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

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EVALUATION OF CAMPHOR DERIVATIVESIN TERPENOID SYNTHESISByMONICA H. PALMEB.Sc., University of British Columbia, 1988A THESIS SUBMITTED IN PARTIAL FULFILLMENT OFTHE REQUIREMENTS FOR THE DEGREE OFDOCTOR OF PHILOSOPHYinTHE FACULTY OF GRADUATE STUDIES(Department of Chemistry)We accept this thesis as conformingto the required standardTHE UNIVERS Y OF BRITISH COLUMBIAApril 1993© Monica H. PalmeIn presenting this thesis in partial fulfilment of the requirements for an advanceddegree at the University of British Columbia, I agree that the Library shall make itfreely available for reference and study. I further agree that permission for extensivecopying of this thesis for scholarly purposes may be granted by the head of mydepartment or by his or her representatives. It is understood that copying orpublication of this thesis for financial gain shall not be allowed without my writtenpermission.(Signature)Department of  C)st---Q-Aev.4.4-7The University of British ColumbiaVancouver, CanadaDate ^VG VzlcktiDE-6 (2/88)AbstractNew enantiospecific syntheses of 5,6-dehydrocamphor (36) and 5-methy1-5,6-dehydrocamphor (178) are reported, and these two compounds were evaluated asintermediates in terpenoid synthesis. Addition of an alkenyl unit to (+)-5,6-dehydro-camphor (36) and subsequent anionic oxy-Cope rearrangement of the resulting 1,5-diene(64) provided hydrindenone 66. Ring expansion of 66 provided decalin intermediate 69which contains the A/B ring system common to many terpenoids; however, the stereo-specific introduction of an angular methyl group to provide a system such as 40 eludedus. Therefore, a similar synthetic strategy using (+5-methyl-5,6-dehydrocamphor (178)was investigated. Isopropenyl addition to 178 and subsequent anionic oxy-Coperearrangement provided hydrindenone 190 which contained the desired angular methylgroup. (-)-5-Methyl-5,6-dehydrocamphor (178) was also converted to enone 204, butstereoselective conjugate addition to this enone (204) was not satisfactory. Addition of amore complex alkenyl unit to (-)-5-methyl-5,6-dehydrocamphor (178) provided 1,5-diene179, however, anionic oxy-Cope rearrangement to provide hydrindenone 180 did notoccur, 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 lattercompound is a potentially useful intermediate in the synthesis of the lanostane group oftriterpenoids whereas its enantiomer (ent-232) derived from (+)-4-methylcamphor (ent-178) could gain access to the euphane group of triterpenoids.36OH 6669 40 180 204232 ent-232RO180 229 25H234, lanosterolHO HOant-i 78111Table of Contents Abstract^ iiTable of Contents^ ivList of Tables viList of Figures^ viiContents of Appendix viiList of Abbreviations^ viiiAcknowledgements xiiiDedication^^ xivChapter 1: The Evaluation of 5,6-Dehydrocamphor (36) and 5-Methyl-5,6-dehydrocamphor (178) as Intermediates in TerpenoidSynthesis^ 11.1: Introduction: The Anionic Oxy-Cope Rearrangement^21.2: Discussion^ 101.2.1: Introduction^ 101.2.2: Synthesis of 5,6-Dehydrocamphor (36)^131.2.3: Synthesis of a Decalin System from5,6-Dehydrocamphor (36) 211.2.4: Angular Functionalization Approaches 231.2.4.1: Hydroxyl-directed Cyclopropanation 231.2.4.2: Radical Cyclization and y-Alkylation 321.2.4.3: Anionic Oxy-Cope Rearrangement 411.2.5: Elaboration of A and B Rings 511.2.5.1: In Situ Methylation 521.2.5.2: C(1)-Oxygenation of Ring A 571.2.6: Evaluation of 5-Methyl-5,6-dehydrocamphor (178)as an Intermediate in Terpenoid Synthesis 59iv1.2.6.1: Synthesis of 5-Methy1-5,6-dehydrocamphor (178)^ 611.2.6.2: Isopropenyl Addition to 5-Methyl -5,6-dehydrocamphor (178) and Anionic Oxy-Cope Rearrangement^ 641.2.6.3: Allyl Addition to Hydrindenone 204 andAttempted Anionic Oxy-Cope Rearrangement^781.2.6.4: Allcynyl Addition to 5-Methy1-5,6-dehydrocamphor (178) and AttemptedAnionic Oxy-Cope Rearrangement^821.3: Conclusion^ 88Chapter 2: A New Enantiospecific Synthesis of 4-Methylcamphor^912.1: Introduction^ 922.2: Discussion 962.3: Conclusion^ 111Experimental^ 113References and Notes 214Appendix^ 222VList of TablesTable 1: Comparison of reaction rates of the oxy-Cope rearrangementand the corresponding anionic oxy-Cope rearrangement^4Table 2: Camphor derivatives in natural product synthesis 11Table 3: Conditions used in the attempted cyclopropanation ofcompound 87^ 28Table 4: Results of COSY experiment done on compound 138^47Table 5: Results of NOE experiments done on compound 138 48Table 6: Results of decoupling experiments done on major isomerof compound 210^ 75Table 7: Results of NOE experiments done on major isomer ofcompound 210^ 77Table 8: Results of NOE experiments done on compound 214^79Table 9: Results of NOE experiments done on compound 255 101Table 10: Specific rotation of (+)-4-methylisoborneol (267)^106Table 11: Specific rotation of (-)-4-methylcamphor (229) 109List of FiguresFigure 1: Chromatograms obtained for Samples A and B of(+)-4-methylisoborneol (267)^ 108Figure 2: 1H NMR (400 MHz) spectra after [Eu(hfc)3] addition to SampleC of (-)-4-methylcamphor (229)^ 110Figure 3: 1H NMR (400 MHz) spectra after [Eu(hfc)3] addition to SampleD of (-)-4-methylcamphor (229)^ 112Contents of AppendiN1. X-ray crystal structure of alcohol 158^ 2222. X-ray crystal structure of ketone 171 223List of Abbreviation Ac^acetylAc0-^acetateAc20^acetic anhydrideAIBN^azobis(isobutyronitrile)Anal.^microanalytically determined mass %aq^aqueousatm^atmosphereax.^axialB-^baseBn^benzylBnBr^benzyl bromidebp^boiling pointbr^broadBu^primary butyln-Bu^primary butylt-Bu^tertiary butylconcentration (g/100 mL, specific rotation)Calc.^calculated mass %Calc. Mass^calculated exact massconc^concentratedCOSY^1H-1H correlation spectroscopy18-cr-6^18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane)doubletdd^doublet of doubletsddd^doublet of doublets of doubletsviiiddm^doublet of doublets of multipletsDHP^dihydropyranDIBAL^diisobutylaluminum hydridediglyme^bis(2-methoxyethyl)etherdm^doublet of multipletsDMAP^4-dimethylaminopyridineDME^1,2-dimethoxyethaneDMF^dimethyl formamideDMS^dimethylsulfideDMSO^dimethyl sulfoxidedq^doublet of quartetsdt^doublet of tripletsE+^electrophilee.e.^enantiomeric excessent-^enantiomer (of)eq.^equatorialEt^ethylEt20^diethyl etherEt0Ac^ethyl acetateEt3N^triethylamineEt0H^ethanol[Eu(hfc)3]^tris[3-(heptafluoropropylhydroxymethylene)-d-camphorato]europium(III)3,2--Me 3,2-exo methyl shiftGC^gas liquid chromatographyh^hour6,2-H^6,2-hydride shiftHMDS^1,1,1,3,3,3-hexamethyldisilazaneixHMPA^hexamethylphosphoramideHMPT^hexamethylphosphorous triamideHOAc^acetic acidHOB ut^tertiary butanoli.d.^inner diameter (capillary gas liquid chromatography column)IR^infraredJ^coupling constantk^rate constantKOBut^potassium tertiary butoxideKHMDS^potassium hexamethyldisilazideLDA^lithium diisopropylamidelit^literature referenceL-Selectride® lithium tri-secondary-butylborohydridem^multipletM^metal or molarity (mol/L)M+^molecular ion (mass spectrometry) or metal cationMe^methylm/e^mass to charge ratioMel^methyl iodideMeas. Mass exact mass determined by high resolution mass spectrometryMe0H^methanolmin^minutemmHg^millimeters of mercuryMOM^methoxymethylmp^melting pointMS^mass spectrumn^normal (primary)xNa0Me^sodium methoxideNMR^nuclear magnetic resonanceNOE^nuclear Overhauser effectNu-^nucleophilePCC^pyridinium chlorochromatePE^low boiling (30-60 0C) petroleum etherPh^phenylppm^parts per millioni-Pr^isopropyli-Pr2NH^diisopropylaminepy^pyridinequartetalkyl groupR'^alkyl group different from RRBF^round bottomed flaskrt^retention timeRT^room temperaturesingletSi02^silica gelSM^starting materialtriplett-^tertiarytemperatureTBAF^tetrabutylammonium fluorideTBDMS^tertiary-butyldimethylsilylTBDMSCI^tertiary-butyldimethylsilyl chloridetd^triplet of doubletsxiTf^trifluoromethanesulfonic (triflic)Tf20^trifluoromethanesulfonic anhydrideTHF^tetrahydrofuranTHP^tetrahydropyranylTLC^thin layer chromatographyTMS^trimethylsilylTMSCI^trimethylsilyl chloridep-Ts0H^para-toluenesulfonic acidTs^para-toluenesulfonylWM^Wagner Meerwein rearrangementwt^weight[a]TD specific rotation at 589 nm at T 0C5^chemical shiftv^absorption frequency10^primary20^secondary30^tertiaryxi iAcknowledgementsI would like to thank my research supervisor, Professor Thomas Money, forhis guidance and support throughout the years I have studied under his direction. Evenduring those times when results came slowly, he could always inspire me to try anotherof his exciting ideas, which came from an apparently limitless supply. His enthusiasmand encouragement increased both my knowledge of chemistry and my confidence, and Iwill always consider Professor Money as my mentor who guided me at the criticalbeginning of my career in chemistry. I shall always strive to achieve his level ofknowledge in so many diverse areas of chemistry, although this will no doubt be adifficult goal.I would like to thank Mike Wong and Scott Richardson, my co-workers, fortheir friendship, help and advice over the years. It was wonderful to share so much timewith two undoubtedly diverse personalities who nevertheless complemented each otherand each contributed to the lab atmosphere in a positive way. I would also like to thankthe many friends, colleagues, and departmental staff members who made my graduateschool years among the best of my life.Finally, I would like to thank my mother, Daisy Palme, for her consistentsupport and encouragement throughout my studies, for her genuine interest in what I do,and for listening to an amazing amount of technical information, especially consideringthat she thought I should have become a chartered accountant.This thesis is dedicated tothe memory of my father, Kurt Palme,from whom I inherited curiosity, patience and perseveranceand tomy mother, Daisy Palme,from whom I inherited drive, ambition and independence.Chapter 1The Evaluation of 5,6-Dehydrocamphor and5-Methyl-5,6-dehydrocamphor AsIntermediates In Telpenoid Synthesis11.1 Introduction: The Anionic Oxy-Cope RearrangementThe anionic oxy-Cope rearrangement is a versatile reaction that has been usedextensively in the synthesis of natural products.1 The work described in Chapter 1 of thisthesis utilizes the anionic oxy-Cope rearrangement as a key step in our route to a decalinsystem and relies on its stereospecificity to introduce three chiral centers.The anionic oxy-Cope rearrangement is a variation of the Cope2 rearrangementwhich is a thermal [3,3] sigmatropic rearrangement of 1,5-dienes. A sigmatropic process2 Ainvolves a concerted reorganization of electrons during which a group attached by aa-bond migrates to a more distant terminus of an adjacent 7r-electron system; there is asimultaneous shift of the it electrons.3 The [3,3] nomenclature comes from splitting themolecule at the migrating sigma bond and numbering the carbon atoms in each resultingfragment from that end. The two digits reflect the numbers of the carbon atoms of eachfragment which are joined as a new sigma bond is formed.The Cope rearrangement is reversible, giving an equilibrium mixture of two1,5-dienes (starting material and product), with the ratio of the two reflecting theirrelative thermodynamic stabilities. Any 1,5-diene will rearrange, but will do so at lowertemperature if there is a substituent on the C(3) or C(4) atom with which the new doublebond that is formed can conjugate.4 If the group is hydroxyl (Z=OH), then the reaction is2C4A^HO.'-'■1111rH+Me0 Me02 _612- .OM66°Ccalled an oxy-Cope5 rearrangement and the product, an enol, tautomerizes to the ketoneor aldehyde, causing the equilibrium to lie far to the right.In 1975, Evans and Golob6 reported that the oxy-Cope rearrangement isaccelerated by factors of 1012-1017 if an allcoxide rather than an alcohol is used, and thisvariation became known as the anionic oxy-Cope rearrangement. The product is anenolate, which may be utilized in situ as will be discussed in Section 1.2.5.1 (p. 52), ormay simply be protonated to provide an aldehyde or ketone. Evans and Golob studiedthe effects of various cations on the anionic oxy-Cope rearrangement of alkoxide 1 inTHF (Scheme 1).Scheme 1In all cases, the temperature was kept at 66 0C and the following results were obtained: Ifthe 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 minutesrespectively, 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 ofup to 3 equivalents of 18-crown-6 resulted in a limiting 180-fold acceleration in rate of3reaction of lb (M=K) at 00C in THF. When HMPT was used as solvent and the reactionwas 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 andthat ion pair dissociation results in maximal rate acceleration.Another set of experiments probed the actual rate accelerations observed when thepotassium alkoxides lb (M=K) and 3b (M=K) were used instead of the correspondingalcohols (Scheme 2). The effect of added ionophore 18-crown-6 was again investigatedand the results are summarized in Table 1.4NI+Me0 23^ 4Scheme 2Table 1: Comparison of the reaction rates of the oxy-Cope rearrangement and thecorresponding anionic oxy-Cope rearrangementAlcohol Alkoxide Temp (0C) Equiv. 18-cr-6 Rate Accel.(kibilci a)la, M=H lb, M=K 25 1.1 10123a, M=H 3b, M=K 40 0 10123a, M=H 3b, M=K 0 1.1 1017These 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 thecorresponding alcohols (la, M=H and 3a, M=H). These results also confirmed thepreviously described reports of rate increases attainable when an ionophore is used as anadditive. In 1984, Bartmess and co-workers7 suggested that a faster rate observed fortertiary alkoxides (as compared to secondary alkoxides) is due to steric hindrance aroundthe anionic site, which results in decreased ion pairing and solvation at that location. Thissuggestion is consistent with the fact that an increase in rate is produced by the additionof 18-crown-6 which complexes potassium ions and hence reduces ion pairing.In order to explain the rate increases observed in the anionic oxy-Coperearrangement, Evans and co-workers8 carried out ab initio C-H bond strengthcalculations for methanol, sodium methoxide, potassium methoxide and the methoxideanion 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 toincreased charge transfer from the cation to the organic fragment and thus a tendency forthe oxygen pit electrons to delocalize back onto the carbon, resulting in a weaker C-Hbond. In the case of the bare, unsolvated methoxide anion, there is further oxygen-centered electron delocalization and the C-H bond becomes even weaker. If thisexplanation is extended to a C-C bond where one carbon atom bears a hydroxylsubstituent, then the C-C bond strength should be weaker in the alkoxide than in theparent alcohol, and cleavage of the bond should be more facile. This explanationaccounts for the rate increases observed in the anionic oxy-Cope reaction; furthermore, italso supports the rate acceleration observed upon the addition of ionophore which shouldfurther weaken the C-C bond.In 1980, Evans and co-workers9 established that the anionic oxy-Coperearrangement, as the Cope rearrangement itself, is a concerted process which usuallyproceeds through a chair-like transition state. Thus the stereochemical outcome of a57reaction can usually be predicted in terms of a preference for the chair-like transition statewhich minimizes steric interactions. As shown in Scheme 3, for example, the Coperearrangement of the meso isomer of 3,4-dimethy1-1,5-hexadiene can exist in onepossible pseudo-chair conformation (5). Rearrangement of this isomer (5) via aconcerted 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 boatconformation 7 or 9 would lead to either the trans, vans product 8 or the c.is, cis product10, neither of which were observed. 1065Me Me^ Me Me9^10Scheme 3The Cope rearrangement of systems such as 11 (Scheme 4) that can proceed viatwo possible chair-like transition states has also been examined.11 Rearrangement of 11was 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 substituentwould favor the equatorial position in the transition state 11a, as opposed to the axialPh^CH3^Ph--ON.-^..1410,.............,v. ,.CH31 laCH311Ph^...----^CH3CH312--4.-7H HPh Ph^ Ph-ill■CH3^CH3^CH3 \^CH31 lb^13Scheme 4CH3H11position as in 11b, where it would experience greater 1,3-diaxial interaction than themethyl group. When enantiopure 11 was used, it was found that the major product 12had an enantiomeric purity of at least 95%. Thus, not only can the stereochemistry of thenewly formed double bonds be predicted, but also, when the starting 1,5-diene isoptically active, the chirality of newly formed tetrahedral centers. A recent example ofsuch a chirality transfer was reported by Nalcai and co-workers12 in their approach to(+)-faranal (18), an ant pheromone (Scheme 5).KH K+ - 0 H+ HO14-\ --j---)---01 8II•-'.. ./*017Scheme 5KH, 18-cr-6^Jo-THF, RT, 2.5 h64%20Diene 14 was prepared in >96% e.e. and upon treatment with KH and 18-crown-6 formedalkoxide 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 determinedto 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 notbe possible; the anionic oxy-Cope rearrangement may then proceed via a boat-liketransition state. An example of such a molecule is the bicyclo [2.2.1] heptenol inter-mediate 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 19rearranged in reasonable yield, and the stereochemistry of product 20 was as predicted.Scheme 6Although the anionic oxy-Cope rearrangement commonly is used to synthesizeacyclic or 6-membered ring products, it can also be used to make medium ring products.8A striking example is Paquette and co-workers'14 synthesis of intermediate 23 (Scheme7).9 _ -Mel_ _22^ 23^ 24Scheme 7Treatment of 22 with ICHMDS caused rearrangement to provide enolate 23. Instead ofprotonation of 23 by the addition of water, methyl iodide was added instead, whichresulted in alkylation of the intermediate enolate 23 to provide 24. This in situmethylation of an enolate resulting from anionic oxy-Cope rearrangement will bediscussed further in Section 1.2.5.1 (p. 52); however, reaction of 22 to provide 24 is anexample of how the anionic oxy-Cope rearrangement can be utilized to provide a highlyfunctionalized, medium ring product.The predictable stereospecificity of the anionic oxy-Cope rearrangement makes ita very useful reaction in organic synthesis. If the starting 1,5-diene is substituted,however, steric interactions may prevent the rearrangement from occurring, thus limitingthe scope of the reaction. We have utilized the anionic oxy-Cope rearrangement in ourefforts towards the enantiospecific synthesis of natural product intermediates. Our use ofthis versatile reaction, and also its limitations due to steric effects, is described in thediscussion of Chapter 1 of this thesis.SO3H3 0(-)-camphorquinone25(+)-camphor29(+)-8-bromocamphor26(+)-camphor-10-sulfonic acid27(+)-9-bromocamphor2 8(+)-9,10-dibromocamphor010AcOrt31OAc^OAc 032 34(+)-bornyl acetate^5-ketobornyl acetateAc0 .411115-ketoisobornyl acetate^(-)-isobornyl acetate1.2: Discussion1.2.1: IntroductionThe use of (+)-camphor (25) or its enantiomer (ent-25) in natural productsynthesis15 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), andC(1)-C(7) bonds in camphor and camphor derivatives can be accomplished to providesynthetically useful intermediates (Scheme 8).10Scheme 8Table 2 shows examples of camphor derivatives and some natural products or syntheticintermediates that have been synthesized using them as precursors. Each derivative canbe synthesized in either enantiomeric form, and thus either enantiomer of the naturalproduct is accessible.Table 2: Camphor derivatives in natural product synthesisCamphor Derivative natural Products or Intermediatescamphor-10-sulfonic acid (26) khusimone,16 zizanoic acid,16quadrone,17 epi-zizanoic acid169-bromocamphor (27) a_santaiene,18,19,20 a-santalo1,21,22,23,24,2513-santalo1,23,24 furodysinin,26epi-3-santalene,19.27 furodysin,26isoepicamphereno1,27 cannabidio1,28cannabidiol dimethyl ether,28 hapalindoleQ,29 helenanolide intermediate,30 vitaminB12 intermediate,31 steroidintermediates32,33.348-bromocamphor (29) campherenone,27.35 a-santalene,27sativene,27,36 copacamphene,27, 36copaborneo1,27, 36 camphereno1,27longiborneo1,35 longifolene,3513-santalene279,10-dibromocamphor (28) estrone,37,38 California red scalepheromone,39 ophiobolin C,40helenanolide intermediate,41steroid intermediates4143,445-ketoisobornyl acetate (33) nojigiku alcohol455-ketobornyl acetate (34) epi43-necrodo146camphorquinone (30) patchouli alcoho1,47 taxusin,48 vitaminB12 intermediates49,50,51,5211 4110- -INN-25 36•■■—40R2A39^ 38Part 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 theresearch described in this thesis was to develop a general strategy towards theenantiospecific synthesis of sesquiterpenoids, diterpenoids, sesterterpenoids andtriterpenoids that contain 4,4,10-trimethyl decalin (35) as a structural sub-unit (A/B ringsystem) in their carbon skeleton (Scheme 9).Scheme 9It was envisioned that an alkoxide (37) derived by the formal addition of a trans-alkenyl unit to (+)-5,6-dehydrocamphor (36) or its enantiomer could undergo anionic12oxy-Cope rearrangement resulting in hydrindenone intermediate 38. The structure of thealkenyl unit would, of course, depend upon the class of terpenoid to be synthesized. Forsesquiterpenoids, R1=H and R2=CH3, CH2OH or CHO. For the larger terpenoids, R1represents an appropriate Cs, C10, or C15 unit.Due to the stereospecificity of the anionic oxy-Cope rearrangement, the ringjunction in hydrindenone 38 is^and the C(9) substituent trans to the ring junctionhydrogens. In addition, the absolute configurations of C(5), C(9) and C(10) aredependent 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 stereo-chemistry of the R2 substituent is dependent upon which face of the enolate is protonatedupon work-up; the C(8) center is, of course, epimerizable. Ring expansion of 38 shouldprovide the decalin system and intermediate 39 contains most structural features inherentin the A/B ring system of many terpenoids: oxygen functionality at C(3) and C(7), thegeminal 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 theC(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 itsenantiomer (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. Oxidationof (+)-bornyl acetate (32) with Cr03/HOAc yields a mixture from which the desiredproduct, 5-ketobornyl acetate (34) is obtained in only 24% yield. Further oxidation of5-ketobornyl acetate (34) with Se02 in Ac20 gave 5,6-dioxobomyl acetate (42) in 56%13viiOAc45i) Na, EtON ii) Ac20 iii) Cr03, HOAc iv) Se02, Ac20v) NH2NH2 H20, EtON vi) Hg0, C6H6 vii) Cu viii) HBr,HOAc ix) Zn, HOAc44i ii(:6iAc0 3214 251iiiV tv4236Scheme 10yield. (+)-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 dependenti ii1OAc32OH41Orf25OCS2MeivTHPO49i) Na, Et0H ii) Ac20 iii) Cr03, AcOH iv) 10% KOHv) DHP, Fl+ vi) Li1JH4 vii) CS2, CH31 viii) heati x) Al[OCH(CH3)03VviiOHent-36on remote oxidation of (+)-bornyl acetate (32) to provide 5-ketobornyl acetate (34) as akey intermediate. Replacement of the acetyl protective group with the tetrahydropyranylprotective group, reduction, and treatment with CS2/CH3I yielded xanthate 50. Afterpyrolysis and oxidation (-)-5,6-dehydrocamphor (ent-36) was finally obtained.Scheme 11The syntheses described above both involve remote oxidation of bornyl acetate(32) as a key step. Considerable experience in our laboratory has shown that this15produces 5-ketobornyl acetate (34) in variable yield.45 Separation of the desired isomerfrom the other major product, 6-ketobornyl acetate, is tedious.Recent investigations in our laboratory have resulted in the development of twoalternative synthetic routes to 5,6-dehydrocamphor (36). The first route (Scheme 12) wasbased 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-catalyzed16II Br^ Br^ HO2C52 53 36^54i) CISO3H ii) KOH, DMSO/H20Scheme 12rearrangement of (+)-endo-3-bromocamphor (55, X=Br, Y=H) to (-)-endo-6-bromo-camphor (56, X=Br, Y=H) is analogous to that reported for the acid-catalyzedracemization 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-6-bromo-8-deuteriocamphor (56, X=Br, Y=D).57A 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).56VVM 3,2 Me5 51 6,2 HOH^3,2 Me^OHX XVVMx- H*Scheme 13(-)-endo-6-Bromocamphor (53) was dehydrobrominated with KOH inDMSO/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-cleavagereaction that produces campholenic acid (54) as a co-product (cf. Scheme 12).17ii 0^iii^078% 78%59 60Br88%Br52Br58 IMIN•18H+Scheme 14A simple two-step synthesis of (+)-5,6-dehydrocamphor (36) is thereforeavailable, and it is also possible to obtain (-)-5,6-dehydrocamphor (ent-36) by the samesequence, 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 iseasily carried out and occurs in good to high yield (Scheme 15). In the first step of theivvi92% 91%ent-36^62^61i) 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 hScheme 15ZnBrBrH20 11OrY5Br 52Et2ZnC6I-16 heat1^[heat59synthesis addition of bromine to (+)-endo-3-bromocamphor (52) in refluxing glacialacetic acid58 provided (+)-3,3-dibromocamphor (58) in 88% yield. Subsequent treatmentwith Et2Zn in refluxing benzene59 gave cyclocamphanone (59) as a white solid in 78%yield. The spectral characteristics of cyclocamphanone (59) were identical to thosereported in the literature and the melting point is 168-169 0C (lit mp: 168-170 oC).59 Themechanism proposed59 for this reaction is outlined in Scheme 16. The reaction was19Scheme 16monitored by GC and an intermediate was seen whose retention time matched that of anauthentic sample of endo-3-bromocamphor (52). Further heating showed disappearanceof the intermediate as the tricyclic product (59) was formed, presumably via a carbeneinsertion reaction. Thus, the GC data is consistent with the proposed mechanism.59Cyclocamphanone (59) was heated at 65 0C with 48% hydrobromic acid in aceticanhydride6o to provide ow-5-bromocamphor (60) in 78% yield as a white crystallinesolid (mp: 109-111 0C, lit mp58: 110-111 0C). The position of the bromine is confirmedby the C(5) endo proton signal in the 