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The chemistry of thujone : new enantioselective syntheses of Ambrox[Registered trade mark] and Epi-Ambrox Cirera, Carles 1993

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THE CHEMISTRY OF THUJONE: NEW ENANTIOSELECTIVE SYNTHESES OF AMBROX® AND EPI-AMBROX. Carles Cirera B. Sc., University of Barcelona, 1988 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Department of Chemistry) We accept this thesis as conforming to the required standard  THE UNIVERSITY OF BRITISH COLUMBIA April 1993 ©Carles Cirera, 1993  In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission.  (Signature)  Department of Ciii-7,C ditlx,C06) The University of British Columbia Vancouver, Canada  Date  DE-6 (2/88)  1,1 -799.3)  ii  Abstract This thesis is concerned with the development of a new synthetic approach to (-)-Ambrox® (2) and epi-Ambrox (3) using thujone (1) as an enantiopure building block.  Thujone (1), a readily available starting material obtained from Western red cedar, can be efficiently converted to D-cyperone (144), which can be chemically elaborated to obtain the key intermediate, enone 143. As a model study for the synthesis of racemic 2 and 3, a synthetic sequence starting with a cyclohexanone derivative has also been developed to afford the racemic intermediate 143. Acid catalyzed Robinson annelation of 2-methylcyclohexanone with  1-chloropentan-3-one gave enone 165. Methylation of 165 to 166 with methyl iodide and potassium tert-amylate proceeded in high yield. Wolff-Kishner reduction of 166 gave 167 which was then oxidized to racemic 143 with sodium dichromate. At this stage, enantiopure 143, obtained via 144, from thujone (1) was prepared and compared with racemic 143. A novel method for the transposition of the carbonyl function in enantiopure 143 to  the isomeric enantiopure enone 172 was developed. Treatment of 143 with manganese (III) acetate allowed introduction of an acetoxy function at the C8 position, to afford a mixture of isomers (185 and 186 4:1 ratio) in excellent yield (86 %). Reduction of 185 and 186 with lithium aluminum hydride provided a mixture of alcohols, which without separation, was treated with p-toluenesulfonic acid to yield 172. This 3 step process, 143 to 172, could be performed without isolation of intermediates and in an overall yield of  64 %. Stereoselective alkylation of 172 with ethyl iodoacetate yielded compound 201 exclusively with entry of the side chain in an axial orientation. Hydrogenation of 201 to 205 and then ketalization, afforded 215. Reduction of the ester, protection of the alcohol  111  functionality, and deprotection of the carbonyl, finally gave compound 219 in excellent yields. Reaction of 219 with the cerium chloride-methyllithium reagent gave 220, which yielded, after hydrogenolysis, diol 221. p-Toluenesulfonic acid catalyzed cyclization of diol 221 provided the potent ambergris odorant (-)-epi-Ambrox (3). Epimerization of the side chain in 219 with sodium methoxide in methanol gave compound 225 which was further converted into (-)-Ambrox® (2) by an identical sequence as for (-)-epi-Ambrox (3).  iv  1  143  165  166  167  ,-COOEt  .-COOEt 0  185/186  172  201 OPh 0  219 Ph  205  OH  O Ph^OH OH  221  Table of contents Abstract ^ ii List of figures ^ viii List of tables ^ List^of schemes ^ xi List of abbreviations ^ xiii Acknowledgements ^ xvi Foreword ^ 1 Chapter 1.^Introduction. 1.1. General introduction ^ 3 1.2. Configuration-odor relationship studies in ambergris fragrances ^7 1.3. Total syntheses of Ambrox® (2) ^ 12 Chapter 2.^Results and discussion. 2.1. The use of thujone (1) as enantiopure building block in the synthesis of decalone systems ^ 33 2.2. Investigations towards the synthesis of 143 from thujone (1) ^41 2.3. Investigations towards the synthesis of racemic 143 from 2-methylcyclohexanone ^ 47 2.4. Ketone transposition studies on racemic and enantiopure 143 ^ 51 2.5. Studies concerning the protection of ketone functionality in enantiopure 205 ^ 73 2.6. Synthesis of enantiopure diol 221 from enantiopure ketal ester 215^ 77 2.7. Studies on the 1,2-addition reaction to the carbonyl function in enantiopure 219 ^ 80 2.8. Cyclization of enantiopure diol 221 to (-)-epi-Ambrox (3) ^83 2.9. Cyclization of enantiopure diol 90 to (-)-Ambrox® (2) ^ 88 2.10. Concluding remarks ^ 90 2.11. Future developments ^ 92 Chapter 3.^Experimental. 3.1. General experimental ^ 94 3.2. Ketodiol 135 ^ 97 3.3. Trienone 142 ^ 98 3.4. Ketone 145 ^ 99  vi 3.5. Alkene 146 ^ 3.6. Triol 150 and ketodiol 151 ^ 3.7. 1-Chloropentan-3-one ^ 3.8. Enone 165 ^ 3.9. Ketones 166 and 230 ^ 3.10. Alkene 167 ^ 3.11. Enone 143 ^ 3.12. enones 185 and 186 ^ 3.13. Diols 187-190 ^ 3.14. Ketone 179 and enones 172 and 191. Method A ^ Method B ^ Method C ^ Method D ^ Method E ^ 3.15. Enone 201 and iodo enone 202 ^ 3.16. Hydroxy ketone 210 ^ 3.17. Keto ester 205 ^ 3.18. Keto ester 211. Method A ^ Method B ^ 3.19. Ketals 215 and 216. Method A ^ Method B ^ Method C ^ 3.20 Hydroxy ketal 217 ^ 3.21. Hydroxy benzyl ketal 218. Method A ^ Method B ^ 3.22. Hydroxy benzyl ketone 219. Method A ^ Method B ^ 3.23. Alcohol 220. Method A ^ Method B ^ 3.24. Diol 221 ^  100 101 103 103 104 106 107 108 109 113 115 115 116 116 117 119 121 122 123 123 125 125 126 127 128 129 130 131 132 133  vii 3.25. (-)-Epi-Ambrox (3). Method A ^ Method B ^ 3.26. Hydroxy ketal 223 ^ 3.27. Hydroxy benzyl ketal 224 ^ 3.28. Hydroxy benzyl ketone 225. Method A ^ Method B ^ 3.29. Alcohol 226 ^ 3.30. Diol 90 ^ 3.31. (-)-Ambrox® (2) ^ Bibliography ^ Appendices. X-ray Structure report on ketodiol 135 ^ X-ray Structure report on racemic alcohol 220 ^  134 135 136 137 138 139 140 141 142 144 151 166  viii  List of figures Figure 1.^Constituents of ambergris ^ 5 Figure 2.^Ally' hydroperoxides from ambrein ^ 6 Figure 3.^Ambraoxide as produced by hydrogenation of enol ether 6^6 Figure 4.^Triaxial rule for ambergris odour sensation ^7 Figure 5.^Stereoisomers of (-)-Ambrox® (2) (trans-fused series) ^ 8 Figure 6.^Homologous series of (-)-Ambrox® (2) ^9 Figure 7.^Stereoisomers of (-)-Ambrox® (2) (cis-fused series) ^ 10 Figure 8.^Acid mediated synchronous cyclization of (E,E)-98 to (±)-Ambrox®(2) ^ 25 Figure 9.^Cyclopropyl ring cleavage to afford a 5-membered ring ^36 Figure 10.^Single crystal X-ray structure of dihydroxy ketone 135 ^38 Figure 11.^Proposed mechanism for a-acetoxylation of a,(3-unsaturated ketones ^ 56 Figure 12.^Proposed mechanism for a-acetoxylation of enone 143^57 Figure 13.^The spatial relationship of the C8 and C9 protons in isomers 185/186 ^ 57 Figure 14.^A summary of proton interactions as determined from an nOe difference experiment with enantiopure 187 ^59 Figure 15.^A summary of proton interactions as determined from an nOe difference experiment with enantiopure 188^60 Figure 16.^A summary of proton interactions as determined from an nOe difference experiment with enantiopure 190 ^60 Figure 17.^Proposed mechanism for the dehydration of enantiopure diols 187-190 ^ 62 Figure 18.^Proposed mechanism of formation of compound 202 ^66 Figure 19.^A summary of proton interactions as determined from an nOe difference experiment with enantiopure 202 ^67 Figure 20.^Mechanistic analysis for the stereoselective alkylation of enantiopure 172 ^ 68 Figure 21.^NOe difference experiment for enantiopure enone 201^69 Figure 22.^Proposed mechanism for ketal isomerization ^74  ix Figure 23.^A summary of proton interactions as determined from an nOe difference experiment with enantiopure ketal 215 ^77 Figure 24.^Single crystal X-ray structure of the enantiomer of alcohol 220 ^82 Figure 25.^Cyclization of diol 32 to afford the Ambrox system (2) ^ 84 Figure 26.^Mechanistic analysis of cyclization of enantiopure diol 221 under acidic conditions ^ 84 Figure 27.^Mechanistic analysis of cyclization of enantiopure diol 90 under acidic conditions ^ 89 Figure 28.^Single crystal X-ray structure of ketodiol 135 (PLUTO drawing) ^ 153 Figure 29.^The unit cell structure of ketodiol 135 (packing diagram) ^ 154 Figure 30.^Single crystal X-ray structure of racemic alcohol 220 (PLUTO drawing) ^ 168 Figure 31.^The unit cell structure of racemic alcohol 220 (packing diagram) ^ 169  List of tables Table 1.^Optimization of ozonation conditions for diol 149^ 45 Table 2.^Percentage of 205, 215 and 216 during ketalization of 205, as determined by GC ^ 75 Table 3.^Percentage of 205, 215 and 216 during ketalization of 205, as determined by GC ^ 76 Table 4.^Percentage of 205, 215 and 216 during ketalization of 205, as determined by GC ^ 76 Table 5.^Final atomic coordinates (fractional) and B eq(A) of ketodiol 135 ^ 155 Table 6.^Hydrogen atom coordinates (fractional) and Big) (A 2) of ketodiol 135 ^ 157 Table 7.^Bond lengths (A) of ketodiol 135 with estimated standard deviations in parentheses ^ 160 Table 8.^Bond angles (deg) of ketodiol 135 with estimated standard deviations in parentheses ^ 161 Table 9.^Torsional or conformational angles (deg) of ketodiol 135^ 163 Table 10.^Final atomic coordinates (fractional) and B eq (A) of racemic alcohol 220 ^ 170 Table 11.^Hydrogen atom coordinates (fractional) and A so (A2) 172 of racemic alcohol 220 ^ Table 12.^Bond lengths (A) of racemic alcohol 220 with estimated standard deviations in parentheses ^ 174 Table 13.^Bond angles (deg) of racemic alcohol 220 with estimated standard deviations in parentheses ^ 175 Table 14.^Torsional or conformational angles (deg) of racemic alcohol 220 ^ 176  xi List of schemes Scheme 1. Scheme 2. Scheme 3. Scheme 4. Scheme 5. Scheme 6. Scheme 7. Scheme 8. Scheme 9. Scheme 10. Scheme 11. Scheme 12. Scheme 13. Scheme 14. Scheme 15. Scheme 16. Scheme 17. Scheme 18.  Scheme 19. Scheme 20. Scheme 21. Scheme 22. Scheme 23.  Hinder and Stoll's synthesis of (-)-Ambrox® (2) from sclareol (30) ^ 12 Nat's synthesis of (-)-Ambrox® (2) from sclareol (30)^ 13 Proposed mechanism for hydroperoxides (35) cleavage^ 14 Coste-Maniere's synthesis of (-)-Ambrox® (2) from sclareol (30) ^ 15 Christenson's synthesis of (-)-Ambrox® (2) from sclareol (30) ^ 16 Ohno's synthesis of (-)-Ambrox® (2) from 1-abietic acid (50)^ 17 Urones' synthesis of (-)-Ambrox® (2) from methyl labdanolate (65) ^ 18 Cambie's synthesis of (-)-Ambrox® (2) from manoyl oxide (68) ^ 19 Cortes' synthesis of (-)-Ambrox® (2) from (-)-drimenol (71)^20 Mori's synthesis of (-)-Ambrox® (2) from geranylacetone (81) ^ 22 Matsui's synthesis of (±)-Ambrox® (2) from dihydro-P-ionone (91) ^ 23 Snowden's synthesis of (±)-Ambrox® (2) and (±)-ep i-Ambrox (3) ^ 24 Snowden's formal synthesis of (±)-Ambrox® (2) from 99^25 Buchi and Wuest's synthesis of (±)-Ambrox®(2) from dihydro-D-ionone (91) ^ 27 Synthesis of (-)-Ambrox® (2) from enone 110 ^28 Paquette's synthesis of (-)-epi-Ambrox (3) from 117^29 Ohloff s synthesis of (-)-Ambrox® (2), (+)-iso-Ambrox (15) and (-)-epi-Ambrox (3) from (+)-sclareolide (31) ^31 Robinson annelation of thujone (1) ^ 34 Hydrogen bromide promoted cyclopropyl ring opening ^35 Proposed mechanism for bromination of thujone (1) ^39  Kutney's synthesis of J3-cyperone (144) from thujone (1)^42 Proposed sequence to enone 143 from 146 ^44 Ozonation of diol 149 ^ 44  xii  Scheme 24. Scheme 25. Scheme 26. Scheme 27. Scheme 28. Scheme 29. Scheme 30. Scheme 31. Scheme 32. Scheme 33. Scheme 34. Scheme 35. Scheme 36. Scheme 37. Scheme 38. Scheme 39. Scheme 40. Scheme 41. Scheme 42. Scheme 43. Scheme 44. Scheme 45.  Envisaged synthetic sequence to enone 143 from 152 ^ 45 Kutney's synthesis of enone 143 from 13-cyperone (144)^ 46 De Groot's synthesis of enone 143 from (-)-dihydrocarvone (159) ^ 47 Synthesis of racemic enone 143 ^ 48 The alkylation process involving racemic enone 165 ^ 49 Robinson annelation of compound 169^ 50 Ketone transposition from position C7 to C8 ^52 De Groot's synthesis of ketone 176 from S(+)-carvone (173) ^ 53 A proposed sequence leading to racemic enone 172 from racemic 143 ^ 54 Synthesis of diene 180 ^ 54 A proposed ketone transposition sequence from enantiopure 143 to enantiopure 172 ^ 55 Formal synthesis of 0-Polywoode (192) and its enantiopure unsaturated analogs starting from thujone (1) ^64 Alkylation of enantiopure enone 172 ^ 65 A proposed sequence to epi-Ambrox (3) from 205^ 71 Isoe's sequence to keto aldehyde 214 from 212 ^ 73 A proposed synthesis of enantiopure diol 221 from enantiopure ketal ester 215 ^ 78 Buchi's 1,2-addition to ketone 87 ^ 80 Synthesis of (-)-epi-Ambrox (3) from enantiopure enone 143 ^ 86 Synthesis of (-)-Ambrox® (2) from enantiopure ketal 216 ^ 87 Synthetic route to (-)-Ambrox® (2) and (-)-epi-Ambrox (3) from enantiopure enone 143^ 91 Production of 228 and 229 by biotechnological methods ^93 Proposed sequence to enantiopure enone 143 from 228^ 93  List of abbreviations [a] ^specific rotation recorded at 25° C using sodium D-line Ac^acetyl AIBN^2,2-azobis(2-methylpropionitrile) anal.^elemental analysis br.^broad Bu^butyl t-Bu^tert-butyl c^concentration C^Celsius cm-1^wave number cont.^continue 8^chemical shift d^doublet dd^doublet of doublets ddd^doublet of doublet of doublets DEG^diethylene glycol deg^degree (angle) DIBAL^diisobutylaluminum hydride DME^dimethoxyethane DMF^N,N-dimethylformamide DMSO^dimethyl sulfoxide dq^doublet of quartets dt^doublet of triplets e^extinction coefficient EG^ethylene glycol equiv.^equivalent Et^ethyl EVK^ethyl vinyl ketone g^gram GC^gas-liquid chromatography h^hour HMDS^1,1,1,3,3,3-hexamethyldisilazane HMPA^hexamethylphosphoramide  xiv Hz^Hertz IR^infrared coupling constant wavelength L-Selectride^lithium tri-sec-butylborohydride LAH^lithium aluminum hydride IDA^lithium diisopropylamide m^multiplet M^molar M+^molecular ion m-CPBA^meta-chloroperbenzoic acid Me^methyl mg^milligram MHz^megahertz microlitre ml mmol^millimole mol^mole mp^melting point Ms^mesityl MS^mass spectrometry MVK^methyl vinyl ketone nVz^mas to charge ratio frequency MTIT^ nuclear magnetic resonance nOe^nuclear Overhauser effect PCC^pyridinium chlorochromate PDC^pyridinium dichromate Ph^phenyl ppb^part per billion ppm^part per million i-Pr^isopropyl pyr•^pyridine q^quartet r. t.^room temperature s^singlet  XV  sept.^septet t^triplet TBDMS^tert-butyldimethylsilyl TBHP^tert-butyl hydroperoxide Tf^trifluoromethanesulfonic THE^tetrahydrofuran TLC^thin layer chromatography TMS^trimethylsilyl (or tetramethylsilane) Ts^para-toluenesulfonyl UV^ultraviolet A^Angstrom  xv i Acknowledgements I would like to thank my supervisor, Professor J. P. Kutney, for his valuable guidance and support during the course of this work and in the preparation of this thesis. I would also like to thank the following people for their constructive criticism and valuable suggestions during the preparation of this thesis: Mijo Samija, Phil Gunning, Dr. Yasuaki Hirai and Gary Hewitt, and the other members, past and present, of the group who I have known during my time here. I would also like to thank Dr. Francisco Kuri-brena, Timothy Wong, Dr. Jacques Roberge and Johanne Renaud for their advice throughout my synthetic studies; the Staff, Faculty and friends in the department for their support and friendship. Especial thanks go to my parents and my fiancee, Monica Monroy, for their unending support and encouragement, that gave me strength throughout these years of education.  1 Foreword  Natural compounds are usually found in nature with high enantiomeric purity. Often the dependence of biological activities on absolute stereochemistry demands that pure la,b, 2a. For the past 20 years, synthesis of such enantiomers be prepared in the laboratory enantiopure * compounds has been a major goal of organic chemists. Enantiomeric purity is a further requirement for commercial drug production. Not only will impurities delay licensing by federal authorities, but racemic mixtures can have reduced or limited biological effect because enantiomers can promote different or opposite effectsla. The production of odoriferous compounds is likewise a delicate process where enantiomers vary greatly in intensity and odour character 3 A. Two important approaches to the production of enantiomerically pure compounds are the use of enantiopure building blocks as starting materials 2b and the use of asymmetric syntheses. The first approach produces enantiomerically pure compounds by integration of the enantiopure building block into the product: the initial building block must be enantiomerically pure and racemization must be avoided in the synthetic sequence. The main drawback of this method may be a limited pool of readily available enantiopure compounds. The second approach provides syntheses of enantiopure molecules via enantiopure auxiliaries, either catalytically or stoichiometrically. A common drawback of this method is to produce the target molecule usually bearing an excess of one enantiomer but not an enantiomerically pure compound. In our laboratory, we aim to produce enantiopure intermediates of several families of natural compounds by the use of a readily available enantiopure building block, thujone (1). We hope to prove thujone to be a versatile starting material for the syntheses of many enantiomerically pure natural compoundssa f. -  * There has been considerable controversy concerning the use of the term "chiral" when referring to an enantiomerically pure molecule. The term "enantiopure" has been selected and is used throughout this thesis. Chem. & Eng. News, October 26 issue, page 2 (1992).  2  The present study illustrates the synthesis from thujone (1), of pure enantiomers of (-)-Ambrox® * (2) and (-)-epi-Ambrox (3), two highly valuable compounds of the perfume industry.  1  ^ ^ 2 3  * Ambrox® is a registered trade name of Firmenich S.A.  3 1 . INTRODUCTION.  1.1. General introduction.  Since ancient times mankind has been fascinated by the fragrances of certain natural substances. If we have to search for their origins, we must look far into the past. The first human beings had to rely on their sense of smell to survive: the search for food (animals, plants and fruits) forced them to recognize and identify the various natural odours present in their surroundings, along with the rest of the animal kingdom. " Odours are a rich language and, for some species, one of the principal systems of orientation and communication. In the context of human civilization, however, man tends to look upon odorous substances and perfumes primarily as sources of more or less pleasing sensations. In doing so, we deprive ourselves of many opportunities to understand their effects upon human feelings, emotions and behavior" 6a. Perfumery as it is known today only started a couple of centuries ago and its birth place was without any doubt France. Before then, only some perfumed oils and resins were playing an important role in human societies and religions, especially in eastern countries like Syria, Egypt and India. Today, the list of known and identified odour substances grows larger each day as a result of great deal of research devoted to this field. A perfume has been defined as a 'composition' of odorous products of various origins; whilst odour is that characteristic of a substance, which makes it perceptible to the sense of smell 6bbc. Perfumes result from a purposeful manipulation in order to achieve particular olfactory stimuli. Historically, research in this field has been largely directed towards the isolation and identification of specific odorous constituents from the complex mixtures present in nature. This work still continues, and many important natural odorants from smoking  4 material, beverages and flowers have only recently been separated and the constituents positively identified. Only compounds with a molecular weight below 400 g/mol and an appreciable vapor pressure at room temperature can be perceived as having odour. The cost of natural isolates, coupled to the often difficult separation of the desirable components, has stimulated the development of chemical syntheses of many substances from more abundant raw materials, including petrochemical sources. An excellent example of the above statement is ambergris and its most important constituents, qualitatively and economically, (-)-Ambrox® (2) and (-)-epi-Ambrox (3). Ambergris is a metabolic product of the sperm whale (Physeter macrocephalus L.) that accumulates as concretions in the intestinal tract of the animal. Specific details of its formation remain a mystery. When the concretion leaves the body of the animal, the diameter is seldom more than 20 cm. As a result of the action of sunlight and seawater, ambergris undergoes an aging process. During this aging process a strong fecal odour and a waxy appearance disappear, and a complex and pleasant fragrance gradually? develops. It has to mature for one to three years, during which time the full and balanced fragrance is developed. The major constituent of ambergris is the triterpene alcohol ambrein (4) 8 which is odourless itself but is responsible for the generation of the odorous compounds 2 and 5-11 in ambergris 9 (Fig. 1). A series of sterols of the cholestanol type occur together with ambrein (4). The ratio of the two groups of terpenes apparently determines the quality of the material. The best samples found (of a grey to golden yellow colour) contain up to 80 % of ambrein while the low quality ones have been found to contain up to 46 % of the sterol derivatives 10 . During the aging process of ambergris, a series of degradation reactions take place that lead to the final composition of the sample. It is believed that singlet oxygen plays a key role in the oxidative degradation 11 . Copper ions released from haemocyanin might also  5  OH  5  ^ ^ 6 2 CH  7  ^ ^ 9 8  10  ^  11  Fig. 1 Constituents of ambergris. act as catalyst in this degradation. Some research in this direction has been done in order to obtain a better understanding of the processes that take place in nature. A singlet oxygen oxygenation 12 of ambrein (4) and subsequent degradation of the primarily formed allyl hydroperoxides 12 and 13 (Fig. 2) led to the naturally ocurring ambergris odorants 6, 7, 8 and 9.  