDMS^  168  OTBDMS  169  To a solution of enone 168 (0.18 g, 0.47 mmol) in Me0H (8.0 mL) and H202 (1.9 mL, 30%) at 0°C was added dropwise NaOH (2.5 mL, 4 M/H20, 0.010 mol).93 The mixture was allowed to warm to RT, then was stirred for 1.5 h. After dilution with water, the mixture was extracted with CH2Cl2 (3x). The combined extracts were dried over  164 MgSO4 and the solvent removed to give the epoxide 169 as a pale yellow liquid (0.15 g, 80% yield) which was not purified but used directly in the next reaction. C21H3605Si Calc. Mass: 396.2332 Meas. Mass: 396.2336 1H NMR (400 MHz, CDC13): 6=0.08 (6H, br s, -Si(Cf_13)2); 0.90 (9H, s, t-Bu); 1.03 (3H, s, CLI3); 1.10-1.25 (1H, m); 1.30-1.40 (1H, m); 1.32 (3H, s, CH.3); 1.65 (1H, br d, J=12 Hz); 1.80 (2H, d, J=12 Hz); 2.09 (1H, br m); 2.90 (1H, br s, C(10)H); 3.14 (1H, d, J=3 Hz, C(1)H); 3.45 (1H, br s, C(2)H); 3.74 (2H, d, J=6 Hz, -CLI2OTBDMS); 3.91 (4H, br s, ketal H's). IR (neat): v=2950, 2900 (C-H); 1705 (C=0) cm-1 MS: m/e(%)=396 (M+, 0.6); 339 (66); 295 (77); 277 (26); 251 (53); 195 (33); 157 (24); 99 (38); 75 (100). Conversion of epoxide 169 to alcohol 170:  169  ^  170  To a solution of PhSeSePh (0.72 g, 2.3 mmol) in absolute Et0H (6.0 inL) under an Ar atm was added in portions NaBH4 (0.17 g, 4.6 mmol).94,95 Into the colourless solution was cannulated a solution of epoxide 169 (0.305 g, 0.77 mmol) in absolute Et0H (4.0 mL) and the resulting yellow solution was stirred at RT overnight. The mixture was diluted with Et0Ac and washed once with brine. Drying over MgSO4 and removal of the solvent gave a yellow oil which was purified by column chromatography using 4:1  165 PE:Et20 as eluant. Two compounds were isolated, the desired keto-alcohol 170 as a colourless liquid (0.183 g, 60% yield) and the enone 168 resulting from dehydration as a colourless liquid (0.028 g, 10% yield). The enone 168 had spectral characteristics identical to those of the previously prepared sample. Data for keto-alcohol 170: C211-12805Si Calc. Mass: 398.2481 Meas. Mass: 398.2481 1H NMR (400 MHz, CDC13): 8=0.10 (3H, s, -SiCH3); 0.11 (3H, s, -SiCH3); 0.92 (9H, s, t-Bu); 1.00 (3H, s, CH3); 1.06 (1H, t, J=13 Hz, C(6)H); 1.33 (3H, s, CH3); 1.42 (1H, dt, J=13, 3 Hz, C(8)H); 1.68 (1H, dt, J=13, 3 Hz, C(6)H); 1.85-1.94 (2H, m); 2.09 (1H, br dd, J=13, 3 Hz); 2.37 (1H, dt, J=13, 3 Hz, C(10)H); 2.67 (1H, s, C(2)H); 2.70 (1H, d, J=2 Hz, C(2)H); 3.78 (1H, dd, J=11, 5 Hz, -CHHOTBDMS); 3.90-3.98 (4H, m, ketal H's); 4.00 (1H, dd, J=11, 1.5 Hz, -CHHOTBDMS); 4.12 (1H, m, C(1)H); 5.49 (1H, br s, exchanges with D20, -OH). IR (neat): v=3400 (br, 0-H); 2960, 2940, 2890 (C-H); 1705 (C=0) cm-1 MS: m/e(%)=398 (Mt, 0.2); 323 (24); 279 (22); 205 (21); 181 (21); 159 (26); 119 (26); 105 (22); 99 (27); 86 (21); 77 (21); 75 (100); 73 (58); 41(30). Protection of keto-alcohol 170 to give silyl ether 171: OTBDMS^ HO^ TBDMS9  OTBDMS  171  166 To a solution of keto-alcohol 170 (0.116 g, 0.290 minol) and 2,6-luticiine (0.070 inL, 0.58 mmol) in dry CH2C12 (10 rnL) at 0 GC under an Ar atm was added ciropwise TBDMSOTf (0.10 mL, 0.44 mmol). After stirring at 0 GC for 1 h, the mixture was stirred at RT for 3 h. Water was added, and the mixture was extracted with Et20 (3x). The combined extracts were washed with 0.25 M HC1 solution and brine (3x), and dried over MgSO4. Removal of the solvent gave a pale yellow oil which was purified by column chromatography using 9:1 PE:Et20 as eluant. The silyl ether 171 was isolated as a white crystalline solid (0.0745 g, 50% yield). mp: 105-106 GC (sealed tube) C23H4305Si2 (M-1--t-Bu)^Calc. Mass: 455.2649 Meas. Mass: 455.2641 C2 711 5 2 0 5S i2  ^  Calc.: C 63.23^H 10.22 %  Anal.: C63.31^H 10.12 % 1H NMR (400 MHz, CDC13): 8=0.04 (3H, s, -Sig_13); 0.05 (3H, s, -SiCI-J3); 0.08 (3H, s, -SiCE3); 0.09 (3H, s, -Sig-13); 0.90 (18 H, s, 2x t-Bu); 1.00 (3H, s, CLI3); 1.14 (1H, t, J=13 Hz, C(6)H); 1.32 (3H, s, CH3); 1.38 (1H, t, J=13 Hz, C(8)H); 1.69 (1H, dt, J=13, 2 Hz, C(6)H); 1.92 (1H, dt, J=14, 4 Hz, C(5)H); 1.98-2.05 (2H, m, C(8)H and C(9)H); 2.42 (1H, dt, J=10, 3 Hz, C(10)H); 2.56 (1H, dd, J=14, 6 Hz, C(2)H); 2.64 (1H, dd, J=14, 10 Hz, C(2)H); 3.63 (1H, t, J=10 Hz, -CHHOTBDMS); 3.80 (1H, dd, J=10, 3 Hz, -CHHOTBDMS); 3.90-3.99 (4H, m, ketal H's); 4.20 (1H, ddd, 6 lines, J=10, 10, 6 Hz, C(1)H). IR (CHC13): v=2960, 2940, 2890, 2860 (C-H); 1705 (C-0) cm-1 MS: m/e(%)=455 (W-t-Bu, 8.4); 323 (12); 249 (18); 195 (30); 171 (20); 147 (18); 75 (100); 41(29).  167 Oxidation of bromide 61 to give ketone 183 and cyclocamphanone ketal (184):  61  184  Silver tetrafluoroborate (2.56 g, 13.1 mmol) was added to a solution of bromide 61 (2.41 g, 8.76 mmol) in dry DMSO (40 mL) under an Ar atm.100 After stirring in the  dark at RT overnight, dry Et3N (1.8 mL, 13 mmol) was added and the reaction was stirred for another hour. Water was cautiously added and the mixture was filtered through Celite. The filter cake was washed well with Et20, and the filtrate was extracted with Et20 (4x). The combined extracts were dried over MgSO4 and the solvent was removed to give a yellow liquid. Column chromatography using 9:1 PE:Et20 as eluant gave the ketone 183 as a colourless solid (0.784 g, 43% yield) and cyclocamphanone ketal (184) as a colourless liquid (0.674 g, 40% yield). Data for ketone 183: C 12111803  ^  Calc. Mass: 210.1256  Meas. Mass: 210.1259 1H NMR (400 MHz, CDC13): 8=0.95 (6H, s, 2x CH3); 1.15 (3H, s, C113); 1.73 (1H, d, J=14 Hz, C(3) endo H); 2.05 (1H, dd, J=18, 1 Hz, C(6) endo H); 2.20 (1H, br d, J=5 Hz, C(4)H); 2.29 (1H, dd, J=14, 5 Hz, C(3) exo H); 2.55 (1H, d, J=18 Hz, C(6) exo H); 3.80 (1H, m, ketal H); 3.90 (2H, m, 2 ketal H's); 4.00 (1H, m, ketal H). IR (CHC13): v=2970, 2887 (C-H); 1752 (C=0) cm-1  MS: m/e(%)=210 (M+, 54); 195 (88); 141 (28); 127 (46); 126 (100).  168 Data for cyclocamphanone ketal (184): C12H1802^Calc. Mass: 194.1306 Meas. Mass: 194.1302 1H NMR (400 MHz, CDC13): 8---0.72 (3H, s, CH3); 0.86 (3H, s, Cf_13); 1.15 (3H, s, C113); 1.19-1.32 (3H, m, C(3)H, C(4)H, C(5)H); 1.58 (1H, d, J=10 Hz, C(6) rado H); 1.76 (1H, d, J=10 Hz, C(6) ow H); 3.79-4.12 (4H, m, ketal H's). IR (neat): u=2959, 2873 (C-H) cm-i MS: m/e(%)=194 (Mt, 35); 179 (95); 150 (12); 138 (42); 135 (34); 121 (25); 108 (61); 107 (100). Hydrolysis of cyclocamphanone ketal (184) to give cyclocamphanone (59):  184  ^  59  A solution of cyclocamphanone ketal (184, 0.873 g, 4.49 mmol) was stirred in acetone (10 mL) and 1 M HC1 (10 mL) at RT for 1 h. The mixture was diluted with water, extracted with Et20 (3x) and the combined extracts were washed with brine (3x). After drying over MgSO4 and removal of the solvent, cyclocamphanone (59, 0.67 g, 100% yield) was obtained as a white solid. Spectral characteristics were identical to those of cyclocamphanone (59) prepared previously.  169 Conversion of ketone 183 to enol triflate 185:  0 183  0^  185  OTf  A solution of ketone 183 (1.80 g, 0.856 mmol) in dry CH2C12 (30 mL) was cannulated into a solution of triflic anhydride (1.5 znL, 8.9 mmol) and 2,6-di-t-buty1-4methylpyridine (1.84 g, 8.96 rnmol) in dry CH2C12 (80 mL) under an As atm.lo After stirring at RT for 4 h, the solvent was removed, pentane (80 mL) was added, and the tan residue was filtered off. The filtrate was washed successively with NH4C1(aq) solution, NaHCO3(ac) solution and brine (2x). After drying over MgSO4, the solvent was removed to yield a yellow liquid which was purified by column chromatography using 9:1 PE:Et20 as eluant. The enol triflate 185 was isolated as a colourless liquid (2.76 g, 95% yield). C12H1703 (M+-S02CF3) Calc. Mass: 209.1178 Meas. Mass: 209.1179 1H NMR (400 MHz, CDC13): 8=0.82 (3H, s, CH3); 0.96 (3H, s, CH3); 0.98 (3H, s, CH3); 1.65 (1H, d, J=12 Hz, C(3) endo H); 1.94 (1H, dd, J=12, 4 Hz, C(3) cm H); 2.23 (1H, br s, C(4)H); 3.25 (1H, m, ketal H); 3.32-3.48 (3H, m, 3 ketal H's); 5.34 (1H, s, C(6)H). IR (neat): D=2961, 2880 (C-H) cm4  MS: m/e(%)=209 (M+-Tf, 100); 137 (35); 123 (15); 109 (32); 86 (45).  170 Conversion of enol triflate 185 to 5-methyl-5,6-dehydrocamphor ketal (186):  A slurry of CuBr.DMS (17.66 g, 85.90 trunol) in dry Et20 (-100 mL) was cooled to -20 0C under an Ar atm. MeLi (-120 mL, 1.4 M/Et20, —172 mmol) was added dropwise until a colourless solution was obtained.105 The triflate (5.656 g, 16.50 mmol) was dissolved in dry Et20 (20 mL) and added dropwise.104 After stirring at -20 0C for 2 h, 5% N1140H in a saturated NH4C1(aq) solution was cautiously added. The reaction mixture was extracted with Et20 (3x) and the combined extracts were washed with 5% NH4OH in a saturated NH4C1(aco solution and brine (3x). After drying over MgSO4, the solvent was removed to yield a pale yellow liquid which was purified by column chromatography using 15:1 PE:Et20 as eluant. 