1H NMR (400 MHz, CDC13) spectrum of 60. Asexpected, it is downfield at 4.06 ppm, due to the electron withdrawing properties of theC(5) bromine. It appears as a doublet of doublets, showing no coupling with the C(4)Hwith which it forms an angle of approximately 90 0. The C(5) endo proton does showcoupling 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 basewould result in dehydrohalogenation to provide (-)-5,6-dehydrocamphor (ent-36).However, treatment with a variety of bases resulted in enolate formation and subsequentloss of bromide to provide cyclocamphanone (59). Thus protection of the carbonyl groupwas 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 stretchwhich 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 vs1.84 ppm for C(3) endo H and 2.11-2.17 vs 2.46 ppm for C(3) ow H) than in thecorresponding carbonyl compound (60).Treatment of ketal 61 with KOH in DMSO/H20 at 100 0C provided 5,6-dehydro-camphor ketal (62) in 92% yield and subsequent hydrolysis with 1 M HC1 in acetonegave (-)-5,6-dehydrocamphor (ent -36) as a white crystalline solid (92% yield):[a] ^0 (c 2.10, 95% Et0H), lit [a]/%5 -735 0 (c 1.0,95% Et0H).53.54 This compoundwas identical in all respects to (+)-5,6-dehydrocamphor (36) prepared via the two-stepsynthesis (cf. Scheme 12, p. 16) except for the sign of optical rotation.2036OH6 4 /ii1.2.3: Synthesis of a Decalin System from 5,6-Dehydrocamphor (36)With 5,6-dehydrocamphor (36) easily accessible in either enantiomeric form, thenext goal was to add an allcenyl unit to the carbonyl group in this compound and toinvestigate the subsequent anionic oxy-Cope rearrangement of this product (Scheme 17).21 OH OH•■•66 0-MM.i) L1C7---CCH2OLi , THE , -78° - AT, 76%^ii) LiAIH4 , THF , 40°, 1 h, 85%iii) KH , THF ,40° , 15 min, 85%Scheme 17The dianion of propargyl alcohol, formed by addition of n-BuLi at -78 0C inTHF61 was added to (+)-5,6-dehydrocamphor (36) to give alkyne diol 63 as a whitecrystalline solid in 76% yield. Reduction of 63 using LiA1H4 in THF62 afforded trans-alkene diol 64 as a white solid in 85% yield. This compound was quite insoluble incommon organic solvents such as Et20 and CHC13; however, its 1H NMR spectrum wasobtained as a solution in CD3CN. The 1H NMR (400 MHz, CD3CN) spectrum of 64supported the reduction of the alkyne to the allcene; however, the signals due to the vinylprotons of the newly formed alkene overlapped with the C(6) vinyl proton signal. Thatthe reduction had occurred trans and not cis could not be proven at this point. In laterexperiments, however, alkene diol 64 was derivatized and X-ray crystallographicevidence supported the irans stereochemistry (see p. 54).Treatment of alkene diol 64 with excess KH in THF at 40 ciC resulted in facileanionic oxy-Cope rearrangement to give hydrindenone 66 in 85% yield. The relativestereochemistry of the product was confirmed by X-ray crystallographic analysis of alater derivative (see p. 54). It was predicted at this point, however, based on thepresumed trans-geometry of the alkene diol and the stereospecificity of the concertedanionic oxy-Cope rearrangement. Therefore, the ring junction hydrogens were assumedto be is and the C(9) hydroxymethylene substituent to be equatorial (trans to the ringjunction protons). Ring expansion of hydrindenone 66 to decalin intermediate 69 wasaccomplished 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, refluxScheme 18Thus protection of the hydroxyl group in 66 to provide acetate 67, followed byozonolysis and reductive work-up provided keto-aldehyde 68. Subsequent treatment withp-Ts0H•H20 in refluxing benzene resulted in acid-catalyzed aldol condensation toprovide enone 69. The structure of 69 was confirmed by the presence of IR carbonylabsorptions 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 theabsence of the original vinyl proton (5.17 ppm in the acetate 67) and the appearance of2271^ 720new 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 thehydroxymethylene group at C(9). As a result we concluded that enone 69 could be apotentially useful intermediate in terpenoid synthesis. A missing structural feature,however, is the C(10) angular methyl group and our next objective was, therefore, tointroduce, stereoselectively, a C(10) angular methyl group into enone 69.1.2.4: Angular Functionalization Approaches1.2.4.1: Hydroxyl-directed CyclopropanationTraditional approaches to introducing an angular methyl group in the synthesis ofterpenoids have often included elaboration of the 10-methyldecalin system (cf. 72) byRobinson annulation63 or modifications thereof.64Other approaches have also been explored. One of these involves cyclo-propanation reactions, and the subsequent opening of the cyclopropane ring provides amethyl group.65 For example, such a sequence was used in a reported synthesis of 10-epi-testosterone (77)66 (Scheme 19).Classical Simmons-Smith conditions67 were used to cyclopropanate 73 andprovide intermediate 74. The stereochemistry of the cyclopropane ring in 74 derives237 7^7 6Scheme 19from the established tendency for allylic and homoallylic hydroxyl groups to direct themethylene carbene attack on the double bond so that the cyclopropane ring is formed ciato the directing group.68 Not only can an allylic or homoallylic hydroxyl substituent actas a directing group, it also enhances the rate of the cyclopropanation,69 and often may benecessary for reaction to occur at 01.70 Oxidation of 74 followed by removal of theprotective group produced intermediate 76. Treatment of 76 with base resulted inremoval of a C(4) proton with subsequent opening of the cyclopropane ring and led to theformation of 10-epi-testosterone (77).A second example of a base-promoted cyclopropane ring opening to provide anangular methyl group is shown in Scheme 20.71 In this work, isomeric cyclopropylalcohols 78 and 80 were both prepared. Treatment of 78 (which has the C(2) hydroxylgroup cj to the cyclopropane ring) with KOBut in HOBut and DMSO gave 79 in highyield. 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 adjacentto the cyclopropane ring, in some cases, may not be enough for base-promoted ring24KOButHOB utDMSOHO HO25KOButHO„,HOButDMSO81Scheme 20opening to occur. A hydroxyl group homoallylic to the double bond from which thecyclopropane 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 groupinto enone 69 was based on this methodology (Scheme 21). Thus we considered thatdeconjugation of the C(1)-C(2) enone double bond in 69 to the C(1)-C(10) positionfollowed by cyclopropanation directed by homoallylic oxygen substituents at C(3) orC(11) would provide intermediate 83. Subsequent cleavage of the cyclopropane ring in83 could then provide the required angularly methylated intermediate 84.By analogy with the related studies in the steroid area (Scheme 20)71 we alsoassumed that the hydroxymethyl group at C(9) could assist in the base-promoted ringcleavage reaction. Evaluation of this general approach to angular methylation is outlinedin Schemes 22 and 23.OAc^ HO268 4^ 83Scheme 21Thus treatment of enone 69 with ethylene glycol and p-Ts0H-F120 in refluxingbenzene for 45 minutes provided the monoketalized acetate 85 in 77% yield. Furthertreatment with ethylene glycol and p-Ts0H-1-120 in refluxing benzene overnight provideda mixture of diketal-acetate 86 and diketal-alcohol 87 in 37% and 48% yieldsrespectively. The two compounds could easily be separated chromatographically and theacetate (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 andthe 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 thedouble bond had occurred was apparent by the presence of only one vinyl proton signal at5.33 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 at3.06 ppm. This signal was absent in the spectrum of the deconjugated alcohol (87).i6 9 8586OH+8 7iiii) 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 87iii) KOH, Me0H, H20, 30 min, 95 c'/c.Scheme 22Several classical cyclopropanation reactions on 87 were attempted; unfortunately, noneyielded any cyclopropyl-containing product as determined by 1H NMR and massspectrometry. Table 3 summarizes the reagents used and products obtained. Thiscomplete lack of success was unexpected and we concluded that the reaction could beinhibited by steric effects. Examination of the structure of alcohol 87 led to thepossibility that either the p C(3) ketal substituent or the 13 C(4) methyl group may beblocking the [3 face of the C(1)-C(10) double bond and preventing cyclopropanation fromoccurring.27Table 3: Conditions used in the attempted cyclopropanation of compound 87Entry Reagents Products172 CHC13, BuN+Et3C1-, 50% Na0F1(ao complex mixture273,74 Et2Zn, toluene, CH2I2, 02 39% recovered alcohol 87and side-products367 Zn-Cu, 12, CH212, Et20 17% recovered alcohol 87and side-products475 Zn, CuCI, Et20, CH2Br2, TiC14 complex mixture8728 87-01/-Base90Scheme 2366HOCH391 92OCH3^ OCH3OCH300OCH3 H^OCH3(—9 4vi VWe decided, therefore, to remove the C(3) ketal group and use a C(3)0 hydroxylgroup to direct the cyclopropanation. For simplicity, and to check the feasibility of thisapproach, the hydroxymethyl group and the C(7) hydroxyl group obtained after reductionof the C(7) carbonyl group in 66 were protected as methyl ethers (Scheme 24).29i) 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 24For this purpose keto-alcohol 66 was treated with LiAlat in THF to give a crudediol that was converted directly to its dimethyl ether (91) using KH and MeI in an overallyield of 83%. The diastereomeric ratio resulting from the stereoselective reduction wasdetermined by 1H NMR spectroscopy to be —4:1. Based on the following analysis, themajor 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 willbe attacked by a hydride reducing agent (or other nucleophile). The first is the presenceCa attackAaof substituents which may block the approach of the hydride reagent. In our cyclo-hexanone derivative 66 these are the C(5) and C(9) axial hydrogens. If the reducing66agent 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 ana-hydroxyl group (i.e. an axial hydroxyl group upon reaction with 66). However, thereducing agent used was LiA11-14 which is relatively small, and may not be subject tosevere steric hindrance from the C(5) and C(9) axial hydrogens and therefore a secondfactor, torsional strain, must be considered.If one looks down the C(7)-C(8) bond of hydrindenone 66, one sees Newmanprojection A:30If the hydride approaches from the a face, then the new C-OH bond is formed withouteclipsing the vicinal C-H bonds (cf. B). If, however, the hydride approaches from the 13face, the new C-OH bond is formed with eclipsing of a vicinal C-H bond (cf. C) and thisresults in torsional strain. When a small reducing agent such as LiA1H4 is used, thetorsional strain factor outweighs any other factors and in cyclohexanone derivatives thisresults, primarily, in the formation of an equatorial hydroxyl group. Thus, LiA1H4reduction of ketone 66 was predicted to result in the p orientation (i.e. in the equatorialposition) of the C(7) hydroxyl group. This stereochemistry was not established at thistime since it was irrelevant to the cyclopropanation investigation. However, as thesynthetic sequence progressed and each compound was purified, the mixture ofdiastereomers became more and more enriched in the major isomer as small amounts ofthe minor isomer were separated.The dimethyl ether (91) was treated with ozone and a reductive work-up using Znand HOAc to give a keto-aldehyde intermediate which was immediately cyclized underacid-catalyzed aldol conditions to give enone 92 in 52% yield (Scheme 24, p. 29). Theenone was deconjugated as before by prolonged treatment with p-Ts0H.H20 andethylene glycol in refluxing benzene to give ketal 93 in 53% yield. The ketal could beremoved without reconjugation of the double bond by short (15 min) acid treatment at70°C to provide deconjugated enone 94 in 95% yield. Infrared spectroscopy showed theC=0 absorption to be at 1714 cm-1, which is significantly higher frequency than whatone would expect if the enone were conjugated (cf. 1679 cm-1 in enone 92). The 1HNMR (300 MHz, CDC13) spectrum of 94 showed only one vinyl proton signal at5.26 ppm due to the C(1)H and the distinctive broad singlet due to the C(10)H at3.12 ppm in the 1H NMR (400 MHz, CDC13) spectrum of enone 92 was absent. Ketone94 was reduced with LiA1H4 to give alcohol 95 in 89% yield. Based on the samerationale 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 Simmons-Smith 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 compoundwhich was probably the cyclopropanation product (96) as shown by a proton signal at0.45 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 rate31OCH3HOtoluene, 50 °COCH3^4%OCH3^ OCH3Et2Zn, CH21296accelerator).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 sterichindrance which makes the 13 face of 95 inaccessible. It is unlikely that cyclopropanationwould occur from the a face as an alternative because that face is the hindered concaveface of 95. Evidence that a small amount of cyclopropyl compound 96 was formed wasgiven by the high resolution mass spectrum of 96 which showed a parent ion peakcorresponding to compound 96 (C16H2803 Calc. Mass: 268.2038, Meas. Mass:268.2029) and the 1H NMR (300 MHz, CDC13) spectrum of 96 showed two characteristiccyclopropyl proton signals at 0.45 and 0.67 ppm.Although the cyclopropyl compound 96 was finally obtained, this route to anangular methyl group was not pursued further, due to the unacceptable yields obtained inthe cyclopropanation reactions.1.2.4.2: Radical Cyclization and y-AlkylationAnother approach to the stereoselective introduction of an angular methyl groupat C(10) involved radical cyclization. It was envisioned that the hydroxymethyl group atC(9) could be used for this purpose. It was expected that a radical intermediate such as97 (Scheme 25) could undergo radical cyclization to produce the synthetically usefulintermediate 98. Intermediate 97 would be designed such that Y=carbon or a heteroatom32CH2—Y0097such as silicon so that facile cleavage of cyclized product 98 would provide an angularly33functionalized decalin (99).8799 98Scheme 25Literature reports indicate that exo ring closure of the hex-5-enyl radical andanalogous systems is kinetically preferred over endo ring closure to give a 5-memberedring product.76,77,78BrBu3SriBu3Sn'2% Bu3Sn'b b98%With radical intermediate 97 (Scheme 25), however, the possible cyclization productswere either a 6-membered ring by exo closure or a 7-membered ring by endo closure andit was hoped that in this case a 6-membered ring would form preferentially. It isexperimentally observed in the formation of 5- and 6-membered bicyclic ring productsthat the newly formed ring junction is predominantly da.79,8° Therefore, if 6-memberedring cyclization of radical 97 could be induced, the new bond to C(10) would be expectedto be cis to the C(9) group in bicyclic product 98, i.e. the C(10) substituent would be inthe 13 orientation, as required. The carbon-centered radical is usually formed from abromide, and the two-atom chain in intermediate 97 should be such that the Y-0 bond in98 can ultimately be cleaved to give angularly functionalized decalin 99.Stork and co-workers79,81 have used compounds such as 100 and 102 and haveshown that 6-membered ring formation is possible using the acetal linkage in 102(Scheme 26).3465% 90%OEt102 CO2Me^ 103 C°2MeScheme 26More recently, Koreeda and co-workers82 have reported successful 6-memberedring formation using the bromomethyldimethylsilyl chain tethered to an allylic hydroxylgroup (Scheme 27).r\•\S i /^r^SiB0^/ ■0\./ 107OH0^0(..0 H 0%)10887( 000\,.-0 H 0E106i i i109 35:104^ 105Scheme 27The silicon tether appealed to us because it is easily cleaved, either reductivelywith TBAF in DMF/THF to give Y'=H, or oxidatively using 30% H202 and 1CF in DMFto give Y1=0H in 99 (Scheme 25, p, 33).82,83,8485 Therefore, both the possibility forintroducing an angular methyl group or an angular aldehyde existed. Although anangular methyl group is more common, some natural products exist in which this methylgroup has been oxidized. Our route is outlined in Scheme 28.i) BrCH2SiMe2CI, Et3N, DMAP, CH2Cl2, RT, 30 min, 76% ii) Bu3SnH, AIBN,C6H6, reflux, 7 h, 79%Scheme 28The diketalized alcohol (87), obtained as before (Scheme 22, P. 27) for use in thecyclopropanation work, was treated with bromomethyldimethylsilyl chloride, Et3N andDMAP 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 benzeneusing AIBN as initiator. Both concentrated conditions with rapid Bu3Stifl addition andhighly dilute conditions with Bu3SnH addition over hours were tried. In all cases, nocyclization products were detected, and only the reduction product 107 was formed in65-80% yield. The structure of the latter compound was confirmed by the presence ofone vinyl proton signal at 5.18 ppm and a singlet due to the trimethylsilyl protons at0.10 ppm in the 1H NMR (400 MHz, CDC13) spectrum of 107. A small sample of 107was treated with TBAF in THF and the product from this reaction was identical tostarting alcohol 87, further confirming the structure of 107. The fact that reduction ratherthan cyclization had occurred shows that hydrogen radical abstraction to quench theinitially formed methylene radical is faster than interaction with the double bond. Theusual source of the quenching hydrogen radical is Bu3SnH and a common solution to thistype of problem is to use high dilution techniques.86 However, these reaction conditionsalso failed to induce cyclization and therefore another source of the quenching hydrogenhad to be considered.Stork has reported that in homoallylic systems, [1,5] hydrogen atom transfer iscommon (Scheme 29).79 If compound 110, for example, is treated with Bu3SnH andAIBN, the major product is the cyclized compound 111; however, significant amounts of112 are also produced. It is believed that 112 is formed by quenching of the radical thatis initially formed at position 1, not by hydrogen radical abstraction from the Bu3SnH,but from the hydrogen that is present in 110 at position 5.36OH0RBu3SnHAIBNOEt37110 111..7rOEtHH^90% yieldcyclization product114 c02me1121Bu3SnHAIBNScheme 29In our case, this hydrogen atom source is the C(9) hydrogen. A possible solutionto the problem is to replace the C(9) hydrogen with an alkyl group; however, in view ofour general synthetic objectives, this approach was not investigated.L)CO H 0■.)^Co0■)Stork has also reported that conjugating the double bond with an ester or ketonefunctionality leads to increased yields of cyclization product and decreased yields ofreduction product (Scheme 29).79 Thus, introducing an ester group at the C(1) position ofour compound 87 may encourage cyclization. Again, however, this solution wouldinvolve too many steps to be practical.38A final solution would be to convert our homoallylic system to an allylic systemby 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 ringcyclization 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 likelybecome trigonal with subsequent loss of the initially introduced stereochemistry. OHAlthough the radical cyclization route was unsuccessful, we thought that thebromomethyldimethylsilyl group used in that approach might be useful as anintramolecular alkylating agent. An enone functionality in ring A of our decalin systemwas readily accessible to us as a result of the ring expansion sequence describedpreviously (Scheme 18, p. 22). Extensive investigations by Fleming and Paterson haveled to the recommended use of electrophiles such as 1,3-dithienium fluoroborate andchloroalkylphenyl sulfides for the y-alkylation of dienolates.87 However, even in caseswhere the yields of the y-alkylated products were reasonable, the alkylations have not11 7 118PhSCH2C1Pri2CHO91%SPh+ Pri2CHO80 20OTMS 116, 8:1^6a: 63PhSC1TMSO^V.-30%TMSOPri2CHO11 9 120, E:Z^70:30^1 2 1 SPhbeen stereoselective and few have been reported where the y position has been tertiary.Scheme 30 shows some representative examples.87Scheme 30In our work, y-alkylation at the C(10) position must be stereoselective for thisroute to be synthetically useful, as a C(10) methyl group or equivalent is tertiary andtherefore not epimerizable.39OROAc^ OHH 0122ii85III 124^123Thus we considered the possibility of achieving stereoselective y-allcylation by anintramolecular approach that involved the use of the bromomethyldimethylsilyl group in122 (Scheme 31) as a potential alkylating agent.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, ATScheme 31The monoketalized acetate 85, obtained as before (Scheme 22, p. 27), was treatedwith 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 bromomethyl-dimethylsily1 chloride, Et3N and DMAP in CH2C12. Upon treatment with base, it washoped that alkylation to compound 124 would occur. With compound 123, a-alkylationis hardly possible as the C(2) center is far from the bromomethyl terminus; however, they, or C(10), position is in reasonable proximity for a 6-membered ring to be formed. As40in the radical cyclization approach, it was assumed that if this 6-membered ring could beformed, the C(10) stereochemistry of 124 would be dictated by the C(9) stereochemistryof 123 and therefore would be 13 as desired. As before, the silicon could be eitheroxidatively or reductively removed from compound 124 to give an angular C(10)aldehyde or methyl group. Unfortunately, however, treatment of 123 with either LDA orKB 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 wereidentified, but they were not y-allcylation products, as determined by 1H NMR and massspectrometry. As a result, this approach to the introduction of a C(10) angular methylgroup was also abandoned.1.2.4.3: Anionic Oxy-Cope RearrangementA final approach to introducing an angular methyl group into our A/B decalinsystem involved a second anionic oxy-Cope rearrangement. It was previously shown inconnection 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 asimilar deconjugated derivative (125, Scheme 32), a 1,5-diene (126) would be producedwhich could potentially undergo anionic oxy-Cope rearrangement to provide 127.1 25 Scheme 3241It is expected that a small nucleophile such as vinylmagnesium bromide wouldattack 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 vinylgroup 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 newlyformed C(10) vinyl group actually originates from the A ring of 125 and therefore has 13stereochemistry.There were two concerns with this approach. Firstly, the C(3) ketone in 125 isquite hindered due to the geminal dimethyl groups at C(4). Vinyl addition could be aproblem, 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-Coperearrangements are quite sensitive to steric hindrance, and thus in a fairly substitutedcompound such as 126, the rearrangement might not occur. However, upon examiningmolecular models, it was felt that the system was only moderately hindered and that thisapproach should be attempted. An advantage of this route is that, if created, the angulargroup in 127 is vinyl and therefore has the potential of being converted to either a methylgroup, or an oxidized substituent (eg. -CHO or -CO2R). The synthetic route to therequired deconjugated enone (135) is shown in Scheme 33.The trans alkene diol (64, obtained as before, Scheme 17, p. 21) was reacted withTBDMSC1 and imidazole in DMF to give primary silyl ether 128 in 97% yield. Anionicoxy-Cope rearrangement using n-BuLi in THF at 40 °C for 15 minutes gavehydrindenone 129 in 73% yield. L-Selectride® reduction of 129 at -78 °C in THF gavealcohol 130 in 78% yield. As this hydride reducing agent is bulky, approach from the aface of the carbonyl group would be hindered by the 1,3-diaxial hydrogen atoms andtherefore addition from the 13 face would be preferred. Thus we assumed that thehydroxyl group in 130 is axial (a).42OTBDMSI vi0017:i^gi'OCH3133OTBDMSH134^ 135A "OC H3viiOH^ii/OTBDMS128OTBDMS•0li^'''" OC H3H131H129OTBDMS"OHH13064iv132i) 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% yieldvi) 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 33Protection of this hydroxyl group as its methyl ether was accomplished using KH andMel in THF at room temperature to give 131 in 95% yield. Ring expansion of compound131 using ozonolysis, reductive work-up and acid-catalyzed aldol condensation providedenone 132 in only 28% yield. The low yield of 132 was believed to be due to the acidsensitivity of the TBDMS protective group, which was partially hydrolyzed under theseconditions and caused by-products to be formed. The analogous reaction using acetate or43methyl 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 ethyleneglycol 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 ketalin 133 was removed using 1 M HC1 and acetone at 70°C, the keto-alcohol 134 wasobtained in 97% yield. Under these acid conditions, the TBDMS group was hydrolyzedcompletely; however, in this reaction no side-products were obtained and the yield wasnot adversely affected. In the last step, the primary alcohol was re-protected to give theTBDMS ether 135. Both infrared and 1H NMR spectroscopy confirmed that the doublebond was deconjugated to the C(1)-C(10) position in structure 135. The carbonylabsorption in the infrared spectrum was at 1715 cm-1, a significantly higher frequencythan that of the carbonyl absorption at 1680 cm-1 in the spectrum of the conjugated enone132. The 1H NMR (400 MHz, CDC13) spectrum of 135 showed only one vinyl protonsignal at 5.23 ppm as compared to the two downfield signals (5.97 and 6.78 ppm) seen inthe spectrum of the enone 132. Also, the characteristic broad singlet at 3.18 ppm due tothe 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 somewhatsterically hindered due to the geminal dimethyl groups at C(4), we were concerned thatdeprotonation at C(2) to form an enolate may compete with vinyl addition to the carbonylgroup. Imamoto and co-workers88 have reported improved yields of addition productswhen the Grignard reagent is complexed with CeC13. The complexed reagent hasincreased nucleophilicity and