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The chemistry of thujone : enantioselective syntheses of drimanetype antifeedants and ambergris fragrances Chen, Yong-Huang 1992

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THE CHEMISTRY OF THIJJONE: ENANTIOSELECTIVE SYNTHESES OF DRIMANETYPE ANTIPEEDANTS AND AMBERGRIS FRAGRANCESYong-Huang ChenB.Sc., Amoy University, 1985A THESIS SUBMflTED 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 UNWERSITY OF BRITISH COLUMBIAJanuary 1992©Yong-Huang Chen, 1992In 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./ ,‘Department of__________________The University of British ColumbiaVancouver, CanadaDate 1/12/L( I, 7 aDE-6 (2/88)AbstractThis thesis is concerned with the development of thujone (3) as an effective chiralbuilding block for natural product synthesis.Treatment of thujone (3) with ozone in solution gave thujonol (94) and thujonone (95)in a good total yield (70%) via oxidation of the tertiary carbon in the isopropyl side chain. Thistype of selective oxidation with ozone was generally applicable to a series of thujonederivatives, thus providing versatile intermediates for the syntheses of compounds of interest inthe fields of insecticides and perfumery chemicals.Studies on acid promoted ring cleavage of cyclopropylcarbinols obtained fromozonation revealed three distinct pathways, depending on substrates and reaction conditions.Treatment of 97 with concentrated hydrochloric acid gave chloride 123 while heating alcohol130, derived from thujone in five steps, in dioxane:water with a catalytic amount of ptoluenesulfonic acid generated homoallylic alcohol 144. On the other hand, concentratedhydrobromic acid treatment of 120, obtained from thujonol (94) by Robinson annulation,resulted in bromide 322.Compound 322 was further reduced with tributyltin hydride to natural (+)-J3-cyperone(8), thus completing a new four step synthesis from thujone (3).In a projected synthesis of drimane antifeedants (-)-polygodial (2) and (-)-warburganal(10), a novel radical-mediated ring expansion from 123 to 126 was discovered when theformer was treated with tributyltin hydride. However, when a related intermediate 132,derived by treatment of 130 with hydrochloric acid, was reacted in this manner, norearrangement but simple reduction to 133 was observed. Clearly, the ring expansion processis critically dependent on the nature of functionality in ring A.Generation of 126 and, in turn, subsequent intermediates afforded a convenient routeto the exclusion of the original isopropyl side chain in many thujone-derived compounds byozonolysis.11An alternative route developed for the exclusion of the isopropyl side chain involvedBaeyer-Villiger oxidation. For example, ketone 131 available from ozonation of alkane 128,when subjected to m-CPBA oxidation, provided acetate 160, which after hydrolysis tocyclopropanol 161 and treatment of the latter with ferric chloride yielded 13-chloroketone 162.The enone 163, obtained from dehydrochlorination of 162, was converted to dienone168 with phenylselenenyl chloride and hydrogen peroxide. Birch reduction of 168 generatedthe crucial intermediate 64. Since enone 64 had been previously converted to (-)-polygodial(2) and (-)-warburganal (10), a formal enantioselective synthesis was thus completed.The enone 163 could also serve as an attractive intermediate for the synthesis of (-)-Ambrox® (179). Stereoselective conjugate addition of enone 163 with vinylmagnesiumbromide and cuprous iodide yielded compound 245 which was further regioselectivelymethylated to 246. Introduction of a double bond into 246 via selenium chemistry as notedabove furnished 250 which was reduced to the trans-fused decalone 251 by Birch reduction.L-Selectride treatment of 251 produced the axial alcohol 253 and subsequent hydroborationyielded the 1,5-diol 255. p-Toluenesulfonic acid catalyzed cyclization of the 1,5-diol 255provided the potent ambergris odorants ()Ambrox® (179) and an interesting rearrangementcompound 257 as major products. At lower temperature (80°C), 179 was the major productwhile 257 became predominant at higher temperature (100°C).Ring expansion of thujone was also investigated in order to explore alternative routesleading to the synthesis of (2) and (179). Reaction of thujone (3) with ethyl diazoacetategenerated 3-Ketoester 270, which upon decarboxylation furnished “homothujone’(272).Robinson annulation of compound 272 yielded enone 274. Alkane 291 was derived from274 in three steps and its ozonation reaction was performed. Surprisingly, the normallyobserved attack at the tertiary carbon of the isopropyl side chain did not occur. Instead, ketone292 was isolated as the major product.111Q”?ll 0’H °i( °H x:::f::<95 0 :97 123O1T_130 144 322 8ç3 cE!3=< “r126 132 133 128 131CI CHOOR ctiCHO160: R=Ac 162 163 168 64 2: R=H161: R=H 10: R=OH0245 246 250 251 253cE;c90o255 179 2570 OEt 272 274 291 292270ivTable of ContentsAbstract.iiList of Figures .ixList of Schemes xiList of Tables xiiiList of Abbreviations xivAcknowledgements xviiChapter 1. General Introduction 11.1. Synthesis of Enantiomerically Pure Compounds 11.2. Thujone as a Chiral Building Block 3Chapter 2. Studies Directed to the Synthesis of (-)-Polygodial and (-)-Warburganal. . . .62.1. Introduction 62.1.1. Drimane-type Antifeedants 62.1.2. Total Synthesis of Drimane-type Antifeedants 112.2. Discussion 242.2.1. General Considerations about the Synthesis of (-) -Polygodial (2)and (-)-Warburganal (10) from Thujone (3) 242.2.2. Ozonation of Thujone and Its Derivatives 252.2.3. Stereochemistry of Hydrogenation of Thujone-derivedTricyclic Enones 342.2.4. Acid Promoted Ring Cleavage of Thujone-derivedCyclopropylcarbinols 412.2.5. The Radical-mediated Rearrangement 452.2.6. Failure of the Radical-mediated Ring Expansion Reaction 492.2.7. Further Studies on the Acid-promoted Ring Cleavage ofCyclopropylcarbinols 582.2.8. Baeyer-Villiger Oxidation of Cyclopropyl Ketones 672.2.9. Regioselective Ring Opening of the Cyclopropyl Alcohol 161 722.2.10. A Formal Enantioselective Synthesis of (-)-Polygodial (2)and (-)-Warburganal (10) 772.3. Experimental 812.3.1. General 812.3.2. Ozonation: thujone (3) to thujonol (94) and thujonone (95) 832.3.3. Catalytic Hydrogenation: enone 7 to ketone 96 84V2.3.4. Ozonation: ketone 96 to ketol 97 and dione 98 .852.3.5. Ozonation: dione 104 to hydroxydione 106 and trione 107 872.3.6. Catalytic Hydrogenation: enone 113 to ketone 114 892.3.7. Aldol Condensation: hydroxydione 106 to hydroxyenones 117and 118 892.3.8. Catalytic Hydrogenation: hydroxyenones 117 and 118 to ketol 120.912.3.9. Methylation: ketol 97 and 120 to ketol 121 922.3.10. Robinson Annulation: thujonol (94) to hydroxyenone 122 932.3.11. Cyclopropane Ring Opening Reaction: ketol 97 to chloroketone 123.942.3.12. Radical-mediated Rearrangement: chioroketone 123 toenones 125 and 126 952.3.13. Methylation: ketone 96 to ketone 119 962.3.14. Woif-Kishner-Huang Minion Reaction: ketone 119 to aikane 128 .972.3.15. Ozonation: alkane 128 to alcohol 130 and ketone 131 982.3.16. Dehydration: alcohol 130 to alkene 138 1002.3.17. Cyclopropane Ring Opening Reaction: alcohol 130 to chloride 132 .1012.3.18. Ozonolysis: alkene 138 to ketone 131 1012.3.20. Conversion of 138 to 133 via 139 1032.3.21. Reduction by Bu3SnH: chloride 132 to alkene 133 1042.3.22. Cyclopropane Sliding Reaction: alcohol 130 to alcohol 144 1042.3.23. Epoxidation: alcohol 144 to epoxyalcohol 147 1052.3.24. Reductive Fragmentation by LAH: epoxyalcohol 147 toallylic Alcohol 151 1062.3.25. Allylic Oxidation by Mn02: homoallylic alcohol 151 to enone 152 .1072.3.26. Cyclopropane Sliding Reaction: alcohol 130 to acetates 153and 154 1082.3.27. Cyclopropane Sliding Reaction: ketol 117 to ketol 155 1102.3.28. HOAc Promoted Ring Opening: ketol 117 to ketoacetates 156and 157 1112.3.30. Saponification: acetate 160 to cyclopropanol 161 1132.3.31. Cyclopropane Ring Opening Reaction by FeCl3: cyclopropanol 157to 13-chloroketone 162 1142.3.32. Dehydrochiorination: f3-chloroketone 162 to enone 163 1152.3.33. Ring Opening Reaction by NBS: cyclopropanol 161 to-bromoketone 167 1162.3.34. Dehydrogenation: enone 167 to dienone 168 117vi2.3.35. Birch Reduction: dienone 168 to enone 64 1182.3.36. Dehydrogenation: ketone 171 to dienone 172 1192.3.37. Birch Reduction: dienone 172 to enone 173 and ketone 174 119Chapter 3. The Synthesis of Ambergris Fragrances 1223.1. Introduction 1223.1.1. Ambergris Fragrances 1223.1.2. Structure and Activity Relationship of Ambergris Fragrances 1253.1.3. Synthesis of Ambrox® 1283.2. Discussion 1373.2.1. Retrosynthetic Analysis for Synthesis of ()Ambrox® (179)from Enone 163 1373.2.2. Studies on Conjugate Addition to Enone 163 and SubsequentMethylation of 245 1393.2.3. Conversion of cis-fused y,-enone 246 to trans-fused y,ö—251 1483.2.4. Synthesis of Diol 255 from trans-Fused y,6-Enone 251 1533.3. Future Developments 1643.4. Experimental 1673.4.1. Conjugate Addition: cL,3-enone 163 to cis-fused y,6-enone 245 1673.4.2. Methylation by LDA and Iodomethane: cis-fused y,ö-enone 245to cis-fused y,-enone 246 1683.4.3. Dehydrogenation by PhSeCI/H20:cis-fused ‘y,6-enone 246to dienone 250 1693.4.4. Birch Reduction: dienone 250 to trans-fused y,ö-enone 251 1703.4.5. Reduction by L-Selectride: trans-fused -enone 251 toalcohol 253 1713.4.6. Hydroboration: alcohol 253 to 1,5-diol 255 1723.4.7. Cyclization: 1,5-Diol 255 to 179, 189, and 257 173Chapter 4 Exploratory Studies of Different Strategies to Develop Thujone as a ChiralBuilding Block 1764.1. Studies on ‘Homothujone” and Its Derivatives: a new strategy 1764.1.1. Regioselective Ring Expansion of Thujone 1784.1.2. Stereoselective Robinson Annulation of Homothujone (272) 1844.1.3. Attempted Generation of the trans-Fused Hydrocarbon 284 1894.1.4. Ozonation of 291 1984.2. Studies on Utilizing the C2-C3 Bond Cleavage Products: a strategy 2004.3. A Formal Synthesis of(+)-13-Cyperone: a ].Q strategy 204vii4.4. Concluding Remarks: prospect of thujone chemistry 2134.5. Experimental 2164.5.1. Ring Expansion: thujone (3) to ketoester 270 2164.5.2. Decarboxylation: ketoester 270 to homothujone (272) 2174.5.3. Robinson Annulation: homothujone (272) to enone 274 2184.5.4. Birch Reduction-CH3I Trapping and Birch Reduction-TMSC1Trapping-Simmons-Smith Reaction-Hydrolysis Sequences: enone274 to ketone 277 2194.5.5. Catalytic Hydrogenation: enone 274 to ketone 278 2214.5.6. Methylation: a,3-enone 274 to 13,y-enone 282 2224.5.7. Wolf-Kishner-Huang Minlon Reaction: 3,y-enone 282 toalkene 283 2234.5.8. Hydroboration: alkene 283 to diol 285 and alcohol 286 2244.5.9. Hydroboration: alkene 283 to diol 285 and alcohol 286 2254.5.10. 0-Methylation: ketone 278/279 to methyl enol ether 280 2264.5.11. Wolf-Kishner-Huang Minlon Reaction: ketone 277 to Alkane 291 . .2274.5.12. Ozonation: alkane 291 to ketone 292 and alcohol 293 2284.5.13. Ketoacid 308 2294.5.14. Methylation by Diazomethane: ketoacid 308 to ketoester 309 2304.5.15. Ozonation: ketoester 309 to compound 310 2304.5.16. Cyclopropane Ring Opening Reaction: thujonol (94)to bromoenone 318 and carvacrol (319) 2314.5.17. Cyclopropane Ring Opening Reaction: thujonol (94)to chloroenone 320 and carvacrol (319) 2334.5.18. Cyclopropane Ring Opening Reaction: hydroxyenone 122 tobromodienone 322 233Bibliography 235Appendix 1 X-ray Structure Report on Epoxide 147 247Appendix 2 X-ray Structure Report on Diol 285 259viiiList of FiguresFigure 1 Drimane Antifeedants .7Figure 2 Analogues of Drimane Antifeedants 9Figure 3 Interaction between Drimane Antifeedants and the Insect’s Receptor:the first hypothesis 9Figure 4 Interaction between Drimane Antifeedants and the Insect’s Receptor:the second hypothesis 10Figure 5 Chiral Starting Materials for the Synthesis of (-)-Warburganal (10) 22Figure 6 Oxygen Insertion into Carbon-Hydrogen Bonds 31Figure 7 Oxygen Insertion into Carbon-Carbon Bonds 32Figure 8 Decoupling Experiments on Ketone 96 36Figure 9 Single Crystal X-ray Structure of 98 (PLUTO Drawing) 37Figure 10 Comparison of CD Spectra of 121 Prepared from Two Different Routes . .40Figure 11 A Notation of Ring Cleavage Reactions 42Figure 12 Rationalization of HC1 Promoted Ring Cleavages 44Figure 13 A Proposed Mechanism for the Novel Ring Expansion of 123 46Figure 14 Rationalization of the “Methyl Effect” 57Figure 15 Single Crystal X-ray Structure of Epoxide 147 (ORTEP Drawing) 60Figure 16 Mechanism of the Fragmentation of Epoxide 147 63Figure 17 Mechanism of the “Cyclopropane Sliding Reaction” 64Figure 18 Regioselective Cleavage of Cyclopropanols 72Figure 19 FMO Interactions of Carbinyl and Oxyl Radicals with Cyclopropane C-CBonds 76Figure 20 The Constituents of Ambergris 123Figure 21 Stereoisomers of ()Ambrox® 126Figure 22 The Effect of the gem-Dimethyl Groups on the Ambergris Odor Activity .. .126Figure 23 Triaxial Rule of Ambergris Odor Sensation 127Figure 24 The Ambergris Triangle Rule 127Figure 25 Several Other Diterpene Starting Materials for ()Ambrox® Synthesis 132Figure 26 Potential Candidate Intermediates for the StereoselectiveConjugate Addition 142Figure 27 Decoupling Experiments of 246 147Figure 28 Stereochemistry of Phenylselenenylation of 246 151Figure 29 Structural Analysis of Stereoselective Reduction Product 253 154ixFigure 30 1,4-Diols Utilized for Acid Catalyzed Cyclization to ()Ambrox® 156Figure 31 Mechanistic Analysis of Cationic Cyclizations of 202 and 235 157Figure 32 Mechanism for the Formation of 257 162Figure 33 The Conversion of 3-13-Friedelanol (263) into 13 (18)-Oleanene (264) 163Figure 34 Decoupling Experiments of 272 181Figure 35 Conformational Analysis of 270cx and 272x 183Figure 36 Explanation for Regioselectivity of the Carbon Insertion Reaction 183Figure 37 2D-HETCOR spectrum of 274 187Figure 38 The ‘3C Broad Band Decoupling (BB) and APT Spectra of 274 188Figure 39 The NOE Experiments of 274 190Figure 40 Single Crystal X-ray Structure of 285 (ORTEP Drawing) 195Figure 41 Novel Cyclopropane Ring Cleavage in the Hydroboration of 283 196Figure 42 A Structural Misperception for 301 203Figure 43 The Endo-type Cleavage Mechanism for the Formation of 318 and 319 . . .208Figure 44 The Ring Opening reaction of 122 via the Endo-type Cleavage Pathway . . .212Figure 45 Incorporation of a Dimethylated Bicylo[3.3.0]octane unit 213Figure 46 Single Crystal X-ray Structure of Epoxide 147 (PLUTO Drawing) 249Figure 47 The Unit Cell Structure of Epoxide 147 (Packing Diagram) 250Figure 48 Single Crystal X-ray Structure of Diol 285 (PLUTO Drawing) 261Figure 49 The Unit Cell Structure of Diol 285 (Packing Diagram) 262xList of SchemesScheme 1 Robinson Annulation of Thujone .4Scheme 2 Ozonation of Thujone and Its Derivatives 5Scheme 3 de Groot’s Synthesis of (±)-Polygodial 12Scheme 4 Cortes’ First Synthesis of (-)-Polygodial (2) 13Scheme 5 Cortes’ Second Synthesis of (-)-Polygodial (2) 14Scheme 7 Mon’s Synthesis of (+)-Polygodial (21) 16Scheme 8 He and Wu’s Synthesis of (-)-Polygodial (2) 17Scheme 9 de Groot’s Synthesis of (-)-Polygodial (2) 18Scheme 10 Kutney’s Synthesis of (-)-Polygodial (2) 19Scheme 11 Goldsmith’s Synthesis of (±)-Warburganal 20Scheme 12 Kende’s Synthesis of (±)-Warburganal 21Scheme 13 Ohno’s Synthesis of (-)-Warburganal (10) 23Scheme 14 The Overall Plan towards the Synthesis of (-)-Polygodial (2) and(-)-Warburganal (10) 25Scheme 15 A Perceived Sequence to Utilize Alcohols Derived from Ozonation ofThujone Derivatives 26Scheme 16 An Ozonation Route to a trans-fused Decalone (Retrosynthetic Analysis) . . .27Scheme 17 Generality of Selective Ozonation of Thujone Derivatives 29Scheme 18 Attempted Catalytic Hydrogenation of Tricyclic Enones 39Scheme 19 Gao’s Synthesis of a (-)-Polygodial Analogue 127 48Scheme 20 Gunning’s Synthesis of Rose Oil Fragrances 48Scheme 21 A Revised Plan to an Enantiomerically Pure, trans-fused Decalone 65 49Scheme 22 Radical-initiated Selective Ring Cleavage of a Vinylcyclopropane 136 54Scheme 23 Radical-initiated Ring Cleavage of Vinylcyclopropane 138 55Scheme 24 Precedents of the Endo-type Cleavage 58Scheme 25 Generality of the Cyclopropane Sliding Reaction 66Scheme 26 Utilization of Cyclopropyl Ketone 131 via Baeyer-Villiger andCyclopropanol Cleavage Reactions 69Scheme 27 The Preparation of Enantiomerically Pure Enone 64 from 163 77Scheme 28 A Possible Sequence to a New (-)-Polygodial Analogue 80Scheme 29 Stoll and Hinder’s Synthesis of ()Ambrox® from Sclareol (187) 129Scheme 30 Nafs Synthesis of ()Ambrox® from Sclareol 130Scheme 31 Christenson’s Synthesis of ()Ambrox® from Sclareol 131xiScheme 32 Coste-Manere’s Synthesis of ()Ambrox® from Sciareol 132Scheme 33 Cortes’ Synthesis of ()Ambrox® from (-)-Drimenol (33) 133Scheme 34 Mori’s Synthesis of ()Ambrox® from Geranylacetone (219) 134Scheme 35 Matsui’s Synthesis of (±)Ambrox® from Dihydro-3-ionone (226) 135Scheme 36 Buchi and Wuest’s Synthesis of (±)Ambrox® fromDihytho--ionone (226) 136Scheme 37 Retrosynthetic Analysis for Synthesis of ()Ambrox® 137Scheme 38 Conjugate Addition of Organocopper Reagents to trans-Fused Octalones ...140Scheme 39 Conjugate Addition of Organocopper Reagents to Cross-conjugatedDienones 140Scheme 40 Conjugate Addition of Organocopper Reagents to a cis-Fused Octalone .. . .141Scheme 41 The Formulation of “lonoxide” 158Scheme 42 A Possible Shorter Route to Compound 257 164Scheme 43 A Possible Synthesis of Compound 192 165Scheme 44 A Possible Synthesis of (-)-epi-Ambrox (190) 166Scheme 45 A Possible Synthesis of Ambraoxide (186) 166Scheme 46 The Potential of a Regioselective Ring Expansion Reaction 177Scheme 47 “Homothujone” Strategy for Syntheses of Various Natural Products 178Scheme 48 An Alternative Sequence to Hydrocarbon 284 193Scheme 49 An Alternative Route to Ketone 277 197Scheme 50 Ring Cleavage of seco-(C2-C3) Cyclopropylcarbinols 200Scheme 51 A Novel Sequence to (-)-Polygodial (7) 201Scheme 52 The Utilization of a seco-(C2-C3) Intermediate 308 202Scheme 53 The Final “seco/corro” Strategy to the Synthesis of (-)-Polygodial (7) . .204Scheme 54 A Formal Synthesis of (+)-13-Cyperone (8) 210Scheme 55 A Potential New jj Strategy 212xiiList of TablesTable 1 Comparison of Dry and Wet Ozonation of Thujone .27Table 2 The Wet Ozonation of 96 to 97 and 98 30Table 3 Yield Optimization for Conversion of 123 to 126 47Table 4 The Optimization of Baeyer-Villiger Reaction of Ketone 131 70Table 5 Cyclization of the 1,5-Diol 255 under Different Conditions 161Table 6 Final Atomic Coordinates (fractional) and Beq (A2)of Epoxide 147 251Table 7 Hydrogen Atom Coordinates (fractional) and B0 (A2) of Epoxide 147 252Table 8 Bond Lengths (A) of Epoxide 147 253Table 9 Bond Angles (deg) of Epoxide 147 254Table 10 Torsional or Conformational Angles (deg) of Epoxide 147 255Table 11 Final Atomic Coordinates (fractional) and Beq (A2) of Diol 285 263Table 12 Hydrogen Atom Coordinates (fractional) and B0 (A2) of Diol 285 264Table 13 Bond Lengths (A) of Diol 285 265Table 14 Bond Angles (deg) of Diol 285 266Table 15 Torsional or Conformational Angles (deg) of Diol 285 267xliiList of Abbreviations2D-HETCOR two dimensional heteronuclear correlation spectroscopy25 . . o1D specific rotation recorded at 25 C using sodium D-lineAc acetylAIBN 2,2-azoisobutylnitrileAPT attached proton test (in ‘3C NMR)aq. aqueousax axialBB broad band decoupling (in 13C NMR)Benz. benzenebs broad singletc concentrationCA Chemical AbstractCD circular dichroismcm1 wave numberconc. concentratedcont. continue6 chemical shiftd doubletdd doublet of doubletsDDQ 2,3-dichloro-5,6-dicyano- 1 ,4-benzoquinonemolar circular dichroismDEG diethylene glycoldeg degree (angle)DHP dihydropyranDIBAL diisobutylaluminum hydrideDMAP 4-dimethylaminopyridineDME dimethoxyethaneDMF N,N-dimethylformamideDMS dimethyl sulfideDMSO dimethyl sulfoxidedt doublet of tripletseq equatorialeqv equivalentxivEt ethylEVK ethyl vinyl ketoneFMO frontier molecular orbitalg gramGC gas-liquid chromatographyHMPA hexamethyiphosphoramidehv light radiationHOMO highest occupied molecular orbital (energetically)Hz Hertzi-Pr isopropylJR infraredJ coupling constantwavelengthL-Selectride lithium tri-sec-butylborohydrideLAH lithium aluminum hydrideLDA lithium diisopropylamidelogE the log of extinction coefficientLTA lead tetraacetateLUMO lowest unoccupied molecular orbital (energetically)M molarm multipletM+ molecular ionm-CPBA meta-chloroperbenzoic acidm.p. melting pointm/z mass to charge ratiomax. maximumMe methylmg milligramMHz megahertzmm minutei1 microlitermmol millimoleMS mass spectrometryMVK methyl vinyl ketonev frequencyNB S N-bromosuccinimidexvnm nanometerNMR nuclear magnetic resonanceNOE nuclear Overhauser effect°C degree CelsiusORTEP oak ridge themal ellipsoid programPCC pyridinium chlorochromatePh phenylppm part per millionpyr. pyridineO effipticity angle[9] molar effipticity angleq quartetr. t. room temperatures singletSOMO singly occupied molecular orbitalt tripletTBDMS t-butyldimethylsilylTHF tetrahydrofuranTMS trimethylsilylTs para-toluenesulfonylUV ultravioletv/v volume to volume ratioA AngstromxviAcknowledgementsI wish to express my gratitude to my research supervisor, Dr. James Kutney, for hisvaluable guidance and advice both during the course of this work and in the preparation of thisthesis.I am thankful to Professor Williams von egger Doering at Harvard University forinitiating the Chemistry Graduate Program (CGP) between the People’s Republic of China anda group of North American Universities, to which I was admitted in 1986. I am also gratefulto the late Professor Xuemin Gu, the former Head of Department of Chemistry at AmoyUniversity, for giving me unforgettable encouragement and help during my preparation for theadmission examination.Financial assistance from the State Education Commision of the People’s Republic ofChina and the University of British Columbia are gratefully acknowledged.The technical expertise of the staff in the NMR, mass spectrometry, X-ray diffractionanalysis, and microanalysis services as well as the glass blowing, mechanical, and electronicshops is very much appreciated.Thanks are also due to Huachun Zeng, Shichang Miao, Duson Milatovic, EdwardKoerp, and Thomas Hu, whose friendships have made my life more pleasant and enjoyable inthe past few years.It is a great pleasure to express my appreciation of past and present members of Dr.Kutney’s research group, Francisco Lopez, Mijo Samija, Kang Han, Francisco Kuri-Brena,Carles Cirera, Kai Li, and many others, for their advice, enlightening discussions, andunending help. I owe the secretary Pat much for her many little nice suggestions.I am indebted to Thomas Hu, Drs. Phil Gunning, and Terry Jarvis for meticulousproofreading and constructive criticism.Especial thanks go to my mother, whose caring, support, and exemplification give mestrength and inspiration throughout these years of education.xviiCD CD B 0 -t 0 B -I.’ CD -IIf there is one way better than another,It is the way of NatureAristotlexvivChapter 1. General Introduction1.1. Synthesis of Enantiomerically Pure CompoundsThe synthesis of a chiral compound in its enantiomerically pure form has become animportant goal for organic chemists in recent years. In addition to aesthetic reasons, the verydependence of various biological activities on absolute stereochemistry”2dictates pureenantiomers to be prepared and investigated in academic research and frequently onlyenantiomerically pure agents to be produced in industry. A racemic drug, (±)-thalidomide, hadto be withdrawn from the market due to a serious side effect of one of the enantiomers. It wasreported3that (R)-(+)-thalidomide (1), an effective sedative, had no teratogenic effects whenadministered to rats and mice even at high doses; but its enantiomer, (S)-(-)-thalidomide, wasdevoid of sedative effect and resulted in deformities in the animal tested. (-)-Polygodial (2), adrimane type sesquiterpene, showed a potent antifeedant activity against African army wormswhile its enantiomer (+)-polygodial and the racemic mixture exhibited an undesirablephytotoxic effect4.:QThree basic methods are available to produce enantiomerically pure compounds,including resolution of racemates, application of asymmetic synthesis, and use of chiralmaterials as building blocks. Each method has its own advantages and drawbacks5:1. ResolutionThe risk associated with a projected synthesis based upon a resolution is evidentbecause of the empirical nature of resolution; resolution is potentially wasteful unless the1 21undesired enantiomer can be recycled; it has to be performed early in the synthetic sequence toavoid further waste of reagents and labor. However, many resolutions have been successfullycarried Out. Resolution provides a rapid access to both enantiomers of a compound, which isdesirable in biological studies.2. Asymmetric SynthesisAsymmetric synthesis holds great promise in producing chiral molecules effectively, asreflected by the vigorous activities in this field in recent years. It has even greater efficiency ifthe chiral auxiliary is employed catalytically. However, only a few asymmetric syntheses canprovide products of high enantiomeric excess reliably without resorting to further enantiomericenrichment.3. Chiral Building BlocksThe third method is to utilize readily available chiral molecules, either naturallyoccurring products or their derivatives, as starting materials (i.e., chiral templates). If thesechiral building blocks are enantiomerically pure and racemization is avoided by choosingreaction conditions carefully, the method is the safest way of obtaining enantiomerically purecompounds. However, the initial chiral molecules have to be consumed during theirincorporation into target molecules. Moreover, because of the limited spectrum of readilyavailable chiral compounds, substantial chemistry has to be implemented for their conversioninto viable enantiomerically pure intermediates, the preparation of which in racemic form issimpler in perception and / or execution.All these methods are in some way related to the ‘chiral pooi derived from Nature. Inresolution, a chiral compound is used to convert enantiomers into two diastereomers or todifferentiate them through chemical reactions (i.e., kinetic resolution); in asymmetric synthesis,a chiral auxiliary is employed either catalytically or stoicheometrically to introducediastereomeric transition states; as a building block, a chiral molecule becomes an integratedpart of the target. Therefore, additions to this ‘chiral pool’ by the introduction of newenantiomerically pure compounds and modification of existing ones are always welcomed.21.2. Thujone as a Chiral Building BlockThe occurrence of thujone (3) in Western red cedar (Thuja plicata Donn) was reported7as early as in 1939 and its absolute stereochemistry was assigned8 in 1964. This naturalproduct is actually a mixture of two epimers, (-)-x-thujone (4) and (+)-f3-thujone (5)(4:5=10:1). Of these two epimers, ct-thujone is slightly more stable. Treatment of thujone (3)with potassium hydroxide in ethanol9gave an equilibrium mixture containing c-thujone and f3-thujone in a ratio of approximately 2 to 1.The logging practice of Western red cedar which is abundant in British Columbiaforests generates a waste product, generally called “slash”. The slash consists of the left-overbranches, and leaves. It often must be removed for reforestation and elimination of thepotential fire hazard. Alternatively, “on-site” steam distillation of the slash produces anessential oil containing thujone up to 88%, thus providing an inexpensive source of thujonewhile also serving as a means of removing the left-over slash7, Although the oil obtained canbe sold for use in the perfumery industry, higher grade chemical products originating from itare well sought after in recent years from the viewpoints of both economic opportunity andenvironmental concern. In fact, recent synthetic work in our laboratories has proven thatthujone is a viable chiral starting material for the enantioselective synthesis of biologicallyactive natural products and their analogues including juvenile hormone analogues’0,pyrethroidinsecticides11,aryl terpenoids’2,sesquiterpenes13,steroids14,and insect antifeedants’5783 4 53The novelty of thujone chemistry stems from its unique structural features. Thebicyclo[3.l.Ojhexane moiety is a cisfusion# of the two smallest odd-rnernbered rings (i.e., 3-membered ring and 5-membered ring). The inherent cyclopropane ring should manifest theclose relevance of thujone chemistry to the chemistry of cyclopropyl group17 since itstransformation is a necessity for most synthetic efforts. The carbonyl group would lend itsversatility to a great range of synthetic elaborations.The Robinson annulation of thujone (3) is a pivotal transformation in which aquaternary carbon center was generated in a highly stereoselective mannerl3aJ8(Scheme 1).Presumably, the approach of Michael acceptors (e.g., MVK and EVK) took place exclusivelyfrom the less hindered convex side of the more stable enolate (i). Subsequent aldolcondensation of the products (ii) generated tricyclic enones 6 and 7.baseR6: R=H7: R=CH3Scheme 1 Robinson Annulation of ThujoneThis newly generated quaternary center became a reference point in correlating thethujone structure with chosen target molecules, for example, (+)--cyperone (8)13a, (polygodial (2)15, and the steroid analogue 9•1413There is no organic molecule known to possess a trans-fused bicyclo[3. 1 .O]hexane moiety (see ref. 16).3 (i)R(ii)R4CHOAnother important transformation recently discovered is the selective functionalizationof the tertiary carbon at the isopropyl side chain of thujone and its derivatives by ozonation(Scheme 2). The importance of such a functionalization lies in the possible utilization of twooperations required in the synthesis of different target molecules by using intermediates derivedfrom the ozonation process. These two operations are the exclusion of the isopropyl side chainand the regioselective ring cleavage of the cyclopropyl group. The ozonation reaction has beenapplied to synthesis of drimane antifeedants’5,rose oil fragrances46,and more recently,ambergris fragrances (to be described in this thesis).03Scheme 2 Ozonation of Thujone and Its DerivativesThis thesis is divided into three parts: the first part deals with a formal enantioselectivesynthesis of (-)-polygodial (2), a potent insect antifeedant; the second part describes thesynthetic studies leading to products of ambergris fragrance, one of the most valuable animalfragrances; the third part discusses some exploratory studies of new strategies to developthujone as a more versatile chiral building block.H08 2 9+5Chapter 2. Studies Directed to the Synthesis of (-)-Polygodial and(-)- Warburganal2.1. Introduction2.1.1. Drimane-type AntifeedantsAlong with herbicides, insecticides are presently the most useful agrochemicals toprotect food and cropsl919.2O. Insecticides can be divided into two groups. The first groupincludes synthetic organochiorines, organophosphates, dinitrophenols, formamidines,carbamates, and pyrethroids together with the naturally occuring nicotine, rotenone (Derris),sabadilla, and ryania. They have wide applications due to their effectiveness, low cost, andeasy usage. However, there are certain disadvantages associated with them: many are quitetoxic to vertebrates, fish or beneficial lower forms of life, and are non-selective, killing bothpest insects and beneficial insects; some are extremely persistent in the environment and arelikely to accumulate in animals; higher and possibly phytotoxic dosages are required becauseof the developed resistance of some pest insects. The second group of insecticides consist ofrepellents, attractants, pheromones, insect growth regulators, oviposition inhibitors, andantifeedants. They promise to overcome drawbacks of the first group agents and are attractingthe attention of researchers worldwide21’2.These compounds are readily degradable and thusfriendly to the environment. They are highly specific in insect-plant, insect-insect relations orcertain processes within the insect, and therefore less toxic to human beings and useful insects.Many of them are mimics of or even the same as compounds which are essential in the lifeprocesses of the pest insect, thus making it more difficult for the insect to restrict the uptakeand detoxify such molecules than in the case of synthetic insecticides. In other words, thedevelopment of resistance from the target insect is less likely to happen.According to Munaka23a,an antifeedant is defined as a chemical which does not kill theinsect directly but inhibits feeding, the insect often remaining near the treated plant material and6possibly dying through starvation. An antifeedant is different from an olfactory repellentwhich is usually a volatile compound that repels the insect before it starts to eat. The exactmode of action of these antifeedants is still largely speculative23”.They are believed to playa major role in the ever continuing battle for survival between insects and plants24. Probablyall plants contain one or more substances which are unpalatable to insects. Plants selectionprogrammes in the evolution process have often chosen varieties with higher contents ofantifeedants. The use of these compounds as crop protection agents seems to bear considerablepromise22’5.12CHCR22: R1=R3H10: =OH,2=R3I-111: R1=OH, R2=H, R3=OH12: =OH, =OAc, R3=HFigure 1 Drimane AntifeedantsSeveral sesquiterpenes, mostly of the drimane type, were isolated from the bark of EastAfrican medical plants Warburgia ugandensis and W. stuhmannii (Cannellaceae). Some ofthese sesquiterpenes (Figure 1)26, (-)-polygodial (2), (-)-warburganal (10), 3-hydroxywarburganal (11), ugandensidial (12), and muzigadial (13), possess strongantifeedant activity against the African army worms, Spodoptera exempta and S. littoralis.More recently, (-)-polygodial (2) and (-)-warburganal (10) were shown to inhibit feeding andcolonization of the aphid of Myzus persicae and to decrease the transmission of different plant1 11146137viruses by the aphid27. Among many other biological activities exhibited by these antifeedants,the hot taste to humans appears the most interesting. Kubo and Ganjain28 suggested acorrelation between the antifeedant activity and the pungent taste experienced by human beings.It should be noted that some of these compounds had also been isolated from other sourceseven before they were tested positive of antifeedant activity, including (-)-polygodial (2) frommarsh pepper Polyonum hydropiper (Polygonaceae)29a)and Drimys lanceolata(Winteraceae)29°,muzigadial (13) identical with canellal from Caneha winterana(Winteraceae)29,and ugandensidial (12) identical with cinnamodial isolated from Cinnmosmafragrans (Canellaceae)29eSIn order to elucidate the relationship between structure and antifeedant activity, a largenumber of compounds, either isolated from plants or prepared by chemical synthesis, havebeen evaluated (Figure 2). The fact that epi-polygodial (14), polygodial derivatives 15, 16,17, 18, cinnamolide (19), and betadiennolide (20), are devoid of any activity, reveals thenecessity of both the C-9f equatorial aldehyde and the enal moiety for the activity in theA/Btrans-fused series26. The (+)-polygodial (21) is as active as naturally occurring (-)-polygodial (2)’, although, earlier, 21 was shown to be highly phytotoxic. Of the two cisfused analogues 22 and 23, only 23 which has a C-9c aldehyde group, has strong activity;this apparent inversion compared with the corresponding trans-fused 2 and 14 wasrationalized3&(see below). The structure and activity of the diastereoisorners saccalutal (24)and isosaccalutal (25) parallel that of (-)-polygodial (2) and epi-polygodial (14): compound24 like compound 2 is active while compound 25 like compound 14 is inactive. Taking thevery active muzigodial (13) into consideration, it is apparent that modification in the ring Aexerts little effect on the activity. Hydroxylation at C9ct enhances the activity, while theintroduction of an acetoxy group at C6 reduces the activity, possibly by steric hindrance.8R1=H,R2=R3CHO=3CH2OH,R2=HR1=CHOH,R2=H,R3=CHO=R3CO2H,R2=H=COMe,R2=H12CHOFigure 2 Analogues of Drimane AntifeedantsBased on the above studies of relationship between structure and antifeedant activity,electrophysiological experiments3la, and biomimetic studies30, two main hypothesesconcerning the actual molecular mechanism were brought forward to correlate structure toactivity. The first suggests (Figure 3) that the enal moiety may act as a thiol acceptor of theinsect’s chemoreceptor membranes in a way similar to the Michael reaction and inhibits theHO HS-RFigure 3 Interaction between Drimane Antifeedants and the Insect’s Receptor: the firsthypothesis14:15:16:17:18:19 2021.CHOLJ24: R=CHO, R2=H25: R1=H,R2=CHO22: R1=CHO, R2=H23: R1=H,R2=CHOCHO CHO9stimuli transduction3la. The lack of activity of epi-polygodial (14) is explained on the basis ofthe steric hindrance of its C-9a aldehyde to the approaching free thiol function on the receptorsurface3lbThe second hypothesis, suggested by Sodano et al.30, assumes that pyrrole formationby reaction of the C8 and C9 dialdehyde moieties with a primary amine of the receptor site isresponsible for the antifeedant activity (Figure 4). Under biomimetic conditions, only theactive (-)-913-polygodial (2) instead of the epi-polygodial (14) reacts with a variety of amines,including L-cysteine, L-lysine, L-alanine, and methyl amine, to give pyrrole derivatives3Oa,b.The shorter distance between the C-8 and C-9 aldehyde groups in (-)-polygodial (2) relative toepi-polygodial (14) is considered to be responsible for its ease of pyrrole ring closure andtherefore the antifeedant activity3oa. The strong activity of the cis-fused dial 23 with an caldehyde group at C-9, in contrast to the cis-fused dial 22 with a 13 aldehyde group at C-9, isrationalized in a similar way using their more stable steroid-like conformationsOc.CHOACHOC/OA14Figure 4 Interaction between Drimane Antifeedants and the Insect’s Receptor: the secondhypothesisBased on these two earlier hypotheses, a new proposal was brought forwardrecently3l , which assumes that a three-pronged interaction between the receptor and the‘OH210substrate, involving pyrrole formation, Michael addition of the thiol group to the enal moiety,and van der Waals interactions involving the ring A (especially at Cl), is responsible for theantifeedant activity.2.1.2. Total Synthesis of Drimane-type AntifeedantsThe discovery of the antifeedant activity of drimane-type sesquiterpenes has stimulateda surging interest in their synthesis in the past decade. An excellent review by de Groot and T.A. van Beekl9bsummarizes all studies prior to 1987. More recently, an updated version by deGroot and Jansen’91describes in detail all published synthetic work prior to early 1990. Sofar, the syntheses of polygodial323,warburganal34’5,cinnamidial36,and muzigodial37 intheir racemic and enantiomerically pure forms have been achieved by different research groups.The following discussion will focus on the enantioselective synthesis of (-)-polygodial and (-)-warburganal. A few racemic syntheses of these two compounds will also be discussed sincethey have direct relevance to our strategy towards the synthesis of drimane-type antifeedants.2.1.2.(a). PolygodialA synthesis of (±)-polygodial and (±)-warbuganal was developed by de Groot et al.32starting from the decalone 26 (Scheme 3). The carbonyl function at C7 was used first tointroduce the necessary functionalized carbon atoms at C8 and C9 and subsequently to generatethe C7, C8 double bond. The fonnylation of 26 and the subsequent dehydrogenation gave theunsaturated keto-aldehyde 27, which underwent a stereoselective conjugate addition bycyanide to 28. The resulting keto-aldehyde 28 was converted to the unsaturated aldehyde 29by reduction of its (n-butylthio)methylene derivative, followed by mild hydrolysis. Protectionof the aldehyde group in 29 and the reduction of the nitrile group in 30 gave compound 31.The epimerization of 31 to 32 was effected by potassium t-butoxide in t-butanol. Acidichydrolysis of 32 then provided (±)-polygodial.1126d, eha, ba) NaH, HCOOMe; b) PhSeC1, H20;c) CN; d) H, HSBu; e) NaBH4,H, H20;(HOCH2);g) DIBAL; h) KOtBu, HOtBu; i) H H20.Scheme 3 de Groot’s Synthesis of (±)-PolygodialSince the conversion of 32 to (±)-warbuganal had been accomplished by MoO5 -hydroxylation of the enolate from 32 followed by the hydrolysis of the resultingcompound32b4,the above sequence also provided a route to (±)-warburganal.CN27 28fCHOg29 30 3132 (±)-polygodial12CHO1) LDA, MoO5HMPT2) H, H20The conversion of (-)-drimenol (33) into the natural enantiomer (-)-polygodial (2) wasreported by Cortes et a133b (Scheme 4). Oxidation of 33 and the subsequent protection of thealdehyde gave 34, which was then oxidized with a catalytic amount of selenium dioxide andbis-(4-methoxyphenyl) selenoxide as co-oxidant to give 35 in 45% yield. Deprotection of 35generated (-)-polygodial (2) in an overall yield of 30%.CH2O(-)-drimenolea, b c2: (-)-polygodiala) PCC; b) HO(CH230H, H; c) Se02,(4-MeOPh)2Se ; d) H, H20.Scheme 4 Corte& First Synthesis of (-)-Polygodial (2)An alternative sequence from (-)-drimenol (33) was published by the same group ofauthors33c(Scheme 5). Acetylation of (-)-drimenol (33) provided acetate 36 which was thenoxidized to produce the allylic alcohol 37. Saponification of 37 by means of potassium32 (±)-warburganal33 34 3513carbonate in methanol resulted in diol 38. Swern oxidation of the diol gave (-)-polygodial (2)in almost quantitative yield. The overall yield of (-)-polygodial was 30% from (-)-drimenol(33).a b c33__CHOOHd2: (-)-polygodiala) Ac20, Pyr.; b) Se02 (cat.), (4-MeOPh)2Se ; c) KOH, MeOH; d) (COd)2,DMSO.Scheme 5 Cortes’ Second Synthesis of (-)-Polygodial (2)A synthesis of both enantiomers of polygodial has been developed by Mon et al.33starting from (S)-3-hydroxy-2,2-dimethylcyclohexanone (40), which was obtained byreduction of dione 39 using Baker’s yeast. The (S)-ketol 40 was converted to diene 42 asindicated in Scheme 6. The Diels-Alder reaction of this diene 42 with dimethylacetylenecarboxylate yielded a 1:1 mixture of 43 and 44. The diastereomeric diesters 43 and44 were separated in 32% and 35% yield by HPLC. They were then utilized as startingmaterials for the preparation of both enantiomers of polygodial.Diester 43 was reduced to trans-fused diester 45. Treatment of 45 with CF3SO2Iand DMPA eliminated the axial hydroxyl group. Hydrogenation of 46 over Pd-C andOAc36 373814reduction of the diester functions gave diol 38. Swem oxidation of this diol 38 provided thenatural (-)-polygodial in an overall yield of 3.0%.a b,c,d[H e,fo)ço HO)(O- I - SiO39 40 41o 0COMe 0 C.QMe 0g, hi:o_c0MMe kC0Me0CH2O CHOj, 1bCH20Hm;:J_CH038 2: (-)-polygodiala) baker’s yeast; b) Me3CMe2SiC1; c) Mel, LDA; d) HCCNa; e) CuSO4;f) H2, Pd-CaCO3;g) MeO2C--C0e; h) HF, CH3N; i) DBU; i) H2, Pd-C; k) CF3SO2I, DMAP; 1) LAH;m) (COC1),DMSO.Scheme 6 Mon’s Synthesis of (-)-Polygodial (2)The diastereomeric diester 44 was transformed into the unnatural (+)-polygodialthrough a slightly different route (Scheme 7). Base-catalyzed isomerization of 44 to a15conjugated diene was followed by elimination of the hydroxyl group to give triene 47.Hydrogenation of this triene afforded the trans-fused diester 48 in 70% yield. LAH reductionof the diester functions produced diol 49 which was then converted to the unnatural (÷)-polygoclial 21 by Swern oxidation in an overall yield of 2.9%.,,0- cOMe 0a,b ‘0Me c44CH2O CHO,CH2O HOe21: (+)-polygodiala) DBU; b) CF3SO21, DMAP; c) H2, Pd-C; d) LAH; e) (COd)2,DMSO.Scheme 7 Mon’s Synthesis of (+)-Polygodial (21)A sequence to (-)-polygodial (2) involving an intramolecular Diels-Alder reaction wasdeveloped by He and Wu33 (Scheme 8). f3-Ionone (50) was treated with sodium hypobromiteto produce 51. Reduction of 51 with LAH, followed by condensation with maleic acid mono1-menthyl ester gave 52 in 36% overall yield. Refluxing of 52 in xylene affordeddiastereomers 53 and 54 in 79% yield at a ratio 1.75:1. The lactone 53 was then reduced to adiol which was cyclized to lactone 55 by p-toluenesulfonic acid in benzene in 76% yield.Oxidative cleavage of 55 with Cr03 furnished 56 in 65% yield which was then hydrogenatedto 57. The carbonyl group in 57 was converted into an olefinic double bond as shown in 58by a three-step sequence in 66% overall yield. LAH treatment of 58 produced the diol 3847 4816which was finally converted to (-)-polygodial (2) by Swern oxidation33b. The overall yieldwas 4.1% from f3-ionone (50).CO2Mendh, i, jH0a) NaClO; b) LAH, 0°C; c)HO2C-CC-COMen,DCC ; d) xylene, reflux, N2; e) p-TsOH,benzene; f) Cr03; g) H2, Pd-C, MeOH; h) NaBH4;i) MeSO2C1, Pyr.; j) DMSO; k) LAH;1) DMSO, (COd)2.Scheme 8 He and Wu’s Synthesis of (-)-Polygodial (2)a b, c50 51 52+55158 38 2: (-)-polygodial17An enantioselective synthesis of (-)-poiygodiai (2) using (-)-carvone (59) as thebuilding block was reported by de Groot et al.