6  12  ^  13  Fig. 2 Allyl hydroperoxides from ambrein. It was established that the amber-like woody odour of the enol ether 6 was retained in its hydrogenation product ambraoxide (14) 13 (Fig. 3).  14  Fig. 3 Ambraoxide as produced by hydrogenation of enol ether 6. a-Ambrinol (8) possesses an exceptionally strong odor of damp earth with a crude civet subnote*. In the late 1950's 14 , the commercial production of tricyclic amber odorants of a woody nature was accomplished. (-)-Ambrox® (2) and (+)-iso-Ambrox (15) have been available in the market for more than 30 years in the form of the base Fixateur 404 (trade name of Firmenich).  * The terms "note", "subnote", "bouquet", "tonality", etc. used to describe the odour characteristics, are widely used in the world of perfumes and they will be employed to describe such characteristics in this thesis. However it must be pointed out that an exact definition of such terms is not given in the literature.  7 1.2. Configuration-odour relationship studies in ambergris fragrances.  The ambergris scent is believed to be strongly related to the structural elements of the labdane skeleton. (-)-Ambroxe (2) is considered the prototype of all ambergris odorants. The main structural features of this group are the presence of a decalin skeleton having at least one alcohol, ether or ester function and alkyl substituents at specific positions. All known ambergris odorants fulfil these general requirements. But on the contrary, it does not mean that a compound fulfilling these requirements will possess an amber-type odour, it may even not smell at all. Thus configuration and conformational features are also of paramount importance for odour profile and strength. The odour profile encountered so far within substituted decalin derivatives and homologous series is dominated by ambergris, woody, vetiver, animal and camphoraceous scents. In the early seventies, Ohloff et al. had established the 'triaxial rule' of odour 15,16a,16b Fig. 4). sensation^(see  R3  Fig. 4 Triaxial rule for ambergris odour sensation. The high specificity of odour sensation had led to various speculations concerning the molecular mechanism involved on the receptor site of the human olfactory system 17,18 . A systematic study with a large number of trans-decalin systems containing oxygen  function showed that the 5,8,10-triaxial arrangement (see Fig. 4) of the R-substituents, with one of these axial groups being preferentially (but not essentially) an oxygen functions, is the geometrical requirement for a molecule in order to exhibit an amber-type  8  odourl 9 a . The scent of ambergris odorants greatly depends on their configuration. Substituents in the 5- and 10- positions can be hydrogen, as their main function is to ensure the trans- configuration of the decalin system. This rule has been studied in detail recently by Winter, Naf and Bruns 19b,c,c1. (-)-Ambroxe (2) presents an exotic woody note of strong warm animal tonality, while (-)-epi-Ambrox (3) possesses the strongest odour and the lowest threshold concentration of the series (0.15 ppb (parts per billion)) but differs slightly from the rich and complex bouquet of 2. The epimer at C8 (16) is unlikely to exist because the trans fusion on the furan ring would force the ring B into a highly strained boat-like conformation.  2  ^ ^ ^ 16 3 15  Fig. 5 Stereoisomers of (-)-Ambrox 9 (2) (trans-fused series). (+)-/so-Ambrox 9 (15) shows considerable deviation from the model (-)-Ambrox 9 (2), especially in the diminution of its odour strength by a factor of one hundred (34 ppb,  compared to the threshold concentration of (-)-Ambrox 9 (2) of 0.3 ppb). Some differences in the odour of both enantiomers of Ambrox® (2) have also been found not only in the threshold concentrations ( (+)-Ambrox 0 , enantiomer of (-)-Ambrox 0 (2), has a higher threshold value of 2.4 ppb) but also in the lack of the strong warm animal  note in (+)-Ambrox 9 , present in its enantiomer. Consequently, (+)-Ambrox 9 is known as  9 "poor man's ambrox" by perfumers. In addition, an exotic and spicy undertone of (+)-Ambrox® disappears in the racemate. A homologous series of Ambrox® (2) has also been evaluated. The importance of the gem-dimethyl groups at position C4 was studied (Fig. 6), showing that nor-derivatives 17-22 presented only small deviations in the quality of odour. The case of compound 19 is remarkable in that it gives a threshold value of 170 ppb (more than 500 times weaker than (-)-Ambrox® (2)). Also within the nor-derivatives series, the ones with an axial methyl group at position C4 (17-19) have greater strength in odour than the ones with an equatorial methyl at C4 (20-22). This result shows that an axial methyl group at position C4 is preferable but not essential. This statement is also supported by the fact that  17  ^  20  18  ^  ^  21  ^  19  22  H 23  ^  24  ^  25  Fig. 6 A homologous series of (-)-Ambrox® (2).  10  dinor-Ambrox (23-25) (homologous series of Ambrox® (2) with two methyl groups missing at position C4) still possess the woody character of Ambrox® (2) even though it is masked under a relatively complex odour. They present a threshold value of 24, 40 and 72 ppb for compounds 23, 24 and 25 respectively, showing that the intensities have decreased when compared to the Ambrox® series. The AB cis-fused20 diasteromers of Ambrox® (2) have also been synthesized and their odour quality and strength has been evaluated (Fig.7). Evaluation of this series has been performed only for the racemates. Only diasteromer 26, with a threshold value of 11 ppb (20 times higher than racemic (±)-Ambrox® (threshold value of 0.6 ppb))presented  26  ^ ^ ^ 29 28 27 Fig 7 Stereoisomers of (-)-Ambrox® (2) (cis-fused series).  an odour quality comparable to Ambrox® (2). The other diasteromers 27-29 are very weak odorants with almost none of the typical ambergris notes. The lack of the structural features in accord with the 'triaxial rule' in diasteromers 27-29 may be responsible for this diminution in quality and strength of odour, presumably the interaction with the odour receptor will not be properly accomplished. Other theories trying to explain the odour-stereochemistry relation have appeared in the literature recently 21 a, but again not all the experimental results fit the postulates 2 lb.  11 To date, the experimental data in the studies on the relation between stereochemistry and odour stimuli show the scope and limitation of odour theories based on the nature and spatial arrangement of molecular odorants. Since none of these theories is conclusive and the precise nature of the ambergris odorant and the receptor interaction is essentially a speculation, more precise models allowing greater prediction are likely to be developed in the future. Studies on the nature of active sites and the recent progress made in isolation of human olfactory receptors 220 will provide an improved assessment of these theories.  12  1. 3 . Total syntheses of Ambrox® (2).  As a reflection of the increasing demand for ambergris-type odorants in the world market and the decreasing availability of natural sources in the past few years, much research is being devoted towards the synthesis of Ambrox® (2). The large number of sequences leading to the synthesis of Ambrox® (2), in its racemic form or as a pure enantiomer, that have appeared in the literature in recent years shows the importance of this compound in the actual market. The commercial production of (-)-Ambrox® (2) 23,24 , is still based on a procedure developed by Hinder and Stoll in 1950 14,25 (Scheme 1), which involves a tedious degradation process (with a maximum overall yield of 52 %) of natural  f  32  30  33  34  2  a) KMnO4; b) 03, heating; c) KOH, then HC1; d) 150° C, vacuum; e) Cr03, AcOH; 0 LAH, Et 20; g) P-naphthalenesulfonic acid  Scheme 1 Hinder and Stoll's synthesis of (-)-Ambrox® (2) from sclareol (30).  13 sclareol (30), the source of which is clary sage (Salvia sclarea L.). Direct degradation of sclareol (30) with chromium trioxide gave lactone 31 25,26 . An alternative route to obtain 31 involves oxidation of 30 with potassium permanganate to give sclareol oxide (33),  ozonolysis of 33, yielded the acetoxy acid 34, which cyclized to lactone 31. Reduction of lactone 31 with lithium aluminum hydride (LAH) and acid catalysed cyclization  14,25  of the  resulting diol (32) gave (-)-Ambrox® (2) (which can isomerize easily under acidic conditions to the more stable (+)-iso-Ambrox® (15)) Another fragmentative degradation process of sclareol (30) towards (-)-Ambrox® (2) has been reported by Naf et al. via an oxygen-centered radicalTh (Scheme 2). Reaction  of sclareol (30) with hydrogen peroxide in the presence of catalytic amounts of acid gave the allyl hydroperoxides 35/36 as an epimeric mixture. This mixture was then reacted with a redox couple27b Fell/Cull and (-)-Ambrox® (2) was directly formed. The overall yield from sclareol (30) was 11-12 %.  a 35/36^2 a) 70 % aqueous H202/p-Ts0H/CH2C12 b) Cu(OAc)2.2H20/FeSO4.7H20/CH3OH, 2 h/50° C  Scheme 2 Nafs synthesis of (-)-Ambrox® (2) from sclareol (30). A mechanism for the catalytic decomposition of the allyl hydroperoxides (35/36) has been proposed (Scheme 3) and is based on the analogy of known related reactions 28 a ,b. First, cleavage of the hydroperoxides 35/36 by Fell to give the radical intermediate 37.  14  1) Fell  35  ^  37  + Cu'  Fein  +^Cu I  5)  ►^Feu^+^Cull  Scheme 3 Proposed mechanism for hydroperoxide (35) cleavage.  Fragmentation of radical 37 gives methyl vinyl ketone and radical 38, which can be oxidized by Cull to give 39. Alternatively, a cyclic organocopper species (40) might be  15  sclareol 30  a  0*  Ac  -.., "'OH  b, c  ).  41/42  43  +  46  14  31  32  2  a) Ac20; b)Pd(OAc)2/dioxane, 100° C/15 min., 100 %; c) LAH, Et20/H + , 2 h, 96 %; d) KMnO4, 24 h, 80 %; e) LAH/THF, 25° C/3 h, 98 %; 0 TsCl/ CH 2C12, 25° C, 90 %; g) LAH, Et20/H + ; TsC1, 2 h, 90 %.  Scheme 4 Coste-Maniere's synthesis of (-)-Ambrox® (2) from sclareol (30).  16 formed. Cation 39 can cyclize directly to (-)-Ambroxe (2). Finally the pair Fell/Cull is regenerated making the sequence catalytic in iron and copper. The synthesis of ambergris fragrance from sclareol (30) developed by Coste-Maniere  et al. 29 (Scheme 4) involves a palladium catalyzed elimination of acetic acid as a key step. A mixture of sclareol acetates (41/42), was reacted with a catalytic amount of palladium acetate 30 affording a mixture of three dienic acetates, which were reduced to dienes 43/44/45 with LAH. Further oxidation of these dienes with potassium permanganate gave a mixture of ambreinolide (46) and sclareolide (31) 3:2 in 77 % overall yield. LAH reduction of 46, followed by acid catalyzed cyclization gave ambraoxide (14). Similar treatment of 31 yielded (-)-Ambrox® (2). A similar sequence to the one of Naf has been developed by Christenson 31 (Scheme 5), through alkoxy radical intermediates. Treatment of sclareol oxide (33) (previously prepared from sclareol (30)32) with hydrogen peroxide gave a diasteromeric mixture of hydroperoxides 47/48. Reaction of 47/48 with ferrous chloride and a catalytic amount of cupric chloride yielded compound 49. Hydrolysis of 49 gave (-)-Ambroxe (2) with an overall yield of 34 % from sclareol (30).  OOH  sclareol ^a  b  30 33  49  ^  47/48  2  a) KMnO4; b) H202, HOAc; c) FeC12, CuC12 (cat.); d) KOH,'PrOH, H20  Scheme 5 Christenson's synthesis of (-)-Ambroxe (2) from sclareol (30).  17 A synthesis towards (-)-Ambrox® (2) has also been developed by Ohno  et al. from 1-abietic acid (50) as an enantiopure synthon 33 (Scheme 6). Selective oxidation of the double bond in ring C was achieved using catalytic amounts of osmium tetraoxide 34  f  OR  r "'OR R= TBDMS  g  h  60/61  k  a) 0s04 cat. amount, Me 3N—> 0; b) CH2N2; c) Pb(OAc)4; d) HSCH2CH 2SH,p-Ts0H ; Raney Ni; e) TMSOTf; 03; 0 LiA1H 4; TBDMSOTf; g) UV irradiation; h) 0s04/ TBHP; 0 MsCl; Li-HMDS; j) reduction; removal of protec. group; MsCI; k) C1PO(NMe2) Li, EtNH 2.  Scheme 6 Ohno's synthesis of (-)-Ambrox® (2) from 1-abietic acid (50).  2;  18 yielding a mixture of diols 51/52, that upon treatment with diazomethane furnished methyl esters 53/54. Oxidative cleavage of 53/54 with lead tetraacetate afforded compound 55 as a single product. Thioacetal formation and subsequent reduction with Raney Ni gave a mixture of olefins 56/57. Formation of the silyl enol ethers of 56/57 and selective ozonolysis yielded aldehydes 58/59 in 49 % yield from 56/57. Reduction of 58/59 with LAH and protection of the alcohols with TBDMSOTf gave 60/61 in 83 % yield. Photo-induced isomerization to the exo olefin (61), and oxidation with osmium tetroxide gave diol 62. Further transformation of 62 into the epoxide 63, reduction of 63, removal of the TBDMS group and cyclization afforded compound 64 in 62 % yield from 62. Reduction of the neopentyl alcohol group was achieved with the Ireland-Liu method 35 0, furnishing (-)-Ambrox® (2) in 8 % overall yield from 1-Abietic acid (50). Another sequence to (-)-Ambrox® (2) has been published by Urones et al. starting from methyl labdanolate (65) 36 (Scheme 7) which can be converted into (-)-Ambrox® (2) by an oxidative degradation. Treatment of methyl labdanolate (65) with lead tetraacetate in presence of iodine 37 gave cyclic ethers 66/67, which were treated with chromium trioxide COOMe a  65  ^  66/67  ^  31  ^  2  a) Pb(OAc)4/12, C6H6, C5H5N, 10° C, 65 %; b) Cr03/AcOH, 77 %; c)B2H2, F3BEt 20, 90 %. Scheme 7 Urones' synthesis of (-)-Ambrox® (2) from methyl labdanolate (65). to yield lactone 31. Reduction of lactone 31 with diborane gave (-)-Ambrox® (2) in an overall yield of 45 % from methyllabdanolate (65).  19 Manoyl oxide (68) has also been an enantiopure synthon from which (-)-Ambrox® (2) has been prepared, in 5 steps, by Cambie et a1. 38 , with an overall yield of 17 %  (Scheme 8). Treatment of manoyl oxide (68) with lithium in liquid ammonia gave alcohol 69 in quantitative yield, which was oxidized with potassium permanganate in neutral  conditions to the ketol 70. Acid catalyzed cyclization of 70 gave the enol ether 33 which  68  33  ^  69  ^  70  ^ ^ 31 34 e  +  2  t  32 f  a) Li, NH 3; b) KMnO4; c) catalytic amount of HC1O4; d) KMnO4, AcOH; e) B2H6, bBEt0; t)p-TsCI, pyr.  Scheme 8 Cambie's synthesis of 0-Ambroxe (2) from manoyl oxide (68).  20 was oxidized with potassium permanganate in acetic acid affording the acetoxy acid 34 in 30 % yield and its corresponding lactone 31 in 22 % yield. The latter compound was reduced directly with diborane yielding (-)-Ambrox® (2) and diol 32, which was cyclized to (-)-Ambrox® (2) with p-toluenesulfonyl chloride in pyridine. The sesquiterpene (-)-drimenol (71), another natural compound possessing most of the stereochemical requirements to lead to (-)-Ambrox® (2), has also been used as an enantiopure synthon in a synthetic sequence towards (-)-Ambrox® (2) developed by M.J. Cortes et al. 39 (Scheme 9). H  a  i  79^80 a) PCC, CH2C12; b) MeOCH2P(Ph3)C1; c) HCI; d) LAH; e) Ac20, pyr; 1) 0s04; g) NaOH, H20; h) MeS02C1, pyr; i) KOH, DEG, N11 2N11 2.  Scheme 9 Cortes' synthesis of (-)-Ambrox® (2) from (-)-drimenol (71).  21 (-)-Drimenol (71) possesses all the carbon units except one, required for (-)-Ambrox® (2). The oxidation of 71 with pyridinium chlorochromate gave aldehyde 72 which was condensed with (methoxymethyl)-triphenyl phosphonium chloride to give the enol ethers 73/74. Hydrolysis of the enol ethers 73/74 and subsequent reduction of the aldehyde functionality in 75 with LAH afforded alcohol 76. Acetylation of 76 followed by dihydroxylation with osmium tetroxide provided the diol 77 which was saponified to triol 78. Cyclization of 78 into 79 was carried out with equimolar amounts of methanesulfonyl chloride. Oxidation of 79 with pyridinium chlorochromate gave ketone 80. Wolff-Kishner reduction of 80 gave (-)-Ambrox® (2) within an overall yield of 19 % from (-)-drimenol (71). The same authors have recently published a synthetic sequence to ambraoxide (14) 40 starting also from (-)-drimenol (71). Mori et a1. 41 a have developed an enantioselective synthesis of both (-)-Ambrox® and (+)-Ambrox® starting from geranylacetone (81) (Scheme 10). The key intermediate, tosylate 83, was prepared enantiomerically pure by optical resolution of the carbamate derivatives of compound 82 4 lb. Reaction of 83 with sodium cyanide gave nitrile 84 which was treated with a Wittig reagent to give nitrile 85. This compound was reduced with DIBAL to give 86, and further reduction of 86 with sodium borohydride yielded alcohol 87. Epoxidation of 87 gave 88/89 in a ratio of 18:1. Reduction of the mixture 88/89 with LAH afforded diols 32/90 which were then cyclized to (-)-Ambrox® (2) and (+)-iso-Ambrox (15). Chromatographic separation of this mixture gave 2 % overall yield for (-)-Ambrox® (2) from geranylacetone (81) in 15 steps. The first synthesis of racemic (±)-Ambrox® (2) was reported by Matsui et al. 42 (Scheme 11). In order to elongate the side chain of dihydro-13-ionone (91), 91 was submited to a Darzen's condensation with ethylchloroacetate. Decarboxylation of the resulting glycidic acid with a catalytic amount of sodium acetate yielded the aldehyde 92.  22 OTs^CN H b  81  83^8 4  c  d  e  f  +  15 a) NaCN, DMSO; b) Ph3P=CH2, DME; c) DIBAL; d) NaBH4, Me0H; e) m-CPBA, CH 202; f) LIAM 4, THF; g) TsC1, C5H5N.  Scheme 10 Mods synthesis of (-)-Ambrox® (2) from geranylacetone (81). Further treatment of 92 with malonic acid in the presence of triethylamine afforded a mixture of trans-P-monocyclohomofarnesic acid (93) and the cis isomer 94. The acid mixture was esterified with titanium tetrachloride in ethanol giving an ester mixture 95/96  23  91  92  93  94  93 g, h  31 a) C1CH2CO2Et, NaOEt; b) NaOAc, 200° C; c) CH2(COOH) 2, Et3N; d) TiC14, EtOH; e) KOH, EtOH; HC1; t) CF3COOH; g) NaA1H2(OCH2CH2OCH3)2; h) TsCI, pyr.  Scheme 11 Matsui's synthesis of (±)-Ambrox® (2) from dihydro-13-ionone (91). which was separated by fractional distillation to each pure ester, and then hydrolyzed back to each pure acid 93 and 94. Stereoselective cyclization was accomplished by treatment of acid 93 with trifluoroacetic acid affording sclareolide (31). This cyclization has also been accomplished with similar yields by Saito et a1.43 , employing stannic chloride. Reduction of the lactone 31 and subsequent ring closure gave (±)-Ambrox® (2), with an overall yield from dihydro-I3-ionone (91) of 7 %. A similar sequence for acid 94 furnished (±)-epi-Ambrox (3) with an overall yield from dihydro-I3-ionone (91) of 7.5 %.  24 An interesting biomimetic approach to (±)-Ambrox® (2) and (±)-epi-Ambrox (3) has been published recently by Snowden et a1. 44 . Based on previous studies in stereselective acid catalyzed polyene cyclizations 45 a,b, they prepared polycyclic ethers in which a hydroxyl group served as an internal nucleophilic terminator (Scheme 12).  a  97  ^  98 (EE/ZE 1:1)  b  2/3 a) Ph 3P[(CH2)30H]te,n-BuLi (2 equi.), THF b) FSO3H, 2-nitropropane, -90° C  Scheme 12 Snowden's synthesis of (±)-Ambrox® (2) and (±)-epi-Ambrox (3).  Homoallylic alcohol 98 was prepared from ketone 97 by a Wittig reaction followed by chromatographic separation of the resulting E/Z stereoisomeric mixture. Cyclization of the alcohol (E,E)-98 (Fig. 8) involved treatment with an excess of fluorosulfonic acid in 2-nitropropane yielding 40 % of 2 and 35 % of 3. Alcohol (Z,E)-98, under the same conditions, afforded 69 % of 3 with no traces of 2 being detected. The stereospecific formation of 2 and 3 from acyclic trienols (E,E)-98 and (Z,E)-98 was rationalized postulating that synchronous internal anti-addition took place via chair-like conformations of the nascent cyclohexane rings. The results of the cyclization process showed that isomerization of (E,E)-98 to (Z,E)-98 was a competitive reaction with cyclization to (±)-Ambrox® (2), and, in contrast, cyclization of (Z,E)-98 to (±)-epi-Ambrox (3) is  25  (E, E)-9 8 .