decreased basicity and therefore there is a reduced tendencyto form the enolate of the substrate ketone. Thus addition is favored, and fewer sidereactions such as reduction or condensation reactions are observed. We therefore triedthe conversion of 135 to 136 using vinylmagnesium bromide complexed to CeCI3, butfound no improvement in yield. In fact, only 6% of alcohol 136 was isolated, in addition44to 6% of starting ketone 135. Although the CeC13 methodology is useful for reactionwith highly enolizable ketones, it is also very sensitive in practice (rigorous drying of theinitial CeC13•7H20 is essential) and, in fact, led to a decrease in yield in our conversionof 135 to 136.45135^ 136^137138i) 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 daysScheme 34Anionic oxy-Cope rearrangement of 136 was attempted using the commonly usedconditions of KH and 18-crown-6 in refluxing THF. After 12 h, the only isolated productwas alcohol 137 in 16% yield. A similar reaction using KHMDS and 18-crown-6 in THFat room temperature also gave 137 in 98% yield. There was no evidence of any anionicoxy-Cope rearrangement product, as shown by the lack of a C=0 absorption in theinfrared spectrum of any side-products. Once again, it was apparent that the TBDMSprotective group was unstable and therefore attempts were made to convert the primaryalcohol (137) to its methyl ether (138) using KH and Mel in TI-IF at 0 °C. Unfortunatelythis product (138) was obtained in only 12% yield, although enough was obtained toattempt the anionic oxy-Cope rearrangement under more rigorous conditions. The yieldof 138 was not optimized; in fact, in the C(3) hydroxyl-directed cyclopropanation workdescribed on p. 29 it was found that protection of the C(11) and C(7) hydroxyl groupsearly in the synthetic sequence occurred in good yield and avoided the problemsencountered here. However, it was established that the low yield of 138 was due to sidereactions such as dimethylation, and was not due to anionic oxy-Cope rearrangementoccurring during the protection. This was confirmed by the lack of a carbonyl absorptionin the infrared spectrum of the crude reaction mixture before isolation of 138. Whilethese investigations were proceeding, COSY and NOE 1H NMR experiments were donein an attempt to confirm the assumed stereochemistries at C(3) and C(7). Bothexperiments were performed on a CDC13 solution of compound 138 using a 400 MHzspectrometer and the following structure shows the numbering used to assign protonresonances in both analyses.H13^138Table 4 shows the results of the COSY experiment. Chemical shift and protonassignments are listed in columns 1 and 2. Chemical shifts and assignments of protonscoupled to the signal listed in column 1 are shown in columns 3 and 4. Signals whichshowed no coupling, such as the geminal dimethyl groups at C(4) are omitted forsimplicity. In the case of the signal at 2.11 ppm, this was a multiplet due to threeoverlapping signals and therefore three protons are assigned to the one signal.The COSY experiment confirmed all proton assignments, although axial andequatorial C(8), C(6) and C(2) protons were not distinguished. The NOE experimentresults are shown in Table 5. The chemical shift of the irradiated signal is shown incolumn 1 with the corresponding proton assignment in column 2. Any resonance which46was affected by the irradiation is shown in column 3, with the proton assignment of thatsignal in column 4.Table 4: Results of COSY experiment done on compound 138Signal (ppm) Proton Assingment Coupled Signal(Ppm)Assignment ofCoupled Proton1.24 C(8)H 2.11 C(6)H2.51 C(9)H3.67 C(7)H1.28 C(8)H 2.11 C(6)H2.51 C(9)H1.58 C(5)H 2.11 C(6)H2.11 2x C(6)H and C(2)H 1.24 C(8)H1.28 C(8)H1.58 C(5)H3.67 C(7)H2.19 C(2)H 5.27 C(1)H2.51 C(9)H 1.24 C(8)H1.28 C(8)H3.45 C(11)H3.57 C(11)H3.45 C(1 1)H 2.51 C(9)H3.57 C(11)H 2.51 C(9)H3.67 C(7)H 1.24 C(8)H1.28 C(8)H2.11 C(6)H5.11 H(13) 5.30 H(14)6.09 H(12)5.27 C(1)H 2.19 C(2)H5.30 H(14) 6.09 H(12)6.09 H(12) 5.11 H(13)5.30 H(14)47Table 5: Results of NOE experiment done on compound 138Irradiation (ppm) Proton Assignment Enhanced Signal(ppm)Assignment ofEnhanced Signal1.24 C(8)H 2.11 C(6)H1.28 C(8)H 2.11 C(6)H3.67 C(7)H2.11 2x C(6)H and C(2)H 0.90 C(4)Me1.24 C(8)H3.67 C(7)H5.27 C(1)H6.09 H(12)2.19 C(2)H 0.90 C(4)Me1.58 C(5)H5.27 C(1)H6.09 H(12)3.45 C(1 1)H 2.51 C(9)H5.27 C(1)H3.57 C(11)H 2.51 C(9)H5.27 C(1)H3.67 C(7)H 1.24 C(8)H2.11 C(6)H5.11 H(13) 5.27 C(1)H6.09 H(12)6.09 H(12) 0.90 C(4)Me1.58 C(5)H2.19 C(2)H5.11 H(13)5.27 C(1)HOverall, the NOE experiment re-confirmed the proton assignments obtained fromboth the COSY experiment and analysis of the simple one dimensional 1H NMRspectrum of compound 138. As the C(6) and C(8) axial and equatorial protons could not48be 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) byX-ray crystallographic analysis as discussed on p. 54 and one can therefore infer that theC(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 enhancementseen 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 obtainthe 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 anNOE effect, it can be deduced that the C(2)H at 2.19 ppm must be a (pseudo-axial). TheH(12) proton on the vinyl group also experienced enhancement when the C(2) a H wasirradiated. Therefore, the vinyl substituent at C(3) is assumed to be a also. Furtherconfirmation of this C(3) stereochemistry is seen when the H(12) signal at 6.09 ppm isirradiated. The C(5)H signal showed enhancement, again suggesting that the vinyl groupat C(3) is a.With the stereochemistry at C(3) established, compound 138 was treated with KHand 18-crown-6 in refluxing xylenes. This time, with methyl ethers as the protectivegroups, no side-products were formed. Yet even after 2 days under these rigorousconditions, no anionic oxy-Cope rearrangement occurred. Starting alcohol 138 wasalmost quantitatively recovered (98% yield). Although this result was disappointing, it isknown that the anionic oxy-Cope rearrangement is sensitive to steric effects. A strikingexample of this sensitivity was reported by Koreeda and co-workers89 in their route todesmosterol. When the steroidal derivative 140 (Scheme 35) was treated with KR inrefluxing dioxane for 1 h, ketone 141 was obtained in 94% yield. The stereospecificgeneration of the 20R stereochemistry was attributed to a chair-like transition state (144).49reflux, lh94%140KH, dioxane141KH, dioxanereflux, lh143144147Scheme 35When the isomeric alcohol 142 was treated under the same reaction conditions, noanionic oxy-Cope rearrangement occurred; instead, a mixture of E and Z isomers ofenone 143 was isolated. That absolutely no anionic oxy-Cope product was obtainedwhen the Z isomer (142) was used was attributed to a quasi 1,3-diaxial interactionbetween 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 transitionstate: as the vinyl terminus approached the a face to form a bond to C(10), it would50_.10.-io^OCH3H1H OCH3H139--,,experience steric interaction with the substituents at C(5) and C(9), presumbablysufficient to prevent any rearrangement of 138 from occurring. The product (139) thatwould be obtained upon rearrangement has a 1,3-diaxial interaction between the newlyformed vinyl group at C(10) and the 0 C(4) methyl group and the interaction in thetransition state that leads to this steric arrangement may also prevent reaction of 138.As this route, also, failed to provide any angularly functionalized product, wedecided to re-direct our approach by introducing the C(10) methyl group at a much earlierstage in the synthetic sequence. This new approach will be discussed later in Section1.2.6, p. 59.1.2.5: Elaboration of A and B RingsIn the course of the angular methylation work, we also investigated thefunctionalization of positions other than the C(10) center of our decalin system.51Many natural products contain oxygen functionality at the C(1) position, as well as analkyl substituent at C(8). Therefore, another objective was to use the existing oxygensubstituents at C(3) and C(7) to introduce these functionalities.1.2.5.1 In Situ MethylationThere have been several reported examples where the enolate resulting fromanionic oxy-Cope rearrangement has been utilized to introduce further functionality. Intheir approach to the ophiobolin ring system, for example, Paquette and co-workersreported90 in situ methylation of such an enolate (Scheme 36).52Li, THF, -78 °C411■■148 149 MEVMel151 IMMI■Scheme 36Treatment of ketone 148 with the lithium anion generated from 1-bromocyclo-pentene at -78 0C in THF resulted in addition followed by anionic oxy-Coperearrangement of the intermediate alkoxide 149. That this rearrangement occurred atsuch a low temperature is attributed to a low activation energy due to the decrease in64i-41(^iiiONE,11•1••ANN157 156158OCH3154—^ —155_OCH31531IMIL-VINO152strain when the 4-membered ring is cleaved. The resulting enolate (150) was treated insitu 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) wouldprovide bicyclic ketone 155 with the required methyl group at C(8). To evaluate thisproposal the primary hydroxyl group in 64 was selectively protected using KH and Meli) 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 3753in THF at 0 0C to give methyl ether 152 in 63% yield. Upon treatment with ICH in THFat 40 0C, anionic oxy-Cope rearrangement of 152 occurred and when the rearrangementwas complete, (as indicated by TLC and GC), the reaction mixture was cooled to -78 °Cand Mel was added. The product of this reaction was obtained in 92% yield and ourinitial assumption was that the expected product 155 had been formed. That methylationhad 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 madeproof of the position of the new methyl group difficult via NMR techniques such as NOEand COSY experiments. Therefore, the methylated ketone was stereoselectively reducedto a crystalline alcohol using L-Selectride® in THF at -78 °C. Subsequent X-raycrystallographic analysis led to structure 158 being assigned to this compound and hencethe original ketone was assigned structure 157. This evidence established the totallyunexpected 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, butfirst it is pertinent to point out that the structure of 158 confirmed assumptions previouslymade (cf. p. 22) about stereochemistry of the product in our anionic oxy-Coperearrangements. Thus it was originally postulated that as a result of the anionic oxy-Coperearrangement of 152 the ring junction in the product 157 would be g. Furthermore, ifthe alkene diol 64 was trans (as predicted from the LiA1H4 reduction of alkyne 63 shownin Scheme 17, p. 21) then the hydroxymethyl group at C(9) would be trans to the ringjunction hydrogens. Finally, reduction of the carbonyl at C(7) in 157 was predicted togive a C(7) a (axial) hydroxyl group in 158 since L-Selectride® is a bulky hydridereducing agent. All of these assumptions were validated by the X-ray crystallographicanalysis of 158.That the methylation occurred at the C(6) and not the C(8) position in 157suggests that the enolate resulting from anionic oxy-Cope rearrangement (154)equilibrated to 156 before alkylation occurred (Scheme 37). Such an isomerization,54iMe0160ii162 1=1■••AIIIMMINNI 161although unusual (and unknown to us at the time), is not unprecedented. In theirapproach to forskolin, for example, Paquette and co-workers have reported a similarresult (Scheme 38).9155i) KH, THF, RT, 60 min; 18-cr-6, 70 °C, 20 minii) PhSeCI, -78 °C, lh, 79% (from 159)Scheme 38Upon treatment with KH and 18-crown-6 in refluxing THF, alcohol 159underwent anionic oxy-Cope rearrangement to provide intermediate 160. In situtreatment with PhSeC1 at -78 0C provided 162 in 79% yield. The position of the PhSe-substituent at C(6) in 162 rather than at C(8) shows that enolate 160 must haveisomerized to enolate 161.Another example of enolate isomerization was reported by Evans and Golob.6 Inthis first report of anionic oxy-Cope rearrangement, the enolate resulting fromrearrangement of 163 was trapped as its enol silyl ether using TMSC1 (Scheme 39).OHKH, TFIFRT, 20 h163Me0Me0A165+HH167OTMSOTMSTMSC1TMSC1Me0Me0 :H166Scheme 39In this case, the enolate did not isomerize completely, but a 1:9 mixture ofisomers 165:167 was obtained. The minor isomer (165) is the one actually derived fromthe initially formed enolate (164) of the anionic oxy-Cope rearrangement, and the majorisomer (167) was derived from the isomerized enolate (166).It is generally assumed that for an enolate to isomerize, a proton source must bepresent so that the parent ketone is formed. Subsequent loss of a proton to form thethermodynamically more stable enolate can then occur. In all the reported examples, apossible proton source is the starting alcohol if the rearrangement is faster than initialdeprotonation. To our knowledge, no examples of enolate isomerization have occurredwithout an alcohol as the starting material. For example, anionic oxy-Cope56rearrangement can occur after nucleophilic addition to a ketone, such as described onpage 52. In cases such as this, where the starting material is a ketone and the source ofthe alkoxide is not deprotonation of an alcohol, no isomerization occurs. Our own workin the in situ rearrangement of an alkoxide derived from Grignard addition to 5-methyl-5,6-dehydrocamphor (178) is discussed in Section 1.2.6.2 (p. 64). Trapping of theenolate in this case showed no evidence of isomerization and this supports the theory thata proton source such as an alcohol is necessary for enolate equilibration to occur.1.2.5.2: C(1)-Oxygenation of Ring AIn 1989 Ayer and Craw92 reported the isolation and structural elucidation ofseveral 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 tointroduce oxygen functionality at C(1). This was accomplished by the followingsynthetic sequence. Enedione 69 was monoketalized and the acetate protective groupremoved 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 hgave 168 in 99% yield. Epoxidation of the A ring enone was accomplished usingalkaline H20293 in Me0H. Epoxide 169 was obtained in 80% yield and its structure wassupported by the carbonyl absorption at 1705 cm-1 in its infrared spectrum which was atsignificantly 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 weresignificantly more upfield than in the 1H NMR (400 MHz, CDC13) spectrum of enone168 (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), asexpected. Epoxide 169 was opened using NaSePh which was generated in situ from57OTBDMS1 ivOTBDMSvi170 ,,,,,#OTBDMSHO,MS0^9H 0173174176, R1 =OH, R2=H, 3a-hydroxyoreadone177, R1=H, R2=CHO, 0-formyloreadone16811 OH^ OTBDMS69171i) 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 40PhSeSePh and NaBH4 according to the method of Sharpless and Lauer." The use of thisreagent for the reduction of a,13-epoxyketones was first reported by Yoshikoshi and58co-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 unstableketo-alcohol (170) was immediately protected using TBDMSOTf and 2,6-lutidine inCH2C12 to give the silyl ether 171 as a crystalline compound in 50% yield. X-raycrystallographic analysis confirmed the structure of 171 and established the a C(1)protected hydroxyl group stereochemistry. Thus, it was established that the epoxidationof enone 168 occurred from the a face to give 169.Having successfully introduced oxygenation at C(1), this investigation was notcarried further. However, structural similarities between intermediates 169 and 171 andtarget structures 175-177 are obvious and it seems reasonable to assume that appropriatefunctional group transformations could lead to advanced intermediates for the synthesisof these compounds. Reduction of the C(3) carbonyl group in 171 would lead to the Aring of 176, whereas deoxygenation using classical techniques such as thioketalization96followed by Raney nickel desulfurization97 would lead to 177. The epoxide 169 could beconverted to mesylate 173 for elimination and ring opening98 to 174. Alternatively,epoxide 169 could be directly converted to 174 using a Wharton99 reaction. In additionto these transformations, the cis ring junction of our intermediates must be converted totrans, presumably via an epimerization of the C(10) proton as there exists a carbonylgroup 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 inTerpenoid SynthesisSince we were unable to angularly functionalize the decalin system obtained afterour initial anionic oxy-Cope rearrangement, we decided to introduce the methyl groupmuch earlier in our sequence. Our overall synthetic plan (Scheme 41) remained similarto our orignal route to a decalin system; however, the methyl group which would59ultimately become the C(10) methyl group in the decalin system (181) would originatefrom the camphor derivative (178) which would be the precursor to the 1,5-diene (179)used in the anionic oxy-Cope rearrangement.60 25 178RO 111RO182^181^ 180Scheme 41The 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-methy1-5,6-dehydrocamphor (178) must have the absolute configuration shown in Scheme 41. Asbefore, formal addition of an appropriately substituted alkene to 178 would provide a1,5-diene (179) which has the potential of undergoing anionic oxy-Cope rearrangement toprovide 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 alkene179 must be cis. It was proposed that if the anionic oxy-Cope rearrangement of 179 to180 were successful under these steric requirements, the hydrindenone 180 would beexpanded to a decalin such as 181 using the ozonolysis, reductive work-up and acid-catalyzed aldol condensation sequence described earlier. Finally, the ring junction would59cf Scheme 15, p.18 C0vi61IIviibe converted from gia to trans; the C(5) proton could presumably be epimerized via anenone 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-dehydro-camphor (178) and this was accomplished by the reaction sequence shown in Scheme 42.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%61Scheme 42Co =187raQ-5-Bromocamphor ketal (61) was obtained from commercially available (+)-endo-3-bromocamphor (52) in 4 steps as previously outlined in Scheme 15, p. 18. Amodificationloo of the Komblum101 oxidation using AgBF4 and DMSO followed by Et3Ngave 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 DMSOoxidations such as the Swern102 oxidation, then one can assume that an intermediate ylide(187) is formed (Scheme 43).bI ....: ,) 1^SIH^H _ CH2'■^b187b 1CO C1//'Scheme 43Subsequent 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 twocompounds were formed in a 1:1 ratio, both protons must be equally accessible. Theby-product 184 was easily recycled, however, to eILQ-5-bromocamphor ketal (61). Acidhydrolysis of the ketal in 184 provided cyclocamphanone (59) quantitatively. el_Q-5-Bromocamphor ketal (61) was originally synthesized from cyclocamphanone (59) byhydrobromic acid ring opening to give 60 and ketalization to give 61 as shown previouslyin Scheme 15, p. 18.62The structure of ketone 183 was supported by the infrared spectrum whichshowed 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 adistinctive 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 bromine-containing fragments, and the high resolution spectrum showed the exact mass of theketone 183 as expected (Calc. Mass: 210.1256, Meas. Mass: 210.1259).Ketone 183 was treated with trifluoromethanesulphonic (triflic) anhydride and2,6-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 the1H NMR (400 MHz, CDC13) spectrum showed a characteristic vinyl proton singlet at5.34 ppm due to the C(6) proton.Enol triflate104 185 was coupled with Me2CuLi (prepared in situ fromCuBr•DMS and MeLilo) and 5-methyl-5,6-dehydrocamphor ketal (186) was obtained in93% 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 wasalways contaminated with a small amount (-5%) of 5,6-dehydrocamphor ketal (62),resulting from protonation of the intermediate in the coupling reaction. We have noexplanation for this result, but found that optimum conditions for the preparation ofmethylated 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-methy1-5,6-dehydrocamphor (178) in 95% yield. Due to the presence of a small amount of (+5,6-dehydrocamphor (ent-36) (not separable from 178), an accurate specific rotation for 178could 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 couldoccur, and since the starting material (52) is enantiopure, one can assume that the63•Ms178 —^188CH2=C(CH3)MgBr^7.-THE, AT, 2 h•=1,OMH30+85%H189.-^ —190(-)-5-methyl-5,6-dehydrocamphor (178) has a similar enantiomeric purity. Noexperiments were done, however, to confirm this. It should be noted that theenantiomeric starting material, (-)-endo-3-bromocamphor (ent-52) is also commerciallyavailable and therefore a route to ent-178 also exists.1.2.6.2: Isopropenyl Addition to 5-Methyl-5,6-dehydrocamphor (178) and AnionicOxy-Cope RearrangementOur initial objective was to add a simple alkenyl unit to (-)-5-methyl-5,6-dehydro-camphor (178) and to determine whether anionic oxy-Cope rearrangement would occur.The Grignard reagent of 2-bromopropene was made and added to (-)-5-methyl-5,6-dehydrocamphor (178) at room temperature (Scheme 44). The reaction was monitored64i reflux, 5.5 hScheme 44by GC, and when addition was complete (after 2 h), the mixture was refluxed for anadditional 5.5 h. This resulted in in situ anionic oxy-Cope rearrangement of alkoxide188, and bicyclic ketone 190 was obtained in 85% yield. Since protonation of theinitially formed enolate 189 could occur from either face, 190 was obtained as a mixtureof diastereomers at the C(8) center. The 1H NMR (400 MHz, CDC13) spectrum of 190showed the diastereomeric mixture to be 1:1. Evidence that rearrangement had occurredwas a single vinyl proton signal for each diastereomer (5.18 and 4.95 ppm) as well as adoublet due to the newly introduced C(8) methyl group (1.01 and 1.03 ppm). Theangular methyl group was also apparent (1.28 and 1.20 ppm) as well as the vinyl methylgroup (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 throughthis route, ring expansion to a decalin (191) was performed (Scheme 45). Hydrindenone190 was subjected to ozonolysis, reductive work-up and acid-catalyzed aldol conden-sation to provide enone 191 (also a mixture of diastereomers) in 59% yield. Absorptionsdue to both saturated (1709 cm1) and a43-unsaturated (1673 cm-1) carbonyl groups wereapparent in the infrared spectrum of 191, and the 1H NMR (400 MHz, CDC13) spectrumshowed 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 inring A was first protected via the following sequence. Selective ketalization of thecarbonyl group in ring B was accomplished using ethylene glycol and p-Ts0H•H20 inrefluxing benzene for 1 h. The ketal 192 was isolated in 70% yield and infraredspectroscopy established that the a,13-unsaturated carbonyl group in ring A was stillpresent (1671 cm-1) and that the carbonyl group in ring B was absent. Dissolving metalreduction106 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 anyvinyl proton signals, indicating that 1,4- and not 1,2-reduction had occurred. As thereduction was done in the presence of a proton source (Et0H) it was expected that theinitially formed enolate would be protonated to give a ketone which would be subject to65•■••■■■)11■■190Me0 Me019119566IIivHO193Me0 Me0196^ 197i) 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 45further reduction to provide the alcohol 193. A broad 0-H absorption (3615 cm-1) in theinfrared spectrum of 193 and the lack of a carbonyl absorption confirmed that completereduction had occurred. Protection of the hydroxyl group in 193 using KR and Me! inTHF gave the methyl ether 194 in 94% yield. The 1H NMR (400 MHz, CDC13) spectrumof 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 metalreduction had not occurred stereoselectively. However, no attempt was made to separatethe diastereomers since the C(8) center would later become trigonal in the syntheticsequence and the stereochernistry at C(3) was not relevant to subsequent functional grouptransformations. Hydrolysis of ketal 194 using 1 M HC1 and acetone at room temperaturefor 1 h provided ketone 195 in 91% yield.Compound 195 is a potentially useful decalin intermediate in terpenoid synthesisas it contains oxygenation at C(3) and C(7), an angular methyl group at C(10), gerninaldimethyl groups at C(4) and a methyl group at C(8). However, its potential could only berealized if it possessed a 13 C(9) substiutent which could be used in the elaboration ofsesquiterpenoids, diterpenoids or triterpenoids. We believed that such a group could bestereoselectively introduced via conjugate addition to an a,13-unsaturated ketone, andtherefore 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. Thisproduct (196) was not purified, but was used directly in the next reaction. However, the1H NMR (400 MHz, CDC13) spectrum clearly showed the loss of the C(8) methyl doubletwhich was at 0.96 ppm in the spectrum of starting ketone 195 and showed a singlet at1.53 ppm due to the C(8) methyl group which is vinyl in 196. A singlet due to thetrimethylsilyl protons was also obvious at 0.18 ppm. Compound 196 was treated withPhSeC1 at -78 0C in THF for 1.25 h. The reaction was monitored by TLC and when allstarting enol silyl ether was absent, the a-phenylseleno ketone intermediate was oxidizedin situ by treatment with H202, H20 and HOAc. Warming to room temperature causedelimination of the phenylselenoxide to provide enone 197 in 58% yield. The structure of197 was confirmed by infrared and 1H NMR spectroscopy. The infrared spectrum of 197showed 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 at67C(9). Such transformations have been extensively investigated on similar systems.1°9.110For example, Kutney and co-workers109 have reported successful vinyl addition to 198 toprovide 199 in 70% yield (Scheme 46).68 198 199202i) 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 46The stereochemistry at C(9) in compound 199 was predicted to be 0 based onconformational analysis and 1H NMR spectroscopy confirmed that this was indeed thecase. Subsequently, a C(8) methyl group was introduced by alkylation of the kineticenolate generated with LDA to give 200. Initially a mixture of diastereomers, compound200 was epimerized using KOH and Me0H to give the isomer shown in an overall yieldof —65%. The cis ring junction in 200 was converted to trans by conversion to the enone201 and subsequent dissolving metal reduction to give 202.As our own compound 197 was very similar to 198, it is expected that thereactions done by Kutney and co-workers would yield similar results on our system;i178.4111F.....