5-Methyl-5,6-dehydrocamphor ketal (186) was isolated as a colourless liquid (3.21 g, 93% yield). It was, however,  contaminated with 5% of 5,6-dehydrocamphor ketal (62) which could not be separated. C13H2002^Calc. Mass: 208.1463 Meas. Mass: 208.1465 1H NMR (400 MHz, C6D6): &LOP (3H, s, CH3); 1.05 (3H, s, Ci_13); 1.22 (3H, s, CH3); 1.48 (1H, d, J=12 Hz, C(3) endo H); 1.62 (3H, d, J=1 Hz, C(5)CH3); 1.95 (1H, d, J=4 Hz, C(4)H); 2.10 (1H, dd, J=12, 4 Hz, C(3) exo H); 3.30-3.40 (1H, m, ketal H); 3.40-3.58 (3H, m, 3 ketal H's); 5.43 (1H, br s, C(6)H). IR (neat): D=2952, 2872, 2726 (C-H) cm4  MS: m/e(%)=208 (M+, 2.5); 193 (1.3); 122 (100); 107 (63).  171 Hydrolysis of 5-methyl-5,6-dehydrocamphor ketal (186) to give (-)-5-methy1-5,6dehydrocamphor (178):  After stirring a solution of ketal 186 (0.379 g, 1.81 mmol) in acetone (8 mL) and 1 M HC1 (8 mL) at RT for 15 min, water was added and the reaction was extracted with Et20 (3x). The combined extracts were washed with NaHCO3(ao solution, brine (3x) and dried over MgSO4. Removal of the solvent gave a colourless liquid which was purified by column chromatography using 4:1 PE:Et20 as eluant. (+5-Methy1-5,6dehydrocamphor (178) was isolated as a colourless liquid (0.297 g, 99% yield). It was contaminated with —5% (-)-5,6-dehydrocamphor (ent-36) which could not be separated. C1 1H160  ^  Calc. Mass: 164.1201  Meas. Mass: 164.1196 1H NMR (400 MHz, C6D6): 8=0.65 (3H, s, CH3); 0.85 (3H, s, CLI3); 1.00 (3H, s, CH3); 1.44 (3H, s, C(5)CLI3); 1.61 (1H, d, J=14 Hz, C(3) endo H); 1.85 (1H, br s, C(4)H); 1.96 (1H, dd, J=14, 4 Hz, C(3) exo H); 4.81 (1H, br s, C(6)H). IR (neat): u=2963 (C-H); 1743 (C=0) cm-1 MS: m/e(%)=164 (M+, 7.1); 149 (8.3); 122 (86); 121 (51); 107 (100). Isopropenyl addition to (-)-5-methyl-5,6-dehydrocamphor (178) and anionic oxy-Cope rearrangement to give ketone 190:  172 A 3-necked 100 mL round bottomed flask equipped with condenser and addition funnel and containing a stir bar and Mg (0.52 g, 0.021 mol) was flame dried and cooled under Ar. A crystal of 12 and dry THF (12 mL) were added and a small amount of 2-bromopropene was added to initiate Grignard formation. A solution of 2-bromopropene (1.3 mL, 0.014 mol) in dry THF (12 mL) was then added dropwise to maintain the exothermic reaction. After 30 min, a solution of (+5-methyl-5,6-dehydrocamphor (178, 1.16 g, 7.08 mmol) in dry THF (12 mL) was added dropwise and the mixture was stirred at RT for 2 h, at which point addition had occurred as evidenced by TLC and GC. Rearrangement was induced by heating at reflux for 5.5 h. The reaction was cooled to RT and NH4C1(aq) solution was cautiously added. The mixture was extracted with Et20 (3x) and the combined extracts were washed with brine (3x). Removal of the solvent gave a yellow liquid which was purified by column chromatography using 15:1 PE:Et20 as eluant. The ketone 190 was obtained as a colourless liquid (1.237 g, 85% yield). 1H NMR spectroscopy showed the diastereomeric mixture to be 1:1. C1414220  ^  Calc. Mass: 206.1671  Meas. Mass: 206.1672 Calc.: C 81.50^H 10.75 % Anal.: C 81.28^H 10.69 % 1H NMR (400 MHz, CDC13, one diastereomer): 8=0.87 (3H, s, CH3); 1.00 (3H, s, CI-_13); 1.01 (3H, d, J=6 Hz, C(8)CH3); 1.28 (3H, s, C(10)CH); 1.60 (4H, m, vinyl CH3 and 1 H); 1.77 (1H, dd, J=13, 5 Hz, C(9)H); 2.04 (1H, t, J=6 Hz); 2.38-2.50 (3H, m, 2xC(6)H and C(8)H); 5.18 (1H, br s, vinyl H). 1H NMR (400 MHz, CDCI3, second diastereomer): 8=0.83 (3H, s, CH3); 1.03 (3H, d, J=6 Hz, C(8)CH3); 1.09 (3H, s, CH3); 1.20 (3H, s, C(10)CH3); 1.50-1.65 (6H, m,  173 vinyl CI-J3 and 3H); 2.05 (1H, q, J=3 Hz); 2.10 (1H, m); 2.39-2.45 (2H, m); 4.95 (1H, br s, vinyl H). IR (neat): D=2926 (C-H); 1714 (C=0) cm-1  MS: m/e(%)=206 (M±, 15); 191 (17); 177 (10); 135 (100); 121 (52); 107 (44); 91(35); 69 (43). Ring expansion of ketone 190 to give enone 191:  190^  191  A solution of ketone 190 (0.404 g, 1.96 mmol) in CH2C12 (10 mL) and Me0H (10 mL) was cooled to -78 0C and 03 was bubbled through the solution until a blue colour persisted (-30 min). Excess 03 was removed by bubbling 02 through the solution until it became colourless. The reaction mixture was poured onto Zn (2.56 g, 39.1 mmol), HOAc (4.5 mL, 78 mmol) was added, and the mixture was stirred at RT for 1 h. The reaction mixture was filtered, washed successively with water (2x), 5% Na0H(aq) solution, water (4x, until neutral) and dried over MgSO4. Removal of the solvent gave the crude aldehyde as a yellow oil (0.36 g, 77% yield). It was not purified, but was immediately dissolved in dry benzene (-50 mL). A catalytic amount of p-Ts0H.H20 was added, and the mixture was refluxed in a Dean-Stark apparatus under an Ar atm for 1 h. Brine was added and the mixture was extracted with Et20 (3x). The combined extracts were washed with brine (3x), dried over MgSO4 and the solvent removed to yield a yellow oil. Purification by column chromatography using 1:1 PE:Et20 as eluant gave the enone 191 as a white crystalline solid (0.255 g, 59% yield from ketone 190).  174 mp: 115-116°C Cl4HO2^Caic. Mass: 220.1463 Meas. Mass: 220.1454 CaIc.: C76.33^H9.15% Anal.: C 76.46^H 8.99 % 1H NMR (400 MHz, CDC13): =O.99 (3H, s, CE3); 1.05 (3H, d, J=8 Hz, C(8)C113); 1.20 (3H, s, CH3); 1.48 (3H, s, C(10)Cjj); 1.82-1.88 (2H, m, 2x C(9)H); 2.22 (1H, dd, J=8, 2 Hz, C(5)H); 2.53-2.68 (3H, m, 2x C(6)H and C(8)H); 5.88 (1H, d, J=8 Hz, C(2)H); 6.56 (1H, d, J=8 Hz, C(1)H). JR (CHCI3): v=2964 (C-H); 1709, 1673 (C=O) cm-1 MS: m/e(%)=220 (M, 7.8); 124 (37); 107 (11); 95 (100); 77 (24); 69 (41); 67 (34); 40 (82). Conversion of enone 191 to ketal 192:  191  A solution of enone 191 (0.34 1 g, 1.55 mmol), ethylene glycol (0.43 mL, 7.7 mmol) and a catalytic amount of p-TsOH•H20 in dry benzene (-60 mL) was refluxed in a Dean-Stark apparatus under an Ar atm for 1 h. After cooling to RT, brine was added, and the mixture was extracted with Et20 (3x). The combined extracts were washed with brine (3x), dried over MgSO4 and the solvent removed to yield a yellow oil. Purification by column chromatography using 4:1 PE:Et20 as eluant gave starting material 191  175 (0.035 g, 10% yield) and the desired ketal 192 as a colourless oil (0.284 g, 70% yield). 1H NMR spectroscopy showed the diastere,omeric mixture to be —2:1. C16H2403^Calc. Mass: 264.1725 Meas. Mass: 264.1723 1H NMR (400 MHz, CDC13, major diastereomer): 8=0.92 (3H, d, J=7 Hz, C(8)C113); 1.15 (3H, s, Cli3); 1.31 (3H, s, CJ-j); 1.34 (3H, s, C(10)CH3); 1.45-1.78 (4H, m); 1.80-1.95 (2H, m); 3.85-4.00 (4H, m, ketal H's); 5.79 (1H, d, J=10 Hz, C(2)H); 6.47 (1H, dd, J=10, 1.5 Hz, C(1)H). IR (neat): v=2935 (C-H); 1671 (C=0) cm-1 MS: m/e(%)=264 (M+, 1.7); 2.50 (3.5); 140(100); 113 (40); 100(12); 95 (15); 86(20); 40 (57). Reduction of enone 192 to give alcohol 193:  HO  A solution of enone 192 (0.284 g, 1.07 mmol) in dry Et20 (3.0 mL) and Et0H (5.0 mL) was added to NH3(J) (-20 rnL) kept cold by a dry ice/acetone bath. Li (0.075 g, 10.7 mmol) was added in small pieces and after stirring the blue mixture for 1 h, NI-14C1(s) was cautiously added, and the NH3(z) was allowed to evaporate overnight.106 The residue was taken up in Et20 and water was added to dissolve the white precipitate. The mixture was extracted with Et20 (3x), the combined extracts were washed with brine (3x) and dried over MgSO4. Removal of the solvent gave a yellow oil which was purified by column chromatography using 4:1 PE:Et20 as eluant. A pale yellow solid  176 was obtained which was recrystallized from 4:1 PE:Et20 to give the alcohol 193 as a white crystalline solid ( 0.156 g, 54% yield). 