■  (Z, E)-9 8  Fig. 8 Acid mediated synchronous cyclization of (E, E)-98 to (±)-Ambrox® (2). considerably faster than the isomerization of the double bond. Assuming that the cyclization transition states bear some structural resemblance to the final product, the slower cyclization of (E,E)-98 is consistent with the molecular model calculations 46 of energies  a  99  a) KCN, NH4C1, DMF-H20, rt, 72 %; b) KOH, Me0H-H20, reflux, 83 %; c) MeLi, THE-Et 20, -60° —>rt; TsOH, toluene, reflux 68 %; d) LAH, Et20, rt, 85 %.  Scheme 13 Snowden's formal synthesis of (±)-Ambrox® (2) from 99.  26  for (±)-Ambrox® (2) and (±)-epi-Ambrox (3) (45.5 and 41.8 Kcal/mole respectively). A formal synthesis to (±)Ambrox® (2) has also been published by Snowden  et al. 47 (Scheme 13). Starting from bicyclic enone 99 48,49 , 1,4-addition with potassium cyanide gave the more stable cyano ketone 84 with the cyanomethyl group in an equatorial position. Hydrolysis of the nitrile group furnished keto acid 100, whose subsequent treatment with methyllithium resulted in stereoselective equatorial attack on the carbonyl group, which under acid catalysis immediately cyclized to the cis-fused y lactone 101. Reduction of lactone 101 gave the known diol 90 which has been reported to cyclize to (±)-Ambrox® (2) under acid catalysis 50. Another synthesis of racemic (±)-Ambrox® (2) has been developed by Buchi and Wuest 50. In a manner similar to Matsui, they started from dihydro-f3-ionone (91) (Scheme 14). Condensation of 91 with dimethylcarbonate afforded 13-keto ester 102 which was cyclized with catalytic amounts of stannic chloride 43 to yield f3-keto ester 103. 0-alkylation of 103 was preferred to C-alkylation and the resulting ally! ether 104 was subjected to a Claisen rearrangement by heating in xylene to give f3-keto ester 105. Demethoxycarbonylation of 105 gave a mixture of 106 and 107 in 86 % and 14 % yields respectively. Ketone 106 was condensed with MeMgI, affording alcohol 108 which was ozonized and the resulting aldehyde reduced to diol 90. Dehydration of diol 90 to (±)-Ambrox® (2) was accomplished with catalytic amounts of p-toluenesulfonic acid in nitromethane.These conditions avoided the formation of the more stable but much weaker odorant iso-Ambrox (15) 14 . Hydroboration of 108 gave diol 109 which was subjected to  the same cyclization conditions as for 90 to yield (±)-ambroxide (14). The overall yields for (±)-Ambrox® (2) and (±)-Ambroxide 14 were 9 % and 5.4 % respectively.  27  a  c  b CO2CH3  91  102  109^  14  103  a) (CH 30) 2CO, NaH, DMF, 20° C; b) SnC14, CH2C12, 5-20° C; c) ally! bromide, NaH, DMF; d) CaC12, DMSO; e) MeMgI; 0 03, Me0H/NaBH4; g)p-TsOH, CH 3NO2; h) BH3-THF/OH -, H20 2.  Scheme 14 Buchi and Wuest's synthesis of (±)-Ambrox 8 (2) from dihydro-f3-ionone (91).  28 Another synthesis of (-)-Ambrox® (2) has been developed recently by other members of our group 51 (Scheme 15), starting from enone 110 which has been previously prepared from thujone 51 (1) in 11 steps within an overall yield of 10.2 %. The convex face of the cis-fused enone 110 ensured a favorable conjugate addition of the required side chain to the 13 face. Reaction of 110 with vinyl magnesium bromide and a catalytic amount of cuprous iodide gave the desired addition product 111 in 70 % yield. Methylation of 111 yielded ketone 112 as a major product. The stereochemical conversion of the A/B cis-fusion of compound 112 to the desired A/B trans-fusion in 114 was realized through a two step sequence: Introduction of a double bond to give 113 and reduction with lithium in ammonia gave the desired trans-fused compound 114. The axial hydroxyl at position C7  f  h  2 a) CH 2=-CHMgBr, CuI, THF; b) LDA, DME; CH 3I; c) LDA, THF, PhSeCl; d) H202, pyr.; e) Li, NH3, Et20; f) L-Selectride, THF; g) BH 3-THF; Olf, H202; h)p-TsOH, toluene, 80° C/2 h.  Scheme 15 Synthesis of (-)-Ambrox® (2) from enone 110.  required for the final cyclization was obtained by treating enone 114 with L-Selectride. Hydroboration of alcohol 115 furnished diol 116 as a major product, which was cyclized to (-)-Ambrox® (2) by treatment with p-TsOH within 6.6 % overall yield from 110.  29  A very different approach to one of the most important ambergris odorants, (-)-epi-Ambrox (3), which possesses the strongest scent and the lowest threshold concentration (0.15 ppb) of all, has been developed by Paquette  et a/. 52a ,b (Scheme 16). In  this case, an anionic oxy-Cope rearrangement provides the key step towards the required tricyclic skeleton. The racemic mixture of alcohol 117 and its enantiomer was converted into the corresponding chloroacetate and hydrolyzed with lipase P-30 53 . By carrying out the  CH  H  A—OH CH3  a, b  CH  CH  CH 3  d  CH 3  117  118  119  e, f  g  ^Ow-  122  j, k  123  124  125  a) C1CH2C0C1, pyr.-THF; lipase P-30; b) 15 % NaOH, THF; PDC, CH2C12; c) 5-lithio-2,3-dihydrofuran, TIE, -78° C; CeC13, THF, -78° C; d) KH 18-cr-6, THF, 80° C; e) PhSeCI, -78° C; 0 Na104, NaHCO 3, Me0H; g) LDA, HMPA, THF; CH3I; h) NaBH 4, CeC13, Me0H; i) 5 % Pd-C H2, EtOAc; j) Nall, CS2; CH 3I; k) (Me3Si)3SiH, AIBN, C6H 6, A.  Scheme 16 Paquette's synthesis of (-)-epi-Ambrox (3) from 117.  30  enzymatic reaction to 60 % completion, isolating and saponifying the unreacted ester, they were able to obtain alcohol (-)-117 in high optical purity (92 % e.e.) and 27 % yield. The absolute configuration was determined by inference from the circular dichroism spectrum of the ketone 118 resulting from the oxidation of alcohol (-)-117. Condensation of 118 with the cerium reagent derived from 5-lithio-2,3-dihydrofuran and anhydrous cerium chloride gave 119 in 65 % yield. Heating the potassium salt of 119 with 18-crown-6 in anhydrous THE allowed a [3,31 sigmatropic shift, through the boat transition state geometry required by the structural features of the molecule. The thermal activation also induced the isomerization of enolate 120 to enolate 121, as the equilibrium proved to be completely in favor of 121. Enolate 121 was quenched with phenylselenenyl chloride followed by oxidative elimination of the a-phenylseleno-ketone formed, yielding enone 122. Introduction of the required methyl group at position C8 was easily accomplished,  since enone 122 is only capable of unidirectional enolization. The fact that the methyl group entered into the axial position could be explained by configurational requirements, since the equatorial entry would require the linkage with the furan ring to adopt a trans-fusion, forcing the B ring to adopt a highly strained, boat-like conformation in the  final product. Reduction of the ketone 123 was accomplished with high stereoselectivity to yield the a-alcohol 124, using sodium borohydride together with CeC13 54 . All the attempts towards a hydroxyl-directed hydrogenation of the double bond exo to ring A with reagents such as [Rh(norbornadiene)(DIPHOS-4)113F4 520 failed, probably due to the high level of steric congestion in the vicinity of the allylic alcohol funtionality. Interestingly, conventional hydrogenation of 124 with 5 % palladium in charcoal gave smoth conversion to the desired trans-junction of the A/B rings, but when the hydrogenation was attempted on 123 under the same conditions, only a cis-fused product was obtained 52b. Finally reduction of the alcohol function in 125 afforded (-)-epi-Ambrox (3) in 89 % yield, 2.7 % overall yield from (±) 117 (10 % from (-) 117).  31 The previous sequence illustrates one of the very few syntheses published to date leading to the strongest scent odorant (-)-epi-Ambrox (3) within the Ambrox series, and in its pure enantiomeric form. Another sequence towards (-)-epi-Ambrox  (3)  has been  described by Ohloff et al. 56 by chemical modification of (+)-sclareolide (31) in  a  a) HCOOH, conc. H2SO4/20° C/4 h; b) like a), but 90° C/5 h; c) LAH, Et20/reflux/1 h; d) POC13, pyr/20° C/5 h  Scheme 17 Ohloff s synthesis of (-)-Ambrox® (2), (+)-iso-Ambrox (15) and (-)-epi-Ambrox (3) from (+)-sclareolide (31).  32 unspecified yields (Scheme 17). Tricyclic ethers 2, 3 and 15 were prepared from diastereomeric sclareolides 31, 101 and 126. Reduction of the lactones with LAH gave diols 32, 90 and 127, and finally, cyclization with POC13 afforded 2, 3 and 15 respectively. In conclusion, a series of synthetic routes have been presented in this chapter, some of them starting from natural compounds already containing the trans-decalin system required for Ambrox®(2) (Schemes 1, 2, 4, 5, 6, 7, 8). In these studies degradation of higher molecular weight terpenes and/or modification of some functional groups had to be applied to access the desired carbon skeleton. Still, the best overall chemical yields are achieved through the commercial procedure involving the degradation of sclareol (Scheme 1). However, the fluctuations in the market prices of the starting material might allow the production of (-)-Ambrox®(2) from sources other than sclareol. It was with this intention that we initiated our research towards the production of (-)-Ambrox®(2) from thujone (1), a natural inexpensive starting material available in large quantities in British Columbia. In the following chapter the research directed towards the synthesis of (-)-Ambrox® (2) and (-)-epi-Ambrox (3), starting from thujone is presented, and its potential commercial applicability discussed.  33  2. RESULTS AND DISCUSSION.  2.1. The use of thujone as enantiopure building block in the synthesis of decalone systems. Thujone (1), a natural monoterpene known since 1939 57 , is currently obtained in British Columbia from the steam distillation of the slash of western red cedar (Thuja plicata  Donn). The essential oil thus obtained contains as much as 88 % of thujone (1). The natural product is actually a 10:1 mixture of two epimers: (-)-a-thujone (128) and (+)-(3-thujone (129) respectively.  1  ^  128^129  The separation of the two isomers has been reported 58 , but for the purpose of this work separation was not required. The unique structural features of thujone (1) will dictate the chemistry required to transform it into highly valuable enantiopure intermediates. The inherent cyclopropane ring proves to be a key feature for further transformation of thujone into more complex enantiopure molecules. The carbonyl group provides an entry to a large range of synthetic elaborations. Previous work in our laboratory has shown the utility of thujone (1) in the syntheses of natural sesquiterpenes 5c ,59 . Robinson annelation of thujone (1) with Michael acceptors such as MVK or EVK generates a new asymmetric center in the molecule (Scheme 18) within a high degree of stereoselectivity 59,60.  34  Base  1  ^  (0 11  R -^  -  130 : R= H 131: R= Me Scheme 18 Robinson annelation of thujone (1).  The cyclopropane ring directs the alkylation towards the less hindered face of the enolate, yielding the ring closed compounds 130/131 as isomerically pure products. The synthesis of 131 from 1 was performed following a method detailed in a previous publication (59), giving 131 in 50-55 % yield. Zoretic in 1975 61 reported the "acid-catalysed Robinson annelation" of 2-methylcyclohexanone, obtaining yields comparable to the "classic Robinson annelation", but the reaction was more convenient to perform. When this method was applied to thujone (1) using 1-chloropentan-3-one (prepared from propionyl chloride by Friedel-Crafts reaction with ethylene 62 ) and a catalytic amount of p-toluenesulfonic acid 63 , the result was a mixture of 131 and the diketone 132 in a 1:4 ratio respectively. The production of 132 was surprising, since in both the base-catalysed annulation of thujone (1) and in the acid-catalysed annulation of 2-methylcyclohexanone, direct dehydration of the cyclized hydroxy ketone took place to produce the corresponding enone.  35  132 Obviously the presence of the cyclopropane funtionality must retard the acid-catalysed aldol reaction required for cyclization. On the basis of the above, compound 131 seemed to be an attractive starting material towards our synthesis of (-)-Ambrox® (2). Since the carbon skeleton of (-)-Ambrox® (2) requires the furan ring attachment in ring B, it was necessary to attach a two carbon-unit at position C9 of 131 and to remove the isopropyl side chain at position C7. To this end a considerable amount of research had been previously done in our laboratory in order to find suitable ways to regioselectively open the cyclopropane ring unit to the 6-membered B -ring 5 a4. 59,63 . Functionalization at C6 or C12 of 131 is generally required in order to promote the ring opening. Previous studies revealed that treatment of ketal 133, derived from 131, with HBr (Scheme 19) afforded an efficient route to be used in a subsequent multi-step synthetic  134 Scheme 19 Hydrogen bromide promoted cyclopropyl ring opening.  36  sequence. If the hydroxyl function is present in the side chain, ring cleavage using reagents such as HC1, MgBr2 64,51 might afford the 5-membered B-ring compounds (Fig. 9).  OH  Fig. 9 Cyclopropyl ring cleavage to afford a 5-membered ring. In such cases, whether the reaction takes place stepwise through a cyclopropylcarbinyl cation or through a SN2' type in a concerted manner, has not been established. Also the use of other nucleophiles such as AcONa with 134 gave low yields of the desired 6-membered B-ring63 and this approach was not useful for our synthetic purposes. In the present studies we indeed tried several other approaches to open the cyclopropane ring: treatment of ketal 133 with LiCH2CO2Et, under different conditions, leads only to the quantitative recovery of unreacted starting material. Not even traces of the desired ring opened product were detected. Even though the preference of the opening to the 5-membered B-ring could be expected since the methylene carbon in 131 (C8) is more accessible, the hindrance to the incoming group ( - CH2CO2E0 and the relatively large size of the nucleophile itself, appears to be playing an important rule in preventing the attack. Prior to this work, it was reported 59 that reaction of ketal 133 with 48 % HBr in petroleum ether at 0° C (Scheme 19) gave enone 134 in 77 % yield. Interestingly when the reaction was performed at -78° C, only dihydroxy ketone 135 was obtained, in 85 % yield, which means that deprotection of the ketone is an easier process compared to the attack by the bromide ion onto the cyclopropyl ring. Compound 135 had a peak at m/z 252 (7.3 %)  37 11  and 234 (19.4 %) corresponding to the molecular ion and the loss of water from the molecule, respectively. The IR spectrum revealed an intense hydroxyl absorption at 3355 cm -1 and a carbonyl stretching band at 1708 cm -1 . Its 1 H nmr spectrum showed one methyl singlet at 8 1.23 ppm, three methyl doublets at 8 0.92, 1.00 and 1.03 ppm (J= 7 Hz), the first two corresponding to the methyl groups in the isopropyl side chain and the third one to the methyl at position C4. A doublet of doublet of doublets at 8 0.30 ppm (J= 8, 5, 1 Hz) corresponded to the C8-a proton since a small coupling with the proton at C6 is detected revealing a W-type of coupling. Such high field signals clearly establish that the opening of the cyclopropyl ring did not take place. A quartet at 8 2.57 ppm was observed, corresponding to the C4 proton. Its 13 C nmr spectrum revealed a peak at 8 212.18 ppm that corresponds to the carbonyl group, and two peaks at 8 82.68 and 81.14 ppm that correspond to the two carbons bearing hydroxyl groups. Recrystalization of 135 in diethyl ether/petroleum ether gave colourless needles which were subjected to X-ray analysis. The crystal structure (Fig. 10) surprisingly showed a 13 orientation of the hydroxyl groups, thereby establishing, that in contrast to previous assumptions as proposed by Kutney and coworkers 59 , hydroxylation (KMnO4) of the 5,6-double bond in the synthetic precursor leading to 133, occurs from the 13 face of the molecule. Clearly the steric hindrance to attack at the 5,6-double bond is dominated by the isopropyl side chain and not by the 13-oriented cyclopropyl ring and the angular methyl group. Subsequent reactions by other members in our laboratory have shown that  38  135  Fig. 10 Single crystal X-ray structure of dihydroxy ketone 135.  39 hydrogenation* or epoxidation** of 136 also proceeded from the 13 face of the double bond. A new and last attempt to open the cyclopropyl ring in the Robinson annelation product 131 was done by using bromine in petroleum ether.  136 Eastman had shown that treatment of thujone with bromine resulted in the formation of tribromide 141 65 46 . The mechanism of this reaction has recently been investigated by Cocker67 (Scheme 20). It was thought that initial bromination occurred to give the  Br  1  ^  137  ^  138  Br  141  ^  139  ^  140  Scheme 20 Proposed mechanism for bromination of thujone (1). * N. Cheng private communication. ** P. Gunning private communication.  40 a-bromoketone 137 which provided the rearranged bromide 138 via a nucleophilic attack by bromide ion, with simultaneous ring-opening of the cyclopropyl ring system. The double bond was then brominated to 139 which underwent dehydrobromination to 140. Allylic bromination of 140 would finally afford the tribromide 141, previously isolated by Eastman. Treatment of 131 using the same conditions as employed by Eastman with thujone (1), resulted in a complex product mixture which could not be further purified by column chromatography. We then focussed our attention towards the transformation of 134 in order to achieve the desired structure that would lead us to (-)-Ambrox® (2), but attempts to perform a nucleophilic displacement of the bromide with the anion of ethyl acetate, generated in similar fashion as in the previous study with 133, met with failure. In all cases only unreacted starting material was recovered. Only when the reaction mixture was heated at reflux for 18 hours, small quantities of a new product were detected on TLC, that after isolation and characterization was shown to be trienone 142.  142  Obviously under such conditions dehydrobromination took place, probably by a proton exchange process between the starting material and the nucleophile used Generation of a negative charge at position C8 is not unexpected since it would be stabilized by conjugation through the two double bonds and the ketone. Elimination then of the halogen atom would result in the formation of the double bond between positions C8 and C9, affording a highly conjugated system. The mass spectrum of 142 showed the molecular ion peak at m/z 216 while the IR spectrum indicated the absorption of a conjugated  41 carbonyl group at 1631 cm -1 and a carbon-carbon double bond stretching frequency at 1566 cm -1 . Its 1 H nmr spectrum showed a doublet at 8 1.14 ppm (6H, J= 8 Hz) corresponding to the two methyl groups of the isopropyl side chain, and two methyl singlets at 8 1.19 and 1.87 ppm corresponding to the methyl at C10 and the vinylic methyl group at C4 respectively. A one proton singlet at 8 6.31 ppm corresponds to the olefinic proton at C6. Two doublets at 8 5.94 and 6.05 ppm are assigned to the olefinic protons at C8 and C9. Its 13 C nmr spectrum displayed a peak at 8 197.7 ppm corresponding to the conjugated carbonyl, and 6 peaks between 8 116 and 159 ppm corresponding to the 6 olefinic carbons C4 to C9. 2.2. Investigations towards the synthesis of 143 from thujone (1).  Unable to find a simple and efficient way of funtionalizing position C9 in such intermediates as 131,134 and 135 directly at the early stages of the synthetic route, we turned our attention to enone 143 which became the target intermediate towards the synthesis of (-)-Ambrox® (2).  143  Previous work in our laboratory had established a plausible sequence towards the natural sesquiterpene 13-cyperone (144) 59 (Scheme 21), and consideration of segments of the chemistry involved was undertaken for the present study. Degradation of the isopropyl group was required in order to achieve a suitable route to enone 143. Different strategies leading to 143 were being tested in our laboratory. The most successful one which has been published recently 5 f, involves the fl-cyperone (144)  42 as an intermediate to the desired enone 143 (Scheme 25). In our efforts to find a more efficient sequence to access enone 143, a different approach was investigated. This study involved methylation of enone 131 in order to obtain the two methyl groups required at position C4, using either potassium tert-butoxide or potassium tert-amylate as bases, in refluxing tert-butanol or benzene respectively, to ensure the formation of the more substituted enolate prior to alkylation. In both cases, the desired compound 145 0 I-  b  \1 / Et Me Et  1  131  d  136  e  OH 133  134  144  a) KOH, EtOH, 53 %; b) 2,2-dimethyl-1,3-propanediol, H + , C6H 6, reflux, 62 %; c) KMnO 4 , OW, t-BuOH/H 20; d) 48 % HBr, pet-ether, 0° C, (83 %; 2 steps); e) IABN, Bu3SnH, C6H 6, 75 %.  