+204^ 203therefore, we did not pursue this route any further. However, having established thataddition of propeny1-2-magnesium bromide to (-)-5-methyl-5,6-dehydrocamphor (178)and subsequent anionic oxy-Cope rearrangement occurred readily, we decided to use theenolate generated from the anionic oxy-Cope rearrangement (189) to introduce a ring Benone at this stage, and to investigate conjugate additions to this hydrindenone (203,Scheme 47).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 47The Grignard reagent of 2-bromopropene was freshly prepared, added to(-)-5-methyl-5,6-dehydrocamphor (178), and subsequent heating resulted in anionic oxy-Cope rearrangement as before. Instead of quenching the resulting enolate (189) by theaddition 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 cooledto 0 °C and the intermediate oc-phenylseleno ketone was oxidized with H202, HOAc andH20. Warming to room temperature caused elimination to provide enone 203 as amixture of exo-and endocyclic double bond isomers as determined by 1H NMRspectroscopy. The mixture was purified by column chromatography to give the mixture69of isomers (203) in 75% yield. Treatment with 6 M HC1 and acetone at 70 0C for 30minutes caused isomerization to the thermodynamically more stable endocyclic isomer(204) which was isolated in 60% overall yield. Infrared spectroscopy showed a carbonylabsorption 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 vinylmethyl groups (1.63 and 1.72 ppm) and three tertiary methyl groups (0.76, 1.00 and1.24 ppm) were also observed.The cis hydrindenone 204 can exist in either conformation A or B. One might70 10-expect conformation B to be favored over A because in B the smallest of the 6-memberedring substituents, a hydrogen atom, is in the axial position and the largest, a tertiary alkylsubstituent, is in the equatorial position. However, although the large tertiary alkyl sub-stituent is in the axial position in A, there are no 1,3-diaxial interactions because the 3positions with respect to that center are trigonal. The doublet due to the C(1) proton inthe 1H NMR specturm of 204, however, showed a coupling constant of 1 Hz which issuggestive of W coupling with the proton at C(5). This W coupling is only possible inconformation B and therefore it is likely that conformation B is preferred. In bothconformations A and B, however, the bottom (a) face is concave due to the cis ringjunction and therefore it is assumed that the top (f1) face is more accessible. Thus it waspredicted that conjugate addition to the enone (204) would occur from the top face to givestereochemistry at C(9).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 inthe presence of TMSC1 which accelerates the rate of reaction and often improvesyields." Treatment of enone 204 under these conditions (Scheme 48) resulted inconjugate addition and trapping of the intermediate enolate to provide enol silyl ether 205in 89% yield.71204 205III207^ 206i) 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 48The 1H NMR (300 MHz, CDC13) spectrum of 205 showed a singlet due to ninetrimethylsilyl 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) at0.93 ppm due to the newly introduced C(9) methyl group was also diagnostic, althoughthe stereochemistry of this methyl group was not determined at this stage. Treatment of205 with 1 M HC1 and acetone at room temperature for 2 h gave the correspondingketone (206) as a 2:1 mixture of diastereomers (as determined by GC) in 70% yield.Isomerization of the mixture using a 9:1 mixture of HOAc:HC1(c0nc) at 80 0C for 1 h gaveclean conversion to the single isomer 207 in 52% yield.Although we expected that the C(9) methyl group in 207 would be introducedfrom the convex (13) face of 204, analysis of the 1H NMR (300 MHz, CDC13) spectrum of207 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 favoredover conformation A since in B the largest 6-membered ring substituent, a tertiary alkylgroup at C(5) is in the equatorial position and the smallest, a hydrogen atom at C(5) is in72 "!. CHAthe axial position. Thus the severe 1,3-diaxial interactions between the C(10) methylgroup and the axial C(8) substituent and between the C(5) tertiary alkyl group and theaxial C(9) group which occur in conformation A are avoided. Furthermore, uponepimerization of 206 to 207 the C(8) methyl group is assumed to be equatorial, as shownin conformation B. The stereochemistry of the C(9) methyl group was determined usingconformation 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 constantof 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) methylgroup and a coupling constant of 13 Hz with the C(9)H. This large J=13 Hz value ischaracteristic 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. Adiaxial relationship between the C(8) and C(9) protons establishes that the C(9) methylgroup is in the equatorial (a) position and therefore conjugate addition to 204 must haveoccurred from the bottom (a) face.To be synthetically useful, we required the addition of a functionalized substituentat C(9) and therefore conjugate addition using both vinyl and cyanide nucleophiles wasattempted (Scheme 49). Treatment of 204 with Et2A1CN112 in THF at room temperature73ii 209208^210i) 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 49for 5.5 hours gave 208 in 68% yield. GC and 1H NMR spectroscopy showed that thiswas a complex mixture of diastereomers, due to conjugate addition to both faces of theenone and not just due to a mixture of epimers at the C(8) center. Evidence thatconjugate addition had occurred, however, was the presence of a characteristic nitrileabsorption (2236 cm-1) in the infrared spectrum of 208 as well as the carbonyl absorptionat 1718 cm-1 as compared to the carbonyl absorption which was at 1662 cm-1 inthe a,3—unsaturated ketone 204. High resolution mass spectrometry also confirmed thepresence of the parent mass (Calc. Mass: 231.1623, Meas. Mass: 231.1623). For thisreaction to be synthetically useful, we required predominant, if not exclusive, attack tothe 13 face of enone 204. We assumed that due to the small size of the cyanidenucleophile it did not experience much steric interaction in its attack from either side ofthe enone (204) and thus no stereoselectivity was observed. Therefore, we focussed ourattention on the conjugate addition of a vinyl group; since this was a slightly moresterically demanding group, the addition would presumably be more stereoselective.The Grignard reagent of vinyl bromide was freshly prepared and added to enone204 in the presence of both a Cu(I) species (to promote 1,4 addition)113 and TMSC1 (arate accelerator).i i i Ketone 209 was isolated in 24% yield, as well as 23% starting enone204. That ketone 209 and not the corresponding enol silyl ether was isolated wasprobably due to hydrolysis of the enol silyl ether which occurred either during theaqueous work-up or upon purification by column chromatography using silica gel. Thediastereomeric mixture (209) was treated with Na0Me in Me0H to epimerize the C(8)center. Ketone 210 was isolated in quantitative yield and 1H NMR spectroscopydetermined this to be a 2:1 mixture of diastereomers. A small amount of the majorisomer was isolated and the following 111 NMR experiments were done to establish thestereochemistry at the C(9) center. It was possible, on the basis of chemical shift andcoupling 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) methylgroup were not distinguished, however, nor were the C(6) axial and equatorial protons.Decoupling experiments verified several of these assignments, particularly the C(8) andC(9) protons of interest, and the results are shown in Table 6:74Table 6: Results of decoupling experiments done on major isomer of compound 210Irradiation(ppm)ProtonAssignmentAffected Signal(PPIn)ProtonAssignmentChange inSignal (Hz)2.14 C(9)H 5.60 RCH=CH2 ddd (J=17, 10,12) to dd (J=17,10)4.94 H trans to dd (J=17, 2) tod (J=17)RCH=CH22.24 C(8)H mtobrm2.24 C(8)H 2.14 C(9)H dd (J=12, 9) tobr m0.95 C(8)Me d (J=7) to s0.95 C(8)Me 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. Originallya 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 thecoupling 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 constantas large as 12 Hz suggests coupling between two axial protons. Therefore, we concludedthat the C(8) and C(9) protons were trans with respect to each other. Upon examining thetwo possible conformations of a QL hydrindenone such as 210, we again assumed thatconformation B is favored over A and the rationale is analogous to that already discussedfor compound 207 (p. 72). As we concluded from the coupling constant between theC(8) and C(9) protons, the C(9) proton is axial (f3), and therefore, conjugate addition ofthe vinyl group occurred predominantly from the a face of enone 204. Having someevidence for the stereochemistries at C(8) and C(9), the major isomer of compound 21075 76!Ais considered to have the conformation and configuration shown:210An NOE experiment was also performed on the major isomer of compound 210and it confirmed the stereochemical deductions made. The results of the NOEexperiment are shown in Table 7. Due to the stereospecificity of the anionic oxy-Coperearrangement it was known that the stereochemistry of the C(5) proton must be 0 and cisto the C(10) angular methyl group. Irradiation at the frequency of the C(5) proton signalshowed enhancement of the C(9) proton. Upon examination of possible conformations of210 it is apparent that an NOE enhancement is only likely if the C(9) proton is gia to theC(5) proton, i.e. also 0. Thus, this experiment also supported the assumption that theconjugate 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 assignedmore specifically to the C(6) 13 proton and therefore the signal at 2.51 ppm was assumedto be the C(6) a proton resonance. Irradiation at the C(8) methyl group frequencyTable 7: Results of NOE experiments done on major isomer of compound 210Irradiation (ppm) Proton Assignment Enhanced Signal(ppm)Assignment ofEnhanced Signal0.95 C(8)Me 2.24 C(8)H2.35 C(6)13H1.96 C(5)H 2.35 C(6)13H2.15 C(9)H2.15 C(9)H 5.60 RCH=CH24.94 H trans toRCH=CH22.24 C(8)H 1.07 C(4)Me0.95 C(8)Me2.35 C(6)13H 2.51 C(6)aH2.51 C(6)aH 2.35 C(6)13Happeared 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 causedenhancement 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 enone204 resulting in a stereochemistry of that group at C(9). When the nucleophile was lesssterically 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 addeven more sterically demanding groups to the C(9) center. However, a recent paper byTaguchi 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 resultsin a concave a face and a more accessible convex 13 face. However, vinyl addition to thesame enone 211 resulted in a approach to give ketone 213 with the resulting a77stereochemistry at C(9). This was attributed to the steric interaction that would be feltbetween the angular trifluoromethyl substituent and the vinyl group if it approached fromthe same ([3) side. Thus, attack by a sterically demanding group such as vinyl wasgoverned by the stereochemistry of the angular substituent whereas addition of a smallnucleophile such as cyanide was governed by the folded shape of the gia decalinstructure. Although our enone 204 was a hydrindenone with an angular methyl group asopposed to the angular trifluoromethyl containing decalin 211 shown in this example, thesame arguments apply and the experimental results are similar.78CN i ii212 211i) KCN, NH4C1, DMF ii) CH2=CHMgBr, CuIScheme 501.2.6.3: Allyl Addition to Hydrindenone 204 and Attempted Anionic Oxy-CopeRearrangementThe previously described approach to C(9) functionalization involved conjugateaddition to enone 204. Another route to C(9) functionalization would be 1,2-addition ofan ally' group to the carbonyl at C(7), followed by anionic oxy-Cope rearrangement ofthe resulting 1,5-diene (214, Scheme 51). Addition of commercially available allyl-magnesium bromide to enone 204 was complete after 30 minutes at room temperature, asindicated by GC and TLC. Heating of the intermediate alkoxide for 3 hours, however,gave no indication of any anionic oxy-Cope rearrangement occurring, therefore thereaction was quenched by the addition of water and alcohol 214 was isolated as a 9:1mixture of isomers (as determined by GC and 1H NMR spectroscopy) in 78% yield. Theiii, iii, iv or v79204 215i) CH2=CHCH2MgBr, THF, AT, 30 min; reflux, 3 h, 78% ii) KH, THF, reflux, 36 hiii) 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 hScheme 51structure of 214 was confirmed by the presence of an 0-H absorption (br, 3413 cm-1) inthe infrared spectrum and the lack of a C=0 absorption. All proton signals in the1H NMR (400 MHz, CDC13, major isomer) spectrum of 214 were identified and NOEexperiments were done to confirm the stereochemistry at C(7). The NOE results areshown in Table 8.Table 8: Results of NOE experiments done on compound 214Irradiation (ppm) Proton Assignment Enhanced Signal(ppm)Assignment ofEnhanced Signal1.90 C(5)H 5.12-5.20 C(9)H and-CH=Cf_122.23, 2.40 -CH2-CH=CH21.76 C(6)13H 5.90 -CH=CH21.90 C(5)H1.36 C(6)aH0.92 C(4)CH31.15 C(10)C113 1.90 C(5)HBased on conformational analysis of the cis fused hydrindenone system (cf. p. 70), it wasexpected that nucleophilic attack would occur predominantly from the top (f3) face ofenone 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 5.12-5.20 ppm and of the signals at 2.23 and 2.40 ppm. The multiplet was due to overlappingsignals due to the C(9)H and the terminal allyl methylene protons and therefore analysisof this enhancement is not valid as it cannot be distinguished with which of the 3 protonsthe C(5) proton is interacting. That enhancement was observed with the signals at 2.23and 2.40 ppm, however, suggests that the allyl group is syn to the C(5)H, i.e. 13, becausethose signals are assigned to the methylene protons of the allyl group. Irradiation at thefrequency of the C(6)13 H showed enhancement of the signals at 1.90, 1.36 and 0.92 ppmas could be expected. However, the most informative enhancement was seen in the signalat 5.90 ppm, which is due to the -CH=CH2 of the allyl group. This result further suggeststhat the allyl group must have been added to the 13 face of enone 204. Finally, irradiationat the frequency of the C(10) methyl group showed enhancement of the signal due to theC(5)H. While this did not give information about the C(7) stereochemistry directly, it didsupport the proton assignments that were made based on coupling constant informationfrom the one-dimensional 111 NMR (400 MHz, CDC13) spectrum of 214. All other NOEexperiment results also supported these assignments.The anionic oxy-Cope rearrangement of 214 was first attempted using thecommonly used conditions of KR in refluxing THF. The only product isolated from thisreaction was enone 204 in 30% yield. There was no evidence of any rearrangementproduct as determined by the lack of a C=0 absorption in the infrared spectrum of thecrude product. The formation of enone 204 can be explained by a retro-ene reactionwhich could occur if the alcohol (214) were not deprotonated before heating began. Weare aware of at least one similar report in the literature. Koreeda and co-workers89 found80 81214^ 204that the E isomer 140 (Scheme 35, p. 50) rearranged smoothly to give ketone 141, but theZ isomer 142 gave a mixture of isomeric enones (143). No explanation was givenregarding 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 onlyoccur if alcohol, and not alkoxide, is the reacting species, and therefore we treatedalcohol 214 with an excess of a strong, readily soluble base (n-BuLi) before anionic oxy-Cope rearrangement was attempted. Thus alcohol 214 was allowed to stand in contactwith n-BuLi for 1 hour at -78 °C, for 1 hour at 0 °C and for 2.5 hours at roomtemperature. Subsequent heating at reflux did not result in anionic oxy-Cope rearrange-ment, and starting alcohol 214 was isolated in 74% yield. That no enone 204 wasrecovered, however, supported our assumptions that a retro-ene reaction of alcohol 214had occurred previously. In a subsequent experiment alcohol 214 was treated with KRand 18-crown-6 in diglyme for 3 days at room temperature to ensure completedeprotonation, and then was refluxed for 24 hours. A complex mixture of products wasisolated, as determined by GC and TLC. None was the desired rearrangement product215, as indicated by the lack of a carbonyl absorption in the infrared spectrum of thecrude mixture. A final reaction using oxy-Cope conditions was tried. Treatment ofalcohol 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 theseinvestigations it seemed evident that neither oxy-Cope nor anionic oxy-Coperearrangement of alcohol 214 to ketone 215 was feasible.1.2.6.4: Alkynyl Addition to 5-Methyl-5,6-dehydrocamphor (178) and AttemptedAnionic Oxy-Cope RearrangementAfter the previously described initial investigations in which we determined thataddition of propeny1-2-magnesium bromide to (-)-5-methyl-5,6-dehydrocamphor (178)followed by anionic oxy-Cope rearrangement was feasible, we returned to our initialobjective of adding a more complex and therefore potentially more useful alkenyl unit to178 (cf. Scheme 41, p. 60). In particular, the allcenyl unit would be designed so that uponanionic oxy-Cope rearrangement of the intermediate alcohol (179), the producthydrindenone (180) would possess the C(9) substituent which could not be successfullyintroduced in the previously described work.82 RO 179 180Propargyl alcohol was protected as its enol silyl ether and upon treatment withn-BuLi at -78 0C for 2.75 h the resulting anion61 was added to (-)-5-methy1-5,6-dehydro-camphor (178) to provide alkyne 216 in 96% yield (Scheme 52). Subsequent reductionwith 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 adjacentvinyl proton signals suggests that the hydrogenation did occur cis as expected.Irradiation at the frequency of one of the -CH2OTBDMS protons simplified the vinylproton signal which was a multiplet to a doublet of doublets with the coupling constant83iHOII IHOiii, iv, v, vi or vii"4- -X- -220 219ix or xHOTBDMSO^217TBDMSO^216i) 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, sealedtube, 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, 5hScheme 52of 12 Hz between adjacent cis protons and the coupling constant of 5 Hz between thevinyl 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 thesubsequent C(9) center. The 1,5-diene 217 was subjected to various conditions in anattempt to effect anionic oxy-Cope rearrangement. Treatment of 217 with KH and18-crown-6 in refluxing THF for 3 hours failed to induce anionic oxy-Coperearrangement as determined by the lack of a carbonyl absorption in the infraredspectrum of the crude product mixture. The diol (219) resulting from enol silyl ethercleavage was isolated in 41% yield. Treatment of 217 with KHMDS in refluxing THFfor 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 thedesired rearrangement product 218.These discouraging results led us to believe that the basic conditions were tooharsh and caused decomposition of 217; thus we tried the rearrangement under oxy-Copeconditions using higher temperatures but no base. Heating of 217 in toluene in a sealedtube115 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 whichacts 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 thepresence of K2CO3.117 A new compound was isolated which could not be identified, butwhich was determined not to be the desired rearrangement product 218. The unknowncompound had the same molecular weight as the starting alkene 217 as determined bymass spectrometry, and it contained two carbonyl absorptions (1718 and 1663 cm-1) in itsinfrared spectrum as well as an 0-H absorption (3571 cm-1); however, 1H NMRspectroscopy established that the compound was not ketone 218. The 1H NMR(400 MHz, CDC13) spectrum of the unknown compound showed three vinyl protonsignals: 5.07 (1H, m), 5.13 (1H, br s) and 6.30 (1H, d, J=10 Hz) as compared to the onesignal expected if compound 218 had been produced. In particular, the proton signalsdownfield at 5.13 and 6.30 ppm suggest that the product is an a,13—unsaturated ketone;84this was supported by a strong carbonyl absorption at 1663 cm-1 in addition to thecarbonyl absorption at 1718 cm-1 in the infrared spectrum.To ensure that the large silyl protecting group in 217 was not interfering withrearrangement, it was removed by treatment of 217 with TBAF in THF for 15 minutes atroom temperature and diol 219 was isolated in 91% yield. The diol (219) was thentreated with KR and 18-crown-6 in refluxing THF for 47 hours; however the onlyproduct that could be isolated was recovered starting material (12%). Since anionic oxy-Cope rearrangement of 219 did not occur, the diol (219) was heated in refluxing decalinin the presence of K2CO3 under oxy-Cope conditions for 5 hours. This led to a complexmixture of products, none of which was the desired rearrangement product 220 asdetermined by infrared spectroscopy.Finally, we prepared the trans compound 222 (Scheme 53). Althoughrearrangement of the trans compound would give a and not p C(9) stereochemistry in theproduct (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 of217. Alkyne 216 was treated with TBAF in THF at room temperature for 30 minutes toprovide alkyne diol 221 in 91% yield. Treatment of 221 with LiA1H4 62 in THF at 40 °Cfor 2 hours gave trans alkene diol 222 in 31% yield. The trans stereochemistry wassupported by coupling constant evidence in the^NMR (400 MHz, CDC13) spectrum of222: the large coupling constant (J=16 Hz) of the doublet signal at 5.67 ppm due to oneof the adjacent vinyl protons (-CH=CHCH2OH) is consistent with a trans relationshipbetween these two protons. Subsequent treatment of 222 with ICHMDS and 18-crown-6at 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 acomplex mixture of products. There was no evidence for the formation of therearrangement product (223) as determined by infrared spectroscopy.85HOTBDMSO/ OH^HOiii223^ 222i) TBAF, THE, AT, 30 min, 91% ii) L1AIH4, THE, 40°C, 2h, 31%iii) KHMDS, THF, RT, 3 d; reflux, 2 dScheme 53It was evident from these investigations that the anionic oxy-Cope rearrangementis very sensitive to steric effects. Paquette and co-workers118 have extensivelyinvestigated the anionic oxy-Cope rearrangement of 1,5-dienes (cf. Scheme 54) derivedfrom bicyclo [2.2.2] octenones and these are comparable, to some extent, with the resultsdescribed 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 temperaturewhile 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 requiredrefluxing TI-IF and longer reaction time when the corresponding alkoxide was generatedin situ from Grignard addition to (-)-5-methyl-5,6-dehydrocamphor (178). The longer86ORHO64, R=H152, R=CH3128, R=TBDMSHO188OR87HO OMe^ 217, R=TBDMS226,R=TBDMS 219, R=H227,R=MOMOHHO\,--/222Scheme 54reaction time is attitributed to the steric effect of the 5-methyl substituent as well as to thefact that magnesium was used as the cation, as opposed to potassium; nevertheless yieldswere excellent. Finally, it is interesting to note that compounds 226 -228 completelyfailed to rearrange. Paquette and co-workers used KH and 18-crown-6 in both refluxing11-1F and diglyme as well as KHMDS and 18-crown-6 under identical conditions andwere only able to isolate starting material in all cases. Paquette's compounds 226 -228 aresimilar to structures 217, 219 and 222, and as discussed previously, we had a completelack of success in our attempts to effect rearrangement of these compounds using avariety of reaction conditions. It is apparent, therefore, that substitution at variouspositions of the 1,5-dienes can inhibit or completely prevent anionic oxy-Coperearrangement, and these observations have been attributed to steric effects.1.3: Conclusion5,6-Dehydrocamphor (36) can be synthesized in either enantiomeric form usingone 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 theconcerted rearrangement reaction (Scheme 55).88AM,^ 1111=1■3740^39Scheme 55Hydrindenone 38 could be easily ring expanded to the familiar A/B decalinsystem of terpenoids (39), however, the stereospecific introduction of an angular methylgroup to provide a system such as 40 eluded us. The introduction of the methyl groupwas tried using such diverse approaches as hydroxyl-directed cyclopropanation, radicalcyclization, y-alkylation and anionic oxy-Cope rearrangement. All routes relied on aC(1)-C(10) double bond as a means toward C(10) functionalization and conformationalanalysis of such systems shows that the 13 face is rather sterically hindered. It wasattempted to alleviate some of these steric interactions by removal of, for example, a13 C(3) substituent; in the case of y-alkylation, the dienolate ion generated in ring A of anenone such as 39 flattens the A ring considerably. However, the 13 C(4) methyl groupmay well have been the major contributor to steric hindrance at the C(10) center, and ofcourse, removal of this substituent is not feasible. Future investigations in this area couldinvolve the introduction of the angular methyl group utilizing a C(10)-C(9) double bondin ring B; however, this would involve losing the C(9) stereochemistry which wasoriginally introduced stereospecifically, and therefore such a route did not appeal to us.We did, however, develop an enantiospecific route to (-)-5-methy1-5,6-dehydro-camphor (178) which via a similar synthetic strategy to that outlined for 5,6-dehydro-camphor (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-dienederivative (188) of (-)-5-methyl-5,6-dehydrocamphor (178) occurred readily to givehydrindenone (190) which was expanded to decalin 197. Conjugate addition to enone197 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 successwere achieved. Thus, the 1,5-dienes 217 and 219 were prepared. Anionic oxy-Coperearrangement of 217 and 219 would provide hydrindenones 218 and 220 respectivelywhich contain both the angular methyl group and a C(9) substituent; however,891 7 8URO^217, R=TBDMS219, R=H90188OR g0^Me0H218, R=TBDMS220, R=H197Scheme 56rearrangement could not be induced under a variety of conditions. This lack of successwas attributed to steric interaction between the C(5) methyl group and the CH2ORsubstituent in dienes 217 and 219, and these results are consistent with reports byPaquette and co-workers118 who studied similar systems. Therefore, future work wouldprobably focus on the simpler system which provided hydrindenone 190 and goals wouldinclude more diverse functionalization of 190 than was achieved in the work described inthis thesis. There is no doubt that the work described in Chapter 1 of this thesis proveddisappointing; although both 5,6-dehydrocamphor (36) and 5-methy1-5,6-dehydro-camphor (178) appeared to be potentially useful chiral starting materials, it becameevident that their use in our synthetic strategy was limited due (to a great extent) to thesteric sensitivity of the anionic oxy-Cope rearrangement which was the basis for many ofour functional group transformations.Chapter 2A New Enantiospecific Synthesis of4-Methylcamphor91HO 15231, R=H232, R=Meent-25, R=H229, R=Me0ent-28, R=H230, R=Me2332.1: IntroductionAs described in Chapter 1, (+)-camphor (25) or its enantiomer (ent-25) is a usefulchiral starting material for the synthesis of natural products because it can befunctionalized at many positions. For example, (-)-camphor (ent-25) is readily convertedto (-)-9,10-dibromocamphor (ent-28) in 4 steps via a series of bromination and selectivedebromination reactions55,119 and it has been shown that ent-28 can be converted to aScheme 57trans-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 similarlytransformed to the corresponding 9,10-dibromo derivative 230, a useful route to trans-hydrindenone 232 could be realized. The latter compound (232) is a potentially usefulintermediate in the synthesis of the lanostane group of triterpenoids (cf. Scheme 58) whileits enantiomer (ent-232) derived from (+)-4-methylcamphor (ent-229) could be used togain access to the euphane group of triterpenoids. The successful outcome of this route92:HO^ HOCI^ 1:1234, lanosterol^ 235, euphol121110115232Ii18122)615ent-2321193Scheme 58is, however, initially dependent on the availability of enantiopure 4-methylcamphor(229). Camphor (25) is commercially available in high enantiomeric purity in eitherenantiomeric form and as no racemization occurs in any of the steps leading tohydrindenone 231, this product is obtained in high enantiomeric purity as well.