1H NMR spectroscopy showed the diastereomeric mixture to be 1:1. C16H2803^Calc. Mass: 268.2038 Meas. Mass: 268.2037  Calc.: C 71.60^H 10.51 % Anal.: C71.69^H 10.42 %  1H NMR (400 MHz, CDC13, one diastereomer): 8=0.90 (3H, d, J=6 Hz, C(8)CE3); 1.00 (6H, s, 2x Cal); 1.07-1.10 (4H, m, CE3 and 1H); 1.25-1.35 (3H, m); 1.50-1.55 (1H, m); 1.65-1.75 (3H, m); 1.89 (1H, dd, J=15, 8 Hz); 2.05 (1H, m); 3.38 (1H, m, C(3)H); 3.85-4.00 (4H, m, ketal H's). IR (CHC13): v=3615 (0-H); 2968 (C-H) cm-1 MS: m/e(%)=268 (M+, 21); 198 (6.3); 151 (18); 140 (51); 113 (100); 100(31); 99(80). Protection of alcohol 193 to give methyl ether 194:  HO  To a slurry of KH (0.022 g, 0.54 mmol) in dry THF (1.0 mL) under an Ar atm was added a solution of alcohol 193 (0.12 g, 0.45 mmol) in dry TI-IF (6.0 rnL) and the mixture was stirred at RT for 25 min. Mel (0.050 rnL, 0.67 mmol) was passed through basic alumina directly into the reaction mixture. After stirring overnight, water was cautiously added and the mixture was extracted with Et20 (3x). The combined extracts  177 were washed with brine (3x), dried over MgSO4 and the solvent was removed to give a yellow liquid. Purification by column chromatography using 4:1 PE:Et20 as eluant gave the methyl ether 194 as a pale yellow oil (0.119 g, 94% yield). 1H NMR spectroscopy and GC showed this to a mixture of all 4 possible diastereomers. C17H3003^Cak. Mass: 282.2195 Meas. Mass: 282.2195 1H NMR (400 MHz, CDC13, major diastereomer): 8=0.81 (3H, d, J=7 Hz, C(8)CH3); 0.99 (3H, s, CE13); 1.10 (3H, s, CLI3); 1.13 (3H, s, CE.3); 1.35-2.05 (10H, m); 2.99 (1H, dd, J=12, 5 Hz, C(3)H); 3.35 (3H, s, -0C113); 3.85-4.00 (4H, m, ketal H's). IR (neat): v=2924, 2818 (C-H) cm-1 MS: mie(%)=282 (M+, 4.9); 268 (8.0); 250 (3.7); 140 (22); 113 (69); 99 (100); 41(21). Hydrolysis of ketal 194 to give ketone 195:  CH30  CH30 195  A solution of ketal 194 (0.124 g, 0.439 mmol) in acetone (3.0 triL) and 1 M HC1 (3.0 mL) was stirred at RT for 1 h. Water was added and the mixture was extracted with Et20 (3x). The combined extracts were washed with brine (3x), dried over MgSO4, and the solvent was removed to give a yellow solid. Purification by column chromatography using 9:1 PE:Et20 as eluant gave ketone 195 as a white crystalline solid (0.096 g, 91% yield). 1H NMR spectroscopy and GC showed the chastereomeric mixture to be 1:1.  178 CI5H2602^Calc. Mass: 238.1933 Meas. Mass: 238.1937 Calc.: C75.58^H 10.99% Anal.: C 75.70^H 11.00% 1H NMR (400 MHz, CDC13, one diastereomer): 8.75 (3H, s, Cf_13); 0.96 (3H, s, Q-_13); 1.01 (3H, d, J=6 H, C(8)CH3); 1.24 (3H, s, C13); 1.30-1.50 (2H, m); 1.60-1.75 (3H, m); 1.85-2.05 (2H, m); 2.20-2.60 (3H, m); 2.79 (1H, br s, C(3)H); 3.26 (3H, s, -OCH.3). 1H NMR (400 MHz, CDC13, second diastereomer): 8=0.93 (3H, s, Cf_13); 0.96 (3H, d, J=7 Hz, C(8)CH3); 1.07 (3H, s, C1j3); 1.14 (3H, s, Clia); 1.30-1.50 (2H, m); 1.601.75 (3H, m); 1.85-2.05 (2H, m); 2.20-2.60 (3H, m); 3.03 (1H, dd, J=11, 4 Hz, C(3)H); 3.34 (3H, s, -OCH3). IR (CHC13): v=2933 (C-H); 1703 (C=0) cm-1 MS: m/e(%)=238 (M+, 14); 206 (51); 191 (21); 163 (27); 111 (34); 83(39); 71(100); 69 (52); 67 (31); 55 (53); 43 (30); 41 (64). Conversion of ketone 195 to enol silyl ether 196:  CH30  CH30 195  ^  196  To a solution of ketone 195 (0.056 g, 0.23 mmol) and HMDS (70 pL, 0.33 mmol) in dry CH2C12 (2.0 mL) at 0 °C under an Ar atm were added successively Li! (0.037 g, 0.28 mmol) and TMSC1 (35 III., 0.28 mmol).107,108 After stirring at 0°C for 1 h, the mixture was poured onto ice and diluted with CH2C12. The layers were separated, and  179 the CH2C12 solution was washed with NaHCO3(aq) solution (2x). After drying over MgSO4, the solvent was removed to yield the enol silyl ether 196 (0.0765 g, >100% weight recovery) as a pale yellow liquid which was not purified but which was used directly in the next reaction. C18H3402Si Calc. Mass: 310.2328 Meas. Mass: 310.2330 1H NMR (400 MHz, CDC13): 6=0.18 (9H, s, -Si(CH3)3); 0.80 (3H, s, Ca3); 0.92 (3H, s, C113); 0.93 (3H, s, CE.3); 0.99-1.12 (2H, m); 1.34 (1H, br d, J=17 Hz); 1.53 (3H, s, vinyl CLI3); 1.62-1.74 (2H, m); 1.86 (1H, br d, J=17 Hz); 2.22 (1H, hr d, J=17 Hz); 2.33 (1H, br d, J=17 Hz); 2.29 (1H, br s); 3.28 (3H, s, -0CL13); 3.293.35 (1H, m, C(3)H). IR (neat): v=2960 (C-H); 1656 (C=C) cm-1  MS: m/e(%)=310 (Mt, 24); 278 (16); 196 (32); 156 (27); 141 (100); 75 (48); 73 (93); 41 (26). Conversion of enol silyl ether 196 to enone 197:  CH30  CH30  A solution of PhSeC1 (0.064 g, 0.33 mmol) in dry Et20 (2.0 mL) was added to a solution of enol silyl ether 196 (0.069 g, 0.22 mmol) in dry Et20 (2.0 mL) at -78 0C under an Ar atm. After stirring at -78 0C for 1.25 h, the solution was warmed to 0°C and water (0.12 mL), HOAc (30 ilL) and H202 (0.11 rnL) were successively added. The mixture was warmed to RT, NaHCO3(aq) solution was added, and the mixture was  180 extracted with Et20 (3x). The combined extracts were washed with 1 M HC1, water, brine (2x), and dried over MgSO4. Removal of the solvent gave a yellow oil which was purified by column chromatography using 9:1 PE:Et20 as eluant. The enone 197 was isolated as a white solid (0.030 g, 58% yield). C151-12402  ^  Calc. Mass: 236.1776  Meas. Mass: 236.1785 1H NMR (400 MHz, CDC13): 6=0.72 (3H, s, CH3); 0.98 (3H, s, CH3); 1.18 (3H, s, CH); 1.38 (1H, m); 1.68-1.78 (6H, m, C(8)CH3 and 3 H's); 2.01 (1H, dt, J=7, 2 Hz, C(5)H); 2.48 (1H, dd, J=18, 2 Hz, C(6)eq H); 2.74 (1H, dd, J=18, 7 Hz, C(6)ax H); 2.83 (1H, br d, J=2 Hz); 3.35-3.40 (4H, m, -OCH3 and C(3)H); 6.40 (1H, br s, C(9)H). IR (CHC13): v=2934 (C-H); 1671 (C=0) cm-1 MS: m/e(%)=236 (Mt, 20); 204 (21); 189 (37); 161 (30); 91(23); 79 (25); 71(100); 41 (49). Conversion of (-)-5-methyl-5,6-dehydrocamphor (178) to enone 204:  178  ^  203  ^  204  Freshly ground Mg (0.55 g, 23 mmol) was added to a 3-necked 200 mL round bottomed flask equipped with condenser and addition funnel. After flame drying and cooling under Ar, dry THF (25 mL) and a crystal of I2 were added. A solution of 2-bromopropene (1.7 mL, 19 mmol) in dry TI-IF (25 rnL) was added dropwise and the Grignard reagent was allowed to form over 30 min. A solution of (-)-5-methy1-5,6dehydrocamphor (178, 1.56 g, 9.50 mmol) in dry THF (20 mL) was added dropwise and  181 the reaction was stirred at RT for 30 min. After heating at 40 °C for 30 min, the reaction was refluxed for 8.5 h. The mixture was cooled to -78 °C and a solution of PhSeC1 (3.64 g, 19.0 mmol) in dry THF (25 mL) was added and the reaction was allowed to warm to RT overnight. The mixture was cooled to 0°C and water (6.0 mL), HOAc (1.5 inL) and H202 (6.0 mL, 30%) were added successively. The reaction was warmed to RT and was stirred until a white precipitate was formed (-30 min). NaHCO3(aco solution was added, the mixture was extracted with Et20 (3x) and the combined extracts were washed successively with 1 M HCI, water and brine (2x). Drying over MgSO4 and removal of the solvent gave a yellow liquid which was purified by column chromatography using 24:1 PE:Et20 as eluant. The enone 203 was obtained as a yellow liquid (1.448 g, 75% yield) and 1E NMR spectroscopy showed this to be a mixture of exo- and endocyclic double bond isomers. Therefore, the liquid was dissoved in acetone (20 mL) and 6 M HC1 (20 mL) and was heated at 70 °C for 30 min. After cooling to RT, the reaction was extracted with Et20 (3x) and the combined extracts were washed with brine (3x). Drying over MgSO4 and removal of the solvent gave an orange liquid which was purified by column chromatography using 24:1 PE:Et20 as eluant. The enone 204 was isolated as a colourless liquid (1.17 g, 60% yield from (+5-methyl-5,6-dehydrocamphor, 178). A small amount could be crystallized from Et20 for elemental analysis. CI4H20^Calc. Mass: 204.1514 Meas. Mass: 204.1514 Calc.: C 82.30^H 9.87 % Anal.: C 82.15^H 9.74 % 1H NMR (400 MHz, CDCI3): 8=0.76 (3H, s, CH3); 1.00 (3H, s, CH3); 1.24 (3H, s, CH3); 1.63 (3H, d, J=1 Hz, vinyl CH3); 1.72 (3H, d, J=1 Hz, vinyl CH3); 2.06 (1H, dt, J=7, 1.5 Hz, C(5)H); 2.53 (1H, dd, J=17, 1.5 Hz, C(6) eq. H); 2.64 (1H,  182 dd, J=17, 7 Hz, C(6) ax. H); 5.16 (1H, d, J=1 Hz, C(1)H); 6.30 (1H, t, J=1 Hz, C(9)H). IR (CHC13): v=2953 (C-H); 1662 (C=0) cm4 MS: m/e(%)=204 (M+, 16); 189 (59); 162(11); 161 (16); 147 (14); 40(50). Conversion of enone 204 to enol silyl ether 205:  204  ^  205  To a slurry of CuBr•DMS (0.10 g, 0.50 nunol) in dry THF (3.0 mL) at -78 0C under an Ar atm was added dropwise MeLi (-0.6 mL, 1.5 WITIF, —1.0 mmol) until the mixture became a colourless solution.105 Following the addition of TMSC1 (0.16 inL, 1.3 mmol),111 a solution of enone 204 (0.052 g, 0.25 mmol) in dry THF (3.0 mL) was added. The solution immediately became yellow, and was stirred at -78 0C for 30 min. A 5% NH4OH in saturated NH4C1(ao solution was added, and the mixture was m exgtract4ed. with Et20 (3x). The combined extracts were washed with brine and dried over so Removal of the solvent gave a yellow liquid which was purified by column chromatography using 15:1 PE:Et20 as eluant. The enol silyl ether 205 