(Scheme 9)33e. Robinson annulation of 59 withMVK produced ketol 60 in 55% yield which was dehydrated to 61 in 87% yield.Dimethylation of 61 afforded 62 in 93%yield which was transformed to conjugated diene 63by the Huang Minion modification of Woiff-Kishner reaction reduction in 70% yield.Selective ozonolysis of diene 63 provided enone 64 which was then further reduced toenantiomerically pure 65 by lithium and ammonia in an overall yield of 70%. Since theracemic mixture of 65, i.e., 26, has been transformed to (±)-po1ygodia132(Scheme 3), 65can be converted into (-)-polygodial (2).(-)-dihydrocarvone2: (-)-polygodial0a) MVK, KOH, 0°C; b) KOH, CH3O , heating; c) CH3I, KOLBu; d) NH2N,KOH, 200°C; e) 03; 1) Li, NH3.Scheme 9 de Groot’s Synthesis of (-)-Polygodial (2)cfa b6062 63 646518Another method to prepare enantiomerically pure 65 by using thujone as the chiralstarting material was published recently by Kutney et al.15 (Scheme 10). (+)-3-Cyperone (8)prepared from thujone (3)13a was methylated to a mixture of dienones 67 and 68 in 61%yield. The mixture was then converted into pure dienone 68 by iodine in refluxing hexane in86% yield. Subsequent reduction of 68 produced diene 63 in 85% yield which wasozonolyzed to enone 64 following the previous conditions by de Groot et al. Compound 64was further transformed into enantiomerically pure 65 by Birch reduction.a) EVK, KOH, EtOH; b) H, (CH32C(CHOH);c) KMnO4;d) HBr (aq); e) Bu3SnH; 1) CH3I, NaOMe,DMSO; g) ‘2, hexane; h) KOH, NN2H DEG; i) O3Scheme 10 Kutney’s Synthesis of (-)-Polygodial2.1.2.(b). WarburganalTwo total syntheses of (±)-wargburganal were achieved starting from 5,5,8a-trimethyl-trans-fused-1-decalone (70). Scheme 11 shows the synthesis by Goldsmith et a134g.aBr__________eb, c,d32278 67g68163 6419Formylation of 70 and subsequent dehydrogenation afforded the unsaturated keto-aldehyde 71in high yield. Selective protection of the aldehyde group and the addition of methyllithiumproduced tertiary alcohol 72, which was dehydrated using the Burgess reagent. Osmylation ofdiene 73 provided diol 74. Oxidation, followed by hydrolysis of the acetal group afforded(±)-polygodial.0a,b ‘CHOc,da) NaH, HCO2Et; b) PhSeC1, Pyr./H20;c) H,CH2(CO );d) CH3Li; e) McO2CN-SO3NEt1) 0s04,Pyr.; g) DMSO, Dcc; h) H, H20Scheme 11 Goldsmith’s Synthesis of (±)-WarburganalKende et al.34h reported the synthesis outlined in Scheme 12. Decalone 70 wasconverted into the selectively protected unsaturated ketone 75 by formylation, dehydrogenationwith DDQ and reaction with 1 ,3-propanediol. The hindered carbonyl function in 75 did notreact with several ylides, but addition of substituted organometallic reagents can beaccomplished in good yield. Thus, addition of [methoxy(trimethylsilyl)-methyl]lithium gave adiastereomeric mixture of alcohols 76, which underwent elimination of trimethylsilanol toafford a 1:3 mixture of (E) and (Z) enol ethers 77 and 78. Epoxidation of the (E) isomer 7770 71 72f73CHO74 (±)-warburganal20gave the x-epoxide 79, which could be hydrolyzed under mild acidic condition to (±)-warburganal. Epoxidation of the (Z) isomer 78 yielded a 4:1 mixture of the 3-and a-epoxides80 and 81, which were hydrolyzed to (±)-epiwarburganal and (±)-warburganal.a, b, cOCH3a) NaH, HCO2Et; b) DDQ; c) H, (CH2OH);d) (MeO)(Me3Si)CHLi; e) KH; 1) m-CPBA;g)H, H20.Scheme 12 Kende’s Synthesis of (±)-WarburganalEnantioselective synthesis of (-)-warburganal (10) has been accomplished bydegradation of diterpenes, abietic acid (82)35b and royleanone (86)”, and triterpene 85’70 76fCHO+gI gH OCH H OCHf21and transformation of functionalized drimanes, drimenol (33)35a, (+)-confertifoline (83)35c,and diene 8435e (Figure 5).CH2OFigure 5 Chiral Starting Materials for the Synthesis of (-)-Warburganal (10)0The first synthesis35bof (-)-warburganal (10) from (-)-abietic acid (82) is outlined inScheme 13. The regioselective osmylation of the double bond of the C ring of 82, followedby esterification of the acid function, afforded a diastereomeric mixture of diols 87. The estergroup was transformed into a methyl group by the procedure indicated in the Scheme 13. Themixture of diols 88 was cleaved with Pb(OAc)4 to give ketoaldehyde 89 and the aldehydefunction was protected as its acetal. The regioselective formation of silylenol ether 90,followed by ozonolysis gave aldehyde 91. Compound 91 was subject to the silyl enol etherformation and ozonolysis again to provide aldehyde 32. x-Hydroxylation of the aldehyde(32) and the removal of the protective group furnished (-)-warburganal (10).CO2H82 338384 85 8622O2Ho2Me______OH c,d OHe,f,g82 87 88CHOIIHOkh89 90 911, k m,CHOOH‘ CHO32 10: (-)-warburganala) 0s04,Me3NO; b) CH2N;c) DHP, H; d) LAH; e) PCC; t) H, H20; g) NH2,KOH;h) Pb(Ac)4;i) H,CH(CO ) j) LDA, TMSC1, HMPA; k) 03, Me2S; I) LDA, TMSCI;m) LDA, MoO5Scheme 13 Ohno’s Synthesis of (-)-Warburganal (10)232.2. Discussion2.2.1. General Considerations about the Synthesis of (-) -Polygodial (2) and(-)-Warburganal (10) from Thujone (3)As discussed in the Introduction, three published sequences, shown in Schemes 1, 9,and 10, to (±)-polygodial and (±)-warburganal utilized trans-fused decalones as their startingmaterials. The essential feature of these studies is to utilize the existing carbonyl groups in thedecalones effectively for the introduction of all necessary carbons and functional groupsrequired in the target molecule.Therefore, we set as our first goal to convert the thujone-derived enone 7 into someenantiomerically pure, functionalized trans-decalones such as 65, 92 and 93 (Scheme 14).2$8)1’CHO(-)-polygodial0etcScheme 14 The Overall Plan towards the Synthesis of (-)-Polygodial (2) and (-)-Warburganal(10)92 65.CHO2 10(-)-warburganal24Elaboration of enantiomerically pure decalones into (-)-polygodial (2) and (-)-warburganal(10) would be completed in a later stage.In formulating our synthetic approach, we recognized two necessary and likelyassociated operations: the exclusion of the isopropyl side chain arid the regioselective cleavageof the internal C-C bond (i.e., C7-C9 bonds ) of the cyclopropyl group. There is no functionalgroup nearby to be used to achieve these aims. Substantial chemistry is thus dictated.2.2.2. Ozonation of Thujone and Its DerivativesOzonation of saturated hydrocarbons into alcohols and ketones by inserting oxygen intoC-H bonds has been well-documented38’9.Usually tertiary carbons are preferentiallyattacked. However, the low solubility of ozone in organic solvents40 (—0.1-0.3% by weight at-78°C) requires a long reaction time, leading to over-oxidation and poor selectivity. A practicalimprovement came from “dry ozonation” in which silica gel rather than organic solvents is usedas the reaction medium41. At -78°C, the silica gel pre-adsorbed with the substrate (—1% byweight) was saturated with ozone; the mixture was then allowed to warm slowly to roomtemperature. Since silica gel adsorbs ozone efficiently at low temperature42(—4.5% by weightat -78°C), a complete oxidation of tertiary carbon-hydrogen bonds of cyclic hydrocarbons withhigh selectivity may be achieved under the reaction condition.The selective “dry ozonation” of thujone at the tertiary carbon of the isopropyl sidechain was first observed in our laboratories by Dr. K. Piotrowska in a study related to thepreparation of steroid analogues’5. Both ketol 94 (i.e., “thujonol’) and dione 95 (i.e.,“thujonone”) were obtained in a ratio of 2 to 1, resembling the selectivity previously observedin the “dry ozonation” of isopropropyl cyclopropane43.However, the low overall conversion£ Numbering for thujone-derived tricyclic intermediate 7 and latter related intermediates is kept similar to thatfor drimane sesquiterpenes such as (-)-polygidial (2) and (-)-warburganal (10) in order to provide facilecomparison.25(—40%) and the inconvenience of handling a large amount of silica gel during scaling updiscouraged further exploration of this reaction.derived fused cyclopropylcarbinols occurred in the desired direction as shown in Scheme 15,the homoallylic halides produced would have an isopropylene side chain which could beoxidatively cleaved to provide a carbonyl group. In short, the ozonation of thujone and itsderivatives could provide an entry to both required operations mentioned earlier (Scheme 14).HXx[0]Scheme 15 A Perceived Sequence to Utilize Alcohols Derived from Ozonation of ThujoneDerivatives* The ratio of silica gel to substrate in weight is usually 100 to 1 in order to observe a complete reaction interms of attack at the tertiary carbon-hydrogen bond of the cyclic hydrocarbon according to the original dryozonation procedure41.033+94 95thujonol thujononeThe use of ozonation reaction in projected syntheses of trans-fused decalones waseasily perceived. The ring cleavage of cyclopropylcarbinols by acids has been well-documented in the 1iterature. For example, treatment of cyclopropylcarbinols with aqueoushydrohalides generated homoallyic halides in good yields. If the ring cleavage of ozonationR—c HXOH26In summary, the following synthetic pathway to a trans-fused decalone was thusenvisaged (Scheme 16):xScheme 16 An Ozonation Route to a trans-fused Decalone (Retrosynthetic Analysis)Thus, efforts were directed to finding a better ozonation condition. Finally, therelatively neglected solution ozonation (“wet ozonation”) was found to be satisfactory. The“wet ozonation” is easier to scale up (up to 30g scale), more reproducible, and easier tomonitor. Complete conversion by wet ozonation can be easily achieved. A comparison of dryand wet ozonation of thujone (3) is shown in Table 1.Table 1 Comparison of Dry and Wet Ozonation of Thujonesamplepreparationconditionworkupconversionyield94:95Dry Ozonaton Methodsolvent evaporation ofthe slurry of silica gel inthujone-petroleum ether solution8 hrs at -78°C, then warm upto r.t.extraction with diethyl ether43%70%2:1Wet Ozonation Methoddissolution of thujone inEtOAc07 hrs at -25 Cwater and sodiumbicarbonate (aq.) extractioncomplete65-70%1.5:1x/27The mass spectrum of thujonol (94)* revealed the molecular ion peak at m/z 168 whilethe JR spectrum indicated intense absorption peaks at 3100-3700 and 1730 cm-1,corresponding to the hydroxyl and carbonyl stretching absorptions. The ‘H-NMR spectrumdisplayed two methyl singlets& at 6 1.22 and 1.32 ppm corresponding to the two methylgroups of the isopropyl side chain and a methyl doublet& at 6 1.18 ppm (J=7.6 Hz)corresponding to the methyl group at C4. A one-proton broad singlet# at 6 1.60 ppm wasassigned to the proton of the hydroxyl group.The mass spectrum of thujonone (94) showed the molecular ion peak at m!z 152 whilethe JR spectrum revealed two intense absorption peaks at 1740 and 1685 cm1, correspondingto absorptions of the C3 carbonyl and the acetyl carbonyl groups. The ‘H-NMR spectrumindicated a methyl doublet at 6 1.22 ppm (3=8.4 Hz) and a methyl singlet at 6 2.09 ppm,correponding to the methyl at C4 and the methyl of the acetyl group respectively.This selective ozonation was generally applicable to other thujone derivatives. Forexample, the ozonation of 99 and 102 has been applied in the syntheses of drimane antifeedantanalogues’5’45and rose oil fragrances46.The ozonation of 105 was explored in an attemptedsynthesis of steroid ana1ogues. Diketol 106 and trione 107 were obtained in 36% and 28%yield respectively. The mass spectrum of 106 showed the molecular ion peak at m,tz 238 whilethe JR spectrum displayed the hydroxyl stretching absorption at 3450 cm-1 and the twocarbonyl stretching absorptions at 1730, 1710 cm1. The1H-NMR spectrum of 106 revealedfour methyl singlet signals at 6 1.00, 1.17, 1.33, 2.15 ppm. The mass spectrum of 107indicated the molecular ion peak at m/z 222 while the JR spectrum showed three carbonyl* Thujone used in this studies was a mixture of a and 3 diastereomers in a ratio of 10:1 as indicated from GC.Accordingly, thujonol and thujonone were mixtures of their a and diastereomers in a similar ratio as analyzedfrom GC. All spectral data were recorded for these diastereomeric mixtures. The1H-NMR spectral datapresented here should belong to a diastereomers only since signals of f3 diastereorners were hardly observablefrom the spectra.& A methyl singlet is a singlet signal corresponding to a methyl group while a methyl doublet is a doubletsignal corresponding to a methyl group.# A one-proton signal is a signal consisting of one proton. Accordingly, a signal consisting of m protons iscalled a m-proton signal.This work carried out by this author is not described in this thesis.28absorption peaks at 1735, 1705, and 1685 cm-1 respectively. The ‘H-NMR spectrum of 107revealed three methyl singlet signals at ö 1.04, 2.09, and 2.12 ppm.EtOAc+-40°C 199 100 :101EtOAc+102 103 10425C°H°1105 106 107 0Scheme 17 Generality of Selective Ozonation of Thujone DerivativesA more detailed study on the ozonation of the cis-fused ketone 96, prepared fromenone 7 by catalytic hydrogenation, was carried out in order to find out factors influencing thewet ozonation reaction. The compound 96 was chosen since it was readily available (see thediscussion on its preparation and stereochemistry in Section 2.2.3.).2903:980Table 2 The Wet Ozonation of9 to 97 and 98Experimentsa #1 #2 #3 #4 #5Solventb EtOAc EtOAc EtOAc EtOAc CH21Temp. (°C) -78 -40 -25 0 -40Time(hrs) 7 7 5 3 7%Recoveryof 90% 12% 0% 0% 10%96%Total Yield 70% 68% 62% 55% 50%97:98c 1.55:1 1.50:1 1.40:1 1.20:1 1.00:1a) 200 mg of 96 was used for every experiment; b) 50 ml of solvent was used for every experiment; c) themolar ratio of 97 and 98 was revealed by comparison of integrations at 6 0.35-0.70 ppm and 6 2.06 ppm of themixture N1vIR spectrum; the signal at 6 0.35-0.70 ppm were due to two of the three cyclopropane protons in 97while the signal at 6 2.06 ppm was from the three methyl protons of the acetyl group in 98.As shown in Table 2, when the temperature increased, the total yield of the twoproducts and the ratio of 98 to 97 dropped down. Changing solvents from ethyl acetate tomethylene chloride decreased the total yield as well as the ratio of 98 to 97.It is of interest to understand these results in terms of the mechanistic proposals ofozonation. For the insertion of oxygen into carbon-hydrogen bonds, a unified proposal wasput forward by Hamilton et al.47 According to this proposal (Figure 6), the transition state (I)can either convert to produce ROH and a singlet oxygen directly by path (2) or collapse to aH2, Pd-CEtOH9630hydrothoxide R000H which then decomposes to product ROll and a singlet oxygen by path(1) or degrades to a triplet oxygen, a hydroxyl radical, and an alkyl radical (II) whichundergoes a chain reaction via an alkoxyl radical (III) to afford ROH by path (3). Theoccurrence of the different reaction paths depends on structural environments near the carbon-hydrogen bonds and the reaction conditions. Carbon-hydrogen bonds adjacent to heteroatoms,such as the c carbon-hydrogen bonds of alcohols, ethers, and amines, and the carbon-hydrogen bond of aldehyde groups favor path (1) because of the greater contribution of theresonant structure (Ib) to the transition state (I)48.c. Clear evidence for hydrotrioxides hasbeen obtained only with ozonation of alcohols, ethers, amines and aldehydes48dl. Carbon-hydrogen bonds not activated by adjacent heteroatoms will go through path (2) to produceROH directly in the liquid phase and at low temperature (<0°C) with the retention ofconfiguration being usually observed47. In the vapor phase and at high temperature (>25°C),the radical-mediated path (3) becomes dominant48’. The mechanism of dry ozonation waspresumed the same as that in liquid phase40.H....0 H....0 (1)R—H + 03 Re I —— R R000HeQ__c(I-a) (I-b)ROH R • + OH + 02 (triplet) ROH + 02(retention of (singlet)configuration)O3HR ROe + 02 (singlet)(III)Figure 6 Oxygen Insertion into Carbon-Hydrogen Bonds31For the production of ketones from tertiary carbons through cleavage of C-C bonds, asimilar insertion mechanism has been proposed for the liquid phase reactions (Figure 7)4349.The transition state (V) was assumed to collapse into a trioxide by cleaving one carbon-carbonbond. The further decomposition of the trioxide provided a ketone and a hydroperoxide. Thealternative mechanism, the fragmentation of alkoxyl radical (IV) generated from the oxygeninsertion into the carbon-hydrogen bond following the Hamilton mechanism in Figure 6, wasconsidered only possible at higher temperature (—25°C)43.R[ R1— I R2 +HR1—C—R3- R1—C--O—O—R3R2R1+ HO—OR3R2Figure 7 Oxygen Insertion into Carbon-Carbon BondsThe selective ozonation of thujone (3) and its derivatives at the tertiary carbon-hydrogen bond of the isopropyl side chain is perhaps due to lower energies of transition states(I) in Figure 6 and (V) in Figure 7 resulting from the participation of the cyclopropyl group inthese two transition states. The cyclopropyl group is known to stabilize neighboring positivecharge in a way similar to an olefinic groupl7a. The oxidation of cx-rnethylene groups ofbicyclo[n.1.O]allcanes to carbonyl groups was also reported5Oa.(V)32Increase of temperature in the ozonation reaction appeared to encourage oxidation inother carbon-hydrogen and carbon-carbon bonds, therefore causing the total yield of 97 and98 to drop. The accompanying increase of the overall reaction rate and the decrease of the97:98 ratio seemed to follow the general relationship between the selectivity of twocompetative reactions and temperature501’. Changing solvents from ethyl acetate to methylenechloride had a dramatic effect on the total yield and the 97:98 ratio. This may reflect theparticipation of solvents in transition states (I) and (V).Ketone 98 might be produced directly from alcohol 97. To test this assumption, asolution of 97 in EtOAc was treated with ozone at -40°C for 7 hours. A new polar spotappeared on TLC plates. As revealed from the1H-NMR spectrum, this spot contained severalcompounds which were not characterized further. Apparently, ketone 98 was not directlygenerated from alcohol 97. The fact that 97 and 98 were produced at an almost constant ratioof approximately 1.5:1 from the beginning to the end of the reaction, as indicated by GCanalysis, supported this conclusion.098A small amount of olefin 108 could be isolated from the reaction. Its molecular ionpeak appeared at mlz 218 in the mass spectrum while the JR absorptions of carbonyl andcarbon-carbon double bonds were observed at 1710 and 1630 cm1. The ‘H-NMR spectrumshowed a characteristic vinylic methyl singlet at 6 1.60 ppm and two overlapped one-proton79710833singlets at 4.65-4.80 ppm corresponding to the two olefinic protons. This result indicatedthat ketone 98 might be produced from 97 via the ozonolysis of the dehydration product 108.The strong acidity accumulated during the reaction could promote the dehydration of 97especially at higher temperature (see the following paragraph).During our studies, a basic workup was found to be necessary to ensure that thealcohol product could be isolated intact; direct evaporation of the ethyl acetate mixture withoutneutralization with sodium bicarbonate aqueous solution led to serious decomposition ofalcohols. A strong acidic medium was produced in the ozonation reaction; the water extract ofthe final reaction mixture had a pH value close to 1 . To test if the acidic by-products wereformed from substrates or solvents, ozone was passed through blank solvents, ethyl acetateand methylene chloride, at -40°C for the same period of time as in the regular ozonation (i.e., 7hours). Water extracts of the resulting solutions showed a similar strong acidity. It appearedthat the acidic by-products were mainly generated by the oxidation of solvents or impuritiespresent in them.2.2.3. Stereochemistry of Hydrogenation of Thujone-derived Tricycli cEnonesAs shown in the Schemes 14 and 16, a trans-fused A/B ring junction was needed indeveloping a sequence to (-)-polygodial (2). Therefore, we hoped the reduction of enone 7(see Scheme 14) would provide a trans-fused tricyclic compound 110.110 96 10934Catalytic hydrogenation of enone 7 by 10% Pd-C in ethanol gave a major product 96 in95% yield and a minor product 109 (2%) instead of the desired trans-fused ketone 110. Theminor product 109 (2%), the epimer of 96 at C4, was very labile. It epimerized to 96completely in CDC13at room temperature overnight. The ‘H-NMR spectrum of ketone 109showed a two-proton multiplet at 6 0.30 ppm, three methyl doublets at 8 0.88 (J= Hz), 0.96(J= Hz), 1.06 (J= Hz) ppm, a methyl singlet at 6 0.99 ppm, a two-proton multiplet at 6 2.00-2.30 ppm, and a one-proton multiplet at 62.45 ppm.Ketone 96 had its molecular ion at m/z 220 in the mass spectrum. The carbonylstretching frequency appeared at 1710 cm-1 in its IR spectrum while the H-NMR spectrumrevealed three methyl doublets at 6 0.85 (J=6.8 Hz), 0.91 (3=6.8 Hz), and 0.94 (7.2 Hz) ppm,a methyl singlet at 6 1.23 ppm, a triplet (1H, J=ll.5 Hz) at 6 1.29 ppm, and one-protonmultiplets at 6 1.34, 1.72, 2.15, 2.42, 2.58 ppm.Assignment of protons in the ‘H-NMR spectrum of 96 was accomplished by thefollowing experiments (Figure 8). Decoupling by irradiation at the 6 2.58 ppm signal causedthe methyl doublet (J=7.2 Hz) at 6 0.94 ppm to collapse to a singlet and a simplification of aone-proton multiplet at 6 1.72 ppm. Thus, the methine proton at C4, the methyl at C4, and themethine proton at CS were assigned to the signals at 6 2.58, 0.94, and 1.72 ppm respectively.The only methyl singlet at 6 1.23 ppm in the off-resonance spectrum was obviously from themethyl at ClO. This ClO methyl signal was very close to a one-proton nuiltiplet at 8 1.34 ppmand a one-proton triplet (3=11.5 Hz) at 6 1.29 ppm. Irradiation at 6 1.23 ppm, which actuallyaffected the multiplet and the triplet simultaneously, led to the collapsing of two methyldoublets (both J=6.8 Hz) at 6 0.85 and 0.91 ppm and the simplification of the C5 protonmultiplet. Therefore, the multiplet at 8 1.34 ppm must be from the methine proton in theisopropyl side chain and the triplet must be due to one of the methylene protons at C6. Themethylene proton must be opposite to the C5 proton with regard to the cyclopentyl ring sincethe coupling constant (J=1 1.5 Hz) for the triplet was relatively large. The closeness of theseproton signals and the complication of six possible conformational structures (two each from3511115V’LjL1A.b)a)Figure 8 Decoupling Experiments on Ketone 96a) off resonance spectrum.b) homonuclear spin decoupling at 1.23 ppm.c) homonuclear spin decoupling at 2.58 ppm.3 (ppm)2912I I I I I2.5 2.0 1.5 1.0 0.5036HH0Figure 9 Single Crystal X-ray Structure of 98 (PLUTO Drawingl66a)HHCHHHHHCHH37trans-fused 110, cis-fused 96, and cis-fused 109 to be considered in the analysis discouragedfurther NOE experiments in order to elucidate the stereochemistry of ketone 96.Fortunately, separation of ozonation products 97 and 98 (see p. 30) by columnchromatography with a mixed solvent system (hexanes:methylene chloride:methanol=10: 1:1)gave fractions containing 98 which crystalized readily upon slow evaporation of the solventupon standing. The crystals were suitable for X-ray diffraction analysis. The crystals werealso prepared from hexanes by Z. Gao in our laboratories and submitted for analysis45. TheX-ray structure of 98 clearly showed an AIBcis-fused ring junction and an ce-orientation of themethyl at C4 (Figure 9). The stereochemistry of 96 was thus established.An attempt to obtain trans-fused compound 110 by Birch reduction using lithium andammonia failed45.The similar phenomenon was observed in a previously published study related tosteroid synthesisl4b. Either catalytic or Birch reduction of 111, followed by acetic anhydridetreatment, gave the same cis -fused enol lactone 112.CO2HA range of enones were hydrogenated under catalytic conditions (Scheme 18).Reduction of the known compound 113 13a gave the cis-fused 114 in 90% yield. Itsmolecular ion peak in the mass spectrum appeared at m/z 206 while its carbonyl absorption wasobserved at 1710 cm-1. The ‘NMR spectrum of 114 showed a one-proton doublet of doublets(J=4.8 and 8.0 Hz) at 0.23 ppm, a one-proton thplet (J=4.8 Hz) at 0.45 ppm, two methyldoublets at 0.86 (J=6.4 Hz) and 0.93 (J= 6.4 Hz) ppm, a methyl singlet at 1.20 ppm, afour-proton multiplet at 2.10-2.55. In order to establish the stereochemistry of 114, it was11238subjected to methylation by treatment with potassium t-butoxide and iodornethane in t-butanol.The major product obtained in 70% yield was identical to the cis-fused ketone 119 preparedfrom the methylation of 96 (see p. 49) in all spectroscopic data. Thus, the cis fusion in 114was confirmed. Two known compounds 115 and 116 with carbon-carbon double bonds atC5 and C6’3were hydrogenated. Complex product mixtures were obtained as indicated fromGC chromatograms and ‘H-NMR spectra. The complication might be due to the cleavage ofconjugated cyclopropyl groups.bH2,Pd-Cttg116122 97Scheme 18 Attempted Catalytic Hydrogenation of Tricyclic EnonesA mixture of 117 and 118, obtained from the pyrrolidine catalyzed aldol condensationof ozonation product 106 (Scheme 17), was reduced to the cis -fused ketol 120 in 70% yield.H2, Pd-C113 11411539The mass spectrum of 120 showed the molecular ion peak at m/z 222 while its JR spectrumindicated stretching absorptions of the hydroxyl and carbonyl groups at 3100-3700 and 1710cm-1. The ‘H-NMR spectrum displayed a one-proton doublet of doublets (3=4.0 and 5.4 Hz)at 8 0.44 ppm, a one-proton doublet of doublets of doublets (3=1.2, 5.4, and 8.6 Hz) at 80.63ppm, three methyl singlets at 6 1.14, 1.21, and 1.25 ppm, a complex four-proton multiplet at 62.12-2.52 ppm. The cis A/B ring junction of 120 was established by correlating it with ketol97 (p. 30) chemically. Thus, compound 120 was converted into a dimethylated compound in60% yield by treatment with iodomethane and potassium t-butoxide in t-butanol. Thiscompound was identical in all spectroscopic data to the cis-fused ketol 121, prepared in 75%yield by treating 97 similarly. The comparison of their CD spectra* is shown in Figure 10.0 I I II.a)b)1.II I I I I t I I I(nm) 40gFigure 10 Comparison of CD Spectra of 121 Prepared from Two Different Routesa) Ketol 121 prepared from 118.b) Ketol 121 prepared from 97.* We are indebted to Dr. Ian Clark who gave us most helpful guidance in running the CD spectrometer.t The observed ellipticity angle 0 is expressed in a relative scale. Curve (a) is moved one devision up verticallyin order to facilitate comparison. Since both measurements were made at 25°C in the same concentration (10.4mg/mi), solvent (dioxane), and cell, there is no need to convert 0 into molar ellipticity angle [0] or molarcircular dichroism Ae.40The mass spectrum of 121 showed the molecular ion peak at m/z 250 while the JRspectrum indicated the absorptions of the hydroxyl and carbonyl groups at 3100-3650 and1705 cm-1. The ‘H-NMR spectrum revealed a one-proton triplet (J=4.8 Hz) at 0.41 ppm, aone-proton doublet of doublets (J=4.8 Hz) at ö 0.58, five methyl singlets at ö 0.96, 1.12,1.22, 1.24, and 1.34 ppm, two one-proton multiplets at 2.17 and 2.70 ppm.The catalytic hydrogenation of 12211 (see Section 4.4. for its stereochemistry),prepared from the Robinson annulation of thujonol (94) with ethyl vinyl ketone in 35% yield,produced a single compound 97 which was again identical to the ozonation product 97previously obtained from 96.Difficulties encountered in the direct preparation of trans-fused compounds byhydrogenation can be understood from a different perspective. The easy access to the 6,5-fused enones and the need to generate a trans-fused /D portion in steroid synthesis providedexamples about reduction of these compounds. In fact, either catalytic hydrogenation5’orBirch reduction52generally gave only or predominantly the cis-fused products. Our tricyclicenones derived from thujone (3) indeed behaved quite similarly. However, this outstandingproblem has been remedied to some extent by recently developed hydroxyl-directed catalytichydrogenation using homogeneous catalysts53.Unable to find a simple and efficient way to obtain trans-fused series of compoundsdirectly, we decided that further effort in this direction would be terminated. The alternative,requiring two extra steps, was to carry on the sequence in the cis-fused series and to correct thestereochemistry at the ring junction in a later stage. From the point of view of preparingdiverse types of analogues, the stereochemical correction alternative has its own advantage.2.2.4. Acid Promoted Ring Cleavage of Thujone-derived Cyclopropylcarbinols11 The tertiary hydroxyl group of the isopropyl side chain of 122 may serve as a directing group for the desireddirect a face hydrogenation, although not explored in present studies53.41It is well known that cyclopropylcarbinols can be cleaved through the pathway asshown in Scheme 15. When the reaction is applied to a non-symmetrically substitutedcyclopropylcarbinols with an achiral center at X position, two different compounds areexpected to be generated, depending on which C-C bond is cleaved. In our specific system,we propose the following notation for the convenience of discussion: the endo-type cleavagewill lead to a 6-membered ring homoallylic halide (X=halides); the exo-type 1 will result information of a 5-membered homoallylic halides (Figure 11). It is obvious that the endo-typecleavage is desirable for our purpose. The novel exo-type 2 cleavage is presented here inadvance for the completeness of the notation and later discussion will indicate this mode offragmentation (see section 2.2.7.).cleavageFigure 11 A Notation of Ring Cleavage ReactionsTreatment of the ketol 97 in either methylene chloride or diethyl ether with concentratedHBr solution (48%) gave a mixture of starting material and a less polar fraction which couldnot be identified by1H-NMR spectrum. The same result was obtained when the reaction wascarried out with anhydrous MgBr2 in refluxing ether55. It was considered that the complicationmight arise from the relatively weak C-Br bond of ring cleavage products and their consequentexo- type 1 cleavageendo- cleavagex42decomposition. If this was the case, the corresponding chioro compounds may be stableenough to allow purification and characterization. In fact, treatment of 97 with concentratedHC1 gave a stable major compound 123 rather than 124 in approximately 75% yield aftercolumn chromatographic purification.In summary, compound 123 arises from the exo-type 1 cleavage. The IR spectrum of123 showed the absence of an absorption corresponding to the hydroxyl stretching frequency.The parent ions at m/z 256 (0.6%) and 254 (2.2%) in the mass spectrum of 123 wereconsistent with two isotopic peaks (C15H23037C1 andC15H23031). The ‘H-NMRspectrum of 123 showed two methyl singlets in 6 1.71 and 1.60 ppm, indicating the presenceof an isopropylidene group; a multiplet (octet) at 6 3.55 ppm, characteristic of the A/B portionof an ABX system, corresponded to the methylene attached to the chlorine.The f3 orientation of the chioromethyl side chain was verified since a sample of theisolated product under stirring overnight in methylene chloride and silica gel regenerated thestarting ketol 97 exclusively.:12443CIsilica gelCH21,r.t.Whether the solvolysis reaction takes place stepwise through a cyclopropylcarbinylcation or in a concerted manner through a SN2’ like transition state has not been established(Figure 12). The regioselectivity is often explained by the SN2 mechanism involvingstereoelectronic and steric factors. Considering the concerted mechanism, the rotation of theisopropyl side chain allows the hydroxyl to align antiparallel to either of the C-C bonds whichmay undergo cleavage. Inspection with molecular models revealed seemingly equal sterichindrance to these two alignments. Therefore, the hindrance to the incoming group, Cl- in thiscase, is likely playing an important role. In the case of the stepwise mechanism, this factorseems to be able to differentiate endo- and exo-type 1 cleavage paths. In any event, thepreference to this exo-type 1 cleavage is likely due to the more exposed and accessible nature ofthe methylene compared to the methine in the cyclopropyl ring.Figure 12 Rationalization of HC1 Promoted Ring Cleavages97C1 Cl-effedstepwise concerted442.2.5. The Radical-mediated RearrangementAlthough the major product from concentrated HC1 (aq.) treatment was initiallydetermined to be the structure 123, we felt that further evidence about this structure could beprovided by a simple reduction. Reduction of 123 using tributyltin hydride as reducing agentwas carried out with the expectation that the reduction product 125 would show a doubletcorresponding to the newly generated methyl group in its1H-NMR spectrum. Surprisingly, inaddition to the expected product 125 which showed an extra methyl doublet (J=7.2 Hz) at 60.92 ppm and absence of the two-proton multiplet at 6 3.5 ppm in 123, another major productwas isolated in 50% yield. Its ‘H-NMR spectrum showed a methyl doublet (J=6.4 Hz) at 61.02 ppm, a methyl singlet at 6 1.26 ppm, and two vinyl methyl singlets at 6 1.64 and 1.66ppm. Thus, this major compound was assigned to be 126. Its mass spectrum confirmed thatit had a parent ion at m/z 254 corresponding to the molecular formulaC15H240of 126.Benz:n:,reflux< +125 126Apparently, a ring expansion took place during the reduction. The followingmechanism was proposed to rationalize this novel reaction (Figure 13).12345LIR3Sn.R3SnC1Figure 13 A Proposed Mechanism for the Novel Ring Expansion of 123In this mechanism, a cyclopropylcarbinyl radical (b) generated from cyclization of theinitial radical (a) is postulated as the intermediate to the final ring-expanded radical (c). Analternative pathway could involve the apparent direct 1, 2-shift from (a) to (c). Thethermodynamic driving force for the radical rearrangement from (a) to (c) is probably theE 126R3SnH(a)R3SnHR3Sn.(c)R3SnHR3Sn.12546greater stability of the secondary radical (c) in comparison with the primary radical (a). Thecyclization step from (a) to (b) is analogous to the cyclization of chloride 123 to 97 (p. 44).We were not able to isolate any compound 96, a possible product resulting from thequenching of (b) during the reaction. A literature survey revealed that the postulation of acyclopropyl carbinyl radical as an intermediate in the rearrangement of homoallylic radicals hasbeen proposed57aand verified by product studies and labelling experiments57b.l. More recentstudies are focusing on the quantitative aspect of this rearrangement571’.To improve the yield of the ring expansion product 126, the direct quenching of radical(a) had to be suppressed. A longer life time for the initial radical (a) by decreasing theconcentrations of both substrate 123 and reducing agent tributyltin hydride should allow itmore likely to undergo a series of rearrangements and therefore improve the yield of 126. Infact, further experiments verified this postulate (Table 3).Table 3 Yield Optimization for Conversion of 123 to I 26k’123 Bu3SnH AIBN benzene 126:12 5 total yield50.4mg 82 I.tl 3.2mg 20m1 2.8:1 80%50.4 mg 82 p1 3.2 mg 4.0 ml 2.4:1 74%: Refluxin was continued for two days for both reactions.In summary, despite the undesirable exo-type 1 cleavage to a hydroindane system in theacid-promoted ring cleavage reaction, the novel radical-mediated ring expansion provided uswith a method to prepare the desired decalin system. Using the ozonation, acid-promoted ringcleavage, and radical-mediated ring expansion reactions as key steps, 127, an analogue of (-)-polygodial (2), was prepared from thujone by Z. Gao’5’45 (Scheme 19; see also Scheme 17for preparation of 100 via ozonation).47.cI03 clcçBu3SnHAIBN, benzencCHOScheme 19 Gao’s Synthesis of a (-)-Polygodial Analogue 127The same sequence was also successfully applied to the synthesis of the rose oilfragrances, 13-damascone and f3-damascenone, from thujone by Philip Gunning46.(Scheme20; see also Scheme 17 for preparation of 103 via oznation).HC1.- .CH21Bu3SnHAIBN, benzeneL.JI\ 13-damasconef3-damascenoneScheme 20 Gunning’s Synthesis of Rose Oil FragrancesHC1127103NCNC482.2.6. Failure of the Radical-mediated Ring Expansion ReactionHaving established the above sequence on the model compound 96, we tried to apply ittowards the synthesis of natural (-)-polygodial (2). The plan is shown in Scheme 21. A cisfused alkane 128 would be derived from ketone 119 which could be obtained by methylationof 96. Applying the established sequence to 128 would generate cis-fused decalone 129,from which a stereochemical correction into A/Btrans-fused decalone 26 would be carried out.The racemate of 26 (i.e., 65) was used as a starting material in the synthesis of (±)-polygodialand (±)-warburgamal by de Groot et al.(Scheme 3). During the course of our study, anenantioselective synthesis of 26 was completed by the same group from (-)-dihydrocarvone(Scheme 9).1) 03, 2) HC13) BuSnHScheme 21 A Revised Plan to an Enantiomerically Pure, trans-fused Decalone 65Following a standard method58,cis-fused ketone 96 was refluxed with iodomethaneand potassium t-butoxide in t-butanol to give the gem-dimethyl ketone 119 in 85% yield. Themass spectrum of 119 revealed the molecular ion peak at m/z=234. Its IR spectrum showedabsorption peaks at 3060 cm1,characteristic of carbon-hydrogen stretching of the cyclopropyl119 128129 6549group, and 1700 cm-1, corresponding to the carbonyl stretching frequency. Its ‘H-NMRspectrum showed two methyl doublets (6 0.85 ppm, J=6.6 Hz; 6 0.90 ppm, J=6.6 Hz)corresponding to the two methyl groups at the isopropyl side chain. Three methyl singlets (60.97 ppm, 1.22 ppm, 1.32 ppm) were observed which corresponded to the gem-dimethylgroups at C4 and the angular methyl at ClO. A two-proton multiplet appeared at 6 2.15-2.70ppm, corresponding to the methylene at C2.KOH, DEGNH2Wolf-Kishner reduction59of 119 gave alkane 128 in 70% yield. The mass spectrumshowed the molecular ion peak at m/z 220. Its JR spectrum was characterized by the absenceof the carbonyl stretching absorption and an absorption peak at 3060 cn1, resulting from thestretching of carbon-hydrogen bonds in the cyclopropyl group. In the1H-NMR spectrum, nosignals above 6 1.80 ppm were noted. Two one-proton multiplets at high field, one at 6 0.04ppm (dd, J=4.5 and 7.5 Hz) and the other at 6 0.40 ppm (t, J=4.5 Hz) corresponded to two ofthe three protons in the cyclopropyl group.03, EtOAc-40°CCH3Li, THF-40°CWhen alkane 128 was treated with ozone at 400C in ethyl acetate for 8 hours, alcohol130 and ketone 131 were obtained in 42% and 27% respectively. To obtain a maximal yieldHOtBu96 119 128128 130 13150of the alcohol, ketone 131 was treated with methyl lithium in THF at -40°C to give alcohol130 in 70% yield. Therefore, the desired alcohol 130 was obtained in 61% overall yield fromalkane 128.In the mass spectrum, alcohol 130 revealed its molecular ion peak at m/z 236 and afragment ion peak at mlz 220 due to the dehydration of the parent molecule. Its JR spectrumwas characterized by a broad hydroxyl stretching absorption near 3400 cm-1 and a carbon-hydrogen stretching absorption at 3060 cm-1 due to the C-H bonds in the cyclopropyl group.Its1H-NMR spectrum showed five methyl singlets at 80.72, 0.92,1.05, 1.10, and 1.19 ppm.There was a complex two-proton multiplet at high field 60.40-0.55 ppm due to two protons inthe cyclopropyl group. The collapse of the two separate one-proton signals originally noted inthe ‘H-NMR spectrum of 128 into this multiplet was probably due to the electronic effect ofthe newly introduced hydroxyl group at the isopropyl side chain.The mass spectrum of ketone 131 showed a molecular ion peak at m/z 220. The IRspectrum had an intense absorption at 1675 cm-1 due to the carbonyl stretching frequency.This bathochromic shift when compared to usual saturated carbonyl absorptions(j—1700 cm1)was the result of conjugation between the carbonyl and cyclopropyl groups6°and thisphenomenon was also observed in diketone 98. The ‘H-NMR spectrum had four methylsinglets at 6 0.83, 1.00, 1.15, and 2.00 ppm. The methyl singlet at 2.00 ppm wasapparently due to the methyl group at the methyl ketone side chain.Treatment of alcohol 130 with concentrated hydrochloric acid in methylene chloride for30 minutes produced homoallylic chloride 132 in 85% by the expected exo- type I cleavage.conc. HC1CH21.01130 13251Compound 132 had a mass spectrum showing molecular peaks at m/z 256 (4.8%) andm/z 254 (14.8%) corresponding to two isotopic isomersC16H27l andC16H27l. Its JRspectrum was devoid of 0-H stretching absorption and the usual C-H stretching absorptionfrom the cyclopropyl group due to the absence of both groups in this new compound. Its 1H-NMR spectrum revealed five methyl singlets: three of them at higher field, 6 0.84, 1.04, and1.22 ppm; two of them at lower field, 6 1.63 and 1.70 ppm, resulting from the two vinylicmethyl groups of the isopropylene side chain. There was a two-proton octet at 6 3.40-3.75ppm, corresponding to the methylene group carrying the chlorine function.Using the condition previously established (Table 3), tributyltin hydride reduction ofchloride 132 in refluxing benzene for 48 hours, generated in this instance only the simplereduction product 133 rather than the expected ring expansion product 134. Compound 133had a peak at m/z 220 corresponding to the molecular ion in the mass spectrum. Its ‘H-NMRspectrum showed five methyl singlets at 6 0.84, 0.87, 1.02, 1.58, 1.62 ppm and a methyldoublet at 6 1.05 ppm (J=6 Hz).Changing the reducing agent to triphenyltin hydride and the solvent to toluene did notresult in any significant change. We also treated alcohol 130 with concentrated hydrobromicacid in order to obtain a different substrate 135 for the radical-mediated ring expansion.13213313452Unfortunately, a complex mixture was obtained after column chromatography. A directtributyltin hydride treatment of the mixture from hydrobromic acid solvolysis without columnseparation produced compound 133 in addition to a large portion of an inseparatable mixture.Therefore, the desired ring expansion for 132 had failed. Guided by the mechanisticproposal in Figure 13, we decided to approach the problem in a different way. According tothis proposal, a cyclization to a cyclopropylcarbinyl radical (see (a) to (b) in Figure 13) fromthe initial primary radical was required before this cyclopropylcarbinyl radical opened to givethe final radical (c), Figure 13). If, for some steric reason, the cyclization step did not takeplace, a simple reduction would be observed. On the other hand, if we could deliberatelygenerate a cyclopropylcarbinyl radical centered at the tertiary carbon of the isopropyl side chainbefore opening the cyclopropane ring, the desired endo- type cleavage might be possible.The way to generate such a cyclopropylcarbinyl radical from a vinylcyclopropane wasreported by Wender et al. in the synthesis of (±)coriolin6la. In their sequence, a regioselectivecleavage of the vinylcylopropane in 136 (Scheme 22) was accomplished by thiophenoladdition. In this reaction, thiophenol provided phenyl sulphuryl radical (PhS.)61Cwhich thenadded to the double bond to generate a cyclopropylcarbinyl radical. The radical was selectivelycleaved to produce intermediate 137. Paquette et al. also used thiophenol to cleavevinylcyclopropanes6lb.Br13553OHHSPh____(±)-coriolinheatingScheme 22 Radical-initiated Selective Ring Cleavage of a Vinylcyclopropane 136After refluxing alcohol 130 and a catalytic amount of pyridinium tosylate in benzenefor 30 minutes, vinylcyclopropane 138 was separated in 95% yield. Its molecular ion at m/z218 was revealed from the mass spectrum. The JR spectrum indicated the absence of 0-Hstretching absorption and a weak absorption peak at 1630 cm-1 due to the stretching of theterminal carbon-carbon double bond. Its ‘H-NMR spectrum showed two proton signals athigh field due to the protons in the cyclopropyl group: one at 6 0.52 (dd, J=7.2 and 4.8 Hz)and the other at 6 0.68 ppm (t, J=4.8 Hz). Four methyl singlets appeared at 6 0.81, 1.00,1.13, and 1.65 ppm; the latter signal at 6 1.65 ppm was due to the vinylic methyl group in theside chain. Two one-proton broad singlets at 6 4.65 and 4.85 ppm corresponded to the twoterminal olefinic protons.TsOHbenzene, refluxRefluxing of vinylcyclopropane 138 and thiophenol in benzene produced a rathercomplex inseparable mixture which may be expected in the form of four geometric isomers,two each of 139 and 140 (Scheme 23). The mixture was then subjected to lithium/ammoniahydrogenolysis at -33°C. In fact, column purification gave a colorless oil in 70% yield basedon vinylcyclopropane 138. The oil was composed of 70% 133 and 30% 128 as revealed byGC and ‘H-NMR comparison with pure samples of these two compounds. Apparently, the136 137130 13854deliberately generated cyclopropylcarbinyl radical (i) cleaved mainly in the exo-type 1 mannerto give geometric isomers of 139. The unexpected product 128 was probably derived fromtwo diastereomers of 141, which were produced by quenching radical (i) with thiophenol.L IScheme 23 Radical-initiated Ring Cleavage of Vinylcyclopropane 138Comparison of the radical-mediated ring expansion reaction of 123, 132, and thehomoallylic chloride derived from 100 (see Scheme 17) revealed the dramatic effect inducedby an extra methyl group in ring A. The radical-initiated ring cleavage reaction ofvinylcyclopropane 138 by thiophenol indicated that a cyclopropylcarbinyl radical could notHSPhbenzeneLi, NH3138E133SPh 140xLi, NH3141 SPh 12855necessarily guarantee the endo-type cleavage. This again indicated that the additional methylgroup in ring A played an important role in determining the overall course of the reaction.This subtle “methyl effect” could be rationalized in terms of the intermediatecyclopropylcarbinyl radical. The reaction of 132 with tributyltin hydride was assumed toinvolve a cyclopropylcarbinyl radical but the unidirectional cleavage of this radical in a waysimilar to the radical i) in Scheme 23 resulted in the observed exo-type 1 cleavage product133. Inspection with molecular models revealed that cis-fused annulated thujone derivativescan have chair-chair and chair-boat conformations as shown in Figure 14. In the chair-chairconformation, the methyl group at ClO and the C4[3 substituent are equatorially oriented withrespect to ring A; the plane C6-C5-C1O is below plane C6-C7-C9-Cl0, making thebicyclo[3.1.O]hexane portion chair-like. The major destabilizing factors are eclipsinginteractions of the equatorial C6-H bond with the C7-C1 1 bond and the CI-ClO bond with theC9-H bond, and the non-bonded interaction between the isopropyl side chain and the axialmethyl group at C4. In the chair-boat conformation, the methyl group at ClO and the C4f3substituent are axially oriented; the plane C6-C5-C1O is above the plane C6-C7-C9-Cl0,making the bicyclo[3.1.0] hexane moiety boat-like. The eclipsing interactions are greatlydiminished. The seemingly important non-bonded interaction between the axial methyl groupat ClO and the axial C4f3 substituent is actually small because the flattening nature of plane C6-C5-C1O-C9 (torsional angel <C6-C5-C10-C9 estimated 250)*62 and the cis ring junction ofthe A and B rings leads to a spreading apart of these two groups63. In short, the chair-boatconformation is greatly preferred regardless if the C413 substituent is either hydrogen ormethyl. This conclusion is well supported by the X-ray diffraction analysis of dione 98(Figure 9) and compound 147 (Figure 15 and Appendix 1), the negative Cotton effect of Ketol121 (Figure 10), and structural studies of substituted bicylo[3. 