(-)-4-Methylcamphor (229), however, must be synthesized, and no enantiospecificsynthesis has yet been reported.Literature methods120,121,122,123for the synthesis of (-)-4-methylcamphor (229) usecommercially available, enantiopure (+)-camphor (25) or (+)-fenchone (237) as startingmaterials (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 theseroutes, however, was not determined. A shorter synthesis of (-)-4-methylcamphor (229)which utilizes an acid-catalyzed rearrangement similar to those shown in Scheme 59 02379425HOAc 11-12SO4HO HOAcH2SO4OAc238^239^229Scheme 59has been developed in our laboratory (Scheme 60)124 and the mechanism of therearrangement has been thoroughly investigated.124 Conversion of (+)-camphor (25) toH2C=PPh3 HOAc OAc 1) LiAIH4H2SO4 2) PCC25^240^239^229Scheme 60(-)-2-methylenebornane (240) in excellent yield was easily accomplished using a Wittigreaction.125 Subsequent treatment of 240 with a 40:1 mixture of HOAc:H2SO4 at roomtemperature 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-catalyzedrearrangement of 240 to provide 239 is believed to occur via the mechanism outlined inScheme 61, and deuterium labelling studies have supported this mechanism.124 Althoughintermediates are represented and referred to as carbocations, they are only used as amodel to explain our results; in fact, there is evidence that exo-methylene intermediates(cf. 2421,, 243b) are involved in this rearrangement. Wagner Meerwein rearrangement ofAc0— OAc239^2446,2 HOAc— OAcent-239 95.....47 Fl+^4•A WM240^ 241^242a^*42b,13,2 gm Me243a^ 243bScheme 61241 followed by a 3,2-exo methyl shift provides 243a. A second Wagner Meerweinrearrangement occurs to give 244 and this carbocation reacts with acetate to provide(+)-4-methylisobornyl acetate (239). However, this intermediate (244) can undergo a6,2-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 andsince partial racemization could occur by the mechanism shown in Scheme 61, theenantiomeric purity of this compound was determined. The lanthanide shift reagent[Eu(hfc)3]126 and 1H NMR spectroscopy were used to determine that the enantiomericpurity of the (+)-4-methylisobornyl acetate (239) obtained in this reaction was —60%.124Thus partial racemization had occured via a 6,2-hydride shift in intermediate 244 toprovide an 80:20 ratio of 239:ent-239. The optical rotation of (+)-4-methylisobornyl21.5acetate (239) prepared via our route ([c]p +35.79,0 c 2.28, Et0H) was compared to the20rotations reported in the literature ([a]D +18.900 and +35.840)122,127,128 and confirmedthat those methods of preparation also did not provide enantiopure 239. This was notsurprising since these routes also relied on a similar acid-catalyzed rearrangementreaction where partial racemization could occur by the 6,2-hydride shift shown in Scheme61. The results of these investigations confirmed that an enantiospecific route to(-)-4-methylcamphor (229) did not exist, since the precursor to 229, (+)-4-methyl-isobomyl acetate (239), had not been obtained as an enantiopure compound.2.2: DiscussionSince (-)-4-methylcamphor (229) and its enantiomer (ent-229) are potentiallyuseful starting materials for the synthesis of triterpenoids (cf. Scheme 58, p. 93), ourobjective was to develop an enantiospecific route to these compounds. Our initialapproach was to use a camphor derivative which would undergo acid-catalyzedrearrangement to lead to (-)-4-methylcamphor (229) or its enantiomer (ent-229), butwhere the 6,2-hydride shift (cf. 244 to ent-244, Scheme 61, p. 95) is prevented orrestricted. Our first approach involved the synthesis of the thioketal derivative of 5-keto-2-methylenebornane (245, Scheme 62).96H*"OAc OAc 246 247 229Scheme 62If the acid-catalyzed rearrangement occurred as it did for (-)-2-methylenebornane(240, Scheme 61, p. 95), then intermediate 246 is analogous to intermediate 244. The59i ithioketalized intermediate (246), however, does not have a hydrogen atom that canundergo 6,2-hydride shift. Trapping of 246 with acetate would then provide enantiopure247 which could subsequently be converted to enantiopure (-)-4-methylcamphor (229).Dithiane 245 was prepared by the reaction sequence outlined in Scheme 63.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 63Thus treatment of cyclocamphanone (59) with H2504 and HOAc at 100 °C for 46 hoursresulted 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 5:1mixture 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 theacetate 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 at1747 cm-1 which was due to both the C(1) carbonyl group and that of the acetate. It wasfound 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, as97expected, and removal of the acetate group to give alcohol 249 in 89% yield. Theinfrared spectrum (CHC13 solution) of 249 showed the absence of any carbonyl peaks andthe 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 at4.66 and 4.72 ppm. In addition, the C(5) proton had shifted from 4.72 ppm in acetate 248to 3.85 ppm in alcohol 249. Swern oxidation102 of 249 provided 5-keto-2-methylene-bornane (250) in 62% yield and thioketalization using ethanedithiol and BF3.0Et2 inCH2C1296 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 duringthese transformations (4.81 and 4.95 ppm, vinyl proton signals), and also showed theexpected multiplet due to the thioketal protons (3.10-3.35 ppm). The infrared spectrumof 245 showed the loss of the carbonyl absorption that had been present at 1742 cm4 inthe spectrum of ketone 250. The yields of these reactions were not optimized as it wasfirst essential to determine whether or not the acid-catalyzed rearrangement of 245 wouldoccur.Dithiane 245 was treated with the identical reaction conditions that were used toprepare (+)-4-methylisobornyl acetate (239) from (-)-2-methylenebornane (240), i.e. withHOAc:H2SO4 (40:1) at room temperature. After 1.5 hours, no reaction had occurred andtherefore the mixture was heated at 100 °C for 2 hours. One product was formed almostexclusively, but it could not be identified. The infrared spectrum of this product showeda 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, 1.21and 1.23 ppm) and the absence of any vinyl protons which suggested that the exomethylene group in 245 had been converted to a fourth methyl group, as desired. Adistinctive 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 that98ORi or ii the harsh reaction conditions resulted in hydrolysis of the thioketal group. Thatrearrangement of 245 did not occur at room temperature suggested that the thioketalgroup was either too sterically demanding for rearrangement to occur, or else thatelectronic effects due to the sulfur atoms prevented the required Wagner Meerweinrearrangement. Reaction did occur at a higher temperature, but the product could not beidentified. It was hoped that rearrangement of a modified derivative would occur at alower temperature than was required for 245, or if a higher temperature was required, thatthe group at C(5) would be stable so that competing reactions due to the loss of that groupwould not occur. Thus ethers 251 and 252 were prepared as outlined in Scheme 64.99249^OH^251, R=Bn252, R.Mei) KH, THE, AT, 30 min; BnBr, 30 min, 84%ii) KH, THF, AT, 15 min; Mel, 15 min, 85%Scheme 64Alcohol 249 was prepared as previously described (Scheme 63, p. 97) and upontreatment with KR in TIM followed by addition of either benzyl bromide or methyliodide, 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 hadbecome —9:1 exo:endo as the minor isomer was partially separated.Treatment of benzyl ether 251 with H2SO4 and HOAc at room temperature for 1hour 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 wasdetermined that the acid-catalyzed rearrangement of substituted 2-methylenebornanes isextremely sensitive to steric and/or electronic effects, resulting in complex mixtures ofproducts which are not synthetically useful.3,2MeFl+254^255gm--4-0Ar--257Ac0258OAcOAcOAcWe 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 WagnerMeerwein rearrangement due to the electron withdrawing effects of the carbonyl group.However, since we had prepared 5-keto-2-methylenebornane (250) as a precursor tothioketal 245 (Scheme 63, p. 97), we decided to test this hypothesis by subjecting 250 tothe normal rearrangement conditions (HOAc/H2SO4).100260^ 259Scheme 65Treatment of 5-keto-2-methylenebornane (250) with H2SO4 and HOAc at roomtemperature 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 toour 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 vinylproton signals at 4.80 and 4.86 ppm led us to conclude that the product was either ketone255 or 257. NOE experiments were done to confirm that the structure was 255, and theresults are summarized in Table 9.Table 9: Results of NOE experiments done on compound 255Irradiation (ppm) Proton Assignment Enhanced Signal(ppm)Assignment ofEnhanced Signal1.07 C(9)Me 1.15 C(8)Me4.80 HB1.15 C(8)Me 2.29 C(4)H2.29 C(4)H 1.15 C(8)Me4.80 HB 4.86 HA4.86 HA 1.30 C(10)Me4.80 HBThat enhancement was seen in the C(8)Me signal when the C(4)H signal was irradiatedsuggests that the product is indeed 255 and not 257. Further evidence is provided fromthe enhancements seen when the vinyl protons HA and HB are irradiated. These resultsshow that a carbonyl group at C(5) in the 2-methylenebornane system does not inhibit thefirst 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 aproton, ketone 255 is isolated. While the synthesis of 255 was not useful in providing asynthetic route to (-)-4-methylcamphor (229) or its enantiomer (ent-229), it did suggestthat the first Wagner Meerwein rearrangement occurs readily.101HBr/HOAcCI3CCO2HHCO2H 263100% ee69% ee26211- c t3c o2At this stage we became intrigued by reports in the early literature (Houben andPfankuch, 1931 and 1933)130,131 on the acid-catalyzed rearrangement of (-)-1-chloro-camphene (261, Scheme 66). These results dramatically illustrate the differences in102OHCO0% ee264Scheme 66enantiomeric purity obtained when different acids are used. Treatment of (-)-1-chloro-camphene (261) with 45% HBr/HOAc solution gave the brominated compound262.130,131 Reconversion of 262 to (-)-1-chlorocamphene (261) showed no loss of opticalactivity; 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 reconvertedto (-)-1-chlorocamphene (261), which only showed 69% of the optical activity of thestarting 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 thatwhen formic acid was used, the product 264 was racemic.255(-)-1-Chlorocamphene (261) is structurally similar to the product (255) weobtained upon acid-catalyzed rearrangement of the 5-keto-2-methylenebornane (250). Inaddition, the carbocation intermediate 265 presumably involved in the rearrangement of261 is very similar to the intermediate 243a proposed for the rearrangement of(-)-2-methylenebornane (240, Scheme 67).103+243 aScheme 67265H+-4---cf, Scheme 66H+250240As 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 6,2-hydride shift to give 262; in pathway ii, bromide adds after 6,2-hydride shift occurs togive ent-262. In the presence of 45% HBrfflOAc, it was observed that only 262 wasformed, and this can be explained by the exclusive operation of pathway i. When an acidother than HBr is used, (eg. formic acid or trichloroacetic acid), then pathway ii competeswith pathway i: enantiomeric products result and enantiomeric purity is lost or decreased.Based on these results, we decided to investigate the rearrangement of (-)-2-methylene-bornane (240) using 45% HBr/HOAc instead of H2SO4 and HOAc as we had usedpreviously.C I262I I I^I I I262^ ent-262Scheme 68(-)-2-methylenebomane (240) was prepared in 87% yield133 by reaction of(+)-camphor (25) with the Wittig125 reagent prepared from methyltriphenylphosphoniumbromide (Scheme 69). Upon treatment of 240 with a 45% solution of HBr in HOAc for5 minutes at room temperature,130.131 a single product was obtained in 87% yield, whichwas 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 ppmdue to the C(2) endo proton. As this compound (266) was not reported in the literature10445, II Br10525^240^ 266i) CH2=PPh3, THF, 24 h, 87% ii) 45% HBr/HOAc, RT, 5 min, 87%Scheme 69and no specific rotation was available for comparison, the enantiomeric purity was notdetermined at this stage, and it was converted to the known compound (+)-4-methyl-isoborneol (267) (Scheme 70). The bromide (266) was found to discolour upon storage OHII266^267 (m OH)^ 229268 (0112.1 OH)i) Mg, THF, RT, 30 min; 02, 1.5 h, 40% ii) Cr03, H2SO4, acetone, H20, RT, 1h, 97%Scheme 70and therefore it was always freshly prepared, purified by column chromatography andimmediately used in the next reaction to provide alcohols 267 and 268. Grignard reagentformation from the bromide 266 followed by reaction with oxygen provided a 1:1mixture of exo and endo alcohols 267 and 268 in 40% yield. Although conversion ofbromide 266 to the corresponding Grignard derivative is slow, satisfactory results (for thepurpose of determining enantiomeric purity) were obtained when the Grignard reactionwas performed under concentrated conditions (-1 M) with rapid addition of the bromideto freshly ground magnesium in dry THF. Attempts to increase the yield of theconversion of 266 to 267/268 are currently being investigated in our laboratory; othersources of oxygen such as Mo05•py-HMPA134 or (camphorylsulfonyl)oxaziridine135willalso be investigated. That a mixture of isomers was obtained in this reaction did notmatter, since the mixture of epimeric alcohols was subsequently oxidized to (-)-4-methyl-camphor (229). Careful column chromatography of the mixture of isomers, however, ledto the separation of (+)-4-methylisoborneol (267) so that its enantiomeric purity could bedetermined. 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 avery high enantiomeric purity. Table 10 compares literature specific rotations of(+)-4-methylisoborneol (267) with those obtained for the alcohol prepared by our newroute. It should be noted that entries 1-3 are rotations that were taken for three differentsamples of 267 prepared by acid-catalyzed (45% HBr/HOAc) rearrangement of(-)-2-methylenebomane (240). These results indicate that the rotation is consistentregardless of slight variations in reaction time or temperature and thus the high specificrotations are a result of the acid catalyst used and are also reproducible.Table 10: Specific rotation of (+)-4-methylisoborneol (267)Entry Specific Rotation [a]l) T (0C) Reference1 +32.9 0 (c 2.7, 95% EtOH) 252 +32.9 0 (c 8.1, 95% Et0H) 263 +33.0 ° (c 3.1, 95% EtOH) 254 +25.200 (c 10.0, Et0H) 20 1215 +14.80 20 1276 +22.69 0 (Et0H) 20 1227 +19.5 0 (c 10.00, Et0H) 30 124Based on the high specific rotations obtained for alcohol 267, we believed that thealcohol synthesized via 45% HBr/HOAc catalyzed rearrangement of (-)-2-methylene-106bornane (240) was of very high enantiomeric purity, and we performed additionalanalyses to confirm this.It was found that a Chirasil-val III column (Alltech, 25 m x 0.25 mm i d) wasable to separate (+)-4-methylisoborneol (267) and (+4-methylisoborneol (ent-267) whenan 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(bocf4D +20.9 0, c 9.4, 95% Et0H, Sample A) was used as standard and it was found thattwo 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 thetwo peaks was consistent when different oven temperatures and injection volumes wereused and the results are consistent with previous determinations.124 A sample of (+)-4-methylisobonieol (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 believethat our new route provides (+)-4-methyl-isoborneol (267) that is at least 95% enantio-merically enriched. Future work may involve obtaining a chiral GC column that iscapable of better resolution of the two enantiomers (267 and ent-267) and with idealresolution 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 alcohols267 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 andacetone.136 The (-)-4-methylcamphor (229) obtained through this route showed spectralcharacteristics identical to those reported in the literature; however, its specific rotation,as expected, was higher. Table 11 (p. 109) compares the specific rotation obtained forour compound with those reported in the literature. Entries 1 and 2 are rotations taken fortwo samples of 229, both prepared via our new route but in separate experiments.107108^ Oven Temp.=60 GC0.762.1829.9030.70RT^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 A38.70^2382.27^VB^18.241Total Area= 13060.30Oven Temp.=60 cC0.7529.93RT^Area^Type^Area %^[a] +33.00, c 3.1, 95% Et0H29.93^12180.00^BH^100.00 Sample BTotal Area=10180.00Figure 1: Chromatograms obtained for Samples A and B of (+)-4-methylisoborneol(267)Table 11: Specific rotation of (+4-methylcamphor (229)Entry Specific Rotation [43 T (0C) Reference1 -27.0 0 (c 0.7,95% Et0H) 242 -26.7 0 (c 3.4,95% Et0H) 253 -14.5 0 (c 10.0, Et0H) 20 1214 -16.0 0 (c 2.00, Et0H) 21 124As for the (+)-4-methylisoborneol (267), the high rotations obtained for(-)-4-methylcamphor (229) obtained via our new route suggested that it was of highenantiomeric purity, and further experiments were done to confirm this. Unfortunately,neither of the two chiral GC columns available to us (the previously described Chirasil-val III or Cyclodex-30N, 30 m x 0.25 mm i.d., film thickness 0.25 m) were able toresolve the two enantiomers present in a test mixture of 4-methylcamphor (229) preparedby the H2SO4/HOAc catalyzed rearrangement of (+2-methylenebornane (246). Earlierstudies, however, had been done using the chiral shift reagent [Eu(hfc)3] and 1H NMRspectroscopy. 127 To a 0.1 M solution of (-)-4-methylcamphor (229) prepared via theH2SO4/HOAc route (Sample C) was added successively 0.10, 0.20 and 0.30 moleequivalents of the chiral shift reagent and a 1H NMR (400 MHz, CDC13) spectrum wasrecorded after each addition. The spectra are shown in Figure 2 (p. 110) and after a totalof 0.60 equivalents of reagent were added, a second signal due to the protons of a methylgroup in a diastereomeric species was detected. Integration of the parent signal and of theminor new signal showed a ratio of —4.3:1, and this suggests that the (-)-4-methyl-camphor (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 usedfor Sample C and 1H NMR (400 MHz, CDC13) spectra were recorded after the1090 equiv. [Eu(hfc)3]110,===zdZWglos0.1 equiv. [Eu(hfc)3]0.3 equiv. [Eu(hfc)3]0.6 equiv. [Eu(hfc)3] 4.3:10 ppm5^4^3Figure 2: 1H NMR (400 MHz) spectra after [Eu(hfc)3] addition to Sample C of(-)-4-methylcamphor (229)successive addition of 0.10, 0.30 and 0.30 mole equivalents of [Eu(hfc)3]. The spectraare shown in Figure 3 (p. 112) and comparison with those obtained for Sample C showsa similar trend in signal broadening and chemical shift change. However, Sample Dshows no extra signals that would indicate the presence of a diastereomeric species, andthus, considering the NMR detection limits, our (-)-4-methylcamphor (229) can beconsidered to be enantiopure.2.3: ConclusionA new short synthetic route to (-)-4-methylcamphor (229) has been developedwhich uses the acid-catalyzed (45% HBr/HOAc) rearrangement of (-)-2-methylene-bomane (240) as a key step. As the starting material, (+)-camphor (25), is available ineither 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 literaturesuggested that these compounds had been obtained enantiopure, and subsequent GCanalyses and NMR experiments showed no evidence of the presence of enantiomersent-267 or ent-229. The availability of enantiopure 4-methylcamphor (229) provides anopportunity to evaluate its potential as an intermediate in the enantiospecific synthesis oftriterpenoids.1110.1 equiv. [Eu(hfc)3]Figure 3: 1H NMR (400 MHz) spectra after [Eu(hfc)3] addition to Sample D of(-)-4-methylcamphor (229)112ExperimentalGeneral Experimental:All reagents used were of commercial grade and were used as received unlessotherwise specified. Reactions involving air- or moisture-sensitive reagents wereperformed 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 fromNa/benzophenone; CH2C12, C6H6, toluene, Me0H, i-Pr2NH, and diglyme were distilledfrom CaH2; pyridine and DMSO were distilled from KOH; TMSC1, xylenes and Et3Nwere distilled from LiA1H4; and DMF and quinoline were stored over 4 A molecularsieves. Absolute Et0H was obtained by refluxing 95% Et0H for 6 h over oven-driedCaO, followed by distillation. Low boiling petroleum ether (PE, bp. 30-60 0C) wasdistilled prior to use in chromatography. Aqueous solutions used in reaction work-upswere saturated unless otherwise specified and MgSO4 used as a drying agent wasanhydrous.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 mmthickness and 4.0-11.25 cm radius. Thin layer chromatography (TLC) was performed onMerck 5735 Precoated Silica Gel 60, PF254 on plastic sheets and visualization wasaccomplished using I2 vapour or an ammonium molybdate/H2SO4 spray. Gas liquidchromatography (GC) was performed on a Hewlett-Packard HP5830A instrument, usingeither a 0.2 mm x 11 m OV-101 column or a 0.25 mm x 25 m Chirasil-val III column (forthe 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 spectrophoto-meter (calibrated using the 1601 cm-1 band of polystyrene) or a Bomem Michelson 100Fourier Transform Infrared spectrometer using internal calibration. Samples were113Br 52 36prepared as neat films between NaCl plates or as solutions in NaC1 cells of 0 1 mm pathlength. 1H NMR spectra were recorded at 300 MHz on a Varian XL-300 spectrometerand at 400 MHz on a Bruker VVH-400 spectrometer and signal positions are given in ppmand are referenced to tetramethylsilane. 31P NMR spectra were recorded at 121.4 MHzon a Varian XL-300 spectrometer and signal positions are given in ppm and arereferenced to 85% H3PO4 in D20. Low resolution mass spectra were obtained using aKratos MS-80 spectrometer and high resolution mass spectra were obtained using aKratos MS-50 spectrometer. Specific rotations aap were recorded on a Jasco J-710spectropolarimeter in a 0.1 dm cell using the sodium D line (589 nm). Elementalanalyses were performed by Mr. P. Borda, Microanalytical Laboratory, Department ofChemistry, 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):114Chlorosulphonic acid (240 mL) was cautiously added to (+)-endo-3-bromo-camphor (52, 60.0 g, 0.26 mol).55 The solution was heated at 55 0C for 15 mm, thencooled 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 solidwhich was not purified. A solution of KOH (26.0 g, 0.46 mol) in water (100 mL) wasadded, followed by DMSO (600 rnL). The solution was heated at 120 0C overnight, thencooled and diluted with water (700 mL). The reaction mixture was extracted with Et200BrBr 5 2 Br 58(3x) and the combined extracts washed with brine (5x) and dried over MgSO4. Removalof 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: 150.1044Meas. Mass: 150.1036111 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-1MS: 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):Bromine (20 mL, 0.39 mol) was added dropwise over 1 h to a refluxing solutionof (+)-rado-3-bromocamphor (52, 69.2 g, 0.299 mol) in HOAc (250 mL).58 After anadditional 30 min, a second portion of bromine (10 mL, 0.19 mol) was added dropwiseover 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. Solid115NaHCO3 was cautiously added until the aqueous layer was saturated. The whiteprecipitate was dissolved with Et20 and the mixture was diluted with water. The mixturewas extracted with Et20 (3x) and the combined extracts were washed with saturatedNaHCO3(ac) solution (5x, until basic) and brine (5x). After drying the extracts overMgSO4, removal of the solvent gave an orange oil which was diluted with PE. Uponcooling, (+)-3,3-dibromocamphor (58, 63.00 g, 68% yield) was obtained as whitecrystals. A second crop of crystals yielded an additional 18.86 g (20% yield) of product.mp: 59-60 0C (lit58 64 0C)C101114079Br79BrCI 011 14079Br8 1 BrC1011140811301BrCalc. Mass:Meas. Mass:Calc. Mass:Meas. Mass:Calc. Mass:Meas. Mass:307.9411307.9417309.9401309.9385311.9381311.9379Calc.: 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-1MS: 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).116Debromination of (+)-3,3-dibromocamphor (58) to give cyclocamphanone (59):Br 0^ °ZsBr 58^ 59To 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 Themixture was refluxed for 24 h, then was cautiously poured onto ice (-100 mL). 