was isolated as a colourless oil (0.065 g, 89% yield). C1811320Si Calc. Mass: 292.2222 Meas. Mass: 292.2226 1H NMR (300 MHz, CDC13): 6=0.18 (9H, s, -Si(CH3)3); 0.82 (3H, s, CH3); 0.88 (3H, s, CH3); 0.93 (3H, d, J=7 Hz, C(9)CH3); 0.95 (3H, s, CE.3); 1.51 (3H, q, J=1.5 Hz, vinyl CH3); 1.60 (3H, d, J=1.5 Hz, vinyl CH3);1.71 (1H, dd, J=9, 3 Hz, C(5)H);  183 1.95 (1H, dm, J=17 Hz, C(6) eq H); 2.10 (1H, br d, J=7 Hz, C(9)H); 2.20(1H, ddm, J=17, 9 Hz, C(6) ax H); 5.39 (1H, br s, vinyl H). IR (neat): v=2936 (C-H); 1680 (C=0) cm-1 MS: trile(%)=292 (Mt, 15); 170 (12); 155 (51); 122 (100); 107 (51); 75 (31); 73 (46). Conversion of enol silyl ether 205 to ketone 207:  205  ^  206  ^  207  A solution of enol silyl ether 205 (0.057 g, 0.19 mmol) in 1 M HC1 (1.0 mL) and acetone (1.0 mL) was stirred at RT for 2 h. After dilution with water, the mixture was extracted with Et20 (3x) and the combined extracts were washed with NaHCO3 (ac0 solution and brine (3x). Drying over MgSO4 and removal of the solvent gave a yellow liquid which was purified by column chromatography using 24:1 PE:Et20 as eluant. The ketone 206 was isolated as a colourless liquid (0.030 g, 70% yield). The diastereomeric mixture was determined to be 2:1 by GC. A sample of this mixture (0.021 g, 0.095 mmol) in a 9:1 mixture of HOAc:HC1(c0nc) (1.0 mL) was heated at 80 °C for 1 h to epimerize the C(8) center. After cooling to RT, the mixture was added to water and extracted with Et20 (3x). The combined extracts were washed with water, NaHCO3 (aq) solution and water (3x) and dried over MgSO4. Removal of the solvent gave a yellow liquid which was only one diastereomer by GC. Purification by column chromatography using 24:1 PE:Et20 as eluant gave the ketone 207 as a colourless liquid (0.011 g, 52% yield).  184 C151124 0  ^  Calc. Mass: 220.1827 Meas. Mass: 220.1818  1H NMR (300 MHz, CDC13): 8=0.91 (3H, s, CH3); 0.93 (3H, d, J=7 Hz, C(9)C113); 1.00 (3H, s, CH3); 1.03 (3H, d, J=7 Hz, C(8)CH3); 1.05 (3H, s, CLI3); 1.62 (3H, d, J=1.5 Hz, vinyl Ck13); 1.69 (1H, m, C(9)H); 1.99 (1H, dd, J=8, 7 Hz, C(5)H); 2.09 (1H, m, C(8)H); 2.37 (1H, ddd, J=13, 8, 1 Hz, C(6) ax H); 2.52 (1H, dd, J=13, 7 Hz, C(6) eq H); 5.33 (1H, d, J=1.5 Hz, vinyl H). IR (neat): v=2940 (C-H); 1714 (C=0) cm-1 MS: m/e(%)=220 (M+, 4.9); 135 (100); 122 (35); 121 (32); 107 (18); 91(14); 40 (45). Conversion of enone 204 to ketone 208: CN  204  ^  208  Et2A1CN (1.9 mL, 1 MfIEF, 1.9 mmol) was added dropwise to a solution of enone 204 (0.095 g, 4.6 mmol) in dry THF (5.0 mL) under an Ar atm.112 After stirring at RT for 5.5 h, the mixture was poured onto 5% Na0H(aq) solution and extracted with Et20 (3x). The combined extracts were washed with 1 M HC1 solution and brine (3x). Drying over MgSai and removal of the solvent gave a yellow oil which was purified by column chromatography using 4:1 PE:Et20 as eluant. The ketone 208 was isolated as a yellow oil (0.073 g, 68% yield). GC and 1H NMR spectroscopy showed this to be a complex mixture of diastereomers.  185 C15H210N Calc. Mass: 231.1623 Meas. Mass: 231.1623 1H NMR (400 MHz, CDC13, a complex mixture of diastereomers) characteristic signals: 8=0.7-1.7 (methyl groups); 5.2-5.4 (vinyl H's) IR (neat): v=2929 (C-H); 2236 (CN); 1718 (C=0) cm-1 MS: m/e (%)=231 (M+, 16); 135 (100); 122 (92); 107 (42); 40 (29). Conversion of enone 204 to ketone 210:  204  ^  209  ^  210  To flame-dried Mg (0.41 g, 17 mmol) was added a crystal of 12 and dry THF (15 mL). Vinyl bromide (-0.4 mL, —8 mmol) was added dropwise to initiate and maintain Grignard formation and after 30 min at RT, the solution was cooled to -78 °C. An additional portion of dry THF (10 mL) was added, followed by CuBr•DMS (0.28 g, 1.4 mmol).113 After stirring at -78 °C for 1 h, TMSC1 (1.9 rriL, 15 mmo1)111 was added and the mixture was stirred for an additional 15 min before the enone 204 (0.075 g, 0.36 mmol) was added. After 2 h at -78 °C, the reaction was allowed to warm to RT overnight. A solution of 5% NH4OH in saturated NH4C1(ao was cautiously added and the mixture was extracted with Et20 (3x). The combined extracts were washed with brine (3x) and dried over MgSO4. Removal of the solvent gave an orange oil which was purified by column chromatography using 24:1 PE:Et20 as eluant. The hydrolyzed product (209) of the intermediate enol silyl ether was isolated as a yellow liquid (0.02 g, 24% yield) as well as recovered starting enone 204 (0.017 g, 23% yield). GC and 1H  186 NMR spectroscopy determined the ketone 209 to be a complex mixture of diastereomers. A solution of this mixture (0.017 g, 0.077 mmol) in Me0H (2 mi.) was added to a solution of Na0Me prepared by adding Na (0.007 g, 0.3 mmol) to Me0H (1 mL). The mixture was stirred at RT for 3.5 h, diluted with water and extracted with Et20 (3x). The combined extracts were washed with brine (3x) and dried over MgSO4. Removal of the solvent gave a yellow liquid which was purified by column chromatography using 24:1 PE:Et20 as eluant. The isomerized ketone 210 was isolated as a yellow liquid (0.017 g, 100% yield). 1H NMR spectroscopy determined this to be a 2:1 mixture of isomers. Cl6H 240  ^  Calc. Mass: 232.1833  Meas. Mass: 232.1825 1H NMR (300 MHz, CDC13, major diastereomer): E0.91 (3H, s, CH3); 0.95 (3H, d, J=7 Hz, C(8) CE3); 1.00 (3H, s, CH3); 1.07 (3H, s, CE3 ) ; 1.59 (3H, d, J=1.5 Hz, vinyl CH3); 1.96 (1H, t, J=7 Hz, C(5)H); 2.14 (1H, dd, J=12, 9 Hz, C(9)H); 2.24 (1H, m, C(8)H); 2.35 (1H, dd, J=14, 7 Hz, C(6)H); 2.51 (1H, dd, J=14, 7 Hz, C(6)H); 4.94 (1H, dd, J=17, s, vinyl H trans to RCH=CH2); 5.08 (1H, dd, J=10, 2, vinyl H cis. to RCE=CH2); 5.16 (1H, d, J=1.5 Hz, C(1)H); 5.60 (1H, ddd, J=17, 10, 12 Hz, RCH=CH2). IR (neat): v=2963, 2930 (C-H); 1706 (C=0) cm-1 MS: m/e(%)=232 (M+, 7.7); 135 (100); 122 (46); 107 (23); 91(16). Allyl addition to enone 204 to give alcohol 214:  204  187 To a solution of enone 204 (0.053 g, 0.26 mmol) in dry THF at 0°C under an Ar atm was added dropwise a solution of allylmagnesium bromide (0.52 mL, 1 WTHF, 0.52 mmol). The solution was warmed to RT and after stirring for 30 min it was heated at reflux for 3 h. NH4C1(aq) solution was cautiously added and the mixture was extracted with Et20 (3x). The combined extracts were washed with brine (3x), dried over MgSO4 and the solvent removed to give a yellow oil. Purification by column chromatography using 9:1 PE:Et20 as eluant gave the alcohol 214 as a colourless liquid (0.050 g, 78% yield). GC and 1H NMR spectroscopy showed this to be a 9:1 mixture of isomers. Cl7H260  ^  Calc. Mass: 246.1984  Meas. Mass: 246.1985 Calc.: C 82.87^H 10.64 % Anal.: C 82.70^H 10.73 % 1H NMR (400 MHz, CDC13, major isomer): 6=0.92 (3H, s, Ca3); 1.13 (3H, s, CH.3); 1.15 (3H, s, CH); 1.36 (1H, t, J=13 Hz, C(6) axial H); 1.53 (3H, d, J=1 Hz, vinyl C113); 1.70 (3H, d, J=1.5 Hz, vinyl CH3); 1.76 (1H, dd, J=13, 5 Hz, C(6) equatorial H); 1.90 (1H, dd, J=13, 5 Hz, C(5)H); 2.23 (1H, dd, J=15, 10 Hz, -CHHCH=CH2); 2.40 (1H, ddd, J=15, 10, 2 Hz, -CHHCH=CH2); 4.97 (1H, s, C(1)H); 5.12-5.20 (3H, m, C(9)H and -CH=CLI2); 5.90 (1H, m, -CH=CH2). IR (neat): v=3413 (0-H); 2949, 2862 (C-H) cm-1 MS: m/e(%)=228(M+-H20, 23); 213 (36); 205 (100; 187 (55); 157 (28) 107 (28) 83 (99).  188 Attempted rearrangement of alcohol 214:  21 5  Anionic oxy-Cope rearrangement attempt A: A solution of alcohol 214 (0.048 g, 0.19 mmol) in dry THF (4.0 mL) was added to a slurry of ICH (0.016 g, 0.39 mmol) in dry THF (0.5 mL) under an Ar atm. The mixture was refluxed for 36 h, cooled to RT and water was cautiously added. The mixture was extracted with Et20 (3x) and the combined extracts were washed with brine (3x). Drying over MgSO4 and removal of the the solvent gave an orange oil which was purified by column chromatography using 24:1 PE:Et20 as eluant. The only product isolated was enone 204 (0.012 g, 30% yield). Anionic oxy-Cope rearrangement attempt B: To a solution of alcohol 214 (0.046 g, 0.14 mmol) in dry THF (4.0 InL) at -78 °C under an Ar atm was added dropwise n-BuLi (0.28 rnL, 1.6 WTHF, 0.45 mmol). The solution was stirred at -78 °C for 1 h, then at 0 °C for 1 h. After a further 2.5 h at RT, the mixture was refluxed for 19 h. After cooling to RT, water was added and the mixture was extracted with Et20 (3x). The combined extracts were washed with brine (3x), dried over MgSO4, and removal of the solvent gave a yellow liquid which was purified by column chromatography using 24:1 PE:Et20 as eluant. Starting alcohol 214 was recovered (0.034 g, 74% yield).  