Scheme 21 Kutney's synthesis of I3-cyperone (144) from thujone (1). was obtained as a major product although the use of potassium tert-amylate provided better yields of ketone 145 (87 % as compared to 62 % when potassium tert-butoxide was used). Compound 145 showed the molecular ion peak at m/z 232 in the mass spectrum, while the IR spectrum indicated a strong absorption of a non conjugated carbonyl group at 1710 cm -1 and a weak absorption at 1620 cm -1 corresponding to the carbon-carbon double bond  43 stretching frequency. Its 1 H nmr spectrum showed three methyl singlets at 8 1.12, 1.19 and 1.22 ppm and a singlet at 8 5.51 ppm which corresponds to the olefinic proton at C6.  Huang-Minlon modification of the Wolff-Kishner reduction with compound 145 yielded compound 146 in 69 % yield. Its mass spectrum showed the molecular peak  at m/z 218 (90.6 %), while the IR spectrum indicated a weak absorption at 1610 cm -1 corresponding to the carbon-carbon double bond.  Ozonization of saturated hydrocarbons yielding ketones and alcohols by an oxygen insertion process into C-H bonds is well documented 68,69 . In general, tertiary carbons are preferentially attacked, however this type of process requires long reaction time, leading sometimes to over-oxidation and poor selectivity. Extensive research in this field has been done in our laboratory5 f,51 , in relation to the chemistry of thujone (1). We envisaged a possible sequence towards our key intermediate, enone 143 (Scheme 22), based on related similar work developed by other members in our group 51 , and hoping that the internal C5-C6 double bond in ring B would be hindered enough to selectively ozonize the isopropyl side chain without affecting it. Unfortunately, that was not the case. Attempts to effect ozonation of compound 146 in order to functionalize the  44 isopropyl side chain prior to the opening of the cyclopropyl ring, showed cleavage of the double bond to be a much faster process than functionalization of the tertiary carbon at the isopropyl side chain, yielding at the end an inseparable mixture of several products.  146  ^  147  ^  148^143  Scheme 22 Proposed sequence to enone143 from 146. In order to avoid that problem, the double bond was first converted to diol 149 with potassium permanganate using the same conditions as for the well established route to f3-cyperone 59 , yielding 149 in 70 % yield. The latter compound was then ozonized to give triol 150 and ketone 151 (Scheme 23). Several conditions and solvents were evaluated  03  +  150  Scheme 23 Ozonation of diol 149. (table 1) to optimize this step. Unfortunately the best yields achieved were too low to make the overall sequence appealing for our purposes.  45 At this stage in our study, it became clear that the proposed strategy consisted of too many steps and low yields in the ozonization process to obtain the required enone 143 (Scheme 24). For this reason, any further studies with the ozonation reaction were dicontinued. Solvent system  Temperature  isolated yields  time  150^151  Me0H/CH2C12 1:9  -10° C  2.5 h  10 %  14 %  CH2C12  0°C  2h  14%  20%  EtOAc  -40° C  6h  25 %  36 %  Table 1 Optimization of ozonization conditions for diol 149. We finally decided to follow the previously established and already published sequence towards enone 143 from I3-cyperone 5 f (Scheme 25).  ..... OR  OR  154  143  Scheme 24 Envisaged synthetic sequence to enone 143 from 152.  OH  46 Some improvements in the yield of the methylation and ozonation steps from the original sequence, were achieved in the present study. Thus consistent isolated yields ranging 35 to 45 % of the methylated ketones 156/157 were obtained when using DMSO dried over molecular seives, as reported 5 f, but the yields were readily increased up to 62 % when freshly distilled DMSO over CaO was used in the reaction. Also the earlier difficulties associated with yield reproducibility in the ozonation of 158 (generally below 50 %) were overcome by changing the solvent system (CH2C12/MeOH) from 9:1 to a 1:3  b  a  144  ^  156/157  ^  157  d  158  ^  143  a) NaOMe, DMSO; MeI; b) 12, hexane, reflux; c) H2N-NH -78° C.  2. KOH, DEG; d) 03,  Me0H/CH2C12  Scheme 25 Kutney's synthesis of enone 143 from 13 - cyperone (144). ratio, as reported by de Groot et al. 70 in their synthesis of enone 143 starting from (-)-dihydrocarvone 159 (Scheme 26).  47  2.3. Investigations towards the synthesis of racemic 143 from 2-methylcyclohexanone. A synthesis of enone 143, in its racemic form, was also performed, in a short four-step sequence starting from 2-methylcyclohexanone (Scheme 27). The idea was  161  162  163  143  158  a) MVK, KOH, 0° C; b) KOH, CH3OH, A; c) KO t-Bu, CH 31; d) H 2N-NH  2,  KOH, 200° C; e) 03.  Scheme 26 De Groot's synthesis of enone 143 from (-)-dihydrocarvone (159).  to effect model synthetic studies towards Ambrox® (2) on the racemic compound first, before applying them to our enantiomerically pure material derived from thujone (1). As previously described, the Robinson annelation reaction is a powerful method for ring construction. Annulation of 2-methylcyclohexanone (1 6 4 ) and 1-chloropentan-3-one 62 with a catalytic amount of p-toluenesulfonic acid in benzene, was done as reported in the literature by Zoretic 61 . This method presumably generates  in situ the  vinyl ketone, using the acid to catalyse not only the Michael addition but also the aldol condensation and subsequent dehydration, affording, at the end, the desired cyclized product 165, in a one-step operation and in reasonable yields. Other methods which  48  a  c  b  164  166  165 d  167  ^li-  ^  143  a) 1-Chloropentan-3-one, p-TsOH, C6H 6, reflux; b) Famylate, CH 31; c) H 2N-NH 2, KOH, DEG; d) Na 2Cr 20 7, HOAc.  Scheme 27 Synthesis of racemic enone 143.  involve the direct use of EVK, or perform the Michael addition reaction first and the aldol condensation in a second step, using either acid or basena -c, have been shown to give lower or similar yields to those achieved by Zoretic's method. Compound 165 showed a peak at m/z 178 corresponding to the molecular ion in the mass spectrum. Its UV spectrum displayed a maximum at X= 249 cm -1 , in accordance with the a,13-unsaturated ketone. Methylation of enone 165 was conducted using potassium tert-amylate (which has previously been shown to give remarkably higher yields of alkylation than the more commonly used potassium tert-butoxide) as basena b in refluxing benzene (Scheme 28). ,  Under these conditions, the thermodynamically more stable enolate (i) is expected to be formed. Indeed, compound 166 was isolated in 88 % yield together with 8 % of the trimethylated product.  49 Compound 166 had a peak at m/z 192 corresponding to the molecular ion in the mass spectrum. Its 1 H nmr showed two methyl singlets at 8 0.99 (3H) and 1.24 (61I) ppm, and a triplet at 8 5.58 ppm (J= 4 Hz) which corresponds to the olefinic proton at C6. The IR spectrum showed a carbonyl absorption at 1710 cm-1 and a carbon-carbon double bond absorption at 1645 cm -1 .  165 Mel  168  Scheme 28 The alkylation process involving racemic enone 165. Reduction of the carbonyl group in 166 was done by the Huang-Minlon modification of the Wolff-Kishner reaction yielding compound 167 in 78 %. The mass spectrum of compound 167 showed a peak at m/z 178 corresponding to the molecular ion. The LR spectrum showed an absorption at 1620 cm-1 corresponding to the carbon-carbon double bond. The 1 1-1 nmr spectrum showed three methyl singlets at 8 0.97, 1.01 and 1.10 ppm; and a triplet at 5.37 ppm (J= 4 Hz) corresponding to the olefinic proton at C6.  50  167  Having compound 167 available only an allylic oxidation 73 remained to be done to obtain enone 143. This was performed by using a slight excess of sodium dichromate in glacial acetic acid following a procedure previously employed on the same molecule 74 , furnishing enone 143 in 75 % yield. Compound 143 thus obtained showed exactly the same spectroscopic data as for the enantiopure enone prepared from thujone through the (3-cyperone (144) intermediate. Therefore preparation of enone 143 in its racemic form  Cco 169  1)base 2) MVK  ^  143  Scheme 29 Robinson annelation of compound 169. is achieved in four synthetic steps within reasonably good overall yield. A further improvement could involve a one-step conversion in order to obtain enone 143 as a racemate from a trimethylated cyclohexanone (Scheme 29). Unfortunately that was not the case. Treatment of the trimethylated ketone 169 with base and MVK; or 1-chlorobutan-3-one and p-toluenesulfonic acid resulted in recovery of the starting material and partial decomposition. This fact is probably due to the high steric congestion of the molecule which possibly prevents the approach of the Michael acceptor. Also part of the difficulty in the methyl vinyl ketone addition seemed to be due to competitive self condensation of the methyl vinyl ketone and/or further condensation of MVK with the  51  initial Michael adduct. To overcome this synthetic failure multi-step procedures have been proposed71 0 5 , but yields ranged usually from 10 to 40 %. 2.4. Ketone transposition studies on racemic and enantiopure 143.  As mentioned earlier (p. 48) studies to obtain racemic 143 from 2-methylcyclohexanone were developed first to be followed by studies to prepare enantiopure 143 from thujone (1). In the discussion which follows, both racemic and enantiopure 143 were converted to the subsequent intermediates required for the synthesis of (±)-Ambrox and (-)-Ambrox respectively. Except for optical activity exhibited by compounds in the enantiopure series, the chemistry and other spectroscopic data is identical for both racemic and enantiopure series. The data reported is for the enantiopure series. In order to functionalize decalone 143 in a way that would lead us to Ambrox® (2), it was evident that a two carbon unit had to be attached at position C9. Previous attempts in our group to undergo 1,4-addition at position C9 on dienone 170 proved to be ineffective. Only 1,2-addition products were consistently isolated* , proving that position C9 was not easily accessible. Probably the presence of an axial methyl group  170  at position C10 is the responsible for such a failure. However when similar reaction was performed with the cis-decalone 171, the 1,4-addition product was isolated in  moderate yields 51 .  * N. Cheng private communication.  52  171  With that information in hand, a ketone transposition process became the logical route to follow (Scheme 30). Many procedures have been published in the literature to effect carbonyl transposition. Most of them are based on two logical synthetic operations :  143  ^  172  Scheme 30 Ketone transposition from position C7 to C8. first, oxidation at the saturated a position of the carbonyl, followed by reduction of the original carbonyl function. These two basic operations usually require a sequence of four or more steps 76,77,78 therefore lowering the efficiency of the overall transposition. In this study it is important to maintain the double bond functionality during the transposition steps, in order to ensure the regioselective alkylation at position C9. Otherwise competing alkylation is expected at C7, when both C7 and C9 positions are accessible for alkylation 79,80 . In effect, the double bond "blocks" the position C7 thus preventing its alkylation. A commonly used and well established procedure consists in initial formation of the corresponding tosylhydrazone, subsequent transformation to the enol thioether and finally hydrolysis to the ketone 81 . A similar problem relating to the above has been encountered by de Groot at (21. 82 in  their attempts to provide an entry to Ambrox® and in routes to polygodial (Scheme 31).  53  ^->  173  ^  159  ^  b, c  a  174  ^  163  175  ^  176  a) PhCHO, NaOH; b) LiA1H 4 / AlC1 3; c) 03 .  Scheme 31 De Groot's synthesis of ketone 176 from S(+)-carvone (173).  They also envisaged the necessity of a ketone transposition from C7 to C9 in order to have access to C9 functionalization. Having prepared enone 143 from (-)-dihydrocarvone (159) 70 , they hydrogenated the double bond to the trans-decalone system before effecting the ketone transposition sequence. First, functionalization at position C8 via benzylidene formation, afforded compound 175. Reduction of the benzylidene derivative 175 with LAH/A1C13 followed by ozonolysis afforded ketone 176 in 17 % yield from 174. This entry towards Ambrox® chemistry illustrates the problem previously mentioned since any attempt of alkylation at the a positions of the carbonyl group is indeed directed towards position C7 instead of C9 79,80 . A similar sequence for ketone transposition was previously evaluated in our laboratory utilizing racemic 143 (Scheme 32) * . The sequence envisaged relied on a selective ozonolysis of the exocyclic double bond in 178 in the final steps. Unfortunately * D. Guggisherg private communication.  54 Ph  Ph^  143  ^  177  ^  178  179  Scheme 32 A proposed sequence leading to racemic enone 172 from racemic 143. the difficulties associated with obtaining intermediate 178 demanded that this sequence be abandoned. Treatment of enone 143 with benzaldehyde and base afforded dienone 177, which was then treated with LAH/A1C13 furnishing racemic diene 180 (Scheme 33) in 18 % yield from racemic enone 143. Ph^  a  143  ^  b  177  ^  a) PhCHO, t-BuOK, Me0H; b) LAH/A1C13, Et20 Scheme 33 Synthesis of racemic diene 180.  180  Ph  55 The direct formation of the conjugated diene 180, instead of the desired non conjugated diene 178 was found to take place. This fact made the sequence useless for the ketone transposition purposes, since ozonolysis of 180 would lead to the ring cleavage product due to the lability of the endocyclic double bond to ozone. In the case of 178 a regioselective cleavage of the side chain by ozone was expected since the endocyclic double bond is relatively more sterically hindered than the exocyclic one. Indeed earlier studies in our laboratory (Scheme 25) had revealed that selective ozonation of an exocyclic double bond is possible without cleavage of the 5,6-double bond in 178.  Scheme 34 A proposed ketone transposition sequence from enantiopure 143 to enantiopure 172. In our case a different approach to the target molecule (enantiopure enone 172) was achieved, and a novel sequence for the transposition of ketone is summarized in Scheme 34. The first step of our sequence requires an oxidation at position C8. The interest in the synthesis of complex natural products such as quassinoids 83 a ,b and corticosteroids has stimulated a search for oxidants capable of effecting a direct hydroxylation of ketones. Literature procedures available commonly involve the use of lead (IV) acetate 84,85 or mercury (II) acetate 84,86 a ,b, but in general the yields vary from poor to acceptable 87,88 : 3-42 % for Pb(OAc)4, and 23-25 % for Hg(OAc)2 when recovered starting material is not taken into account. In 1976 Williams and Hunter89 reported the a-hydroxylation of a,(3-unsaturated ketones by using manganese (III) acetate but only modest yields were  56 obtained. Reinvestigation of this reaction by Watt et a1. 90,91 was undertaken, suspecting that manganese (III) acetate might be less reactive than lead (IV) acetate and the absence of water might improve the yields reported by Williams and Hunter. Indeed, when the manganese (III) acetate was carefully dried 91 , the yields of the desired oxidations were improved to 80-90 % 91 . The proposed mechanism92 for this oxidation is analogous to the one proposed by Corey and Schaefer for acetoxylation of ketones 89,93 using lead (IV) acetate. It is postulated to go through an interaction of the a,(3-unsaturated ketone with the manganese complex resulting in intramolecular acetate transfer via metal-enolate formation (Fig. 11).  )  Fig. 11 Proposed mechanism for a-acetoxylation of a,(3-unsaturated ketones. In one of the publications by Watt et al. 94 a very similar molecule to ours was reported to give 84 % of the acetoxylated product. When the reported conditions were applied to 143 only low to moderate yields (35-60 %) of the acetoxylated product were obtained even though special care was taken in drying the manganese (III) acetate 94 . Since manganese (III) acetate is commercially available in its hydrated form, the reported drying method (phosphorus pentoxide and high vacuum for several days) proved to be insufficient for our purpose. Indeed when azeotropic removal of water was carried out, the lower yields obtained by Watt 90,91 could be improved and the desired acetoxyketones 185/186 were obtained in 86 % yield (Fig. 12).  57  143  186 Fig. 12 Proposed mechanism for oc-acetoxylation of chiral enone 143.  a-Acetoxylation of enone 143 resulted in an inseparable mixture of isomers 185/186 in 4:1 ratio. Assignment of the structures was done based on the analysis of the C8 proton signal in the Ili nmr spectrum. The proton at position C8 of the major isomer displayed a triplet at 8 5.25 ppm (J= 4 Hz) which is in accordance with an equatorial position at C8 since it resides at an equal angle from the C9-ocH and C94311 (Fig. 13).  13  a  Fig. 13 The spatial relationship of the C8 and C9 protons in isomers 185/186.  On the other hand, the minor isomer, with its acetoxyl group in the a-orientation, displayed a doublet of doublets at 8 5.60 ppm (J= 12, 4 Hz) for the axial C8 proton, being  58 antiperiplanar to the C9-aH, and displaying therefore a large coupling constant (J= 12 Hz) when coupled with this hydrogen, and a small coupling constant (J= 4 Hz) when coupled with C9-1311, which corresponds to an angle of — 60°. The mass spectrum of 185/186 showed a peak at m/z 250 corresponding to the molecular ion. The IR spectrum of the mixture displayed two intense absorptions at 1718 and 1660 cm -1 corresponding to the ester group and the a,(3-unsaturated ketone respectively. A carbon-carbon double bond absorption was present at 1596 cm -1 . The 1 H nmr spectrum of the mixture revealed also eight methyl singlets, four at 6 1.180, 1.250, 1.400 and 2.120 ppm corresponding to the major isomer, and four corresponding to the minor isomer at 6 1.175, 1.245, 1.395 and 2.115 ppm. The mixture of isomers 185/186 was reduced with LAH yielding a mixture of four isomeric diols 187/188/189/190 in a ratio of 50:1:3:18, as observed after isolation of the pure diols. The diols 1 8 7-1 90 were separated by column chromatography for characterization purposes. Assignment of the different configurations was done by 1 H nmr nOe difference experiments. It was expected that the two major isomers should possess the hydroxyl group at position C7 in the 13 orientation, since the reducing agent was expected to approach the carbonyl function predominantly from the less hindered side (a face). The major isomer (187) displayed a peak at m/z 210 in the mass spectrum corresponding to the molecular ion. Its lR spectrum showed a hydroxyl stretching frequency at 3349 cm -1 and a carbon-carbon double bond absorption at 1627 cm -1 . Its 1 H nmr spectrum displayed three methyl singlets at 6 1.09, 1.16 and 1.35 ppm. A doublet of doublet of doublets at 6 3.93 ppm (J= 7, 4, 3 Hz) corresponded to the proton at C8 position, a doublet of doublets at 6 4.21 ppm (J= 4, 4 Hz) could be assigned to the proton at C7, while the doublet at 8 5.45 ppm (J= 4 Hz) corresponded to the olefinic proton at C6. A nOe difference experiment showed that irradiation of the singlet resonating at 6 1.09 ppm enhanced the doublet resonating at 6 5.45 ppm, revealing, as expected, that of the two methyls at position C4 only one of these, close in space to the olefinic proton, is expected  59 to produce enhancement. Indeed, irradiation of the doublet at 6 5.45 ppm enhanced the methyl signal at 6 1.09 ppm and the signal at 8 4.21 ppm which corresponds to the proton at C7. Therefore the methyl at 6 1.09 ppm corresponds to the aCH3 at position C4 (Fig. 14).  Fig. 14 A summary of proton interactions as determined from an nOe difference experiment with enantiopure 187. Irradiation of the signal at 8 1.35 ppm produced an enhancement on the signal at  8 1.16 ppm, and as expected, no enhancement at 6 3.93 ppm was observed, suggesting that the proton at position C8 is oriented on the a face (pseudoequatorial). In addition, enhancement at 6 1.51 ppm was also detected, for the C9-H, so the signal at 8 1.35 ppm must correspond to the axial methyl group at position C10. Irradiation of the signal at 8 3.93 ppm enhanced the signal at 8 4.21 ppm, thereby affording evidence for the C7-a hydrogen or, in turn, placing the C7 hydroxyl function in the pseudoaxial orientation. This result is not surprising since reduction of the carbonyl at position C7 was expected to take place predominantly from the a face since the 0 face is more sterically hindered due to the presence of the axial methyl groups, which are expected to hinder the approach of the reducing agent. We could conclude then that diol 187 corresponds to the 70, 813-dihydroxy functionalized decalin system. NOe difference experiment for diol 188 (Fig. 15) showed that the proton at position C8 is 0-oriented since irradiation of the methyl singlet resonating at 6 1.24 ppm  60 gave enhancement to the signal at 8 3.95 ppm, and to the signal resonating at 6 1.10 ppm. On this basis, the methyl signal at 8 1.35 ppm must correspond to the C10-CH3 while the  C 14C e ---  —"  i  H OH  Fig. 15 A summary of proton interactions as determined from an nOe difference experiment with enantiopure 188.  