1.01 hexanes62* . . . .The estimation follows the average value provided by the studies on a series of bicylo[3. 1.0] hexanecompounds62.561endo-type cleavageFigure 14 Rationalization of the “Methyl Effect’In the endo-type cleavage, the immediate product64from the active reactant chair-boatconformer should have a torsional angle <C6-C5-C1O-C9 close to 55; the methyl group atClO and the substituent at C4f3 approaches each other during the cleavage, causing an increasein the energy of the transition state. If the substituent is methyl, the even greater increase in thetransition state energy will probably forbid the endo-type cleavage from happening. In the exotype 1 cleavage, the immediate product has a cis-fused hydroindene conformation. Thereshould be little change in the <C6-C5-C1O-C9 and therefore the distance between the ClOmethyl group and the C43 substituent. Thus, change from hydrogen to methyl for the C413substituent will not cause much difference for this exo-type 1 pathway.# 550 is the average value for the torsional angle of a saturated cyclohexane ring.$ 30° is the average value for the torsional angle of a saturated cyclopentane ring.3 8 R=H or CH3Rchair-chair.103chair-boatexo-type 1 cleavage572.2.7. Further Studies on the Acid-promoted Ring Cleavage ofCyclopropylcarbinolsThe unsuccessful efforts with the radical-mediated ring expansion and cleavagereactions required a return to studies on the acid-promoted ring cleavage reaction of thujonederived cyclopropylcarbinols in greater detail. There are examples in the literature showing theuse of other solvolysis conditions. In studies65 on the preparation of vitamin D analogues, theconversion of compound 142 into the trienes 143Z and 143E, which are geometric isomerswith regard to the newly formed double bond, was reported (Scheme 24). Obviously,compound 142 bears a close structural similarity to our thujone-derived cyclopropylcarbinols.The poor nucleophilicity of the attacking groups (e.g., H20 and HOAc) in this set ofconditions may allow the ring cleavage reaction to occur in a less synchronized mechanism inwhich the C-C bond cleavage occurs faster (see also Figure 12). The endo-type cleavageproceeds through a more stable transition state because the tertiary nature of C5 accommodatesthe partial charge developed better than the primary nature of C6. Therefore, the endo-typecleavage prevails.a) orb)a)H20/dioxane, HOTs, 55°C Ri=OHb) HOAc, 55°C Ri=OAcScheme 24 Precedents of the Endo-type CleavageHR142+143Z 143E58The orientation of the newly introduced group (OH or OAc) at C5 agrees well withconcertedness of the nucleophilic attack and the C5-C1 bond cleavage.Treatment of 130 in dioxane:H2O (1:1) with a catalytic amount of p-toluenesulfonicacid at 80°C for 1 hour generated a novel rearrangement product 144 in 85% yield rather thaneither of the ring cleavage products 145 and 146. The absence of any signals at 6 3.0-4.0ppm in the NMR spectrum clearly revealed the product obtained cannot be a primary orsecondary alcohol. The homoallylic tertiary alcohol 144 was characterized by its mass, JR and‘H-NMR spectra. Its mass spectrum indicated a peak at m/z 236 corresponding to themolecular ion and a fragment ion peak at nl/z 218 due to loss ofH20. The IR spectrum showeda broad absorption at 3100-3650 cm1 corresponding to the hydroxyl stretching frequencywhile the1H-NMR spectrum contained five methyl singlets at 6 0.87, 1.01, 1.17, 1.21, and1.22 ppm, a four-proton multipiet at 6 2.10-2.40 ppm corresponding to protons of two allylicmethylene groups, and a one proton broad singlet at 6 5.33 ppm corresponding to the olefinicproton.OH146The most convincing evidence about the structure of 144 came from the X-raydiffraction analysis of its epoxide derivative 147. Treatment of 144 with rn-CPBA inHOTs 144130 +14559methylene chloride for one hour produced 147 in 90% yield, which was crystai.ized frommethylene chloride. The structure of 147 established by X-ray analysis is shown in Figure 15(See Appendix 1). The cis A/B ring junction in 147 and the I face epoxidation are revealed.The mass spectrum of 147 showed its molecular ion peak at m/z 252 and a fragment peak atm/z 234 due to the loss of H20. Its IR spectrum was characterized by a strong hydroxyl147Figure 15 Single Crystal X-ray Structure of Epoxide 147 (ORTEP Drawing’661’)00CC60absorption at 3700 cm-1 (CHC13). The ‘H-NMR spectrum indicated a one-proton singlet at ö2.85 ppm corresponding to the proton on the epoxide ring, and five methyl singlets at ö 0.80,0.98, 1.20, 1.24, and 1.31 ppm.m-CPBACH21144)cc;147Before the crystal structure of 147 was revealed by X-ray analysis, the allylic alcohol148 was mistakenly assumed as the ring cleavage product, since the spectral data noted abovecould be consistent with such a proposal. Mechanistically, the formation of 148 from 130 via146 by some familiar rearrangement steps was also perceivable.Based on the structure 148, a sequence shown below was proposed to obtain the cisfused decalone 128. The epoxidation of 148 would generate 149, which should give glycol150 by hydride attack from the less substituted carbon upon lithium aluminium hydridetreatment66. The latter would then be cleaved to 128 by lead tetraacetate.148 149 150Pb(OAc)412861Therefore, epoxide 147, mistaken as 148, was treated with LAH in THF at 70°C for 2hours. To our surprise, allylic alcohol 151 was obtained in almost quantitative yield. Themass spectrum showed its molecular ion peak at m/z 194, corresponding to a loss of an acetonemolecule (m/z=58) from 147 or 148. The JR spectrum displayed absorptions at 3 100-3650,3060, and 1650 cm-1 corresponding to hydroxyl, olefinic carbon-hydrogen, and carbon-carbondouble bond stretching frequencies. The1H-NMR spectrum indicated oniy three methylsinglets at 6 0.82, 1.02, and 1.14 ppm, a complex two-proton multiplet at 6 2.20-2.60 ppmcorresponding to the allylic methylene protons, a one-proton singlet at 6 3.80 ppmcorresponding to the allyic tertiary proton a. to the hydroxyl group, and two olefinic one-protonsinglets at 6 5.06 and 5.21 ppm. The 3 orientation of the hydroxyl group was assigned basedon a mechanistic argument shown in Figure 16.Mn02CH21To confirm the structural assignment of 151, it was subjected to allylic oxidation bymanganese dioxide67 in methylene chloride at room temperature for two days. The enone 152was obtained in a 70% yield. The mass spectrum showed the molecular ion peak at m/z 192.Its UV spectrum in methanol displayed an intense absorption at 235 nrn (log e=4.0) and aweaker one at 278 nm (loge=2.5). The JR spectrum indicated a carbonyl absorption at 1710cm1,and a carbon-carbon double bond absorption at 1635 cm1.OH147 151 15262LiH20Figure 16 Mechanism of the Fragmentation of Epoxide 147We also treated 147, still then mistaken as 148, with ‘superhydride’ (lithiumtriethylaluminium hydride) in order to see if the the desired reduction rather than thefragmentation would take place. However, the same compound 151 was obtained as the onlyproduct. This puzzling fragmentation is finally understood when the structure of 147 waselucidated by X-ray analysis. Since the epoxide ring is on the convex side of the carbonframework, the nucleophilic ring opening of the epoxide by hydride has to take place from theconcave side. The unusually severe hindrance promotes the other pathway, that is,fragmentation. The deprotonation of the tertiary hydroxyl group with hydride is proposed toresults in the intermediate alkoxide first and the latter then undergoes the fragmentation shownin Figure 16.The novel rearrangement from 130 to 144 involved the insertion of the cyclopropanemethylene into the position between the cyclopentyl ring and the isopropyl side chain. Thecleavage of the carbon-carbon bond (i.e., the exo-type 2 cleavage, see the notation in Figure11) in the original cyclopropyl ring was observed for the first time. The mechanism in Figure17 is proposed to rationalize the reaction. Cyclopropylcarbinyl cation (i) is first formed by aproton-catalyzed elimination of the hydroxyl function in 130. The 1,3-shift of the methylenecan result in another cyclopropylcarbinyl cation (ii). Further cleavage of (ii) in a selectivefashion to form a more stable homoallylic cation (iii) occurs and the latter, upon reaction withwater, converts to 144. The transformation between two cyclopropylcarbinyl cations in a147 15163manner similar to that between (i) and (ii) was termed as a “cyclopropane sliding reaction” byH. Shirahama, who studied this type of transformation in greater detail with his system68. Themechanistic proposals involving this novel “sliding reaction” are scattered through theliterature69.H20Figure 17 Mechanism of the “Cyclopropane Sliding Reaction’Treatment of 130 with acetic acid at 85°C for one hour produced the exo-type 2cleavage product 153 in 60% yield in addition to the exo-type 1 cleavage product 154 in 6%yield. The competition of exo-type 1 cleavage is likely because 154 could only slowly convertto the cyclopropylcarbinyl cation (i) shown in Figure 17 once it is formed. The exo-type 1product 145 could not be isolated in the previous reaction since it likely converts back to (i)rapidly under the acid catalysis.The mass spectrum of 153 showed an intense fragment peak at m!z 218 due to the lossof an acetic acid molecule from the parent molecule (m/z=278). The chemical ionization massspectrum using ammonia as carrier gas showed the protonated molecular ion (M+Hj peak atm/z 279. The JR spectrum indicated carbonyl and carbon-carbon double bond stretching130 (i) (ii)(iii) 14364absorptions at 1735 and 1650 cm-1 respectively. In the ‘H-NMR spectrum, six methyl singletswere observed at 6 0.85, 1.00, 1.15, 1.38, 1.45, and 1.97 ppm. The lowest field methylsinglet was due to the methyl protons of the acetate group. A complex multiplet at 6 2.02-2.62ppm integrating for four protons was assigned to the two allylic methylene groups. There wasa one-proton singlet at 65.26 ppm, corresponding to the olefinic proton.The minor product 154 had its mass spectrum showing the molecular ion at m/z 278and a fragment ion at m/z 218 due to loss of an acetic acid molecule. Its IR spectrum displayeda carbonyl stretching absorption at 1730 cm-1. In the1H-NMR spectrum, six methyl singletswere observed at 6 0.85, 1.03, 1.14, 1.61, 1.69 and 2.01 ppm. The two singlets at 6 1.61and 1.69 ppm were assigned to the two vinylic methyl groups of the isopropylidene group andthe signal at 6 2.01 was clearly due to the methyl of the acetate group. A two-proton multipletat 6 2.10-2.32 was due to the allylic methylene while a one-proton triplet (J=5.6 Hz) at 8 2.39ppm was from the allylic methine proton. A two-proton multiplet at 6 3.92-4.25 ppm, whichhad a shape characteristic of the A/B portion of an ABX system, was assigned to the methyleneattached to the acetate group.To test the generality of the cyclopropane sliding reaction, ketol 120 was employed assubstrate under the two conditions previously used (Scheme 25). The endo-type cleavageproduct 155 was obtained in 87% yield underp-toluenesulfonic acid catalysis in dioxane:water(1:1) mixture. It was characterized by its ion molecular peak at m/z 222 and JR absorptions at3050-3650, 1700, and 1650 cm due to hydroxyl, carbonyl, and carbon-carbon double bondstretching frequencies. Three methyl singlets, one at 6 1.20 ppm and two at 8 1.23 ppm, andan olefinic one-proton broad singlet at 6 5.20 ppm were observed in its1H-NMR spectrum.65OAcHOAc+oxan:HOQAc QAc++Scheme 25 Generality of the Cyclopropane Sliding ReactionTreatment of 120 with acetic acid gave mainly the cleavage products 156 (56%, exotype 1 cleavage) and 157 (14%, exo-type 2 cleavage). Although a very minor peak at ö 5.17ppm in the1H-NMR spectrum of 156 indicated a probable presence of 158, the very minoramount present prevented its isolation. Presumably, the faster rate of these more directcleavage reactions and perhaps the higher stability of the acetate products, prevent theformation of a cyclopropylcarbinyl cation like (i) in Figure 17 and therefore the sliding reactionfrom taking place. The keto-acetate 156 was characterized by its molecular ion peak at m/z264, carbonyl stretchings at 1735 and 1705 cmt in the JR spectrum, and a two-protonmultiplet at 3.95-4.20 ppm corresponding to the methylene attached to the acetate group inthe NMR spectrum. The electron impact mass spectrum of 157 revealed a fragment ion peak130 153 154HOAc66at m/z 204 due to loss of a molecule of acetic acid; The chemical ionization mass spectrumusing ammonia as carrier gas showed (M+I[H) at m/z 282 and (M+H) at m/z 265. The IRspectrum exhibited a carbonyl stretching absorption at 1710 cm-1. Two vinylic methyl singletsappeared at 8 1.65 ppm and 1.72 ppm. A methyl singlet at 6 2.10 ppm corresponding to themethyl of the acetate group and a one-proton doublet of doublets at 5.19 ppm (J=4.2 and10.2 Hz) corresponding to the methine attached to the acetate group were observed. Theacetoxyl group was assumed to have 3-orietation, following the observed stereochemistry forthe ring cleavage of related systems under similar conditions and the argument presented forthis observation (Scheme 24).2.2.8. Baeyer-Villiger Oxidation of Cyclopropyl KetonesOur other efforts on applying the alcohols derived from ozonation of thujonederivatives were to consider alternatives to the synthetic sequence shown in Scheme 21 byrearranging some steps involved. The successful radical-mediated ring expansion product 126might be methylated to 159, which could be then decarbonylated and ozonolyzed to give 129.Unfortunately, methylation of 126 by KOtBu and CH3I in anhydrous t-butanol did notproceed at all at room temperature. Heating up the mixture gave a complex mixture. Althougha protection of the methylene at C2 and the use of a strong base like LDA may eventually allowmethylation proceed as desired, the added extra steps seemed to give very little advantage tosuch an effort. The other alternative sequence involved the use of 122A, resulting frommethylation of 122. The mass spectrum of 122A showed the molecular ion peak at m/z 248while the JR spectrum indicated absorptions of the hydroxyl and carbonyl groups at 3100-3700and 1705 cm1. The ‘H-NMR spectrum revealed a one-proton triplet at 3 0.44 ppm (J=4.4Hz), a one-proton doublet of doublets at 6 1.04 ppm (3=4.4 and 8.0 Hz), five methyl singletsat 6 1.16, 1.19, 1.23, 1.26, and 1.28 ppm, two one-proton multiplets at 3 2.50 and 2.70 ppm,and a one-proton broad singlet at 6 5.62 ppm. Unfortunately, treatment of 122A withhydrochloric acid in methylene chloride gave an intractable mixture rather than the desired67122B. The low yield (30%) of 122, obtained from Robinson annulation of 94 with EVK,also discouraged further effort in this direction.Therefore, the application of alcohols derived from ozonation of thujone derivatives tothe synthesis of natural (-)-polygodial (2) had not met with any success. Our nextconsideration then to cyclopropyl ketones derived from ozonation, especially 131. It wasperceived that a Baeyer-Villiger reaction7’would cleave the side chain in a regioselectivemanner to give 160 (Scheme 26). The preferential insertion of oxygen into the cyclopropylgroup side during the Baeyer-Villiger reaction of methyl cyclopropyl ketone had been observedpreviously70. The cyclopropanol 161 from saponification of 160 would be cleaved via theinternal carbon-carbon bond (i.e., endo-type 1 cleavage) by ferric chloride to generate the bchioroketone 162. It was recorded that the more substituted bonds of cyclopropanols werecleaved preferentially73.Subsequent elimination of HC1 would afford enone 163 and the lattercould be elaborated to intermediates 65 in Scheme 9 by standard methods, thereby completinga formal synthetic sequence to (-)-polygodial (2).126 159 129122A 122B 6568- --Scheme 26 Utilization of Cyclopropyl Ketone 131 via Baeyer-Villiger and CyclopropanolCleavage ReactionsFor this purpose, compound 131 was treated with m-CPBA in methylene chloride atroom temperature for 2 days to produce 160 in 79% yield based on the recovery of 46%starting material 131. An optimization of the reaction was carried out according to Table 4.p-Toluenesulfonic acid had little catalytic effect on the m-CPBA oxidation reaction. Underrefluxing conditions, the reaction appeared to accelerate at the beginning but slowed downquickly after a few hours and started to afford some unidentified by-products. When theconcentration of the substrate was increased to 0.82 M, the reaction was quite complete afterrefluxing in methylene chloride for 12 hours and the yield of 160 was 82%. Although the useof trifluoroperacetic acid70 improved the yield to as high as 94%, the reaction seemed noteasily reproducible. This was likely due to the instability of trifluoroperacetic acid. Therefore,the preferred procedure for the preparation of 160 was to employ a high concentration ofsubstrate 131 with m-CPBA as the oxidizing agent in refluxing methylene chloride.131 160 161162 16369Table 4 The Optimization of Baever-Villier Reaction of Ketone 131Experiment 1 2 3 4 5131 176mg 176mg 176mg 93mg 1.80gPeracids’ m-CPBA m-CPBA m-CPBA CF3OH m-CPBA346 mg 346mg 346mg 312 il (2.7M) 4.45 g(2.0 eqv.) (2.0 eqv.) (2.0 eqv.) (2.0 eqv.) (2.5 eqv.)CH21 5.0 ml 5.0 ml 5.0 ml 2.0 ml 10 mlHOTs(mg) 0 39 0 0 0Temp. r.t. r.t. reflux r.t. refluxTime (hrs) 48 48 24 48 12%recovery 46 46 30 48 5of 131%yieldof 79 78 60 94 82%160: m-CPBA (80-85% mire) was used without further yurification while CF3OHwas preDaredin situ according to ref. 70a.Acetate 160 had its mass spectrum showing the molecular ion peak at m!z 236. The JRspectrum had a carbonyl absorption at 1735 cm1 while the1H-NMR spectrum displayed fourmethyl singlets at 0.80, 0.97, 1.05, and 2.10 ppm. The methyl singlet at 2.10 ppm wasobviously due to the acetate group, which unambiguously demonstrated the insertion ofoxygen into the position between the quaternary cyclopropyl carbon (C7) and and the carbonylcarbon.According to the accepted mechanism of the Baeyer-Villiger reaction, a tetrahedral“Criegee intermediate” rearranges to ester products after it is formed by the peracid addition tothe ketone carbonyl72. (I), the transition state of this rearrangement step, can be described byfour resonance structures, Ia, Ib, Ic, and Id. The structure Ic implies that the preferredmigration group will be the one that best accommodates a positive charge. Methyl cyclopropyl70OHO O2CRAs mentioned previously, ketone 131 was obtained in only 25% yield from theozonation of alkane 128. Therefore, a sequence was developed to convert alcohol 130 toketone 131 in order to optimize the yield of 131. Vinylcyclopropane 138, prepared bydehydration of 130 (p. 54), was ozonized to 131 in only 60% yield. A two-step procedure,involving the treatment of 138 with potassium permanganate in 1:1 t-butanol:water and thesubsequent oxidative cleavage of the non-purified crude mixture of diols by lead tetraacetate inbenzene, was then developed. In this case, 131 was obtained in 83% yield from 130. Thus,the overall yield of 131 from alkane 128 was improved to 65%.ketone was unreactive to m-CPBA; only the much more reactive agent peroxytrifluoroaceticacid could make the oxygen insertion proceed to give cyclopropyl acetate7ob. This is probablybecause the cyclopropyl group cannot accommodate a positive charge well. The smoothreaction of 131 with m-CPBA at room temperature shows that the transition state involved islikely stabilized by the fused cyclopentyl group, which can presumably stabilize a positivecharge better than the cyclopropyl group..HRCO3H Ri___RCO2HR1—C—R2 1’IcQ_cQR (I) R1—C--0R2R21Criegee intermediateOHI 1I R IL O—O2CRTa TbOHCR1R2 IIO O2CRIcOHCR1R2 IOCRIdKMnO4138Pb(OAc)4131712.2.9. Regioselective Ring Opening of the Cyclopropyl Alcohol 161Regioselective ring opening of alkyl substituted cyclopropanols by ferric chloride hasbeen studied extensively by DePuy73. The more substituted C-C bond is preferentiallycleaved. The reaction (Figure 18) involves a cyclopropoxyl radical (i) which undergo ahomolytic scission of the more substituted C-C bond to give a carbinyl radical (ii). Thesubsequent abstraction of a chlorine from ferric chloride produces the 3-chloroketone. Thisreaction was successfully applied to ring expansion of cyclic ketones via their derivatives 1-trimethylsilyloxybicyclo[n.1.Ojalkanes74.More recently, a different reagent, iodosobenzene,was developed to effect the same ring expansion of cyclic ketones and lactones via similarderivatives75.FeCI2 + HCIRL(iii)FeC13R OH R(i) R (ii)R0eCl3FeC12Figure 18 Regioselective Cleavage of CyclopropanolsSaponification of 160 was carried out in dilute potassium hydroxide-ethanol solutionfor 30 minutes. The rather polar 161 was obtained in almost quantitative yield. The reactionhad to be worked up immediately because 161 could be further converted into 164. The massspectrum of 161 indicated the molecular ion peak at m/z 194. Its IR spectrum showed thehydroxyl stretching frequency at 3050-3650 cm1 and the absence of ester carbonyl absorption.The ‘H-NMR spectrum displayed three methyl singlets at ö 0.80, 0.96, and 1.01 ppm, a two-72proton multiplet at 5 1.98 ppm. The spectrum was contaminated by ketone 164 resulting fromrapid decomposition of 161.The lability of cyclopropanol 161 dictated its immediate application to the next reaction.The mixture of anhydrous ferric chloride and 161 in anhydrous N,N-dimethylformamide wereagitated under nitrogen at room temperature for 24 hours. The major product 162 was isolatedin addition to a small amount of 164.The 13-chloroketone 162 had its mass spectrum showing molecular ion peaks at m/z230 (0.2%) and 228 (0.6%) corresponding to formulasC13H21037andC13H21035. ItsJR spectrum displayed carbonyl stretching absorption at 1720 cnr1 while the ‘H-NMRspectrum indicated three methyl singlets at 5 0.76, 0.90, and 1.25 ppm, a complex four-protonmultiplet at 5 2.10-3.00 ppm, and a one-proton doublet of doublets at 4.70 ppm (J=6.0 and12 Hz) corresponding to the methine proton attached to the chlorine bearing carbon. Theorientation of the chlorine function in 162 was uncertain.The mass spectrum of 164 indicated the molecular ion peak at rn/z 194 while the IRspectrum revealed the carbonyl absorption at 1725 cm1. The ‘H-NMR spectrum displayedtwo methyl singlets at 5 0.80 and 0.99 ppm, a methyl doublet at ö 0.93 ppm (J=7.2 Hz), aone-proton triplet at 5 1.77 ppm (J=8.0 Hz), a one-proton quartet at 2.06 ppm (J=7.2 Hz),and a complex one-proton multiplet at 52.15-2.35 ppm.KOH160 161FeC!3DMF+162:016473The -chloroketone 162 underwent elimination of hydrogen chloride to give enone163 easily even without addition of any base. The crude product from the above ring cleavagereaction was treated with sodium acetate in refluxing methanol for a few hours. The overallyield of 163 from acetate 160 was 80%, equivalent to a 93% yield for each step. The ketone163 was a white solid with a m.p. of 64-66°C (literature value m.p. 68°C )76. The massspectrum of 163 indicated its molecular ion peak at mlz 192. The JR spectrum showed anintense conjugated carbonyl stretching frequency at 1664 cm-1. Three methyl singlets appearedat 60.77,0.96, and 1.22 ppm in the1H-NMR spectrum. A complex two-proton multiplet at 82.50-2.80 ppm corresponded to the methylene cx to of the carbonyl function. Two doublets at6 5.95 and 6.27 ppm with a coupling constant, J=9.6 Hz were assigned to the two olefinicprotons.The racemate of 163 was prepared previously by an interesting photochemicalepimerization76.The ether 165, prepared from the trans-fused isomer of 163, was irradiatedto generate 166 which then, upon hydrolysis, afforded (±)-163. The transformation from165 to 166 was mediated by an achiral triene and therefore the chirality of starting material165 was lost completely during the reaction. In other words, this method is inherently notenantioselective.H3OOCH3(±)-163hv165 166/74The cyclopropylcarbinyl radical (i) and the cyclopropoxyl radical (ii) appears to havedistinctly different cleavage pathways. Why are not the conformational factors previouslyconsidered in the cleavage of carbinyl radical (i) in Figure 14 playing any major role in thecleavage of the oxyl radical (ii).carbinyl radical 0) oxyl radical (ii)A beautiful frontier molecular orbital (FMO) rationalization offered by Mariano andBay77 is adopted here (Figure 19). As we know, the SOMO of the oxygen-centered radicalhas much lower energy than that of the carbon-centered radical due to the greaterelectronegativity of oxygen. In general, the oxyl radical SOMO and the HOMO of acyclopropane C-C bond are closer in energy than the SOMO-LUMO pair. Therefore, theSOMO-HOMO interaction contributes more to the stabilization of the transition state. A morealkyl substituted C-C bond has higher HOMO energy due to the electron donating nature ofalkyl groups78 and therefore has an enhanced SOMO-HOMO interaction. As a result, the moresubstituted C-C bond is preferentially cleaved. In the case of the oxyl radical (ii), such aSOMO-HOMO stabilizing interaction for the more substituted internal C-C bond overridesthose unfavorable conformatiomal factors considered in the case of carbinyl radical (i) (Figure14). Therefore, the endo-type cleavage is observed for the oxyl radical (ii). Using a similarargument, the kinetically controlled cleavage of cyclopropylcarbinyl radical (i) will go throughthe exo-type 1 pathway. The thermodynamically favorable endo-type cleavage cannotmaterialize even under the most favorable condition (i.e., high dilution and slow reaction rate)probably because of the great transition barrier present in this pathway (see Figure 14).75LUMOSOMOSOMOHOMO0-C-..-0:::I IFigure 19 FMO Interactions of Carbinyl and Oxyl Radicals with Cyclopropane C-C BondsThe preferential cleavage of the less substituted C-C bond in cyclopropanols by otherreagents, which has a complementary regioselectivity to the ferric chloride reaction were alsorecorded73. We were curious to see if the exo-type 1 cleavage of the cyclopropanol 161,which represents the cleavage of the less substituted C-C bond, could be effected by usingsimilar conditions. Indeed, the 13-bromoketone 167 was obtained in 60% yield after 161 wastreated with NBS in DMSO:CHC13(1:1) at room temperature. The mass spectrum of 167revealed two isotopic molecular ion peaks at mlz 274 (2.4%) and 272 (2.5%) while the JRspectrum showed the carbonyl stretching absorption at 1730 cm-1. The ‘H-NMR spectrumindicated three methyl singlets at 6 0.82, 1.00, and 1.14 ppm, a two-proton multiplet at 6 2.32ppm, a triplet at 6 2.55 ppm (J=5.4 Hz), and a complex two-proton multiplet at 6 3.35-3.65ppm.NBS0DMSO:CHC13161 167Br76Therefore, the cyclopropyl ketone 131, much less considered than the other ozonationderived compound — cyclopropylcarbinol 130, turned out to be the more versatile intermediatefor further elaboration. The cyclopropanol group in 161 may give a better control ofregioselective ring cleavages than the cyclopropylcarbinol group in 130. In retrospect, we feltsatisfied with what the ozonation method had brought us in terms of excluding the isopropylside chain and controlling the regioselectivity of cyclopropane ring cleavage.2.2.10. A Formal Enantioselective Synthesis of (-)-Polygodial (2) and (-)-Warburganal (10)de Groot et al. have synthesized enantiomerically pure 64 from (-)-dihydrocarvone(Scheme 9)33e. Ketone 64 was then converted to natural (-)-polygodial (2) and (-)-warburganal (10) using a sequence previously developed (Scheme 3). Consequently, If thecis-fused enone 163 were transformed into enone 64, a formal enantioselective synthesis of (-)-Polygodial (2) and (-)-warburganal (10) from thujone was at hand.2 8 1)LDA Li, NH3173 2) PhSeC13) H20Scheme 27 The Preparation of Enantiomerically Pure Enone 64 from 163To this end, LDA and phenylselenenyl chloride treatment of compound 163 in THF,followed by hydrogen peroxide oxidation, generated dienone 168 in very good yield (92%)(Scheme 27). Dienone 168, in its mass spectrum, showed the molecular ion peak at mlz 190while its UV spectrum displayed a broad absorption peak at 2. 241 nm (log e=4.0). The JRspectrum indicated a conjugated carbonyl stretching absorption at 1660 cm1 and a weak C=Cabsorption at 1620 cm-1. Three methyl singlets appeared at 8 1.22, 1.30, and 1.35 ppm in the163 168 6477‘H-NMR spectrum. The olefinic proton at C8 was a doublet of doublets at ö 6.14 ppm due tothe couplings with the proton at C9 (J=9.9 Hz) and with the proton at C6 (W coupling, 1=0.2Hz). The proton at C9 was a doublet at 6 6.25 ppm due to coupling with the the proton at C8(J=9.9 Hz). The proton at C6 appeared as a doublet at 6 6.70 ppm (J=0.2 Hz) resulting fromthe above mentioned W coupling with the C8 proton.Birch reduction of dienone 168 without adding any proton donor gave the desiredenone 64 in 70% yield. The specific rotation of compound 168 ([cL]5=-l00, c=l.00,CHC13)is in close agreement to the value reported by de Groot ([a]5=-105, c=l.0,CHC13)3e. This kind of selective reduction of the less substituted double bond of ananalogous dienone 169 was observed previously79.Presumably the higher reduction potentialLi, NH3170of the less substituted double bond led to a faster reaction. The spectroscopy data of 64obtained by us was identical to that reported by de Groot33e. Thus, a formal syntheticsequence of (-)-polygodial (2) and (-)-warburganal (10) was completed.The complete sequence from thujone (3) to enone 64 is summarized in the followingscheme. This sequence consisting of 11 steps is considerably longer than the 5-step sequencedeveloped by de Groot (Scheme 9). However, our sequence can be simplified by carrying outseveral continuous steps without purification of intermediates. Specifically, steps from b) tof), steps from g) to h), and steps from i) to j) have been performed in this manner. For thesake of completing a formal synthesis, we purposely intercepted enone 64 by conversion ofenone 163. Consequently, the A/B cis fusion became a complete handicap. In other words,the real strength of enone 163 as a chiral template and therefore thujone as a chiral buildingblock could not be shown. As will be demonstrated in the synthesis of ambergris fragrances16978a b, c, d e, fg, h, i, ja) EVK, KOH, EtOH; b) H2, Pd-C; c) Mel, KOtBu, LBUOH; d) NH2,KOH, DEG; e) 03;f) KMnO4/Pb(OAc);g) m-CPBA; h) KOH, MeOH; i) FeC13,DMF; j) NaOAc, MeOH;k) LDA, PhSeC1/H20;1) Li, Nil3.(Chapter 3), the direct application of the cis-fused enone 163 as a chiral template is much moreadvantageous*.Ketone 171, which was an intermediate used in the preparation of a (-)-polygodialanalogue (Scheme 17), was converted to 173 and 174 using a similar dehydrogenationreduction sequence. Dienone 172 was obtained in 80% yield by treatment of 161 with DDQin refluxing dioxane80. This product was characterized by its molecular ion peak at mlz 176 inthe mass spectrum, a conjugated carbonyl and carbon-carbon double bond absorptions at 1650and 1620 cm-’ in the JR spectrum as well as typical ‘H-NMR signals. In the latter spectrum, amethyl doublet at 1.14 ppm (J=6 Hz), a methyl singlet at 1.27 ppm, a one-proton septet(J=6 Hz) corresponding to the methine proton at C4, a singlet at 6.11 ppm corresponding tothe olefinic proton at C6, a doublet at 6.21 ppm (J=9.0 Hz) corresponding to the olefinicproton at C8, and another doublet at ö 6.78 ppm (J=9.0 Hz) corresponding to the proton at C9were observed.Birch reduction of 172 gave both enone 173 (42%) and the saturated ketone 174(25%). The double reduction of 172 was probably due to the presence of a trace amount of* Following the synthetic plan presented there (Section 3.2.1.), one may also envisage a new route to (-)-polygoclial and (-)-warburganal, starting with the cis-fused enone 163.128131 0 163 6479water which could protonate the enolate of 173, generated in the initial reduction of the lesssubstituted carbon-carbon double bond, to produce 173 in situ. The further reduction of 173yielded 174.The mass spectrum of 173 indicated the molecular ion peak at m/z 178. The JRspectrum showed a conjugated carbonyl stretching absorption at 1660 cm-1 and a carbon-carbon double bond stretching absorption at 1610 cm4. The NMR spectrum displayed amethyl doublet at 6 1.06 (J=6 Hz), a methyl singlet at 6 1.25 ppm, a complex three-protonmultiplet corresponding to the allylic C4 proton and the methylene group a to the carbonylfunction, and one singlet for the olefinic proton at 65.79 ppm.25The saturated ketone 174 had a specific rotation [aID =-39.7 (c=1.00, CHC13), whichis in good agreement with the reported value ([a]=-39.0, c=1.0, CHC13)80. Its massspectrum showed the molecular ion peak at m/z 180. In the JR spectrum, the carbonylstretching absorption appeared at 1702 cm-1. The1H-NMR spectrum indicated a methyldoublet (J=6 Hz) at 6 0.81 ppm, a methyl singlet at 6 1.05 ppm, and a complex four-protonmultiplet at 6 2.00-2.55 ppm corresponding to the two methylene groups a to the carbonylgroup.174Scheme 28 A Possible Sequence to a New (-)-.Polygodial AnalogueTransformation of 173 and 174 into another (-)-polygodial analogue 175 using asequence similar to that developed by de Groot (Scheme 3) can be perceived (Scheme 28).9238 DDQ‘7Li, NH3171 172 173175802.3. Experimental2.3.1. GeneralSolvents as provided from the Chemistry Store were used for chromatography withoutfurther purification. Petroleum ether refers to the fraction boiling in the range of 30-60°C.Anhydrous diethyl ether, tetrahydrofuran, and benzene were prepared by distillation from amixture containing sodium and benzophenone. Anhydrous methylene chloride, chloroform,and n-pentane were prepared by distillation from phosphorus pentoxide. Anhydrousisopropylamine, HMPA, DMF and DMSO were prepared by distillation from calcium hydrideand stored in the presence of molecular seives (3 A) under nitrogen. Anhydrous methanol andethanol were distilled from magnesium.Commercial reagents were purified, when necessary, by procedures described in Perrinand Perrin’62. n-Butyllithium, LDA, and vinylmagnesium bromide solutions werestandardized by titration against sec-butanol in benzene using 1,10-phenanthroline as indicatorunder nitrogen’65.Borane in THF and L-Selectride were standardized by measuring hydrogenreleased from their reaction with 1:1 glycerol:water solution130. Thujone was distilled fromWestern red cedar leaf oil which was generously donated by Intrinsic Research andDevelopment Incorporated.Syringes and needles were oven-dried at 120°C for a minimum of 4 hours and stored ina desiccator. Unless stated otherwise, all reactions were carried out under a positive pressureof dry nitrogen. Reactions at -7 8°C, -40°C, -25°C, and 0°C were performed with dry ice!acetone, dry ice/acetonitrile, dry ice/carbon tetrachioride, and ice/water cooling bathsrespectively. Air-sensitive materials were transferred inside a glove bag filled with nitrogenduring weighing. All glassware was assembled under nitrogen immediately after being ovendried. Alternatively, it was flame-dried with nitrogen flowing through the reaction setup.Reactions were monitored by thin layer chromatography (TLC) and/or gaschromatography (GC). Analytical TLC was carried out on aluminium-backed silica gel plates81(Merck Silica Gel 60F254). Visualization was realized by ultraviolet light and/or by heatingafter spraying with 10% ammonium molybodate in 10% sulfuric acid. Gas chromatographywas performed on a Hewlett-Packard 5890A gas chromatograph, using a flame ionizationdetector and a 14.5 m x 0.252 mm fused silica capillary column coated with cyanopropylphenyl silicone gum (DB 1701). Unless otherwise stated, all reaction products were purifiedby “flash chromatography” using silica gel (230-400 mesh) supplied by E. Merck Co. with airpressure to obtain a suitable flow163.Melting points were measured using a Kofler block melting point apparatus and areuncorrected. Optical rotations were recorded on a Perkin-Elmer 141 automatic polarimeter inchloroform solution using a quartz cell of 10 cm path length with the concentration (in g/100ml) given in brackets. The ultraviolet spectra were recorded on Cary 15 or Perkin-ElmerLambda 4B UV/VIS spectrometers using quartz cells of 1 cm path length. The infrared spectrawere recorded on Perkin-Elmer 710, 7 lOB, and 1710 spectrometers in chloroform solutionusing NaCl cells of 0.1 mm path length or as thin film using NaCl plates. The ‘H-NMRspectra were obtained from Bruker WH-400, AE-200 or Varain XL-300 spectrometers withduteriochloroform as solvent and the chemical shifts are reported in the delta (6) scale in ppmrelative to tetramethylsilane. The 13C spectra were taken on Bruker AE-200, or XL-300spectrometers and chemical shifts are reported in the delta (6) scale in ppm relative totetramethylsilane. The low and high resolution mass spectra were recorded on AEI-MS-9 orKRATOS-MS-50 spectrometers using the electron impact ionization method while the chemicalionization mass spectra were recorded on a Delsi Nermag RiO-i OC spectrometer usingammonia as carrier gas. CD spectra were recorded on a JASCO J-20 automatic recordingspectropolarimeter. Elemental analyses were performed by Mr. P. Borda, MicroanalyticalLaboratory, University of British Columbia. Previously known compounds, some byproducts or unstable intermediates may not have elemental analysis. Single Crystal X-raystructure determinations were performed by Dr. S. Rettig on a Rigaku AFC6S or Enraf-NoniusCAD4-F diffractometers.82All compounds are named in accordance with IUPAC and CA rules. For compoundsof the tricyclo[4.4.0.07’9]decane skeleton (i.e., the cyclopra[a]indene skeleton), their vonBaeyer names are also included in order to facilitate comparison with other similar compoundspreviously prepared and named by our group. However, the numbering system employed inall Introduction and Discussion sections follows the normal conventions of terpenoid andsteroid literature in order to have convenient comparison with natural products and withthemselves.2.3.2. Ozonation: thujone (3) to thujonol (94) and thujonone (95)[1R-( 1 c,4c/f3,5cc)] 1 -(1 -hydroxyl- 1 -methylethyl)-4-methyl-bicyclo{3. 1.01 hexan-3-one (94)[1 R-( 1 c,4a/f3,5 ct)] 1 -acetyl-4-methyl-bicyclo[3. 