189 Anionic oxy-Cope rearrangement attempt C: A solution of alcohol 214 (0.032 g, 0.095 mmol) and 18-cr-6 (0.13 g, 0.48 mmol) in dry diglyme (1.0 mL) was added to a slurry of KH (0.019 g, 0.48 mmol) in dry diglyme (0.5 mL) under an Ar atm. The mixture was stirred at RT for 3 d, then was refluxed for 24 h. The mixture was cooled to RT and passed through silica (230-400 mesh) using 1:1 PE:Et20 as eluant to remove polar decomposition products. Removal of the solvent gave a yellow liquid which was a complex mixture by GC and TLC. There was no evidence of any anionic oxy-Cope rearrangement product, as indicated by IR spectroscopy. Oxy-Cope rearrangement attempt: A mixture of alcohol 214 (0.050 g, 0.15 mmol) and anhydrous K2CO3 (0.10 g, 0.74 mmol) in dry decalin (3.0 mL) was refluxed for 3 d. After cooling to RT the reaction mixture was passed through silica (230-400 mesh) using PE as eluant until all decalin had been eluted, then increasing the polarity to 24:1 PE:Et20. Starting alcohol 214 (0.019 g, 38% yield) was recovered, as well as enone 204 (0.012 g, 40% yield).  Protection of propargyl alcohol as its TBDMS ether: -=.___/  OH  ^/  OTBDMS  A solution of propargyl alcohol (10 mL, 0.17 mol), imidazole (17.5 g, 0.258 mol) and TBDMSCI (30.9 g, 0.206 mol) was stirred overnight at RT under an Ar atm. Brine was added and the mixture was extracted with Et20 (3x). The combined extracts were washed with brine (3x), dried over MgSO4 and the solvent removed to give a yellow oil. Purification by distillation (T=-80 °(, P=-15mmHg) afforded silyl-protected propargyl alcohol as a colourless liquid (25 g, 86% yield).  190 C9H18OS i^Calc. Mass: 170.1127 Meas. Mass: 170.1124 1H NMR (400 MHz, CDC13): &--0.11 (6H, s, Si(fl)2); 0.90 (9H, s, t-Bu); 2.37 (1H, t, J=2.5 Hz, HC-); 4.30 (2H, d, J=2.5 Hz, -CLI2OTBDMS). IR (neat): v=3300 (--H); 2930, 2900, 2870, 2830 (C-H) cm-1 MS: m/e(%)=170 (M+, 1.0); 113 (99); 83 (100); 75(59). Conversion of (-)-5-methyl-5,6-dehydrocamphor (178) to alkyne 216: HO  178  216  To a solution of silyl-protected propargyl alcohol (0.864 g, 5.07 mmol) in dry THF (20 mL) at -78 °C under an Ar atm was added dropwise n-BuLi (2.9 rnL, 1.6 M/hexane, 4.6 mmol).61 After stirring at -78 °C for 2.75 h, a solution of (-)-5-methy15,6-dehydrocamphor (178, 0.562 g, 3.42 mmol) in dry THF (20 mL) was cooled to -78 °C and cannulated into the reaction mixture. The solution was gradually allowed to warm to RT overnight. Water was added, the mixture was extracted with Et20 (3x) and the combined extracts were washed with brine (3x). Drying over MgSO4 and removal of the solvent gave an orange liquid which was purified by column chromatography using 15:1 PE:Et20 as eluant. The alcohol 216 was isolated as a white solid (1.10 g, 96% yield). mp: 78-79 °C  191 C20113402Si Calc. Mass: 334.2328 Meas. Mass: 334.2322 1H NMR (400 MHz, CDC13): 8=0.09 (6H, s, Si (CH3)2); 0.89 (9H, s, t-Bu); 0.91 (3H, s, CH3); 1.04 (3H, s, CH3); 1.05 (3H, s, CH3); 1.67 (3H, d, J=1.5 Hz, vinyl CH); 1.81 (1H, d, J=13 Hz, C(3) endo H); 2.04 (1H, d, 1=3 Hz, C(4)H); 2.18 (1H, dd, J=13, 3 Hz, C(3) el_co H); 4.29 (2H, s, -CH2OTEDMS); 5.22 (1H, br s, C(6)H). IR (CHC13): D=3596 (0-H); 2943, 2862 (C-H) cm-1 MS: m/e(%)=334 (M-1-, 0.4); 278 (26); 277 (100); 249 (20); 173 (26); 155 (36); 123 (26); 122 (81); 107 (30). Reduction of alkyne 216 to give alkene 217: HO  HO  /.....) TBDMSO^217  Lindlar's catalyst (Pd on CaCO3, poisoned with Pb, 0.15 g, 40% by wt of alkyne) and quinoline (14 }AL, 0.015 g, 10% by wt of catalyst) in a 2:1 mixture of hexane:Et0Ac (-15 mL) were stirred under a H2 atm in a hydrogenation apparatus for 30 min.114 A solution of alkyne 216 (0.37 g, 1.1 mmol) in 2:1 hexane:Et0Ac (-15 mL) was added and the mixture was stirred under H2 until the rate of uptake of H2 slowed (-1 h). The mixture was filtered and the solvent removed to give a colourless oil which was purified by column chromatography using 15:1 PE:Et20 as eluant. The^alkene 217 was isolated as a soft white solid (0.285 g, 77% yield).  192 mp: 27-28 0C C20}13602S1 Calc. Mass: 336.2484  Meas. Mass: 336.2491 1H NMR (400 MHz, CDC13): 8=0.08 (6H, s, Si(CH)2); 0.90 (12H, br s, t-Bu and Cii3); §_Ldj) H); 1.64 0.95 (3H, s, C_Fi3); 1.12 (3H, s, CH3); 1.61 (1H, d, J=13 Hz, C(3)r (3H, d, J=1.5 Hz, vinyl CH); 2.24 (1H, d, J=3.5 Hz, C(4)H); 2.28 (1H, dd, J=3.5, 13 Hz, C(3) exo H); 4.30 (1H, ddd, J=13, 6, 1 Hz, -CHHOTBDMS); 4.37 (1H, ddd, J=13, 5, 1 Hz, -CHHOTBDMS); 5.16 (1H, br s, C(6)H); 5.43 (1H, m, -CH=CHCH2OTBDMS); 5.52 (1H, dt, J=12, 1 Hz, -CH=CHCH2OTBDMS). IR (CHC13): D=3599, 3401 (0-H); 2860 (C-H) cm-1 MS: m/e(%)=318 (M+-H20, 2.7); 261 (6.4); 205 (14); 145 (40); 143 (30); 122 (68); 84 (53); 75 (100). Attempted rearrangement of alcohol 217:  HO  TBDMSO  217  218  Anionic oxy-Cope rearrangement attempt A: A solution of alcohol 217 (0.37 g, 0.11 mmol) in dry THF (5.0 mL) was cannulated into a slurry of KR (0.032 g, 0.80 mmol) in dry THF (2.0 mL) under an Ar atm. After stirring at RT for 15 min, 18-cr-6 (0.21 g, 0.80 mmol) was added and the reaction mixture was refluxed for 3 h, then cooled to RT. NH4C1(aq) solution was cautiously added, and the mixture was extracted with Et20 (3x). The extracts were dried  193 over MgSO4 and the solvent removed to give a yellow oil. Purification by column chromatography using 1:1 PE:Et20 as eluant gave a white solid (0.010 g, 41% yield) which was determined to be diol 219 resulting from silyl ether cleavage. mp: 54-55 °C C14H2202^Calc. Mass: 222.1619 Meas. Mass: 222.1613 1H NMR (400 MHz, CDC13): 8=0.90 (3H, s, CH3); 0.95 (3H, s, CH3); 1.10 (3H, s, CH3); 1.64 (3H, d, J=1.5 Hz, vinyl CH3); 1.67 (1H, d, J=12 Hz, C(3) endo H); 2.08 (1H, d, J=4 Hz, C(4)H); 2.35 (1H, dd, J=12, 4 Hz, C(3) ra2H); 2.58 (2H, br s, exchanges with D20, 2x01-_1); 4.21-4.32 (2H, m, -C.t_120H); 5.09 (1H, s, C(6)1-1); 5.50-5.10 (2H, m, gill vinyl H's). IR (CHC13): p=3394 (0-H); 2940, 2869 (C-H) cm-1 MS: m/e(%)=204 (M+-18, 6.1); 161 (24); 143 (29); 133 (56); 131 (30); 122 (100). Anionic oxy-Cope rearrangement attempt B: To a slurry of ICH (0.115 g, 2.87 mmol) in dry THF (5.0 inL) under an Ar atm was added HMDS (0.61 mL, 2.9 mmol) and the mixture was stirred at RT for 1 h. A solution of alcohol 217 (0.162 g, 0.481 mmol) in dry TIT (5.0 mL) was added and the reaction mixture was refluxed for 17 h, then cooled to RT. NH4C100 solution was cautiously added and the mixture was extracted with Et20 (3x). The combined extracts were washed with brine (3x) and dried over MgSO4. Removal of the solvent gave a yellow oil which was a complex mixture of products as determined by GC and TLC. Purification by column chromatography using 15:1 PE:Et20 as eluant was attempted. None of the major products isolated was the desired anionic oxy-Cope product, as determined by IR and IH NMR spectroscopy.  194 Oxy-Cope rearrangement attempt A: A solution of alcohol 217 (0.050 g, 0.15 mmol) in dry toluene (0.60 mL) was sealed under vacuum (-15 mmHg) in an oven-dried Pyrex tube which had been soaked in 35% KOH solution for 2 days, then washed with deionized water. The tube was heated at 140 0C for 14 h. Removal of the solvent gave a yellow liquid which was a complex mixture as determined by TLC and GC. Isolation of some of the major compounds by purification by column chromatography using 9:1 PE:Et20 as eluant showed no evidence of being the desired product as determined by IR and 1H NMR spectroscopy. Oxy-Cope rearrangement attempt B: A solution of alcohol 217 (0.068 g, 0.20 mmol) and propylene oxide (0.42 rnL, 6.1 mmol) in dry toluene (4.0 mL) was heated under an Ar atm at reflux for 66 h. Removal of the solvent gave a yellow liquid which was purified by column chromatography using 24:1 PE:Et20 as eluant. Starting alcohol 217 (0.024 g, 35% yield) was isolated. There was no evidence of the desired rearrangement product as indicated by IR spectroscopy. Oxy-Cope rearrangement attempt C: Anhydrous K2CO3 (0.127 g, 0.920 mmol) was added to a solution of alcohol 217 (0.062 g, 0.18 mmol) in dry decalin (3.7 mL) and the mixture was refluxed under an Ar atm for 2.75 h. After cooling to RT, the liquid was purified by column chromatography eluting first with PE then switching to 24:1 PE:Et20 after all the decalin had been eluted. A colourless liquid (0.037 g) was obtained. It was determined not to be the desired oxyCope rearrangement product, and yet it could not be identified. 