1 M HC1was 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 overMgSO4. Removal of the solvent gave an orange solid which was purified by columnchromatography using 24:1 PE:Et20 as eluant. Cyclocamphanone (59) was isolated as awhite solid (2.21 g, 78% yield).mp: 168-169 0C (lit59 168-170 0C)C101-1140^Calc. Mass: 150.1044Meas. Mass: 150.1044Calc.: 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-1117MS: m/e(%)=150 (M+, 27); 135 (44); 121 (12); 108 (22); 107 (100).Bromination of cyclocamphanone (59) to give em-5-bromocamphor (60):11859^60To 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).60The 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 andwashed with water (2x), NaHCO3(aq) solution (2x), and brine (3x). After drying overMgSO4, removal of the solvent gave a yellow solid which was recrystallized from 4:1PE: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: 230.0306Meas. Mass: 230.0307C101-115081Br^Calc. Mass: 232.0286Meas. Mass: 232.0288Calc.: 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) endoH); 2.27 (1H, dd, J=16, 5 Hz, C(6) 02 H); 2.46 (1H, dd, J=18, 5 Hz, C(3) tl_CQ H);2.52 (1H, d, J=5 Hz, C(4)H); 4.06 (1H, dd, J=8, 5 Hz, C(5)H).IR (CH2C12): D=3058, 2969 (C-H); 1745 (C=0) cm-1MS: 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 61:11960^61To a solution of gLco-5-bromocamphor (60, 18.93 g, 81.91 mmol) in ethyleneglycol (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) anddried over MgSO4. Removal of the solvent gave a yellow solid which was recrystallizedfrom 4:1 PE:Et20. The ketal 61 was isolated as a white crystalline compound (20.72 g,92% yield).mp: 72-74 °CC12H190279Br^Calc. Mass: 274.0568Meas. Mass: 274.0569C12H 0281Br^Calc. Mass: 276.0548Meas. Mass: 276.0553Calc.: 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) endoH); 2.11-2.17 (2H, m, C(4)H and C(3) em2H); 2.61 (1H, dd, J=14, 8 Hz, C(6) Q_CQH); 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-1MS: 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):12061^ 62A solution of bromoketal 61 (0.94 g, 3.4 mmol) and KOH (1.23 g, 21 9 mmol) inDMSO (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 extractswere washed with brine (3x) and dried over MgSO4. Removal of the solvent gave5,6-dehydrocamphor ketal (62) as a pale yellow oil (0.60 g, —91% yield) which was notpurified but which was used directly in the next reaction. A small sample was purifiedfor elemental analysis by column chromatography using 9:1 PE:Et20 as eluant. The pureketal 62 was isolated as a very volatile colourless liquid.C12H1802^Calc. Mass: 194.1307Meas. Mass: 194.1315Calc.: 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);62 ent-362.37 (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-1MS: 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):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 extractedwith Et20 (3x). The combined extracts were washed with water (3x), dried over MgSO4and the solvent removed to yield a white solid. Purification by column chromatographyusing 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: 150.1045Meas. Mass: 150.10381H 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).121IR (CHC13): v=2969 (C-H); 1734 (C=0) cm-1MS: 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 63:122x...T5.0 OH36^ 63^I IOHn-BuLi (58 mL, 1.6 M/hexanes, 93 mmol) was added dropwise to a solution ofpropargyl alcohol (2.7 mL, 47 mmol) in dry THF (150 mL) at -78 0C under an Ar atmand 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 reactionmixture which was stirred for another hour before being allowed to warm to RTovernight. 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 solidwhich was recrystallized from CH2C12 to afford pure alkyne diol 63 (4.84 g, 76% yield)as a white solid.mp: 1181200CC13H1802^Calc. Mass: 206.1307Meas. Mass: 206.1300Calc.: C 75.69^H 8.79%Anal.: C 75.77^H 8.59%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-1MS: 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 64:123OH I I63 OHOHA solution of alkyne diol 63 (6.04 g, 29.2 mmol) in dry THF (50 mL) wascautiously 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 andcautiously quenched by the addition of water. 1 M HC1 was added to dissolve theresulting grey precipitate. The solution was extracted with Et20 (4x) and the combinedextracts washed with brine (3x, until neutral). Removal of the solvent gave a pale yellowsolid which was recrystallized from Et20 to afford the alkene diol 64 (5.16 g, 85% yield)as white crystals.mp: 158-161 °C124C13H2002^Calc. Mass: 208.1463Meas. Mass: 208.14591H 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{QH); 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-1MS: 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: 66A solution of alkene diol 64 (3.51 g, 16.8 mmol) in dry THF (70 mL) wascannulated into a slurry of KR (2.03 g, 50.6 mmol) in dry THF (100 mL) under an Aratm. After 15 min at 40 0C the reaction was cooled to RT, cautiously quenched byaddition 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). Dryingover MgSO4 followed by removal of the solvent gave a red oil which was purified bycolumn chromatography using 2:1 PE:Et20 as eluant. The keto-alcohol 66 was isolatedas a yellow liquid (2.98 g, 85% yield).C13H2002^Calc. Mass: 208.1463Meas. Mass: 208.1466OH^ OAc66^ 671H 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-1MS: 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: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 reactionmixture was diluted with water and extracted with CH2C12 (3x). The combined extractswere 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 columnchromatography using 4:1 PE:Et20 as eluant. The keto-acetate 67 was isolated as acolourless oil (4.17 g, 95% yield).Ci3H2002^Calc. Mass: 250.1569Meas. Mass: 250.1572125126Calc: 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^ OAc^ OAc0I HSi.67^68^69A 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 bluecolour persisted (-1 h). Excess 03 was removed by bubbling 02 through the solutionuntil 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. Themixture was filtered, washed successively with water, 5% Na0H0q) solution, water (4x,until neutral) and dried over MgSO4. Removal of the solvent yielded the crude keto-aldehyde 68 as a yellow oil which was not purified but which was used directly in thenext reaction. The IR and 1H NMR spectra were consistent with those expected for thealdehyde 68.IR (neat): u=2970 (C-H); 1735, 1715, 1705 (C=0) cm-I1H 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 keto-aldehyde 68 in dry benzene (-100 mL). The reaction was refluxed in a Dean-Starkapparatus under an Ar atm for 1 h. After cooling to RT, brine was added. The mixturewas 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 yellowliquid was obtained. The crude product was purified by column chromatography using1:1 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 formicroanalysis.C15H2004^Calc. Mass: 264.1361Meas. Mass: 264.1357Calc. 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).127IR (neat): u=3050, 2980, 2900 (C-H); 1740, 1720, 1680 (C=0) cm-I69 85OAc^ OAcMS: 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:To a solution of enone 69 (3.23 g, 12.2 mmol) in dry benzene (-100 mL) wereadded a catalytic amount of p-Ts0H•H20 and ethylene glycol (8.25 mL, 148 mmol), andthe mixture was refluxed under an Ar atm for 45 min in a Dean-Stark apparatus. Aftercooling to RT, the mixture was poured onto brine and extracted with Et20 (3x). Thecombined extracts were washed with NaHCO3(aq) solution, brine (2x) and dried overMgSO4. Removal of the solvent gave a yellow oil which was purified by columnchromatography using 2:1 PE:Et20 as eluant. The ketal 85 was isolated as a colourlessoil (2.91 g, 77% yield).Cl7H2405^Calc. Mass: 308.1623Meas. Mass: 308.16231H 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-112887OAc^ OAc0CO H 086MS: 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 87:129Ethylene glycol (3.9 mL, 70 trump and a catalytic amount of p-Ts0H.H20 wereadded to a solution of acetate 85 (1.08 g, 3.5 mmol) in dry benzene (-50 mL). Afterrefluxing under an Ar atm in a Dean-Stark apparatus overnight, the reaction was cooledto RT and poured onto brine. The mixture was extracted with Et20 (3x) and thecombined extracts were washed with NaHCO3(ac) solution and brine (2x). After dryingover MgSO4 the solvent was removed to yield a yellow oil which was purified by radialchromatography (4 mm plate) using 1:1 PE:Et20 as eluant. Two compounds wereisolated: the dilcetalized acetate 86 as a colourless oil (0.46 g, 37% yield) and thediketalized alcohol 87 also as a colourless oil (0.52 g, 48% yield).Data for diketalized acetate 86:C19H2806^Calc. Mass: 352.1886Meas. Mass: 352.18851H 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-1MS: m/e (%)=352 (M+, 2.0); 309 (30); 223 (32); 171 (81); 114(100); 86(66).Data for diketalizetl alcohol 87:Ci7H2605^Calc. Mass: 310.1780Meas. Mass: 310.17861H 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-1MS: 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< OS )0■,.0 H 0,/8 6 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 RTfor 30 min, the mixture was diluted with water and extracted with Et20 (3x). Thecombined extracts were washed with brine (3x), dried over MgSO4 and the solventremoved to provide a pale yellow oil. Purification by column chromatography using 1:1PE: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.130Attempted cyclopropanation of diketalized alcohol 87:131 -ON-87^88Cyclopropanation attempt A72:To a solution of diketalized alcohol 87 (0.115 g, 0.40 mmol) in CHC13 (2 mL) at0 °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 wasadded and the mixture extracted with Et20 (3x). Drying over MgSO4 and removal of thesolvent gave a yellow oil which was purified by column chromatography using 1:1PE:Et20 as eluant. None of the products obtained showed evidence of being a cyclo-propanation 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) followedby CH2I2 (0.21 mL, 2.6 mmol). The system was flushed with 02 and the reaction stirredat 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 ayellow oil which was a complex mixture by TLC and GC. The mixture was purified bycolumn 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 1HNMR and mass spectrometry.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 reactionwas 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 finalportion of CH2I2 (0.15 mL, 1.8 mmol) was added and the reaction was refluxedovernight. After cooling to RT, NH4C1(aq) solution was added and the mixture wasfiltered 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 recoveredstarting material as the major product (0.033 g, 17% recovery). Minor products showedno evidence of being cyclopropanation products as determined by 1H NMR or massspectrometry.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 ofdiketalized 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). Afterrefluxing for 2 h, the reaction was cooled to RT and NII4C1(aco solution was added. Afterfiltration 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 ayellow liquid which was purified by column chromatography using 4:1 PE:Et20 aseluant. Many products were obtained, none of which appeared to be cyclopropanationproducts as determined by 1H NMR and mass spectrometry.132OH^ OC H3OCH366Reduction and protection of keto-alcohol 66 to give dimethyl ether 91:To a slurry of LiA1H4 (0.12 g, 3.2 mmol) in dry THF (15 mL) at -78 0C under anAr 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 wascautiously 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 whichshowed the following spectral characteristics, suggesting that the diol was formed:C13H2202^Calc. Mass: 210.1619Meas. Mass: 210.16131H 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-1MS: 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 ofKH (0.26 g, 6.5 mmol) in dry THE (10 mL) under an Ar atm. The reaction was stirred atRT for 45 min and then Mel (0.40 mL, 6.5 mmol) was added. After stirring for anadditional 60 min, water was cautiously added, and the reaction was extracted with Et20133OCH3^ OCH3OCH3OCH391^ 92(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 columnchromatography using 15:1 PE:Et20 as eluant. The dimethyl ether 91 was isolated as acolourless liquid (0.515 g, 83% yield from keto-alcohol 66). 1H NMR spectroscopyshowed the diastereomeric mixture to be —4:1.Ci5H2602^Calc. Mass: 238.1932Meas. Mass: 238.19271H 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-1MS: 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:A solution of dimethyl ether 91 (0.91 g, 3.8 mmol) in CH2C12 (10 mL) andMe0H (10 rnL) was cooled to -78 0C and 03 was bubbled through the solution until ablue colour persisted (-45 min). Excess 03 was removed by bubbling 02 through thesolution 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 for1 h. The mixture was filtered, washed successively with water (2x), 5% Na0H(aq)134OCH3^ OCH3OCH392OCH3solution (2x), water (4x, until neutral) and dried over MgSO4. Removal of the solventgave the crude keto-aldehyde as a yellow oil which was not purified. To the keto-aldehyde in dry C6H6 (-50 mL) was added a few crystals of p-Ts0H.H20 and themixture was refluxed in a Dean-Stark apparatus under an Ar atm for 1 h. After cooling toRT brine was added and the mixture was extracted with Et20 (3x). The combinedextracts 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 chromato-graphy using 4:1 PE:Et20 as eluant. The enone 92 was isolated as a colourless oil(0.502 g, 52 % yield).C15H2403^Calc. Mass: 252.1725Meas. Mass: 252.17191H 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-1MS: 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 93:135OCH3^ OCH3 OC H3 OCH393^94A 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 Aratm in a Dean-Stark apparatus for 3 days. After cooling to RT, brine was added and themixture was extracted with Et20 (3x). The combined extracts were washed withNaHCO3(4 solution, brine (3x) and dried over MgSO4. Removal of the solvent gave apale yellow oil which was purified by column chromatography using 15:1 PE:Et20 aseluant. The ketal 93 was isolated as a colourless liquid (0.301 g, 53% yield).C17H2804^Calc. Mass: 296.1987Meas. Mass: 296.19901H 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-1MS: m/e(%)=296 (M+, 2.9); 251 (7.1); 221 (13); 114 (100).Conversion of ketal 93 to deconjugated enone 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 withEt20 (3x) and the combined extracts were washed with brine (3x) and dried over MgSO4.136Removal 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: 252.1725Meas. Mass: 252.17331H 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-1MS: 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^ OCH3HO OCH3A solution of deconjugated enone 94 (0.31 g, 1.2 mmol) in dry THF (5.0 mL) wascooled to -78 0C and was cannulated into a slurry of LiA1H4 (0.053 g, 1.4 mmol) in dryTHE (5.0 mL), also at -78 0C and under an Ar atm. The mixture was allowed to warm toRT over 2 h, then was cautiously quenched by the addition of water. After dilution with1 M HC1, the mixture was extracted with Et20 (3x) and the combined extracts werewashed with water and brine (2x). Drying over MgSO4 and removal of the solvent gavethe alcohol 95 as a colourless liquid (0.275 g, 89% yield).137138C15H2603^Calc. Mass: 254.1881Meas. Mass: 254.18811H 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 andC(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-1MS: 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: "OCH3HO =4:51 OCH3I;9 6HOCyclopropanation attempt E67:A slurry of Zn-Cu (0.032 g, 0.50 mmol) and CH2C12 (0.040 mL, 0.50 mmol) indry 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 addeddropwise. 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 wascooled to RT and stirred under an Ar atm overnight. It was then warmed to 50 0C andanother portion of CH2I2 (0.040 mL, 0.50 mmol) was added. After 30 min, the reactionwas cooled to RT, another portion of Zn-Cu (0.032 g, 0.50 mmol) was added and themixture was refluxed for 45 min. One last portion of CH2I2 (0.040 mL, 0.50 mol) wasadded and reflux was continued 5 h. After cooling to RT, 0.5 M HCI was added and themixture 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 columnchromatography using 9:1 PE:Et20 as eluant gave a colourless liquid (0.028 g) whichwas 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 cyclopropylcompound (tentatively assigned structure 96), as indicated by an NMR signal at0.45 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) andEt2Zn (2.3 mL, 1.1 M/toluene, 2.5 mmol) at 50°C under an Ar atm was added dropwiseCH2I2 (0.20 mL, 2.5 mmol) in dry toluene (2.0 mL). After heating for 30 min, thesystem was flushed with 02 and heated for a further 1 h. After cooling to RT, 0.5 M HC1was added, and the mixture was extracted with Et20 (3x). The combined extracts werewashed with brine (3x) and dried over MgSO4. Removal of the solvent gave a brown oilwhich was subjected twice more to the above cyclopropanation conditions. After thefinal work-up, the oil was purified by column chromatography using 9:1 PE:Et20 aseluant. The cyclopropyl compound 96 was isolated as a colourless oil (0.006 g, 4%yield).CI6H2803^Calc. Mass: 268.2038Meas. Mass: 268.20291H 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); 0.95-0.99 (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).139MS: 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^Br\> /c)140e oOle^00N....0^(...0 H 010687To 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 addedbromomethyldimethylsilyl chloride (0.24 mL, 1.7 mmol) and the mixture was stirred atRT under an Ar atm for 30 min. Water was added and the mixture was extracted withCH2C12 (3x). The combined extracts were washed with brine (3x) and dried overMgSO4. Removal of the solvent gave an orange liquid which was purified by columnchromatography using 4:1 PE:Et20 as eluant. The silyl ether 106 was isolated as acolourless liquid (0.46 g, 76% yield).C201-13305Si79Br^Calc. Mass: 460.1280Meas. Mass: 460.1288C20113305Si81Br^Calc. Mass: 462.1260Meas. Mass: 462.12701H 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 and106-CHHOSi(CH3)2CH2Br); 5.18 (1H, br s, C(1)H).IR (neat): u=2970, 2890 (C-H) cm-1MS: 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:Br^I.,^ \S'/1\S'/0 / 01410(..0 H 0107Radical 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 anAr atm for 45 min. The solvent was removed and the residue was purified by columnchromatography using first PE as eluant, then gradually increasing the polarity until theeluant was 4:1 PE:Et20. A colourless liquid was isolated, which was not the desiredcyclization 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-1A small sample of 107 was treated with TBAF in THF. The product, as expected, wasthe diketalizetl alcohol 87, showing spectral characteristics identical to the previouslyprepared product.Radical cyclization attempt B (dilute conditions):A solution of Bu3SnH (0.27 mL, 0.99 mmol) and a catalytic amount AIBN in drybenzene (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 removedand the residue was purified by column chromatography using 9:1 PE:Et20 as eluant. Asbefore, no cyclization product was obtained, only the trimethylsilyl ether reductionproduct 107 as a colourless liquid (0.30 g, 79% yield).Deprotection of acetate 85 to give alcohol 122:142OAc 85^122To a solution of acetate 85 (2.90 g, 9.4 mmol) in Me0H (40 mL) was added asolution of KOH (1.58 g, 28 mmol) in water (40 mL). After stirring at RT for 30 min, thereaction was diluted with water and extracted with Et20 (3x). The combined extractswere washed with brine (2x) and dried over MgSO4. Removal of the solvent yielded thealcohol 122 as a pale yellow oil (2.16 g, 86% yield). A small amount could becrystallized from Et20 for microanalysis.mp: 149-151 °CC15H2204^Calc. Mass: 266.1518Meas. Mass: 266.1524Calc. 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) cm4MS: m/e(%)=266 (M+, 15); 140 (24); 129 (100); 86 (25).Conversion of alcohol 122 to silyl ether 123:122^ 123A 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 DMAPin dry CH2C12 (20 mL) was stirred under an Ar atm for 30 min. Water was added and themixture 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 waspurified by column chromatography using 1:1 PE:Et20 as eluant. The silyl ether 123 wasisolated as a colourless liquid (0.96 g, 100% yield).C18112904Si79Br^Calc. Mass: 416.1018Meas. Mass: 416.1018143144C18H2904Si81Br^Calc. Mass: 418.0998Meas. Mass: 418.09951H 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-1MS: 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 122:123^122y-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 andthen 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 warmgradually to RT and stirred overnight. Water was added and the mixture was extractedwith Et20 (3x). The combined extracts were washed with brine (3x) and dried overMgSO4. Removal of the solvent gave a red liquid which was purified by columnchromatography 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, asdetermined 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 anAr 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 extractswere washed with 1 M HC1 and brine (3x) and dried over MgSO4. Removal of thesolvent gave a yellow liquid which was a complex mixture by GC and TLC. Purificationby column chromatography using 2:1 PE:Et20 as eluant gave the alcohol 122 resultingfrom silyl ether cleavage as a colourless liquid (0.021 g, 22% yield). Spectral character-istics were identical to the alcohol 122 prepared previously. None of the other side-products isolated were the desired y-alkylation product as determined by 1H N1VIR andMS.Protection of alkene diol 64 to give silyl alcohol 128:OH^ OH64^OH^128 OTBDMSTo a solution of alkene diol 64 (4.47 g, 21.4 mmol) in dry DMF (-100 mL) underan 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 drying145over MgSO4 and removal of the solvent, a yellow oil was isolated which was purified bycolumn chromatography using 4:1 PE:Et20 as eluant. The silyl alcohol 128 was isolatedas a white solid (6.66 g, 97% yield).mp (sealed tube): 108-110 'DCC19H3402Si Calc. Mass: 322.2328Meas. Mass: 322. 2334Calc. 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-1MS: 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:OTBDMS1 29To a solution of silyl alcohol 128 in dry THF (5.0 naL) under an Ar atm wasadded dropwise n-BuLi (0.16 mL, 1.6 M/hexanes, 0.26 mmol). The resulting yellow146129 130OTBDMS^ OTBDMSs"OHilsolution was warmed to 40 0C for 15 min then water was added. The mixture wasextracted with Et20 (3x) and the combined extracts were washed with brine (3x), driedover MgSO4, and the solvent removed to give a yellow liquid. Purification by columnchromatography using 9:1 PE:Et20 as eluant gave ketone 129 as a pale yellow liquid(0.040 g, 73% yield).CoH3402Si Calc. Mass: 322.2328Meas. Mass: 322.23251H 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-1MS: 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:To a solution of ketone 129 (3.51 g, 10.8 mmol) in dry THF (70 mL) at -78 0Cunder 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 was147OTBDMSs'OCH3diluted 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 apale yellow oil which was purified by column chromatography using 15:1 PE:Et20 aseluant. Some starting material 129 (0.26 g, 7% yield) was recovered along with thealcohol 130 (2.73 g, 78% yield) as a colourless oil.C19H3602Si Calc. Mass: 324.2484Meas. Mass: 324.2486Calc.: 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-1MS: m/e(%)=267 (M-4--t-Bu, 22); 249 (20); 192 (100); 175 (74); 159 (75); 135 (61); 105148(66); 75 (90); 73 (73).Protection of alcohol 130 to give methyl ether 131:OTBDMS130^ 131OTBDMS^ OTBDMS is'OCH3132A solution of alcohol 130 (1.62 g, 5.0 mmol) in dry THF (40 mL) was cannulatedinto a slurry of ICH (0.30 g, 7.5 mmol) in dry THF (20 mL) under an Ar atm. Afterstirring at RT for 1.5 h, Mel (0.50 rnL, 7.5 rnmol) was passed through basic aluminadirectly into the reaction mixture. After stirring overnight, NH4C1(aq) solution wascautiously added and the reaction was extracted with Et20 (3x). The combined organicextracts were washed with brine (3x) and dried over MgSO4. Removal of the solventgave a yellow liquid which was purified by column chromatography using 24:1 PE:Et20as eluant. The methyl ether 131 was obtained as a colourless liquid (1.60 g, 95% yield).C201-13802Si Calc. Mass: 338.2641Meas. Mass: 338.26441H 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-1MS: 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 132:149A 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 becamecolourless. 