1 .0]hexan-3-one (95)Thujone (3) (10.00 g, 65.8 mmol) dissolved in EtOAc (500 ml) was subjected to astream of ozone-oxygen at -25°C for 10 hours. After the ozonizer was turned off, the gas flowwas allowed to continue for 15 minutes to remove the residual ozone. After addition ofdimethyl sulfide (5 ml), the reaction mixture was warmed to room temperature with stirring for15 minutes, washed with water (100 ml) and saturated sodium bicarbonate solution (2X50 ml),and dried over magnesium sulfate. Solvent evaporation in vacuo gave an oil which waschromatographed using a mixture of isopropanol:hexanes (3:7) to afford compound 94 (4.70 g,47%) and 95 (2.32 g, 23%).The physical properties of 94 are as follows*:JR (film) vmax.: 3 100-3700 (0-H stretching), 1730 (C=0 stretching).* All spectral data were taken from spectra of the mixture containing a and I diastereomers at a ratio of 10:1 asanalyzed by OC. The1H-NMR spectral signals should be those of the major a diastereomer since they can be940H I195 083‘H-NMR (400 MHz, CDC13)6: 0.11(1H, t, J=4.8 Hz), 1.13 (1H, m), 1.18(3H, d, J=7.6Hz), 1.22 (3H, s), 1.32 (3H, s), 1.35 (1H, dd, J=4.0 and 8.0 Hz), 1.60 (1H, bs), 2.19 (1H,d, J=16.4 Hz), 2.29 (1H, q, J=7.6 Hz), 2.79 (1H, dm, J=16.4 Hz).MS m/z: 168 (M, 10.0%), 150 (4.0%), 107 (69.5), 43 (100.0%). High resolution massmeasurement: calculated forC1OH6O: 168.1150; found: 168.1146.The physical properties of 95 are as follows*:JR (film) Vmax.: 1740 (C=O stretching), 1685 (C=O stretching).‘H-NMR (400 MHz, CDC13)6: 0.75 (1H, t, J=4.8), 1.22 (3H, d, J=8.4 Hz), 1.86-1.98(2H, m), 2.09 (3H, s), 2.30-2.4 1(2H, m), 3.25 (1H, m).MS m/z: 152 (M, 35.0%), 137 (11.0%), 124 (32.0%), 109 (100.0%). High resolutionmass measurement: calculated forC9H120: 152.0837; found:. 152.0839.2.3.3. Catalytic Hydrogenation: enone 7 to ketone 96[1 aS-(1 act, 1b13,5a,5a13,6aa)] 1 a, lb,2,3,5,5a,6,6a-Octahydro- lb,5-dimethyl-6a-( 1-methylethyl)cycloprop[a] inden-4( 1H)-one (96) or [1R,2S,6S ,7S ,9Rj 2,6-Dimethyl-9-( 1-methylethyl)tricyclo [4.4.0.07’9.]decan-3-one (96)96Enone 7 (62.00 g, 282 mmol) was dissolved in ethanol (500 ml). 10% palladium-charcoal catalyst (1.50 g) was added. The mixture was vigorously stirred under 1 atm H2 for 8hours and filtered through a thick Celite cake. Evaporation of ethanol gave 96 as a colorlessoil (62.06 g, 99.1%).readily recognized from the integrations. The signals of the minor 3 diastereomer were hardly observable fromthe spectrum. See footnote at p. 28.84The physical properties of 96 are as follows:[a]=+61.5 (c=1.00, CHC13).IR (film) vmax.: 3050 (C-H stretching of the cyclopropyl group), 1710 (C=O stretching) cm-’.‘H-NMR (400 MHz, CDC13)& 0.20 ( 1H, J=4.8 and 8.0 Hz), 0.42 (111, t, J=4.8 Hz), 0.85(3H, d, J=6.8 Hz), 0.87-1.00 {7H, including 0.91 (3H, d, J=6.8 Hz) and 0.94 (3H, d, J=7.2Hz)}, 1.10-1.40{5H, m, including 1.24 (3H, s)}, 1.45-1.90 (4H, m), 2.15 (1H, m), 2.42(1H, m), 2.58 (1H, m).MS m/z: 220 (M, 8.0%), 205 (5.1%), 159 (%), 93 (75.2%), 86 (100.0%). High resolutionmass measurement: calculated for C15H240: 220.1821; found:. 220.1815.Elemental analysis: calculated forC15H240: C 81.76, H 10.98; found: C 81.67, H 11.002.3.4. Ozonation: ketone 96 to ketol 97 and dione 98[1 aR-( lax, 1bf,5ct,5a,6ac)] 1 a, lb,2,3,5,5a,6,6a-Octahydro-6a-( 1 -hydroxyl- 1-methylethyl)-Cycloprop[a]indene-4( 1H)-one (97) or [1R,2S ,6S ,7R,9S] 2,6-Dimethyl-9-( 1-hydroxyl- 1 -methylethyl)tricyclo[4.4.0.07’9.Jdecan-3-one (97)[[laR-( 1 ao, 1bf,5cc5af3,6ax)] 6a-Acetyl- 1 a, lb,2,3,5,5a,6,6a-octahydro- 1 ,5-dimethyl-cycloprop [a]indene-4( 1H)-one (98) or [1 R,2S,6S,7R,9S1 9-Acetyl-2,6-dimethyltricyclo[4.4.0.07’9.Jdecan-3-one (98)Method A:Ketone 96 (1.03 g, 4.68 mmol) in EtOAc (100 ml) was cooled to -40°C. A stream ofozone-oxygen was passed for 10 hours. The oxygen flow continued for another 15 minutes to85remove residual ozone. After dimethyl sulfide (1.0 ml) was added, the mixture was warmedslowly to room temperature with stirring, washed with water (50 ml), saturated sodiumbicarbonate solution (2x50 ml), and brine (30 ml), dried palladium. Solvent evaporation gavean oil which was chromatographed with isopropanol:hexanes (1:10) to give compounds 97(0.42 g, 40%) and 98 (0.27 g, 28%) in a total yield 68% in addition to starting material 96(0.06 g, 6%).Method B:Compound 122 (100 mg, o.427 mmol) in ethanol (10 ml) was treated with 10%palladium-charcoal catalyst (10 mg) and stirred under 1 atm hydrogen for 1 hour. Filtration ofthe reaction mixture and concentration of the filtrate gave compound 97 (95 mg, 95%) as anoil.The physical properties of 97 are as follows:m.p.: 45-47°C.[cL]=+1.36x102 (c=l.00, CHC13).JR (film) Vmax.: 3000-3650 (0-H stretching), 3050 (C-H stretching of the cyclopropyl group),1710 (C=0 stretching) cm1.1H-NMR (400 MHz, CDC13)& 0.42 (1H, t, J=4.4), 0.62 (1H, dd, J=4.4 and 8.0), 0.95(3H, d, J=6.4), 1.10-1.35 { 1OH, including 1.15( 3H, s), 1.23 (3H, s) and 1.26 (3H, s)},1.41(1H, m), 1.59(1H, bs), 1.65-1.95 (4H, m), 2.21 (1H, m), 2.44 (1H, m), 2.61 (1H, m).MS m/z: 236 (M, 2.3%), 218 (17.8%), 203(10.7%), 178 (35.4%), 161 (24.5%), 147(26.0%0,133 (100.0%). High resolution mass measurement: calculated forC15H240:236.1776; found:. 236.1778.The physical properties of 98 are as follows:m.p.: 100-102°C.[c]=+1.72X 102 (c=1.00, CHC13).86IR Vm (film): 3020 (C-H stretching of the cyclopropyl group), 1713 (C=O stretching),1680 (conjugated C=O stretching).‘H-NMR (400 MHz, CDC13)6: 0.99 (3H, d, J=7.2), 1.05 (1H, t, J=6.0), 1.31 (311, s), 1.38(1H, dd, J=6.0 and 8.8), 1.65-2.02 (8H, m), 2.06 (3H, s), 2.17 (1H, m), 2.44 (1H, m),2.62 (1H, m).MS m/z: 220 (M, 15.3%), 205 (3.2%), 192 (5.1%), 177 (10.4%), 43 (100.0%). Highresolution mass measurement: calculated forC14H220:220.1463; found:. 220.1461.Elemental Analysis: calculated forC14H220:C 76.33, H 9.15; found: C 76.28, H 9.13.2.3.5. Ozonation: dione 105 to hydroxydione 106 and trione 107[1R-( 1 a,4oL,5ct)J 1 -(1 -Hydroxyl- 1 -methylethyl)-4-methyl-4-(3-oxobutyl)-bicyclo[3. 1.01 hexan-3-one (106)[1R-( 1 x,4a,5cx)] 1 -Acetyl-4-methyl-4-(3-oxobutyl)-bicyclo[3. 1 .0]hexan-3-one (107)106 107 0Diketone 105 (1.00 g, 4.50 mmol) in ethyl acetate (100 ml) was cooled to -25°C andpassed with a stream of ozone-oxygen for 10 hours. After the continuation of oxygen flow foranother 15 minutes, the mixture was treated with dimethyl sulfide (1.0 ml) and warmed slowlyto room temperature. Washing with water and saturated sodium bicarbonate solution andevaporation of solvent gave an oil which was chromatographed with a mixed solvent systemisopropanol:hexanes (3:7) to give 106 (0.39 g, 36%) and 107 (0.28 g, 28%).Compound 106 was also prepared from ketol 94 in the following way:87The solution of thujonol 94 (52 mg, 0.31 mmol) in toluene (5.0 ml) was mixed withdistilled water (5.0 ml), methyl vinyl ketone (77 .tl, 0.93 mmol), potassium hydroxide (93 mg,—80% pure, 1.3 mmol), and tetrabutylammonium iodide (28 mg, 0.076 mmol) under nitrogen.This mixture was stirred for 10 hours at room temperature. After the mixture was saturatedwith sodium chloride, the organic layer was separated and concentrated to give a yellowish oil.Column chromatography of this oil afforded compound 106 (45 mg, 62%).The physical properties of 106 are as follows:[]5=44•7 (c=1.09, CHC13).JR (film) vmax.: 3450 (0-H stretching), 1730, 1710 cm1.‘H-NMR (400 MHz, CDC13)& 0.00 (1H, m), 0.96 (1H, m), 1.00 (3H, s), 1.17 (3H, s),1.33 (3H, s), 1.41 (1H, dd, J=4.2 and 8.4 Hz), 1.59 (1H, bs), 1.77 (2H, m), 2.10-2.25{4H, including 2.15 (3H, s)}, 2.51 (2H, m), 2.97 (1H, m).MS m/z: 238 (M, 0.2%), 220 (4.0%), 202 (1.4%), 43 (100.0%). High resolution massmeasurement: calculated forC14H2203:238.1569; found: 238.1568.The physical properties of 107 are as follows:[a]=+15.5 (c=1.03, CHC13).JR (film) vmax.: 1735 (cyclopentanone C=0 stretching), 1705 (aliphatic C=0 stretching), 1680(conjugated C=0 stretching).cm‘H-NMR (400 MHz, CDC13)6: 0.62 (1H, t, J=5.6 Hz), 1.04 (3H, s), 1.70-1.90 (3H, m),2.03 (1H, dd, J=5.6 and 8.6 Hz), 2.09 (3H, s), 2.12 (3H, s), 2.30-2.45 (3H, m), 3.30 (1H,dd, J=2.4 and 19.0 Hz).MS m/z: 222 (M, 11.6%), 207 (1.7%), 179 (11.9%), 164 (100.0%). High resolution massmeasurement: calculated forC13H803:222.1256; found: 222.1261.882.3.6. Cataiytic Hydrogenation: enone 113 to ketone 114[1 aS-( 1 acx, 1b13,5aJ3,6acz)] 1 a, lb,2,3,5,5a,6,6a-Octahydro- lb-methyl-6a-( 1 -methylethyl)cycloprop[ajinden-4( 1H)-one (114) or [1R,6S,7S,9R] 6.-Methyl-9-( 1 -methylethyl)tricyclo[4.4.0.07’9.]decan-3-one (114)114Enone 113 (0.45 g, 2.2 mmol) in methylene chloride (20 ml) was treated with 5%palladium-charcoal (0.76 g) at room temperature. The mixture was stirred under 1 atmhydrogen for 12 hours, filtered, and concentrated in vacuo. Ketone 114 was obtained in 90%yield (0.41 g).The physical properties of 114 are as follows:JR (film) vmax.: 3040 (C-H stretching), 1710 (C=O stretching) cm1.‘H-NMR (400 MHz, CDC13)6: 0.23 (1H, dd, 3=4.8 and 8.0 Hz), 0.45 (1H, t, 1=4.8 Hz),0.80-0.99 {7H, m, including 0.86 (3H, d, J=6.4 Hz), 0.93 (3H, d, J=6.4 Hz)), 1.20 (3H,s), 1.25-1.50 (2H, m), 1.60-1.95 (4H, m), 2.10-2.25 (2H, m), 2.30-2.55 (2H, m).MS m/z: 206 (M, 23.4%), 191 (6.3%), 188 (10.6%), 173 (16.7%), 163 (38.6%), 93(100.0%).2.3.7. AIdol Condensation: hydroxydione 106 to hydroxyenones 117 and 118[1 aR-( 1 aa, 1b13,5a13,6ac)] 1 a, 1 b,2,3,6,6a-Hexahydro-6a-( 1 -hydroxyl- 1 -methylethyl)- 1 bmethyl-cycloprop[a]inden-4( 1H)-one (117) or [6R,7R,9R] 9-( 1 -Hydroxyl- 1 -methylethyl-6-methyl)tricyclo [4.4.0.07’9.]dec-1(10)-en-3-one (117)89[1 aR-( 1 ax, 1 b13,5a13,6aa)J 1 a, lb,2,3,5 ,6a-Hexahydro-6a-( 1 -hydroxyl- 1 -methylethyl)- ibmethyl--cycloprop[a]inden-4( 1H)-one (118) or [6R,7S,9R] 9-( 1 -Hydroxyl- 1 -methylethyl)6-methyltricyclo [4.4.0.07’9.]dec-1 (10)-en-3-one (118)118Compound 106 (1.94 g, 8.15 mmol) in benzene (50 ml) was treated with pyrrolidine(0.82 ml, 9.8 mmol) and refluxed for 5 hours with a dean-stark trap. Concentration in vacuogave a brown viscous oil which was chromatographed with ethyl acetate:hexanes mixture (1:1,v/v) to provide 117 (0.54 g, 30%) and 118 (0.79 g, 44%) in a total yield 74%.The physical properties of 117 are as follows:[aJ=+119 (c=1.OO, CHC13).UV (MeOH, c=20.0 mg/i) max.: 234 nm (log e=4.21 1).JR (film) vmax.: 3420 (0-H stretching), 3050 (C-H stretchings of cyclopropyl group), 1655(conjugated C=0 stretching) cm1.‘H-NMR (400 MHz, CDC13)& 0.80 (1H, J=4.4 Hz), 1.12 (3H, s), 1.20 (6H, s), 1.32 (1H,dd, J=4.4 and 8.8 Hz), 2.00-2.85 (6H, m), 5.60 (1H, bs).MS m/z: 220 (M, 0.8%), 202 (9.1%), 57 (34.7%), 43 (100.0%) High resolution massmeasurement: calculated forC14H200:220.1463; found: 220.1464.The physical properties of 118 are as follows:m.p.=70-7 1°C.[c]=+6l (c=0.58, CHC13).JR (CHC13)vmax.: 3450 (0-H stretching), 1702 (C=0 stretching), 1642 (C=C stretching)cm1.117901H4MR (400 MHz, CDC13)6: 0.34 (1H, t, J=4.4 Hz), 1.06 (1H, dd, J=4.4 and 8.2 Hz),1.19 (3H, s), 1.25 (3H, s), 1.27 (3H, s), 1.50-1.70 (2H, m), 1.87 (1H, m), 2.35-2.65 (2H,m), 2.80-3.10 (211, m), 5.53 (1H, d, J=1.2 Hz).MS m/z: 220 (M, 3.5%), 202 (23.3%), 187 (15.0%), 43 (100.0%). High resolution massmeasurement: calculated forC14H2002: 220.1463; found: 220.1471.2.3.8. Catalytic Hydrogenation: hydroxyenones 117 and 118 to ketol 120[1 aR-( 1 acz,213,5a13,6aa)1 1 a, 1 b,2,3,5 ,5a6,6a-Octahydro-6a-( 1 -hydroxyl- 1 -methylethyl)- 1 bmethylcycloprop[a] inden-4( 1H)-one (120) or [1 R,6S ,7R,9S] 9-( 1 -Hydroxyl- 1-methylethyl)-9-methyhricyclo [4.4.0.07’9.]decan-3-one (120)0tt”,’120To enones 117 and 118 (536 mg, 2.44 mmol) in ethanol (20 ml) solution was added10% palladium on charcoal catalyst (130.3 mg). The mixture was then stirred under 1 atmhydrogen (1 atm) for 1.2 hours. After the mixture was filtered through a layer of Celite andwashed with additional ethanol (20 ml), the solution was concentrated in vacuo. Columnchromatography of the crude oil with hexanes:ethyl acetate (1:1) gave ketol 120 (519 mg,96.0%).The physical properties of 120 are as follows:[aJ=+61.8 (c=1.00, CHC13).JR (film) Vmax.: 3100-3700 (0-H stretching), 1710 (C=O stretching) cm1.‘H-NMR (400 MHz, CDC13)6: 0.44 (1H, dd, J=4.0 and 5.4 Hz), 0.63 (111, ddd, J=1.2,5.4, and 8.6 Hz), 1.06 (1H, bs), 1.10-1.30 {(1OH, m, including 1.14 (311, s), 1.21 (3H, s)91and 1.25 (3H, s)}, 1.63 (1H, m), 1.72-1.92 (4H, m), 2.12-2.25 (2H, m), 2.35-2.52 (2H,m).MS m/z: 222 (M, 1.4%), 204 (16.9%), 189 (13.5%), 133 (74.9%), 59 (100.0%). Highresolution mass measurement: calculated forC14H220:222.1620; found:. 222.1618.2.3.9. Methylation: ketol 97 and 120 to ketol 121[1 aR-( 1 aa, 1 bf3,5af,6aa)] 1 a, 1 b,2,3,5,5a,6,6a-Octahydro-6a-(1 -hydroxyl- 1 -methylethyl)1 b,5 ,5,trimethyl-cycloprop [a]inden-4( IH)-one (121) or [1 S,6R,7R,9R] 9-( 1 -Hydroxyl- 1-methylethyl)-2,2,6-trimethyltricyclo [4.4.0.07’9.]decan-3-one (121)121Method A:To the solution of ketol 120 (50 mg, 0.23 mmol) in anhydrous t-butanol (2.0 ml) wasadded potassium t-butoxide (174 mg, 1.42 mmol) and iodomethane (85 .tl, 1.4 mmol). Themixture was then refluxed under nitrogen for 2 hours, cooled, and quenched with water (10ml). Extraction with diethyl ether (2x10 ml), drying with magnesium sulfate, and evaporationof solvent in vacuo gave an oil which was chromatographed to afford 121 (33 mg, 62%).Method B:Ketol 97 (48 mg, 0.20 mmol) in t-butanol (2.0 ml) was treated with potassium tbutoxide (124 mg, 1.01 mmol) and iodomethane (65 p.1, 1.0 mmol) under nitrogen. Themixture was refluxed for 1.5 hours, cooled down, and quenched with water (10 ml).Extraction with diethyl ether (2x10 ml), drying with magnesium sulfate, and evaporation of92ether in vacuo provided an oil which was chromatographed with ethyl acetate:hexanes mixture(3:7, v/v) to give 121 (41 mg, 8 1%).The physical properties of 121 are as follows:[x]=-19.2 (c=0.0832, dioxane).JR Vmax. (film): 3 100-3650 (0-H stretching), 1705 (C=0 stretching).‘H-NMR (400 MHz, CDC13)8: 0.41 (1H, dd, J=4.8 Hz), 0.58 (1H, dd, J=4.8 and 7.8 Hz),1.05-1.40 { 18H, m, including 0.96 (3H, s), 1.12 (3H, s), 1.22 (3H, s), 1.24 (3H, s) and1.34 (3H, s)}, 1.46-1.62 (2H, m), 1.75-1.90 (2H, m), 2.17 (1H, m), 2.70 (1H, m).MS m/z: 250 (M, 1.7%), 235 (9.4%), 232 (3.7%), 217 (6.4%), 192 (30.5%), 177 (18.1%),133 (47.1%), 59 (100.0%). High resolution mass measurement: calculated forC16H20:250.1934; found: 250.1936.2.3.10. Robinson Annulation: thujonol (94) to hydroxyenone 122[1 aR-( 1 ao, 1 b3,6act)] 1 a, 1 b,2,3,6,6a-Hexahydro-6a-( 1 -hydroxyl- 1 -methylethyl)- 1 b,5-dimethyl-cycloprop[a]inden-4(1H)-one (122) or [6R,7R,9R1 9-( 1 -hydroxyl- 1 -methylethyl)2,6-dimethyltricyclo [4.4.0.07’9.]dec-1 (2)-en-3-one (122)°‘IH122To 1-dimethylaminopentan-2-one--iodomethane salt (2.84 g, 9.44 mmol) in ethanol (80ml) was added the solution of ketol 94 (1.43 g, 8.51 mmol) in ethanol (20 ml). Afterpotassium hydroxide (0.92 g, —80% pure, 13 mmol) was added, the mixture was refluxedunder nitrogen for 3 hours. Concentration of the reaction mixture in vacuo gave a yellow oil93which was chromatographed using ethyl acetate:hexanes mixture (1:1, vlv) to providecompound 122 as a colorless oil (636 mg, 32%).The physical properties of 122 are as follows:[x]=+90.3 (c2.03, CHC13).UV (MeOH, c=40.6 mg/l) max.: 248 nm (loge=4.04).JR (film) vmax.: 3200-3600 (0-H stretching), 1645 (C=0 stretching) cm-1.‘H-NMR (400 MHz, CDC13)& 0.76 (1H, t, J=4.7 Hz), 1.11 (3H, s), 1.20 (611, s), 1.67(3H, s) ppm.MS m/z: 234 (M, 1.2%), 216 (3 1.5%), 201 (48.0%), 173 (34.7%), 59 (100.0%). Highresolution mass measurement: calculated forC15H220:234.1619; found: 234.1613.2.3.11. Cyclopropane Ring Opening Reaction: ketol 97 to chloroketone 123[1 R-( 1 a,3ax,413,7act)] 3,3a,4,6,7,7a-Hexahydro- 1 -chloromethyl-4,7a-dimethyl-2( 1I1)-( 1-methylethylidene)-5H-inden-5-one (123)123Ketol 97 (78 mg, 0.33 mmol) in methylene chloride (5.0 ml) was stirred withconcentrated hydrochloric acid (5.0 ml) at room temperature for 30 minutes. Water (20 ml)was added to quench the reaction. After methylene chloride extraction (2x10 ml), drying overmagnesium sulfate, and evaporation of solvent in vacuo, the crude product waschromatographed with ethyl acetate:hexanes mixture (1:8, v/v) to afford the starting ketol 97(15 mg, 19%) and chloride 123 (51 mg, 74%).94The physical properties of 123 are as follows:[czJ=+1.4x102 (c=0.50, CHC13).JR Vmax. (film): 1700, 1641 cm1.‘H-NMR (400 MHz, CDC13) & 1.00 (3H, d, J=7.0 Hz), 1.05 (1H, m), 1.24 (1H, m), 1.44(3H, s), 1.58-1.80 {7H, including 1.60 (3H, s) and 1.71 (3H, s)}, 2.10 (6H,m), 3.45-3.65(2H, m).MS m/z: 256/254 (M, 0.6%/2.2%), 239 (0.5%), 218 (34.6%), 203 (18.4%), 133 (85.0%),41 (100.0%). High resolution mass measurement: calculated forC15H2301: 254.1437,found: 254.1437; calculated forC15H230371: 256.1408, found: 256.1412.2.3.12. Radical-mediated Rearrangement: chloroketone 123 to enones 125and 126[1R-( 1 ct,3 aa,43,7ax)] 3,3a,4,6,7 ,7a-Hexahydro- 1 ,4,7a-trimethyl-2( 1H)-( 1-methyl-ethylidene)-5H-inden-5-one (125)[1 S-( 1 x,4af3,8a)] 4,4a,5,6,8 ,8a-Hexahydro- 1 ,4a-dimethyl-7(3H)-( 1 -methylethylidene)naphthalen-2( 111)-one (126)125 126Chloride 123 (50.4 mg, 0.198 mmol) in benzene (20 ml) was treated with tributyltinhydride (82 p.1, 0.30 mmol, 1.5 eqv.) and AIBN (3.2 mg, 0.019 mmol, 0.10 eqv.) undernitrogen. This mixture was then refluxed for 2 days. Concentration in vacuo gave the crudeproduct which was chromatographed with ethyl acetate:hexanes mixture (1:8) to afford 12695(19.9 mg) and 125 (7.1 mg) in a total yield 80%, based on the recovery of chloride 123 (12.0mg).The physical properties of 126 are as follows:m. p.=85°C.[c]=-23.9 (c=1.00, CHC13).JR Vm (CHC13): 1700 cm1.‘H-NMR (400 MHz, CDC13)& 0.90-2.00 { 17H, m, including 1.02 (3H, d, J=), 1.26 (3H,s), 1.64 (3H, s) and 1.66 (3H, s)), 2.20-2.65 (6H, m), 2.93 (JH, m).MS m/z: 220 (M, 44.4%), 203 (8.2%), 187 (8.7%), 148 (47.3%), 135 (100.0%). Highresolution mass measurement: calculated forC15H240: 220.1827; found:. 220.1822.The physical properties of 125 are as follows:[aj=+35 (c=0.94, CHC13).IRVm, (film): 1710 cm-’.1HNMR (400 MHz, CDC13)6: 0.80-2.00{ 18H, m, including 0.92 (3H, d, J=), 0.99 (3H,d, J=), 1.22 (3H, s), 1.54 (3H, s), 1.64 (3H, s)}, 2.10 (4H, m), 2.50 (1H, m), 2.57 (1H,m).MS m/z: 220 (M, 23.5%), 205 (8.2%), 187 (4.9%), 175 (11.4%), 163 (50.3%), 135(100.0%). High resolution mass measurement: calculated forC15H240: 220.1827; found:220.1822.2.3.13. Methylation: ketone 96 to ketone 119[1 aS-( lacc, 1bf3,5af3,6ac)] 1 a, lb,2,3,5,5a,6,6a-Octahydro- lb,5,5-trimethyl-6a-( 1-methylethyl)-cycloprop[a]inden-4(1H)-one (119) or [iS ,6R,7S,9S1 2,2,6-triimethyl-9-( 1-methylethyl)tricyclo [4.4.0.07’9.]decan-3-one (119)96119To the solution of ketone 96 (62.0 g, 0.282 mol) in anhydrous t-butanol (700 ml) wasadded potassium t-butoxide (130.5 g, 1.07 mol) slowly under nitrogen. lodomethane (66.6ml, 1.07 mol) was added in a dropwise manner with stirring to ensure a gentle reflux. Uponfinishing the addition, refluxing continued for 30 minutes. The mixture was cooled down,quenched with water (700 ml), extracted with petroleum ether (3x500 ml). evaporation ofsolvent gave an oil which was chromatographed to provide the methylated ketone 119 (55.1 g,84%).The physical properties of 119 are as follows:[x]5=+14.0 (c=0.993, CHC13); [aj=0.00 (c=0.993, CHC13).JR Vmax (film): 3060, 1700 cm1.1H4MR (400 MHz, CDC13): 0.18 (1H, dd, J=4.0 and 8.0 Hz), 0.40 (1H, t, J=4.0 Hz),0.80-0.88 {4H, m, including 0.85 (3H, d, J=7.2 Hz)}, 0.90 (3H, d, J=7.2 Hz), 0.97 (3H,s), 1.22 (3H, s), 1.25-1.50 (6H, m, including 1.32 (3H, s)}, 1.65-1.90 (3H, m), 215 (1H,td, J=4.4 and 15.2 Hz), 2.70 (1H, m).MS m/z: 234 (M, 55.8%), 219 (14.3%), 201 (22.0%), 191 (29.9%), 173 (51.1%), 43(100.0%). High resolution mass measurement calculated forC16H20: 234.1983; found:234.1986.2.3.14. WoIf-Kishner-Huang Minion Reaction: ketone 119 to alkane 128[1 aS-( 1 aa, 1 b3,5a3,6act)J Decahydro- 1 b,5,5-trimethyl-6a- (1 -methylethyl)cycloprop[a]indene (128) or [1 R,6S ,7S,9R] 9-( 1 -Methylethyl)-2,2,6-thmethyltricyclo[4.4.0.07’9.]decane (128)97128Ketone 119 (42.0 g, 180 mmol) in diethylene glycol (300 ml) was treated withpotassium hydroxide (37.0 g, -80% pure, 528 mmol) and hydrazine monohydrate (26.8 ml,552 mmol). The mixture was heated at 100°C for 1.5 hours under nitrogen. The temperaturewas then raised to 220°C to distill away water and excess hydrazine. Refluxing continued at2 10°C for 4 hours. The mixture was cooled down, diluted with water (11), and extracted withpetroleum ether (3X600 ml). Evaporation of the solvent gave a brown oil which waschromatographed with petroleum ether through a short column gave 128 as a colorless oil(24.50 g, 62%).The physical properties of 128 are as follows:[cx ]=+42.5 (c=1.00, CHC13).JR Vm (film): 3060 cm1.‘H-NMR (400 Mhz, CDC13)& 0.04 (1H, dd, 3=4.6 and 8.4 Hz), 0.40 (1H, t, J=4.6 Hz),0.72-0.82 (4H, including 0.78 (3H, s)}, 0.82-1.65 {22H, including 0.88 (3H, d, J=7.2 Hz),0.95 (3H, d, J=7.2 Hz), 0.98 (3H, s) and 1.07 (3H, s)}.MS m/z: 220 (M, 3.4%), 205 (10.3%), 177 (45.5%), 109 (100.0%). High resolution massmeasurement: calculated forC16H28: 220.2191; found: 220.2198.2.3.15. Ozonation: alkane 128 to alcohol 130 and ketone 131[1 aR-( 1 aa,2a13,5af3,6acc)] Decahydro-cc-hythoxy-cx,cc, 1 b,5 ,5-pentamethylcycloprop[a] inden-6a-methanol (130) or [1 R,6S ,7R,9S] 9-( 1 -Hydroxyl- 1 -methylethyl)-2,2,6-trimethyltricyclo[4.4.0.07’9.jdecane (130)98[1 aR-(1 acc2af3,5a13,6acx)] 6a-Acetyl-decahydro- 1 b,5,5-trimethylcycloprop[ajindene (131) or[1 R,6S ,7R,9S] 9-Acetyl-2,2,6-trimethyltricyclo decan-3-one (131)130 131Compound 128 (4.50 g, 20.4 mmol) in ethyl acetate (500 ml) was cooled to -40°C. Astream of ozone in oxygen (90 volts, flow rate 9.1 mi/sec) was passed for 6.5 hours. Theoxygen flow continued to pass the solution till the blue color disappeared. Dimethyl sulfide(1.0 ml) was added and the mixture was warmed slowly to room temperature with stirring.After washed with water and saturated sodium bicarbonate solution, the mixture was dried withmagnesium sulfate. Solvent evaporation gave an oil which was chromatographed to affordcompounds 130 (2.01 g, 42%) and 131 (1.23 g, 27%) in a total yield 69%.The physical properties of 130 are as follows:[cc]=+49.2 (c=0.995, CHC13).JR Vm. (film): 3 400 (0-H stretching), 3060 (C-H stretching) cm1.1HJ4MR (400 MHz, CDC13)6: 0.40-0.55 (2H, m), 0.72 (3H, s), 0.80-1.90 (23H,including 0.92 (3H, s), 1.05 (3H, s), 1.10 (3H, s) and 1.19 (3H, s)}.MS m/z: 236 (M, 1.0%), 218 (35.8%), 203 (26.9%), 178 (41.3%), 163 (59.5%), 59(100.0%). High resolution mass measurement: calculated forC16H280: 236.2140; found:236.2140.Elemental analysis: caic. forC16H280: C 81.29, H 11.94; found: C 81.23, H 12.00.The physical properties of 131 are as follows:[cc]=+82 (c=0.24, CHC13).IR Vm. (film): 1675 cm1 (C=0 stretching).99‘H-NMR (400 MHz, CDC13)& 0.83 (3H, s), 1.00 (3H, s), 1.05 (1H, m), 1.10-1.70 {12H,m, including 1.15 (3H, s)}, 1.80 (1H, dd, 3=4.0 and 12.0 Hz), 2.00 (3H, s), 2.20 (1H, t,J=12.0 Hz).MS m/z: 220 (M, 33.6%), 205 (16.5%), 177 (17.0%), 109 (33.9%), 43 (100.0%). Highresolution mass measurement: calculated forC15H240: 220.1827; found: 220.1825.2.3.16. Dehydration: alcohol 130 to alkene 138[laR-( 1 acç 1bI3,5aI3,6ac)] Decahydro- lb,5,5-trimethyl-6a-( 1 -methylethenyl)-cycloprop[a]indene (138) or [1R,6S ,7R,9Sj 9-( 1 -methylethenyl)-2,2,6-trimethyltricyclodecane (138)1_—_138To the alcohol 130 (171 mg, 0.724 mmol) in benzene (15.0 ml) solution was addedpyridinium tosylate (28 mg, 0.11 mmol, 0.15 eqv.). The mixture was refluxed with a Dean-Stark trap on for 15 minutes. After the reaction mixture was washed with saturated sodiumbicarbonate solution (10 ml), the organic layer was separated and concentrated in vacuo.Column chromatograghy by ethyl acetate:hexanes mixture (8:1, vlv) gave the vinylcyclopropane 138 (127 mg, 91%) and the starting alcohol 130 (20.0 mg, 11.7%).The physical properties of 138 are as follows:[x]5=+87.9 (c=1.09, CHC13).JR Vm (film): 3075, 1650 cm-1.100‘H-NMR (400 MFIz, CDC13)ö: 0.52 (1H, dd, 1=4.8 and 8.8 Hz), 0.68 (1H, t, J=4.8 Hz),0.81 (3H, s), 1.00 (3H, s), 1.02-1.58 (11H, m, including 1.13 (3H, s)}, 1.65 (3H, s), 1.70-1.92 (2H, m), 4.65-4.85 (2H, two broad singlets).MS m/z: 218 (M, 26.5%), 203 (23.2%), 189 (4.2%), 175 (20.9%), 147 (3 1.3%), 147(5 1.3%), 109 (100.0%). High resolution mass measurement calculated forC16H2:218.2035; found: 218.2030.2.3.17. Cyclopropane Ring Opening Reaction: alcohol 130 to chloride 132[1R-( 1 3ac,7a)] 3a,4,5 ,6,7,7a-Hexahydro- 1 -chloromethyl-2(3H)-( 1 -methylethylidene)4,4,7a-trimethyl- 1H-indene (132)132Alcohol 130 (100 mg, 0.420 mmol) in methylene chloride (5.0 ml) was stirred withconcentrated hydrochloric acid (5.0 ml) at room temperature for 30 minutes. Separation andconcentration of the methylene layer gave the crude product which was chromatographed withethyl acetate:hexanes (1:8, v/v) to afford 132 as a colorless oil (92 mg, 85%).The physical properties of 132 are as follows:[aJ=+33.5 (c=1.00, CHC13).IR Vmax (film): 2910 (C-H stretching).1H-NMR (400 MHz, CDC13) 8: 0.75-1.85 {22H, m, including 0.84 (3H, s), 1.04 (3H, s),1.22 (3H, s), 1.63 (3H, s) and 1.70 (3H, s), 2.04-2.55 (3H, m), 3.40-3.75 (2H, m).101MS m/z: 256/254 (M, 4.8/14.8%), 241 (12.8%), 239 (37.6%), 203 (96.4%), 109(100.0%). High resolution mass measurement: calculated for C16H27371: 256.1772, found:256.1763; calculated for C16112735: 254.1801, found: 254.1801.2.3.18. Ozonolysis: alkene 138 to ketone 131Method A:To a solution of vinylcyclopropane 138 (200 mg, 0.9 17 mmol) in a mixture solvent tBuOH:water (9.0 ml, 2:1, v/v) was added potassium permanganate (436 mg, 2.76 mmol) atroom temperature; the dark purple solution was stirred first at room temperature for 40minutes.and then at 40°C for 10 minutes. Afterwards, the mixture was diluted with water(20.0 ml) and extracted with ethyl acetate (2x25m1). The combined extract was washed withbrine (10 ml) and concentrated in vacuo.The oil obtained above was then dissolved in methanol (10 ml) and treated withPb(OAc)4 (313 mg, 0.706 mmol) for 1 hour at room temperature. After concentration invacuo, the crude product was column chromatographed using ethyl acetate:hexanes mixture(1:8, v/v) to give the starting vinylcyclopropane 138 (4.1 mg, 2.0%) and ketone 131 (180mg, 91% based on recovery).Method B:A stream of ozone was passed through a solution of vinylcyclopropane 138 (117 mg,0.536 mmol) in methylene chloride (5.0 ml) at -40°C for 30 minutes. After the addition ofdimethyl sulfide (2.0 ml), the mixture was warmed up slowly and then stirred at room131102temperature for two days. Concentration of the reaction mixture in vacuo gave a crude productwhich was chromatograghed with ethyl acetate:hexanes mixture (1:8, v/v) to provide ketone131 (73 mg, 62%).2.3.19. Nucleophilic Addition by MeLi: ketone 131 to alcohol 130To compound 131 (91 mg, 0.41 mmol) in anhydrous THF (2.0 ml) was added methyllithium (1.40 M, THF) in a dropwise manner at -40°C with bipyridyl as the indicator till anorange color was observed persistently. The mixture was warmed to room temperature, stirredfor an additional 60 minutes, quenched with water (15 ml), and extracted with diethyl ether(2x15 ml). The ether solution was dried over magnesium sulfate. Solvent evaporation gavean oil which was chromatographed with ethyl acetate:hexanes mixture (1:8, v/v) to providealcohol 130 as a colorless oil.(65.5 mg, 75% based on recovery of starting material) and thestarting compound 131 (9.1 mg, 10%).2.3.20. Conversion of 138 to 133 via 139[1R-( 1 cc,3acç7ac)j 3a,4,5 ,6,7,7a-Hexahydro- 1 ,4,4,7a-tetramethyl-2(3H)-(1-methylethylidene)- 1H-indene (133)[1 R-( 1 ct,3acx,7ac.t)j 3a,4,5 ,6,7 ,7a-Hexahydro- 1 ,4,4,7a-tetramethyl-2-( 1-(phenylthiomethyl)ethylidene-1H-indene (139)The mixture of vinylcyclopropane 138 (50.5 mg, 0.23 mmol) and thiophenol(50 .tl, 0.49 mmol, 2.0 eqv.) in benzene (2.0 ml) was refluxed for 24 hours under nitrogen.This mixture was concentrated and chromatographed to give the starting vinyl cyclopropane103139 133mixture was concentrated and chromatographed to give the starting vinyl cyclopropane 138(10.1 mg, 20%) and and a polar fraction containing 139 (mg).The concentrated polar fraction was dissolved in THF (2.0 ml). To this solution wasdistilled ammonia (-3 ml) under nitrogen. Small pieces of lithium were added with stirring tilla dark blue color persisted. The reaction mixture was then treated with ammonium chloride,filtered, and concentrated to provide a crude product. The crude product was purified bycolumn chromatography to afford a mixture (28 mg, 69%) containing 133 and 128 (2.3:1) asindicated by GC.2.3.21. Reduction by Bu3SnH: chloride 132 to alkene 133133Homoallylic chloride 132 (50.2 mg, 0.197) in benzene (19 ml) was treated withtributyltin hydride (66 p1, 0.24 mmol, 1.2 eqv.) and AIBN (3.2 mg, 0.19 mmol, 0.15 eqv.)under nitrogen. The mixture was refluxed for 2 days. Evaporation of the solvent gave an oilwhich was then chromatographed with hexanes to give hydrocarbon 133 as a colorless oil (30mg, 69%).The physical properties of 133 are as follows:JR (film) vmax.: 2950 cm1.1H-NMR (400 MHz, CDC13)& 0.84 (3H, s), 0.87 (3H, s), 1.02 (3H, s), 1.05 (3H, d),1.58 (3H, s), 1.62 (3H, s), 2.04-2.35 (3H, m).MS m/z: 220 (M, 23.1%), 205 (77.6%), 177 (30.6%), 41(100.0).2.3.22. Cyclopropane Sliding Reaction: alcohol 130 to alcohol 144104[3aS-(3ax,7acc)] 3a,4,5,6,7,7a-Hexahydro-a,x,3a,7,7-pentamethyl- JH-indene-2-ethanol(144)b144To the solution of alcohol 130 (80 mg, 0.34 mmol) in a dioxane:water mixture solvent(4.00 ml, 1:1, v/v) was addedp-toluentsulfonic acid hydrate (20 mg, 0.10 mmol, 0.30 eqv.).The mixture was heated at 85°C for 1 hour and cooled to room temperature. Water (10 ml)was added and methylene chloride (2x10 ml) was used to extract the aqueous solution. Themethylene solution was washed with brine (10 ml), dried over magnesium sulfate, andconcentrated in vacuo. Column chromatography of the crude product with ethylacetate:hexanes mixture (1:8, v/v) gave homoallylic alcohol 144 (70 mg, 87%).The physical properties of 144 are as follows:[cxJ=+45.2 (c=l.00, CHC13).JR Vmax. (film): 3 100-3650 (OH stretching).1H-NMR (400 MHz, CDC13)& 0.88(3H, s), 1.02(3H, s), 1.07-1.70{ 18H, m, including1.18 (3H, s), 1.21 (3H, s) and 1.22 (3H, s)}, 2.05-2.45 (4H, m), 5.33 (1H, bs)MS m/z: 236 (M, 0.1%), 218 (1.6%), 203 (5.0%), 178 (7.1%), 163 (100.0%), 135(21.1%). High resolution mass measurement: calculated forC16H280: 236.2140; found:236.2145.2.3.23. Epoxidation: alcohol 144 to epoxyalcohol 147[2R-(2a,3c,3ax,7ac)] 2,3,3a,4,5,6,7,7a-Octahydro-a,x,3a,7,7-pentamethyl- 1H-2,3-epoxyindene-2-ethanol (147)105147To a solution of alcohol 144 (172 mg, 0.729 mmol) in chloroform (5.0 ml) was addedm-CPBA (243 mg, --80% pure, 1.1 mmol, 1.5 eqv.). The mixture was stirred at roomtemperature for 1 hour. After addition of methylene chloride (5.0 ml) and washing withsodium bicarbonate solution (10 ml, 10%), the mixture was dried over magnesium sulfate andconcentrated in vacuo. Column chromatography of the crude product with ethylacetate:hexanes mixture (2:8, v/v) gave epoxide 147 (159 mg, 87%).The physical properties of 147 are as follows:m.p.: 82-84°C.[cxJ=+56.7 (c=1.00, CHC13).JR Vmax. (film):3700 (0-H stretching).‘H-NMR (400 MHz, CDC13)ö: 0.70-1.70 (24H, m, including 0.80 (3H, s), 0.98 (3H, s),1.20 (3H, s), 1.24 (3H, s) and 1.31 (3H, s)}, 1.75-2.02 (2H, m), 2.04-2.15 (1H, dd, J=7.2and 13.6 Hz), 2.85 (1H, s).MS m/z: 252 (M, 0.2%), 234 (4.1%), 219 (6.9%), 194 (17.9%), 179 (19.8%), 161(19.3%), 123 (100.0%), 109 (90.4%). High resolution mass measurement: calculated forC16H280:252.2089; found: 252.2088.Elemental Analysis: calculated forC16H2802: C 76.14, H 11.18; found: C 76.14, H 1.05.2.3.24. Reductive Fragmentation by LAH: epoxyalcohol 147 to allylicAlcohol 151[1 S-( 1 c,3ax,7ac)] 3a,4,5,6,7 ,7a-Hexahydro-4,4,7-trimethyl-2(3H)-methylene- 1H-inden- 1-ol (151)106OH151Epoxide 147 (30.3 mg, 0.583 mmol) in anhydrous THF (1.0 ml) was added in adropwise manner to a slurry of LAH (18.4 mg) in THF (1.0 ml) under nitrogen. The mixturewas then heated at about 70°C (bath temperature) for 2 hours. After cooling to roomtemperature, ethanol (5.0 ml) was added and stirring continued for 10 minutes. Subsequently,water (15 ml) was added and the resulting mixture was extracted with ethyl acetate (2X10 ml).The ethyl acetate solution was dried over magnesium sulfate and concentrated in vacuo..Column chromatography of the crude product with ethyl acetate:hexanes mixture (1:8, v/v)gave allylic alcohol 151 (20 mg, 87%)The physical properties of 151 are as follows:[c]=+5.4 (c=1.00, CHC13).JR vmax. (film): 3 100-3650 (0-H stretching), 3060 (C-H stretching, olefinic), 1650 (C=Cstretching).‘H-NMR (400 MHz, CDC13) ö: 0.82 (3H, s), 1.02 (3H, s), 1.05-1.72 { 13H, m, including1.14 (3H, s)}, 1.78 (1H, t, J=8.8 ), 2.20-2.60 (2H, m).MS m/z: 194 (Mt13.l %), 179 (21.6%), 161 (13.0%), 123 (100.0%), 109 (85.5%). Highresolution mass measurement: calculated for Ci3H220: 194.1670; found: 194.1661.2.3.25. Allylic Oxidation by Mn02: homoallylic alcohol 151 to enone 152[3aR-(3act,7act)] 3a,4,5,6,7,7a-Hexahydro-4,4,7a-trimethyl-2(3H)-methylene-1H-inden- 1-one (152)107152Allylic alcohol 151 (29 mg, 0.15 mmol) in methylene chloride (2.0 ml) was treatedwith manganese dioxide (65 mg, 0.75 mmol). The slurry was stirred at room temperature for72 hours. After Filtering of the slurry and washing with methylene chloride (10 ml), themethylene chloride solution was concentrated in vacuo. Column chromatography of the crudeproduct gave enone 152 (8.0 mg, 67% based on recovery)and starting allylic alcohol 151 (17mg, 59% recovery).The physical properties of 152 are as follows:[a]=÷57 (c=0.58, CHC13).UV (MeOH, c=23 mg/l) max.: 235 nm (log e=4.0), 278 (log E=2.5).JR Vm. (film): 1710 (C=O stretching), 1635 (C=C stretching) cm1.11NMR (400 MHz, CDC13)6: 0.75-1.70 { 1611, m, including 0.85 (311, s), 1.07 (3H, s)and 1.22 (3H, s)), 2.35-2.65 (2H, m), 5.37 (3H, bs), 6.07 (311, bs).MS m/z: 192 (M, 49.9%), 177 (20.3%), 149 (28.9%), 123 (80.7%), 68 (100.0%). Highresolution mass measurement: calculated forC13H200: 192.15 14; found: 192.15 15.2.3.26. Cyclopropane Sliding Reaction: alcohol 130 to acetates 153 and 154[1 aS-(3ac,7acz)] 3a,4,5 ,6,7,7a-Hexahydro-c,a,3 a,7 ,7-pentamethyl- 1H-indene-2-ethylacetate (153)[1 R-( 1 x,3ax,7ac)] 1 ,3,3a,4,5,6,7,7a-Octahydro-4,4,7a-trimethyl-2H-indene- 1-methylacetate (154)108OAC<153 154A solution of alcohol 130 (60 mg, 0.26 mmol) in acetic acid (2.5 ml) was heated at65°C for 2 hours. After cooling to room temperature, methylene chloride (10 ml) was addedand the mixture was extracted with 10% sodium bicarbonate solution (10 ml). The methylenechloride solution was dried over magnesium sulfate and concentrated in vacuo. Columnchromatography of the crude product with ethyl acetate:hexanes mixture (1:25, v/v) yieldedacetate 153 (41 mg, 60% based on recovery), acetate 154 (4.0 mg, 6% based on recovery),starting alcohol 130 (2.9 mg, 5%) and vinyl cyclopropane 138 (3.1 mg, 6% based onrecovery).The physical properties of 153 are as follows:[x]=+41.7 (c=1.00, CHC13).IR Vm. (film): 1735 (C=O stretching), 1650 (C=C stretching).1H-NMR (400 MHz, CDC13)& 0.85 (3H, s), 1.00 (311, s), 1.03-1.60 { 16H, including 1.15(3H, s), 1.38 (3H, s) and 1.45 (3H, s)}, 1.97 (3H, s), 2.02-2.35 (2H, m), 2.39-2.62 (2H,AB type, J=7.2 Hz), 5.2 6(111, s).MS ni/z: 218 (M - HOAc, 37.0%), 203 (100.0%), 175 (16.7%), 147 (21.5%). Highresolution mass measurement: calculated forC16H(C18H3002- HOAc): 218.2034; found:218.2030. Chemical ionization (NH3 as carrier gas): 279 (M+Hj, 219, 203.The physical properties of 154 are as follows:[cz]=+63 (c=0.20, CHC13).IR Vm (film): 1730 cm1 (C=O stretching).1091H-NMR (400 MHz, CDC13)& 0.75-1.80 (22H, m, including 0.85(3H, s), 1.03 (3H, s),1.14 (3H, s), 1.61 (3H, s) and 1.69 (3H, s)}, 2.01 (3H, s), 2.10-2.32 (2H, m), 2.39 (1H, t,J=5.6 Hz)MS m/z: 278 (M, 0.3%), 218 (26.0%), 203 (100.0%). High resolution mass measurement:calculated forC18H3002:278.2246; found: 278.2248.2.3.27. Cyclopropane Sliding Reaction: ketol 117 to ketol 155[3aR-(3ax,7acx)] 3,3a,4,6,7,7a-Hexahydro-2-(2-hydroxyl-2-methylpropyl)-7a-methyl-5H-inden-5-one (155)To the solution of ketol 117 (82 mg, 0.37 mmol) in a dioxane :water mixture solvent(4.00 ml, 1:1, v/v) was added p-toluenesulfonic acid hydrate (22 mg, 0.11 mmol, 0.30 eqv.).The mixture was heated at 85°C for 3.8 hours. After cooling to room temperature, the mixturewas diluted with water (10 ml) and extracted with methylene chloride (2x10.0 ml). Themethylene solution was extracted with brine (10 ml), dried over magnesium sulfate andconcentrated in vacuo. Column chromatography of the crude mixture with ethylacetate:hexanes mixture (2:8, v/v) gave product 155 (72 mg, 87%).The physical properties of 155 are as follows:[a]=+111 (c=1.00, CHC13).JR Vm. (film): 3050-3650 (0-H stretching), 1700 (C=0 stretching), 1650 (C=C stretching).‘H-NMR (400 MHz, CDC13)& 1.10-1.90 { 13H, m, including 1.20 (3H, s) and 1.23 (6H,two singlets)}, 1.95-2.60 (7H, m), 2.75 (1H, dd, 3=8.8 and 17 Hz), 5.20 (lH, bs).110MS m/z: 222 (M+, 2.8%), 204 (13.6%), 189 (10.0%), 147 (100.0%), 133 (34.6%), 106(47.4%). High resolution mass measurement: calculated forC14H2O:222.1620; found:222.1618.2.3.28. HOAc Promoted Ring Opening: ketol 117 to ketoacetates 156 and 157[1 R-( 1 x,3aa,7a)] 1 -Acetoxymethyl-3,3a,4,6,7,7a-hexahydro-7a-methyl-2(1H)-( 1-methylethylidene)-5H-inden-5-one (156)[4aS-(4ax,5a,8ax)] 5-Acetoxyl-3,4,4a,5,8,8a-hexahydro-4a-methyl-7(6H)-(1-methylethylidene)-naphthalen-2( 1H)-one (157)ccA solution of alcohol 117 (65.2 mg, 0.294 mmol) in acetic acid (2.5 ml) was heated at85°C for 2 hours. After cooling to room temperature, methylene chloride (10 ml) was addedand the mixture was extracted with 10% sodium bicarbonate solution (10 ml). The methylenechloride solution was dried over magnesium sulfate and concentrated in vacuo. Columnchromatography of the crude product with hexanes : ethyl acetate (1:8, vlv) yielded acetate 156(44 mg, 56% ) and acetate 157 (11 mg, 14%).The physical properties of 156 are as follows:[cz]=+63.0 (c=1.00, CHC13).IR Vm (film): 1735 (C=O stretching of the acetate group), 1705 (C=O stretching) cm1.‘H-NMR (400 MHz, CDC13)6: 1.28 (3H, s), 1.50-1.85 (8H, m, including 1.59 (3H, s) and1.70 (3H, s)}, 1.92 (1H, m), 2.06 (3H, s), 2.10-2.60 (7H, m), 3.95-4.20 (2H, m).111MS m/z: 264 (M, 0.1%), 204 (23.6%), 189 (13.2%), 147 (100.0%), 134 (85.1%), 119(44.4%). High resolution mass measurement: calculated forC16H2403:264.1725; found:264.1720.The physical properties of 157 are as follows:[z]=+30 (c=0.66, CHC13).JR Vm. (film): 1710 (C=O stretching) cm-1.1H-NMR (400 MHz, CDC13)ö: 1.17 (3H, s), 1.40-1.80 {8H, m, including 1.65 (3H, s), and1.72 (3H, s)), 1.90-2.80 (12H, m, including 2.10(3H, s)}, 5.19 (1H, dd, 3= 4.2 and 10.2Hz).MS m/z: 204 (M-HOAc, 43.5 %), 189 (19.2%), 147 (91.9%), 133 (100.0%), 119 (54.4%),105 (5 1.2%). High resolution mass measurement calculated forC14H200(M-HOAc):204.1514; found: .204.1508. Chemical ionization (NH3): 282 (M+NH4),265 (M+Hj, 222(M-HOAc+NT14), 205 (M-HOAc+Hj.2.2.29. Baeyer-Villiger Reaction: ketone 131 to acetate 160[1 aR-(1 ax,ibf,5a13,6ac)] Decahydro- 1 b,5,5-thmethylcycloprop[a]inden-6a-yl acetate (160)or [1 R,6S ,7R,9S] 9-Acetoxyl-2,2,6-trimethyhricyclo [4.4.0.07’9.Jdecane (160)160To the solution of ketone 131 (1.80 g, 8.18 mmol) in methylene chloride (10.0 ml)was added m-CPBA (4.45 g, 80-85% pure, 2.1 mmol, 2.5 eqv.). The above mixture wasrefluxed for 12 hours during which a milky thick slurry was observed. After cooling to roomtemperature, methylene chloride (50 ml) was added and the mixture was washed with 10%rapidly solution (50 ml). The organic layer was separated, washed with brine (20 ml), dried112with magnesium sulfate, and concentrated in vacuo. Column chromatography of the crudeproduct gave acetate 160 (1.50 g, 82% based on starting material recovery) and starting ketone131 (0.09 g).The physical properties of 160 are as follows:[]=÷36.7 (c=0.995, CHC13).IR Vmax. (film): 3050 (C-H stretching), 1735 (C=O stretching) cm1.1H-NMR (400 MHz, CDC13)ö: 0.70 (1H, m), 0.80 (3H, s), 0.90-1.02 (4H, m, including0.97 (3H, s)), 1.05 (3H, s), 1.10-1.70 (8H, m), 1.90-2.10 {4H, including 2.10 (3H, s)},2.23 (1H, dd, J=8.0 and 12.0 Hz).MS m/z: 236 (M, 1.1%), 221 (19.0%), 194 (21.5%), 179 (22.2%), 109 (100,0%). Highresolution mass measurement: calculated forC15H240:236.1776; found:. 236.1774.2.3.30. Saponification: acetate 160 to cyclopropanol 161[1 aR-( 1 aa, 1 bf3,5af3,6aa)] Decahydro- 1 b,5,5-trimethylcycloprop [a]inden-6a-ol (161) or[1 R ,6S ,7R,9S1 2,2,6-Trimethyltricyclo decan-9-ol (161)161Acetate 160 (589 mg, 2.50 mmol) was dissolved in ethanol (20 ml) at roomtemperature. To this solution was added grounded potassium hydroxide (230 mg, ‘—80% pure,3.28 mmol) under nitrogen. The resulting mixture was stirred for 30 minutes, diluted withwater (20 ml), and extracted with methylene chloride (2x20 ml). The methylene chloridesolution was dried over magnesium sulfate, concentrated to provide alcohol 161 as an oil (490mg, 100%).The physical properties of 161 are as follows:113[a]=+34.5 (c=1.00, CHC13).JR Vm (film): 3050-3650 cm’.1H.NMR (400 MHz, CDC13)6: 0.80 (3H, s), 0.96 (3H, s), 1.01 (3H, s), 1.98 (2H, m).MS m/z: 194 (M, 3.2%), 179 (4.6%), 124 (28.8%), 109 (100.0%), 81(22.6%). Highresolution mass measurement: calculated for C13H220: 194.1672; found:.194.1665.2.3.31. Cyclopropane Ring Opening Reaction by FeCI3: cyclopropanol 157to -chtoroketone 162[4aS-(4acL,8acL)] 4-Chloro-3,4,4a,5,6,7,8,8a-octahydro-4a,8 ,8-trimethylnaphthalen-2( 1H)-one (162)[1 R-( 1 a,3 aa,7act)] 1,3 ,3a,4,5,6,7,7a-Octahydro- 1 ,4,4,7a-tetramethyl-2H-inden-2-one(164)162 164The alcohol 161 (490 mg, 2.53 mmol) obtained from above was dissolved inanhydrous DMF (12.5 ml) under nitrogen and cooled to 0°C. Dry ferric chloride (1.03 g, 6.35mmol) was added to this solution. After stirring for 1 hour, the resulting brown mixture waswarmed up to room temperature and remained stirred for 24 hours. Addition of 1 Mhydrochloric acid (20 ml), extraction with diethyl ether (2x20 ml), and drying over magnesiumsulfate was followed by concentration to give the crude product containing 162 and 164which was subject to elimination in the next step without separation.The physical properties of 162 are as follows:JR Vmax. (film): 1720 cm1.1141H-J4),4R (400 MHz, CDC13) 6: 0.76 (3H, s), 0.90 (3H, s), 1.25 (3H, s), 2.10-3.00 (4H,m), 4.70 (1H, dd, J=6.0 and 12.0 Hz).MS m/z: 228/230 (M, 0.6%/0.2%), 206 (1.0%), 193 (7.5%), 43 (100.0%). Highresolution mass measurement: calculated for C13H210371: 230.1251, found: 230.1223;calculated C13H210351: 228.1281, found: 228.1276.The physical properties of 164 are as follows:JR (film) vmax.: 1725 cm1.1H-NMR (400 MHz, CDC13)6: 0.84 (3H, s), 0.91 (3H, s), 1.17 (3H, s), 1.24 (3H, s), 1.74(1H, t, J=10.6 Hz), 2.00 (1H, q, J=7.2 Hz), 2.04-2.35 (2H, m).MS m/z: 194 (M, 3.2%), 124 (28.8%), 109 (100.0%), 81(22.6%).2.3.32. Dehydrochlorination: -chIoroketone 162 to enone 163[4aR-(4acç8x)] 4a,5,6,7 ,8,8a-Hexahydro-4a,8 ,8 -trimethylnaphthalen-2(1H)-one (163)163The above crude product containing f3-chloro-ketone 162 was dissolved in a saturatedsodium acetate methanol solution (10 ml). This mixture was refluxed for 3 hours andconcentrated in vacuo. Purification by column chromatography with ethyl acetate: hexanes(2:8) gave enone 163 (384 mg, 80% from acetate 160) and ketone 164 (24 mg, 5%).The physical properties of 163 are as follows:m.p.: 64-66°C.