signal at 8 1.10 ppm can be assigned to the C4-f3CH3. Information about the position of the C7 proton could not be obtained from the results of the nOe experiment, but was assumed to be a by comparison with the other C8 a-hydroxy isomer. The later was shown to have an nOe enhancement at 8 3.85 ppm when irradiation at 8 1.28 ppm was done (Fig. 16). Irradiation of the C7 proton at 8 4.08 ppm produced an enhancement of the olefinic proton signal and an enhancement of the C9-aH. Therefore the configuration of the remaining diol (189) was tentatively assigned to be the 7a, 813-diol, a minor product if, as noted above, reduction of the carbonyl group, occurs from the 13 face of the molecules.  r IACM,4 -  OH OH  Fig. 16 A summary of proton interactions as determined from an nOe difference experiment with enantiopure 190.  61 The following dehydration step was experimentally rather "delicate". A selective dehydration of the hydroxyl at position C7 was required in order to furnish the desired ketone 172. It is well known that allylic hydroxyls can dehydrate readily in view of the expected formation of a resonance-stabilized carbocation intermediate. The expected different reactivity of the two hydroxyl groups was a key factor for the success of the sequence. Discrimination of the hydroxyls groups under acidic conditions was indeed achieved and the hydroxyl at C7 underwent selective dehydration and conversion to the desired product 172 (Fig. 17). Loss of a proton from position C8 generates the enol form which equilibrates to the ketone form. Finally migration of the double bond towards the conjugated position furnishes enone 172. The elimination of the hydroxyl group at C8 would simply regenerate the initial enone 143 but this was not observed. The final step, in which the migration of the double bond occurs, was expected to take place easily under acidic conditions, fortunately towards the desired trans-decalone system. It has been reported that ketone 179 under acidic or basic conditions 95 isomerizes predominantly to the cis-decalone system, which seems to be the thermodynamically more stable product. Different acids, as well as solvent systems, have been evaluated by Snowden 95 and Kato96 . These workers found that only by using p-toluenesulfonic acid in methanol, were they able to obtain a 1:1 ratio of cis/trans products, in all the other cases the cis-decalone was always the major product. In our case, we were able to obtain the 'kinetic' product (trans-decalone) by using 1.2 equivalents of p-toluenesulfonic acid and 0.1 M concentration of diols 187-190 in anhydrous THF. Under these conditions, 64 % of the trans-enone (172), 25 % of the non conjugated enone (179), and less than 2 % of the cis-enone (191) were isolated. These results suggested that an equilibrium between the conjugated and non conjugated systems existed, with the trans isomer predominating. Indeed, when enone 179 was submitted to the same conditions, a 65 % yield of the trans-decalone (172), and 31 % of the non conjugated enone (179) was obtained, while no cis-decalone was isolated.  62  OH  191 187 -190 OH  143  Fig. 17 Proposed mechanism for the dehydration of enantiopure diols 187-190. The overall yield in the three steps for the conversion,187-190 to 172, was 64 % when the isolated non conjugated enone (179) was recycled. A notable advantage of this novel sequence is that these three operations can be done without isolation of the intermediates, so that an effective route to 172 was now available. For preparative purposes, the sequence, 143 -4 185/186 ---) 187-190 -4 172, can be conducted without isolation of the pure components in the various stages. Compound 172 displayed a peak at m/z 192 in the mass spectrum corresponding to the molecular ion. Its 1 H and 13 C nmr spectra agreed with the published data 95 although an authentic sample was unavailable for direct comparison, similarly the data for the cis-decalone (191) and the non conjugated enone (179) were also in agreement with the published data95 . Confirmation of the stereochemistry for the cis-decalone (191) was done  63 by a nOe difference experiment, since irradiation of the methyl at C10 (S 1.00 ppm) enhanced the signal corresponding to the proton at C5 (8 1.91 ppm) as expected. In accordance with this supposition, such enhancement was not observed with the corresponding trans isomer. Enone 172 as well as 179 have been prepared as racemic intermediates, by a completely different route, by Snowden et al. 95 in their synthesis of (f)-Polywood® *  (192) and its unsaturated analogs. On this basis, a formal synthesis of (-)-Polywood® (192) and its enantiopure unsaturated analogs has been completed starting from thujone (1) (Scheme 35). Having found an efficient procedure to obtain ketone 172, we focussed our attention on the alkylation step which we expected to take place at position C9 by generating the kinetic enolate (i).  i  * Polywood® is a trade name from Finnenich S.A.  64  1  143 ,,OH  a  +  OAc c  192  OAc  ,OAc  195  196 ,.OH  a  +  ,,OAc  192  199  200  a) NaBH4 , Me0H; b) Ac 2 0, pyr.; c) H2 Pd-C, EtOH.  Scheme 35 Formal synthesis of (-)-Polywood® (192) and its enantiopure unsaturated analogs starting from thujone (1).  65 A two-carbon unit was required at position C9. The fact that in earlier studies no reaction at all was detected when ethylene oxide97,98,99 or 2-bromoethyl methyl ether were used as electrophiles cast some doubt about the formation of the enolate and/or its subsequent reaction. To ensure that formation of the enolate was taking place, an evaluation of incorporation of deuterium was performed. Generation of the enolate with lithium diisopropylamine at -78° C, 0° C and 25° C and then quenching with deuterated water, showed good incorporation of deuterium even at -78° C. Confirmation of the extent of the incorporation of deuterium was done by 1 H nmr analysis, since the integration of the signal corresponding to the two C9 protons (8 2.21 ppm) was reduced by almost 50 % when deuterium was incorporated. These results established that the formation of the enolate was not the reason for the above failures. Clearly a more reactive electrophile had to be found in order to undergo reaction with the enolate. Ethyl iodoacetate proved to be sufficiently reactive to give alkylation in reasonable yields (73 %). The product was isolated together with unreacted starting enone (172) (18 %) and a new compound (202) (8 %) (Scheme 36). This new compound 202 showed a peak at m/z 318 in the mass I  172  ^  201  ^  202  Scheme 36 Alkylation of enantiopure enone 172.  spectrum corresponding to the molecular ion, and a peak at m/z 191 corresponding to the loss of iodide, therefore indicating that an atom of iodine had been incorporated into the molecule. Probably iodide ion released in the alkylation process, dimerizes to iodine and this then proceeds to react with the anion to afford 202 (Fig. 18).  66 The IR spectrum of compound 202 revealed a conjugated carbonyl absorption at 1675 cm -1 and a carbon-carbon double bond stretching frequency at 1610 cm -1 . Its 1 H nmr spectrum displayed three methyl singlets at 8 0.95, 1.11 and 1.16 ppm. A doublet corresponding to the C9 proton (8 4.26 ppm, J= 1.4 Hz) indicates a W coupling with the olefinic proton signal at C7 resonating at 8 6.12 ppm. The presence of such coupling can only be explained if we consider the C9 proton to be in an equatorial position, indicating then that the iodide must be axially oriented, this fact was latter confirmed by an nOe difference experiment. A doublet of doublet of doublets at 6 6.12 ppm (.1.-- 10, 3, 1.4 Hz) corresponded to the olefinic proton at C7 which is in turn coupled with the C6 proton  (J= 10 Hz), with the C9 proton by a W coupling (J= 1.4 Hz) and with the C5 proton by a long range coupling constant (J= 3 Hz). A doublet of doublets at 8 6.89 ppm corresponded to the olefinic proton at C6 which is coupled with the C7 proton (J= 10 Hz) and the C5  H  204  202  Fig. 18 Proposed mechanism of formation of compound 202.  67  proton (J= 2 Hz). An nOe difference experiment showed that irradiation at 8 1.16 ppm produced enhancement of the signals at 5 0.95 and 4.26 ppm indicating that this signal  Fig 19 A summary of proton interactions as determined from an nOe difference experiment with enantiopure 202. corresponds to the C10 methyl group and in turn, also revealing that the C9 proton is in the pseudoequatorial orientation as shown in Fig. 19. The mass spectrum of 201 showed the molecular ion peak at m/z 278, while the IR spectrum revealed the absorption of two carbonyl groups at 1737 and 1679 cm -1 corresponding to the ester group and the unsaturated ketone respectively, and a carbon-carbon double bond stretching frequency at 1612 cm -1 . The 1 H nmr spectrum displayed three methyl singlets at 8 0.92, 1.06 and 1.08 ppm, and a methyl triplet (J= 8 Hz) at 8 1.25 ppm. A one-proton doublet of doublets (J= 15, 8 Hz) corresponding to one of the protons at position C11, and a one-proton doublet of doublets at 5 2.50 ppm (J= 8, 8 Hz) corresponding to the C9 proton were also observed. A doublet of doublets resonating at 6 2.64 ppm (J= 15, 8 Hz) was assigned to the other proton at position C11. A quartet (J= 8 Hz) at 5 4.15 ppm corresponded to the methylene of the ethyl ester function. Two olefinic protons resonating at S 6.00 and 6.85 ppm corresponded to the C7-H and C6-H respectively. An nOe difference experiment revealed that the ethyl ester side chain,  like the iodide in compound 202, is oriented in an axial position, indicating that the approach of the electrophile again has taken place from the a face of the molecule. The  68 axial methyl group at position C10 is probably responsible in controlling the approach of the electrophile (Fig. 20), resulting in a highly stereoselective process since none of the C9 oc-epimer has been observed. Irradiation of the methyl singlet resonating at 8 1.08 ppm enhanced the signals at 8 0.92 and 2.50 ppm, corresponding to the axial methyl group at position C4 and the  203 COOEt !  0  H ( ii )  /---COOEt -  201  Fig. 20 Mechanistic analysis for the stereoselective alkylation of enantiopure 172.  proton at C9 respectively (Fig. 21). Conversely, irradiation of the methyl singlet at  8 1.06 ppm enhanced the signals at 8 0.92, 2.14 and 6.85 ppm, which corresponded to the C4 13-Methyl, C5-H and C6-H respectively. On this basis, the signal at 8 1.06 ppm was assigned to be the equatorial methyl group at position C4. Since the alkylation process took place in the desired manner, we had a potentially very attractive entry towards the synthesis of epi-Ambrox (3), the C9 isomer of Ambrox® (2), which as mentioned in the introduction, showed the strongest scent of the entire series. The presence of the side chain in an axial position, suggested the possibility of  irradiation at 1.08 ppm  irradiation at 1.06 ppm  0 -012- C H3  C6-H^C7-H lul 71-I11TT  -11-  r  -r -T - 7 -  111.  11i1i-r-1-1■■1^ 1 17 I 1-1-1^  r  TTT  1 1-1t  - I-  1-  r  r r r r  rt  6. 5^6. 0^5. 5^5. 0^4. 5^4. 0^3. 5^3. 0^2. S^2. 0^1. 5^1 0 PPM  Fig. 21 NOe difference experiment for enantiopure enone 201.  rr  70 isomerization of the side chain to a more stable equatorial position at a later stage in the sequence. On this basis, the synthetic route permits the synthesis of both, Ambrox® (2) and epi-Ambrox (3). Catalytic hydrogenation of the double bond in 201 was achieved in quantitative yield by using catalytic amounts of 10 % palladium on charcoal in ethanol at 40 psi of hydrogen. Under these conditions the double bond in compound 201 was selectively hydrogenated in 20 minutes without reducing the carbonyl group. The mass spectrum of the hydrogenated compound(205) showed the molecular peak at m/z 280 while the IR spectrum indicated only an intense carbonyl absorption at 1732 cm -1 . Its 1 H nmr spectrum displayed three methyl singlets at 8 0.87, 0.98 and 0.99 ppm, a methyl triplet at 8 1.24 ppm (J= 8 Hz) and a methylene quartet at 8 4.11 ppm (J= 8 Hz) characteristic of the ethyl ester function. Its 13 C nmr spectrum revealed a peak at 8 213.04 ppm corresponding to the saturated carbonyl of the ketone and a peak at 8 171.72 ppm which corresponded to the carbonyl of the ester group. At this stage, selective 1.2-addition to the ketone functionality was attempted. Organocerium reagents, generated by the reaction of organolithium reagents with cerium (III) halides 100a-c have been reported to be excellent reagents for 1,2-additions to ketones and aldehydes 101,102,103 . They undergo efficient carbonyl addition, even in cases where substrates are susceptible to enolization or conjugate addition. Selectivity of the cerium reagent towards the carbonyl function of a ketone in preference to an ester, when both are present in a molecule, has also been reported to proceed in excellent yields 102 . Based on this information, a 3-step sequence to epi-Ambrox (3) was envisaged from 205 (Scheme 37). In our case, unfortunately, such selectivity was not observed. Reaction of racemic keto ester 205 with a methyl cerium (III) reagent, generated by reaction of the methyllithium with anhydrous cerium (III) chloride 100 a, at 0° C, afforded only an inseparable mixture of several compounds and a majority (72 %) of starting material  71 recovered. The 1 H nmr spectrum of the complex mixture showed the absence of the characteristic ethyl ester signals thereby suggesting that reaction with the ester function had indeed occurred. COOEt  COOEt  0^  OH^  OH CH3  205  3  207  206  Scheme 37 A proposed sequence to epi-Ambrox (3) from 205. The mass spectrum also showed a peak at m/z 266 which would correspond to the hydroxy ketone 208. If an attack at the carbonyl of the ketone had taken place, a peak at 296 would have been observed, corresponding to the hydroxyl ester 206; if on the other hand, 206 gave spontaneous lactonization to 209, a peak at 249 would have been expected, none of them have been observed in the mass spectrum. HO 0  1 21  206  *0  0 CH3  _  H  208^209  The same reaction was attempted on keto ester 201. In this case 201 was shown to be more reactive towards the organocerium reagent than 205, since reaction at -78°C already led to a 71 % consumption of the starting keto ester. Chromatographic purification of the reaction mixture led to the isolation of the starting keto ester 201 and keto alcohol 210 in 29 % and 22 % yields respectively. Several other byproducts, not identified, were noted. Keto alcohol 210 showed a molecular ion peak at m/z 264 in the  72 noted. Keto alcohol 210 showed a molecular ion peak at m/z 264 in the mass spectrum. Its IR spectrum displayed a hydroxyl absorption at 3380 cm -1 . An absorption at 1674 cm -1 indicated the presence of the unsaturated carbonyl function while a weak absorption at 1630 cm-1 corresponded to the presence of a carbon-carbon double bond.  Therefore and in contrast to the literature data, selective attack at the ketone carbonyl was not achieved, another sequence involving protection-deprotection of the different functionalities was now a necessity. Isomerization of 205 at position C9 was also attempted under basic conditions but only low yields of the isomeric product 211 were obtained. However no unreacted starting material was recovered, indicating that probably hydrolysis of the ester took place to the more polar carboxylic acid. A low recovery of material, and no further decomposition products were isolated during chromatography. It was felt that the resulting carboxylic acid was probably lost on the column. Compound 211 showed a peak at m/z 280 in the mass spectrum and this corresponded to the molecular ion. Its IR spectrum displayed two intense  73 carbonyl absorptions at 1733 and 1723 cm -1 corresponding to the ester and ketone groups. Its 1 H nmr spectrum displayed three methyl singlets at 8 0.74, 0.86 and 0.98 ppm, a methyl triplet at 8 1.26 ppm (J= 7 Hz) and a methylene double quartet at 8 4.12 ppm (J= 7, 2 Hz) which corresponded to the ethyl ester function.  2.5. Studies concerning the protection of the ketone functionality in enantiopure 205. Protection of the ketone group in compound 205 was required prior to reduction of the ester with LAH. Several methods were studied and their efficiency evaluated. Isoe et al. reported a quantitative yield in the protection of the ketone functionality in an intermediate (214) (Scheme 38) similar to our compound 205, in their total synthesis of a natural labdanoid dialdehyde 49 . Corey et al. also reported a high yield in the protection of a ketone function in a similar compound, an intermediate in their total synthesis of (±)-aphidicolin 104 using the same conditions. When similar conditions were applied to our case, the ketal 215, ketal 216 and recovered starting material were isolated in 46, 29 and 10 % yields respectively. Longer reaction times were noted to increase the yield of ketal 216 (up to 61 %) while lowering the ketal 215 to 11 %. This result seems to prove the existence of an equilibrium  c, d  a, b  212  ^  84  ^  e  213  ^  a) KCN, DMF; b) 112 Pd-C, (90 %; 2 steps); c)p-TsOH, EG; d) DIBAH, hexane; e) 50 % AcOH, (100 %; 3 steps).  Scheme 38 Isoe's sequence to keto aldehyde 214 from 212.  214  ^  74 between the two isomeric ketals (Fig. 22) which might evolve through a carbocation intermediate. The ketal 215 is considered to be the kinetic product since longer equilibration times are shown to yield ketal 216 as a major product, thereby confirming the assumption that ketal 216 is the thermodynamically more stable ketal, with its side chain oriented in an equatorial position. ^,--COOEt^ ,—COOEt 0--\ +l ^°OH OH  215  216  Fig. 22 Proposed mechanism for ketal isomerization.  A method which prevented such equilibration had to be found. Two related methods seemed to be suitable to perform the required kinetic ketalization, avoiding  75 equilibration. The first one implies the use of triflic acid as a catalyst 105 . The second one uses TMS-triflate as a catalyst 1060. Both methods have been reported to give good yields of the kinetic ketalization product and minimizing equilibration. The different conditions and reaction times studied are summarized in tables 2 and 3 for triflic acid, and in table 4 for TMS-triflate. When triflic acid was evaluated, 0.2 equiv. were shown to give better selectivity towards the desired ketal 215, although much longer times were required than when 0.8 equiv. were employed. However although these latter conditions accelerated the reaction, poorer selectivity in terms of the ratio 215/216 was observed. ^ Tiiflic acid 0.2 equiv. ^ 2 equiv. 1,2-Bis(TMS0)-ethane ^ Ketoester 205 0.08 M Yield (%, as determined by GC)  Time  205^215^216  3h  61  34  1  5h  40  49  2  8h  25  64  4  14 h  10  79  9  Table 2 Percentage of 205, 215 and 216 during ketalization of 205, as determined by GC.  76  ^  0.8 equiv. Triflic acid ^ 1,2-Bis(TMS0)-ethane 2 equiv. ^ 0.09 M Ketoester 205 Yield (%, as determined by GC)  Time  205^215^216 1h  62  29  4  3h  15  64  11  5h  11  66  14  Table 3 Percentage of 205, 215 and 216 during ketalization of 205, as determined by GC. ^ 0.1 equiv. TMS-triflate ^ 2 equiv. 1,2-Bis(TMS0)-ethane Ketoester 205^0.2-0.3 M Yield (%, as determined by GC)  Time  205^215^216 2h  2  93  5  Table 4 Percentage of 205, 215 and 216 during ketalization of 205, as determined by GC. When aprotic conditions were used, employing 0.1 equiv. of TMS-triflate, excellent yields of ketal 215 were obtained in short reaction times. Compound 215 showed a molecular ion peak at m/z 324 in the mass spectrum. Its IR spectrum showed an intense absorption at 1735 cm -1 corresponding to the ester group. The axial position of the side chain was determined by an nOe difference experiment. Irradiation of the methyl singlet at 8 1.19 ppm enhanced the methyl signal at 8 0.82 ppm  77 and the one-proton signal resonating at 8 2.08 ppm; irradiation of the signal at 8 2.08 ppm enhanced the methyl signal resonating at 8 1.19 ppm and the proton resonating at 8 2.47 ppm. Therefore the signal at 8 1.19 ppm corresponds to the C10-methyl, the signal  Fig. 23 A summary of proton interactions as determined from an nOe difference experiment with enantiopure ketal 215. at 8 0.82 ppm corresponds to the C4-13CH3 and the proton at 8 2.08 ppm must be located in the C9 equatorial ((3) position (Fig. 23). Ketal 216 displayed a peak at m/z 324 in the mass spectrum corresponding to the molecular ion. Its IR spectrum showed a carbonyl absorption at 1736 cm -1 corresponding to the ester functionality. 