1H NMR (400 MHz, CDC13): 8=0.12 (6H, s); 0.80-0.90 (18 H, m); 1.55 (3H, br s); 2.23 (1H, br m); 2.30 (1H, dd, J=7, 18 Hz); 2.45 (1H, dd, J=7, 18 Hz); 2.68 (1H, t, J=7 Hz); 2.97 (2H, d, J=7 Hz); 5.07 (1H, m); 5.13 (1H, br s); 6.30 (1H, d, J=10 Hz).  195 IR (neat): u=3571 (0-H); 2959 (C-H); 1718, 1663 (C=0) cm-1 MS: m/e(%)=336 (3.6); 171 (54); 123 (78); 122 (100); 115 (61); 81(24); 75 (38); 73 (90). Deprotection of silyl ether 217 to give diol 219: HO  217  TBDMSO  HO  A solution of silyl alcohol 217 (0.107 g, 0.318 mmol) and TBAF (0.64 mL, 1.0 M/THF, 0.64 mmol) in dry THF (2.0 mL) was stirred at RT under an Ar atm for 15 min. Water was added and the mixture was extracted with Et20 (3x). The combined extracts were washed with brine (3x) and dried over MgSO4. Removal of the solvent gave a yellow liquid which was purified by column chromatography using 1:1 PE:Et20 as eluant. The diol 219 was isolated as a white solid (0.064 g, 91% yield). Spectral characteristics were identical with those of the diol 219 previously described. Attempted rearrangement attempt of diol 219:  HO  HO^219  220  Anionic oxy-Cope rearrangement attempt: A solution of diol 219 (0.051 g, 0.23 mmol) and 18-cr-6 (0.30 g, 1.1 mmol) in dry THF (5.0 mL) was cannulated into a slurry of KH (0.046 g, 1.1 mmol) in dry TI-IF  196 (5.0 mL) under an Ar atm. The reaction was stirred at RT for 1 h, then at reflux for 47 h. After cooling to RT, NH4C1(aq) solution was cautiously added and the mixture was extracted with Et20 (3x). The combined extracts were washed with brine (3x) and dried over MgSO4. Removal of the solvent gave an orange oil which was purified by column chromatography using 1:1 PE:Et20 as eluant. The only compound which was isolated was starting diol 219 (0.006 g, 12% yield). Oxy-Cope rearrangement attempt: Anhydrous K2CO3 (0.10 g, 0.77 mmol) was added to a solution of diol 219 (0.034 g, 0.15 mmol) in dry decalin (3.0 mL) and the mixture was refluxed under an Ar atm for 5 h. After cooling to RT, the complex mixture was purified by column chromatography using first PE as eluant until all the decalin had been eluted, then increasing the polarity of eluant until a 1:1 mixture of PE:Et20 was used. None of the products isolated were determined to be the desired rearrangement product, as determined by IR and 1H NMR spectroscopy. Deprotection of silyl ether 216 to give diol 221: HO  HO  221  A solution of silyl ether 216 (0.29 g, 0.86 mmol) and TBAF (1.3 mL, 1.0 M/THF,  1.3 mmol) in dry THE (15 mL) was stirred at RT under an Ar atm for 30 min. Water was added, and the mixture was extracted with Et20 (3x). The combined extracts were washed with brine (3x) and dried over MgSO4. Removal of the solvent gave an orange  197 liquid which was purified by column chromatography using 1:1 PE:Et20 as eluant. The diol 221 was isolated as a yellow oil (0.174 g, 91% yield). C14H2002^Calc. Mass: 220.1463 Me as. Mass: 220.1457 1H NMR (400 MHz, CDC13): 8=0.94 (3H, s, CH3); 1.08 (6H, s, 2x CE.3); 1.63 (2H, br s, exchanges with D20, 2x Off); 1.70 (3H, d, J=2 Hz, C(5)H3); 1.83 (1H, d, J=13 Hz, C(3) pndo H); 2.09 (1H, d, J=4 Hz, C(4)H); 2.23 (1H, dd, J=13, 4 Hz, C(3) c_(Q H); 4.27 (2H, s, -CH2OH); 5.22 (1H, br s, C(6)H). IR (neat): D=3467 (0-H); 2953 (C-H) cm-1 MS: in/e(%)=220 (M+, 1.2); 177 (20); 122 (100); 107 (88); 91(45); 77 (26); 41(36). Reduction of alkyne diol 221 to give alkene diol 222:  HO  HO  221  To a slurry of LiA1H4 (0.078 g, 2.1 mol) in dry THF (10 mL) under an Ar atm was added a solution of alkyne 221 (0.174 g, 0.789 mmol) in dry THF (10 mL).62 The mixture was heated at 40 0C for 2 h, then cooled to RT and water was cautiously added. 1 M HC1 was added to dissolve the white precipitate that formed. The mixture was extracted with Et20 (4x) and the combined extracts were washed with brine (3x). Drying over MgSO4 and removal of the solvent gave a yellow liquid which was purified by  198 column chromatography using 1:1 PE:Et20 as eluant. The alkene diol 222 was isolated as a white solid (0.054 g, 31% yield). 1H NMR (400 MHz, CDC13): 5=0.90 (3H, s, CH3); 0.92 (3H, s, CLI3); 1.16 (3H, s, Cli3); 1.57 (1H, d, J=13 Hz, C(3) endo H); 1.70 (3H, s, C(5)2L13); 2.11 (1H, d, J=4 Hz, C(4)H); 2.15 (1H, dd, J=13, 4 Hz, C(3) ra_cg H); 4.15 (2H, t, J=5 Hz, -CH2OH); 5.13 (1H, br s, C(6)H); 5.67 (1H, d, J=16 Hz, -CH=CHCH2OH); 5.77 (1H, m, -CH=CIICH2OH). IR (CHC13): v=3606 (0-H); 2948, 2871 (C-H) cm-1  Attempted anionic oxy-Cope rearrangement of alkene diol 222: HO  222  To a slurry of ICH (0.084 g, 2.1 mmol) in dry TI-IF (3.0 mL) under an Ar atm was added HMDS (0.45 mL, 2.1 mmol), and the mixture was stirred at RT for 4 h. A solution of alkene diol 222 (0.047 g, 2.1 mmol) and 18-cr-6 (0.55 g, 2.1 mmol) in dry 11-IF (2.0 mL) was added. After 3 days at RT, the mixture was refluxed 2 days, then cooled to RT and water was cautiously added. After extraction with Et20 (3x) the combined extracts were washed with brine (3x) and dried over MgSO4. Removal of the solvent gave a yellow liquid which was a complex mixture of compounds as indicated by TLC and GC. There was no evidence of the desired rearrangement product as determined by IR and 1H NMR spectroscopy.  199 Conversion of cyclocamphanone (59) to keto-acetate 248):  OrL  59^  248  OAc  To a solution of cyclocamphanone (59, 8.2 g, 54 mmol) in HOAc (35 mL) was added H2SO4(conc) (0.9 mL) and the mixture was heated at 100 0C under an Ar atm for 46 h. The black solution was cooled to RT, diluted with water and extracted with Et20 (3x). The combined extracts were washed with NaHCO300 solution (4x), brine (3x) and dried over MgSO4. Removal of the solvent gave a yellow liquid which was purified by column chromatography using 4:1 PE:Et20 as eluant. Some starting material 59 was recovered (1.05 g, 13% yield) and the product which was obtained as a yellow liquid. Further purification by Kugelrohr distillation gave the keto-acetate 248 as a colourless liquid (5.65 g, 50% yield). GC and 1H NMR spectroscopy showed the diastereomeric mixture to be 5:1 exo:endo. Cl2H180  ^  Calc. Mass: 210.1256  Meas. Mass: 210.1258 Calc.: C 68.55^H 8.63 % Anal.: C 68.39^H 8.56 % 1H NMR (400 MHz, CDC13, major (exo) diastereomer): 5=0.83 (3H, s,CLI3); 0.91 (3H, s, CH3); 1.12 (3H, s, CH); 1.80 (1H, d, J=18 Hz, C(3) endo H); 1.91 (1H, dd, J=14, 8 Hz, C(6) endo H); 2.03 (3H, s, -02CCH3); 2.07 (1H, d, J=5 Hz, C(4)H); 2.33 (1H, dd, J=14, 5 Hz, C(6) exo H); 2.37 (1H, dd, J=18, 5 Hz, C(3) exo H); 4.72 (1H, dd, J=8, 4 Hz, C(5)H). IR (neat): v=2966 (C-H); 1747 (br, C=0) cm-1  200 MS: m/e(%)=210 (6.4); 168 (19); 150 (34); 125 (24); 108 (100); 93 (61). Conversion of keto-acetate 248 to alcohol 249:  248  OAc^249 OH  CH2I2 (9.6 rriL, 0.12 mol) was cautiously added over 30 min to a vigorously stirred slurry of Zn (14.0 g, 0.214 mol) in dry THF (220 inL) under an Ar atm.129 After an induction period (-15 min) the reaction became highly exothermic and was kept under control by periodic cooling with an ice bath. Upon completion of the CH2I2 addition the mixture was stirred at RT for 30 min. After cooling to 0 0C, TiC14 (2.6 mL, 24 mmol) was cautiously added and after vigorous fuming had subsided the mixture was warmed to RT and stirred for 30 min. A solution of keto-acetate 248 (1.00 g, 4.8 mmol) in dry TIM (20 mL) was added and the mixture was stirred for 1.25 h. Et20 (120 mL) was cautiously added, then brine. The layers were separated and the organic layer was washed with brine (3x). Drying over MgSO4 and removal of solvent gave a pale yellow liquid which was purified by column chromatography using 4:1 PE:Et20 as eluant. The alcohol 249 was isolated as a colourless liquid (0.70 g, 89% yield) which solidified upon standing. C1111180^Calc. Mass: 166.1358 Meas. Mass: 166.1359 Calc.: C 79.47^H 10.91 % Anal.: C79.19^H 11.10 % 1H NMR (400 MHz, CDC13): 8=0.73 (3H, s, CH3); 0.93 (3H, s, Cli3); 1.13 (3H, s, CH3); 1.58 (1H, d, J=3 Hz, exchanges with D20, -OM; 1.68-1.85 (4H, m, C(3)  201 gndo H, C(4)H and C(6) cas cl and endo H's); 2.34 (1H, dm, J=16 Hz, C(3) gm2H);  3.85 (1H, br dd, J=12, 5 Hz, C(5)H); 4.66 (1H, br s, vinyl H); 4.72 (1H, br s, vinyl H). IR(CHC13): v=3613, 3445 (0-H); 3013, 2957, 2874 (C-H) cm-I MS: m/e(%)=166 (M+, 30); 133 (70); 123 (87); 105 (100); 95 (80); 93 (83); 91(75). Oxidation of alcohol 249 to give ketone 250:  A solution of DMSO (38 gL, 0.54 mmol) in dry CH2C12 (1.0 rnL) was added dropwise to a solution of oxalyl chloride (47 pL, 0.54 mmol) in dry