[x]=+47.6 (c=1.00 , CHC13).UV (MeOH, c=20.0 mg/i) Amax.: 235 nm (log e3.842).115IR nmax. (film): 1664 cm-’ (C=O stretching).1H4s4MR (400 MHz, CDC13)6: 0.77 (3H, s), 0.96 (3H, s), 1.22 (3H, s), 1.22 (3H, s),1.27-1.75 (7H, m), 2.50-2.80 (2H, m), 5.95 (1H, d, 3=9.6 Hz), 6.27 (1H, d, J=9.6 Hz).MS m/z: 192 (M, 13.3%), 150 (45.1%), 69 (100.0%). High resolution mass measurement:calculated forC13H20: 192.1514; found: 192.1518.Elemental Analysis: calculated forC13H200: C 81.20, H 10.50; found: C 81.13, H 10.48.2.3.33. Ring Opening Reaction by NBS: cyclopropanol 161 to 13-bromoketone 167[1 R-( 1 x,3a,7aa)] 1 -Bromomethyl- 1,3 ,3a,4,5,6,7 ,7a-octahydro-4,4,7a-trimethyl-2H-inden-2-one (167)167Cyclopropanol 161 (12.8 mg, 0.066 mmol) in dimethy1su1foxide:chlorofom (4.0 ml,1:1, v/v) mixture solvent was stirred with NBS (23.5 mg, 0.132 mmol, 2.0 eqv.) at roomtemperature for 3 hours. Water (5 ml) was added and methylene chloride (10 ml) was used toextract the aqueous solution. Magnesium sulfate drying and concentration in vacuo resulted inan oil which was chromatographed with ethyl acetate:hexanes mixture (2:8, v/v) to afford 13-ketobromide 167 (6.3 mg, 60%) and cyclopropanol 161 (5.3 mg).The physical properties of 167 are as follows:JR (film) vmax.: 1730 cm1 (C=O stretching).1HNMR (400 MHz, CDC13)6: 0.82 (3H, s), 1.00 (3H, s), 1.14 (3H, s), 1.91 (1H, t, 3=9.0Hz), 2.32 (2H, m), 2.55 (1H, t, J=5.4 Hz), 3.35-3.65 (2H, m).116MS m/z: 274/272 (M, 2.4% /2.5%), 193 (7 1.2%), 175 (16.1%), 109 (100.0%).2.3.34. Dehydrogenation: enone 163 to dienone 168[4aR] 5,6,7,8-Tetrahydro-4a,8,8-trimethylnaphthalen-2(4aH)-one (168)c1o168The solution of 0.42 M LDA (1.84 ml) in n-pentane was concentrated to a viscousmixture and cooled to -78°C. To this mixture was added THF (1.0 ml) and introduced thesolution of 163 (135 mg, 0.703 mmol) in THF (1.5 ml) in a dropwise manner under nitrogenprotection. After stirring for 1 hour, phenylselenenyl chloride (183 mg, 0.844 mmol, 1.2eqv.) in anhydrous THF (0.50 ml) was added rapidly. The reaction mixture was warmed toroom temperature, stirred for another 1 hour, and treated with 30% hydrogen peroxide (0.72ml). After stirring for 5 hours, saturated sodium carbonate (aq., 5 ml) and diethyl ether (5 ml)were added. The organic layer was separated, washed with brine, dried over magnesiumsulfate, concentrated in vacuo to afford the crude product. The crude product was purified bycolumn chromatography using ethyl acetate:hexanes mixture (2:8, v/v) to provide dienone 168(111 mg, 92% based on recovery of starting material) and the starting enone 163 (13 mg).The physical properties of 168 are as follows:[ct]=+57.3 (c=1.00, CHC13).UV (MeOH, c=20 mg/I) max.: 241 nm (log E=4.00).JR Vmax. (film): 1660 (C=O stretching), 1620 (C=C stretching) cm1.117‘H-NMR (400 MHz, CDC13)& 1.15-2.10 { 15H, m, including 1.22 (3H, s), 1.30 (3H, s),1.35 (3H, s)}, 6.14 (1H, dd, J=0.2 and 9.9 Hz), 6.25 (1H, d, J=0.2 Hz), 6.70 (1H, d, J=9.9Hz).MS m/z: 190 (M+, 6.1%), 175 (12.0%), 147 (9.9%), 41(21.2%). High resolution massmeasurement: calculated forC13H80: 190.1357; found: 190.1358.2.3.35. Birch Reduction: dienone 168 to enone 64[4aR] 4,4a,5 ,6,7,8-Hexahydro-4a,8,8-trimethylnaphthalen-2(3H)-one (64)64To the solution of dienone 168 (85.9 mg, 0.452 mmol) in anhydrous THF (2.0 ml)was distilled ammonia (4 ml) from sodium under nitrogen. Small pieces of lithium were addedfor 30 minutes until a dark blue color persisted. After stirring was continued for 30 minutes,ammonium chloride powder was added to remove excess lithium. Evaporation of ammoniaand THF gave a yellowish oil which upon column chromatography produced the desired enone64 (58.0 mg, 74.2%) and the starting dienone 168 (8.5 mg).The physical properties of 64 are as follows:[cc]=-100 (c=1.00, CHC13).UV (MeOH, c=20.0 mg/I)2max: 242 nm (log e=4.10).JR Vmax (film): 1665 cm1 (C=O stretching).‘H-NMR (400 MHz, CDC13)ö: 1.14 (3H, s), 1.19 (3H, s), 1.34 (3H, s), 1.40-2.00 (8H,m), 2.38 (1H, m), 2.59 (1H, m), 5.96 (1H, s).118MS m/z: 192 (M, 100.0%), 177 (30.7%), 164 (12.8%), 149 (37.0%). High resolutionmass measurement: calculated forC13H200: 192.15 14; found: 192.15 12.2.3.36. Dehydrogenation: ketone 171 to dienone 172[4aR-( 1 cz,8)] 5,6,7,8-Tetrahydro-4a,8-dimethylnaphthalen-2(4aH)-one (172)b0172The mixture of ketone 171 (2.64 g, 14.7 mmol) and DDQ (7.41 g, 32.2 mmol, 2.2eqv.) in dioxane (50 ml) was refluxed under nitrogen for 24 hours. Evaporation of the solventin vacuo gave a brown oil which was purified by column chromatography with ethylacetate:hexanes mixture (2:8, v/v) to provide dienone 172 in 80% yield (1.65 g) and thestarting material 0.53 g.The physical properties of 172 are as follows:JR (film) vmax.: 1650 (C=O stretching), 1620 (C=C stretching) cm-1.1H-NMR (400 MHz, CDC13): 0.95-1.45 (8H, m, including 1.14 (3H, d, 3=6.0 Hz) 1.27(3H, s)}, 1.65-2.10 (4H, m), 2.51 (1H, septet, J=6.0 Hz), 6.11 (1H, s), 6.21 (1H, d, J=9.0Hz), 6.78 (1H, d, J=9.0 Hz).MS m/z: 176 (M, 5.1%), 161 (3.1%), 149 (16.2%), 43 (100.0%). High resolution massmeasurement: calculated forC12H60: 176.1201; found: 176.1198.2.3.37. Birch Reduction: dienone 172 to enone 173 and ketone 174[4aR-( 1 a,8 [3)] 4,4a,5,6,7, 8-Hexahydro-4a,8-dimethylnaphthalen-2(3H)-one (173)[4aR-( 1 x,8 [3)] 3 ,4,4a,5,6,7,8 , 8a-Octahydro-4a,8-dimethylnaphthalen-2( 1H)-one (174)119dc0a173 :174To a solution of dienone 172 (200 mg, 1.14 mmol) in anhydrous diethyl ether (3.0 ml)was distilled anhydrous ammonia (—4 ml) from sodium. Small pieces of lithium were addedunder nitrogen for 30 minutes until a steady dark blue was observed. This solution was stirredat -33°C for another 30 minutes, quenched with ammonium chloride powder, warmed to roomtemperature. Concentration of the mixture in vacuo gave the crude product which waschromatographed with ethyl acetate:hexanes mixture (2:8, v/v) to provide enone 173 (75 mg,42%), ketone 174 (45 mg, 25%), and the starting material 171 (21 mg).The physical properties of 173 are as follows:[a]=-193 (c=1.03, CHC13).UV (EtOH, c=10.3 mg/i) max.: 240 nm (log e=4.025)JR (film) vmax.: 3052 (olefinic C-H stretching), 1660 (C=O stretching), 1610 (C=Cstretching) cm1.‘H-NMR (400 MHz, CDC13)ö: 1.06 (3H, s), 1.15 (1H, m), 1.25 (3H, s), 1.38 (1H, m),1.55-2.00 (6H, m), 2.25 (3H, m), 5.79 (1H, s).MS m/z: 178 (M, 76.0%), 162 (25.8%), 150 (54.7%), 79 (100.0%). High resolution massmeasurement: calculated forC12H80: 178.1357 ; found: 178.1354.The physical properties of 174 are as follows:[x]=-39.7 (c=0.985, CHC13).JR (film) vmax.: 1702 cm1 (C=O stretching).‘H-NMR (400 MHz, CDC13)6: 0.81 (3H, d, J=6.0 Hz), 0.93 (1H, m), 1.05 (3H, s), 1.12(1H, m), 1.30-1.80 (8H, m), 2.00 (1H, t, J=14 Hz), 2.25-2.55 (3H, m).120MS m/z: 180 (M, 50.1%), 165 (9.3%), 109 (100.0%). High resolution mass measurement:calculated forC12H200: 180.1514; found: 180.1517.121Chapter 3. The Synthesis of Ambergris Fragrances3.1. Introduction3.1.1. Ambergris FragrancesAmbergris is one of the most valuable animal perfumes, like civet, musk, andcastoreum81. Its outstanding fragrance and mysterious effects of its odor account for man’sfamiliarity with this material since long before the Christian era in all great civilizations. It is ametabolic product of the sperm whale (Physeter macrocephalus L.), which accumulates asconcretions in the gut of the animal. After the concretion leaves the animal body, an agingprocess takes place over time, as a result of the action of sunlight and oxygen when floating inwaves. During this process, the strong stecoraceous indole of fecal note and the waxyconstituency disappear. At the same time, a complex yet balanced fragrance that is composedof a series of notes and subnotes, develops gradually to give a harmonious character82.The major constituent of ambergris is an odorless triterpene alcohol (-)-ambrein (176)83which is responsible for the generation of odoriferous compounds 17718484 found in thesteam volatile fraction (Figure 20). It can be presumed that the tricyclic compounds 177, 178,and ()Ambrox®* (179) are derived from the bicyclic part of (-)-ambrein (176), while thesmaller fragments 180-184 are from the monocyclic part of the molecule. Ambrinol (181)and (+)-dihydro-’—ionone (180) are structurally related and in fact a racemate of 181 can beformed stereoselectively from the racemate of 180 in 70% yield by an intramolecular Prinsreaction with Bronsted or Lewis acids as catalysts85. The facile formation of (+)-ambreinolide(185) and (+)-dihydro-y-ionone (180) during oxidation of 176 with permanganate supportsthis structural correlation86.*Ambrox® is a registered trade name of Firmenich SA. Systematic name of ()Ambrox® (179): [3aR-(3acz,5a,9aa,9bI3)]-dodacahydro-3a,6,6,9a-tetramethy1naphtho[2,1-b]furan.122CH(178CICH2179184Figure 20 The Constituents of AmbergrisAccording to one hypothesis8lb, (-)-ambrein (176) is degraded by autooxidationduring the aging process. Singlet oxygen may be considered as an active agent while copperions from haemocyanin may function as a catalyst in this degradation. Porphyrins, known tobe efficient photosensitizers, have been identified in ambergrisS7. This theory is supported by(-)-ambrein (176)177180 181183182123a photooxygenation experiment in which (-)-ambrein (176) was converted to compounds 178,180, 181, and 182 by the cleavage of its allylic hydroperoxide87b.Ambergris is disappearing from the world market due to excessive whale hunting. Inaddition, the continued increase in the pollution of coasts makes it more difficult to find prime-quality material which is more and more rarely washed ashore. In the future, the perfumeindustry must meet its needs for the natural product with a synthetic equivalent. The racemicform of cx-ambrinol (181), possessing an exceptionally strong odor of damp earth with a crudecivet subnote, is the only naturally occurring amber odorant for which a fully syntheticequivalent is used commercially. In 1950, it was established that the amber-like odor (woodynature) of the enol ether 178 was retained in its hydrogenation product, ambraoxide (186)88.The following search for adequate odorants resulted in the discovery of ()Ambrox®*, adegradation product of easily accessible sclareol (187); a breakthrough was then achieved inthe commercial production of tricyclic amber odorants of woody nature in the late 1950’s89.The mixture of ()Ambrox® (179) and (+)isoAmbrox® (189) in the form of the baseFixateur 404 (trade name of Firmenich) has been available in perfumery for more than 30years.*The identification of ()Ambrox® (179) from ambergris is a much later event84b.185 186 1871243.1.2. Structure and Activity Relationship of Ambergris FragrancesWith ()Ambrox® (179) as a model compound, a large number of compounds havebeen prepared for the correlation of structure and odor relationship. For example, the stableA/B transfused9Oaand cis-fused91diastereomers of ()Ambrox® (179) have been preparedand their odor quality and strength have been evaluated* (Figure 21). The difference in theodors of ()Ambrox® (179) and (+)Ambrox® (188) is rather small. (+)Ambrox® (188)with its higher threshold value (2.4 ppb) and accentuated woody note lacks the strong andwarm animal note of its enantiomer 179 (threshold value 0.3 ppb). Therefore, (+)Ambrox®has been called poor man’s ambrox” by perfumers. The exotic, spicy undertone in (+)-.Ambrox® (188) disappears in its racemate, for which a threshold concentration of 0.5 ppbwas measured. (+)IsoAmbrox® (189) has a threshold value of 34 ppb which is more than ahundred times weaker than its model compound 179, showing the importance of an axialmethyl at C8 for the receptor event. Surprisingly, ()9epiAmbrox® (190) possesses thestrongest odor and the lowest threshold concentration of 0.15 ppb; it lacks slightly the rich andcomplex bouquet of 179. The diastereomer 191 is unlikely to exist because the trans fusionwould force the B ring into a highly strained boat-like conformation. Among the A/B cis-fusedseries, only racemic diastereomers were evaluated*. Only diastereomer 192 has an odorquality comparable to the prototype ()Ambrox® (179); it has a threshold value of 11 ppbwhich is 20 times higher than that of racemic Ambrox®. Racemic diastereomers 193, 194,and 195 are very weak odorants and almost devoid of any ambergris odor.*A comparison of these racemic diastereomers with 179 seems permissible since there is only a small differencein the odor of ().ambrox® (179) and (+)ambrox® (188). The organoleptic evaluation was carried out using athreshold concentration method90k1251213ç;E188Figure 21 Stereoisomers of ()Ambrox®The significance of the gem-dimethyl groups at C4 for the ambergris odor sensationwas assessed (Figure 22)90. Both nor-methyl Ambrox® 196 and 197 have the Ambrox®note although 196 with an axial methyl at C4 (threshold value 1.4 ppm) has a greater strengththan 197 with an equatorial methyl at C4 (threshold value 3 ppm). (±)DinorAmbrox® 198without gem-dimethyl group possesses the same woody character of Ambrox® and a dominantearthy odor reminiscent of a freshly plowed earth; it has a threshold value 2.4 ppm. Therefore,the gem-dimethyl group at ring A has considerable influence on the quality and strengthalthough their presence is not an absolute necessity for the ambergris sensation.Figure 22 The Effect of the gem-Dimethyl Groups on the Ambergris Odor Activity189 190 191192 193 194 195196 197 198126Based on a large number of analogues assessed, Ohloff92 proposed a qualitative“triaxial rule of odor sensation” to summarize the minimal structural requirements for acompound to have ambergris odor activity: 5, 8, lO-triaxial arrangement of the substituentsR’, R”, and Ra in the trans-fused decalin ring system is the geometric requirement for amolecule in order to exhibit an ambergris type odor (Figure 23). The compound must possessan oxygen-containing group, the incorporation of which into the R’, R”, or Ra substituents isadvantageous but not indispensable. Based on this rule, it is speculated that the specific site ofthe human olfactory receptor system reacts with the stimulating substance by an intermolecularthree-point interaction in three dimensional space. Therefore, the related cis-fused decalylderivatives, for obvious conformational reasons, do not in general fulfill the stereochemicalrequirements for odorants with ambergris-like properties.z#1Figure 23 Triaxial Rule of Ambergris Odor SensationMore recently, a so-called “ambergris triangle” rule was established by analyzing bothelectronic structures and stereochemical features of substituted decalin compounds93.According to this rule, an odorous compound should contain an “ambergris triangle” of certaindimensions formed by a carbon-attached oxygen atom (0) and two carbon-attached hydrogen2.90±0.40 AH 02.8Aan ambergris odorantFigure 24 The Ambergris Triangle Rule3.2A127atoms (H1 and H) making major contribution to the LUMO of this compound (Figure 24).Typically, H and Hj are allylic, tertiary, or axial. A specific example is given in Figure 24.According to this group of authors, the interaction between the active odorous molecule and thereceptor is molecular orbital controlled.However, as indicated by Winter94a,many inactive compounds also fulfil the generalstructural conditions postulated as being necessary for ambergris-type activity. He explored anapproach using the concepts of oriented profile and steric accessibility of the functional group,focussing on a quantitative estimation of the degree of interaction between the poiar (hydrogenbond acceptor, e.g., oxygen) part of an odorant molecule and the hypothetical hydrogen bonddonor group (e.g., hydroxyl) on the receptor site941’. The accessible polar surface area, ameasure of the steric accessibility, was calculated for each structure after optimization bymolecular mechanics calculations. A lower limit of accessibility necessary for activity wasfound to 6 A. So far, only a limited range of molecules have been tested by this approach.The precise nature of the ambergris odorant and the receptor interaction is essentially aspeculation. Each model reveals certain truth since each can make certain successfulpredictions. More precise models of greater power in the quantitative prediction are likely toevolve in the future as chemists get more acquainted with ever more sophisticatedcomputational technology. In addition, very recent exciting progress has been made in theisolation of human olfactory receptors95. Studies of receptor structures and the nature of activesites will enhance our understanding of the sense of smell as a whole as well as the ambergrisolfaction.3.1.3. Synthesis of Ambrox®Many synthetic sequences leading to ()Ambrox® (179) and its racemate haveappeared in the past few years, which reflects the reduction in available natural sources and theincreasing market demand for ambergris fragrances. Most enantioselective syntheses involve128the use of naturally derived diterpenes or sesquiterpenes as starting material. A brief summaryof the more typical synthetic sequences is presented below.The commercial production96 of ()Ambrox® (179) is based on proceduresdeveloped by Hinder and Stoll in l95O96 (Scheme 29). These procedures involveddegradation of natural sciareol (187), the principal source of which is clary sage (salvia sciareaL.). Direct treatment of sciareol (187) with chromium trioxide gave lactone 20196c. Analternative way96dof obtaining 201 consisted of a sequence of reactions: the conversion of187 into sclareol oxide (199) by potassium permanganate, ozonolysis of 199 to yield theacetoxy acid 200, and the cyclization of 200 to lactone 201. LAH reduction of lactone 201generated diol 202 which was then cyclized to ()Ambrox® (179) employing a catalyticamount of of f3-naphthalene sulfonic acid. Usually, (+)isoAmbrox® (189) was generated asa minor by-product.a) KMnO4;b) 03, heating; c) KOH, then HC1; d) 150°C, vacuum; e) Cr03,AcOH;f) LAH, Et20; g) f3-naphthalenesulfonic acidScheme 29 Stoll and Hinde?s Synthesis of ()Ambrox® from Sciareol (187)OH187tc’d202199 200 179129A short sequence using sciareol (187) as starting material was reported by Naf et al.97(Scheme 30) Catalytic hydrogenation of sciareol (187) gave dihydrosclareol (203) in goodyield. The reduction of this double bond was necessary to ensure a regioselective cleavage inthe next step. The diol 203 in carbon tetrachloride was then treated with aqueous sodiumhypochiorite to provide hypochlorite 204 which was then decomposed to chloride 205 via analkoxyl radical fragmentation mechanism. The cycization of 205 by means of sodium hydridein THF afforded ()Ambrox® (179). The overall yield from sclareol (187) was 11-12%.sclareol a c187da) 5% Pd-C, H2, EtOH; b) aq. NaOC1, CCL1;c) 30-35°C, 3h; d) NaH, THF, 3h, refluxScheme 30 Nafs Synthesis of ()Ambrox® from SclareolA similar sequence from sclareol (187) based on the fragmentation of an alkoxyl radicalwas also reported by Christenson98a(Scheme 31). Sclareol oxide (199), previously preparedfrom sclareol (187)98, was treated with hydrogen peroxide to produce a diastereomerichydroperoxide mixture (206). Reaction of 206 with ferrous chloride and a catalytic amount ofcupric chloride provided a bifunctional compound 207 which was then hydrolyzed to (-)-Ambrox® (179). The overall yield from sclareol (187) was 34%.cc’Ilggb203 204205 179130sclareol a1Xb199 206OAc d207 179a) KMnO4;b) H20,HOAc; c) FeC12,CuC12(cat.); d) KOH, ‘PrOH, H20Scheme 31 Christenson’s Synthesis of ()Ambrox® from SciareolThe fourth sequence towards ()Ambrox® (179) using sciareol (187) as startingmaterial was reported by I. C. Coste-Manere et al.99 (Scheme 32). Sciareol was acetylated toafford 208 which was then converted, in quantitative yield, to diene 209 by treatment with acatalytic amount of palladium acetate in quantitative yield. Reaction of 209 with potassiumpermanganate generated a mixture of ambreinolide (185) and sciareolide (201) (3:2) in anoverall yield of 80%. LAH reduction of 185 and subsequent cyclization by p-toluenesulfonylchloride provided ambraoxide (186). Similar treatment of 201 furnished ()Ambrox® (179).131QAcsciareolab, d208 209185 + 2O1186 179a) Ac20; b) Pd(Ac)2/dioxane, 100°C/l5min, 100%; c) LAH,Et2O/H, 2h, 96%; d) KMnO4,24hr,80%; e) LAH/THF, 25°C/3hr, 98%; 1) TsCI/CH2C1 25°C, 90%; g) LAH,Et2O/H; TsC1, 2hr, 90%Scheme 32 Coste-Manere’s Synthesis of ()Ambrox® from SciareolSeveral other diterpenes (Figure 25), abietic acid (82)100, manoyl oxide (211)101, andmethyl labdanolate (212) 102, were also degraded into ()Ambrox® (179).82 211 212Figure 25 Several Other Diterpene Starting Materials for ()Ambrox® Synthesis132M. 3. Cortes et al.103 (Scheme 33) reported the conversion of the sesquiterpene (-)-drimenol (33) into ()Ambrox® (179). Oxidation of 33 by pyridinium chlorochromateresulted in aldehyde 213 which was homologated to enol ether 214. Hydrolysis of 214 andthe following LAH reduction provided alcohol 215. Protection of the hydroxyl group in 215as acetate and subsequent dihydroxylation afforded 216 which was then cyclized into furan217. Oxidation of 217 led to ketone 218 which was further reduced into ()Ambrox®(179). The overall yield of ()Ambrox® (179) from (-)-drimenol (33) was 19%. Notably,the ether linkage cx to the carbonyl group in 218 survived during the Woif-Kishner reduction.HCH2O CHO OMea b c, d33 213 214g, h215 216 217çj%%Qi ç±°218 179a) PCC, CH21;b)Ph3=CH(OMe); c) H3O; d) LAH; e) Ac20, Pyr.;f) 0s04;g) NaOH,H20; h) MeSO2C1, Pyr.; i) KOH, DEG, NH2Scheme 33 Cortes’ Synthesis of ()Ambrox® from (-)-Drimenol (33)133Mon et al.1 (Scheme 34) developed an enantionselective synthesis of ()Ambrox®(179) from geranylacetone (219). Enantiomerically pure tosylate 220 was previouslyprepared from 219 by the same group°41’. The substitution of the tosyl group in 220 gavenitrile 221 which was treated with a Wittig reagent to give the methylene nitrile 222. Thisnitrile was reduced with DIBAL to provide 223 and further reduction with sodiumborohydride yielded alcohol 224. Stereoselective epoxidation of 224 resulted in 225.Reduction of 225 with LAH generated diol 202 which was then cyclized to ()Ambrox®(179). The overall yield of 179 from geranylacetone (219) was 2.2% in 15 steps.OTs225 202 179a) NaCN, DMSO; b) Ph3=CH2,DME; c) DIBAL; d) NaBH4,MeOH; e) m-CPBA,CH21; LiA1H, TUF; g) TsC1,C5HNbScheme 34 Mon’s Synthesis of ()Ambrox® from Geranylacetone (219)219C220 221222d e223 224134The first synthesis of racemic Ambrox® was reported by Matsui et aL105 (Scheme 35)Darzen’s condensation of dihydro-3-ionone (226) with ethyl chloroacetate anddecarboxylation of the resulting glycidic acid with a catalytic amount of sodium acetate gave analdehyde 227. Treatment of 227 with malonic acid and subsequent ethylation by titaniumtetrachioride in ethanol afforded ethyl trans- 3-monocyclohomofarnesate (228). Thecyclization of 228 by means of trifluoroacetic acid yielded tricyclic sclareolide (201).Reduction of this lactone and subsequent ring closure furnished (±)Ambrox®. The overallyield of (±)Ambrox® from dihytho--ionone (226) was 4.9%.c,d228 201 179a) C1CHCO2Et,NaOEt b) NaOAc, 200°C; c) CH2(COOH) Et3N; d) TiCI4,EtOH;e) CF3OOH; f) NaA1H2(OCCHO3g) TsC1, Pyr.Scheme 35 Matsui’s Synthesis of (±)Ambrox® from Dihytho--ionone (226)The second racemic synthesis of Ambrox® by Buchi and Wuest106 also started withdihydro-3-ionone (226) (Scheme 36). Condensation of 226 with dimethyl carbonate gave themonocyclic f3-ketoester 229 which was cyclized to the bicyclic 13-ketoester 230 using stannicchloride as catalyst. The 0-allylation of 230 provided an allyl ether which was heated inxylene to afford 231. Demethoxycarbonylation led to a mixture of 232 and 233 (6:1). Theaddition of MeMgI to 232, the ozonolysis of the resulting alcohol 234, and the subsequenttreatment with sodium borohydride afforded diol 235. The cyclization of this diol with a226 227135catalytic amount of p-toluenesulfonic acid in nitromethane furnished (±)Ambrox® as majorproduct. The hydroboration of 234 yielded a diol 236 which was cyclized to (±)-ambraoxide(186). The overall yields of (±)Ambrox® and (±)-ambraoxide from dihytho--ionone (226)were 9.0% and 5.4% respectively.a-ThrcooCH3CO2H3226 229230CO2H3 / -—c d+232 233f gh, 235 179g236 186a) (CH3O)2C0, NaH, DMF, 20°C; b) SnCI4,CH21,520°C; c) allyl bromide, Nail, DMF;d) CaC12,DMSO; e) MeMgI; 1)03, MeOH/NaBH g)p-TsOH, CH3NO2;h) BH3-THF/OH, H20Scheme 36 Buchi and Wuest’s Synthesis of (±)Ambrox® from Dihydro-3-ionone (226)1363.2. Discussion3.2.1. Retrosynthetic Analysis for Synthesis of ()Ambrox® (179) fromEnone 163After the completion of the formal sequence to (-)-polygodial (2), we turned our attentionto ()Ambrox® (179), the synthesis of which from thujone was vigorously pursued in ourlaboratories. ()Ambrox® may be considered as a homo-drimane sesquiterpene. The syntheticsequence we perceived is shown in Scheme 37.Scheme 37 Retrosynthetic Analysis for Synthesis of ()Ambrox®The cis-fused enone 163 was a promising starting material: the convex f face and thesteric hindrance from the axial methyl at C4 in the ring A of the major conformer (nonsteroidal) should ensure a favorable conjugate addition (e.g., by a vinyl anion equivalent) fromthe face of the ring B segment thereby, generating a chiral center C9 of the sameconfiguration as that in the ()Ambrox® (179). The conjugate addition might provide a good23163 179(-)-Ambrox®II ii189(+)isoAmbrox®246 251 255137opportunity of introducing a methyl group into C8 regioselectively, by trapping the enolateproduced in the addition reaction with methylating reagents like iodomethane. The cis-fusedy,6-enone 246 thus obtained would undergo a stereochemical correction step at C5 to itsepimer, the trans-fused y6-enone 251.We also envisaged that the furan ring C of ()Ambrox® (179) or (+)isoAmbrox®(189) may be formed by an acid catalyzed cyclization of the trans-fused 1,5-diol 255 whichwould be prepared by stereoselectuive reduction of 251 and subsequent hydroboration.Compound 251 was expected to possess the conformation as drawn below. An axialorientation of the secondary hydroxyl group at C7 would be necessary to ensure a facilemigration of the axial hydride from the vicinal tertiary carbon C8. Alternatively, an equatorialorientation of the secondary hydroxyl group would probably lead to some skeletalrearrangement as shown.OH98the major conformer of 163255 2601383.2.2. Studies on Conjugate Addition to Enone 163 and SubsequentMethylation of 245To complete the synthesis of ()Ambrox® (179) as planned above, a diastereoselectiveconjugate addition to enone 163 from the 13 face was necessary. Conjugate addition to enonesby organocopper reagents has been most widely used in organic synthesis107. Thestereochemistry of such conjugate addition to octalones analogous to 163 was first examined.Cuprous chloride-catalyzed addition of (2-propenyl) magnesium bromide to trans-fusedoctalones 237A and 237B (Scheme 38), gave exclusively the products 238A and 238Brespectively, resulting from the a face attack108. This facial preference can be explained in thefollowing manner109: the incoming group has to be perpendicular to the enone plane in orderto have maximal orbital overlap during the progress of the reaction and therefore a minimaltransition state energy (stereoelectronic requirement); as a result, the antiparallel attack* fromthe a face would go through a half-chair (chair-like) transition state while the parallel attack*from the 13 face will involve a skew-boat (boat-like) transition state. The highly strained skew-boat transition state would require much higher activation energy and therefore the antiparallelattack from the a face prevailed.* An antiparallel attack to a carbon-carbon double bond of a cyclohexene ring is defined as the attack antiparallelto the neighboring pseudoaxial group while a parallel attack as the attack parallel to the neighboring pseudoaxialgroup.139CH2=CH(CH3)MgBr237A, R=H 238A, R=H237B, R=CH3 238B, R=CH3antiparallel attack parallel attackScheme 38 Conjugate Addition of Organocopper Reagents to trans-Fused OctalonesEven for cross-conjugated dienones 239A, 239B, and 239B (Scheme 39), the x faceattack still predominated’ 10(CH3)2CuLi:R1239A, R,=CH3R2=H 240A, R,=CH3R2=H239B,1=CO2CHR2=H 240B, R,=CO2CHR2=H239C, Rl=CH3=—C(=CH)CH3 240C, Rl=CH3=-C(CH) H3Scheme 39 Conjugate Addition of Organocopper Reagents to Cross-conjugated Dienones140In the case of cis-fused octalone 242 (Scheme 40), only the product 243 resultingfrom face attack was obtained by lithium dimethylcuprate addition”1. Since octalone 242does not have a rigid conformation, a consideration of all its conformers is necessary tounderstand this reverse facial stereoselectivity. For the steroid-like conformer 239a, whichshould be more stable, the parallel attack from the a face is especially disfavored because of thehighly hindered concave geometry of the a face and the skew-boat transition state involved.For the non-steroid-like conformer 239b, the antiparallel attack from the a face is effectivelyblocked by the concave face and the axial acetoxyl grouping which remains in the approachingpath of the reagent, despite that the transition state of this antiparalell attack has a half-chairconformation. In the event, the 3 face attack was the reaction path observed.(CH3)2CuLi242a 242bScheme 40 Conjugate Addition of Organocopper Reagents to a cis-Fused OctaloneUsing the same argument, we concluded that f3 face attack of the cis-fused enone 163would be the favored mode. It is expected that 163 may exist in a conformational equilibriabetween 163a and 163b. In contrast to 242, the non-steroid-like conformer (i.e., 163b) ismore stable than the steroid-like conformer (i.e., 163a). The f3 face attack at 163a is favoredover the a face attack since it represents an antiparalle which requires a half-chair transitionstate rather than the less favorable skew-boat essential for the a face attack. The face attack242 243141at 163b is expected as preferred because the severe steric hindrance from the axial methyl at C4of ring A and the concave geometry of cc face would block the cc face antiparallel attack.163bNuThe use of the trans-fused enone 244 and dienone 165 (Figure 26), which werederivable from 160112, would probably produce a face addition compounds. Thus, these twocompounds were very unlikely to be the backup or alternative intermediates towards thesynthesis of ()Ambrox® (179).Figure 26 Potential Candidate Intermediates for the Stereoselective Conjugate AdditionExperimentally, conjugate addition of 163 with 2.0 equivalents of vinyl magnesiumbromide and a catalytic amount of cuprous iodide in dimethyl sulfide:THF (1:5, v/v) solutionNu163a 0244 168 163142gave the f face addition product 245 in 70% yield, the stereochemistry of which wasconfirmed by the ‘H-.NMR spectrum of the methylation product 246 (see Figures 27 and 28and the corresponding discussion). The absence of dimethyl sulfide113 or the use of cuprousbromide as catalyst led to decrease in yields, likely due to the formation of competing 1,2-addition by-products. Some poiar by-products were often observed in the reaction. y,6-Enone245 had its mass spectrum showing the molecular ion peak at m/z 220 while its IR spectrumindicated absorptions at 1710 and 1635 cm-1, corresponding to the presence of the carbonylgroup and the terminal carbon-carbon double bond. Its ‘H-NMR spectrum displayed threemethyl singlets at 60.90, 0.95, and 1.09 ppm, a complex five-proton multiplet at 6 2.25-3.10ppm corresponding to the two methylene groups x to the carbonyl group and the tertiary allylicproton, and a three-proton multiplet at 6 4.95-5.80 ppm corresponding to the three olefinicprotons in the terminal carbon-carbon double bond.CH2=CHMgBr 1) LDA, DMETNF, Cul 2) CH3IDMS 3) KOH, MeOHAfter y,6-enone 245 was treated with LDA in DME”4 initially at -78°C for 30minutes, the mixture was warmed to approximately 45°C. lodomethane (5.0 eqv.) was addedrapidly to the mixture. Compound 246 together with its minor epimer 247 (6:1) was isolated163 245 246247143in 60-70% yield. Since these two epimers were not separable, a basic treatment withpotassium hydroxide in methanol was performed to convert the epimeric mixture into the morestable compound 246 (--97% pure by GC). When THF was used as the solvent for themethylation reaction, a very large recovery (>60%) of starting material was observedpresumably because the sluggishness of the methylation reaction led to a quick equilibration ofthe initially generated enolate with the methylation products through proton exchange”5.Theuse of DME as a solvent to improve the ailcylation reaction has been reported”6. Theimprovement can be rationalized as follows: the bidentate chelation of DME causes theequilibration of the enolate mixture in the direction of the monomer which is more reactive andthe alkylation reaction is thus The mass spectrum of 246 revealed themolecular ion peak at mlz 234. Its JR spectrum indicated an olefinic C-H stretching absorptionat 3060 cnv’, a carbonyl stretching absorption at 1700 cm-1,and a carbon-carbon double bondstretching absorption at 1630 cm-1. Its ‘H-NMR spectrum in CDC13 displayed three methylsinglets at 60.82, 0.94, and 1.14 ppm and one methyl doublet (J=6 Hz) at 6 1.04 ppm. Therewere a one-proton multiplet at 62.30 ppm and a complex three-proton mukiplet at 62.40-2.70ppm, corresponding to the allylic proton at C9 and three protons c to the carbonyl group. Theolefinic signal at 6 5.01 ppm appeared as a doublet of doublets of doublets (J=17.0, 1.8, and0.5 Hz). This signal was assigned to Rb since the resonance of Hb was expected to have alarge J value (—15-20 Hz), due to coupling with Hc which was trans to Hb, and two small Ivalues due to coupling with Ha and H9. Thus, the three J value were tentatively assigned as I(Hb,Hc)17.0 Hz, J (Ha,Hb)=1.8 Hz, and J (Hb,H9)=0.5 Hz. The olefinic proton signal at 65.14 ppm appeared as a doublet of doublets (J=10.2 and 1.8 Hz). This signal was assigned toHa since the resonance of Ha should have a 3 value at 8-12 Hz, due to coupling with Hc whichwas cis to Ha, and a small J value of 1.8 Hz due to coupling with Rb. Thus, we obtained I(Ha,Hc)10.2 Hz. The olefinic proton signal at 6 5.55 appeared as a doublet of triplets(J=17.0 and 10.2 Hz). It was assigned to Hc since the resonance of Hc was expected to appearat lower field and should show 3 values of 17.0 and 10.2 Hz. Thus, we obtained 3 (Hc,H9)=J144(Ha,Hc)10.2 Hz. The large coupling constant between Hc and H9 (J=10.2 Hz) indicated anear coplanarity of the C9-H9 and Cl l-Hc bonds. In the nonsteroid-like conformer 246a, thevinyl side chain is drawn as shown in order to portray this situation and to indicate minimalinteractions with neighboring groups, as revealed from molecular models.HaThe epimer 247, generated as a minor product together with 246 during the methylationof 245, was not characterized by spectroscopy since its separation from 246 was verydifficult. However, a partially enriched sample (50% by GC) obtained from the methylation inTHF was converted into 246 (97% pure by GC) by treatment of the mixture with a diluteKOH-methanol solution. The existence of 247 was then indirectly confirmed.To confirm the stereoselectivity of the conjugate addition reaction and the regioselectivityof the methylation reaction, a detailed ‘H-NMR spectrum analysis of 246 was conducted(Figure 27). The ‘H-NMR spectrum in deuteriated benzene118 afforded a clear resolution ofthe four proton signals at 2.20-2.70 ppm previously observed in the spectrum taken in246 248247145deuteriated chloroform. Decoupling by irradiation at 6 5.75 ppm (Hc signal) caused a one-proton triplet (J=1O.2 Hz) at 6 2.42 ppm to collapse into a doublet (J=1O.2 Hz) in addition tothe collapsing of the Ha signal at 6 4.94 ppm and Hb at 6 4.82 ppm into two broad singlets.Therefore, the triplet signal at 6 2.42 ppm was clearly due to the allylic proton (H9) whichapparently coupled only with Hc and one neighboring axial proton (J=10.2 Hz). Thus, themethylation of 245 must have taken place at C8 rather than at C6. The methylation at C6would have produced 248 which should have a more complex signal (doublet of doublets ortriplet) for the allylic proton (H9) if irradiation at the Hc signal had occurred. The only methyldoublet signal in the CDC13 spectrum appeared at 6 1.15 (J=5.l Hz) was assigned to themethyl group at C8. A one-proton mutiplet, consisting of six lines of equal spacing (5.1 Hz)and an intensity ratio 1:3:4:4:3:1, appeared at 6 1.90 ppm in the C6D spectrum and at 62.28ppm CDC13 respectively. The splitting pattern of this signal was indeed a doublet of quartetswith J=10.2 Hz for the doublet coupling and J=5.1 Hz for the quartet coupling. Thus, thissignal was assigned to the ct methine proton at C8.246HcHcHb246a249H5249a146Figure 27 Decoupling Experiments of 246a) the ‘H-NMR off-resonance spectrum in CDC13.b) proton-proton homonuclear decoupling at 5.75 ppm (C6D6).c) the ‘H-NMR off-resonance spectrum in C6D6.a)b)c)iJjij_Iz ss147In fact, the structure 249a (a conformer of compound 249 which had reverseconfigurations at C8 and C9 with regard to 246) could also account for the result ofdecoupling experiments, especially the large coupling constant between Hc and Hi (J(H,H1)=10.2 Hz) due to the diaxial orientation of these two protons. Therefore, to eliminatefurther doubt about the stereochemistry of 246, NOE difference experiments were carried out.Unfortunately, this effort did not prove to be productive. The crowdedness of signals in thealiphatic proton region in both CDC13 and C6D spectra caused the interpretation of NOEdifference experiments very difficult. However, important evidence was later obtained fromcompound 251, the epimer of 246 (see section 3.2.3.).To obtain 246 more effectively, we had tried to carry out an “one-pot reaction” byquenching the enolate generated in the conjugate addition with iodomethane. The one-potoperation would eliminate intermediate isolation and could be an efficient way to ensure thedesired regioselective methylation”9.However, the one pot operation proved to be verysluggish and produced mostly by-products in addition to compound 246 (10%) and 245(10%). Attempts to improve the reaction by changing solvents (Et20, THF, DME),temperature, and using HMPA as additive failed. Since the conjugate addition worked well toproduce 245 in good yield, the methylation step must be responsible for the sluggishness ofthis one-pot operation. The slowness of the methlyation reaction under the experimentalconditions could lead to the proton exchange between the initially formed enolate from theconjugate addition reaction and the methylation product 246. The enolate of 246 thusgenerated would be then further methylated. 