2.6. Synthesis of enantiopure diol 221 from enantiopure ketal ester 215.  Having found a suitable protection method for the ketone functionality we turned our attention to the synthetic steps required to reach diol 221. Reduction of the ester in 215, protection of the alcohol, deprotection of the ketone, Grignard reaction and finally deprotection of the primary alcohol were the synthetic steps envisaged in order to obtain diol 221 (Scheme 39). Ketal ester 215 was reduced with an excess of LAH in diethyl ether in 10 minutes at room temperature, affording compound 217 in quantitative yield.  78 /  --  215  OH  217  /----OR  218  ^>  220 Scheme 39 A proposed synthesis of enantiopure diol 221 from enantiopure ketal ester 215. Compound 217 showed a peak at m/z 282 corresponding to the molecular ion in the mass spectrum. Its IR spectrum showed a hydroxyl stretching frequency at 3300 cm -1 . Its 1H  nmr spectrum displayed two multiplets at 8 3.49 and 3.68 ppm corresponding to the  two protons of the carbon next to the hydroxyl group. Protection of the primary alcohol was required before further transformation could be done since deprotection of the ketone under mild acid conditions proved to give low recoveries of the desired keto alcohol, indicating that decomposition took place to a considerable extent. In addition, attempted purification of the expected keto alcohol showed that this compound is unstable and leads to a mixture of different compounds (TLC). Dehydration of the alcohol, cyclization to a 5-membered ring or condensation, are some of the possible reactions that could be taking place. No efforts were made to isolate these products. Instead, we focused our attention on the protection of the hydroxyl functionality. We needed a protecting group which would be  79 stable to the acidic conditions required for the deketalization and which be subsequently removed under mild conditions. For this purpose, the benzyl group  107 appeared ideal since  it is expected to be stable under acidic conditions and could be removed latter by catalytic hydrogenolysis using palladium in charcoal, a condition which generally proceeds in high yieid108a-c. Reaction of 217 with benzyl chloride in ethanol heated at reflux for 12 hours, in the presence of sodium hydride, potassium carbonate and catalytic amounts of sodium iodide furnished the desired product in 68 % yield (87 % based on starting material recovered). It was felt that higher yields should be possible with further studies. A method reported by Provelenghiou et al. 109 , used in the protection of hydroxyls groups in carbohydrates, and claimed to be simple, rapid and quantitative, was also evaluated. Removal of the weakly acidic alcoholic proton in compound 217 was done with sodium hydride, followed by addition of excess of benzyl bromide and 0.1 equiv. of tetrabutylammonium iodide. As in the previous case, the reaction proved to be much slower than expected. A period of 22 hours heating at reflux was required in order to achieve total conversion of starting material. Under these conditions, essentially quantitative yields were obtained. Increasing the quantity of tetrabutylammonium iodide to 1 equiv., did not shorten the reaction time. The mass spectrum of compound 218 showed a peak at m/z 372 corresponding to the molecular ion, and a peak at m/z 281 (42.1 %) corresponding to the loss of PhCH2. Its 1 11 nmr spectrum displayed a doublet at 6 4.52 ppm (J= 3 Hz) corresponding to the methylene group adjacent to the aromatic ring while a five-proton multiplet at 8 7.25-7.32 ppm was in support of the expected aromatic protons. Having the alcohol protected, the next sequence of reactions required was deketalization and Grignard reaction with the regenerated carbonyl group in order to attach the last carbon unit required for the carbon skeleton of Ambrox® (2). Deprotection of the carbonyl was achieved easily under acidic conditions (1 M HC1) at room temperature. The new compound 219 showed a peak at m/z 328 in the mass spectrum corresponding to the molecular ion. Its IR spectrum showed a characteristic  80 absorption at 1708 cm -1 corresponding to the carbonyl group. Its 13 C nmr spectrum displayed a peak at 8 215.00 ppm in accordance with the presence of a carbonyl group. These last three steps (reduction, protection of the alcohol and deprotection of the carbonyl) could be done in a one-pot operation without isolation of intermediates, thereby obtaining good yields of the overall process.  2.7. Studies on the 1,2-addition reaction to the carbonyl function in enantiopure 219. With the ketone 219 available from the above studies, a standard Grignard reaction was performed using methylmagnesium iodide in ether heated at reflux. Surprisingly only 15 % of the anticipated alcohol 220 was isolated, and most of the original ketone was recovered unreacted. It has been reported by Buchi et al. 50 that reaction of ketone 87 with the Grignard reagent under the same conditions, afforded the methylated compound 88 in 98 % yield (Scheme 40).  87  ^  88  Scheme 40 Buchi's 1,2-addition to ketone 87.  The steric hindrance caused by the axial methyl group at position C10 dictates the high stereoselectivity observed with the 1,2-addition to the carbonyl group. Approach by the Grignard reagent is therefore preferred from the a face of the molecule providing the  81 stereochemistry at C8 as noted in 220 and 88. In fact, formation of the other possible C8 isomer has not been observed. In our case, having the C9 side chain in an axial position and adjacent to the carbonyl group, could possibly be the reason for low yields in the Grignard reaction. The steric hindrance provided by the  cio-o methyl and the C9-a-side chain effectively restrict  the approach of the Grignard from either side of ketone 219 thereby translating in large recovery of unreacted starting material, as observed. In spite of the apparent difficulties noted above, it was desirable to maintain the side chain in the axial position since this feature would lead us to epi-Ambrox (3). We turned our attention to the organocerium reagents once more, hoping that in this case the addition reaction to the carbonyl would work. It has been reported that for many substrates studied, the organocerium (III) reagent proved to furnish much higher yields than the Grignard or organolithium equivalent 100c. This enhancement in the yields has been explained by the strong oxophilicity of the cerium chloride, being capable to activate carbonyl components by coordination 110,111 . This activation is probably the most important driving force for cerium (III) chloride promoted carbonyl additions. Another important factor might be that the strong basicity of the Grignard reagents is weakened by mixing with cerium (III) chloride. Reaction of ketone 219 with the methyl cerium (III) reagent, generated by reaction of methyllithium with anhydrous cerium (III) chloride 100a afforded the desired alcohol 220 in quantitative yield. Compound 220 showed a peak at ink 344 corresponding to the molecular peak in the mass spectrum. Its IR spectrum showed a characteristic hydroxyl stretching absorbance at 3397 cm-1 . Its 1 11 nmr spectrum displayed four methyl singlets at 8 0.83, 0.86, 1.25 and 1.27 ppm. Confirmation of the structure was established by X-ray analysis (on the racemic compound) showing that the newly introduced methyl group was present in the desired stereochemical orientation (Fig. 24).  H3  C12 H13^H2 H12^ 18  H22  H28 C16 H29^H26  Ph  Fig. 24 Single crystal X-ray structure of the enantiomer of alcohol 220.  83 In summary, it is worthy to emphasize the preferred utility of this new type of organocerium reagents over that of the classical Grignard or organolithium reagents. The cerium reagent provided a complete reaction in 10 minutes and in quantitative yield, as compared to methylmagnesium iodide which afforded only 15 % of the product after five hours of heating at reflux in diethyl ether. The only two synthetic operations remaining were cleavage of the benzyl protecting group and finally cyclization to complete the synthesis of the Ambrox family. The benzyl protecting group can be removed by lithium in ammonial 12 and potassium carbonate in methano1 113 , but the most common method of cleavage is by hydrogenolysis with palladium in charcoa1 114,115,116 . The use of a 1:1 ratio of catalyst to substrate (by weight) was shown to increase the rate of hydrogenolysis thereby shortening the reaction timesl° 8b. The diol thus obtained showed a molecular ion peak at m/z 254 in the mass spectrum. Its IR spectrum showed a strong absorbance at 3315 cm -1 corresponding to a hydroxyl stretching frequency. Its 1 H nmr spectrum showed four methyl singlets at 8 0.84, 0.88, 1.27 and 1.29 ppm. A doublet of doublets resonating at 8 3.57 ppm (J= 8, 8 Hz) corresponded to the C12 protons. In a decoupling experiment, irradiation of the signal resonating at 8 3.57 ppm led to the assignment of the two protons at position Cl 1. One of these resonated at 8 1.34 ppm , since the original multiplet was simplified to a doublet of doublets (J= 3, 13 Hz), thus indicating a small coupling with the C9 proton and a large geminal coupling with the other C11 proton. The other C11 proton was found to resonate at 8 1.84 ppm as its signal was also simplified to a doublet of doublets (J= 4, 13 Hz) confirming the geminal coupling value and confirming a small coupling with the C9 proton. 2.8. Cyclization of enantiopure diol 221 to (-)-epi-Ambrox (3).  The final step to complete the sequence was the cyclization of diol 221 to epi-Ambrox (3). Two methods of cyclization for such types of molecules are commonly  84 reported in the literature. One of these involves the use of p-toluenesulfonylchloride or POC13 to effect cyclization with retention of configuration at C8 (Fig. 25).  32  ^  2  Fig. 25 Cyclization of diol 32 to afford the Ambrox system (2).  This procedure often furnishes high yields in the cyclization reaction 25 a ,b ,29,38 (80-92 %). The other method which involves inversion of configuration at C8 proceeds through a tertiary carbocation (i) which is formed by elimination of the tertiary hydroxyl group at C8 (Fig. 26).  221  Fig. 26 Mechanistic analysis of the cyclization of enantiopure diol 221 under acidic conditions.  85 Formation of the tertiary carbocation (i) is expected to predominate when 221 is treated under acidic conditions. Cyclization of (i) via (ii) is kinetically preferred to form 3 since a chair-like conformation shown in (ii) is preferable to the alternative cyclization via the latter requiring a higher energy boat-like transition state. Thus only the equatorial approach (ii)—+3 is then expected to prevail. A common acid catalyst used for this type of cyclization is p-toluenesulfonic acid50 , but a cation-exchange resin "KU-23" has also been used to effect such cyclization 117 . In our case, cyclization using p-toluenesulfonic acid as a catalyst was the chosen method. Since X-ray analysis of compound 220 established that the tertiary hydroxyl at position C8 is 13-oriented (axial), inversion of configuration at this centre was therefore required. Under these conditions, the desired product (3) was obtained in 83 % yield. A mixture of alcohols, tentatively assigned the general structure 222, were also isolated (11 % yield), this mixture revealed a complex pattern of olefinic proton signals in the 1H  nmr spectrum. This mixture could not be further purified by column chromatography.  222 The mass spectrum showed a molecular ion peak at m/z 236. The IR spectrum showed a hydroxyl stretching at 3400 cm-1 . Therefore this mixture is composed of isomeric alkenes obtained by dehydration of diol 221, although further studies were not pursued to clarify this assumption. Compound (3) showed a molecular ion peak at m/z 236 in the mass spectrum. All physical properties and spectroscopic data for compound 3 agree well with the reported  86  values in the literature for epi-Ambrox 52b ,56 . (-)-Epi-Ambrox (3) has also been prepared from enantiopure ketone 219 in 80 % overall yield without isolation of intermediates. Therefore we can conclude that a novel and efficient synthesis of (-)-epi-Ambrox (3) from enantiopure enone 143 (previously prepared from thujone) has been developed in 5 one-pot operations, in 33% overall yield (Scheme 41).  a, b, c 143  d  e, f^a..  172  ..,-COOEt g, h, i  215  a) Mn(OAc) 3, C 6H 6; b) LiA1H4, Et20; c)p-TsOH, TIT; d) LDA; ICH 2C0 2Ef; e) H  2 Pd-C; f) 1,2-bis(TMSO)ethane, TMS-triflate; g) LiA1H4; h) NaH, PhCH2Br, n-Bu 4NI; i) HC1, acetone; D MeLi, CeC13; k) H2 Pd-C; 1)p-Ts0H, CH 3NO 2.  Scheme 41 Synthesis of (-)-epi-Ambrox (3) from enantiopure enone 143. A similar sequence to the one reported for (-)-epi-Ambrox (3) has been followed  for the synthesis of (-)-Ambrox® (2). In this case the secondary product 216 from the ketalization reaction under protic conditions (and the main product when thermodynamic equilibration conditions were applied), was used to develop a parallel sequence towards (-)-Ambrox® (2) (Scheme 42). The starting material 216 contains the desired equatorial  side chain required for Ambrox® (2). Reduction of ketal 216 with LAH afforded alcohol  87 223 in 92 % yield. The mass spectrum of compound 223 showed a peak at m/z 282  corresponding to the molecular ion, and a peak at m/z 264 corresponding to the loss of water by the molecule. Its IR spectrum showed a hydroxyl stretching frequency at 3228 cm -1 .  216  ^  223  ^  224  ^  225  f  90  2  a) LiA1H 4; b) NaH, PhCH2Br,n-Bu 4N1; c) HCI; d) MeLi, CeC1 3 ; e) H 2 Pd-C; Op-TsOH, CH 3N0 2.  Scheme 42 Synthesis of (-)-Ambroxe (2) from enantiopure ketal 216. Benzylation of the hydroxyl group was performed as for compound 217 yielding compound 224 in 92 % yield. Compound 224 showed a molecular ion peak at m/z 372 in the mass spectrum. Its 1 H nmr spectrum displayed two multiplets at 8 7.27 and 7.34 ppm, integrating for one and four protons respectively, readily assigned to the aromatic ring protons. A characteristic two-proton doublet at 8 4.50 ppm (J= 3 Hz) corresponding to the  benzylic methylene group was also observed. Deprotection of the carbonyl group in 224 was performed as indicated for compound 218 although in this case longer reaction times were required when the same  88 conditions were employed. The mass spectrum of 225 showed a peak at m/z 328 corresponding to the molecular ion. Its IR spectrum showed a carbonyl stretching frequency at 1709 cm -1 . Ketone 225 was also obtained by isomerization of the axial side chain in compound 219 under equilibrating conditions (sodium methoxide in THF/MeOH, 22 hours reflux).  Under these conditions, an equilibrium mixture containing a 9:1 ratio of 225:219 respectively was observed. Methylation of the carbonyl function in 225 was performed as for compound 219 using the organocerium reagent chemistry described earlier. Although in this case, having the side chain in an equatorial position may well facilitate also the attack by a classical (and less reactive) Grignard reagent (as used by Buchi 50), to achieve the desired stereochemistry at C8. Hydrogenolysis of the benzyl group using palladium on charcoal, afforded diol 90. The mass spectrum of 90 showed a peak at m/z 254 corresponding to the molecular ion. Its ER spectrum showed two hydroxyl stretching frequencies at 3358 and 3322 cm -1 . 2.9. Cyclization of enantiopure diol 90 to (-)-Ambrox® (2).  The cyclization was performed as for compound 221. It was recognized that in this case the cyclization step, under acidic conditions, could generate the thermodynamically more stable cis-fused tetrahydrofuran ring, giving iso-Ambrox (15) instead. It has been established that Ambrox® (2), with a trans-fused tetrahydrofuran ring, isomerizes to iso-Ambrox (15) when treated with acid 14 , demonstrating that the latter is the thermodynamically preferred isomer. Equatorial approach to the tertiary carbocation at C8 should be preferred over the axial approach due to steric hindrance from the angular methyl group (transition state (ii)) (Fig. 27). Therefore, Ambrox® (2) is preferentially produced through a lower energy transition state (i). However, iso-Ambrox (15), resulting from the f3 face attack, becomes  89  the major product under prolonged reaction times under the same conditions. Investigation of the optimum conditions to effect such a cyclization by Buchi et a1. 50 , showed that treatment of diol 90 with a catalytic amount of p-toluenesulfonic acid in nitromethane at 80° C minimizes the formation of 15 in favor of Ambrox® (2). In our case, under the same conditions no formation of 15 was observed. All  spectroscopic data of 2 were consistent with those reported in the literature for Ambrox® (2) 50,56 . The melting point and specific rotation [a]D of the obtained (-)-Ambrox® (2)  fast -He  90 slow -H+  15  Fig. 27 Mechanistic analysis for cyclization of enantiopure diol 90 under acidic conditions. were measured to be 76-77° C and -24.1° (c= 1.00, CHC13) respectively. They agree well with the reported values (mp 77-77.5° C and -24.7 (c= 1.00, CHC13) 56 . A mixture of alcohols, tentatively assigned the general structure 227, was also isolated (21 % yield). This mixture revealed a complex pattern of olefinic proton signals in the 1 11 nmr spectrum. This mixture could not be further purified by column chromatography.  90  The IR spectrum of the mixture showed a hydroxyl stretching absorption at 3450 cm -1 and a molecular ion peak at m/z 236 in the mass spectrum. Therefore this mixture is composed of isomeric alkenes obtained by dehydration of diol 90.  2.10. Concluding remarks In summary we can conclude that an efficient route to (-)-Ambrox® (2) and (-)-epi-Ambrox (3) has been developed from enantiopure enone 143. The latter can be prepared in its enantiomerically pure form starting from thujone (1) , via r3 cyperone (144), -  in 9 steps (Schemes 21 and 25). It is highly likely that a number of steps in this sequence, for example, 131 136 133 134, can be performed without isolation of intermediates, although these studies still remain to be completed. Other studies, as noted in Future Developments, have recently provided an improved route to P-cyperone (144, Scheme 21) and these, in turn, serve to further improve the sequence to 143. Also, a novel ketone-transposition method has been developed (Scheme 34). From a preparative point of view, the conversions, 143 -4 181 -3 182 172, are performed without isolation of intermediates, that is, a one-pot process with an overall yield of 64 % with respect to enantiopure 172. Further transformations of 172 (Scheme 43) can also be achieved without isolation of intermediates. The conversion, 201-4 215, is a one-pot process, as are the sequences,  215 -4 219; 219 -3 3; 219 -4 2. In effect, the overall conversion from 143 to (-)-epi-Ambrox (3) proceeds in 5 one-pot operations and an overall yield of 33 %, while  91 the synthetic route to (-)-Ambrox® (2) from 143 involves 6 one-pot operations and an overall yield of 27 %. Alternatively, an efficient route to racemicenone 143, from 2-methylcyclohexanone, involving a 4 step conversion, has been developed (Scheme 27). We believe this later sequence, leading to the racemic series, to be one of the most efficient routes to racemic 143 published thusfar.  9 steps  /\  a, b, c  1  ^Iv-  143 ./'  201  d  COOEt  215  a) Mn(OAc) 3, C 6H 6; b) LiA1H4, Et20; c)p-TsOH, TIM; d) LDA; ICH2C0 2Et; e) H 2 Pd-C; 0 1,2-bis(TMSO)ethane, TMS-triflate; g) LiA1H 4; h) NaH, PhCH2Br, n-Bu 4NI; i) HC1, acetone; j)MeLi, CeC13; k) H2 Pd-C; 1)p-Ts0H, CH 3 NO 2;m) Na0Me/Me0H.  Scheme 43 Synthetic route to (-)-Ambrox® (2) and (-)-epi-Ambrox (3) from enantiopure enone 143.  92 2.1 1. Future developments.  As is clear from the above Discussion, the enone 143 is a crucial intermediate in the synthetic routes leading to the Ambrox family. For this reason, studies by other researchers in our laboratory are presently directed toward developing a shorter and more efficient route to 143 from the readily available enantiopure synthon thujone (1). An exciting and potentially important approach is to utilize fermentation technology with either microorganisms (fungi and bacteria) and/or plant cell cultures to achieve such objectives. Indeed in recent, already completed studies by other researchers (J. Wagner and Y. Hirai), success in this direction has been obtained. Their studies utilize the tricyclic enone 131, obtained in one step via Robinson annelation reaction with thujone (1), as the precursor in biotransformation studies with the above biological media. For example, 131 when incubated with the fungus, Rhizopus oryzae ATCC 11145, for 24 hours, is converted to the tertiary alcohol 228 in 71 % yield while with the plant cell culture line of Triptetygium wilfordii (coded as TRP4a), a 76 % yield of the secondary alcohol 229 is obtained (Scheme 44). This latter bioconversion with T. wilfordii cells can be performed in a semi-continuous process, that is, successive  additions of 131 to a single batch of cells, behaving as a "biological factory", thereby affording a highly attractive and inexpensive synthesis of 229. The conversion of 228 to enone 143 is envisaged, via essentially known methodology, already available from previous studies in our laboratory (Scheme 45). As above, a number of these steps can be conducted without isolation of intermediates.  