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 mixturewas 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 keto-aldehyde as a yellow oil which was not purified but which was immediately dissolved indry benzene (-50 mL). A catalytic amount of p-Ts011•1120 was added, and the solutionwas refluxed under an Ar atm in a Dean-Stark apparatus for 3 h. After cooling to RT, themixture was poured onto brine and extracted with Et20 (3x). The combined extractswere washed with NaHCO3(aq) solution, brine (3x) and dried over MgSO4. Removal ofthe solvent gave a yellow oil which was purified by column chromatography using 9:1PE: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-1MS: m/e(%)=295 (M+-t-Bu, 31); 265 (28); 189 (61); 161 (30); 147 (30); 119 (71); 105(27); 91(36); 89 (100).150OTBDMS^ OTBDMS"OCH3132Protection of enone 132 to give ketal 133: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 refluxedunder an Ar atm in a Dean-Stark apparatus for 24 h. After cooling to RT, the mixturewas poured onto brine and extracted with Et20 (3x). The combined extracts were washedwith NaHCO3(ao solution and brine (3x). Drying over MgSO4 and removal of thesolvent gave a yellow oil which was purified by column chromatography using 15:1PE:Et20 as eluant. The ketal 133 was isolated as a colourless liquid (0.068 g, 25%yield).C22H4004Si Calc. Mass: 396.2695Meas. Mass: 396.27011H 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-1MS: m/e(%)=396 (M+, 8.0); 353 (27); 339 (52); 251 (37); 171 (43); 119 (28); 115 (33);114 (100); 99 (48).151s'OCH3OTBDMS^ OH134Hs'OCH3Hydrolysis of ketal 133 to give deconjugated enone 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 themixture 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 acolourless liquid (0.036 g, 97% yield) which was not purified but was used directly in thenext reaction.C14H2203^Calc. Mass: 238.1568Meas. Mass: 238.15671H 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-1MS: m/e(%)=238 (M+, 14); 220 (48); 206 (50); 175 (88); 145 (65); 119 (91); 117 (48);107 (50); 105 (93); 91 (100).152Protection of alcohol 134 to give silyl ether 135:153134^ 135To a solution of alcohol 134 (0.036 g, 0.15 mmol) in dry DMF (1.0 mL) wasadded imidazole (0.021 g, 0.31 mmol) and TBDMSC1 (0.035 g, 0.23 mmol) and themixture was stirred under an Ar atm at RT overnight. Water was added, the mixture wasextracted with Et20 (3x) and the combined extracts were washed with NH4Cloco solutionand brine (3x). Drying over MgSO4 and removal of the solvent gave the silyl ether 135as a pale yellow oil (0.050 g, 95% yield) which was not purified but which was useddirectly in the next reaction.C20H3603Si Calc. Mass: 352.2433Meas. Mass: 352.24281H 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-1MS: m/e(%)=295 (M+- t-Bu, 33); 263 (54); 237 (42); 171 (71); 89 (100); 75 (97); 73(94).OTBDMS^ OTBDMSs'OCH3135^136lSgHOVinyl addition to ketone 135 to give alcohol 136:Preparation A:To flame-dried Mg (0.055 g, 2 3 mmol) in a 3-necked, 25 mL round bottomedflask equipped with an addition funnel and condenser and kept under an Ar atm wasadded 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 theGrignard reaction, then at a rate to maintain reflux. After refluxing for a further 5 minafter the addition was complete, the reaction mixture was cooled to RT and a solution ofketone 135 (0.135 g, 3.83 mmol) was added. The mixture was refluxed for 1 h, cooled toRT 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 chromatographyusing 4:1 PE:Et20 as eluant. The alcohol 136 was isolated as a white solid (0.082 g, 57%yield).C221-14003Si Calc. Mass: 380.2746Meas. Mass: 380.27501H NMR (400 MHz, CDC13): 8=0.05 (6H, s, Si(CL13)2); 0.90 (16 H, br s, t-Bu and 2xCH.3); 1.08-1.17 (2H, m); 2.10 (21-1, br d, J=12 Hz); 2.15 (1H, br s); 2.25 (1H, brd, J=12 Hz); 2.66 (1H, br s, C(9)H); 3.33 (3H, s, -OCE3); 3.57 (1H, dd, J=10,1548 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-1MS: 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 for2 h was added dry THF (20 mL) and the slurry was kept under an Ar atm and cooled to0 °C. A solution of vinylmagnesium bromide, prepared as described above by theaddition 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 theslurry. A solution of ketone 135 (0.552 g, 1.56 mmol) in dry THF (10 mL) was addedand 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 combinedextracts were washed successively with brine, NaHCO3(aco solution and brine. Afterdrying over MgSO4, removal of the solvent gave a yellow oil which was purified bycolumn 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 spectralcharacteristics as described previously.155136 137OTBDMS^ OH11„HO 40CH3Conversion of alcohol 136 to diol 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 atmwas added alcohol 136 (0.0060 g, 0.016 mmol) in dry THF (1.0 mL). The mixture wasstirred at RT for 1 h, then 18-cr-6 (0.028 g, 0.079 mmol) was added. After refluxing for12 h, the mixture was cooled to RT and water was cautiously added. The mixture wasextracted with Et20 (3x) and the combined extracts were washed with brine (3x). Afterdrying over MgSO4, removal of the solvent gave a brown-yellow solid which waspurified 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 rearrange-ment product, but which was identified as the diol 137 resulting from silyl ether cleavage.C16H2603^Calc. Mass: 266.1881Meas. Mass: 266.18871H 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).156IR (CHC13): v=3620 (br, 0-H); 2940 (C-H) cm-1440CH3OH^ OCH3138HO "OCH3HMS: 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 Aratm 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 RTfor 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 MgSO4and removal of the solvent gave a yellow gum. Purification by column chromatographyusing 2:1 PE:Et20 as eluant gave a pale yellow liquid (0.030 g, 98% yield) which was notthe desired anionic oxy-Cope product, but which was identified as the diol 137 resultingfrom silyl ether cleavage as before. Spectral characteristics of the diol 137 were identicalto those described above.Protection of alcohol 137 to give methyl ether 138:To a slurry of ICH (0.012 g, 0.30 mmol) in dry THF (1.0 mL) under an Ar atm andat 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). Thecombined extracts were washed with brine (3x) and dried over MgSO4. Removal of thesolvent gave an orange oil which was purified by column chromatography using 9:1157OCH3^ OCR3 410-s'OCH3 s'OCH3138^ 139PE:Et20 as eluant. The dimethyl ether 138 was isolated as a white solid (0.0050 g, 12%yield).C17H2803^Caic. Mass: 280.2038Meas. Mass: 280.20341H 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 andC(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-1MS: 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:To a slurry of KH (0.0014 g, 0.036 mmol) in dry xylenes (0.5 rnL) was added asolution of alcohol 138 (0.0050 g, 0.018 mmol) and 18-cr-6 (0.0094 g, 0.036 nunol). Themixture 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,158third portion of ICH (0.0014 g, 0.036 mmol) and 18-cr-6 (0.0094 g, 0.036 mmol) wasadded and reflux was continued for another 21 h. The mixture was cooled to RT, waterwas cautiously added, and the mixture was extracted with Et20 (3x). The combinedextracts were washed with brine (3x), dried over MgSO4 and the solvent removed to yielda yellow solid. Purification by column chromatography using 9:1 PE:Et20 as eluant gavea 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 atmwas added a solution of diol 64 (2.53 g, 12.1 mmol) in dry THF (30 mL) also cooled to0 °C. After 15 min, Mel (0.76 mL, 12 mmol) was passed through basic alumina directlyinto the reaction mixture. After another 45 min at 0 °C, NH4C100 solution wascautiously added and the mixture was extracted with Et20 (3x). The combined extractswere washed with brine (3x) and dried over MgSO4. Removal of the solvent gave ayellow liquid which was purified by column chromatography using 4:1 PE:Et20 aseluant. The methyl ether 152 was isolated as pale yellow liquid (1.67 g, 63% yield).C14H2202^Calc. Mass: 222.1619Meas. Mass: 222.16291H 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); 3.91159(2H, d, J=4 Hz, -Cf_120CH3); 5.64 (1H, d, J=6 Hz, C(6)H); 5.71 (2H, m, transvinyl H's); 6.03 (1H, dd, J=6, 3 Hz, C(5)H).IR (neat): u=3450 (0-H); 2950, 2870 (C-H) cm-1MS: 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:i152 OCH3 157A solution of alcohol 152 (0.24 g, 1.1 mmol) in dry THF (6.0 rriL) was cannulatedinto a slurry of KH (0.051 g, 1.3 mmol) in dry THF (10 mL) under an Ar atm. Themixture was warmed to 40 0C for 20 min (at which point rearrangement had occurred, asindicated by TLC and GC), then cooled to -78 °C. Mel (0.66 mL, 11 mmol) was passedthrough basic alumina, dissolved in dry TI-IF (1.0 mL), cooled to -78 c•C and the solutionwas added to the reaction mixture. After warming to RT overnight, NH4C1(aco solutionwas cautiously added and the mixture was extracted with Et20 (3x). The combinedextracts were washed with brine (3x) and dried over MgSO4. Removal of the solventgave a yellow oil which was purified by radial chromatography (1 mm plate) using 2:1PE:Et20 as eluant. The ketone 157 was isolated as a pale yellow oil (0.23 g, 92% yield).C15H2402^Calc. Mass: 236.1776Meas. Mass: 236.1770160157 158OCH3^ OCH3"OH1H 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-1MS: 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:To a solution of ketone 157 (1.88 g, 7.98 mmol) in dry THF (40 mL) at -78 0Cunder an Ar atm was added dropwise L-Selectride® (16 mL, 1 MfTHF, 16 mmol). Thesolution was stirred at -78 0C for 1 h, then 3 M Na0H(ac) solution (4.2 mL) wascautiously 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 ayellow liquid. Purification by column chromatography using 4:1 PE:Et20 as eluant gaverecovered starting material (0.187 g, 9% yield) and the desired alcohol 158 (1.49 g, 79%yield) as a white crystalline solid.161mp (sealed tube): 109-110 0COH^ OTBDMS0 0I:1^ 1:1^•-..?122 168162Ci5H2502^Calc. Mass: 238.1933Meas. Mass: 238.1937Calc.: 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-1MS: 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: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 anAr atm overnight. Water was added and the mixture was extracted with Et20 (3x). Thecombined extracts were washed with NH4C1(aco solution and brine (3x) and dried overMgSO4. Removal of the solvent gave a yellow liquid which was purified by column168 169OTBDMS^ OTBDMSchromatography using 2:1 PE:Et20 as eluant. The silyl ether 168 was isolated as acolourless liquid (0.18 g, 99% yield).C211-13604Si Calc. Mass: 380.2383Meas. Mass: 380.23821H 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-1MS: 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: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 Themixture 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 over163MgSO4 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: 396.2332Meas. Mass: 396.23361H 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-1MS: 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 170:169^170To a solution of PhSeSePh (0.72 g, 2.3 mmol) in absolute Et0H (6.0 inL) underan Ar atm was added in portions NaBH4 (0.17 g, 4.6 mmol).94,95 Into the colourlesssolution 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 wasdiluted with Et0Ac and washed once with brine. Drying over MgSO4 and removal of thesolvent gave a yellow oil which was purified by column chromatography using 4:1164HO^ TBDMS9OTBDMS^ OTBDMS171PE:Et20 as eluant. Two compounds were isolated, the desired keto-alcohol 170 as acolourless liquid (0.183 g, 60% yield) and the enone 168 resulting from dehydration as acolourless liquid (0.028 g, 10% yield). The enone 168 had spectral characteristicsidentical to those of the previously prepared sample.Data for keto-alcohol 170:C211-12805Si Calc. Mass: 398.2481Meas. Mass: 398.24811H 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-1MS: 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 171:165To 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 addedciropwise TBDMSOTf (0.10 mL, 0.44 mmol). After stirring at 0 GC for 1 h, the mixturewas 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), anddried over MgSO4. Removal of the solvent gave a pale yellow oil which was purified bycolumn chromatography using 9:1 PE:Et20 as eluant. The silyl ether 171 was isolated asa white crystalline solid (0.0745 g, 50% yield).mp: 105-106 GC (sealed tube)C23H4305Si2 (M-1--t-Bu)^Calc. Mass: 455.2649Meas. Mass: 455.2641C27115205S 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-1MS: m/e(%)=455 (W-t-Bu, 8.4); 323 (12); 249 (18); 195 (30); 171 (20); 147 (18); 75(100); 41(29).166Oxidation of bromide 61 to give ketone 183 and cyclocamphanone ketal (184):16761 184Silver tetrafluoroborate (2.56 g, 13.1 mmol) was added to a solution of bromide61 (2.41 g, 8.76 mmol) in dry DMSO (40 mL) under an Ar atm.100 After stirring in thedark at RT overnight, dry Et3N (1.8 mL, 13 mmol) was added and the reaction wasstirred for another hour. Water was cautiously added and the mixture was filteredthrough Celite. The filter cake was washed well with Et20, and the filtrate was extractedwith Et20 (4x). The combined extracts were dried over MgSO4 and the solvent wasremoved to give a yellow liquid. Column chromatography using 9:1 PE:Et20 as eluantgave the ketone 183 as a colourless solid (0.784 g, 43% yield) and cyclocamphanoneketal (184) as a colourless liquid (0.674 g, 40% yield).Data for ketone 183:C12111803^Calc. Mass: 210.1256Meas. Mass: 210.12591H 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, ketalH).IR (CHC13): v=2970, 2887 (C-H); 1752 (C=0) cm-1MS: m/e(%)=210 (M+, 54); 195 (88); 141 (28); 127 (46); 126 (100).Data for cyclocamphanone ketal (184):C12H1802^Calc. Mass: 194.1306Meas. Mass: 194.13021H 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) radoH); 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-iMS: 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):168184^ 59A solution of cyclocamphanone ketal (184, 0.873 g, 4.49 mmol) was stirred inacetone (10 mL) and 1 M HC1 (10 mL) at RT for 1 h. The mixture was diluted withwater, 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 tothose of cyclocamphanone (59) prepared previously.Conversion of ketone 183 to enol triflate 185:1690183 0^ 185 OTfA solution of ketone 183 (1.80 g, 0.856 mmol) in dry CH2C12 (30 mL) wascannulated into a solution of triflic anhydride (1.5 znL, 8.9 mmol) and 2,6-di-t-buty1-4-methylpyridine (1.84 g, 8.96 rnmol) in dry CH2C12 (80 mL) under an As atm.lo Afterstirring at RT for 4 h, the solvent was removed, pentane (80 mL) was added, and the tanresidue 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 removedto yield a yellow liquid which was purified by column chromatography using 9:1PE:Et20 as eluant. The enol triflate 185 was isolated as a colourless liquid (2.76 g, 95%yield).C12H1703 (M+-S02CF3) Calc. Mass: 209.1178Meas. Mass: 209.11791H 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) cm4MS: m/e(%)=209 (M+-Tf, 100); 137 (35); 123 (15); 109 (32); 86 (45).Conversion of enol triflate 185 to 5-methyl-5,6-dehydrocamphor ketal (186):170A slurry of CuBr.DMS (17.66 g, 85.90 trunol) in dry Et20 (-100 mL) was cooledto -20 0C under an Ar atm. MeLi (-120 mL, 1.4 M/Et20, —172 mmol) was added drop-wise until a colourless solution was obtained.105 The triflate (5.656 g, 16.50 mmol) wasdissolved 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 reactionmixture 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, thesolvent was removed to yield a pale yellow liquid which was purified by columnchromatography 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: 208.1463Meas. Mass: 208.14651H 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, ketalH); 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) cm4MS: m/e(%)=208 (M+, 2.5); 193 (1.3); 122 (100); 107 (63).Hydrolysis of 5-methyl-5,6-dehydrocamphor ketal (186) to give (-)-5-methy1-5,6-dehydrocamphor (178):171After stirring a solution of ketal 186 (0.379 g, 1.81 mmol) in acetone (8 mL) and1 M HC1 (8 mL) at RT for 15 min, water was added and the reaction was extracted withEt20 (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 waspurified by column chromatography using 4:1 PE:Et20 as eluant. (+5-Methy1-5,6-dehydrocamphor (178) was isolated as a colourless liquid (0.297 g, 99% yield). It wascontaminated with —5% (-)-5,6-dehydrocamphor (ent-36) which could not be separated.C1 1H160^Calc. Mass: 164.1201Meas. Mass: 164.11961H 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-1MS: 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-Coperearrangement to give ketone 190:A 3-necked 100 mL round bottomed flask equipped with condenser and additionfunnel and containing a stir bar and Mg (0.52 g, 0.021 mol) was flame dried and cooledunder Ar. A crystal of 12 and dry THF (12 mL) were added and a small amount of2-bromopropene was added to initiate Grignard formation. A solution of 2-bromo-propene (1.3 mL, 0.014 mol) in dry THF (12 mL) was then added dropwise to maintainthe 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 wasstirred 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 toRT 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 solventgave a yellow liquid which was purified by column chromatography using 15:1 PE:Et20as eluant. The ketone 190 was obtained as a colourless liquid (1.237 g, 85% yield). 1HNMR spectroscopy showed the diastereomeric mixture to be 1:1.C1414220^Calc. Mass: 206.1671Meas. Mass: 206.1672Calc.: 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 CH3and 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,172vinyl 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-1MS: 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 191:173190^ 191A 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 bluecolour persisted (-30 min). Excess 03 was removed by bubbling 02 through the solutionuntil 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 for1 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 thesolvent 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 ofp-Ts0H.H20 was added, and the mixture was refluxed in a Dean-Stark apparatus underan Ar atm for 1 h. Brine was added and the mixture was extracted with Et20 (3x). Thecombined extracts were washed with brine (3x), dried over MgSO4 and the solventremoved to yield a yellow oil. Purification by column chromatography using 1:1PE:Et20 as eluant gave the enone 191 as a white crystalline solid (0.255 g, 59% yieldfrom ketone 190).mp: 115-116°CCl4HO2^Caic. Mass: 220.1463Meas. Mass: 220.1454CaIc.: 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-1MS: 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 192:174 191A 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 refluxedin 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 withbrine (3x), dried over MgSO4 and the solvent removed to yield a yellow oil. Purificationby column chromatography using 4:1 PE:Et20 as eluant gave starting material 191(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: 264.1725Meas. Mass: 264.17231H 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-1MS: 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 193:175HOA 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.106The 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 waspurified by column chromatography using 4:1 PE:Et20 as eluant. A pale yellow solidwas obtained which was recrystallized from 4:1 PE:Et20 to give the alcohol 193 as awhite crystalline solid ( 0.156 g, 54% yield). 1H NMR spectroscopy showed thediastereomeric mixture to be 1:1.C16H2803^Calc. Mass: 268.2038Meas. Mass: 268.2037Calc.: 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-1MS: 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 194:176HOTo a slurry of KH (0.022 g, 0.54 mmol) in dry THF (1.0 mL) under an Ar atmwas added a solution of alcohol 193 (0.12 g, 0.45 mmol) in dry TI-IF (6.0 rnL) and themixture was stirred at RT for 25 min. Mel (0.050 rnL, 0.67 mmol) was passed throughbasic alumina directly into the reaction mixture. After stirring overnight, water wascautiously added and the mixture was extracted with Et20 (3x). The combined extractswere washed with brine (3x), dried over MgSO4 and the solvent was removed to give ayellow liquid. Purification by column chromatography using 4:1 PE:Et20 as eluant gavethe methyl ether 194 as a pale yellow oil (0.119 g, 94% yield). 1H NMR spectroscopyand GC showed this to a mixture of all 4 possible diastereomers.C17H3003^Cak. Mass: 282.2195Meas. Mass: 282.21951H 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-1MS: 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 195:177 CH30 CH30195A 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 withEt20 (3x). The combined extracts were washed with brine (3x), dried over MgSO4, andthe solvent was removed to give a yellow solid. Purification by column chromatographyusing 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 1:1.178CI5H2602^Calc. Mass: 238.1933Meas. Mass: 238.1937Calc.: 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); 1.60-1.75 (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-1MS: 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 CH30195^ 196To 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, themixture was poured onto ice and diluted with CH2C12. The layers were separated, andthe CH2C12 solution was washed with NaHCO3(aq) solution (2x). After drying overMgSO4, 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 useddirectly in the next reaction.C18H3402Si Calc. Mass: 310.2328Meas. Mass: 310.23301H 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); 3.29-3.35 (1H, m, C(3)H).IR (neat): v=2960 (C-H); 1656 (C=C) cm-1MS: 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 197:179 CH30 CH30A solution of PhSeC1 (0.064 g, 0.33 mmol) in dry Et20 (2.0 mL) was added to asolution of enol silyl ether 196 (0.069 g, 0.22 mmol) in dry Et20 (2.0 mL) at -78 0Cunder an Ar atm. After stirring at -78 0C for 1.25 h, the solution was warmed to 0°C andwater (0.12 mL), HOAc (30 ilL) and H202 (0.11 rnL) were successively added. Themixture was warmed to RT, NaHCO3(aq) solution was added, and the mixture wasextracted 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 waspurified by column chromatography using 9:1 PE:Et20 as eluant. The enone 197 wasisolated as a white solid (0.030 g, 58% yield).C151-12402^Calc. Mass: 236.1776Meas. Mass: 236.17851H 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-1MS: 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 204:180178^ 203^204Freshly ground Mg (0.55 g, 23 mmol) was added to a 3-necked 200 mL roundbottomed flask equipped with condenser and addition funnel. After flame drying andcooling under Ar, dry THF (25 mL) and a crystal of I2 were added. A solution of2-bromopropene (1.7 mL, 19 mmol) in dry TI-IF (25 rnL) was added dropwise and theGrignard reagent was allowed to form over 30 min. A solution of (-)-5-methy1-5,6-dehydrocamphor (178, 1.56 g, 9.50 mmol) in dry THF (20 mL) was added dropwise andthe reaction was stirred at RT for 30 min. After heating at 40 °C for 30 min, the reactionwas 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 towarm 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 warmedto RT and was stirred until a white precipitate was formed (-30 min). NaHCO3(acosolution was added, the mixture was extracted with Et20 (3x) and the combined extractswere washed successively with 1 M HCI, water and brine (2x). Drying over MgSO4 andremoval of the solvent gave a yellow liquid which was purified by column chromato-graphy 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- andendocyclic 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, thereaction 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 waspurified by column chromatography using 24:1 PE:Et20 as eluant. The enone 204 wasisolated 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: 204.1514Meas. Mass: 204.1514Calc.: 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,181dd, 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) cm4MS: m/e(%)=204 (M+, 16); 189 (59); 162(11); 161 (16); 147 (14); 40(50).Conversion of enone 204 to enol silyl ether 205:182204^ 205To a slurry of CuBr•DMS (0.10 g, 0.50 nunol) in dry THF (3.0 mL) at -78 0Cunder an Ar atm was added dropwise MeLi (-0.6 mL, 1.5 WITIF, —1.0 mmol) until themixture 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) wasadded. 