0-methylation of enolates might be alsoresponsible for some by-reactions.3.2.3. Conversion of cis-fused y,-enone 246 to trans-fused y,-25lThe stereochemical conversion of the A/B cis fusion in compound 246 to the desiredA/B trans fusion in 251 was realized through a two-step sequence: the introduction of a148double bond to give 250 and a stereoselective reduction of 250 to produce the trans-fusedcompound 251.1)LDA,TF]F Li, NH32) PhSeC1 E203) 11202, Pyr.Slow addition of 246 dissolved in THF solution to a lithium diisopropylamide-THFsolution at -78°C under nitrogen was followed by a rapid injection of a phenylselenenylchloride-THF mixture. After stirring 1 hour at room temperature, THF was evaporated invacuo. Methylene chloride, pyridine, and hydrogen peroxide were added and the resultingmixture was stirred overnight. Dienone 250 was then isolated in 65% yield based on a 25%recovery of starting material. The mass spectrum of 250 indicated a molecular ion peak at m/z232. The UV spectrum showed maximal absorptions at 242 nm (log E=3.96) and 383 nm (logc=3.46) corresponding to it-it’ and n1t* transition absorptions of the enone moiety. The IRspectrum displayed an olefinic carbon-hydrogen stretching absorption at 3060 cm-1, aconjugated carbonyl stretching absorption at 1660 cm1, and a carbon-carbon double bondstretching absorption at 1630 cm1. The1H-NMR spectrum revealed a methyl doublet (J=5.1Hz) at 6 1.07 ppm and three methyl singlets at 6 1.17, 1.22, 1.25 ppm. A triplet (J=10.2 Hz)at 6 2.12 ppm and a multiplet at 6 2.40 ppm, consisting of six equally-spaced (5.1 Hz) lineswhich had an intensity ratio 1:3:4:4:3:1, were assigned to the allylic proton at C9 and themethine proton at C8 (dq, J=10.2 and 5.1 Hz). Four olefinic protons at 6 5.05 (dd, J=17.0and 1.8 Hz), 5.18 (dd, J=10.2 and 1.8 Hz), 5.64 (dt, J=17.0 and 10.2 Hz), and 6.00 (s)ppm, were attributed to Hb, Ha, Hc, and H6.Hb246 250 251149To reduce the large recovery of starting material and improve the yield ofdehydrogenation, different conditions were applied’20. One-phase elimination of thephenylselenide oxide by directH20(30%) addition to the phenylselenide prepared in THF orDME (dimethoxylethane) led to a even greater recovery of starting material (50%) and a loweryield of 250 (50% based on recovery). Another one-phase elimination of phenylselenideoxide by transferring the phenylselenide into a sodium periodate solution in methanol-H20(1:1) mixture resulted in the formation of a new compound of unknown structure (25% basedon recovery) in addition to 250 (40% based on recovery) and the recovered starting material(25%).TLC monitoring of the reaction showed that little starting material 246 was left after theintroduction of phenylselenenyl chloride and the newly generated phenylselenides appeared astwo UV active spots of apparenly different intensities. Attempts to separate these two spots bysilica gel chromatography failed as only the starting material 246 was isolated. Apparently, theselenides were very labile. In fact, even leaving the phenylselenides in THF-H20 mixtureovernight regenerated the starting material 246 as exclusive product.It was expected that the phenylselenylation of 246 would produce two diastereomers(iv) and (v), resulting from the attacks on a and 13 faces of the enolate of 246 (Figure 28).The 13 face attack of phenylselenenyl chloride on the dominant conformer (i) of the enolate hasthe advantage of going through a less strained half-chair transition state (ii) but suffers thesteric hindrance from the angular methyl group. The a face attack has to go through a strainedskew-boat transition state (iii) and suffers the hindrance from the gem-dimethyl groups in ringA’21. Therefore, the 13 face attack has some advantage overall. As we know, the [2,3]sigmatropic elimination of selenoxides goes through a syn-coplanar transition state’22.Therefore, only the selenoxide derived from (iv) will undergo elimination to afford 250 whilethe selenoxide from (iv) will likely decompose back to the starting material 246.150ciFigure 28 Stereochemistry of Phenylselenenylation of 246In another attempt, the trimethylsilyl enolether 252 was prepared by reaction of 246with LDA and trimethylsilyl chloride in THF and subsequent treatment with different oxidizingagents, DDQl23c,palladium (II) acetatel23d,and trityl fluoroborate (ie., triphenylcarbeniumtetrafluoroborate)’231’.None of these treatments gave any new product.The stereochemistry of Birch reduction on octalones has been well studied124 andtheories to rationalize the data have been forwarded125’6.For simple octalones, the transfused products were frequently obtained. It is assumed that the reduction goes through adianion intermediate (i). The protonation of (i) at the 3 position produces enolate (ii) which isthen hydrolyzed to give the saturated product. Thus, the stereochemistry of the final product isdecided by the protonation step of dianion (i). Stork et al.125 assumed the dianion (i) has a(i) SePh(iii)CI(v)252151tetrahedral 13 carbon while Robinson126 instead proposed that the 13 carbon is trigonal. Theimportance of orbital overlap in the transition state of the transformation between (i) and (ii)was recognized by both groups.Li, NH3 H20Treatment of 250 in anhydrous ether:ammonia (1:2) employing a slightly excessivelithium for one hour and quenching the resulting mixture by ammonium chloride, afforded 251in 90% yield. The GC retention times of the epimers 246 and 251 were very different fromeach other. The mass spectrum of 251 showed its molecular ion peak at m/z 234 while the JRspectrum indicated the carbonyl stretching absorption at 1706 cm’. The ‘H-NMR spectrum inCDC13 displayed three methyl singlets at 60.88, 0.90, and 1.09 ppm, a methyl doublet (J=6.0Hz) at 60.93 ppm, a four-proton multiplet at 62.00-2.50 ppm, and three olefinic protons at 6H248(i) (ii)1524.98 ppm (dd, J=16.8 and 1.6 Hz), 5.12 ppm (dd, J=l0.0 and 1.6 Hz), and 5.56 ppm (dt,J=16.8 and 10.0 Hz). As in the case of 246, these three olefinic signals were assigned to Hbat C12, Ha at C12, and Hc at Cli respectively. The large coupling constant (J=12.0 Hz)between the H9 and H8 was again observed from the H9 signal ( 1.96 ppm, t, J=12.0 Hz) inthe ‘H-NMR spectrum (C6D), which proved beyond any doubt that the diequatorialorientation of vinyl group at C9 and methyl group at C8 in 251. Therefore, the diequatorialorientation of these two groups in the structure 246a were further confirmed. The structure249a can now be firmly excluded since its corresponding trans-fused product would havethese two groups diaxially oriented.3.2.4. Synthesis of Diol 255 from trans-Fused y,6-Enone 251As stated earlier, an axial secondary hydroxyl group at C7 in the diol 255 was requiredfor the cyclization to occur in a desired manner.1) BH3-TFIF2) H20To this end, ‘y,S-enone 251 was treated with L-Selectride (i.e., lithium tn-sec -butylborohydride) in THF at -78°C. The axial alcohol 253 was isolated in nearly quantitativeyield. The mass spectrum indicated the molecular ion peak at m/z 236 and a fragment ion atm/z 218 due to the loss of a water molecule. The IR spectrum showed a broad intensehydroxyl stretching absorption near 3450 cm1 and a carbon-carbon double bond stretchingabsorption at 1630 cm1. The ‘H-NMR spectrum revealed a quartet (J=3.0 Hz) at ö 3.92 ppmcorresponding to the ct proton of the axial hydroxyl group and three one-proton multiplets at 8•‘ L-Selecinde251 253 2551534.94 (dd, J=17.2 and 2.4 Hz), 5.02 (dd, J=10.4 and 2.4 Hz), and 5.52 (dt, J=17.2 and 10.4Hz) ppm. The fact that the a proton of the newly introduced secondary hydroxyl appeared as aquartet at 6 3.92 ppm with a small coupling constant (J=3.0 Hz) confirmed its equatorialorientation. As shown in Figure 29, an equatorial proton at C7 in compound 253 is expectedto couple nearly equally with the vicinal axial protons (Hax at C8 and Hax at C6) and theequatorial proton (Heq) at C6 because of the close dihedral angles, <Heq(7)-C7-C8-Hax(8),<Heq(7)-C7-C6-Hax(6), and <Heq(7)-C7-C6-Heq(6)127.Therefore, a quartet with a smallcoupling constant is expected for an equatorial proton at C7. Instead, an axial proton at C7 incompound 254 would couple nearly equally with the axial protons at C6 and C8 but differentlyto the equatorial proton at C6. A doublet of triplets with Jax,eq - 3 Hz and Ja,(ax 10Hz wouldbe expected for this axial proton at C7.253 254HC8Heq OHC4T’HeOH q eqFigure 29 Structural Analysis of Stereoselective Reduction Product 253The stereochemical outcome of the reaction between cyclic ketones and varioushydrides has been frequently reviewed128. For highly hindered hydride reagents like lithiumthsecbutylborohydridel29aand lithium tris(trans2methylcyclopentyl)borohydridel9b,theproduct from the less hindered face attack is usually expected. The most remarkable feature ofthese hindered hydride reagents lies in their ability to deliver the hydride almost exclusively inOH154an equatorial manner, even in the absence of any other nearby differentiating groups in thecyclohexanone ring, to give an axial alcohol. Therefore, we could predict with confidence thatlithium tri-sec-butylborohydride reduction of 251 would produce the axial alcohol 253. Thisis indeed the case.equatorial face 253axial faceThe hydroboration of 253 with borane in ThF, followed by basic hydrogen peroxideworkup, produced mainly the 1,5-diol 255 (70%) in addition to a minor 1,4-diol 256 (10%).Diol 255 had its mass spectrum showing the molecular ion peak at m/z 254 and two fragmentions at m/z 236 and 218 corresponding to loss of one and two water molecules from the parentmolecular ion. The ‘H-NMR spectrum revealed two overlapping methyl singlets at 6 0.82ppm, one methyl singlet at 6 0.85ppm, a methyl doublet at 6 0.98 (J =6.0 Hz), a one-protonmultiplet (dt, J=7.2 and 9.6 Hz) at 6 3.50, a one-proton multiplet at 6 3.62 ppm (J=5.6 and9.6 Hz), and a quartet (J=3.0 Hz) at 6 3.85 ppm corresponding to the c hydrogen attached tothe secondary hydroxyl group at C7. The two one-proton multiplets at 6 3.50 and 3.62 ppmwere due to the methylene group attached to the newly created primary hydroxyl group.Therefore, the hydroboration reaction of 253 proceeded regioselectively according to thegeneral rule that the hydroxyl group is preferentially situated at the less substituted end of adouble bond in hydroboration reaction130.25112 12255 256155The minor product 256 appeared to be a mixture of two diastereomers with a ratio of4:1, as indicated in the ‘H-NMR spectrum. These two diastereomers were difficult to separateby column chromatography. The mass spectrum of the mixture revealed a molecular ion peakat m/z 254. The JR spectrum showed an intense hydroxyl absorption at 3400 cm1. In the ‘HNMR spectrum, the minor diastereomer had a broad singlet at 63.77 ppm corresponding to H7and a quartet (J=8.0 Hz) at 6 4.12 ppm corresponding to the a proton at Cli while the majorisomer had a broad singlet at 3 3.87 ppm corresponding to H7 and a quartet (J=8.0 Hz) at 64.21 ppm corresponding to the a proton at Cii in the ‘H-NMR spectrum. Further assignmentof the stereochemistry at Cii to these two diastereomers was not possible based on the aboveobtained data.3.2.5. Cyclization of Diol 255 to ()Ambrox® (179)As shown in the Introduction, most of the synthetic sequences to natural or racemicAmbrox® involved a cyclization of a 1,4-difunctional (at C8 and C12) intermediate to form thetetrahydrofuran ring. Cyclizations of the the 1,4-diol 199 by -naphthalenesulfonic acid intoluene96 or p-toluenesulfonyl chloride in pyridine99”°4and the epimeric 1 ,4-diol 232 by ptoluenesulfonic acid in nitromethane106are of more direct relevance to our designed cyclizationof diol 255 (Figure 30).Figure 30 1,4-Diols Utilized for Acid Catalyzed Cyclization to ()Ambrox®It is assumed106 that these cyclization reactions catalyzed by acids proceed through atertiary carbocation (i) which is formed by elimination of the tertiary hydroxyl group at C2202 235156(Figure 31). The x face attack by the primary hydroxyl is kinetically preferred to the faceattack because the latter would be subjected to steric hindrance from the angular methyl groupin the transition state (iii). Thus, Ambrox® (179) is preferentially produced through a lowerenergy transition state (ii). However, iso-Ambrox® (189) resulting from the face attack willbecome the major product under prolonged treatment and can actually be obtained fromAmbrox® (179) under the same condition96. This reflects that (+)isoAmbrox® (189) with acis-fused tetrahydrofuan ring is thermodynamically more stable.4SOHH(ii)slow-HFigure 31 Mechanistic Analysis of Cationic Cyclizations of 202 and 235Under even more dramatic condition, i.e., boiling toluene with a cation-exchange resinas catalystl3l , ()Ambrox® (179), initially formed from diol 202, was rapidlyconverted to a hydrocarbon mixture of unidentified structures (60%) and a new tetrahydrofuran* The Chemical Abstract registry number for KU-23 is [9049-63-2]. This resin was first recorded in ChemicalAbstract in 1966 (CA 65: 15600a). Regretfully, we have no access to the corresponding original article13lbby Soviet chemists. Later reports on the application of KU-23 contain no specific information about itspreparation and structural characterization. Since KU-2, another cation exchange resin, is a sulfonatedcopolymer of styrene and divinyl benzene13 (CA 55: 27959i) and KU-21, also a cation exchange resin, is amodification of KU-2 containing additional hydroxyl and carboxyl groups13 (CA 55: 4819g), KU-23 isprobably a modification of KU-2, i.e., a modified sulfonated copolymer of styrene and divinyl benzene./(i)179(iii)189157KU-23Hydrocarbonstoluene257 of a rearranged bicyclofarnesane skeleton (32%) in addition to a small amount of epiAmbrox® (190) and isoAmbrox® (189) (Scheme 41). This resulting dehydration product ofdefinite chemical composition was called “ionoxide”. It was claimed that the ‘ionoxide’ had avery distinct musk-ambergris odor and a very high rating as a perfume. On the whole, thesmell of “ionoxide” was determined by the tricyclic compound 258, which had a strong muskodor, reminiscent of the odor of muscone. At lower temperature (90°C), the major productswere detected to be Ambrox® (179), (+)isoAmbrox® (189) and a mixture of unsaturatedalcohols 259 as shown in Scheme 41.+ +202 257190 189 179 258Scheme 41 The Formulation of “lonoxide”The gross structure and stereochemistry of 257 was establishedl3l by a chemicalcorrelation with the known compound 259. The configurational reversal at C5 is especiallynoteworthy.259158The choice of diol 255 as the substrate to be cyclized to ()Ambrox® (179) has beenbriefly justified in Section 3.2.1. Diol 260, the epimer of 255, has an equatorial hydroxylgroup at C7 and therefore it is very likely to undergo a skeletal rearrangement (ringcontraction), as indicated below, when treated with acids*.2 106 OH OH260It is well known that 3-hydroxy-thterpenoids, e.g., (i), undergo ring A contraction togive isopropylidene derivatives of partial formula (iii) via carbocation (ii) when treated withacids132’3. This rearrangement is of diagnostic value, since 3c-hydroxytriterpenoids (iv),when treated under the same conditions, yield principally products of partial structures (v) and(vi) due to a simple 1,2-elimination and a methyl migration. It is assumed that the four centersinvolved in the migration or elimination should adopt an anti co-planar conformation.* It should be noted that no precedent for the cyclization of a 1 ,5-diol into a tetrahydrofuran could be found in theliterature.H255(i) (ii)(iv)(iii)(vi)(v)159The cyclization of 255 was effected under different conditions, as is summarized inTable 5. Treatment of 255 with p-toluenesulfonic acid (2.0 eqv.) in nitromethane at 80°C for2 hours gave ()Ambrox® (179) (31%), (+)isoAmbrox® (189) (30%), a mixture ofalcohols 261 (15%), and a mixture of hydrocarbons. All spectroscopic data of 179, 189were consistent with those recorded in literature. The yield of 179 increased to 48% and theproduction of (+)isoAmbrox® (189) decreased to 15% by using toluene as the solvent.The melting point and specific rotation of the obtained ()Ambrox® weremeasured to be 74-76°C and -25.1 (c=l.00, CHC13).They agree well with the reported values[m.p. 77-77.5°C; [aJ=-24.7 (c=1.0, CHC13)190. The IR, ‘H-NMR, and massspectroscopic data are identical with those recorded in the literature.The melting point and specific rotation [z] of the obtained (+)isoAmbrox® weremeasured to be 57-59°C and +7.3 (c=1.00, CHCI3). They agree well with the reported values[m.p. 60-60.5°C; [a]=+7.5 (c=1 .0, CHC13)]90 The IR, ‘H-NMR, and mass spectroscopicdata are identical with those recorded in the literature90.The mixture of alcohols 261 contained a few compounds, as shown the gaschromatogram and the complex ‘H-NMR spectrum. This mixture could not be further purifiedby column chromatography. It displayed a hydroxyl stretching absorption at 3450 cm1 in themass spectrum and a molecular ion peak at m/z 220 in the mass spectrum. Thus, this mixturewas probably composed of monodehydrated compounds from diol 255.The non-polar hydrocarbon mixture was obtained from the earliest fractions fromcolumn chromatography. It contained several compounds, as revealed from the gaschromatogram. The JR spectrum indicated no hydroxyl stretching absorption while the massspectrum showed a molecular ion peak at m/z 218. Thus, this mixture must be a doublydehydrated product of diol 255. The ‘H-NMR spectrum displayed poorly resolved aliphaticproton signals at 30.60-2.65 ppm and olefinic proton signals at 3 5.00-5.60 ppm. It could notbe further separated.160Under a more dramatic condition (CH3NO2,100°C, 3.0 eqv. HOTs), the cyclizationproduced compound 257, the principal component of “ionoxide”, in 34% yield and (+)-isoAmbrox® (189) in 19% yield. The specific rotation [cL]5 of compound 257 was +37.1(c=1.00, CHC13),which is in good agreement with the reported value ([ct18=+39. , c= 6.7,CHC13)131a. Its other spectroscopic data, including IR, ‘H-NMR, and MS spectra areconsistent with those reportedl3la. Similar to what was reported by Viad et al.l3, ahydrocarbon mixture was isolated in large amount (41%) from this reaction.Table 5 Cyclization of the 1,5-Diol 255 under Different ConditionsComposition of dehydration products, %Conditions 179 189 257 261 hydrocarbonsHOTs (2.0 eqv.), CH3NO2 31 30-- 15 2280°C, 2 hrsHOTs (2.0 eqv.), Toluene48 10 15 880°C, 2 hrsHOTs (3.0 eqv.), CH3NO2-- 19 34 -- 40100°C, 0.5 hrsNo significant difference was observed when p-toluenesulfonic acid was replaced with3-naphthalenesulfonic acid.Non-protonic, poorly ionizing solvents, i.e., nitromethane and toluene, were used forour cyclization of the 1,5-diol-255. These two solvents have been employed previously in thecyclization of 1,4-diols to ()Ambrox® (179)96.106.131. The yield of 1,2-elimination(dehydration) by-products 258 (Scheme 41) was minimized by using these solvents.Presumably, mainly ion pairs rather than free carbocations are involved under theseconditions’34.The loss of I protons has to take place from the same side of the leaving group161Presumably, mainly ion pairs rather than free carbocations are involved under theseconditions134.The loss of f3 protons has to take place from the same side of the leaving group(i.e., H20) which, instead of the solvent, acts as the base. Such a stereochemical requirementreduces the possibilities of 1,2-eliminations in rigid trans-fused decalone systems. If highlyionizing solvents were used, free planar carbocations would be formed and therefore the lossof j3 protons would occur from either the same or the opposite side of the leaving group.The mechanism for the formation of 257 from (+)isoAmbrox® (189)13 as well asfrom our 1,5-diol 255 is proposed (Figure 32). The consecutive 1,2-shifts of peripheral axialhydrogens and the angular methyl group as indicated may produce an olefin 261 which hastwo conformers 262 (i) and 262 (ii). Cyclization of the more stable conformer (ii) via anintramolecular anti addition produces 257, the principal component of “ionoxide”.____CH3_____262 (i) OHFigure 32 Mechanism for the Formation of 257CH3257262 (ii)162the triterpenoid 3-3-friedelanol (263) was transformed into 13 (18)-oleanene (264) by acidcatalysis135. Presumably, the carbocation (i) (Figure 33) generated from 263 undergoes sixstereoelectronically controlled 1,2-shifts as shown to afford the carbocation (ii). The loss of aproton results in 13 (18)-oleanene 264.ILIn conclusion, we have succeeded in synthesizing ()Ambrox® (179) enantioselectively from the thujone-derived enone 163 in seven steps in an overall yield of 9.5%.Moreover, a novel synthesis of 257, the principal component of “ionoxide”, was discovered.The successful strategy should be applicable to the synthesis of other ambergris fragrances,which will be discussed in the next section.263H264H(i)HFigure 33 The Conversion of 3-13-Friedelanol (263) into 13 (18)-Oleanene (264)(ii)1633.3. Future DevelopmentsThe synthesis of ()Ambrox® (179) dictates the preparation of its precursor 255(Scheme 37). During the preparation of 255 from enone 163, two steps, i.e., 246 to 250and 250 to 251 (Section 3.2.3.) are required in order to reverse the configuration at C5.However, for the direct synthesis of 257 (i.e., the principal component of “ionoxidet)fromenone 163, it is unnecessary to have these two steps, since the configuration at C5 ofcompound 257 is the same as that of 163. Thus, a shorter route is perceived, as shown inScheme 42.%S-H20 CH3CH3.CH3CH3-CH3CH3CH3257Scheme 42 A Possible Shorter Route to Compound 257cis-Fused Ketone 246, prepared in two steps from 163 (Section 3.2.3.), might besubjected to L-Selectride reduction and hydroboration to give the cis—fused diol 265. An acid-catalyzed cyclization of 265 could then provide 257. Mechanistically, a series of consecutive1,2-shifts of peripheral axial groups in 265 would first generate the tertiary carbocation (i).The subsequent ring closure of (i) should afford the desired product 257.0Hb) BH3246 257265265CH3(i)164The developed strategy (Scheme 37) to the synthesis of ()Ambrox® (179) may befurther extended to the synthesis of other diastereomers possessing significant odoriferousproperties, for example, the cis-fused isomer 189 and ()epiAmbrox® (187).The diol 265, if prepared as outlined in Scheme 42, would be cyclized to afford 192under mild acid catalysis (Scheme 43). Functioning as the reactive species, the stableconformer of 265 could follow the reaction path as envisaged to yield the desired 192stereoselectively.CH3 H CH3265 192Scheme 43 A Possible Synthesis of Compound 192To synthesize ()epiAmbrox® (190), dienone 168, prepared previously from 163(Section 2.2.9.), would be converted to 266 by a cuprous iodide-catalyzed conjugate additionand a subsequent methylation (Scheme 44). According to the argument presented in Section3.2.2.(Scheme 39), the x face attack in the conjugate addition reaction is expected to bedominant. Birch reduction of compound 266 could generate the trans-fused ketone 267,which might undergo L-Selectride reduction and hydroboration to provide diol 268. Thestereoselective cyclization of this diol by acid catalysis, following the reaction path as shown,could finally lead to the ()epiAmbrox® (190).265 192165Li, NH3a) LDA, PhSeC1b) H20163a) Cul(CH2=CH)MgBrb) LDA, CH3I168 266a) L-Selectrideb)BH3267 268 190Hc268 190-H20Scheme 44 A Possible Synthesis of (-)-epi-Ambrox (190)In replacing vinylmagnesium bromide with allylmagnesium bromide in the conjugateaddition step, it should be possible to obtain the 1,6-diol 269 from enone 160, by using thesame strategy (Scheme 37). The acid-catalyzed cyclization of 269 would then furnish anotherambergris odorant: ambraoxide (186), the homologue of (.)Ambrox® (179) (Scheme 45).0HH-H20Scheme 45 A Possible Synthesis of Ambraoxide (186)163 269 1861663.4. ExperimentalSee Section 2.3.1. for General experimental.3.4.1. Conjugate Addition: c-enone 163 to cis-fused y,ö-enone 245[4R-(4cc,4ax,8act)] 4-Ethenyl-3,4,4a,5,6,7,8,8a-octahydro-4a,8,8-trimethylnaphthalen-2(1H)-one (245)245To a solution of enone 163 (718 mg, 3.74 mmol) in anhydrous THF (20.0 ml),cuprous iodide (112 mg, 0.59 mmol, 0.15 eqv.) and dimethyl sulfide (5.0 ml) were introducedunder a nitrogen atmosphere. This mixture was cooled to 0°C and 0.66 M vinylmagnesiumbromide in TFIF solution (8.2 ml, 5.41 mmol, 1.4 eqv.) was added in a dropwise manner overa period of 1 hour. After the mixture was warmed to room temperature and stirred for another1 hour, saturated sodium chloride (20 ml) was introduced to quench the excessvinylmagnesium bromide. The organic layer was separated; the aqueous layer was extractedwith diethyl ether (10 ml). The combined organic solution was dried over magnesium sulfateand concentrated in vacuo to give a crude oil which was then chromatographed to provideenone 245 in 70% yield (576 mg).The physical properties of 245 are as follows:[(x]=+22.2 (c=1.00, CHC13).IR Vm (film): 3065(C-H stretch , olefinic), 1710(C=O stretch), 1635(C=C stretch).1H-NMR (400 MHz, CDC13)6: 0.80-1.70 { 14H, including 0.90 (3H, s), 0.95 (3H, s) and1.09 (3H, s)}, 1.90 (1H, m), 2.25-3.10 (5H, m), 4.95-5.15 (2H, m), 5.70 (111, m).167MS m/z: 220 (M, 15.6%), 205 (4.0%), 123 (67.8%), 43 (100.0%). High resolution massmeasurement: calculated forC15H240: 220.1828; found:. 220.1831.3.4.2. Methylation by EDA and lodomethane: cis-fused y,&enone 245 to cisfused y,-enone 246[3S-(3cc,4I3,4a3,8af3)J 4-Ethenyl-3,4,4a,5,6,7,8,8a-octahydro-3,4a,8,8-tetramethylnaphthalen-2(1H)-one (246)246A LDA / n-pentane solution (0.68 M, 2.6 ml, 1.77 mmol) was concentrated to removen-pentane. The resulting white viscous mixture was cooled to -40°C, to which anhydrousdimethoxyethane (1.0 ml) was then added under nitrogen. Enone 245 (350 mg, 1.59 mmol)in dimethoxyethane (3.5 ml) was introduced to the LDA solution in a dropwise manner over aperiod of 1 hour. This enolate solution was warmed rapidly to 50°C and freshly distillediodomethane (0.40 ml, 6.42 mmol) was added rapidly. The resulting turbid yellowish mixturewas stirred at 50°C for 30 minutes and quenched with a solution of potassium hydroxide (100mg) in methanol (10 ml). After stirring for 30 minutes, the reaction mixture was concentratedin vacuo to give the crude product which was chromatographed with ethyl acetate:hexanes (1:8,v/v) to afford 246 (207 mg, 65% based on recovery of 245) and the starting enone 245 (53mg, 15%).The physical properties of 246 are as follows:[aJ=+29.3 (c=1.00, CHC13).JR Vm. (film): 3060 (C-H stretching, olefinic), 1700 (C=O stretching), 1630 (C=C168stretching).‘H-NMR (400 MHz, CDC13)8: 0.70-1.60 (18H, m, including 0.82 (3H, s), 0.94 (311, s)and 1.04 (3H, d, J=6.4 Hz), 1.14 (3H, s)}, 1.90 (1H, m), 2.30 (1H, m), 2.45-2.70 (3H, m),4.95-5.20 (2H, m), 5.55(111, m).MS m/z: 234 (M, 1.7%), 219 (0.5%), 167 (35.7%), 149 (100.0%).3.4.3. Dehydrogenation by PhSeCI/H20:cis-fused y,6-enone 246 to dienone250[3S-(3a,4f.,4a3,8a)] 4-Ethenyl-4,4a,5 ,6,7 ,8-hexahydro-3 ,4a,8,8-tetramethylnaphthalen-2(3H)-one (250)250A LDA solution in n-pentane (0.50 M, 2.30 ml, 1.15 mmol) was concentrated in vacuoto remove n-pentane. The viscous mixture was cooled to -40°C and THF (1.0 ml) was thenadded under nitrogen. The solution of 246 (250 mg, 1.07 mmol) in THF (3.0 ml) was addedin a dropwise manner with stirring over a 45 minute period. The resulting mixture waswarmed to room temperature and phenylselenyl chloride (212 mg, 1.10 mmol) was introduced.Stirring at room temperature was continued for 1.5 hours before addition of pyridine (0.50ml), methylene chloride (5.0 ml), and hydrogen peroxide (0.50 ml of 30% H20in 3.0 ml ofwater). The two-phase mixture was stirred at room temperature for 5 hours and separated.The aqueous layer was extracted with methylene chloride (5.0 ml). The combined organiclayers were dried over magnesium sulfate and concentrated in vacuo to yield a crude product.Purification by column chromatography with ethyl acetate:hexanes (1:8, v/v) afforded dienone169250 (134 mg, 62% based on recovery of starting material) and the starting material 246 (31mg).The physical properties of 250 are as follows:[(x]=-4.2 (c=1.0O, CHC13).UV (MeOH, c=40.0 m g/l) 242 nm (log c=3.96).JR Vm. (film): 3060 (olefinic C-H stretching), 1665 (C=O stretching).1H-NMR (400 MHz, CDC13) 6: 0.80-1.90 { 18H, m, including 1.07 (3H, d, J=5.1 Hz), 1.17(3H, s), 1.22 (3H, s) and 1.25 (3H, s}, 2.12 (1H, t, J=10.2 Hz), 2.40 (1H, m), 5.00-5.25(2H, m), 5.69 (1H, m), 6.00 (1H, s).MS m/z: 232 (M, 21.2 %), 217 (17.2%), 189 (2.7%), 178 (7.7%), 164 (100.0%), 149(48.7%), 121 (14.9%). High resolution mass measurement calculated forC16H240:232.1827; found: .232.1829.3.4.4. Birch Reduction: dienone 250 to trans-fused ‘y,6-enone 251[3S-(3a,413,4a13,8ax)] 4-Ethenyl-3,4,4a,5,6,7,8,8a-octahydro-3,4a,8,8-tetramethylnaphthalen-2(1H)-one (251)251To a solution of dienone 250 (300 mg, 1.29 mmol) in anhydrous THF (2.0 ml),anhydrous ammonia (4 ml) was distilled from sodium under a nitrogen atmosphere. Smallpieces of lithium were added slowly over a 30 minute period until a persistent dark blue colorremained. After stirring for 1 hour at -33°C, ammonium chloride powder was introduced to170quench excess lithium. Evaporation of ammonia and THF gave a yellowish oil which waschromatographed to afford the trans-fused decalone 251 (268 mg, 90%).The physical properties of 251 are as follows:[a}=-8.38 (c=2.40, CHC13).JR Vm. (film): 3060 (C-H stretching, olefinic), 1706 (C=O stretching).1H-NMR (400 MHz, CDC13)ö: 0.75-1.80 { 19H, m, including 0.88 (3H, s), 0.90 (3H, s),0.97 (3H, d 3=6.0 Hz), and 1.09 (3H, s)}, 2.00-2.50 (4H, m), 4.98 (1H, dd, J=1.6 and 16.8Hz), 5.12 (1H, dd, J=1.6 and 10.0 Hz), 5.56 (1H, dt, 3=10.0 and 16.8 Hz)MS m/z: 234 (M, 33.8%), 219 (8.8%), 203 (0.3%), 137 (10.8%), 123 (100.0%), 109(19.2%). High resolution mass measurement calculated forC16H20: 236.2140; found:236.2097.3.4.5. Reduction by L-Selectride: trans-fused 7,8-enone 251 to alcohol 253[2R-(2a,3a,4f3,4a,8aa)j 4-Ethenyl-decahydro-3 ,4a,8 ,8-tetramethylnaphthalen-2-ol (250)253The trans-fused ketone 251 (250 mg, 1.07 mmol) in anhydrous THF (2.0 ml) wasadded in a dropwise manner to L-Selectride (0.72 M, 3.0 ml, THF) at -78°C for 30 minutes.The solution was stirred for 1.5 hour, warmed to 0°C, and stirred for an additional 1 hour.Aqueous sodium hydroxide solution (3.0 ml, 3 M) and aqueous 30% hydrogen peroxide (3.0ml) were then introduced. The resulting mixture was stirred 30 minutes, saturated withpotassium carbonate, and separated. The aqueous layer was further extracted with diethyl ether(2x10 ml). The organic solutions were combined and concentrated in vacuo. Purification by171column chromatography with ethyl acetate:hexanes (2:8, v/v) gave alcohol 253 (240 mg,95%).The physical properties of 253 are as follows:[cL]=-40.9 (c=1.00, CHC13).JR Vm. (film): 3450 (0-H stretching), 3060 (C-H stretching, olefinic), 1630 (C=Cstretching).‘H-NMR (400 MHz, CDC13)& 0.70-1.85 {24H, m, including }, 3.92 (1H, q, J=3.0 Hz),4.94 (1H, dd, 3=2.4 and 17.2 Hz), 5.02 (1H, dd, J=2.4 and 10.4 Hz), 5.52 (1H, td, J=10.4and 17.2 Hz).MS m/z: 236 (M, 2.4%), 218 (2.1%), 203 (4.5%), 123 (100.0%). High resolution massmeasurement: calculated forC16H280: 236.1240; found: 236.2136.Elemental Analysis: calculated forC16H280:C 81.29, H 11.09; found: C 81.22, H 11.113.4.6. Hydroboration: alcohol 253 to 1,5-diol 255[1 S-( 1 ,4,4a,8acc)] Decahydro-3-hydroxyl- 2,5,5,8a--tetramethylnaphthalene- 1-ethanol (255)çbE:H255To a cooled solution (0°C) of alcohol 253 (300 mg, 1.27 mmol) in THF (2.0 ml) wasadded borane in THF solution (7.0 ml, 0.56 M) in a dropwise manner under nitrogen over aperiod of 30 minutes. The solution was warmed to room temperature and then stirred for 1.5hours. After water (1.0 ml), aqueous sodium hydroxide (3.0 ml, 3M), and aqueous hydrogen172peroxide (3.0 ml, 30%) were introduced, the resulting mixture was stirred overnight, saturatedwith sodium chloride, and separated. The aqueous layer was further extracted with diethylether (10 ml). The organic solutions were combined, dried over magnesium sulfate, andconcetrated in vacuo to give the crude product. The crude product was chromatographed withethyl acetate: methanol:hexanes (1:1:2, v/v/v) to afford diol 255 in 71% yield (229 mg).The physical properties of 255 are as follows:m.p.: 128-130°C.[c]=-16.9 (c=1.00, CHC13).JR Vmax. (film): 3400 (0-H stretching).‘H-NMR (400 MHz, CDC13)& 0.70-1.80 {27H, m, including 0.82 (6H, two overlappedsinglets), 0.86 (3H, s), and 0.98 (3H, d, 3=6.0 Hz)), 3.50 (1H, dt, J=7.2 and 9.6 Hz), 3.62(1H, dt, J=5.6 and 9.6), 3.85 (1H, q, 3=3.0 Hz).MS m/z: 236 (M-H20, 6.6%), 221 (6.5%), 191 (16.9%), 177 (6.0%), 167 (18.9%), 138(62.2%), 123 (100.0%). High resolution mass measurement: calculated forC1613002:254.2236; found: .254.2241.Elemental Analysis: calculated forC16H3002:C 75.53, H 11.89; found: C 75.75, H 12.00.3.4.7. Cyclization: 1,5-Diol 255 to 179, 189, and 257[3aR-(3aa,5aI3,9acc9b)] Dodecahydro-3a,6,6,9a-tetramethyl-1H-naphtho[2, 1 -blfuran (179)[3aS-(3acc,5acx,9a,9bct)] Dodecahydro-3a,6,6,9a-tetramethyl- 1H-naphtho[2, 1-b] furan (189)[3aR-(3arx,4cç6ax, lOaS *)j Dodecahydro-3a,4,7,7-tetramethyl-2H-naphtho[8a, 1 -b]furan (257)179 189 257173Procedure #1:Diol 255 (20 mg, 0.079 mmol) in anhydrous toluene (2.0 ml) was treated with ptoluenesulfonic acid (27 mg, 0.16 mmol, 2.0 eqv.) under a nitrogen atmosphere. This solutionwas then heated at 80°C for 2 hours. The resulting mixture was transferred by diethyl ether(10 ml) to a separatory funnel, washed with saturated sodium carbonate solution, dried overmagnesium sulfate, and concentrated in vacuo. Column chromatography with hexanes, ethylacetate :hexanes (1:50, v/v), ethyl acetate:hexanes (1:20, v/v), and ethyl acetate:hexanes (1:8,v/v) consecutively gave a mixture of hydrocarbons (1.4 mg, 8%), (+)isoAmbrox® (189)(1.9 mg, 10%), ()Ambrox® (179) (8.9 mg, 48%), and a mixture of alcohols 258 (2.8 mg,15%).Procedure #2:Diol 255 (20 mg, 0.079 mmol) in nitromethane (2.0 ml) was treated with ptoluenesulfonic acid (40 mg, 0.23 mmol, 3.0 eqv.) under a nitrogen atmosphere. The solutionwas then heated at 100°C for 30 minutes. After a workup similar to that in the procedure #1,the crude product was chromatographed with hexanes and ethyl acetate:hexanes (1:50, v/v) togive a mixture of hydrocarbons (7.0 mg, 40%), the ionoxide principal 257 (6.4 mg, 34%),and (+)isoAmbrox® (189) (3.5 mg, 19%).The physical properties of 179 are as follows:m.p.=74-76°C.[z]=-25.1 (c=1.00, CHC13).JR (CHC13)vmax.: 1455, 1380, 1000, 975 cm1.‘H-NMR (400 MHz, CDC13)6: 0.83 (3H, s), 0.84 (311, s), 0.88 (3H, s), 1.09 (3H, s), 3.83(1H, q, J=8.0 Hz), 3.92 (1H, m).MS m/z: 236 (M, 3.4%), 221 (100.0%), 205 (6.8%), 177 (3.8%), 137 (40.2%), 97(37.5%), 84 (23.8%), 81(20.3%), 69 (20.4%), 59 (22.8%), 55 (18.8%), 43 (20.6%). Highresolution mass measurement: calculated forC16H280: 236.2140; found: 236.2139.174The physical properties of 189 are as follows:m.p.=57-59°C.[cc]=+7.4 (c=1.00, CHC13).JR (CHC13)vmax.: 1450, 1375, 1070, 1035 cm-1.1H-N4R (400 MHz, CDC13)6: 0.86 (3H, s), 0.89 (3H, s), 0.90 (3H, s), 1.06 (3H, s), 3.70(q, J=8.0 Hz), 3.80 (1H, dt, J=3 and 8.0 Hz).MS m/z: 236 (M, 0.0%), 221 (M-CH3,100.0%), 177 (1.7%), 137 (21.3%), 109 (7.9%),97 (33.0%), 84 (3 1.6%), 69 (21.5%), 55 (34.0%), 47 (7.5%), 43 (49.8%). High resolutionmass measurement: calculated forC15H20(M-CH3): 221.1905; found: 221.1906.Chemical ionization MS using methane as carrier gas: 251 (M÷CH), 237 (M-i-Hj.The physical properties of 257 are as follows:[a]=÷37.1 (c=1.00, CHC13).JR (film) vmax.: 1455, 1370, 1040, 1025 cm1.‘H-NMR (400 MHz, CDC13)6: 0.81 (3H, s), 0.83 (3H, d, 3=6.6 Hz), 0.87 (3H, s), 0.94(3H, s), 3.70 (1H, dt, J=2 and 8.0 Hz), 3.81 (1H, q, J=9 Hz). ‘H-NMR (400 MHz, CC14)6: 0.80 (3H, s), 0.82 (3H, d, 3=6.6 Hz), 0.87 (3H, s), 0.92 (3H, s), 3.67 (111, dt, 3=2 and8.0 Hz), 3.76 (1H, q, 3=8.0 Hz).MS m/z: 236 (M, 7.7%), 221 (7.0%), 194 (13.7%), 193 (100.0%). High resolution massmeasurement: calculated forC16H280: 236.2140; found: 236.2146.175Chapter 4 Exploratory Studies of Different Strategies to DevelopThujone as a Chiral Building BlockThe synthetic strategy described in the previous two chapters focussed primarily on thecleavage of the isopropyl side chain of thujone as an important operation, to afford eventuallytarget molecules like (-)-polygodial (2) and ()Ambrox® (179). A direct result of such astrategy is that the synthesized target molecule always incorporates seven of the ten carbonatoms in the starting thujone molecule. A question is then raised: is it possible to developother strategies which incorporate different number of carbon atoms into these targetmolecules? If developed, each of such new strategies would be characteristic of its own carbonincorporation, providing novel entries into various natural products. A closely related issue isthat, in principle, for a given strategy which incorporates a certain number of carbons, therecan be various methods which integrate the same number of carbon atoms into targetmolecules, depending on how the starting structure is incorporated or how and where someparts of the starting structure are removed during the incorporation.With these general considerations in mind, we decided to integrate the isopropyl sidechain of thujone into target molecules as much as possible, rather than to cleave the isopropylside chain completely as in the previous studies. Thus, strategies of different degrees ofcarbon incorporation can be developed. This chapter summarizes some exploratory studies inthis direction. For the purpose of presentation, strategies incorporating seven, nine, and tencarbons are called 2, and £1Q strategies respectively.4.1. Studies on “Homothujone” and Its Derivatives: a new.7. strategyAs shown in Section 2.2.4. and 2.2.7., previously synthesized thujone-derivedcyclopropylcarbinols of the general skeleton (i) (Scheme 46) usually undergo acid-promotedring cleavage reactions through exo-type 1 and exo-type 2 cleavage pathways, rather than theendo-type cleavage pathway to provide the desired cyclohexane ring (Figure 11). It was176hypothesized that the preferred exo-type 1 cleavage was due to the exposed nature of themethylene in the cyclopropyl ring, towards the incipient nucleophiles (Figure 12).If the bicylo[3.1.O]hexane system (i) could be expanded to the bicyclo[4.1.O]heptanesystem (ii) in a regioselective manner shown in Scheme 46, the homoallylic halide (iii) with adesired cyclohexane ring would become the “logical product” due to the preferred exo-type 1cleavage. With a versatile homoallylic halide group, (iii) may be readily elaborated into (-)-polygodial (2) and ()Ambrox® (179).ringexpansion-- -(ii)Scheme 46 The Potential of a Regioselective Ring Expansion ReactionThis ring expansion reaction had not been considered in our earlier studies nor in otherlaboratories in which other avenues of thujone chemistry had been developed. Therefore, itsevaluation would also make a fundamental contribution to thujone chemistry.Scheme 47 shows the overall plan in which this strategy may afford alternativesyntheses of (-)-polygodial (2) and ()Ambrox® (179). Ring expansion of thujone may beexpected to generate a “homothujone” (272) which could be then converted to enone 274.Birch reduction followed by enolate trapping should produce a trans-fused ketone 281 whichwould be reduced to hydrocarbon 284. Ozonation should then form both alcohol 294 andketone 295. Exo-type 1 cleavage of alcohol 294 would result in homoallylic chloride 296and the latter could be ozonized to a 3-chloro-ketone 298 while the ketone 295 could beconverted to f3-bromoketone 297 using m-CPBA and NBS as described in Section2.2.8..Versatile functional groups in both 297 and 298 would allow them to be readilyconverted to either (-)-polygodial (2) or ()Ambrox® (179).(i)* *(iii)177272-Scheme 47 “Homothujone” Strategy for Syntheses of Various Natural ProductsThe apparent advantage of the homothujone strategy is that the trans A/B ring fusioncould be possibly realized by Birch reduction directly, rather than through a tediousstereochemical correction sequence from the A/B cis-fused systems obtained earlier. As a new2 strategy, the homothujone strategy incorporates seven of the original ten carbon atomspresent in thujone into potential target molecules in a novel way.4.1.1. Regioselective Ring Expansion of ThujoneThe desired regioselective ring expansion of thujone was accomplished by treatingthujone with ethyl diazoacetate and boron trifluoride etherate under nitrogen at roomtemperature’37.The 13-ketoester 27O, which existed mainly in its enol form, was isolated in$ Because thujone in use was a mixture of a-thujone and f-thujone (10:1), the product 270 was a mixture oftwo diastereomers in a similar ratio, as revealed by GC. No attempt was made to separate these twodiastereomers. The 1H-NMR spectral data presented here represent the characterization of the major c274281 284+x295 297: X=Br298: X=Cl 29617870% yield. The mass spectrum of 270 showed a molecular ion at mlz 238. The UV spectrumindicated an absorption band at 258 nm (log e=3.980) while the JR spectrum displayed a broadhydroxyl absorption at 3370 cm’-1, an intense conjugated ester carbonyl stretching absorption at1655 cm-1, and a weak carbon-carbon double bond stretching absorption at 1615 cnr’. TheN2CHCOEtBF3-Et20presence of an intense UV absorption and the lack of any non-conjugated carbonyl absorptiondemonstrated domination of the enol form in compound 270138. The ‘H-NMR spectrumrevealed three separate one-proton signals at high field 6 0.30 (dd, J=4.4 and 8.8 Hz), 0.39 (t,J=4.4 Hz), and 0.68 (dd, J=4.4 and 8.8 Hz), corresponding to the three protons in thecyclopropane ring. Two methyl doublets (J=5.6 and 4.4 Hz), corresponding to the two methylgroups at the isopropyl side chain, overlapped at 6 0.98 ppm. There were a one-protonmultiplet at 8 1.03 ppm corresponding to the methine proton at C8, a methyl doublet (J=7.2Hz) at 6 1.24 ppm corresponding to the methyl at C2, and a methyl triplet (J=6.8 Hz) at 6 1.31ppm corresponding to the methyl of the ethyl ester group. A two-proton signal of AB type at 62.25-2.57 ppm (J=16 Hz) was assigned to the methylene at C5 while a quartet (J=7.2 Hz) at 62.64 ppm was due to the methine at C2. The 3 coupling constant between the methine protonsat Cl and C2 was zero!. A two-proton multiplet at 64.21 ppm corresponded to the methylenein the ethyl ester group and a very low field singlet signal at 6 12.24 ppm was due to thehydroxyl proton in the enol form of 270.The spectroscopic data presented above could not differentiate the enol form of 2703diastereomer while other spectroscopic data are the gross properties of the diastereomeric mixture. This situationremains the same for homothujone 272.179from that of 271, which would be the product of carbon insertion from the more substitutedside of carbonyl function in thuj one. Crucial evidence was obtained, however, from the nextstep, i.e., the decarboxylation of the 3-keto ester.T r e a t m e n tproduced 272# in 95% yield’39. The mass spectrum of 272 showed its molecular ion at m/z166 while the IR spectrum indicated a carbonyl absorption at 1700 cm-1. It is expected that272 would have its three a protons (to the carbonyl group) in the region between 62.00 ppmand 6 3.00 ppm in the ‘H-NMR spectrum whereas 273 available from 271 would reveal fourprotons in this region. To our surprise, 272 contained four protons in this region: two at 62.10 ppm (m), one at 6 2.35 ppm (m), and one at 6 2.47 ppm (dt, J=3.0 and 8.0 Hz). Aseries of decoupling experiments were performed to clarify the situation (Figure 34).frradiation of the one-proton signal at high field (60.72 ppm), which was assigned to one ofthe three cyclopropane protons, caused the multiplet at 6 2.47 ppm to collapse into a quartet(J=8.0 Hz) in addition to the simplification of the complex two-proton signal at high field (60.50 ppm), which was assigned to the two remaining cyclopropane protons. frradiation of thesignal at 60.50 ppm resulted in only the collapse of the signal at 60.72 ppm. Thus, the signalat 60.72 ppm was clearly due to the Cl proton while the signal at 62.47 ppm was assigned tothe methine proton at C2. Irradiation of the methyl doublet resonance (J=8.0 Hz) at 6 1.22# The product 272 was a mixture of a and I diastereomers (10:1), as indicated by GC. The1H-NMR datadescribed here represent the characterization of the major a diastereomer while other spectroscopic data are thegross properties of the diastereomeric mixture. See also the footnote at p. 178.271180e)__uLLJC)____ ___b)a)3.0 2.0 1.0 0.06 (ppm)Figure 34 Decoupling Expenments of 272a) off-resonance spectrum.b) proton-proton homonuclear decoupling at 0.50 ppm.c) proton-proton homonuclear decoupling at 0.72 ppm.d) proton-proton homonuclear decoupling at 1.22 ppm.e) proton-proton homonuclear decoupling at 2.47 ppm.181ppm led to the collapse of the C2 proton signal into a doublet (3=3.0 Hz) and irradiation at 62.47 ppm transformed the methyl doublet signal at 6 1.22 ppm into a singlet and the Cl protonsignal at 6 0.72 ppm into a doublet of doublets (J=4.8 and 8.8 Hz), further confirming theassignment. The fact that the C2 proton was coupled only to the Cl proton and and the methylprotons at 6 1.22 ppm suggested the correct structural assignment to 272 and thus 270. Theproton at C2 of 273 would have coupled to the C3 protons in addition to the methyl protonsand the Cl proton. Seemingly, one of the methylene protons at C5 of 272 had an unusuallyhigh chemical shift between 62.00 to 2.70 ppm.DMSO270H20, NaC1DMSO271H20, NaC1273: a/f3It is noteworthy that the coupling between the Cl proton and the C2 proton incompound 272 (J=3.0 Hz) was rather different from that in 270 (3=0 Hz). This can beexplained when one considers the possible conformations of these two compounds (Figure35). The enol form of compound 270ct* can have two boat-like conformers 270a and 270b.Conformer 261b is less stable because of the repulsion between the axial methyl at C2 and theaxial hydrogen at C5. Inspection of models reveals a dihedral angel <H1-C1-C2-H2 close to900 in conformer 261a which possesses an equatorial methyl group at C2. Therefore, thecoupling constant between Hi and H2 is expected to be small. Among the two half-chair* As indicated in the footnotes at p. 178 and p. 180, the1H-NIvIR data thus far described for 270 and 272represent their a diastereomers only.78272: aJI182conformers of 272cx*, 272b with an axial methyl group is considered more stable because it isdevoid of the C2-methyl bond and the Cl-Hi bond eclipsing interaction present in 272a andthe flat nature of the plane involving C2-C1-C6-C5 also greatly reduces the repulsion betweenthe axial methyl at C2 and the axial proton at C4 in 272b. The dihedral angle <Hi-C i-C2-H2is approximately 300 and therefore a larger coupling constant between Hi and H2 is expected.22272bFigure 35 Conformational Analysis of 27Oc and 272x;The insertion reaction of a ketone by ethyl diazoacetate usually take place from the lesssubstituted or less bulky side. The formation of the reactive conformer shown in Figure 36 ispresumably faster than other possible conformers due to minimal gauche steric repulsions140.Assuming that the subsequent migration is a faster process than the internal rotation about thecarbon-carbon bond, the insertion from the less substituted side becomes the dominantproduct.0 BF3R(’R2 N2CHCOEt+ OBF3(M) N2•yCOEt (L)(L) R(’R2 (S or M) R1COCHR2OEtH(S)Figure 36 Explanation for Regioselectivity of the Carbon Insertion Reaction5 L270a22270b272a41834.1.2. Stereoselective Robinson Annulation of Homothujone (272)The Robinson annulation of homothujone (272) was carried out by refluxing thestarting material with potassium hydroxide and the salt of 1-diethylaniino-3-pentanone and oneequivalent iodomethane in ethanol. Enone 274 as shown was isolated in 70% yield.EVK, KOHEtOH, refluxThe mass spectrum of 274 indicated the molecular ion at mlz 232 corresponding to theformulaC16H240. The UV spectrum showed an intense absorption band at 250 nm (logc=4. 133) corresponding to the it to it transition in the enone chromophore. The JR spectrumdisplayed a conjugated carbonyl absorption at 1660 cm-1. The ‘H-NMR spectrum was fairlywell resolved. Three low field one-proton signals at 5 0.30 (dd, J=4.8 and 9.6 Hz), 0.50 (dd,3=4.8 and 9.6 Hz), and 0.66 ppm (t, 3=4.8 Hz) were assigned to the cyclopropane protons.Two methyl doublets (both J=7.2 Hz) at 5 0.90 and 0.93 ppm were due to the two methylgroups of the isopropyl side chain while a neighboring multiplet at 5 0.95 was assigned to themethine proton of the side chain. Two methyl singlets at 5 1.16 and 1.74 ppm corresponded tothe angular methyl (at ClO) and the vinylic methyl (at C4) protons respectively. Threemultiplets at 3 1.58 (2H), 1.82 (1H), and 1.93 ppm (1H) were assigned to the methyleneprotons at Cl and C7 while two other lower field multiplets at 5 2.12 ppm (1H, dt, J=5.2 and14.0 Hz) and at 32.35-2.70 ppm (3H) were due to the four methylene protons at C2 and C6.The structure of 274 was further confirmed by a series of NMR experiments. Thestructure 275, which might possibly be formed by the EVK Robinson annulation from the lesssubstituted side of the carbonyl group, is inconsistent with the fact that only two methyldoublets were observed in the spectrum of the isolated product 274. However, the structure272 274184276, which was possibly generated from the face attack of the more substituted side, couldaccommodate all the spectroscopic data so far obtained. More evidence was needed todifferentiate 274 and 276.Inspection of molecular models reveals that the angular methyl groups at ClO havedifferent spatial relationships with the three cyclopropane protons in the diastereomers 274 and276. In the case of 274, the angular methyl is relatively close to the cyclopropane methyleneproton directed into the concave face of the bicyclo[4. 