CH2C12 (1.0 mL) at -78 °C under an Ar atm.IO2 After 15 min, a solution of alcohol 249 (0.075 g, 0.45 mmol) in dry CH2C12 (2.0 mL) was added dropwise, and the reaction mixture was stirred at -78 °C for 1 h. Et3N (0.19 mL, 1.4 mmol) was added and the reaction was allowed to warm to RT overnight. Water was added and the mixture was extracted with CH2C12 (3x). The combined extracts were washed with brine (3x), dried over MgSO4 and the solvent removed to give a yellow liquid. Purification by column chromatography using 4:1 PE:Et20 as eluant gave the ketone 250 as a colourless solid (0.046 g, 62% yield). Cl1H160  ^  Calc. Mass: 164.1201  Meas. Mass: 164.1196 Calc.: C 80.44^H 9.82% Anal.: C 80.27^H 9.72 %  202 1H NMR (300 MHz, CDC13): 5=0.85 (3H, s, CH3); 0.96 (3H, s, CH3); 1.06 (3H, s, CH3); 1.83 (1H, d, J=17 Hz, C(6) endo H); 2.15-2.25 (3H, m, C(6) exo H, C(3) endo H and C(4)H); 2.60 (1H, dm, J=15 Hz, C(3) exo H); 4.85 (1H, br s, vinyl H);  4.90 (1H, br s, vinyl H). IR(CH2C12): v=2924, 2877 (C-H); 1742 (C=0) cm-1 MS: m/e(%)=164 (M+, 7.5); 121 (12); 93 (100); 79 (13); 40 (12). Protection of ketone 250 to give dithiane 245:  To a solution of ketone 250 (0.034 g, 0.21 mmol) in dry CH2C12 (2.0 mL) under an Ar atm were added successively ethanedithiol (0.020 mL, 0.25 mmol) and BF3.0Et2 (13 gL, 0.10 mmol).96 After stirring at RT overnight, the reaction mixture was diluted with Et20 and washed successively with 5% Na0H(aco solution (3x), water and brine (3x). The organic layer was dried over MgSO4 and the solvent removed to yield a pink liquid. Purification by column chromatograhy using 15:1 PE:Et20 as eluant gave the dithiane 245 as a colourless liquid (0.021 g, 42% yield). C13H20S2^Calc. Mass: 240.1006 Meas. Mass: 240.1008 1H NMR (400 MI-1z, CDC13): 8=0.96 (6H, br s, 2xCH3); 1.02 (3H, s, CH); 1.58 (1H, d, J=12 Hz, C(3) endo H); 1.81 (1H, ddd, J=12, 4, 2 Hz, C(3) exo H); 1.94 (1H, d, J=18 Hz, C(6) endo H); 2.46 (1H, dd, J=18, 4 Hz, C(6) exo H); 2.67 (1H, br s,  203 C(4)H); 3.10-3.35 (4H, m, thioketal H's); 4.81 (1H, s, vinyl H); 4.95 (1H, vinyl H). IR (neat): v=2961, 2923, 2869 (C-H) cm-1 MS: m/e(%)=240 (M+, 53); 212 (44); 121 (75); 118 (63); 107 (100); 105 (72); 91(38). Attempted acid-catalyzed rearrangement of dithiane 245: OAc 245 S.....)  247  To a solution of dithiane 245 (0.013 g, 0.054 mmol) in HOAc (1.0 mL) was added H2SO4(conc) (0.024 mL) and the mixture was stirred at RT for 1.5 h. As no reaction occurred, as indicated by TLC and GC, the mixture was heated at 100 0C for 2 h. After • cooling to RT, water was added and the mixture was extracted with Et20 (3x). The combined extracts were washed with NaHCO3(ac) solution (3x) and brine (3x). Drying over MgSO4 and removal of the solvent gave a yellow oil which was purified by column chromatography using 15:1 PE:Et20 as eluant to give a white solid (5 mg) which could not be identified, but which was determined not to be the desired acetate 247. 1H NMR (400 MHz, CDC13): 5=0.89 (3H, s, CH3); 1.07 (3H, s, CH3); 1.21 (3H, s, CH3); 1.23 (3H, s, CH3); 1.40-1.46 (1H, m); 1.63-1.85 (3H, m); 2.43 (1H, d, J=18 Hz); 2.52 (1H, dd, J=18, 1.5 Hz). IR (CHC13): v=2958 (C-H); 1755 (C=0) cm-1  MS: m/e(%)=258 (6.6); 172 (14); 139 (46); 122 (12); 112 (33); 86(53); 69(81); 55(50); 43 (66).  204 Protection of alcohol 249 to give benzyl ether 251:  249  OH^251  A solution of alcohol 249 (0.13 g, 0.77 mmol) in dry THF (5.0 mL) was added to a slurry of KR (0.062 g, 1.6 rnmol) in dry THF (1.0 mL) under an Ar atm. After stirring at RT for 30 min, BnBr (0.11 mL, 0.92 mmol) was added. After 30 min, water was cautiously added and the mixture was extracted with Et20 (3x). The combined extracts were washed with brine (3x), dried over MgSO4 and removal of the solvent gave a yellow liquid. Purification by column chromatography using first PE as eluant then increasing the polarity to 24:1 PE:Et20 gave the benzyl ether 251 as a colourless liquid (0.165 g, 84% yield). Cl8H240  ^  Calc. Mass: 256.1827 Meas. Mass: 256.1819  Calc.: C 84.32^H 9.43 % Anal.: C 84.63^H 9.53 % 1H NMR (400 MHz, CDC13): 8=0.75 (3H, s, CH3); 0.95 (3H, s, CH3); 1.14 (3H, s, CH3); 1.65 (1H, dd, J=13, 8 Hz, C(6) endo H); 1.71 (1H, dt, J=16, 1 Hz, C(3) endo H); 1.83 (1H, dd, J=13, 4 Hz, C(6) exo H); 2.04 (1H, d, J=5 Hz, C(4)H);  2.37 (1H, dm, J=16 Hz, C(3) exo H); 3.52 (1H, dd, J=8, 4 Hz, C(5)H); 4.40 (1H, d, J=12 Hz, -OCHHPh); 4.48 (1H, d, J=12 Hz, -OCHHPh); 4.66 (1H, br s, vinyl H); 4.72 (1H, br s, vinyl H). IR (neat): v=2950, 2870 (C-H) cm-1 MS: m/e(%)=256 (M+, 5.4); 150 (36); 121 (36); 91 (100); 69 (25).  205 Protection of alcohol 249 to give methyl ether 252:  249  ,...-..0Me OH^252  A solution of alcohol 249 (0.17 g, 1.0 mmol) in dry THF (5.0 rilL) was added to a slurry of ICH (0.081 g, 2.0 mmol) in dry THF (2.0 mL) under an Ar atm. After stirring at RT for 15 min, Mel (0.075 mL, 1.2 mmol) was added. After 15 min, water was cautiously added and the mixture was extracted with Et20 (3x). The combined extracts were washed with brine (3x), dried over MgSO4 and removal of the solvent gave a colourless liquid. Purification by column chromatography using 9:1 PE:Et20 as eluant gave the methyl ether 252 as a colourless liquid (0.153 g, 85% yield). C12H200^Calc.  Mass: 180.1514  Meas. Mass: 180.1511 Calc.: C79.94^H 11.18% Anal.: C 79.70^H 11.21 % 1H NMR (400 MHz, CDC13): 8=0.74 (3H, s, C113); 0.94 (3H, s, CH3); 1.07 (3H, s, CH3); 1.63 (1H, dd, J=13, 8 Hz, C(6) exo H); 1.68-1.75 (2H, m, C(6) endo H and C(3) endo H); 1.99 (1H, d, J=5 Hz, C(4)H); 2.37 (1H, dm, J=16 Hz, C(3) exo H); 3.26 (3H, s, -OCH3); 3.33 (1H, m, C(5)H); 4.67 (1H, br s, vinyl H); 4.72 (1H, br s, vinyl H). IR (neat): v=2954 (C-H) cm-1 MS: m/e(%)=180 (M+, 22); 148 (59); 133 (100); 105 (82); 87 (84); 79 (45).  206 Attempted acid-catalyzed rearrangement of benzyl ether 251: complex mixture  To a solution of benzyl ether 251 (0.136 g, 0.53 mmol) in HOAc (2.0 mL) was added H2SO4(conc) (0.048 mL) and the mixture was stirred under an Ar atm at RT for 1 h. The reaction was added to water and the mixture was extracted with Et20 (3x). The combined extracts were washed with NaHCO300 solution (3x) and brine (3x). Drying over MgSO4 and removal of the solvent gave a yellow liquid (0.165 g) which was a highly complex mixture as determined by TLC and GC. Attempted acid-catalyzed rearrangement of methyl ether 252: complex mixture OMe 252  To a solution of methyl ether 252 (0.115 g, 0.639 mmol) in HOAc (1.0 mL) was added dropwise H2SO4(conc) (24 III.) and the solution was stirred under an Ar atm at RT for 45 min. After addition to water, the mixture was extracted with Et20 (3x) and the combined extracts were washed successively with NaHCO3(ao solution (3x), water, and brine (2x). After drying over MgSO4 the solvent was removed to give a yellow oil (0.085 g) which was a complex mixture as determined by TLC and GC.  207 Acid-catalyzed rearrangement of ketone 250 to give ketone 255:  CI^255  To a solution of ketone 250 (0.011 g, 0.067 mmol) in HOAc (1.0 mL) was added H2SO4(conc) (24 gL) and the reaction was stirred under an Ar atm at RT for 4 d. After addition to water, the mixture was extracted with Et20 (3x) and the combined extracts were washed with NaHCO3(aq) solution (3x) and brine (3x). After drying over MgSO4 and removal of the solvent a pale yellow oil was isolated which was purified by column chromatography using 24:1 PE:Et20 as eluant. A colourless liquid was isolated (6 mg, 55% yield) which was determined to be ketone 255. Cl1H160  ^  Calc. Mass: 164.1201  Meas. Mass: 164.1208 1H NMR (400 MHz,CDC13): 8=1.07 (3H, s, CH3); 1.15 (3H, s, CE3); 1.30 (3H, s, CH3); 1.63 (1H, d, J=11 Hz); 1.78-1.90 (2H, m); 2.29 (1H, s, C(4)H); 4.80 (1H, s, vinyl H); 4.86 (1H, s, vinyl H). IR (neat): v=2961, 2927 (C-H); 1741 (C=0) cm-1 MS: m/e(%)=164 (M±, 4.4); 121 (15); 107 (18); 71(30); 57 (56); 43 (100); 32 (26). Conversion of (+)-camphor (25) to (-)-2-methylenebornane (240):  25^  240  208 To methyltriphenylphosphonium bromide (79.7 g, 0.223 mol) which had been dried under vacuum (-0.1 ton) for 12 h to remove traces of moisture was added dry THF (-200 mL) and the slurry was kept under an Ar atm. n-BuLi (-139 mL, 1.6 M/hexane, 0.223) was added dropwise until a red solution was obtained.125 After heating the solution at 50°C for 2 h, a solution of (+)-camphor (25, 21.2 g, 0.139 mol) in dry THF (80 mL) was slowly added. A white precipitate was obtained and the yellow-orange reaction mixture was refluxed for 24 h. After cooling to RT, approximately half of the solvent was removed and water was added to the remaining mixture which was then extracted with pentane (3x). The combined extracts were washed with water (3x), dried over MgSO4, and the solvent removed to give a mixture of yellow liquid and white solid. The mixture was purified by column chromatography using PE as eluant to provide (+2-methylenebornane (240) as a white solid (18.17 g, 87% yield). Cii 1 1 18 -  ^  Calc. Mass:^150.1409  Meas. Mass: 150.1400 Calc.: C 87.93^H 12.07 % Anal.: C87.87^H 11.99 % 1H NMR (400 MHz, CDC13): 6=0.76 (3H, s, CH3); 0.89 (3H, s, CH3); 0.92 (3H, s, CH3); 1.15-1.30 (2H, m, C(5) and C(6) endo H's); 1.64 (1H, ddd, J=12, 12, 4 Hz, C(6) = H); 1.73 (1H, dd, J=8, 4 Hz, C(4)H); 1.78 (1H, m, C(5) g2_cg H); 1.91 (1H, dt, J=16, 1.5 Hz, C(3) endo H); 2.38 (1H, br d, J=16 Hz, C(3) o_co H); 4.63 (1H, s, vinyl H); 4.69 (1H, s, vinyl H). IR (CHC13): v=2942, 2873 (C-H); 1655 (C=C); 878 (vinyl C-H) cm-1 MS: m/e(%)=150 (M+, 22); 135 (38); 107 (100); 93 (66); 79 (72); 67 (19).  