93  biotransf. OH  1  131  228 DE  229  Scheme 44 Production of 228 and 229 by biotechnological methods.  1)Wolff-Kishner 2)HBr  Kt-amylate  ---11..  CH 31 OH  228  3) Reduction OH 4) 03  0  230  Scheme 45 Proposed sequence to enantiopure enone 143 from 228.  94  3.^EXPERIMENTAL.  3.1. General experimental.  Solvents used for chromatographic separations were glass-distilled prior to use. The term 'petroleum ether' refers to a commercially available hydrocarbon mixture boiling in the 35-60 ° C range. Anhydrous benzene, tetrahydrofuran (THF) and diethyl ether were distilled from sodium and benzophenone,under nitrogen atmosphere, prior to use. Anhydrous methylene chloride was prepared by distillation from phosphorus pentoxide. Anhydrous diisopropylamine was prepared by distillation from calcium hydride and was stored in the presence of potassium hydroxide pellets, under nitrogen. Anhydrous ethanol was distilled from magnesium. Commercial reagents were purified, when necessary, by procedures described in Perrin and Perrin 118 . n-Butyllithium and methyllithium solutions were standardized by titration against diphenyl acetic acid in anhydrous THF. Thujone was distilled from Western red cedar leaf oil which was generously donated by Intrinsic Research and Development Incorporated. All glassware was flame-dried under a stream of nitrogen prior to use. Needles and syringes were oven-dried overnight at 180° C and stored in a desiccator. Reactions at -78° C, 40° C, -20 ° C and 0° C were performed with dry ice/acetone, dry ice/acetonitrile, ice/NaC1 and ice/water cooling baths, respectively. Unless otherwise noted, anhydrous magnesium sulfate was used to dry organic solutions prior to solvent removal. All reactions were performed under a positive pressure of argon. Reactions were monitored by analytical TLC and/or gas chromatography. Analytical TLC were performed using Merck pre-coated silica gel 60  F254 aluminum  backed TLC  plates. Visualization of the samples was realized with UV light and/or by spraying with a 10% solution of ammonium molybdate in 10% sulfuric acid followed by heating at 180° C  95 until blue spots developed. Gas chromatography analyses were performed on a Hewlett-Packard 5890A gas chromatograph fitted with a fused silica capillary column coated with cyanopropylphenyl silicone gum (DB 1701) (J & W Scientific: 15 m x 0.262 mm) connected to a Hewlett-Packard 3388A integrator and Flame Ionization Detector (carrier gas: helium. Injection temperature: 250 ° C). Ozone was generated in a Welsbach model T-23 laboratory ozonator. Purification of all reaction products was carried out, unless otherwise stated, by flash chromatography using silica gel (Sigma, 10-40 gm), with nitrogen gas pressure to obtain a suitable flow. Bulb to bulb distillation was performed using a Kugelrohr distillation apparatus (the air bath temperature at which distillation occurred is given in parenthesis). 1 H nmr spectra were recorded in CDC13 at 400 MHz on a Bruker WH 400  spectrometer, unless otherwise noted. Chemical shifts were recorded in ppm relative to TMS (internal standard). 13 C nmr spectra were recorded on a Bruker AE-200 spectrometer and chemical  shifts are reported in ppm relative to TMS. Low resolution mass spectra were recorded on Kratos MS 50 and MS 80 mass spectrometers. High resolution mass spectra were recorded on a Kratos MS 50 mass spectrometer. Chemical ionization mass spectra were recorded on a Delsi-Nermag R10-10C mass spectrometer using ammonia as carrier gas. All melting points were recorded on a Reichert melting point apparatus and are uncorrected. Optical rotations were recorded on a Perkin-Elmer 141 automatic polarimeter using quartz cells of 10 cm path length, in chloroform solution unless otherwise stated. The concentration (g/100 ml) is given in parenthesis. UV spectra were recorded on a Perkin-Elmer Lambda 4B UV/VIS spectrophotometer using quartz cells of 1 cm path length.  96 Elemental analyses were carried out by Mr. P. Borda of the Microanalytical Laboratory, University of British Columbia, Vancouver. IR spectra were recorded on a Perkin-Elmer 710B infrared spectrophotometer.  Fourier transform IR spectra were recorded on either Perkin-Elmer 1710 or Bomen Michelson 100 Fourier transform infrared spectrophotometers. Single crystal X-ray structure determinations were performed by Dr. S. Rettig with a Rigaku AFC6S diffractometer. All compounds are named in accordance with Chemical Abstracts rules. The skeletal numbering system employed in the Introduction and Discussion, as well as proton and carbon designations to interpret the nmr spectra, follows the normal conventions of terpenoid and steroid literature. This allows an easier comparison between the compounds under discussion with related natural products.  97 3.2. lacc,lb,2,3,5,5a,6,6a-Octahydro-54,613-dihydroxy-lb13,5adimethyl-6aa-(1-methylethyl)-cycloprop[a]inden-4(1H)-one (135).  A solution of dihydroxyketal 133* (337 mg, 1.0 mmol) in petroleum ether (5.5 ml) was added to 48 % HBr solution (5.5 ml) cooled to -78° C. The reaction mixture was stirred at that temperature for 2 hours, then poured into water (25 ml). The solution was extracted with methylene chloride (30 ml). The combined organic layers were washed with saturated sodium bicarbonate solution (20 ml) and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Chromatographic purification of the residue using EtOAc/petroleum ether 3:2 as eluent, gave bromodienone 134 (5.9 mg, 2 %) as a yellowish oil and dihydroxyketone 135 (213.6 mg, 85 %) as a white solid with mp 102-103° C (ether/petroleum ether); [42:5, = +74.8° (c=1.00); IR (KBr) V max : 3355, 2963, 1708 cm-1 ; 1 H nmr 8: 0.30 (111, ddd, J= 8, 5, 1 Hz, C8-H), 0.92 (311, d, J= 7 Hz, C11-CH3A), 1.00 (3H, d, J= 7 Hz, C11-CH3B), 1.03 (3H, d, J= 7 Hz, C4-CH3), 1.06 (1H, m), 1.13 (1H, dd, J= 5, 5 Hz), 1.23 (3H, s, C10-CH3), 1.54 (2H, m), 1.71 (1H, ddd, J= 14, 8, 4 Hz, Cl-HA), 1.91 (111, ddd, J= 14, 9, 4 Hz, Cl-HB), 2.22 (111, ddd,  J= 16, 9, 4 Hz, C2-HA), 2.45 (1H, ddd, J= 16, 8, 4 Hz, C2-HB), 2.57 (1H, q, J= 7 Hz, C4-H), 3.06 (1H, br s, 0-H), 3.93 (1H, br s, C6-H); 13 C nmr 8: 7.04, 10.16, 20.24, 20.29, 20.57, 31.69, 34.22, 35.86, 36.56, 37.19, 44.58, 51.64, 81.14, 82.68, 212.18; MS m/z: 252 (M+, 7.3), 234 (19.4), 219 (8.6), 201 (5.5), 181 (100); HRMS * 133 was prepared following the published procedure in reference 59.  98 calcd. for C15H2403: 252.1725; found: 252.1727; Anal. calcd. for C15H2403: C 71.41, H 9.58; found: C 71.68, H 9.57.  3.3. 3,4-Dihydro-1,40-dimethy1-7(1-methylethyl)-naphthalen-2(3H)one (142).  142  To a solution of diisopropylamine (0.32 ml, 2.2 mmol) in anhydrous THF (3 ml) at -78° C was added n-butyllithium (1.39 ml, 2.22 mmol). The solution was stirred at -15° C for 30 minutes, cooled to -78° C, and ethyl acetate (0.20 ml, 2.0 mmol) was added. The solution was stirred at -78° C for 30 minutes, then warmed to 0° C and stirred at that temperature for 30 minutes. The solution was cooled again to -78° C and a solution of bromodienone 134 (200 mg, 0.67 mmol) in anhydrous THF (20 ml) was added. The mixture was heated at reflux for 18 hours, cooled to room temperature and poured into saturated ammonium chloride solution (100 ml). The aqueous layer was extracted with diethyl ether (100 ml). The combined organic layers were washed with water (100 ml), dried and concentrated in vacuo. Chromatographic purification of the residue eluting with diethyl ether/petroleum ether 1:9, gave unreacted bromodienone 134 (150 mg, 75 %), and trienone 142 (24 mg, 16 %) as a yellowish oil. Trienone 142: [a] ; = +161.6 ° (c= 1.40); IR (CHC13) v max : 3011, 2930, 1631,  1566 cm -1 ; 1 H nmr 6: 1.14 (6H, d, J= 8 Hz), 1.19 (3H, s), 1.25 (1H, m), 1.80 (1H, m), 1.87 (3H, s), 2.05 (1H, m), 2.50-2.65 (2H, m), 5.94 (1H, d, J= 8 Hz), 6.05 (1H, d,  99  J= 8 Hz), 6.31 (1H, s, C6-H);  13 C  nmr 8: 10.25, 21.27, 21.31, 26.26, 33.52, 34.30,  34.38, 37.79, 116.66, 121.99, 128.63, 142.88, 149.07, 158.51, 197.71; UV (methanol) Amax(log E ): 350 (4.0), 235 (3.8); MS m/z: 216 (M+, 27.3), 201 (8.5), 188 (11.2), 173 (44.2), 145 (100); HRMS calcd. for C15H200: 216.1514; found: 216.1515. 3.4. laa,lb,2,3,5,6a-Hexahydro-1143,5,5-trimethy1-6aa-(1methylethyl)-cycloprop[a] inden-4(1H)-one (145).  145  A solution of enone 131 (5.01 g, 23.0 mmol) in anhydrous THF (50 ml) was added to a solution of potassium tert-butoxide (3.60 g, 32.1 mmol) in anhydrous THF (50 ml). The mixture was stirred at room temperature for 1 hour. Iodomethane (4.3 ml, 69.1 mmol) was added. After 50 minutes analytical TLC (diethyl ether/petroleum ether 1:9) showed total consumption of starting material. 0.5 M HC1 (150 ml) was added and the solution was extracted with diethyl ether (400 ml). The combined organic layers were dried, filtered and concentrated in vacuo. Chromatographic purification of the residue eluting with diethyl ether/petroleum ether 1:9, gave ketone 145 (3.31 g, 62 %) as a colourless oil. [a]D = +197.9° (c= 1.88); IR (neat) V max : 3050, 2947, 1710, 1620 cm -1 ; 1 H nmr 8:  0.31 (1H, dd, J= 4, 4 Hz), 0.68 (1H, dd, J= 4, 8 Hz), 0.85 (3H, d, J= 7 Hz),  0.96 (3H, d, J= 7 Hz), 1.12 (3H, s), 1.19 (3H, s), 1.22 (3H, s), 1.25 (1H, m), 1.40 (1H, sept., J= 7 Hz, Cll-H), 1.70 (1H, ddd, J= 12, 12, 7 Hz, Cl-HA), 1.80 (1H, ddd,  J= 12, 7, 2.5 Hz, Cl-HB), 2.45 (1H, ddd, J= 17, 7, 2.5 Hz, C2 - HA), 2.65 (1H, ddd, J=  100 17, 12, 7 Hz, C2-HB), 5.51 (1H, s, C6-H); 13 C nmr 8: 20.28, 20.49, 20.71, 22.22, 24.87, 26.07, 30.77, 35.03, 35.42, 37.93, 39.00, 47.34, 48.24, 127.25, 152.03, 215.53; MS m/z: 232 (Mt, 92.9), 217 (39.1), 189 (99.5), 161 (100); HRMS calcd. for C16H240: 232.1828; found: 232.1829; Anal. calcd. for C16H240: C 82.71, H 10.40; found: C 82.90, H 10.37. 3.5. 1,1aa,lb,2,3,4,5,6a-Octahydro-lb13,5,5-trimethyl6aa-(1-methylethyl) cycloprop[a]indene (146).  146  A solution containing ketone 145 (2.51 g, 10.8 mmol), hydrazine (2.50 g, 78.1 mmol) and potassium hydroxide (2.17 g, 38.7 mmol) in diethylene glycol (30 ml) was heated to 130-135° C for 1 hour. When analytical TLC (diethyl ether/petroleum ether 3:2) showed total consumption of starting material, a Dean-Stark apparatus was installed, and the mixture was heated to 205-210° C for 1 hour, with removal of the excess of hydrazine and water. The cooled reaction mixture was poured into water (30 ml) and extracted with diethyl ether (200 ml). The combined organic layers were washed with water (100 ml), dried, filtered and concentrated in vacuo. Chromatographic purification of the residue, eluting with petroleum ether gave alkene 146 (1.64 g, 69 %) as a colourless oil. [e]D = +112.4° (c= 1.45); IR (neat) V max : 3010, 2920, 1610 cm -1 ; 1 H nmr 8: 0.30 (1H, dd, J= 4, 4 Hz, C9-H), 0.54 (1H, dd, J= 8, 4 Hz, C8-HA), 0.89 (3H, d, J= 7 Hz, Cl 1-CH3A), 0.98 (311, d, J= 7 Hz, C11-CH3B), 0.99 (311, s), 1.12 (3H, s), 1.17 (111,  101 dd, J= 8, 4 Hz, C8-HB), 1.20 (1H, ddd, J= 13, 12.5, 4 Hz), 1.21 (3H, s), 1.32 (1H, ddd, J= 13, 12.5, 3 Hz), 1.37 (1H, sept., J= 7 Hz, C11-H), 1.48-1.61 (3H, m), 1.82 (1H, m), 5.30 (1H, s, C6-H); 13 C nmr 8: 19.26, 20.14, 20.59, 20.74, 22.50, 23.75, 24.90, 31.20, 34.70, 36.57, 38.02, 42.25, 44.73, 48.20, 123.59, 156.64; MS m/z: 218 (M+, 90.6), 203 (100), 175 (77.4); HRMS calcd. for C16H26: 218.2034; found: 218.2034; Anal. calcd. for C16H26: C 88.01, H 11.99; found: C 87.88, H 11.95. 3.6. Decahydro-a,5(3,6(3-trihydroxy-aa,1b13,5,5-pentamethyl cycloprop[a]inden-6aa-methanol (150) and 6aa-acetyldecahydro-5a13,6f3-dihydroxy-1bf3,5,5-trimethylcycloprop[a] indene (151).  To a solution of diol 149 (1.31 g, 5.20 mmol) in EtOAc (40 ml), sodium bicarbonate (539 mg) was added. The mixture was cooled to -40° C and ozone gas was bubbled through the solution. After 6 hours, analytical TLC (EtOAc/petroleum ether 3:2) showed total consumption of starting material. Dimethyl sulfide (273 p1) was added and the reaction mixture was allowed to warm to room temperature under stirring for 1 hour. Concentration in vacuo afforded 1.52 g of colourless oil. Chromatographic purification of the residue, using acetonitrile/methylene chloride 1:4 as eluent, gave ketodiol 151 (332 mg, 25 %) as a white solid, and triol 150 (499 mg, 36 %) as a colourless oil.  102 Triol 150: [a]i; = +166.7° (c= 0.84, EtOH); IR (neat) V m ax : 3470, 2932 cm -1 ; 1 H nmr (benzene-d6) 8: 0.35 (1H, m), 0.80 (111, dd, J= 8, 4 Hz), 0.88 (3H, s), 0.92  (3H, s), 1.02 (3H, s), 1.14 (3H, s), 1.25 (3H, s), 1.25-1.60 (8H, m), 2.52 (1H, br s, 0-H), 2.57 (1H, br s, 0-H), 4.62 (1H, s, C6-H); 13 C nmr (benzene-d6) 5: 8.89, 18.60, 20.43, 23.85, 28.29, 27.73, 28.15, 37.02, 37.61, 38.47, 39.37, 41.07, 43.67, 71.51, 75.04, 80.17; MS m/z: 268 (M+, 0.1), 250 (7.8), 232 (33.8), 217 (12.8), 140 (100); HRMS calcd.for C16H2803: 268.2038; found: 268.2035; Anal. calcd. for C16H2803: C 71.62, H 10.51; found: C 71.78, H 10.68. Ketodiol 151: mp 94-95° C (EtOAc); [a]b5 = +99.0 ° (c= 1.00); IR (CHC13) Vmax: 3505, 2930, 1665 cm -1 ; 1 H nmr 5: 0.89 (3H, s), 0.97 (3H, s), 1.19 (3H, s), 1.20 (1H, m), 1.37 (4H, m), 1.68 (2H, m), 1.73 (1H, dd, J= 9, 6 Hz), 1.98 (3H, s, CO-CH3), 2.22 (1H, dd, J= 6, 6 Hz), 2.39 (1H, br. s, 0-H), 2.55 (1H, s, 0-H), 4.9 (1H, br. s, C6H); 13 C nmr 8: 17.46, 17.93, 19.89, 23.32, 24.48, 26.99, 38.16, 38.66, 40.75, 42.56, 43.76, 44.08, 72.48, 91.97, 208.15; MS m/z: 252 (M+, 12.5), 234 (15.6), 219 (8.5), 191 (23.4), 167 (45.8), 140 (100); HRMS calcd. for C15H2403: 252.1725; found: 252.1732;  Anal. calcd for C15H2403: C 71.41, H 9.58; found: C 71.52, H 9.48. 1 H nmr decoupling experiment: irradiation of the signal resonating at 5 1.73 ppm  simplified the multiplet resonating at 8 1.20 ppm and the doublet of doublets resonating at  8 2.22 ppm was simplified to a doublet with a coupling constant value of 6 Hz; irradiation of the signal resonating at 8 2.22 ppm simplified the multiplet resonating at 5 1.20 ppm and the doublet of doublets resonating at 8 1.73 ppm was simplified to a doublet with a coupling constant value of 9 Hz.  103 3.7. 1-Chloropentan-3-one.  0 ,,,,,/■.,,.  S CI  To a solution of propionyl chloride (93.0 g, 1.00 mol) in methylene chloride (600 ml), cooled to -20° C, powdered anhydrous A1C13 (160 g, 1.20 mol) was added slowly with good stirring. Dry ethylene gas was bubbled through the solution for 5 hours at -20 ° C. The reaction was then poured into a mixture of 1 M HC1 (400 ml) and ice (600 g). The aqueous layer was extracted with methylene chloride (600 ml). The combined organic layers were washed with 1M HC1 solution (200 ml), dried, filtered and concentrated in vacuo, yielding 84.2 g of crude product as a yellowish oil. Distillation of the crude afforded 68.0 g of a colourless oil (56% yield) (bp 35 ° C at 0.5 mm Hg). 1 H nmr 6: 1.10 (3H, t, J= 7 Hz, 0:13- CH2), 2.52 (2H, q, J= 7 Hz, CH3-M2), 2.95  (2H, t, J= 8 Hz, CO-CH2-CH2), 3.76 (21-1, t, J= 8 Hz, CH2-Cl). 3.8. 4,4a,5,6,7,8-Hexahydro-1,4a-dimethylnaphthalen-2(3H)-one (165).  9 2^10^8  0  165  A solution of 1-chloropentan-3-one (69.0 g, 0.573 mol), 2-methylcyclohexanone  (42.0 g, 0.375 mol) and p-toluenesulfonic acid (2.25 g, 11.8 mmol) in anhydrous benzene  104 (150 ml) was heated at reflux for 18 hours (azeotropic removal of water). The reaction mixture was cooled to room temperature, poured into a solution of sodium bicarbonate (200 ml) and extracted with diethyl ether (400 ml). The combined organic layers were washed with water (200 ml), dried, filtered and concentrated in vacuo , giving 91.0 g of a yellow residue. Distillation of the crude product afforded enone 165 (45.0 g, 67.4 %) as a pale yellow oil as well as 16.8 g of unreacted starting materials. The unreacted starting materials were dissolved in anhydrous benzene (40 ml), to which p-toluenesulfonic acid (0.5 g) was added. The reaction was heated at reflux for 18 hours, yielding after work-up and distillation enone 165 (4.80 g)(total yield of 165: 74.5%). bp: 104 ° C at 0.5 mm Hg; IR (neat) V max : 2928, 1666, 1609 cm -1 ; 1 11 nmr 8: 1.22 (311, s, C10-CH3), 1.37 (1H, ddd, J= 14, 4, 4 Hz), 1.76 (3H, s, C4-CH3), 1.58-2.14 (8H, m), 2.35-2.58 (2H, m), 2.71 (1H, br d, J= 16 Hz); 13 C nmr 8: 10.76, 21.41, 22.42, 26.79, 27.66, 33.77, 36.15, 37.63, 42.06, 128.28, 162.88, 199.02; UV (methanol) X max (log E ): 249 (4.11). MS m/z: 178 (M+, 82.1), 163 (56.2), 150 (13.7), 136 (100); HRMS calcd. for C1211180: 178.1359; found: 178.1358. Anal. calcd. for C1211180: C 80.86, H 10.17; found: C 80.94, H 10.20. 3.9. 3,4,4a,5,6,7-Hexahydro-1,1,4a-trimethylnaphthalen-2(1H)-one (166) and 3,4 1 4a 1 5,6,7-Hexahydro-1,1,3,4a-tetramethylnaphthalen2(1H)-one (230).  166  ^  230  105 Potassium metal (6.65 g, 0.17 mol) was added to a solution of 2-methyl-2-butanol (14.98 g, 0.17 mol) in anhydrous benzene (500 ml) and stirred at room temperature for 15 hours. The suspension was then heated at reflux until all the potassium metal had reacted. After cooling the reaction to 0° C, enone 165 (22.57 g, 0.13 mol) was added dropwise with maintenance of the temperature at 0° C. After addition was complete, the reaction was warmed to 50-60° C for 1 hour, then cooled to 0° C and iodomethane (31 ml, 0.5 mol) was added dropwise. The reaction was heated at reflux for 2 hours. After cooling to room temperature, 0.5 M HC1 (400 ml) was added to the reaction and the aqueous layer extracted with diethyl ether (600 ml). The combined organic layers were washed with saturated sodium bicarbonate solution (200 ml), then sodium thiosulfate solution (200 ml), dried, filtered and concentrated in vacuo. Distillation of the residue afforded 25.45 g of a yellowish oil (bp 87 ° C at 6.5 mm Hg). Chromatographic purification of the oil using diethyl ether/petroleum ether 1:9 as eluent system gave ketone 166 (21.29 g, 88%) as a colourless oil. Further elution afforded trimethylated ketone 230 (2.10 g, 8%) as a mixture of isomers (ratio 2:5). ketone 166: IR (neat) V max : 3020, 2940, 1710, 1645 cm-1 ; 1 H nmr 8: 0.99 (3H, s), 1.24 (6H, s), 1.35-2.12 (8H, m), 2.55 (2H, m, C2-H), 5.58 (1H, t, J= 4 Hz, C6-H); 13 C nmr 8: 18.15, 24.34, 25.37, 27.28, 29.01, 33.97, 34.11, 35.45, 38.76, 48.77,  120.72, 148.47, 204.03; MS m/z: 192 (M+, 100), 177 (72.6), 149 (68.5); HRMS calcd. for C13H200: 192.1514; found: 192.1512; Anal. calcd. for C13H200: C 81.21, H 10.47; found: C 81.22, H 10.46. Ketone 230 (mixture of isomers, ratio 2:5): IR of the mixture (neat) V max : 3050, 2918, 1720, 1700, 1630 cm -1 ; 1 H nmr (mixture of isomers), (signals corresponding to the minor isomer) 5: 1.04 (3H, s), 1.10 (3H, d, J= 2 Hz, C2-CH3), 1.22 (3H, s), 1.25 (3H, s), 2.52 (1H, m, C2-H), 5.60 (1H, t, J= 4 Hz, C6-H); (signals corresponding to the major isomer) 8: 1.14 (3H, s), 1.15 (3H, d, J= 2 Hz, C2-CH3), 1.22 (3H, s), 1.26 (3H, s), 2.75 (1H, m, C2-H), 5.55 (1H, dd, J= 5, 4 Hz, C6-H); MS m/z: 206 (Mt, 93.1), 191  106 (65.9), 163 (70.0), 107 (100); HRMS calcd. for C14H220: 206.1671; found 206.1665; Anal. calcd. for C14H220: C 81.51, H 10.74; found: C 81.79, H 10.77.  3.10. 1,2,3,4,4a,5,6,7-Octahydro-1,1,4a-trimethylnaphthalene (167).  167  Potassium hydroxide (15.10 g, 0.27 mol) was added to a solution of ketone 166 (19.25 g, 0.10 mol) and hydrazine 99 % (24 ml, 0.76 mol) in diethylene glycol (200 ml). The mixture was heated to 130-135 ° C for 1 hour. When all the starting ketone had reacted, a Dean-Stark apparatus was attached and the reaction mixture heated to 205-210 ° C for 1 hour, at which time no more hydrazone was detected by TLC (diethyl ether/petroleum ether 3:2). The reaction was cooled to room temperature and water (300 ml) was added. The reaction was extracted with diethyl ether (500 m1). The organic layer was washed with water, dried, filtered and concentrated in vacuo. Distillation of the crude oil gave alkene 167 (13.85 g, 78%) as a colourless oil (bp 70 ° C at 15 mm Hg); IR (neat) V max : 3055,  2950, 1620 cm-1 ; 1 H nmr 8: 0.97 (3H, s), 1.01 (3H, s), 1.10 (3H, s), 1.05-2.05 (12H, m), 5.37 (1H, t, J= 4 Hz, C6-H); 13 C nmr 8: 18.38, 18.79, 26.39, 27.61, 29.93, 32.18, 34.27, 35.63, 41.92, 42.18, 42.74, 118.41, 149.75; MS m/z: 178 (M+, 52.5), 163 (100); HRMS calcd. for C13H22: 178.1723; found: 178.1719; Anal. calcd. for C13H22: C 87.57, H 12.42; found: C 87.49, H 12.49.  107 3.11. 4,4a,5,6,7,8-Hexahydro-4a,8,8-trimethylnaphthlen-2(3H)-one (143).  