1 .O]heptane moiety (i.e., Hi11) but distantfrom the cyclopropane methine proton (i.e., H9) and the other methylene proton which isdirected away from the concave face of the bicyclo[4.1.O]heptane moiety (i.e., H). For276, the angular methyl is relatively close to H9 but distant from both methylene protons Hj11and HQUI. Thus, if the the angular methyl is irradiated, a positive NOE enhancement for Hwill indicate the presence of 274 while a positive enhancement for 119 will suggest theexistence of 276.Hin Hout276274 276H274185Fortunately, the ‘H-NMR spectrum was fairly well resolved. The methyl singlet signalat 6 1.22 ppm, previously assigned to the angular methyl, was well separated from nearbysignals and the three cyclopropane proton signals at high field were also well separated fromeach other. From a large number of recorded spectra of substituted cyclopropanes, it isgenerally observed that, in any designated cyclopropane, the magnitude of the vicinal couplingconstant for cis protons (protons on the same side of a cyclyopropane plane, e.g., H9 andH) is always larger than that for trans protons (e.g., H9 and Hj)141. Since each of the threecoupling constants in the AMX system, composed by the three cyclopropane protons of 274or 276, had to be either 4.8 Hz or 9.6 Hz , the coupling constant between H9 and Huit 1)(H9,H)] and the coupling constant between H9 and Hin [J (H9,Hin)] should have values 9.6Hz and 4.8 Hz respectively, in order to satisfy the relationship: J (H9,Hjjj> J (H9,Hm). 3(Ht,Hin) had to be 4.8 Hz to produce a thplet of J=4.8 Hz observed in the spectrum and thistriplet signal was due to Hin. Otherwise, if J (Hi,Hjn) were 9.6 Hz, a triplet of 3=9.6 Hzwould have been observed and this triplet would have been due to H. Thus, theconsideration of magnitude for coupling constants enabled us to assign the triplet (J=4.8 Hz) at6 0.66 ppm to Hj but the two doublet of doublets signals at 6 0.30 and 0.50 ppm cannot beassigned further.A two dimensional1H-’3Cheteronuclear correlation spectrum (2D-HETCOR, Figure 37)further confirmed the assignment. The proton (doublet of doublets) at 60.50 ppm correlatedintensely with a tertiary carbon at 6 33.00 ppm but weakly with a secondary carbon at 6 12.60ppm. Both the proton (triplet) at 60.66 pm and the proton (doublet of doublets) at 60.30 ppmcorrelated intensely with the secondary carbon at 6 12.60 ppm but not with the tertiary carbonat 6 33.00 ppm. This suggested that the proton (doublet of doublets) at 60.50 ppm was due toH9 and the quartet proton at 60.30 ppm was due to HQUI.The determination of substitution of the above mentioned carbons was facilitated by anAPT (Attached Proton Test) experiment (Figure 38). The carbon at 6 12.60 ppm was assignedas secondary since it was very intense in the off-resonance spectrum and did not invert its186F2 (PPM)—D4.0153.02826242.22.0181.61.4121.00.8060.40.2Figure 37 2D-HETCOR spectrum of 274a) H (0.30 ppm) ---C (12.60 ppm).b) H (0.66 ppm) ---C (12.60 ppm).c) H (0.50 ppm) ---C (33.00 ppm).187(BB)IIIIIII806040FillIii111111I20PP.4000 00220200180160140120100IIIILii.1L(APT)—.—.—.-..—-t..-w-2202001801601401201008060Figure38The‘3CBroadBandDecoupling(BB)andAPTSpectraof274401firIhurTII2(E’lCphase in the APT spectrum. Among the six carbons of inverse phase (which can be eitherprimary or tertiary carbons) in the APT spectrum, four of them were sorted out as primarycarbons since they had low chemical shifts in the ‘3C spectrum (6: 10.35, 18.55, and 19.20ppm). As shown from the HETCOR spectrum, these four carbons also correlated well withfour methyl singlets in the1H-NMR spectrum. Thus, the other two carbons at 6 33.00 and36.65 ppm must be tertiary carbons.NOE experiments’43were then carried out on compound 274 (Figure 39). Irradiation atthe angular methyl signal at 6 1.22 ppm resulted in a 4.0% enhancement of H111 at 60.66 ppmbut no enhancement of either 119 or H. Therefore, the stereochemistry of 274 was finallyconfirmed. Irradiation of Hm at 6 0.66 ppm did not give a clear enhancement of the angularmethyl signal but did cause a 10% enhancement of Hui and a negative enhancement of 119.4.1.3. Attempted Generation of the trans-Fused Hydrocarbon 284Having obtained the desired intermediate 274 in good overall yield from thujone, it wasappropriate to evaluate some chemistry with this compound. Birch reduction of 274, followedby iodomethane addition to trap the generated enolate1,gave the gem-dimethylated ketone277 in low yield (15%). Attempts to improve this reaction by addition of proton donors (i.e.,water and t-butanol) during the Birch reduction step, quenching of excess lithium withisoprene, and removal of ammonia prior to iodomethane addition proved to be infertile. Theby-products were relatively non-polar and difficult to separate from each other. Simplereduction of 274 and polymethylation of 274 and 277 might be responsible for theirgeneration.1) Li, NH3 THF2) CH3I274 277189c)b)a)Figure 39 The NOE Experiments of 274a) off-resonance spectrum.b) irradiation at 0.62 ppm.c) irradiation at 1.22 ppm.3.0 2.0 1.0 0.08 (ppm)190The mass spectrum of 277 revealed the molecular ion peak at m/z 248 while the JRspectrum indicated a carbonyl absorption at 1703 cm1. The relatively complex1H-NMRspectrum could be analyzed in support of structure 277. Two multiplets appearing at 6 0.08ppm (1H) and at 6 0.35 (2H), corresponded to the three cyclopropane protons. A triplet(J=2.4 Hz) at 6 0.85 ppm consisted of six protons, probably due to the overlapping of twodoublets of the methyl groups of the isopropyl group. Three methyl singlets at 8 1.03, 1.21,and 1.22 ppm and two multiplets at 8 2.30 ppm (2H) and 2.62 ppm (1H) were also observed.The A/B ring junction was assumed to be trans, in accord with the expected stereochemistry ofBirch reduction ( see Chapter 3, Section 3.1.3.) although insufficient evidence is available tobe certain. The poorly resolved ‘H-NMR spectrum discouraged attempts to use NOEexperiments to elucidate the nature of A/B ring junction at this stage.An alternative route to 277 was perceived. Reduction of 274 by lithium and ammoniaproduced a mixture of two compounds 278 and 279 in a ratio of 4:1. Because these twocompounds were not convertible by reaction with potassium hydroxide in methanol, they wereassumed to be two diastereomers of opposite A/B ring fusion with the major isomer 278presumed to possess the trans ring fusion as in compound 277. These two compounds weredifficult to separate by column chromatography. The mass spectrum of the mixture (278 and279) indicated a molecular ion at m/z 236.while the JR spectrum showed a carbonyl absorptionat 1700 cm1. Catalytic hydrogenation of 274 with 5% Pd-C at room temperature in ethanolgenerated 278 and 279 in a ratio of 6:1. Thus, the ‘H-NMR spectrum of this mixture couldreveal some characteristic signals of 278. Two multiplets appeared at 8 0.09 ppm (1H, t,J=5.2 Hz) and 0.40 ppm (2H, m), corresponding to the three cyclopropane protons. Threemethyl doublets at 6 0.85 ppm (J=6.0 Hz), 0.88 ppm (J=6.0 Hz), and 0.93 ppm (J=8.0 Hz)corresponded to the two methyl groups of the isopropyl side chain and the methyl group at C4.The angular methyl appeared at 8 1.35 ppm as a singlet.191Li, NH3or H2, Pd, EtOH278/279CH3I277HOtBu, KOtBuRefluxing the reduction mixture containing 278 and 279 with iodomethane andpotassium t-butoxide in anhydrous t-butanol under nitrogen resulted in a mixture which did notcontain 277, as indicated by GC. No further attempt was made to elucidate this mixture. Thereaction carried out at room temperature gave only recovered starting material.280I’”øTreatment of the mixture of 278 and 279 (6:1) with sodium methoxide andiodomethane produced 280 in 54% yield. This compound was characterized by a molecularion peak at m/z 248 in its mass spectrum, a carbon-carbon double bond stretching absorption at1680 cm1 in its JR spectrum, and two methyl singlets at ö 1.57 and 3.50 ppm, correspondingto the vinylic methyl and the methoxyl methyl in the ‘H-NMR spectrum. The A/B ringjunction of 280 was assumed to be trans, the same as that of 278 and 277.At this point, an alternative sequence to the A/B trans-fused hydrocarbon 273, whichwas based on the rearrangement of the original sequence as shown in Scheme 47, wasconsidered. The order of steps involved in this new sequence (Scheme 48) would bemethylation, decarbonylation, hydrogenation; whereas the original sequence would have stepsin a different order: hydrogenation, methylation, decarbonylation.274HH192NaOMe, DMSO 21*12274 KOH,DEGCH3I1)BH3-THF2) HOAc, heatingScheme 48 An Alternative Sequence to Hydrocarbon 284Enone 274 was first methylated to 282 in 60% yield using sodium methoxide inDMS 0145. The mass spectrum of 282 showed its molecular ion at m/z 246 while the JRspectrum displayed a carbonyl absorption at 1700 cm-1. The ‘H-NMR spectrum revealed threemethyl singlets at 6 1.01, 1.18, and 1.20 ppm, corresponding to the angular methyl group andthe two geminal methyl groups, and a one-proton triplet (J=4.0 Hz) at 6 5.42 ppmcorresponding to the olefinic proton.Decarbonylation of 282 utilizing the Woif-Kishner-Huang Minion conditionsproceeded smoothly to give 283 in 67% yield. The mass spectrum of 283 revealed themolecular ion peak at m/z 232 while the JR spectrum indicated the absence of carbonylabsorption. The1H-NMR spectrum showed three one-proton multiplets at 6 0.14, 0.36, and0.50 ppm, corresponding to the three cyclopropane protons, and a one-proton triplet (J=4.0Hz) at 65.30 ppm corresponding to the olefinic proton.Treatment of carbon-carbon double bonds by borane to form organoboranes which arethen decomposed with acetic acid to produce saturated C-C bonds is a useful indirect method ofcarbon-carbon double bond reduction146. However, such a treatment of 283 generated acomplex mixture which was composed of several compounds as detected by GC and the ‘HNMR spectrum.282 283284193111) BH3-T F13 51 712) H20OH286To understand the complication, an oxidative treatment of the intermediateorganoboranes by basic hydrogen peroxide was carried out. Diol 285 and alcohol 286 wereisolated in 39% and 29% yield respectively. The mass spectrum of 285 had its molecular ionpeak at m/z 268 while the JR spectrum indicated an intense hydroxyl absorption near 3500 cm1 The1H-NMR spectrum showed three methyl singlets at 6 0.96, 0.98, 1.00 ppm and twomethyl doublets at 6 1.01 ppm (J=7.0 Hz) and 1.15 ppm (J=7.0 Hz). Two multipletsappearing at 6 3.72 ppm (211) and 4.04 ppm (111) corresponded to the the methylene andmethine protons attached to Cli and C7. An X-ray structure of 285 (crystalized frommethylene chloride) is shown in Figure 40 (see also Appendix 2). The cis A/B ring fusion isclearly indicated.Alcohol 286 had its molecular ion peak at m/z 250 in the mass spectrum and anhydroxyl absorption at 3450 cm1 in the JR spectrum. The ‘H-NMR spectrum indicated threemultiplets at 6 0.14, 0.45, and 0.64 ppm, corresponding to the three cyclopropane protons.Two methyl doublets appeared at 60.85 ppm (J=6.0 Hz) and 0.90 ppm (J=6.0 Hz) while threemethyl singlets were observed at 60.98, 1.10, and 1.16 ppm. A doublet of doublets at 6 2.14ppm (111, J=5.2 and 7.4 Hz) was probably due to one of the methylene protons at C7 whichwas neighboring to the cyclopropane ring). A one-proton complex multiplet at 6 3.87 ppmwas assigned to the proton at C6. By analogy to structure 285 and the following mechanisticexplanation, the ring fusion of 286 was presumed to be cis and the hydroxyl should haveorientation.283 285194Figure 40 Single Crystal X-ray Structure of 285 (ORTEP Drawing)The oxidation of 286 by Jones reagent produced ketone 287 in 80% yield.Compound 287 was characterized by its molecular ion peak at m/z 248 in the mass spectrum, anon-conjugated carbonyl absorption at 1700 cmt in the IR spectrum, and a two-proton signal195285of strongly coupled AB type at 62.29 ppm corresponding to the two methylene protons at C7in the ‘H-NMR spectrum.11OH286Jones reagent287[0]diol 285BR2Figure 41 Novel Cyclopropane Ring Cleavage in the Hyciroboration of 283The formation of 285 and 286 can be rationalized as follows (Figure 41). Thehydroboration of the carbon-carbon double bond in 283 probably takes place from the f faceto generate the cis-fused organoborane (i) which undergoes a direct oxidation to yield alcohol286. Isomerization of (i) may afford another organoborane (ii) which rearranges to the thirdalcohol286[011NBR2283 (i) (ii)BR2HBBR2(iii) (iv)196organoborane (iii) via a novel cyclopropane ring cleavage. A stereoselective hydoboration of(iii) provides the fourth organoborane intermediate (iv) and a two-fold oxidation of the latterresults in the isolated diol 285. Cleavage of vinyl cyclopropanes has been previouslyobserved147 but usually a drastic condition is required. Notably, the cleavage reaction of 283took place at room temperature. After all, the complication of this indirect reduction was due tothe unexpected conversions occurring during the hydroboration step.1) Li, NH32742) TMSC1KOH, MeOH0Scheme 49 An Alternative Route to Ketone 277In a last attempt to improve the yield of 277, the sequence in Scheme 49 wasconsidered and put into experimental test. Trimethylsilyl enol ether 288 was prepared bytrapping the enolate generated in the Birch reduction of 274 with trimethylsilyl chloride148.The crude product thus obtained was then converted into a mixture of trimethylsilylcyclopropyl ethers (289/290) using the Simmons-Smith reaction149”501.This mixtureprobably contained two diastereomers 289 and 290 which had the newly created cyclopropylring and f oriented since ThC indicated more than two spots. The crude product fromSimmons-Smith reaction was hydrolyzed in warm potassium hydroxide-methanolsolution150’1.A major compound isolated was identified as 277 by comparing its MS, IR,CH21Et20 H288 289/290277197NMR data with 277 previously obtained in the Stork enolate trapping reaction. The nature ofA/B ring junction in 288, 289, and 299 was uncertain although tentatively assumed to betrans as for 277. The overall yield of 277 from 274 was 45%.291The reduction of 277 by the Woif-Kishner-Huang Minion method gave hydrocarbon291 in 70% yield. The mass spectrum of 291 indicated the molecular ion at ni/z 234 while theIR spectrum showed the absence of carbonyl absorption. The ‘H-NMR spectrum revealed twomuitiplets at 6 0.07 ppm (1H) and 0.40 ppm (2H), corresponding to the three cyclopropaneprotons. A triplet (6H, J=2.5 Hz) and three methyl singlets appeared at 6 0.84 ppm, 1.10,1.20, and 1.22 pm respectively.4.1.4. Ozonation of 291Ozonation of hydrocarbon 291 in ethyl acetate, as before, resulted in the isolation ofketone 292 (35%) and alcohol 293 (5%) instead of the expected compounds 294 and 295.cHOçOH7 292 293291 +294 295198Ketone 292 in its mass spectrum revealed a molecular ion at m/z 248 and its JRspectrum displayed a conjugated carbonyl absorption at 1665 cm-1. Its ‘H-NMR spectrumindicated two methyl doublets at 6 0.84 ppm (J=6.6 Hz) and 0.94 ppm (J=6.6 Hz),corresponding to the two methyl groups of the isopropyl side chain, and three methyl singletsat 6 0.78, 1.11, and 1.30 ppm. A one-proton septet (J=6.6 Hz) corresponding to the methineproton in the isopropyl side chain appeared at 6 1.84 ppm. A multiplet containing two protonsat 6 2.00-2.30 ppm corresponded to the two methylene protons at C6. An attempt to preparesuitable crystals for X-ray diffraction analysis of the solid 292 was not successful. The massspectrum of alcohol 281 showed the molecular ion peak at m/z 250 and its JR spectrumrevealed a broad absorption band near 3405 cm-1 which corresponded to hydroxyl stretchingabsorption. Its ‘H-NMR spectrum indicated two multiplets at 60.13 ppm (1H) and 0.45 ppm(2H), corresponding to the three cyclopropane protons, and two methyl doublets at 60.89 and0.98 ppm, corresponding to the two methyl groups of the isopropyl side chain. Three methylsinglets appeared at 6 0.86, 1.10, 1.20 while a multiplet (1H) at 64.16 ppm corresponded tothe proton at C8, the hydroxyl bearing carbon. The orientation of the hydroxyl group was notdetermined.It is surprising that the previously noted selective ozonation of thujone derivatives couldnot be applied to the homothujone derivative 291. The reasons for this reactivity change areunknown. Generally, a cyclohexane ring is more puckering than a cyclopentane. This mayallow one of carbon-hydrogen bonds at C7 properly oriented towards the cyclopropane ring in291. This orientation may then facilitate the participation of the cyclopropyl group in theozone insertion into this particular carbon-hydrogen bond*. The unusual reactivity of thecarbon-hydrogen bonds of the methylene neighboring to the cyclopropane ring in homothujonederivatives was assumed to be general, which discouraged further pursuit of the homothujonestrategy at that time. Since the oxidation of cyclopropylmethylene to cyclopropylketone has* For discussion on the mechanism of ozone insertion into carbon-hydrogen bonds, see Section 2.2.2.199been observed by other oxidizing reagents’52,the oxidation of homothujone derivatives mayfind application in a way complementary to the ozonation of thujone derivatives in the future.4.2. Studies on Utilizing the C2-C3 Bond Cleavage Products: a j strategyCyclopropylcarbinol of the general structure (ii) was considered as potentially usefulintermediate in the thujone chemistry (Scheme 50). They might be available from thujonederived cyclopropylcarbinol (i) by cleavage of the C2-C3 bond. Because the relief of thecyclopentane ring constraint, this seco-(C2-C3) cyclopropylcarbinol could possibly undergoacid-promoted ring opening via the cleavage of C1-C5 bond (endo type cleavage), rather thanthe cleavages of C1-C6 and C5-C-6 bonds (exo-type 1 and exo-type 2) usually observed for(i).HX(ii)Scheme 50 Ring Cleavage of seco-(C2-C3) CyclopropylcarbinolsA more attractive sequence leading to syntheses of (-)-polygodial (7) and its analoguesinvolved the utilization of a seco-(C2-C3) intermediate (Scheme 51). Trione 107, whichcould not find a ready application like its congener 106*, might undergo aldol condensation toafford enone 299 which would subsequently be methylated and selectively reduced to 300.An oxidative cleavage of the C2-C3 bond should produce trione 301 which could be thenrecyclized to 303. The seco-(C2-C3) compound 301 was considered equivalent to 302.Conjugate addition of geminally diactivated cyclopropane 3o353 would then generate* Both 106 and 107 were derived from ozonation (Section 2.2.2., Scheme 17) Compound 106 was used inthe studies on synthesis of steroid analogues from thujone, which is not described in this thesis.(i) (iii)200compound 304 and the latter could then be reduced to the trans-fused decalone 305 by Birchreduction. Application of 305 in the syntheses of (-)-polygodial (7) and its analogues can bereadily perceived.10 2 10 6 20: CHOCCHOcorro-... -9302 30310 1010seco•CHO304 305 (-)-polygodial (7)Scheme 51 A Novel Sequence to (-)-Polygodial (7);This novel sequence belongs to strategy in which nine of the ten carbons in thujoneis incorporated into the target molecule (-)-polygodial (7). The cleavage of the C2-C3 bondand the following cyclization are interesting from the structural point of view and they aretermed seco (from seco -thujone) and corro (from corre lation or connection of two seeminglydistant carbons C3 and C9#) operations. These two operations reveal an inherent topology orconnectivity of the thujone carbon skeleton. The direct creation of a trans A/B ring fusion andthe use of a electrophilic cyclopropane are quite appealing from the chemical point of view.The numbering for the structural segment derived from thujone is kept the same as that for thujone tofacilitate analysis.201Experimentally, the cyclization of 107 turned out to be a difficult reaction to perform.Treatment of 107 with pyrrolidine in refluxing benzene produced a rather complex mixture.Thus, no further attempt was made to carry out the above sequence. Fortunately, Dr. DominikGuggisberg obtained ketoacid 308 as a by-product in the preparation of diol 307 from olefin306*. A similar sequence to that in Scheme 51 was perceived starting with 308 (Scheme 52).KMnO4 CH2NH20:tBuOH Et2003, EtOAc0°C310 311Scheme 52 The Utilization of a seco-(C2-C3) Intermediate 308Thus, methylation of ketocarboxylic acid 308 with diazomethane in diethyl ether gaveketoester 309 in 95% yield’54. had The mass spectrum of compound 309 showed themolecular ion at m/z 280 corresponding to the molecular formulaC17H2803while Its JRspectrum revealed absorptions at 1710 cm1 and 1685 cm1 corresponding to the stretchingabsorptions of the conjugated ester carbonyl and the carbonyl in the cyclohexane ring. Twomethyl doublets at 0.67 ppm (J=7.2 Hz) and 0.92 ppm (J=7.2 Hz) corresponding to the twomethyl groups of the isopropyl side chain and three methyl singlets at 1.11, 1.13, and 1.20ppm were observed in the ‘H-NMR spectrum. A methyl singlet at 3.65 corresponded to themethyl of the methoxycarbonyl group.* I am grateful to Dr. Dominik Guggisberg for providing a sample of compound 308.306 307 308309202The ozonation of 309 in ethyl acetate at 0°C generated 310 in 45% yield. The tertiaryalcohol 312 (Scheme 53) was not isolated. Probably it was rapidly dehydrated to a terminalolefin at 0°C; the latter was then ozonized to 310 (see Section 2.2.2.). Diketoester 310 hadits mass spectrum showing the molecular ion at m/z 280 ppm and the IR spectrum showingcarbonyl stretching absorptions at 1710 cm1 and 1690 cm-’. The ‘H-NMR spectrum indicateda methyl singlet at 6 1.08 ppm, an overlap of two methyl singlets as a broad singlet at 6 1.10ppm, a methyl singlet at 6 2.28 ppm corresponding to the methyl of the acetyl group, and amethyl singlet at 63.76 ppm corresponding to the methyl of the methoxycarbonyl group.LDA treatment of 310 in THF resulted in only recovery of the starting material.Instead, pyrrolidine treatment in refluxing benzene resulted in a messy mixture which was notanalyzed further.At this stage, we realized that a mistake had been made. Compound 301 is notequivalent to 302 at all (Scheme 51) but actually identical to 313 (Figure 42). Therefore, thecyclization of 301 and 310 would not produce 303 and 311 as drawn in Scheme 51 and 52but highly stained compounds 314 and 315 (Figure 42) which have trans-fusedbicyclo[4. 1.0] heptane moieties16.314Figure 42 A Structural Misperception for 301301313 302312 315203With this consideration in mind, a new sequence was devised as shown in Scheme 53.A selective conjugate addition of the geminally diactivated cyclopropane 308 from the lesssubstituted carbon155 would generate 316 which could be cyclized to the highly functionalizedoctalone 317. The further elaboration of 317 to (-)-polygodial (7) can be readily envisaged.This new sequence has the advantages stated for that in Scheme 51 and is no doubt aworthwhile undertaking in the future.4.3. A Formal Synthesis of (+)-3-Cyperone: a ClO strategyThujonol (94)* as prepared earlier (Section 2.2.2.) was treated with concentratedhydrobromic acid in methylene chloride at room temperature for two hours. Enone 318 andphenol 319 were isolated in 85% and 10% yield respectively..CO2Me3100316 317(-)-polygodial (7)Scheme 53 The Final “seco/corro” Strategy to the Synthesis of (-)-Polygodial(7);*“Thujonol” was a mixture of x and f3 diastereomers in a ratio of 10:1. See the footnote at p. 28.204HBr+CH21The specific rotation [a] of 318 was measured to be +42 (c=0.29, CHC13). The UVspectrum displayed a broad absorption peak maximal at 234.3 nm (loge=3.95, CH3O ,c=20 mg/i), corresponding to the it to iu transition of the enone chromophore. The massspectrum indicated the molecular ion peaks at m/z 232 and 230 (intensity ratio = 1:1),corresponding to two isotopic parent ions of formulasC10H5O81BrandC10H5O79Br. TheJR spectrum showed an intense conjugated carbonyl absorption at 1670 cm1 and a weakcarbon-carbon double bond absorption at 1630 cm-1. The ‘H-NMR spectrum was wellresolved. An apparent doublet at 6 1.11 ppm (J=6.8 Hz), corresponding to the two methylgroups of the isopropyl side chain. A methyl doublet at 6 1.34 ppm (J=7.1 Hz) correspondedto the methyl at C4. A septet at 6 2.43 ppm (1H), a multiplet at 6 2.55 ppm (1H), and anothermultiplet at 62.92 ppm (2H) were assigned to the methine proton of the isopropyl side chain,the methine proton at C4, and the two methylene protons at C6. A doublet of triplets signal at6 4.19 ppm (J=4.4 and 10.2 Hz) was due to the methine proton at C5 (i.e., the brominebearing carbon) while a broad singlet at 6 5.97 ppm was clearly due to the olefinic proton atC2.c diastereomer of 94 3 diastereomer of 94Since the x diastereomer of thujonol (94) was the predominant component (—90%) of6 694 318 319205the starting material*, it was reasonable to assume that the major ring cleavage product 318(85%) had the configuration at C4 as shown. The configuration at C5 was assigned as shownby analogy with the observed nucleophilic attack on C5 from the back side of the cleaving ClC5 bond during the acid promoted ring cleavage of an analogous cyclopropylcarbinol.These two configurational assignments were supported by the ‘H-NMR spectral data.As indicated above, the methine proton at C5 appeared as doublet of triplets at 4.19 ppm withJ=4.4 for doublet and J=1O.2 Hz for triplet. This can be well understood from theconformational analysis of 318. As shown below, compound 318 have two half-chair-likeconformer 318a and 318b. Conformer 318a is the predominant one since it has both themethyl group at C4 and the bromo group at C5 equatorially oriented. The gross ‘H-NMRspectrum can be approximately represented by conformer 318a. The axial proton at C5 of318a should couple with two axial protons at C4 and C6 nearly equally (J8-13 Hz) and withthe equatorial proton at C6 relatively weakly (J3-5 Hz). We may predict with confidence thatthe methine proton at CS will appear as a triplet splitting into three doublets with J values in318a 318bR=-CH(CH3)294* See footnotes at page 28 and 204.206ranges just indicated. This is indeed the case. In fact, except the enantiomer of 318, no otherdiastereomer of 318 can explain the particular splitting pattern of the signal at 84.19 ppm.Phenol 319 is known as carvacrol164. The mass spectrum of 319 indicated themolecular ion peak at m/z 150, consistent with the formulaC10H40. The JR spectrumshowed an intense hydroxyl absorption at 3300 cm-1. The ‘H-NMR spectrum wasexceedingly simple. An apparent doublet at 6 1.22 ppm (6H, J=7.2 Hz) was assigned to thetwo methyl groups of the isopropyl side chain. A methyl singlet at 6 2.20 was due to themethyl group at C4 while a one-proton septet was assigned to the methine proton of theisopropyl side chain. A broad one-proton singlet at 63.96 ppm corresponded to the hydroxylproton. Three olefinic proton signals at 6 6.65 (1H, d, J=1.8 Hz), 6.73 (1H, dd, J=7.5 and1.8 Hz), and 7.04 (1H, d, J=7.5 Hz) corresponded to protons at C2, C6 and CS respectively.When thujonol (94) was treated with concentrated hydrochloric acid at roomtemperature, chioro-enone 320 and carvacrol (319) were isolated in 45% and 40% yieldrespectively.HC1CH2IThe mass spectrum of compound 320 revealed molecular ion peaks at m/z 188 and 186(intensity ratio 1 :3), corresponding to two isotopic parent ions of formulasC10H50371andC10H5031. The IR spectrum indicated an intense conjugated carbonyl stretching absorptionat 1675 cm-’ and a weak carbon-carbon double bond absorption at 1630 cm-’. This chioroenone was rather unstable and the obtained ‘H-NMR spectrum always contained extra signalsdue to the presence of carvacrol (319). However, a “difference spectrum” between the“contaminated spectrum” and the spectrum of 319 revealed all signals of 320 clearly. In fact,this “difference spectrum” of 320 was very similar to the spectrum of 318. An apparent694+320 319207doublet at 6 1.09 ppm (6H, J=7.2 Hz) was due to the two methyl groups of the isopropyl sidechain while a methyl doublet at 6 1.30 ppm was assigned to the methyl group at C4. A septetat 6 2.43 ppm (1H), a multiplet at 62.54 ppm (1H), and another multiplet at 6 2.78 ppm (2H)were further assigned to the methine proton of the isopropyl group, the methine proton at C4,and the two methylene protons at C6. A doublet of triplet signal at 64.06 ppm (1H, J=4.4 and9.8 Hz) corresponded to the methine proton at C5 (i.e., the chlorine bearing carbon) while abroad singlet at 6 5.95 ppm (1H) was due to the olefinic proton at C2. Based on the analysisof the splitting pattern of the CS methine proton signal in a way similar to that for 318, thestereochemistry of 320 was determined to be as shown.BrNi4i -HBr_____(iii) 319Figure 43 The Endo-type Cleavage Mechanism for the Formation of 318 and 319The mechanism in Figure 43 was proposed to explain the formation of 318 and 319.The HBr promoted ring opening through the C1-C5 bond cleavage (i.e., the endo-typecleavage) produces (i) which undergoes a double bond migration to give the more stable isomer(ii), i.e., 318 and its C4 epimer 321. The acid catalyzed enolization of (ii) generates dienol(iii) and the latter may lose a HBr molecule either through a 1,2-elimination to yield 319directly or through a 1,4-elimination to afford dienone (iv) first and then 319 later.2bOHBrHBr294 (i)Br(ii): 318/321208It is noted above that chioroenone 320, although structurally similar to bromoenone318, was much less stable. It decomposed into carvacrol (319) in deuteriated chloroform atroom temperature. This instability may account for the fact that more carvacrol (319) wasisolated from the HC1 promoted ring cleavage of thujonol (94). Both 318a and 320a, themajor half-chair-like conformers of 318 and 320, are suitable for acid catalyzed enolizationsince they all have axial protons at C4.X=Br, 318a X=Br, 318bX=Cl, 320a X=Cl, 320bR=-CH(CH3)2However, the formation of enol from 318a is likely to be more difficult because of thegreater steric interaction (allylic strain) between the more bulky equatorial bromine at C5 andthe methyl at C4 during the enolization. The relative ease of enolization for 320a allows thefollowing dehydrobromination to take place (Figure 43) and carvacrol (319) is thus morereadily converted from 320.[ IX=Br, ClR=-CH(CH3)2The endo-type cleavage pathway during the acid promoted ring opening of anotherthujone-derived cyclopropylcarbinol was again observed (Scheme 54). Hydroxyenone 122,209previously obtained from Robinson annulation of thujonol (94) with EVK in 35% yield(Section 2.2.3.), was treated with hydrobromic acid in methylene chloride. Bromo-dienone322 was isolated in 91% yield. Compound 322 has been previously reduced to (+)--cyperone (8) by tributyltin hydride in an earlier synthesis of (+)-3-cyperone from thujonel3a.Thus, a new sequence to (+)-3-cyperone was completed in four steps using ozonation ofthujone, Robinson annulation of thujonol (94), ring opening of 122, and radical-mediatedreduction of 322. The new sequence incorporates all the ten carbons of thujone into the targetmolecule (+)--cyperone (8). This synthesis provides an example ofj.Q strategy.EVK rN HBrfHKOH, EtOHTrHCH2I122BrHSnBu3MEN(+)--cyperone (8)Scheme 54 A Formal Synthesis of (+)--Cyperone (8)The specific rotation [aj5 of 322 was measured to be +420 (c=1.00, CHC13), whichis in good agreement with the reported value +430 (c=1 .0, CHC13)13a. The UV spectrumdisplayed an intense absorption peak maximal at 2. 293 nm (log =4.40, MeOH). Thus, aconjugation among the carbonyl group, the C4-C5 double bond, and the C6-C7 double bondwas suggested. The mass spectrum indicated molecular ion peaks at m/z 298 and 296(intensity ratio 1:1), corresponding to two isotopic parent ions of formulasC15H21O8BrandC15H21O79Br. The JR spectrum revealed a intense conjugated carbonyl absorption at3222101660 cm-1 and a weak carbon-carbon double bond absorption at 1620 cm1. The1H-NMRspectrum showed an apparent doublet at 6 1.12 ppm (6H, J=6.0 Hz), corresponding to the twomethyl groups of the isopropyl side chain, and two methyl singlets at 6 1.17 and 1.86 ppm,corresponding to the angular methyl group at ClO and the vinylic methyl group at C4. A one-proton doublet of doublets signal at 6 4.14 (J=6.0 and 10.0) was assigned to the methineproton at the bromine bearing carbon (C9) while a one-proton singlet at 66.31 ppm was clearlydue to the olefinic proton at C6. The particular splitting pattern of the signal at 6 4.14 ppmallowed the assignment of the configuration at C9. The molecular model of 322 revealed arather rigid conformation in order to accommodate the full conjugation of the three doublebonds. The axial proton at C9 would couple with the axial proton at C8 (usually, J=8-13 Hz)and the equatorial proton at C8 (usually, J=3-5 Hz) quite differently and a doublet of doubletswith 3 values in regions just indicated should be expected for the C9 proton signal. Thisprediction is quite close to what was observed. Compound 323, the epimer of 322 with thebromine at C9 x oriented, would show the C9 proton signal as a triplet with 3=3-5 Hz or adoublet of doublets with both 3=3-5 Hz. The slightly larger 3 value for the coupling betweenthe C9 axial proton and the C8 equatorial proton in 322 (3=6.0 Hz), than normally observedfor the coupling between an axial proton and an equatorial proton, is probably due to somegeometric distortion.The mechanism shown in Figure 44 was proposed to rationalize the formation of 322from 122, which is similar to what was proposed for the formation of 318 from thujonol (94)(Figure 43). The nucleophilic ring opening generates an unstable intermediate (i) which thenH322 323211rearranges to the more stable dienone 322 with a fully conjugated dienone system. The ringopening reaction proceeds through the cleavage of C1-C5 bond* , i.e., the endo-type cleavage.The bromide anion attacks on the C5 from the backside of the cleaving C1-C5 bond, leavingthe 13 orientation of the bromo group in (i) and thus 322.Figure 44 The Ring Opening reaction of 122 via the Endo-type Cleavage PathwayIt is speculated that the interaction of the double bond exo to the bicyclo[3. 1 .O]hexaneand the C1-C5 bond in hydroxyenone 122 and thujonol (94) leads to the weakening of C1-C5and eventually its facile cleavage under acidic conditions,A possible new way of incorporating all the ten carbons into target molecules is shownin Scheme 55. Rearrangement of vinylcyclopropanes of general structure 324 available fromozonation of thujone derivatives may provide useful intermediates of general structure 325 tosynthesis of polyquinanes which possess a bicylo[3.3.O]octane unit. It also serves as one wayto correlate two “distant carbons”: C6 and C8.Scheme 55 A Potential New £J Strategy* In order to facilitate the comparison with the ring opening of thujonol 94, the numbering of those carbons inthe bicyclo[3. 1 .Olhexane moiety in 120 is, at this point, kept the same as that in thujonol (94).Br Br I BrH—122 (i) 3221010324 325212A few polyquinanes containing such a dimethylated bicyclo[3.3.O]octane unit areknown, for example, (-)-retigeranic acid 304. In a recent total synthesis of 304, a chiralstarting material 305 of the dimethylated bicylo[3.3.O]octane unit was incorporated into thetarget molecule157 (Figure 45).0+ HI’ll’’,Figure 45 Incorporation of a Dimethylated Bicylo[3.3.O]octane unit4.4. Concluding Remarks: prospect of thujone chemistry328The abstract of this thesis summarizes the highlights on applying the ozonationmethodology into specific directions of investigation. Solutions to some remaining problemsin these directions are suggested along the presentation while some possible extensions of thepresent work are also discussed. It remains to present some reflections on the subject ofthujone chemistry as a whole.The enrichment of thujone chemistry and the enhancement of its versatility as a chiralstarting material for the synthesis of biologically active natural products depend largely on theaccumulation of fundamental knowledge about this unique entity in structurally diverseenvironments.HHO2C326 327CO2Et213The ozonation of thujone and its derivatives allowed a novel functionalization of thesemolecules and opened the door to apply the cyclopropane chemistry on a different level in thelast few years. This kind of carbon-hydrogen bond functionalization may be realized throughother more recently developed reagents’591’, for example, dioxyranel59 and should beexplored in the future. Functionalization of other positions in the thujone framework should beconsidered too.Ring expansion or contraction of thujone may provide interesting new avenues ofthujone chemistry with regard to cyclopropane ring opening control and carbocyclic ringincorporation.The Robinson annulation of thujone is regioselective and stereoselective due to thesubstitution pattern of the thujone frame work and the particular geometry of thebicyclo[3.1.O]hexane unit. Annulations of opposite or complementary regioselectivity andstereoselectivity will enhance the versatility of thujone as a chiral building block. The 6-membered ring annulation may be changed to annulations forming other ring sizes, forexample, 5-membered and 4-membered rings when suitable new target molecules are chosen.Bridged and spiral annulations should be subjected to similar studies when needed.The degree of carbon incorporation may guide the planning in a more thorough andsystematic manner. The seco and corro operations reveal an inherent connectivity of thethujone skeleton and allow novel chemistry to unfold. This may provide some novel solutionsto difficult problems, for example, the direct creation of 6,6-A/B trans ring fusion. Abstractionof such formal operations from synthetic studies is intellectually inspiring and may findapplications somewhere else*.As stated in Section 1.1. of Chapter 1 (General Introduction), the often tedious andlengthy process to prepare an intermediate, the racemate of which could be synthesized in asimple manner, is a serious drawback of using chiral building block. To avoid this problem,* For relevant discussion on general problem solving techniques, see ref. 156, under “Can you use the result?”.214such simple intermediates possibly derived from chiral building blocks should not beconsidered favorably. Highly functionalized intermediates, like functionalized cyclopropanes,cyclopentanes, cyclohexanes, and bicyclo systems like decalones, indenone, pentalenones areto be chosen as sub-goals early in the planning stage.There are other versatile chiral starting materials in use, for example, camphor and Dglucose. Applications of D-glucose and other simple sugars have been numerous and providethe major basis for a systematic analysis of some synthetic problems, the so-called “chiron”approach’60. Since sugars are highly functionalized molecules, the application of themfrequently requires the removal of functional groups, a feature contrasting very much toOHD-glucose (pyranose)the application of terpenes as starting materials. The camphor has been established as a veryversatile chiral starting material*161. Comparison of thujone and the camphor chemistry willreveal some important elements responsible for their own effectiveness as chiral buildingblock. The cross fertilization from the chemistry of camphor and other monoterpenes willcertainly stimulate the chemistry of thujone.Different from camphor, thujone has not been employed as a chiral auxiliary so far.The diastereomeric impurity of thujone and unavailability of its enantiomer can attenuate itsusefulness in this regard. However, derivatization of the diastereomeric mixture by convertingthe C4 chiral center into a trigonal center or into a quartery center may providediastereomerically pure thujone derivatives useful as chiral auxiliaries.* We would like to thank Dr. T. Money for providing his newest review on this subject for our reference.HOcamphor2154.5. ExperimentalSee Section 2.3.1. for General experimental.4.5.1. Ring Expansion: thujone (3) to ketoester 270[1 R-( 1 x,2a/I3,6c)] 4-Ethoxycarbonyl-2-methyl-6-( 1 -methylethyl)bicyclo[4. 1 .0]heptan-3-one(270, the ketoester form)[1 R-( 1 cc,2a/f3,6x)] 4-Ethoxycarbonyl-2-methyl-6-( 1 -methylethyl)bicyclo[4. 1 .0]hept-3-ene-3-ol (270, the enolester form)To a cooled solution (0°C) of thujone (3) (3.04 g, 20.0 mmol) and boron trifluorideetherate (4.26 g, 30.0 mmol) in anhydrous diethyl ether (25 ml), ethyl diazoacetate (3.42 g,30.0 mmol) in anhydrous diethyl ether (5 ml) was added dropwise over a period of 30minutes. The resulting solution was stirred under nitrogen at room temperature overnight,made basic with saturated aqueous sodium carbonate solution, and extracted with diethyl ether.The diethyl ether solution was washed with brine, dried over magnesium sulfate, andconcentrated in vacuo. Column chromatography of the crude product with ethylacetate:hexanes (1:30, v/v) mixture produced 13-ketoester 270 in 70% yield (3.34 g).The physical properties of 270 are as follows*:UV (MeOH, c=20.4 mg/I) max.: 258 nm (log e=3.980).* All data were taken from spectra of the mixture of a and 1 diastereomers (9:1 from GC). The1H-NMRspectral signals should be those of the predominant a diastereomer since these signals can be easily selected bycomparing the integrations. The1H-NMR spectral signals of the minor f3 diastereomer were hardly observablefrom the spectrum. See foots at p. 178 and 180.216JR (film) vmax.: 3370 (0-H stretching), 1655(C=0 stretching), 1615 (C=C stretching) cm-1.1HNMR (400 MHz, CDC13)& 0.30 (1H, dd, J=4.4 and 8.8 Hz), 0.39 (1H, t, J=4.4 Hz),0.68 (1H, dd, J=4.4 and 8.8 Hz), 0.98 (6H, two overlapped doublets, J=5.6 and 4.4 Hz),1.03 (1H, m), 1.24 (3H, d, J=7.2 Hz), 1.31 (3H, t, J=6.8 Hz), 2.25-2.57 (2H, AB type,J=16 Hz), 2.64 (1H, q, J=7.2 Hz), 4.21 (2H, m), 12.24 (1H, s).MS m/z: 238 (M, 35.0%), 192 (79.7%), 177 (66.4%), 149 (100.0%). High resolutionmass measurement calculated forC14H2203:238.1569; found: 238.1570.4.5.2. Decarboxylation: ketoester 270 to homothujone (272)[1 R-( 1 2a/f3,6c)] 2-Methyl-6-( 1 -methylethyl)bicyclo[4. 1 .0]heptan-3-one (272)I..—...272To ketoester 270 (2.70 g, 11.3 mmol) in DMSO (20 ml) was added sodium chloride(1.20 g, 20.9 mmol) and water (1.0 ml). The resulting mixture was refluxed at 140°C for 4hours, cooled down, diluted with water (40 ml), and extracted with diethyl ether (3X25 ml).The ether solution was dried over magnesium sulfate and concentrated in vacuo to give a crudeproduct which was chromatographed with ethyl acetate:hexanes (1:8, v/v) mixture.Homothujone 272 was obtained in 96% yield (1.80 g).The physical properties of 272 are as follows*:JR (film) vmax.: 3060, 1700 cm-1.