209 Acid-catalyzed rearrangement of (-)-2-methylenebornane (240):  f...)&Br 240  266  To a solution of (-)-2-methylenebornane (240, 1.91 g, 12.7 rrunol) in HOAc (8.0 mL) was added 45% HBr/HOAc solution (8.0 ,j,) 130,131 After 5 min, the mixture was cautiously poured onto water, extracted with Et20 (3x) and the combined extracts were washed with water (3x), NaHCO3(aq) solution (3x) and water (3x). Drying over MgSO4 and removal of the solvent gave a yellow solid which was purified by flash column chromatography using 15:1 PE:Et20. 4-Methylisobornyl bromide (266) was isolated as a white solid (2.55 g, 87% yield). This compound discoloured upon storage and was therefore always freshly prepared and immediately used in the next reaction. C11H1979Br Calc. Mass: 230.0670 Meas. Mass: 230.0663 C111 11981Br Calc. Mass: 232.0650 -  Meas. Mass: 232.0645 1H NMR (CDC13): 5=0.72 (3H, s, CH30; 0.91 (3H, s, CH3); 1.00 (3H, s, C113); 1.07 (3H, s, CH3); 1.15-1.22 (2H, m); 1.42-1.49 (1H, m); 1.70-1.76 (1H, m); 2.10-2.15 (2H, m, C(3) exo and endo H's); 4.15 (1H, dd, J=8, 5 Hz, C(2) endo H). IR (CHC13): v=2955, 2872 (C-H) cm-1 MS: m/e(%)=232, 230 (M+, 0.4, 0.5); 217, 215 (4.2, 3.7); 151 (89); 150 (71); 135 (82); 121 (75); 107 (100); 95 (91); 81(86).  210 Conversion of 4-methylisobornyl bromide (266) to (+)-4-methylisoborneol (267) and 4-methylborneol (268):  OH 266  ^  267 (g2a OH) 268 (endo OH)  To freshly ground, flame-dried Mg (0.60 g, 0.025 mol) under an Ar atm was added a crystal of 12 and dry TI-IF (6.0 mL). After the dropwise addition of dibromoethane (0.51 mL, 6.0 mmol) to initiate Grignard formation, a solution of 4-methylisobornyl bromide (266, 2.76 g, 11.9 mmol) in dry TI-IF (5.0 mL) was added at a rate to maintain vigorous reaction. The mixture was stirred until exothennicity ceased (-30 min), then dry THF (19.0 mL) was added to increase the volume. In the next step of the reaction, potentially explosive peroxides are formed and therefore the use of a blast shield is recommended. 02 (dried by passage through 4A molecular sieves and Drieritee) was bubbled through the reaction mixture for 1.5 h and the mixture was kept under a positive Ar atm overnight. 1 M HC1 was cautiously added to decompose any unreacted Mg and to hydrolyze the Grignard complex, and the mixture was extracted with Et20 (3x). The combined extracts were washed with water (2x), NaHC)3(aco solution (2x) and water (2x), dried over MgSO4 and the solvent removed to give a pale yellow liquid. Purification by column chromatography using 9:1 PE:Et20 as eluant gave (+)-4-methylisoborneol (267, 0.2592 g, 13% yield) as a white solid and a 6:1 mixture of (+)-4-methylisoborneol (267) and 4-methylborneol (268) (0.5300 g, 27% yield) also as a white solid. C1 1H200^Calc. Mass: 168.1514 Meas. Mass: 168.1511  211 Calc.: C78.51^H 11.98% Anal.: C78.53^H 12.12% 1H NMR (400 MHz, CDCI3, 267): 8=0.68 (3H, s, CLI3); 0.87 (3H, s, CJ); 0.90 (3H, s, CLI3); 0.94 (3H, s, C113); 0.95-1.11 (2H, m, C(5) and C(6) endo H's); 1.35-1.46 (2H, m, C(6) and C(3) endo H's); 1.51 (1H, ddd, J=8, 8, 4 Hz, C(5) mo H); 1.74 (1H, dd, J=14, 8 Hz, C(3) v_cQH); 3.61 (1H, dd, J=8, 4 Hz, C(2)H). 1H NMR (400 MHz, CDC13, 268): 8=0.71 (3H, s, CH3); 0.73 (3H, s, Cli3); 0.83 (3H, s, CH3); 0.86 (3H, s, CE.3); 1.02 (1H, dd, J=13, 4 Hz); 1.18-1.30 (2H, m); 1.44-1.51 (1H, m); 1.82-1.90 (1H, m); 1.93-2.03 (1H, m); 3.94 (1H, br d, J=11 Hz, C(2)H). IR (CHC13): v=3615 (0-H); 2951, 2871 (C-H) cm-1 MS: m/e(%)=168 (M+, 2.6); 124 (28); 109 (100); 84 (29); 55 (28); 41(35). [4 +32.9 ° (c 8.1, 95% Et0H) for (+)-4-methylisobomeol (267). Separation of 267 and ent-267 by GC using a chiral column: Sample A of (+)-4-methylisoborneol (267, previously prepared by the H2SO4/HOAc rearrangement of (-)-2-methylenebornane (240) route) was known to contain both enantiomers 267 and ent-267 and its specific rotation was determined to be +20.9 0 (c 9.4, 95% Et0H). Separation of the two enantiomers was accomplished by using a Chirasil-val III capillary column (Alltech, 25 m x 0.25 mm i.d.). With a He flow rate of 1.46 mL/min and an oven temperature of 60 °C, the rt of (+)-4-methylisoborneol (267) was 29.90 min (br peak) and the rt of (-)-4-methylisoborneol (ent-267) was 30.70 min. Sample B of (+)-4-methylisoborneol (267) was prepared by the 45% HBr/HOAc route described above. When a GC was taken under the identical conditions  212 as for Sample A, there was no evidence of (-)-4-methylisoborneol (ent-267); a single peak (rt=29.36 min) corresponding to (+)-4-methylisoborneol (267) was obtained. Oxidation of (+)-4-methylisoborneol (267) and 4-methylborneol (268) to (-)-4-methylcamphor (229): f...7T5err OH 267 (mg OH) 268 (endo OH)  26,0 229  A solution of Cr03 (0.089 g, 0.89 mmol) in water (1.2 mL) and H2SO4(conc) (0.3 mL) was added dropwise to a solution of mixture of (+4-methylisoborneol (267) and 4-methylborneol (268) (0.075 g, 0.45 mmol) in acetone (5.0 mL) at 0 °C.136 After the addition of the orange reagent was complete, the reaction mixture turned green and was stirred at RI for 1 h. Water was added and the mixture was extracted with Et20 (3x). The combined extracts were washed successively with water (3x), NaHCO3(ao solution (2x) and water (2x), dried over MgSO4 and the solvent removed to give a white solid. Purification by column chromatography using 15:1 PE:Et20 as eluant gave (-)-4-methyl-camphor (229) as a white solid (0.072 g, 97% yield). C1111180^Calc. Mass:^166.1358 Meas. Mass: 166.1358 Calc.: C 79.47^H 10.91 % Anal.: C 79.79^H 10.91 % 1H NMR (400 MHz, CDC13): 8=0.71 (3H, s, CH3); 0.83 (3H, s, CH3); 0.92 (3H, s, CH3); 1.04 (3H, s, CH3); 1.35-1.43 (2H, m, C(5) and C(6) endo H's); 1.57-1.75 (2H, m, C(5) and C(6) exo H's); 1.87 (1H, d, J=18 Hz, C(3) endo H); 2.08 (1H, dd, J=18, 3 Hz, C(3) exo H).  213 IR (CHC13): v=2959, 2874 (C-H); 1734 (C=0). MS: m/e(%)=166 (Mt, 30); 122 (44); 109 (90); 82 (100); 55 (33). [a]r, -26.7 ° (c 3.4,95% Et0H)  Chiral shift reagent and 1H NMR experiment done on (-)-4-methylcamphor (229): Sample C of (-)-4-methylcamphor (229, 0.014 g, 0.086 mmol)) was taken from the preparation described above, dissolved in CDC13 (1.0 mL, dried by passage through basic alumina), and transferred to a 5 mm NMR tube. A 0.17 M stock solution was prepared by dissolving [Eu(hfc)31 (0.099 g, 0.17 mmol) in CDC13 (0.50 rnL, also passed through basic alumina). A 1H NMR (400 MHz, CDC13) spectrum was recorded before the addition of any shift reagent and was identical to the spectrum described above. [Eu(hfc)3] solution (50 pL, 0.17 M/CDC13, 0.0086 mmol) was added and the NMR tube was vigorously shaken. Another 1H NMR spectrum was recorded which showed broadening of most signals and changes in chemical shift. Another portion of [Eu(hfc)3] solution (0.15 mL, 0.17 M/CDC13, 0.026 mmol) was added and after vigorous shaking, another 1H NMR spectrum was recorded. A final addition of [Eu(hfc)3] solution (0.15 mL, 0.17 M/CDC13, 0.026 mmol) was done and a 1H NMR spectrum taken. The results of these studies have been presented in discussion of Chapter 2 (p. 109).  ^ 214 References and Notes  1.  For recent reviews see a) Paquette, L. A. Angew. Chem., Int. Ed. Engl. 1990, 29, 609. b) Paquette, L. A. Synlett 1990, 67.  2.  Cope, A. C.; Hardy, E. M. J. Am. Chem. Soc. 1940, 62, 441.  3.  Carey, F. A; Sundberg, R. J. 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