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 mexgtract4ed.with Et20 (3x). The combined extracts were washed with brine and dried over soRemoval of the solvent gave a yellow liquid which was purified by column chromato-graphy using 15:1 PE:Et20 as eluant. The enol silyl ether 205 was isolated as acolourless oil (0.065 g, 89% yield).C1811320Si Calc. Mass: 292.2222Meas. Mass: 292.22261H 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);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-1MS: trile(%)=292 (Mt, 15); 170 (12); 155 (51); 122 (100); 107 (51); 75 (31); 73 (46).Conversion of enol silyl ether 205 to ketone 207:183205^206^207A solution of enol silyl ether 205 (0.057 g, 0.19 mmol) in 1 M HC1 (1.0 mL) andacetone (1.0 mL) was stirred at RT for 2 h. After dilution with water, the mixture wasextracted with Et20 (3x) and the combined extracts were washed with NaHCO3 (ac0solution and brine (3x). Drying over MgSO4 and removal of the solvent gave a yellowliquid which was purified by column chromatography using 24:1 PE:Et20 as eluant. Theketone 206 was isolated as a colourless liquid (0.030 g, 70% yield). The diastereomericmixture 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 toepimerize the C(8) center. After cooling to RT, the mixture was added to water andextracted 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 yellowliquid which was only one diastereomer by GC. Purification by column chromatographyusing 24:1 PE:Et20 as eluant gave the ketone 207 as a colourless liquid (0.011 g, 52%yield).184C1511240^Calc. Mass: 220.1827Meas. Mass: 220.18181H 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-1MS: 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:CN204^ 208Et2A1CN (1.9 mL, 1 MfIEF, 1.9 mmol) was added dropwise to a solution ofenone 204 (0.095 g, 4.6 mmol) in dry THF (5.0 mL) under an Ar atm.112 After stirring atRT for 5.5 h, the mixture was poured onto 5% Na0H(aq) solution and extracted withEt20 (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 bycolumn chromatography using 4:1 PE:Et20 as eluant. The ketone 208 was isolated as ayellow oil (0.073 g, 68% yield). GC and 1H NMR spectroscopy showed this to be acomplex mixture of diastereomers.C15H210N Calc. Mass: 231.1623Meas. Mass: 231.16231H 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-1MS: m/e (%)=231 (M+, 16); 135 (100); 122 (92); 107 (42); 40 (29).Conversion of enone 204 to ketone 210:185204^209^210To 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 andmaintain 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 addedand 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 RTovernight. A solution of 5% NH4OH in saturated NH4C1(ao was cautiously added andthe mixture was extracted with Et20 (3x). The combined extracts were washed withbrine (3x) and dried over MgSO4. Removal of the solvent gave an orange oil which waspurified by column chromatography using 24:1 PE:Et20 as eluant. The hydrolyzedproduct (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 1HNMR 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 asolution of Na0Me prepared by adding Na (0.007 g, 0.3 mmol) to Me0H (1 mL). Themixture was stirred at RT for 3.5 h, diluted with water and extracted with Et20 (3x). Thecombined extracts were washed with brine (3x) and dried over MgSO4. Removal of thesolvent gave a yellow liquid which was purified by column chromatography using 24:1PE: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.Cl6H240^Calc. Mass: 232.1833Meas. Mass: 232.18251H 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-1MS: m/e(%)=232 (M+, 7.7); 135 (100); 122 (46); 107 (23); 91(16).Allyl addition to enone 204 to give alcohol 214:186 204To a solution of enone 204 (0.053 g, 0.26 mmol) in dry THF at 0°C under an Aratm 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 heatedat reflux for 3 h. NH4C1(aq) solution was cautiously added and the mixture was extractedwith Et20 (3x). The combined extracts were washed with brine (3x), dried over MgSO4and the solvent removed to give a yellow oil. Purification by column chromatographyusing 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: 246.1984Meas. Mass: 246.1985Calc.: 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, vinylC113); 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-1MS: m/e(%)=228(M+-H20, 23); 213 (36); 205 (100; 187 (55); 157 (28) 107 (28) 83 (99).187Attempted rearrangement of alcohol 214:188 21 5Anionic oxy-Cope rearrangement attempt A:A solution of alcohol 214 (0.048 g, 0.19 mmol) in dry THF (4.0 mL) was added toa slurry of ICH (0.016 g, 0.39 mmol) in dry THF (0.5 mL) under an Ar atm. The mixturewas refluxed for 36 h, cooled to RT and water was cautiously added. The mixture wasextracted with Et20 (3x) and the combined extracts were washed with brine (3x). Dryingover MgSO4 and removal of the the solvent gave an orange oil which was purified bycolumn chromatography using 24:1 PE:Et20 as eluant. The only product isolated wasenone 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 °Cunder an Ar atm was added dropwise n-BuLi (0.28 rnL, 1.6 WTHF, 0.45 mmol). Thesolution was stirred at -78 °C for 1 h, then at 0 °C for 1 h. After a further 2.5 h at RT, themixture was refluxed for 19 h. After cooling to RT, water was added and the mixturewas extracted with Et20 (3x). The combined extracts were washed with brine (3x), driedover MgSO4, and removal of the solvent gave a yellow liquid which was purified bycolumn chromatography using 24:1 PE:Et20 as eluant. Starting alcohol 214 wasrecovered (0.034 g, 74% yield).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 drydiglyme (0.5 mL) under an Ar atm. The mixture was stirred at RT for 3 d, then wasrefluxed for 24 h. The mixture was cooled to RT and passed through silica (230-400mesh) using 1:1 PE:Et20 as eluant to remove polar decomposition products. Removal ofthe solvent gave a yellow liquid which was a complex mixture by GC and TLC. Therewas no evidence of any anionic oxy-Cope rearrangement product, as indicated by IRspectroscopy.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 thereaction mixture was passed through silica (230-400 mesh) using PE as eluant until alldecalin had been eluted, then increasing the polarity to 24:1 PE:Et20. Starting alcohol214 (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:OTBDMS-=.___/OH ^/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. Brinewas added and the mixture was extracted with Et20 (3x). The combined extracts werewashed 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 propargylalcohol as a colourless liquid (25 g, 86% yield).189190C9H18OS i^Calc. Mass: 170.1127Meas. Mass: 170.11241H 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-1MS: m/e(%)=170 (M+, 1.0); 113 (99); 83 (100); 75(59).Conversion of (-)-5-methyl-5,6-dehydrocamphor (178) to alkyne 216: HO178216To a solution of silyl-protected propargyl alcohol (0.864 g, 5.07 mmol) in dryTHF (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-methy1-5,6-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 towarm to RT overnight. Water was added, the mixture was extracted with Et20 (3x) andthe combined extracts were washed with brine (3x). Drying over MgSO4 and removal ofthe solvent gave an orange liquid which was purified by column chromatography using15:1 PE:Et20 as eluant. The alcohol 216 was isolated as a white solid (1.10 g, 96%yield).mp: 78-79 °CHO/.....)TBDMSO^217C20113402Si Calc. Mass: 334.2328Meas. Mass: 334.23221H 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-1MS: 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:HOLindlar'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 Asolution of alkyne 216 (0.37 g, 1.1 mmol) in 2:1 hexane:Et0Ac (-15 mL) was added andthe mixture was stirred under H2 until the rate of uptake of H2 slowed (-1 h). Themixture was filtered and the solvent removed to give a colourless oil which was purifiedby column chromatography using 15:1 PE:Et20 as eluant. The^alkene 217 wasisolated as a soft white solid (0.285 g, 77% yield).191HOTBDMSO 217 218mp: 27-28 0CC20}13602S1 Calc. Mass: 336.2484Meas. Mass: 336.24911H NMR (400 MHz, CDC13): 8=0.08 (6H, s, Si(CH)2); 0.90 (12H, br s, t-Bu and Cii3);0.95 (3H, s, C_Fi3); 1.12 (3H, s, CH3); 1.61 (1H, d, J=13 Hz, C(3)r§_Ldj) H); 1.64(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-1MS: 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:Anionic oxy-Cope rearrangement attempt A:A solution of alcohol 217 (0.37 g, 0.11 mmol) in dry THF (5.0 mL) wascannulated into a slurry of KR (0.032 g, 0.80 mmol) in dry THF (2.0 mL) under an Aratm. After stirring at RT for 15 min, 18-cr-6 (0.21 g, 0.80 mmol) was added and thereaction mixture was refluxed for 3 h, then cooled to RT. NH4C1(aq) solution wascautiously added, and the mixture was extracted with Et20 (3x). The extracts were dried192over MgSO4 and the solvent removed to give a yellow oil. Purification by columnchromatography 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 °CC14H2202^Calc. Mass: 222.1619Meas. Mass: 222.16131H 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, brs, 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-1MS: 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 atmwas added HMDS (0.61 mL, 2.9 mmol) and the mixture was stirred at RT for 1 h. Asolution of alcohol 217 (0.162 g, 0.481 mmol) in dry TIT (5.0 mL) was added and thereaction mixture was refluxed for 17 h, then cooled to RT. NH4C100 solution wascautiously added and the mixture was extracted with Et20 (3x). The combined extractswere washed with brine (3x) and dried over MgSO4. Removal of the solvent gave ayellow 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, asdetermined by IR and IH NMR spectroscopy.193Oxy-Cope rearrangement attempt A:A solution of alcohol 217 (0.050 g, 0.15 mmol) in dry toluene (0.60 mL) wassealed under vacuum (-15 mmHg) in an oven-dried Pyrex tube which had been soaked in35% KOH solution for 2 days, then washed with deionized water. The tube was heated at140 0C for 14 h. Removal of the solvent gave a yellow liquid which was a complexmixture as determined by TLC and GC. Isolation of some of the major compounds bypurification by column chromatography using 9:1 PE:Et20 as eluant showed no evidenceof 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 chromato-graphy using 24:1 PE:Et20 as eluant. Starting alcohol 217 (0.024 g, 35% yield) wasisolated. There was no evidence of the desired rearrangement product as indicated by IRspectroscopy.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 Aratm for 2.75 h. After cooling to RT, the liquid was purified by column chromatographyeluting 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 oxy-Cope 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).194HOHO^219 220IR (neat): u=3571 (0-H); 2959 (C-H); 1718, 1663 (C=0) cm-1MS: m/e(%)=336 (3.6); 171 (54); 123 (78); 122 (100); 115 (61); 81(24); 75 (38); 73195(90).Deprotection of silyl ether 217 to give diol 219:HO217TBDMSO HOA 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 for15 min. Water was added and the mixture was extracted with Et20 (3x). The combinedextracts were washed with brine (3x) and dried over MgSO4. Removal of the solventgave a yellow liquid which was purified by column chromatography using 1:1 PE:Et20as eluant. The diol 219 was isolated as a white solid (0.064 g, 91% yield). Spectralcharacteristics were identical with those of the diol 219 previously described.Attempted rearrangement attempt of diol 219: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 dryTHF (5.0 mL) was cannulated into a slurry of KH (0.046 g, 1.1 mmol) in dry TI-IF(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 wasextracted with Et20 (3x). The combined extracts were washed with brine (3x) and driedover MgSO4. Removal of the solvent gave an orange oil which was purified by columnchromatography using 1:1 PE:Et20 as eluant. The only compound which was isolatedwas 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 Aratm for 5 h. After cooling to RT, the complex mixture was purified by column chromato-graphy using first PE as eluant until all the decalin had been eluted, then increasing thepolarity of eluant until a 1:1 mixture of PE:Et20 was used. None of the products isolatedwere determined to be the desired rearrangement product, as determined by IR and 1HNMR spectroscopy.Deprotection of silyl ether 216 to give diol 221:196HO HO221A 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 wasadded, and the mixture was extracted with Et20 (3x). The combined extracts werewashed with brine (3x) and dried over MgSO4. Removal of the solvent gave an orangeliquid which was purified by column chromatography using 1:1 PE:Et20 as eluant. Thediol 221 was isolated as a yellow oil (0.174 g, 91% yield).C14H2002^Calc. Mass: 220.1463Me as. Mass: 220.14571H 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-1MS: 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 222:197HO HO221To a slurry of LiA1H4 (0.078 g, 2.1 mol) in dry THF (10 mL) under an Ar atmwas added a solution of alkyne 221 (0.174 g, 0.789 mmol) in dry THF (10 mL).62 Themixture 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 wasextracted with Et20 (4x) and the combined extracts were washed with brine (3x). Dryingover MgSO4 and removal of the solvent gave a yellow liquid which was purified bycolumn chromatography using 1:1 PE:Et20 as eluant. The alkene diol 222 was isolatedas 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-1Attempted anionic oxy-Cope rearrangement of alkene diol 222:198HO 222To a slurry of ICH (0.084 g, 2.1 mmol) in dry TI-IF (3.0 mL) under an Ar atm wasadded HMDS (0.45 mL, 2.1 mmol), and the mixture was stirred at RT for 4 h. A solutionof 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 toRT and water was cautiously added. After extraction with Et20 (3x) the combinedextracts were washed with brine (3x) and dried over MgSO4. Removal of the solventgave a yellow liquid which was a complex mixture of compounds as indicated by TLCand GC. There was no evidence of the desired rearrangement product as determined byIR and 1H NMR spectroscopy.Conversion of cyclocamphanone (59) to keto-acetate 248):OrL 59^ 248 OAcTo a solution of cyclocamphanone (59, 8.2 g, 54 mmol) in HOAc (35 mL) wasadded H2SO4(conc) (0.9 mL) and the mixture was heated at 100 0C under an Ar atm for46 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) anddried over MgSO4. Removal of the solvent gave a yellow liquid which was purified bycolumn chromatography using 4:1 PE:Et20 as eluant. Some starting material 59 wasrecovered (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 colourlessliquid (5.65 g, 50% yield). GC and 1H NMR spectroscopy showed the diastereomericmixture to be 5:1 exo:endo.Cl2H180^Calc. Mass: 210.1256Meas. Mass: 210.1258Calc.: 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-1199MS: m/e(%)=210 (6.4); 168 (19); 150 (34); 125 (24); 108 (100); 93 (61).Conversion of keto-acetate 248 to alcohol 249:200248 OAc^249 OHCH2I2 (9.6 rriL, 0.12 mol) was cautiously added over 30 min to a vigorouslystirred slurry of Zn (14.0 g, 0.214 mol) in dry THF (220 inL) under an Ar atm.129 Afteran induction period (-15 min) the reaction became highly exothermic and was kept undercontrol by periodic cooling with an ice bath. Upon completion of the CH2I2 addition themixture 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 toRT 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) wascautiously added, then brine. The layers were separated and the organic layer waswashed with brine (3x). Drying over MgSO4 and removal of solvent gave a pale yellowliquid which was purified by column chromatography using 4:1 PE:Et20 as eluant. Thealcohol 249 was isolated as a colourless liquid (0.70 g, 89% yield) which solidified uponstanding.C1111180^Calc. Mass: 166.1358Meas. Mass: 166.1359Calc.: 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)gndo H, C(4)H and C(6) cascl 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, vinylH).IR(CHC13): v=3613, 3445 (0-H); 3013, 2957, 2874 (C-H) cm-IMS: m/e(%)=166 (M+, 30); 133 (70); 123 (87); 105 (100); 95 (80); 93 (83); 91(75).Oxidation of alcohol 249 to give ketone 250:201A solution of DMSO (38 gL, 0.54 mmol) in dry CH2C12 (1.0 rnL) was addeddropwise 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 towarm 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 thesolvent removed to give a yellow liquid. Purification by column chromatography using4:1 PE:Et20 as eluant gave the ketone 250 as a colourless solid (0.046 g, 62% yield).Cl1H160^Calc. Mass: 164.1201Meas. Mass: 164.1196Calc.: C 80.44^H 9.82%Anal.: C 80.27^H 9.72 %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-1MS: m/e(%)=164 (M+, 7.5); 121 (12); 93 (100); 79 (13); 40 (12).Protection of ketone 250 to give dithiane 245:202To a solution of ketone 250 (0.034 g, 0.21 mmol) in dry CH2C12 (2.0 mL) underan 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 dilutedwith 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 pinkliquid. Purification by column chromatograhy using 15:1 PE:Et20 as eluant gave thedithiane 245 as a colourless liquid (0.021 g, 42% yield).C13H20S2^Calc. Mass: 240.1006Meas. Mass: 240.10081H 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,C(4)H); 3.10-3.35 (4H, m, thioketal H's); 4.81 (1H, s, vinyl H); 4.95 (1H, vinylH).IR (neat): v=2961, 2923, 2869 (C-H) cm-1MS: m/e(%)=240 (M+, 53); 212 (44); 121 (75); 118 (63); 107 (100); 105 (72); 91(38).Attempted acid-catalyzed rearrangement of dithiane 245:203OAc245 S.....) 247To a solution of dithiane 245 (0.013 g, 0.054 mmol) in HOAc (1.0 mL) was addedH2SO4(conc) (0.024 mL) and the mixture was stirred at RT for 1.5 h. As no reactionoccurred, 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). Thecombined extracts were washed with NaHCO3(ac) solution (3x) and brine (3x). Dryingover MgSO4 and removal of the solvent gave a yellow oil which was purified by columnchromatography using 15:1 PE:Et20 as eluant to give a white solid (5 mg) which couldnot 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-1MS: m/e(%)=258 (6.6); 172 (14); 139 (46); 122 (12); 112 (33); 86(53); 69(81); 55(50);43 (66).Protection of alcohol 249 to give benzyl ether 251:204249 OH^251A solution of alcohol 249 (0.13 g, 0.77 mmol) in dry THF (5.0 mL) was added toa slurry of KR (0.062 g, 1.6 rnmol) in dry THF (1.0 mL) under an Ar atm. After stirringat RT for 30 min, BnBr (0.11 mL, 0.92 mmol) was added. After 30 min, water wascautiously added and the mixture was extracted with Et20 (3x). The combined extractswere washed with brine (3x), dried over MgSO4 and removal of the solvent gave ayellow liquid. Purification by column chromatography using first PE as eluant thenincreasing the polarity to 24:1 PE:Et20 gave the benzyl ether 251 as a colourless liquid(0.165 g, 84% yield).Cl8H240^Calc. Mass: 256.1827Meas. Mass: 256.1819Calc.: 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, vinylH); 4.72 (1H, br s, vinyl H).IR (neat): v=2950, 2870 (C-H) cm-1MS: m/e(%)=256 (M+, 5.4); 150 (36); 121 (36); 91 (100); 69 (25).Protection of alcohol 249 to give methyl ether 252:205 ,...-..0Me249 OH^252A solution of alcohol 249 (0.17 g, 1.0 mmol) in dry THF (5.0 rilL) was added to aslurry of ICH (0.081 g, 2.0 mmol) in dry THF (2.0 mL) under an Ar atm. After stirring atRT for 15 min, Mel (0.075 mL, 1.2 mmol) was added. After 15 min, water wascautiously added and the mixture was extracted with Et20 (3x). The combined extractswere washed with brine (3x), dried over MgSO4 and removal of the solvent gave acolourless liquid. Purification by column chromatography using 9:1 PE:Et20 as eluantgave the methyl ether 252 as a colourless liquid (0.153 g, 85% yield).C12H200^Calc. Mass: 180.1514Meas. Mass: 180.1511Calc.: 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 andC(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, brs, vinyl H).IR (neat): v=2954 (C-H) cm-1MS: m/e(%)=180 (M+, 22); 148 (59); 133 (100); 105 (82); 87 (84); 79 (45).Attempted acid-catalyzed rearrangement of benzyl ether 251:206 complex mixtureTo a solution of benzyl ether 251 (0.136 g, 0.53 mmol) in HOAc (2.0 mL) wasadded 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). Thecombined extracts were washed with NaHCO300 solution (3x) and brine (3x). Dryingover MgSO4 and removal of the solvent gave a yellow liquid (0.165 g) which was ahighly complex mixture as determined by TLC and GC.Attempted acid-catalyzed rearrangement of methyl ether 252:complex mixtureOMe252To a solution of methyl ether 252 (0.115 g, 0.639 mmol) in HOAc (1.0 mL) wasadded dropwise H2SO4(conc) (24 III.) and the solution was stirred under an Ar atm at RTfor 45 min. After addition to water, the mixture was extracted with Et20 (3x) and thecombined extracts were washed successively with NaHCO3(ao solution (3x), water, andbrine (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.25^ 240Acid-catalyzed rearrangement of ketone 250 to give ketone 255:207 CI^255To a solution of ketone 250 (0.011 g, 0.067 mmol) in HOAc (1.0 mL) was addedH2SO4(conc) (24 gL) and the reaction was stirred under an Ar atm at RT for 4 d. Afteraddition to water, the mixture was extracted with Et20 (3x) and the combined extractswere washed with NaHCO3(aq) solution (3x) and brine (3x). After drying over MgSO4and removal of the solvent a pale yellow oil was isolated which was purified by columnchromatography 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: 164.1201Meas. Mass: 164.12081H 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, vinylH); 4.86 (1H, s, vinyl H).IR (neat): v=2961, 2927 (C-H); 1741 (C=0) cm-1MS: 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):To methyltriphenylphosphonium bromide (79.7 g, 0.223 mol) which had beendried 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 thesolution 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-orangereaction mixture was refluxed for 24 h. After cooling to RT, approximately half of thesolvent was removed and water was added to the remaining mixture which was thenextracted with pentane (3x). The combined extracts were washed with water (3x), driedover 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:^150.1409Meas. Mass: 150.1400Calc.: 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-1MS: m/e(%)=150 (M+, 22); 135 (38); 107 (100); 93 (66); 79 (72); 67 (19).208Acid-catalyzed rearrangement of (-)-2-methylenebornane (240): f...)&Br266240To 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 mixturewas cautiously poured onto water, extracted with Et20 (3x) and the combined extractswere washed with water (3x), NaHCO3(aq) solution (3x) and water (3x). Drying overMgSO4 and removal of the solvent gave a yellow solid which was purified by flashcolumn chromatography using 15:1 PE:Et20. 4-Methylisobornyl bromide (266) wasisolated as a white solid (2.55 g, 87% yield). This compound discoloured upon storageand was therefore always freshly prepared and immediately used in the next reaction.C11H1979Br Calc. Mass: 230.0670Meas. Mass: 230.0663C111-11981Br Calc. Mass: 232.0650Meas. Mass: 232.06451H 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-1MS: 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).209Conversion of 4-methylisobornyl bromide (266) to (+)-4-methylisoborneol (267) and4-methylborneol (268):210 OH266^267 (g2a OH)268 (endo OH)To freshly ground, flame-dried Mg (0.60 g, 0.025 mol) under an Ar atm wasadded a crystal of 12 and dry TI-IF (6.0 mL). After the dropwise addition of dibromo-ethane (0.51 mL, 6.0 mmol) to initiate Grignard formation, a solution of 4-methyliso-bornyl bromide (266, 2.76 g, 11.9 mmol) in dry TI-IF (5.0 mL) was added at a rate tomaintain 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 ofthe reaction, potentially explosive peroxides are formed and therefore the use of a blastshield is recommended. 02 (dried by passage through 4A molecular sieves andDrieritee) was bubbled through the reaction mixture for 1.5 h and the mixture was keptunder a positive Ar atm overnight. 1 M HC1 was cautiously added to decompose anyunreacted Mg and to hydrolyze the Grignard complex, and the mixture was extracted withEt20 (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 yellowliquid. 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 awhite solid.C1 1H200^Calc. Mass: 168.1514Meas. Mass: 168.1511211Calc.: 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-1MS: 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 theH2SO4/HOAc rearrangement of (-)-2-methylenebornane (240) route) was known tocontain 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 byusing a Chirasil-val III capillary column (Alltech, 25 m x 0.25 mm i.d.). With a He flowrate 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) was30.70 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 conditionsas for Sample A, there was no evidence of (-)-4-methylisoborneol (ent-267); a singlepeak (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 OH267 (mg OH)268 (endo OH) 26,0229A 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 Afterthe addition of the orange reagent was complete, the reaction mixture turned green andwas 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(aosolution (2x) and water (2x), dried over MgSO4 and the solvent removed to give a whitesolid. 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:^166.1358Meas. Mass: 166.1358Calc.: 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).212IR (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 fromthe preparation described above, dissolved in CDC13 (1.0 mL, dried by passage throughbasic alumina), and transferred to a 5 mm NMR tube. A 0.17 M stock solution wasprepared by dissolving [Eu(hfc)31 (0.099 g, 0.17 mmol) in CDC13 (0.50 rnL, also passedthrough basic alumina). A 1H NMR (400 MHz, CDC13) spectrum was recorded beforethe 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 tubewas vigorously shaken. Another 1H NMR spectrum was recorded which showedbroadening 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. Theresults of these studies have been presented in discussion of Chapter 2 (p. 109).213References and Notes1. 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. 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(U.S.S.R.) 1948, 18, 499.124. Clase, J. A.; Li, D. L. F.; Lo, L.; Money, T. Can. J. Chem. 1990, 68, 1829.125. for a general review of the Wittig reaction see Maercker, A. Org . React. 1965, 14,270.126. Fraser, R. R.; Petit, M. A.; Saunders, J. K. J. Chem. Soc., Chem. Commun. 1971,1450.127. Simonsen, J. L.; Owen, L. N. The Temenes Vol. II, Cambridge: 1957, p. 447 and579.220128. Dimmel, D.R.; Fu, W. Y. J. Org . Chem. 1973, 38, 1973.129. Hibino, J-i.; Okazoe, T.; Takai, K.; Nozalci, H. Tetrahedron Lett. 1985, 26, 5579.130. Houben, J.; Pfankuch, E. Justus Liebigs Ann. Chem. 1931, 489, 193.131. Houben, J.; Pfankuch, E. Justus Liebigs Ann. Chem. 1933, 507, 37.132. Joshi, G. C.; Warnhoff, E. W. J. Org . Chem. 1972, 37, 2383.133. note: the use of TiC14an/CH2Br2 (Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H.Bull. Chem. Soc. Jpn. 1980, 53, 1698.) gave yields >95%134. a) Vedejs, E. J. Am. Chem. Soc. 1974, 96, 5944. b) Vedejs, E.; Telschow, J. E.J. Org . Chem. 1976, 41, 740. c) Vedejs, E.; Engler, D. A.; Telschow, J. E. ibid.1978, 43, 188.135. a) Davis, F. A.; Wei, J.; Sheppard, A. C.; Gubernick, S. Tetrahedron Lett. 1987,28, 5115. b) Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703.136. Bowers, A.; Halsall, T. G.; Jones, E. R. H.; Lemin, A. J. J. Chem. Soc. 1953,2548.221Appendix1. X-ray crystal structure of alcohol 158:2222. X-ray crystal structure of ketone 171:223

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