‘H-NMR (400 MHz, CDC13) 6: 0.50 (2H, m), 0.72 (1H, m), 0.95 (3H, d, J=6.4 Hz), 0.98* All data were taken from spectra of the mixture of a and f diastereomers (9:1 from GC). The1H-NMRspectral signals should be those of the predominant a diastereomer since these signals can be easily selected bycomparing the integrations. The1H-NMR spectral signals of the minor f3 diastereomer were hardly observablefrom the spectrum. See also foots at p. 178 and 180.217(3H, d, J=6.4 Hz), 1.06 (1H, m), 1.22 (3H, d, J=8.0 Hz), 1.84 (1H, m), 2.10 (2H, m), 2.35(1H, m), 2.47 (1H, m).MS m/z: 166 (M, 18.3%), 123 (29.7%), 109 (58.0%), 96 (91.2%), 41 (100.0%). Highresolution mass measurement calculated forC11H8O: 166.1358; found: 166.1360.4.5.3. Robinson Annutation: homothujone (272) to enone 274[1 aR-( 1 ax,7a13,7bx)J 1,1 a,2,3 ,6,7,7a,7b-Octahydro-4,7a-dimethyl- 1 a-( 1 -methylethyl)-5H-cyclopropa[ajnaphthalen-5-one (274)274Homothujone 272 (341 mg, 2.05 mmol) was mixed with 1-diethylamino-3-pentanone-ioclomethane salt (675 mg, 2.26 mmol) in anhydrous ethanol (20 ml) under an atmosphere ofnitrogen. After the addition of potassium hydroxide (184 mg, —80% putre, 2.57 mmol), thereaction mixture was heated to reflux for 1 hour, cooled down, and diluted with water (30 ml).Petroleum ether (2x20 ml) was used to extract the above aqueous mixture. Concentration ofthe combined petroleum ether solution in vacuo furnished an oil which was chromatographedto provide 274 in 70% yield (332 mg).The physical properties of 274 are as follows:[a]t=+1.94X102 (c=1.00, CHC13).UV (MeOH, c=20.0 mg/I) max.: 250 nm ((log e=4.133).JR (film) vmax.: 3060, 1660, 1620 cm-’.‘H-NMR (400 MHz, CDC13)& 0.30 (1H, dd, J=4.8 and 9.6 Hz), 0.50 (1H, dd, 3=4.8 and9.6 Hz), 0.66 (1H, t, J=4.8 Hz), 0.90 (3F1, d, J=7.2 Hz), 0.93 (3H, d, J=7.2 Hz), 1.01 (1H,218m), 1.16 (3H, s), 1.58 (2H, m), 1.74 (3H, s), 1.82 (1H, m), 1.93 (1H, m), 2.12 (1H, dt,J=5.2 and 14.0 Hz), 2.35-2.70 (3H, m).MS m/z: 232 (M, 57.2%), 217 (18.3%), 189 (60.1%), 161 (100.0%). High resolutionmass measurement calculated forC16H24O: 232.1827; found: 232.2819.Elemental analysis: calc. forC16F1240: C 82.70, H 10.41; found: 82.58, H 10.44.4.5.4. Birch Reduction-CH3ITrapping and Birch Reduction-TMSCI Trapping-Simmons-Smith Reaction-Hydrolysis Sequences: enone 274 to ketone 277[1 aR-( 1 7af,7bc)] Decahydro-4,4,7a-trimethyl- 1 a-( 1 -methylethyl)-5H-cyclopropa[a}naphthalen-5-one (277)cyt277MethodA:Ammonia was distilled from sodium to a flask charged with enone 274 (419 mg, 1.81mmol) under nitrogen. Pieces of lithium metal (13.8 mg, 1.99 mmol, 1.1 eqv.) were addedand the resulting dark purple solution was stirred at -33°C for 1 hour before iodomethane (1.3ml) and anhydrous diethyl ether (5.0 ml) were introduced. The dry ice-acetone condenser wasremoved to allow ammonia to evaporate. The reaction mixture was stirred overnight andtransferred to a separatory funnel containing water (15 ml) and ether (20 ml). The ether layerwas separated, washed with brine (10 ml), dried over magnesium sulfate. Evaporation ofdiethyl ether in vacuo resulted in a yellowish oil which was chromatographed first with ethylacetate:hexanes (1:15, v/v) and then benzene to furnish ketone 277 in 15% yield (63 mg).219Method B:Ammonia (—20 ml) was distilled from sodium to a solution of enone 274 (1.10 g, 4.74mmol) in anhydrous ether (10 ml) under nitrogen. Lithium (35 mg, 4.98 mmol,1.05 eqv.)was added. The dark purple mixture was stirred for 1.5 hours at -33°C before freshly distilledtrimethylsilyl chloride (1.20 ml, 2.0 eqv.) was injected. The resulting yellowish solution waswarmed to room temperature and stirred for 1 hour. Evaporation of ammonia and ether gave ayellowish crude oil.Anhydrous ether (10.0 ml) was introduced to the above crude product. Half of thesolution (—5.0 ml) thus prepared was transferred to a new dry flask. Zinc-copper couple(powder, 314 mg) and distilled diiodomethane (0.80 ml) were added and the greyish mixturewas refluxed overnight. Filtration through a layer of Celite afforded an ether solution whichwas condensed to a colorless oil.This oil was then dissolved in methanol (10 ml). After introduction of potassiumhydroxide (100 mg, —80% pure, 1.78 mmol), the solution was refluxed 1 hour and cooleddown. Evaporation of solvent in vacuo and repeated column chromatography with ethylacetate:hexanes (1:8, v/v) mixture yielded 277 in 45% (262 mg).The physical properties of 277 are as follows:[a]=-8.3 (c=0.42, CHC13).JR (film) Vmax.: 1703 cm1 (C=O stretching).‘H-NMR (400 MHz, CDC13) 6: 0.08 (1H, m), 0.35 (2H, m), 0.70-1.55 {20H, including0.85 (6H, t, J=2.4 Hz), 1.04 (3H, s), 1.21 (3H, s), 1.22 (3H, s)}, 1.70 (1H, m), 1.85 (1H,m), 2.30 (2H, m), 2.62 (1H, m).MS m/z: 248 (M, 18.6%), 230 (12.0%), 205 (27.2%), 41(100.0%). High resolution massmeasurement calculated forC17H280: 248.2140; found: 248.2135.2204.5.5. Catalytic Hydrogenation: enone 274 to ketone 278[1 aR-( 1 7a,7bc)] Decahydro-4,7a-dimethyl- 1 a-( 1 -methylethyl)-5H-cyclopropa[aJnaphthalen-5-one (278)Method A:Ammonia (5 ml) was distilled from sodium to a flask containing 274 (151 mg, 0.500mmol) in anhydrous ether (3.0 ml) under an atmosphere of nitrogen. While the flask was keptat -33°C, small pieces of lithium were added slowly for about 1 hour until a blue colorpersisted. After further stirring for 30 minutes, ammonium chloride was added to destroyexcess lithium and ammonia was evaporated during warming up to room temperature.Concentration of the reaction mixture gave an oil which was chromatographed with ethylacetate:hexanes (1:8, v/v) mixture to give a mixture of 278 and 279 (124 mg, 82%) of at aratio 4.3:1 as indicated by GC.Method B:The solution of enone 274 (368 mg, 1.59 mmol) in ethanol (15.9 ml) was mixed with10% palladium-charcoal catalyst (85 mg). The mixture was charged with 1 atm hydrogen atroom temperature and stirred for 2 hours. Filtration through a layer of Celite gave a colorlesssolution which was then concentrated in vacuo. A mixture of 278 and 279 at a ratio 6:1 asshown from GC were thus obtained (350 mg, 95% yield).278221The physical properties of 278 are as follows:*JR (film) vmax.: 1705 cm’ (C=O stretching).‘H-NMR (400 MHz, CDC13) 6: 0.09 (1H, t, J=5.2 Hz), 0.40 (2H, m), 0.85 (3H, d, J=6.0Hz), 0.88 (3H, d, J=6.0 Hz), 0.93 (3H, J=8.0 Hz), 1.45 (3H, s), 1.73 (1H, m), 1.87 (1H,m), 2.24 (2H, m), 2.50 (1H, m), 2.89 (1H, m).MS m/z: 234 (M, 30.6%), 219 (16.3%), 191 (20.2%), 41 (100.0%). High resolution massmeasurement: calculated forC16H20: 234.1984; found: 234.1980.4.5.6. Methylation: c,I3-enone 274 to 13,y-enone 282[1 aS-( 1 x,7a3,7ba)] 1,1 a,2,4,6,7 ,7a,7b-Octahydro-4,4,7a-trimethyl- 1 a- (1 -methylethyl)-5H-cyclopropa[ajnaphthalen-5-one (282)To the solution of enone 274 (109 mg, 0.470 mmol) in anhydrous DMSO (5.0 ml)was added sodium methoxide (55 mg, 1.0 mmol, 2.1 eqv.) under nitrogen. After the mixturewas stirred for 5 hours, iodomethane (100 p1, 1.61 mmol, 4.0 eqv.) was injected. Stirringcontinued for another 3 hours. The reaction mixture was poured to a funnel containing 20 mlwater. The aqueous mixture was extracted with hexanes (2X15ml). After drying overmagnesium sulfate, evaporation of solvent in vacuo, and chromatography with ethyl* All data were taken for the spectra of the mixture. The1H-NMR spectral signals were those of thepredominant diastereomer 278 since they can be easily selected by comparing the integrations while the 1H.NMR spectral signals of 279 were difficult to observe from the spectrum. See also footnotes at p. 178 and180.282222acetate:hexanes (1:8, v/v) mixture, ketone 282 was obtained (62 mg, 60 % yield based on10% recovery of starting material).The physical properties of 282 are as follows:JR (film) vmax.: 1700 cm-1‘H-NMR (400 MHz, CDC13) 8: 0.20 (1H, t, 3=4.0 Hz), 0.39 (1H, dd, J=4.0 and 10.0 Hz),0.58 (1H, dd, J=4.0 and 10.0 Hz), 0.80-1.40 { 16 H, m, including 0.94 (6H, d, J=6.0 Hz),1.01 (3H, s), 1.18 (3H, s), 1.20 (3H, s)}, 1.84 (1H, m), 1.98 (1H, m), 2.14-2.35 (2H, m),2.38-2.65 (2H, m), 5.41 (1H, t, 3=4.0 Hz).MS m/z: 246 (M, 36.4%), 231 (42.1%), 218 (5.9%), 203 (50.2%), 105 (100.0%).4.5.7. WoIf-Kishner-Huang Minion Reaction: f3,y-enone 282 to alkene 283[1 aS-( 1 cc7aI3,7bct)] 1 a,2,4,5 ,6,7 ,7a,7b-Octahydro-4,4,7a-trimethyl- 1 a-( 1 -methylethyl)- 1H-cyclopropa[ajnaphthalene (283)283To the mixture of ketone 282 (500 mg, 2.03 mmol) in diethylene glycol (10 ml) wasadded potassium hydroxide (422 mg, —80% pure, 6.02 mmol) and hydrazine hydrate (300 tl,6.18 mmol) under nitrogen. After refluxing at 100-150°C for 1 hour, water and excesshydrazine hydrate were distilled away through a Dean-Stark trap until the temperature reached250°C. Further refluxing at 200°C continued for 4 hours. The reaction mixture was thencooled to room temperature and and diluted with water (20 ml). The aqueous mixture wasextracted with petroleum ether (3x 10 ml). Evaporation of solvent in vacuo and columnchromatograghy with petroleum ether afforded 283 (316 mg, 67%).223The physical properties of 283 are as follows:JR (film) vmax.: 3050 cm-1 (C-H stretching).1H-NMR (400 MHz, CDC13) 6: 0.15 (1H, m), 0.40 (2H, m), 0.87 (6H, d, J=6.0 Hz), 1.05(3H, s), 1.09 (3H, s), 1.16 (3H, S), 5.30 (1H, t, 3=4.0 H).MS m/z: 232 (Mt 53.4%), 217 (39.3%), 204 (6.7 %), 189 (62.1%), 105 (100.0%).4.5.8. Hydroboration: alkene 283 to diol 285 and alcohol 286[1 S-( 1 a,213,3cx,4aa,8aa)J Decahydro-3-hydroxy-5,5,8a-trimethyl-2-( 1 -methylethyl)naphthalenemethanol (285)[1 aS-( 1 3f,3a3,7af3,7bc)} Decahydro-4,4,7a-Trimethyl- 1 a-( 1 -methylethyl)-3H-cyclopropa[a]naphthalen-3-ol (286)OH285 286To the solution of 283 (100 mg, 0.43 mmol) in THF (5.0 ml) at 0°C under nitrogenwas added borane (0.35 M in THE, 1.0 ml) in a dropwise manner. The resulting mixture wasstirred for 5 hours at room temperature and cooled to 0°C again. Aqueous sodium hydroxidesolution (3.0 M, 1.0 ml) and hydrogen peroxide solution (aq., 30%, 1.0 ml) were addedslowly. The resulting two-phased mixture was warmed to room temperature, stirred for 2hours, and saturated with sodium chloride. The THF layer was separated and the aqueouslayer was extracted with ether (5 ml). The organic layers were combined and concentrated invacuo. Column chromatography of the crude product with ethyl acetate:hexanes mixture (1:8first and then 3:7, v/v) generated 285 (45 mg, 39%) and 286 (31 mg, 29%).The physical properties of 285 are as follows:224m.p.=136-138°C.[a]=+23 (c=0.84, CHC13).JR (film) vmax.: 3500 (0-H stretching) cm1.‘H-NMR (400 MHz, CDC13) & 0.90-1.80 {26H, 0.96 (3H, s), 0.98 (3H, s), 1.00 (3H, s),1.01 (3H, d, J=7.0), 1.15 (3H, d, J=7.0)}, 1.97 (2H, m), 2.18 (1H, m), 3.72 (2H, m), 4.04(1H, m).MS m/z: 250 (M-H2, 1.2%), 235 (3.1%), 232 (1.7%), 123 (100%). High resolution massmeasurement calculated forC17H3202268.2402; found: 268.2215. Chemical ionizationMS (using NH3 as carrier gas) mlz: 286 (M+NH), 269 (M+Hj.Elemental Analysis: calculated forC17H3202:C 76.06, H 12.02; found: C 76.26, H 12.02.The physical properties of 286 are as follows:[x]=+13 (c=0.50, CHC13).JR (film) vmax.: 3400(0-H stretching), 3060 (cyclopropane C-H stretching) cm1.1H-NMR (400 MHz, CDC13) & 0.14 (1H, dd, J=4.4 and 8.8 Hz), 0.45 (lH, dd, J=4.4 and8.8 Hz), 0.64 (1H, t, J=4.4 Hz), 0.85 (3H, d, J=6.0 Hz), 0.90 (3H, d, 3=6.0 Hz), 0.98 (3H,s), 1.10 (3H, s), 1.16 (3H, s), 2.14 (JH, dd, J=7.5 and 15.0), 3.87 (1H, m).MS m/z: 250 (M, 2.1%), 232 (10.5%), 217 (12.8%), 207 (10.6%), 109 (100.0%). Highresolution mass measurement: calculated forC17H300: 250.2297; found: 250.2307.4.5.9. Oxidation by Jones Reagent: alcohol 286 to ketone 287[1 aS-( I a,3a13,7aI3,7bc)] Decahydro-4,4,7a-trimethyl- 1 a- (1 -methylethyl)-311-cyclopropa[a]naphthalen-3-one (287)287225To the solution of alcohol 286 (20 mg, 0.080 mmol) in acetone (2.5 ml) was addedJones reagent (12M Cr03 in concentrated sulfuric acid) in a dropwise manner until the mixturechanged to a steady orange color. Water (10 ml) was added and the aqueous mixture wasextracted with hexanes (2x5 ml). Evaporation of solvent in vacuo and column chromatographywith ethyl acetate:hexanes (1:8, v/v) mixture afforded 287 (16 mg, 80%).The physical properties of 287 are as follows:JR (film) vmax.: 1700 cm-1.‘H-NMR (400 MHz, C6D)8: 0.18 (2H, m), 0.53 (1H, m), 0.65 (3H, d, J=7.2 Hz), 0.90(3H, d, J=7.2 Hz), 0.97 (3H, s), 1.01 (3H, s), 1.19 (3H, s), 2.29 (2H, AB type, J=16.0Hz).MS m/z: 248 (M, 10.6 %), 233 (2.8%), 205 (5.2%), 177 (9.6%), 109 (100.0%).4.5.10. 0-Methylation: ketone 278/279 to methyl enol ether 280[laR-( 1 a,7aI3,7bc)J 1 a,2,3,3a,6,7,7a,7b-Octahydro-4,7a-dimethyl- 1 a-( 1 -methylethyl)-5-methoxyl- 1H-cyclopropra[a]naphthalene (280)280Ketone 278/279 (6:1, 200 mg, 0.855 mmol), obtained from palladium-charcoalcatalyzed hydrogenation of 274, was treated with sodium hydride (70 mg, 2.0 eqv., 60% inmineral oil) in anhydrous DMSO (5.0 ml) under nitrogen at room temperature for 1 hour.Freshly distilled iodomethane (106 p.1, 1.71 mmol, 2.0 eqv.) was added rapidly and theresulting mixture was stirred for another 1 hour. The reaction mixture was then poured towater (20 ml) and the aqueous mixture was extracted with hexanes (2X15ml). Evaporation of226hexanes in vacuo and column chromatography with ethyl acetate:hexanes (1:8, v/v) mixturegave 280 (91 mg, 54% based on recovery of starting material) and starting material 278/279(42 mg).The physical properties of 280 are as follows:JR (film) vmax.: 3050, 1680 (C=C stretching) cm1.lH4sMR (400 MHz, CDC13)& 0.08 (1H, m), 0.30 (2H, m), 0.70-1.70 {(22H, m,including 0.87 (6H, t, J=6.0 Hz), 0.95 (3H, s), 1.60 (3H, s)}, 3.47 (3H, s).MS m/z: 248 (M, 40.2%), 233 (8.4%), 216 (2.9%), 137 (90.2%), 41(100.0%).4.5.11. WoIf-Kishner-Huang Minion Reaction: ketone 277 to Alkane 291[1 aR-( 1 a,7a3,7bcL)] Decadydro-4,4,7a-thmethyl- la-( 1 -methylethyl)- 1H-cyclopropa[a]naphthalene (291)Ketone 277 (250 mg, 1.01 mmol) in diethylene glycol (20 ml) was treated withpotassium hydroxide (370 mg, 5.28 mmol) and hydrazine monohydrate (270 p.1, 5.56 mmol).The mixture was heated at 100-150°C for 1.5 hours under nitrogen. The temperature was thengradually raised up to 220°C to distill away water and excess hydrazine over a period of 1.5hours. Refluxing continued at 210°C for 4 hours. The mixture was cooled down, diluted withwater, and extracted with petroleum ether (3X20 ml). Evaporation of the solvent in vacuo gavea brown oil which was chromatographed with petroleum ether through a short column to yield291 as a colorless oil (175 mg, 75%).The physical properties of 291 are as follows:JR (film) vmax.: 3050 (cyclopropane C-H stretching) cm1.2912271H-NMR (400 MHz, CDC13)6: 0.07 (1H, m), 0.40 (2H, m), 0.84 (6H, t, J=3.0 Hz), 1.10(3H, s), 1.20 (3H, s), 1.22 (3H, s).MS m/z: 234 (M, 2.7%), 219 (4.5%), 191 (11.0%), 43 (100.0%). High resolution massmeasurement: calculated forC17H30: 234.2348; found: 234.2358.4.5.12. Ozonation: alkane 291 to ketone 292 and alcohol 293[1 aS-( 1 a,7a13,7bx)] 1,1 a,3,3a,4,5,6,7,7a,7b-Decahydro-4,4,7a-trimethyl-1 a-(1 -methylethyl)-2H-cyclopropra[a]naphthalen-2-one (292)[1 aS-( 1 cz,7a13,7ba)] 1,1 a,3,3a,4,5,6,7,7a,7b-Decahydro-4,4,7a-trimethyl- 1 a-( 1 -methylethyl)-2H-cyclopropra[a]naphthalen-2-ol (293)ccI292 293A stream of ozone-oxygen gas was passed through the solution of 291 (200 mg, 0.855mmol) in ethyl acetate (10.0 ml) at -40°C for 7 hours. Oxygen was passed through thesolution for 15 minutes to remove the residual ozone in the solution. The reaction mixture wasthen treated with dimethyl sulfide (0.5 ml), extracted with water (10 ml), and 10% aqueoussodium bicarbonate solution (10 ml). Removal of solvent in vacuo and chromatography of thecrude product with ethyl acetate:hexanes (2:8, v/v) mixture provided ketone 292 (74 mg, 35%)and alcohol 293 (10 mg, 5%).The physical properties of 292 are as follows:IR (film) vmax.: 1665 (C=O stretching) cm1.1H4JMR (400 MHz, CDC13)6: 0.75-1.35 (23H, m, including 0.78 (3H, s), 0.84 (3H, d,J=6.6 Hz), 0.97 (3H, d, J=6.6 Hz), 1.11 (3H, s), 1.30 (3H, s)}, 1.47 (1H, m), 1.63 (1H,228m), 1.84 (1H, septet, J=6.6 Hz), 2.00-2.30 (2H, m).MS m/z: 248 (M, 18.4%), 233 (15.2%), 205 (23.2%), 177 (42.3%), 41(100.0%). Highresolution mass measurement: calculated forC17H280: 248.2140; found: 248.2135.The physical properties of 293 are as follows:1R (film) Vmax.: 3405 cm’ (0-H stretching).‘H-NMR (400 MHz, CDC13)6: 0.13 (1H, m), 0.45 (2H, m), 0.86 (3H, s), 0.89 (3H, d,J=6.0 Hz), 0.98 (3H, d, J=6.0 Hz), 1.10 (3H, s), 1.20 (3H, s), 4.16 (1H, m).MS m/z: 250(M, 0.8%), 232 (5.3%), 217 (4.5%), 43 (100.0%). High resolution massmeasurement: calculated forC17H300: 250.2297; found: 250.2301.4.5.13. Ketoacid 308[1 S,2R, 1 ‘(2)R] 2- (2’-oxo- 1 ‘,3’,3’-trimethylcyclohexyl)cyclopropaneformic acid (308)oco(308The physical properties of 308, which was provided by Dr. Dominik Guggisberg areas follows:m.p.: 88-90°C.[x]=-4.9 (c=1.00, CHC13).JR (film) vmax.: 2300-3650 (0-H stretching), 1685 (C=0 stretching), 1645 (carboxylic acidgroup’s C=0 stretching) cm1.‘H-NMR (400 MHz, CDC13)6: 0.62 (1H, dd, J=5.6 and 8.8 Hz), 0.85-1.30 (19H,including 0.93 (1H, t, J=8.8)}, 1.60-1.95 (6H, m).MS m/z: 266 (M, 21.0%), 251 (4.9%), 238 (3.0%), 220 (15.0%), 205 (10.8%), 195229(3.3%), 109 (100.0%). High resolution mass measurement: calculated forC16H203:266.1881; found: 266.1874.4.5.14. Methylation by Diazomethane: ketoacid 308 to ketoester 309[2R, 1 ‘(2)R,2’(2)S] 2- [2-( 1-Methylethyl))-2-(methoxycarbonyl)Jcyclopropyl-2,6,6,-trimethylcyclohexanone (309)oco2X309To the solution of 308 (500 mg, 1.88 mmol) in anhydrous diethyl ether (10.0 ml) at0°C was added 0.35M diazomethane-diethyl ether solution (6.0 ml, 2.1 mmol) in a dropwisemanner. The resulting mixture was stirred at room temperature for 2 hours. Solvent removalin vacuo and column chromatography with diethyl ether:hexanes (2:8, v/v) yielded ketoester309 (501 mg, 95% yield).The physical properties of 309 are as follows:IR (film) vmax. 2960 (C-H stretching), 1710 (C=O stretching), 1685 (CO stretching) cm1.‘H-NMR (400 MHz, CDC13)& 0.67 (1H, dd, J=4.8 and 9.6 Hz), 0.92 (3H, d, J=7.2 Hz),1.07 (3H, d, J=7.2 Hz), 1.11 (3H, s), 1.13 (3H, s), 1.17-1.82 {12H, m, including 1.20 (3H,s)}, 3.65 (3H, s).MS m/z: 280 (M, 13.1%), 265 (2.3%), 248 (3.7%), 233 (2.4%), 220 (14.9%), 205(10.0%), 177 (11.8%), 69 (100.0%). High resolution mass measurement: calculated forC161203:280.2038; found: 280.2035.4.5.15. Ozonation: ketoester 309 to compound 310[2R, 1 ‘(2)R,2’(2)R] 2- [2-Acetyl-2-(methoxycarbonyl)]cyclopropyl-2,6,6,-trimethylcyclohexanone (310)230310The solution of ketoester 309 (241 mg, 0.861 mmol) in ethyl acetate (20 ml) wascooled to 0°C and passed with ozone-oxygen stream through a gas dispersion tube for 6 hours.The stream of oxygen was passed for 15 minutes to remove excess ozone. Dimethyl sulfide(0.5 ml) was added and the resulting mixture was stirred for 10 minutes at room temperature,extracted with water (10 ml), 10% aqueous sodium bicarbonate solution (2x10 ml), dried overmagnesium sulfate, and concentrated in vacuo. The crude product was purified by columnchromatography (petroleum ether:ether 8:2, v/v) to give 310 (63 mg, 45% based on recoveryof starting material) in addition to the starting material 309 (101 mg, 42%).The physical properties of 310 are as follows:IR (film) vmax.: 1725, 1690 cm1.1H-NMR (400 MHz, CDC13) & 1.08 (3H, s), 1.10 (6H, bs), 1.34 (1H, dd, 3=4.7 and 9.0Hz), 1.50-2.05 (9H, m), 2.10 (1H, t, J=9.0 Hz), 2.28 (3H, s), 3.76 (3H, s).MS m/z: 280 (M, 0.5%), 262 (2.9%), 252 (4.8%), 43 (100.0%). High resolution massmeasurement: calculated forC16H2404:280.1675; found: 280.1675.4.5.16. Cyclopropane Ring Opening Reaction: thujonol (94) to bromoenone318 and carvacrol (319)[2R,3S] 3-Bromo-2-methyl-5-( 1 -methylethyl)cyclohex-5-en- 1-one (318)2-Methyl-5-( 1 -methylethyl)phenol (319)231x5 HJCy318 319Thujonol (94) (600 mg, 3.57 mmol) in methylene chloride (25 ml) was stirred withconcentrated 48% hydrobromic acid (25 ml) for 1.5 hours at room temperature. The organiclayer was separated, dried over magnesium sulfate, and concentrated in vacuo. The crudeproduct was purified by column chromatography using ethyl acetate:hexanes (1:15, v/v)mixture to provide bromoenone 318 (700 mg, 85%) and carvacrol (319) (51 mg, 10%).The physical properties of 318 are as follows:[a]=+42 (c=0.29, CHC13).UV (MeOH, c=20 mg/I) ?max.: 234 nm (log E=3.95)IR (film) Vmax.: 1670 (C=0 stretching), 1630 (C=C stretching).1HNMR (400 MHz, CDC13)ö: 1.11 (6H, d, J=6.8 Hz), 1.34 (3H, d, J=7.1 Hz), 2.43 (1H,septet, J=6.8 Hz), 2.55 (1H, m), 4.19 (1H, dt, J=4.4 and 10.2 Hz), 5.97 (1H, bs).MS m/z: 232/230 (M, 1.1%/1.3%), 151 (100.0%), 135 (33.6%), 123 (60.2%). Highresolution mass measurement: calculated forC10H5O81BrandC15HO79Br: 232.0287 and230.0130; found: 232.0280 and 230.0116.The physical properties of 319 are as follows:IR (film) vmax.: 3400 (0-H stretching) cm1.1144MR (400 MHz, CDC13) ö: 1.22 (6H, d, J=6.6 Hz), 2.21 (3H, s), 2.82 (1H, septet,3=6.6 Hz), 3.96 (1H, bs), 6.66 (1H, d, 3=1.8 Hz), 6.72 (1H, dd, J=1.8 and 7.1), 7.04 (1H,d, J=7.1 Hz).MS m/z: 150 (M, 35.5%), 135 (100.0%), 107 (15.6%). High resolution massmeasurement: calculated forC10H40: 150.1045; found: 150.105 1.2324.5.17. Cyclopropane Ring Opening Reaction: thujonol (94) to chioroenone320 and carvacrol (319)[2R,3S1 3-Chloro-2-methyl-5-( 1 -methylethyl)cyclohex-5-en- 1-one (320)Thujonol (94) (500 mg, 2.98 mmol) was treated with concentrated 35—36%hydrochloric acid (25 ml) in methylene chloride (25 ml) at room temperature for 1.5 hours.The methylene chloride solution was separated, dried over magnesium sulfate, andconcentrated in vacuo. Column chromatography with ethyl acetate:hexanes (1:20, v/v) providechloro-enone 320 (252 mg, 45%) and carvacrol (319) (177 mg, 40%).The physical properties of 320 are as follows:IR (film) vmax.: 1675 (C=O stretching), 1630 (C=C stretching) cm1.‘H-NMR (400 M}lz, CDC13)& 1.09 (6H, d, J=7.2 Hz), 1.30 (3H, d, J=7.8 Hz), 2.43 (1H,septet, J=7.2 Hz), 2.54 (1H, m), 2.78 (2H, m), 4.06 (1H, dt, 1=4.4 and 9.8 Hz), 5.95 (1H,bs) ppm.MS m/z: 188/186 (M, 5.8%/19.1%), 151 (100.0%), 135 (15.9%).4.5.18. Cyclopropane Ring Opening Reaction: hydroxyenone 122 tobromodienone 322[4aS-(4acz,5a)] 5-Bromo-2,3,3a,4,5,6-hexahydro- 1 ,4a-dimethyl-( 1 -methylethyl) naphthalen2(3H)-one (322)233322Hydroxyl-enone 122 (39 mg, 0.17 mmol) in methylene chloride (5 ml) was stirredwith concentrated 48% hydrobromic acid (5 ml) at room temperature for 3 hours. Themethylene chloride layer was separated and the aqueous layer was extracted with methylenechloride (5 ml). The combined methylene chloride solution was dried over magnesium sulfateand concentrated in vacuo. Column chromatography of the crude product afforded bromodienone 322 (45 mg, 9 1%).The physical properties of 322 are as follows:[a]=+42O (c=1.00, CHC13).UV (MeOH, c=20 mg/i) max.: 293 nm (log E4.40)JR (film) vmax.: 1660 (C=O stretching), 1620 (C=C stretching) cm1.‘H-NMR (400 MHz, CDC13)ö: 1.12 (6H, d, J=6.0 Hz), 1.17 (3H, s), 1.86 (3H, s), 2.00-2.90 (7H, m), 4.14 (JH, dd, J=6.0 and 10.0 Hz), 6.31 (1H, s).MS m/z: 298/296 (M, 80.0%/88.5%), 217 (100.0%), 175 (56.3%). High resolution massmeasurement: calculated forC15H21O79Br: 296.0775; found: 296.0768.234BibliographyChapter 11. E. 3. Ariens, W. Soudijn, and P. B.M. W. M. Timmermans; Stereochemistry andBiological Activity ofDrugs; Blackwell Scientific: Palo Alto, CA, 1983.2. E. J. Ariens, J. S. van Rensen, and W. Welling, eds.; Stereochemistry of Pesticides:Biological and Chemical Problems; Elsevier Science Publishers B. V., 1988.3. G. 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Chem. 43, 2923 (1978).164. a) M. S. Carpenter and W. M. Easter; J. Chem. Soc. 20, 401 (1955).b) E. Zavarin and A. B. Anderson; J. Chem. Soc. 20, 83 (1955).165. S. W. C. Watson and J. F. Eastham; J. Organometal. Chem. 9,165-168 (1967).166. a) S. Motherwell and W. Clegg; PLUTO: programfor plotting molecular and crystalstructures; University of Cambridge, England, 1978.b) C. K. Johnson; ORTEP II: Report ORNL-5138; Oak Ridge National Laboratory,Oak Ridge, Tennessee, 1976.246Appendix 1. X-ray Structure Report on Epoxide 147A. Crystal DataEmpirical FormulaFormula WeightCrystal Color, HabitCrystal Dimensions (mm)Crystal SystemNo. Reflections Used for UnitCell Determination (28 range)Omega Scan Peak Widthat Half—heightLattice Parameters:Di ffractometerRadiationTempe ratureTake—off AngleDetector ApertureC16H280252.40colorless, prism0.300 X 0.400 x 0.500monoclinic25 (100.7 — 109.00)0.37P21 (44)21.068 g/cm32804.97 cme men t SRigaku AFC6SCuK (X — 1.54178 A)21°C6.0°6.0 mm horizontal6.0 mm verticala— 6.767 (1)A9.616 (1)A12.205 (l)A98.84 (1)°784.7 (2)A3Space GroupZ valueDcalcF000( CuK)B. Intensity Measur247Crystal to Detector DistanceScan TypeScan RateScan WidthNo. of Reflections MeasuredCorrectionsC. Structure Solution andStructure SolutionRefinementFunction MinimizedLeast—squares Weightsp—factorAnomalous DispersionNo. Observations (I>4.OOu(I))No. VariablesReflection/Parameter RatioResiduals: R;Goodness of Fit IndicatorMax Shift/Error in Final CycleMaximum Peak in Final Diff. MapMinimum Peak in Final Diff. Map285 mm>— 2 e32.0°/mm (in omega)(8 rescans)-(1.15 + 0.20 tane)°154.6°Total: 1929Unique: 1776 (Rjt — .035)Lorentz—polarizationAbsorption(trans. factors: 0.82— 1.00)Secondary Extinction(coefficient: 0.70718E—04)RefinementDirect MethodsFull—matrix least—squaresZ w (IFol — IFCI)24Fo2/a(Fe2)0.04All non—hydrogen atoms16561679.920.045; 0.0672.830.010.24 e/A3—0.12 e/A3248Figure 46 Single Crystal X-Ray Structure of Epoxide 147 (PLUTO Drawing)** The numbering of carbon atoms here is different from that used in the Discussion (Section 2.2.7.).249H26H22H23Hi:H14Figure 47 The Unit Cell Structure of Epoxide 147 (Packing Diagram)250Table 6 Final Atomic Coordinates (fractional) and B (A2)of Epoxide 147x y zatom B0(1) 0.1042(3) 0.3562 0.3502(2) 5.46(7)0(2) 0.1848(3) 0.0318(3) 0.5658(1) 5.04(7)C(1) 0.2368(3) 0.1703(3) 0.2154(1) 4.00(7)C(2) 0.3048(4) 0.0589(4) 0.1368(2) 5.5(1)C(3) 0.5313(5) 0.0506(5) 0.1542(3) 7.7(2)C(4) 0.6307(4) 0.1929(6) 0.1443(3) 7.9(2)C(S) 0.5753(3) 0.2917(5) 0.2316(2) 6.6(1)C(6) 0.3497(3) 0.3117(3) 0.2235(2) 4.56(8)C(7) 0.3116(3) 0.3663(3) 0.3346(2) 4.81(8)C(S) 0.2487(3) 0.2547(3) 0.4026(2) 3.87(6)C(9) 0.2407(3) 0.1229(3) 0.3363(2) 4.23(7)C(10) 0.2170(8) —0.0818(5) 0.1588(3) 9.3(2)C(11) 0.2282(5) 0.0955(6) 0.0149(2) 7.6(2)C(12) 0.2684(6) 0.4159(5) 0.1330(3) 7.7(2)C(13) 0.2878(4) 0.2592(3) 0.5272(2) 4.67(8)C(14) 0.1451(4) 0.1742(3) 0.5876(2) 4.41(8)C(15) —0.0724(4) 0.2082(4) 0.5470(2) 5.7(1)C(16) 0.1953(5) 0.1997(4) 0.7123(2) 6.7(1)251Table 7 Hydrogen Atom Coordinates (fractional) and Bj0 (A2)of Epoxide 147z B soatom xH(1) 0.100(4) —0.016(4) 0.599(3) 5.3(6)H(2) 0.0969 0.1913 0.1864 4.8H(3) 0.5773 0.0131 0.2284 9.2H(4) 0.5719 —0.0120 0.0984 9.2H(5) 0.7762 0.1813 0.1549 9.5H(6) 0.5850 0.2316 0.0705 9.5H(7) 0.6273 0.2543 0.3050 7.9H(8) 0.6370 0.3823 - 0.2223 7.9H(9) 0.3944 0.4422 0.3702 5.8M(10) 0.1198 0.0699 0.3437 5.1H(11) 0.3589 0.0655 0.3608 5.111(12) 0.0707 —0.0758 0.1462 11.2H(13) 0.2601 —0.1512 0.1085 11.211(14) 0.2635 —0.1094 0.2357 11.211(15) 0.2920 0.1816 —0.0047 9.111(16) 0.2610 0.0198 —0.0330 9.111(17) 0.0829 0.1084 0.0048 9.111(18) 0.3456 0.5024 0.1438 9.311(19) 0.2798 0.3767 0.0601 9.3H(20) 0.1276 0.4355 - 0.1371 9.3H(21) 0.4236 0.2244 0.5513 5.6H(22) 0.2794 0.3565 0.5499 5.611(23) —0.0979 0.3058 0.5631 - 6.911(24) —0.1022 0.1924 0.4669 6.911(25) —0.1578 0.1483 0.5848 6.911(26) 0.1112 0.1403 0.7513 8.111(27) 0.3364 0.1778 0.7374 8.111(28) 0.1705 0.2975 0.7282 8.1252Table 8 Bond Lengths (A) of Epoxide 147with Estimated Standard Deviations in Parenthesesatom atom distance atom atom distance0(1) C(7) 1.448(3) C(4) C(S) 1.517(5)0(1) C(8) 1.459(3) C(5) C(6) 1.527(3)0(2) C(14) 1.428(3) C(6) C(7) 1.513(3)C(1) C(2) 1.554(3) C(6) C(12) 1.530(4)C(1) C(6) 1.55S(3) C(7) C(8) 1.460(3)C(1) C(9) 1.541(3) C(8) C(9) 1.500(3)C(2) C(3) 1.517(4) C(8) C(13) 1.503(3)C(2) C(10) 1.519(5) C(13) C(14) 1.537(3)C(2) C(11) 1.539(4) C(14) C(15) 1.515(4)C(3) C(4) 1.537(7) C(14) C(16) 1.527(3)253Table 9 Bond Angles (deg) of Epoxide 147with Estimated Standard Deviations in Parenthesesatom atom atom angle atom atom atom angleC(7) 0(1) C(8) 60.3(1) C(7) C(6) C(12) 109.1(2)C(2) C(1) C(6) 116.9(2) 0(1) C(7) C(6) 113.4(2)C(2) C(1) C(9) 115.1(2) 0(1) C(7) C(8) 60.2(1)C(6) C(1) C(9) 105.2(2) C(6) C(7) C(8) 111.0(2)CCI) C(2) C(3) 109.8(2) 0(1) C(8) C(7) 59.5(1)C(1) C(2) C(10) 110.1(2) 0(1) C(8) C(9) 111.3(2)C(1) C(2) C(11) 110.6(3) 0(1) C(8) C(13) 115.2(2)C(3) C(2) C(10) 110.0(3) C(7) C(8) C(9) 107.7(2)C(3) C(2) C(11) 109.3(2) C(7) C(8) C(13) 122.2(2)C(10) C(2) C(11) 107.0(3) C(9) C(8) C(13) 123.8(2)C(2) C(3) C(4) 112.8(3) C(1) C(9) C(8) 105.1(2)C(3) C(4) C(5) 110.1(2) C(8) C(13) C(14) 116.4(2)C(4) C(S) C(6) 112.7(2) 0(2) C(14) C(13) 105.7(2)C(1) C(6) C(S) 111.8(2) 0(2) C(14) C(15) 110.3(2)CU) C(6) C(7) 102.2(2) 0(2) C(14) C(16) 108.7(2)C(1) C(6) C(12) 114.1(2) C(13) C(14) C(15) 112.3(2)C(5) C(6) C(7) 107.0(2) C(13) C(14) C(16) 109.4(2)C(S) C(6) C(12) 112.0(2) C(15) C(14) C(16) 110.3(2)254Table 10 Torsional or Conformational Angles (deg) of Epoxide 147(1) (2)0(1) C(7)0(1) C(7)0(1) C(7)0(1) C(7)0(1) C(7)0(1) C(8)0(1) C(8)0(1) C(8)0(1) C(8)0(1) C(8)0(1) C(8)0(1) C(8)0(1) C(8)0(2) C(14)(3) (4)C(6) C(1)C(6) C(S)C(6) C(12)C(8) C(9)C(8) C(13)C(7) C(6)C(7) H(9)C(9) C(1)C(9) H(1O)C(9) H(11)C(13)C(14)C(13)H(21)C(13 )H(22)C(13)C(8)(3) (4)C(10)H(13)C(10 )H(14)C ( 11 ) H C 15)C( 11 )H( 16)C(11)H(17)C(5) C(4)C(S) H(7)C(S) H(8)C(7) C(8)C(7) H(9)C( 12 )H( 18)C(12)H(19)C(12)H(20)angle180—6066—174—5448.9(3)—7216918.4(2)164179—6159angle—47.1(2)—164.7(2)74.0(3)104.7(2)—102.3(2)—105.6(2)10946.1(2)—7316586.4(2)—153—3567.7(3)—53—171179—6159—6159179—53.1(3)67—17460(1)C(1)C(1)C(1)C(1)C(1)C(1)CU)C(1)C(1)C(1)C(1)C(1)CU)C(1)C(1)C(2)C(2)C(2)C(2)C(2)C(2)C(2)C(2)C(2)C(3)C(3)(2)C(2)C(2)C(2)C(2)C(2)C(6)C(6)C(6)C(6)C(6)C(6)C(6)C(6)C(9)C(9)C(1)C(1)C(1)C(1)C(1)C(1)C(3)C(3)C(3)C(2)C(2)0(2)0(2)0(2)0(2)0(2)0(2)0(2)0(2)C(1)C(1)C(1)C(1)C(14)C(13)H(21)C(14)C(13)H(22)C(14)C(15)H(23)C(14)C(15)H(24)C(14)C(15)H(25)C(14)C(16)H(26)C(14)C(16)H(27)C(14)C(16)H(28)C(2) C(3) C(4)C(2) C(3) H(3)C(2) C(3) H(4)C(2) C(10)H(12)C(8) C(7) —17.3(2)C(8) C(13) —169.8(2)C(6) C(S) —43.3(3)C(6) C(7) —157.4(2)C(6) C(12) 85.0(3)C(9) C(8) 158.8(2)C(9) H(10) —82C(9) H(11) 39C(4) C(S) 60.9(4)C(4) H(S) —179C(4) H(6) —59C(1) C(6) 45.2(3)C(1) C(9) —79.1(3)The sign is positive if when looking from atom 2 to atom 3 a clock—wise motion of atom 1 would superimpose it on atom 4.255Table 10 Torsional or Conformational Angles (deg) of Epoxide 147 (cont)(1) (2) (3) (4) angle (1) (2) (3) (4) angleC(9) C(1) C(2) C(1O) 42.2(3) C(13)C(14)O(2) H(1) —178(2)C(9) C(1) C(2) C(l1) 160.2(2) C(13)C(14)C(lS)H(23) —63C(9) C(1) C(6) C(12) —145.9(2) C(13)C(14)C(15)H(24) 57C(9) C(8) C(7) H(9) —146 C(13)C(14)C(15)H(25) 177C(9) C(8) C(13)C(14) —56.5(3) C(13)C(14)C(16)H(26) —176C(9) C(S) C(13)H(21) 64 C(13)C(14)C(16)H(27) —56C(9) C(S) C(13)H(22) —178 C(13)C(14)C(16)H(28) 64C(10)C(2) C(1) H(2) —75 C(15)C(14)O(2) B(1) —57(2)C(10)C(2) C(3) H(3) —54 C(15)C(14)C(13)H(21) —174C(10)C(2) C(3) H(4) 65 C(15)C(14)C(13)H(22) 68C(10)C(2) C(11)H(15) —175 C(15)C(14)C(16)H(26) 60C(10)C(2) C(11)H(.16) —55 C(15)C(14)C(16)H(27) —180C(10)C(2) C(11)H(17) 65 C(15)C(14)C(16)H(28) —60C(11)C(2) C(1) H(2) 43 C(16)C(14)O(2) H(1) 64(2)C(11)C(2) C(3) 11(3) —171 C(16)C(14)C(.13)H(21) 64C(11)C(2) C(3) 11(4) —52 C(16)C(14)C(13)H(22) —54C(11)C(2) C(10)H(12) —61 C(16)C(14)C(15)H(23) 59C(11)C(2) C(10)H(13) 59 C(16)C(14)C(15)H(24) 179C(11)C(2) C(10)H(14) 179 C(16)C(14)C(15)H(25) —61C(12)C(6) C(1) 11(2) —33 11(2) C(1) C(9) H(10) 35C(12)C(6) C(S) 11(7) 159 11(2) C(1) C(9) H(11) 157C(12)C(6) C(S) H(S) 40 11(3) C(3) C(4) 11(5) 61C(12)C(6) C(7) 11(9) —75 11(3) C(3) C(4) 11(6) —180C(13)C(8) C(7) 11(9) 7 11(4) C(3) C(4) H(S) —58C(13)C(8) C(9) 11(10) 71 11(4) C(3) C(4) 11(6) 61C(13)C(8) C(9) H(11) —50 H(S) C(4) C(S) H(7) —57The sign is positive if when looking from atom 2 to atom 3wise motion of atom 1 would superimpose it on atom 4.256a clock—Table 10 Torsional or Conformational Angles (deg) of Epoxide 147 (cont)(1) (2) (3) (4) angle (1) (2) (3) (4) angleC(3) C(2) C(1) H(2) 164 C(6) C(1) C(9) 11(10) 148C(3) C(2) C(10)H(12) —179 C(6) C(1) C(9) 11(11) —91C(3) C(2) C(i0)H(13) —59 C(6) C(5) C(4) H(S) —178C(3) C(2) C(10)H(14) 61 C(6) C(S) C(4) H(6) 62C(3) C(2) C(11)H(15) —55 C(6) C(7) 0(1) C(8) 101.7(2)C(3) C(2) C(11)H(16) 65 C(6) C(7) C(S) C(9) —0.9(2)C(3) C(2) C(11)H(17) —175 C(S) C(7) C(8) C(13) 152.0(2)C(3) C(4) C(S) C(6) —57.9(4) C(7) 0(1) C(S) C(9) —98.6(2)C(3) C(4) C(S) 11(7) 63 C(7) 0(1) C(8) C(13) 113.9(2)C(3) C(4) C(S) 11(8) —178 C(7) C(S) C(1) C(9) —28.3(2)C(4) C(3) C(2) C(10) —174.5(3) C(7) C(6) C(1) 11(2) 84C(4) C(3) C(2) C(11) 68.3(4) C(7) C(6) C(5) 11(7) 39C(4) C(5) C(6) C(7) 160.0(3) C(7) C(6) C(S) 11(8) —80C(4) C(S) C(6) C(12) —80.5(4) C(7) C(6) C(12)H(18) 66C(S) C(4) C(3) 11(3) —60 C(7) C(6) C(.12)H(19) —174C(5) C(4) C(3) 11(4) —179 C(7) C(6) C(12)H(20) —54C(S) C(6) C(1) C(9) 85.8(2) C(7) C(8) C(9) 11(10) —137C(5) C(S) C(1) 11(2) —162 C(7) C(S) C(9) 11(11) 102C(S) C(6) C(7) C(8) —99.1(2) C(7) C(8) C(13)C(14) 154.9(2)C(S) C(6) C(7) 11(9) 46 C(7) C(8) C(13)H(21) —84C(S) C(6) C(12)H(18) —52 C(7) C(8) C(13)H(22) 34C(S) C(6) C(12)H(19) 68 C(8) 0(1) C(7) 11(9) —109C(S) C(6) C(12)H(20) —172 C(S) C(7) C(6) C(12) 139.S(3)C(6) C(1) C(2) C(10) 166.5(3) C(S) C(9) C(1) 11(2) —84C(6) C(1) C(2) C(11) —75.S(2) C(8) C(13)C(14)C(15) —52.6(3)C(6) C(1) C(9) C(S) 28.6(2) C(8) C(13)C(14)C(16) —175.4(2)The sign is positive if when looking from atom 2 to atomwise motion of atom 1 would superimpose it on atom 4.3 a clock—257Table 10 Torsional or Conformational Angles (deg) of Epoxide 147 (cont)(1) (2) (3) (4) angle (1) (2) (3) (4) angleH(5) C(4) C(5) R(8) 62H(6) C(4) C(5) R(7) —177H(6) C(4) C(5) 14(8) —58The sign is positive if when looking from atom 2 to atom 3 a clockwise motion of atom 1 would superimpose it on atom 4.258Empirical FormulaFormula WeightCrystal Color, HabitCrystal Dimensions (mm)Crystal SystemNo. Reflections Used for UnitCell Determination (2 range)Omega Scan Peak Widthat Half—heightLattice Parameters:Space GroupZ valueDcalcF0001’(CuK)DiffractometerRadiationTemperatureTake—off AngleDetector ApertureCrystal to Detector Distance259C17H3202268.44colorless, needle0.120 x 0.180 X 0.480orthorhombi c25 ( 57.4 — 81.8°)0.37Appendix 2. X-ray Structure Report on Diol 285A. Crystal Dataa = 10.730 (2)Ab — 20.411 (2)Ac — 7.484 (l)AV — 1639.0 (3)AP212 (*19)41.088 g/cm36004.97 cm1B. Intensity MeasurementsRigaku AFC6SCuK (X = 1.54178 A)21°C6.0°6.0 mm horizontal6.0 mm vertical285 mmScan Width2emaxNo. of Reflections MeasuredCorrectionsStructure SolutionRefinementFunction MinimizedLeast—squares Weightsp—factorAnomalous DispersionNo. Observations (I>3.00(I))No. VariablesReflection/Parameter RatioResiduals: R;Goodness of Fit IndicatorMax Shift/Error in Final CycleMaximum Peak in Final Diff. MapMinimum Peak in Final Diff. Map-2 e16.0°/mm (in omega)(8 rescans)(0.94 + 0.20 tan8)°155.00Total: 1921Lorentz—polari zationAbsorption(trans. factors: 0.92 — 1.07)Secondary Extinction(coefficient: 0.26140E—04)RefinementDirect MethodsFull—matrix least—squaresE w (IFol — (Fc()24Fo2/(Fo2)0. 025All non—hydrogen atoms15701818.670.036; 0.0471.930.0020.18 e/A3—0.11 e/A3Scan TypeScan RateC. Structure Solution and260H202HiSH27-415H18H29H13 C12C16Cli H28H17 HiSH14 co C2 H32C13Hilci H3 31H12 C3C17CSH20Cs C4 H30H6 HiCS HG 23HID C14CS HS 01C7H22 H7H21H24 CiSH26 H25Figure 48 Single Crystal X-ray Structure of Diol 285 (PLUTO Drawing)** The numbering of carbon atoms here is different from that used in the Discussion (Section 4.1.3.).261L’J‘71 H CD C. (-) CD C,) C) C. 0 0 :1Table 11 Final Atomic Coordinates (fractional) and B (A2) of Diol 285atom x Y z Beg0(1) 0.3431(2) 0.47048(9) 0.7356(2) 4.39(7)0(2) 0.3951(1) 0.51200(9) 0.0739(2) 4.28(7)C(1) 0.4487(2) 0.3707(1) 0.2595(3) 3.66(9)C(2) 0.5054(2) 0.4402(1) 0.2899(3) 3.27(8)C(3) 0.4447(2) 0.4791(1) 0.4452(3) 3.35(8)C(4) 0.4255(2) 0.4375(1) 0.6131(3) 3.49(8)C(S) 0.3754(2) 0.3697(1) 0.5802(3) 3.82(9)C(6) 0.4429(2) 0.3302(1) 0.4364(3) 3.8(1)C(7) 0.5628(2) 0.2940(1) 0.5021(4) 4.5(1)C(8) 0.6244(3) 0.2597(1) 0.3415(5) 6.0(1)C(9) 0.6465(3) 0.3047(2) 0.1864(4) 6.4(2)C(10) 0.5229(3) 0.3310(1) 0.1208(4) 5.6(1)C(11) 0.3155(2) 0.3759(1) 0.1845(4) 4.8(1)C(12) 0.5111(2) 0.4819(1) 0.1214(3) 4.1(1)C(13) 0.5125(2) 0.5433(1) 0.5005(4) 4.9(1)C(14) 0.6601(2) 0.3372(1) 0.5965(4) 5.4(1)C(15) 0.5242(3) 0.2405(1) 0.6344(5) 6.7(2)C(16) 0.4755(3) 0.6043(1) 0.3994(5) 6.5(1)C(17) 0.6530(3) 0.5358(2) 0.5186(51 6.6(2)—eq263Table 12 Hydrogen Atom Coordinates (fractional) and (A2) of Diol 285atomH(1)H(2)H(3)H(4)H(5)H(6)H(7)H(8)H(9)H(10)H(11)H(12)H(13)H(14)H(15)H(16)H(17)H(18)H(19)H(20)H(21)H(22)H(23)H(24)x0.269(3)0.372(3)0.59220.36160.50660.28790.38080.38480.57000.70470.68760. 69960.53900.47160.31720.26260.28200.57290.53760.48380.72950.62150.69130.4663y0.472(1)0.500(2)0.43290.49200.43290.37380.34520.29460.22400.24180.28060.34130.35940.29380.39990.39930.33190.51660.45400.55140.30980.35890.37030.2102z0.694(4)—0.029(4)0.32560.40410.67200.54450.69250.40870.30220.38000.08980.22420.01780.08340.07110.27010.16460.14010.02210.62280.63750.69930.51280.57596.2(7)5.9(8)3.94.04.24.64.64.67.27.27.77.76.76.75.85.85.84.9- 4.95.96.56.56.58.0Bso264Table 12 Hydrogen Atom Coordinates (fractional) and B0 (A2) of Diol 285 (cont.)x y 20.4832 0.2606 0.73790.5982 0.2165 0.67410.5116 0.6029 0.27910.5064 0.6430 0.46280.3844 0.6064 0.39050.6718 0.4953 0.58400.6869 0.5733 0.58400.6908 0.5337 0.3995Table 13 Bond Lengths (A) of Diol 285with Estimated Standard Deviations in ParenthesesatomH(25)H(26)H(27)H(28)H(29)H(30)H(31)H(32)atomC(4)C(12)C(2)C(6)C(10)C(11C(3)C(12)C(4)C(13)Biso8.08.07.87.87.88.08.08.0distance1.505(3)1.527(3)1.563(3)1.540(4)1.538(4)1.532(4)1.500(4)1.512(5)1.510(4)1.522(4)atom0(1)0(2)C(1)C(1)CU)C(1)C(2)C(2)C(3)C(3)distance1.440(2)1.432(3)1.560(3)1.562(3)1.539(3)1.539(3)1.552(3)1.523(3)1.531(3)1.553(3)atomC(4)C(5)C(6)C(7)C(7)C(7)C(8)C(9)C(13)C(13)at oznC (5 )C(6)C(7)C(8)C(14)C(15)C(9)C(10)C(16)C(17)265Table 14 Bond Angles (deg) of Diol 285with Estimated Standard Deviations in Parenthesesatom atom atom angle atom atom atom angleC(2) C(1) C(6) 111.9(2) C(1) C(6) C(S) 109.7(2)C(2) C(l) C(1O) 112.0(2) C(1) C(6) C(7) 119.0(2)C(2) C(1) C(11) 110.6(2) C(5) C(6) C(7) 114.7(2)C(6) C(1) C(10) 108.3(2) C(6) C(7) C(8) 108.8(2)C(6) C(1) C(11) 108.0(2) C(6) C(7) C(14) 115.6(2)C(10) C(1) C(11) 105.7(2) C(6) C(7) C(15) 108.5(2)C(1) C(2) C(3) 114.3(2) C(8) C(7) C(14) 109.1(2)C(1) C(2) C(12) 113.8(2) C(8) C(7) C(1S) 107.2(2)C(3) C(2) C(12) 110.5(2) C(14) C(7) C(15) 107.2(2)C(2) C(3) C(4) 112.8(2) C(7) C(8) C(9) 113.2(2)C(2) C(3) C(13) 115.8(2) C(8) C(9) C(10) 109.3(3)C(4) C(3) C(13) 108.2(2) C(1) C(10) C(9) 114.9(2)0(1) C(4) C(3) 110.2(2) 0(2) C(12) C(2) 114.2(2)0(1) C(4) C(S) 108.4(2) C(3) C(13) C(16) 116.0(2)C(3) C(4) C(S) 115.1(2) C(3) C(13) C(17) 113.8(2)C(4) C(S) C(6) 115.6(2) C(16) C(13) C(17) 112.8(2)266Table 15 Torsional or Conformational Angles (deg) of Diol 2853 a clock—(1) (2) (3) (4) angle (1) (2) (3) (4) angle0(1) C(4) C(3) C(2) —166.2(2) C(2) C(1) C(1O)C(9) 74.5(3)0(1) C(4) C(3) C(13) 64.4(2) C(2) C(1) C(10)H(13) —460(1) C(4) C(3) H(4) —SO C(2) C(1) C(10)H(14) —1650(1) C(4) C(S) C(6) 173.2(2) C(2) C(1) C(11)H(15) 590(1) C(4) C(S) H(6) 52 C(2) C(1) C(11)H(16) —610(1) C(4) C(S) H(7) —66 C(2) C(1) C(11)H(17) 1790(2) C(12)C(2) C(1) 79.5(2) C(2) C(3) C(4)C(5) -43.2(2)0(2) C(12)C(2) C(3) —50.6(2) C(2) C(3) C(4) H(S) 770(2) C(12)C(2) H(3) —165 C(2) C(3) C(13)C(16) 87.6(3)C(1) C(2) C(3) C(4) 44.7(2) C(2) C(3) C(13)C(17) —45.7(3)C(1) C(2) C(3) C(13) 170.1(2) C(2) C(3) C(13)H(20) —159C(1) C(2) C(3) H(4) —72 C(2) C(12)0(2) H(2) —121(2)C(1) C(2) C(12)H(18) —160 C(3) C(2) C(1) C(6) —50.9(2)C(1) C(2) C(12)H(19) —41 C(3) C(2) C(1) C(10) —172.7(2)C(1) C(6) C(S) C(4) —53.3(2) C(3) C(2) C(1) C(11) 69.7(2)C(1) C(6) C(S) H(6) 68 C(3) C(2) C(12)H(18) 70C(1) C(6) C(5) H(7) —174 C(3) C(2) C(12)H(19) —171C(1) C(6) C(7) C(8) —44.2(3) C(3) C(4) 0(1) H(1) 69(2)C(1) C(6) C(7) C(14) 79.0(3) C(3) C(4) C(S) C(6) 49.3(2)C(1) C(6) C(7) C(15) —160.6(2) C(3) C(4) C(5) H(6) —72C(1) C(10)C(9) C(8) 60.5(3) C(3) C(4) C(5) H(7) 170C(1) C(10)C(9) B(11) —179 C(3) C(13)C(16)H(27) —74C(1) C(10)C(9) H(12) —59 C(3) C(13)C(16)H(28) 166C(2) C(1) C(6) C(S) 53.2(2) C(3) C(13)C(16)H(29) 46C(2) C(1) C(6) c(7) —81.6(2) C(3) C(13)C(17)H(30) —45C(2) C(1) C(6) H(8) 164 C(3) C(13)C(17)H(31) —165The sign is positive if when looking from atom 2 to atomwise motion of atom 1 would superimpose it on atom 4.267Table 15 Torsional or Conformational Angles (deg) of Diol 285 (cont.)(1) (2) (3) (4) angle (1) (2) (3) (4) angleC(3) C(13)C(17)H(32) 75 C(6) C(7) C(8) H(9) —68C(4) C(3) C(2) C(12) 174.6(2) C(6) C(7) C(8) H(10) 173C(4) C(3) C(2) H(3) —71 C(6) C(7) C(14)H(21) 177C(4) C(3) C(13)C(16) —144.7(2) C(S) C(7) C(14)H(22) 57C(4) C(3) C(13)C(17) 82.0(3) C(S) C(7) C(14)H(23) —63C(4) C(3) C(13)H(20) —31 C(6) C(7) C(15)H(24) 58C(4) C(5) C(6) C(7) 83.6(2) C(6) C(7) C(15)H(25) —62C(4) C(S) C(6) H(8) —164 C(6) C(7) C(15)H(26) 178C(S) C(4) 0(1) H(1) —58(2) C(7) C(6) C(1) C(1O) 42.3(3)C(5) C(4) C(3) C(13) —172.6(2) C(7) C(6) C(1) C(11) 156.4(2)C(S) C(4) C(3) H(4) 73 C(7) C(6) C(S) H(6) —1SSC(S) C(6) C(1) C(10) 177.2(2) C(7) C(6) C(S) H(7) —37C(S) C(6) C(1) C(11) —68.8(2) C(7) C(8) C(9) C(10) —61.5(3)C(S) C(6) C(7) C(8) —176.9(2) C(7) C(8) C(9) H(11) 179C(S) C(6) C(7) C(14) —53.7(3) C(7) C(8) C(9) H(12) 58C(S) C(6) C(7) C(15) 66.7(3) C(8) C(7) C(6) H(8) 71C(S) C(1) C(2) C(12) —179.1(2) C(8) C(7) C(14)H(21) —SOC(6) C(1) C(2) H(3) 65 C(8) C(7) C(14)H(22) —180C(6) C(1) C(10)C(9) —49.4(3) C(8) C(7) C(14)H(23) 60C(S) C(1) C(10)H(13) —170 C(8) C(7) C(15)H(24) —59C(6) C(1) C(10)H(14) 71 C(8) C(7) C(15)H(2S) —179C(6) C(1) C(11)H(1S) —178 C(8) C(7) C(1S)H(26) 61C(6) C(1) C(11)H(16) 62 C(8) C(9) C(10)H(13) —179C(S) C(1) C(11)H(17) —58 C(8) C(9) C(10)H(14) —SOC(S) C(S) C(4) H(S) —71 C(9) C(8) C(7) C(14) —74.5(3)C(6) C(7) C(8) C(9) 52.5(3) C(9) C(8) C(7) C(15) 169.7(2)The sign is positive if when looking from atom 2 to atom 3 a clockwise motion of atom 1 would superimpose it on atom 4.268Table 15 Torsional or Conformational Angles (deg) of IDiol 285 (cont.)(1) (2) (3) (4) angle (1) (2) (3) (4) angleC(9) C(10)C(1) C(11) —164.9(2) C(15)C(7) C(8) H(10) —70C(10)C(l) C(2) C(12) 59.1(2) C(15)C(7) C(14)H(21) 56C(10)C(1) C(2) H(3) —57 C(15)C(7) C(14)H(22) —64C(10)C(1) C(6) H(8) —72 C(15)C(7) C(14)H(23) 176C(10)C(1) C(11)H(15) —62 C(16)C(13)C(3) H(4) —31C(10)C(1) C(11)H(16) 178 C(16)C(13)C(17)H(30) —179C(10)C(1) C(11)R(17) 58 C(16)C(13)C(17)H(31) 61C(10)C(9) C(8) H(9) 59 C(16)C(13)C(17)H(32) —59C(10)C(9) C(8) H(10) 178 C(17)C(13)C(3) H(4) —164C(11)C(1) C(2) C(12) —58.6(2) C(17)C(13)C(16)H(27) 59C(11)C(1) C(2) H(3) —174 C(17)C(13)C(16)H(28) —61C(1l)C(1) C(6) H(8) 42 C(17)C(13)C(16)H(29) 179C(11)C(1) C(10)H(13) 74 H(1) 0(1) C(4) H(5) —174C(11)C(1) C(10)H(14) —44 H(2) 0(2) C(12)H(18) 118C(12)C(2) C(3) C(13) —60.0(2) 14(2) 0(2) C(12)H(19) 0C(12)C(2) C(3) 14(4) 58 14(3) C(2) C(3) 14(4) 172C(13)C(3) C(2) 14(3) 54 14(3) C(2) C(12)H(18) —44C(13)C(3) C(4) H(S) —53 14(3) C(2) C(12)H(19) 75C(14)C(7) C(6) 14(8) —166 14(4) C(3) C(4) H(S) —167C(14)C(7) C(8) 14(9) 165 14(4) C(3) C(13)H(20) 83C(14)C(7) C(8) 14(10) 46 14(5) C(4) C(S) 14(6) 168C(14)C(7) C(15)H(24) —176 H(S) C(4) C(S) H(7) 50C(14)C(7) C(15)H(25) 64 H(6) C(5) C(6) 14(8) —43C(14)C(7) C(15)H(26) —56 H(7) C(S) C(6) 14(8) 75C(15)C(7) C(6) 14(8) —46 14(9) C(S) C(9) H(11) —61C(15)C(7) C(S) H(9) 49 14(9) C(S) C(9) 14(12) 179The sign is positive if when looking from atom 2 to atom 3 a clockwise motion of atom 1 would superimpose it on atom 4.269Table 15 Torsional or Conformational Angles (deg) of Diol 285 (cont.)(1) (2) (3) (4) angle (1) (2) (3) (4) angleH(10)C(8) C(9) H(l1) 58H(lO)C(8) C(9) H(12) —62H(11)C(9) C(l0)FI(13) —59H(1l)C(9) C(1O)H(14) 60H(12)C(9) C(10)H(13) 61H(12)C(9) C(1O)H(14) 180H( 20)C(13)C( 16 )H( 27) 172H(20)C(13 )C(16)H(28) 52H( 20)C(13 )C(16 )H( 29) —68H(20)C(13)C(17)H(30) 68H(20)C(13 )C( 17 )H( 31) —52H(20 )C(13 )C( 17)H( 32) —172The sign is positive if when looking from atom 2 to atom 3 a clockwise motion of atom 1 would superimpose it on atom 4.270

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