143  To a solution of alkene 167 (15.03 g, 84.4 mmol) in glacial acetic acid (290 ml), sodium dichromate dihydrate (35.22 g, 11.8 mmol) was added. The reaction mixture was stirred at room temperature overnight, then heated at reflux for 2.5 hours. After cooling to room temperature, water (500 ml) was added. The aqueous layer was extracted with diethyl ether (600 ml). The combined organic layers were washed with saturated sodium bicarbonate solution (300 ml), water (300 ml), dried, filtered and concentrated in vacuo to leave a yellow oil (16.40 g). Distillation of the oil gave enone 143 (12.10 g, 75%) as a colourless oil (bp 112 ° C at 10 mm Hg); IR (neat) V max : 3052, 2921, 1673, 1597 cm -1 ; 1H  nmr 8: 1.15 (3H, s), 1.20 (3H, s), 1.35 (3H, s), 1.36-1.95 (8H, m), 2.38 (1H, m,  C8-HA), 2.58 (1H, ddd, J= 18, 15, 5 Hz, C8-HB), 5.96 (1H, s, C6-H);  13 C  nmr 8:  18.00, 25.23, 29.73, 31.05, 33.88, 35.63, 36.74, 40.25, 40.70, 40.95, 123.36, 177.82, 200.62; UV (methanol) X max (log E  ):  241 (4.10); MS m/z: 192 (M+, 61.7), 177 (15.1),  164 (49.7), 149 (81.1), 136 (87.6), 123 (89.2), 41 (100); HRMS calcd. for C13H200: 192.1515; found: 192.1516; Anal. calcd. for C13H200: C 81.21, H 10.47; found: C 81.30, H 10.50. The optically active enone 143, as derived from thujone, has been prepared previously in our laboratory and the studies are published5f.  108 3.12.^4,4a,5,6,7,8-Hexahydro-3-acetyloxy-4a13,8,8trimethylnaphthalen-2(3H)-one (185/186).  185/186  To a solution of enone 143 (5.10 g, 26 mmol) in anhydrous benzene (280 ml), manganese triacetate dihydrate (20.40 g, 76 mmol) was added. The brown suspension was heated at reflux for 1 hour with azeotropic removal of water. After cooling to room temperature, additional manganese triacetate dihydrate (20.40 g, 76 mmol) was added and the mixture was heated at reflux for 20 hours. The reaction was then cooled to room temperature, diluted with ethyl acetate (500 ml) and washed with 1M HC1 (200 ml), saturated sodium bicarbonate solution (200 ml) and brine (200 ml). The organic fraction was dried, filtered and concentrated in vacuo to yield 9.03 g of a yellow oil. Chromatographic purification of the oil using diethyl ether/hexanes 3:7 as eluent gave 5.71 g (86%) of a white solid. GC analysis (200° C) of this product showed a 4:1 mixture of isomers (185/186). Recrystallization from ethyl acetate gave colourless needles with the same isomeric ratio, mp 114-115° C; IR (CHC13) of the mixture V max : 3051, 2917, 1718, 1660, 1596 cm -1 ; 1 H nmr of the mixture, (signals corresponding to the major isomer, (3 acetate) 6 : 1.180 (3H, s), 1.250 (3H, s), 1.400 (3H, s), 2.120 (3H, s), 5.25 (1H, t,  J= 4 Hz, C8-H), 6.07 (1H, s, C6-H); (signals corresponding to the minor isomer, a acetate) 8: 1.175 (3H, s), 1.245 (3H, s), 1.395 (3H, s), 2.115 (3H, s), 5.60 (1H, dd,  J= 12, 4 Hz, C8-H), 5.98 (1H, s, C6-H); 13 C nmr (signals corresponding to the major isomer) 8: 17.86, 21.13, 29.29 (x2), 31.42, 36.44, 37.59, 39.89, 40.65, 44.58, 70.18, 122.44, 170.03, 179.00, 194.30; 13 C nmr (signals corresponding to the minor isomer) 8:  109 17.79, 20.92, 25.83, 29.28 (x2), 36.93, 38.01, 40.22, 40.83, 46.74, 71.00, 121.99, 170.31, 177.68, 194.85; UV (methanol)  Amax(log  C ): 240 (3.99); MS m/z: 250 (M+,  2.9), 208 (4.1), 193 (1.6), 164 (100); HRMS calcd. for C15H2203: 250.1570; found: 250.1568; Anal. calcd. for C15H2203: C 71.98, H 8.85; found: C 72.19, H 8.82.  3.13. 2,3,4,4a 9 5,6,7,8-Octahydro-20,30-dihydroxy-443,8,8trimethylnaphthalene (187), 2,3,4,4a,5,6,7,8-octahydro-2a,3adihydroxy-4af3,8,8-trimethylnaphthalene (188), 2,3,4,4a,5,6,7,8octahydro-2a,313-dihydroxy-4a13,8,8-trimethylnaphthalene (189) and 2,3,4,4a,5,6,7,8-octahydro-213,3a-dihydroxy-44,8,8-trimethyl naphthalene (190).  187  189  ^  188  ^  190  To a solution of 185/186 (1.44 g, 5.76 mmol) (4:1 isomeric mixture) in anhydrous THE (80 ml) was added lithium aluminum hydride (LAH) (726 mg, 19.1 mmol). After stirring at room temperature for 10 minutes, the reaction was quenched by adding 1M HC1 (100 ml) slowly to the suspension and then extracted with diethyl ether (400 ml). The combined organic layers were washed with water (100 ml), dried over  110 anhydrous Na2SO4, filtered and concentrated in vacuo, to yield 1.45 g of the crude products 187-190. Chromatographic purification using EtOAc/petroleum ether (3:2) as eluent afforded 713, 813 diol 187 (770.8 mg, 63.7 %) as well as 7a, 8a diol 188 (15.4 mg, 1.3 %). Further elution afforded 7a, 813 diol 189 (46.2 mg, 3.8 %) and 713, 8a diol 190 (277.5 mg, 23 %). V, 813-Diol 187: mp 103-104° C (EtOAc); [a] D = +41.8° (c= 1.00); IR (KBr) V max : 3349, 3012, 2927, 1627 cm -1 ; 1 H nmr 8: 1.09 (3H, s, C4-aCH3), 1.16 (3H, s, C4-13CH3), 1.35 (3H, s, C10-CH3), 1.10-1.60 (5H, m), 1.51 (1H, dd, J= 14, 3 Hz, C9-H), 1.85 (2H, dd, J= 13, 8 Hz), 2.08 (2H, br s, 0-H), 3.93 (1H, ddd, J= 7, 4, 3 Hz, C8-H), 4.21 (1H, dd, J= 4, 4 Hz, C7-H), 5.45 (1H, d, J= 4 Hz, C6-H); 13 C nmr 5: 18.59, 28.28, 29.22, 32.67, 35.51, 36.57, 42.09, 42.16, 45.30, 67.08, 68.58, 118.85, 154.15; MS m/z: 210 (Mt, 21.2), 192 (33.6), 177 (21.1), 166 (17.5), 151 (36.1), 135 (100); HRMS calcd. for C13H2202: 210.1620; found: 210.1615; Anal. calcd. for C13H2202: C 74.25, H 10.53; found: C 74.36, H 10.60. 1 H nmr decoupling experiment: irradiation of the signal resonating at 5 3.93 ppm  simplified the doublet of doublets resonating at 6 4.21 ppm to a doublet with a coupling constant of 4 Hz, and the doublet of doublets resonating at 5 1.51 ppm to a doublet with coupling constant of 14 Hz. Irradiation of the signal resonating at 5 4.21 ppm collapsed the doublet resonating at 8 5.45 ppm to a singlet, and the doublet of doublet of doublets resonating at 6 3.93 ppm was simplified to a doublet of doublets with coupling constants of 3 and 7 Hz. 1H  nmr nOe difference experiment: irradiation of the singlet resonating at  61.09 ppm led to enhancement of the signal resonating at 8 5.45 ppm; irradiation of the singlet resonating at 8 1.16 ppm led to enhancement of the signal resonating at 6 1.35 ppm; irradiation of the singlet resonating at 6 1.35 ppm led to enhancement of the signals resonating at 6 1.16 and 1.51 ppm; irradiation of the signal resonating at 8 3.93 ppm led to enhancement of the signal resonating at 6 4.21 ppm; irradiation of the doublet of doublets  111  resonating at 8 4.21 ppm led to enhancement of the signals resonating at 8 3.93 and 5.45 ppm; irradiation of the doublet resonating at 8 5.45 ppm led to the enhancement of the signals resonating at 8 1.09 and 4.21 ppm. 7a, 8a-Diol 188: mp 139-140° C (EtOAc); IR (KBr) V max : 3456, 3295, 3002, 2921, 1631 cm-1 ; 1 H nmr 8: 1.10 (3H, s, C4-(3CH3), 1.11 (3H, s, C4-aCH3), 1.24 (3H, s, C10-CH3), 1.10-1.90 (9H, m), 2.34 (1H, br s, 0-H), 3.95 (1H, m, C8-H), 4.10 (1H, dd, J= 5, 5 Hz, C7-H), 5.66 (1H, d, .1= 5 Hz, C6-H); 13 C nmr 8: 18.17, 27.08, 29.35, 32.19, 35.81, 37.69, 41.18, 41.49, 45.47, 66.40, 66.73, 118.86, 156.66; MS m/z: 210 (M+, 13.1), 192 (39.8), 177 (7.2), 166 (100); HRMS calcd. for C13H2202: 210.1620; found: 210.1612; Anal. calcd. for C13H2202: C 74.25, H 10.53; found: C 74.10,  H 10. 63 . 1 H nmr decoupling experiment: irradiation of the multiplet resonating at 8 3.95 ppm  collapsed the doublet of doublets resonating at 8 4.10 ppm to a doublet of coupling constant value of 5 Hz; irradiation of the doublet of doublets resonating at 8 4.10 ppm collapsed the doublet resonating at 8 5.66 ppm to a singlet and altered the multiplet resonating at 8 3.95 ppm. 1 H nmr nOe difference experiment: irradiation of the singlet at 8 1.24 ppm led to  enhancement of the signals resonating at 8 1.10 and 3.95 ppm; irradiation of the signal resonating at 6 3.95 ppm led to enhancement of the singlet resonating at 6 1.24 ppm; irradiation of the signal resonating at 8 4.10 ppm led to enhancement of the doublet resonating at 8 5.66 ppm.  7a, 8[3—Diol 189: mp 73 - 74° C (EtOAc); IR (KBr) V max : 3337, 3011, 2926, 1638 cm - 1 ; 1 H nmr 8: 1.10 (3H, s), 1.16 (311, s), 1.22 (3H, s), 1.10-1.60 (6H, m), 1.67 (1H, dd, J= 13, 4 Hz, C9-H), 1.80 (1H, m), 2.17 (2H, br s, 0-H), 3.51 (1H, ddd,  J= 11, 7, 4 Hz, C8-H), 4.00 (1H, dd, J= 7, 2 Hz, C7-H), 5.35 (1H, d, J= 2 Hz, C6-H); 13 C nmr 6: 19.35, 28.12, 29.86, 32.92, 36.75, 38.23, 41.04, 41.71, 46.18, 71.49,  112 74.24, 121.18, 152.07; MS m/z: 210 (Mt, 45.7), 192 (7.4), 177 (5.5), 166 (100); HRMS calcd. for C13H2202: 210.1620; found: 210.1614; Anal. calcd. for C13H2202: C 74.25, H 10.53; found: C 74.36, H 10.57. 1 H nmr decoupling experiment: irradiation of the signal resonating at 8 3.51 ppm  collapsed the doublet of doublets resonating at 6 4.00 ppm to a doublet of coupling constant value of 2 Hz; irradiation of the doublet resonating at 8 4.00 ppm simplified the doublet of doublet of doublets resonating at 8 3.51 ppm to a doublet of doublets with coupling constant values of 4 and 11 Hz, and the doublet resonating at 8 5.35 ppm collapsed to a singlet.  7P, 8a-Dio1190: mp 92-93° C (EtOAc); [a]g= -28.8 ° (c= 1.00); IR (KBr) Vmax: 3329, 3005, 2925, 1640 cm -1 ; 1 H nmr 8: 1.08 (3H, s, C4-aCH3), 1.11 (3H, s, C4-(3CH3), 1.28 (3H, s, C10-CH3), 1.20-1.70 (7H, m), 1.80 (1H, m, C2-(311), 3.75 (2H, br s, 0-H), 3.85 (1H, ddd, J= 12, 8, 4 Hz, C8-H), 4.08 (111, dd, .1= 8, 2.5 Hz, C7-H), 5.35 (1H, d, J= 2.5 Hz, C6-H); 13 C nmr 6: 18.35, 27.80, 29.03, 32.36, 35.54, 37.37, 41.62, 41.94, 48.95, 70.67, 75.58,120.44, 152.45; MS m/z: 210 (Mt, 8.3), 192 (52.0), 177 (23.0), 135 (100); HRMS calcd. for C13H2202: 210.1620; found: 210.1625;  Anal. calcd. for C13H2202: C 74.25, H 10.53; found: C 74.10, H 10.47. 1 H nmr decoupling experiment: irradiation of the signal at 8 3.85 ppm collapsed the  doublet of doublets at 8 4.08 ppm to a doublet with a coupling constant value of 2.5 Hz and simplified the multiplet resonating at 8 1.50 ppm. Irradiation of the doublet of doublets resonating at 8 4.08 ppm collapsed the signal resonating at 8 5.35 ppm to a singlet, and simplified the signal at 8 3.85 ppm to a doublet of doublets with coupling constant values of 4 and 12 Hz. 1 H nmr nOe difference experiment: irradiation of the singlet resonating at  6 1.28 ppm led to enhancement of the signals resonating at 8 1.11, 1.50, 1.80 and 3.85 ppm; irradiation of the signal resonating at 8 1.80 ppm led to enhancement of the  113 singlets resonating at 6 1.11 and 1.28 ppm; irradiation of the signal resonating at 8 3.85 ppm led to enhancement of the signals resonating at 6 1.28 and 5.35 ppm;  irradiation of the doublet of doublets resonating at 8 4.08 ppm led to enhancement of the signals resonating at 6 1.50 and 5.35 ppm; irradiation of the doublet resonating at 8 5.35 ppm led to enhancement of the signals resonating at 6 1.08 and 4.08 ppm. 3.14. 4aa,5,6,7,8,8a-Hexahydro-5,5,8a13-trimethylnaphthalen-2(1H)-one (172), 3,5,6,7,8,8a-hexahydro-5,5,8a13-trimethylnaphthalen-2(1H)one (179) and 44,5,6,7,8,8a-hexahydro-5,5,84-trimethyl naphthalen-2(1H)-one (191).  172  ^  179  ^  191  Method A To a solution of isomeric diols 187-190 (1.35 g, 6.4 mmol) in glacial acetic acid (80 ml), concentrated sulfuric acid (3950) was added. The reaction mixture was heated at reflux for 2 hours, cooled to room temperature and diluted with water (300 ml). The aqueous layer was extracted with diethyl ether (400 ml). The combined organic layers were washed with saturated sodium bicarbonate solution (200 ml), water (200 ml), dried, filtered and concentrated in vacuo. Chromatographic purification of the residue using EtOAc/pet ether 5:95 as eluent , gave ketone 179 (60.9 mg, 5 %) as a colourless oil, enone 191 (50.5 mg, 4 %) as a light yellow oil and enone 172 (72.5 mg, 6 %) as a colourless  oil that solidified upon standing.  114 Enone 172: mp 33-34 ° C; = -169.7 ° (c= 1.00); IR (CHC13) V max : 3015, 2931, 1681 cm -1 ; 1 H nmr 8: 0.92 (3H, s), 1.01 (3H, s), 1.04 (3H, s), 1.20-1.80 (611, m), 2.21 (2H, s), 2.23 (111, dd, J= 3, 3 Hz), 6.06 (1H, dd, J. 10, 3 Hz), 6.97 (1H, dd,  J= 10, 3 Hz); 13 C nmr 8: 18.40, 18.72, 22.00, 32.39, 32.47, 39.75, 40.24, 41.31, 54.47, 57.88, 130.11, 150.61, 199.84; UV (methanol) X max (log E ): 234 (3.84); MS m/z: 192 (M+, 36.5), 177 (7.5), 149 (14.2), 135 (18.6), 122 (63.6), 109 (100); HRMS calcd. for C13H200: 192.1515; found: 192.1515; Anal. calcd. for C13H200: C 81.21, H 10.47; found: C 81.30, H 10.49. Ketone 179: [a]D = -263.8 ° (c= 1.00); IR (neat) V max : 3050, 2932, 1719 cm-1 ; 1H  nmr 8: 1.10 (311, s), 1.12 (311, s), 1.16 (311, s), 1.30-1.90 (611, m), 2.16 (1H, d,  J= 14 Hz, C9-HA), 2.42 (1H, d, 14 Hz, C9-HB), 2.75 (1H, dd, J= 21, 3 Hz, C7-HA), 2.98 (111, dd, J= 21, 4 Hz, C7-HB), 5.58 (1H, dd, J= 4, 3 Hz, C6-H); 13 C nmr 8: 18.38, 26.71, 30.86, 31.71, 35.48, 38.85, 40.29, 40.77, 41.19, 57.19,  115.75, 151.50, 210.82; MS m/z: 192 (M+, 38.0), 177 (18.0), 150 (32.0), 135 (100); HRMS calcd. for C13H200: 192.1515; found: 192.1508; Anal. calcd. for C1311200: C 81.21, H 10.47; found: C 81.10, H 10.41. enone 191: [a]i; = +75.3 ° (c= 1.00); IR (neat) V max : 2927, 1675 cm -1 ; 1 11 nmr 8: 0.87 (3H, s, C4-aCH3), 1.00 (311, s, C10-CH3), 1.06 (3H, s, C4-(3CH3), 1.20-1.70  (6H, m), 1.86 (1H, d, J= 18 Hz, C9-(3H), 1.91 (1H, d, J= 6 Hz, C5-H), 2.75 (111, d,  J= 18 Hz, C9-aH), 6.11 (111, d, J=10 Hz, C7-H), 6.98 (111, dd, J= 10, 6 Hz, C6-H); 13 C nmr  8: 18.68, 22.30, 23.04, 31.67, 32.70, 34.97, 40.10, 41.14, 46.28, 52.81,  129.46, 150.84, 200.84; UV (methanol) Amax(log  e ): 235 (3.7); MS m/z: 192 (M+,  22.6), 177 (9.1), 164 (56.6), 149 (48.7), 109 (100); HRMS calcd. for Ci3H200: 192.1515; found: 192.1514; Anal. calcd. for C13H200: C 81.21, H 10.47; found: C 81.12, H 10.60. 1 H nmr nOe difference experiment: irradiation of the singlet resonating at  8 0.87 ppm led to enhancement of the signals resonating at 8 1.06 and 2.75 ppm;  115 irradiation of the singlet resonating at 8 1.00 ppm led to enhancement of the signals resonating at 61.86 and 1.91 ppm; irradiation of the singlet resonating at 6 1.06 ppm led to enhancement of the signals resonating at 8 0.87, 1.91 and 6.98 ppm; irradiation of the signal resonating at 8 1.86 ppm led to enhancement of the signals resonating at 6 1.00 and 2.75 ppm; irradiation of the signal resonating at 6 1.91 ppm led to enhancement of the signals resonating at 8 1.00, 1.06 and 6.98 ppm; irradiation of the signal resonating at 8 2.75 ppm led to enhancement of the signals resonating at 8 0.87 and 1.86 ppm; irradiation of the doublet resonating at 8 6.11 ppm led to enhancement of the signal resonating at 8 6.98 ppm; irradiation of the signal resonating at 6 6.98 ppm led to enhancement of the signals resonating at 6 1.06, 1.91 and 6.11 ppm. Method B A mixture of 70, 80-diol 187 (1.090 g, 5.2 mmol) and p-toluenesulfonic acid (1.190 g, 6.2 mmol) in anhydrous THF (50 ml ) was heated at reflux for 24 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue was chromatographed on silica gel using Et0Ac/cyclohexane 1:9 as eluent, affording ketone 179 (250.5 mg, 25 %) as a colourless oil. Further elution afforded enone 191 (18.0 mg,  2 %) as a light yellow oil and enone 172 (643.0 mg, 64 %) as a colourless oil that solidified on standing. Method C To a solution of 70, 8a-diol 190 (25.0 mg, 0.12 mmol) in anhydrous THF (5 ml), p-toluenesulfonic acid (27.0 mg, 0.14 mmol) was added. The mixture was heated at reflux for 24 hours. After cooling the reaction to room temperature, the solvent was removed in vacuo and the residue was purified by column chromatography on silica gel using  Et0Ac/cyclohexane 1:9 as eluent, affording ketone 179 (3.0 mg, 13 %) and enone 172 (15 mg, 66 %).  116 Method D To a solution of enone 143 (2.30 g, 12.0 mmol) in anhydrous benzene (130 ml) was added manganese triacetate dihydrate (9.00 g, 33.5 mmol). The brown suspension was heated at reflux for 1 hour with azeotropic removal of water. After cooling to room temperature, additional manganese triacetate dihydrate (9.00 g, 33.5 mmol) was added and the mixture was heated at reflux for a further 20 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (200 ml) and sequentially washed with 1 M HC1 (75 ml), saturated sodium bicarbonate solution (75 ml) and brine (75 ml). The organic layer was dried, filtered and concentrated in vacuo. The residue was dissolved in anhydrous THF (160 ml) and LAH (1.60 g, 42 mmol) was added. After stirring for 10 minutes at room temperature, the suspension was slowly poured into 1M HC1 (200 ml) and extracted with diethyl ether (600 ml). The combined organic layers were washed with water (100 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield a crude mixture of isomeric diols 187-190 (3.12 g) as a white solid. This solid was dissolved in anhydrous THE (115 ml). p-Toluenesulfonic acid (2.70 g, 14.2 mmol) was added and the mixture was heated at reflux for 24 hours. After cooling to room temperature, the reaction was diluted with diethyl ether (500 nil), washed with saturated sodium bicarbonate solution (200 ml), water (200 ml), dried, filtered and concentrated in vacuo to yield 2.35 g of residue. Chromatographic purification of the crude using  EtOAc%yclohexane 1:9 as eluent gave ketone 179 (342 mg, 15 %), enone 191 (40.5 mg, 2 %) and enone 172 (1.12 g, 49 %). Method E A solution of ketone 179 (230.7 mg, 1.2 mmol) and p-toluenesulfonic acid (286.8 mg, 1.5 mmol) in anhydrous THF (18 ml) was heated at reflux for 24 hours. After cooling the reaction mixture to room temperature, the solution was concentrated in vacuo, and the residue was chromatographed on silica gel using Et0Ac/cyclohexane 1:9 as eluent  117 yielding unreacted ketone 179 (72.0 mg, 31 %), enone 191 (3.0 mg, 1 %) and enone 172 (149.3 mg, 65 %).  3.15. 4acc,5,6,7,8,8a-Hexahydro-5,5,80-trimethy1-2-oxo-la-naphthalene acetic acid ethyl ester (201) and 4aa,5,6,7,8,8a-hexahydro-laiodo-5,5,8a13-trimethylnaphthalen-2(1H)-one (202). ,COOEt  202  ^  201  A solution of diisopropylamine (1.47 ml, 10.5 mmol) in anhydrous THF (12 ml) was cooled to -78 ° C and n-butyllithium (7.33 ml, 9.17 mmol) was added. The solution was allowed to warm up to -15 ° C for 30 minutes, then cooled to -78 ° C and a solution of enone 172 (1.26 g, 6.56 mmol) in anhydrous THF (50 ml) was added dropwise. The reaction was warmed to 0 ° C for 30 minutes, then cooled to -78 ° C and freshly distilled ethyl iodoacetate (2.32 ml, 19.65 mmol) was added. The reaction mixture was stirred at -78 ° C for 1 hour and then warmed to 0 ° C for another hour, poured into a saturated ammonium chloride solution (200 ml) and extracted with diethyl ether (400 ml). The organic extracts were washed with water (200 ml), dried, filtered and concentrated in vacuo  to yield 2.12 g of residue as a yellow oil. Chromatographic purification of the residue using EtOAc/hexanes 1:9 as eluent, gave unreacted starting material 172 (230 mg, 18 %), enone 202 (185 mg, 9 %) as a white solid, and enone 201 (1.33 g, 73 %) as a yellowish oil.  118 Enone 202: mp 109410 ° C (EtOAc); [a]il = -164.6 ° (c= 1.00); IR (KBr) Vmax: 3006, 2927, 1675, 1610 cm -1 ; 1 H nmr 5: 0.95 (3H, s, C4-(3CH3), 1.11 (3H, s, C4-aCH3), 1.16 (3H, s, C10-CH3), 1.19-1.70 (6H, m), 2.16 (1H, dd, J= 3,2 Hz, C5-H), 4.26 (1H, d, J= 1.4 Hz, C9-H), 6.12 (1H, ddd, J= 10, 3, 1.4 Hz, C7-H), 6.89 (1H, dd, J= 10, 2 Hz, C6-H); 13 C nmr 8: 15.34, 18.54, 22.40, 32.22, 32.45, 39.14, 40.74, 41.68, 50.79, 51.59, 127.23, 149.94, 193.08; UV (methanol) Vmax(log E): 245 (3.6); MS m/z: 318 (M+, 1.1), 191 (66.7), 147 (39.9), 135 (37.3), 121 (100); HRMS calcd. for C13111901: 318.0479; found: 318.0481; Anal. calcd. for C13I-1190I: C 49.07, H 6.01, I 39.88; found: C 49.00, H 6.00, I 39.73. 1H  nmr nOe difference experiment: irradiation of the singlet resonating at  8 0.95 ppm led to enhancement of the signals resonating at 5 1.16 and 6.89 ppm;  irradiation of the singlet resonating at 5 1.11 ppm led to enhancement of the signals resonating at 5 2.16 and 6.89 ppm; irradiation of the singlet resonating at 5 1.16 ppm led to enhancement of the signals resonating at 5 0.95 and 4.26 ppm; irradiation of the signal resonating at 5 2.16 ppm led to enhancement of the signals resonating at 5 1.11 and 6.89 ppm; irradiation of the doublet resonating at 5 4.26 ppm led to enhancement of the signal resonating at 8 1.16 ppm; irradiation of the signal resonating at 5 6.89 ppm led to enhancement of the signals resonating at 8 0.95, 1.11, 2.16 and 6.12 ppm. Enone 201: [a]D = -126.8 ° (c= 1.00); IR (neat) V max : 3051, 2936, 1737, 1679, 1612 cm -1 ; 1 H nmr 5: 0.92 (3H, s, C4-(3CH3), 1.06 (3H, s, C4-aCH3), 1.08 (3H, s, C10-CH3), 1.25 (3H, t, J= 8 Hz, CH3-CH2), 1.28-1.80 (6H, m), 2.14 (1H, dd, .1= 3, 2 Hz, C5-H), 2.22 (1H, dd, J= 15, 8 Hz, C11-HA), 2.50 (1H, dd, J= 8, 8 Hz, C9-H), 2.64 (1H, dd, J= 15, 8 Hz, C11-Hg), 4.15 (2H, q, J= 8 Hz, CH3-CH9), 6.00 (1H, ddd,  .1= 10, 3, 1 Hz, C7-H), 6.85 (1H, dd, J= 10, 2 Hz, C6-H); 13 C nmr 5: 14.13, 18.16, 21.38, 22.80, 31.81, 32.62, 32.69, 35.16, 40.87, 41.16, 48.40, 57.61, 60.87, 128.62, 149.25, 171.94, 201.33; UV (methanol) V max (log E): 236 (3.6); MS m/z: 278 (M+, 36.5),  119 263 (31.9), 232 (79.2), 217 (100); HRMS calcd. for C17H2603: 278.1883; found 278.1884; Anal. calcd. for C17H2603: C 73.36, H 9.41; found: C 73.29, H 9.42. 1 H nmr nOe experiment: irradiation of the singlet resonating at  8 0.92 ppm led to  enhancement of the signals resonating at 5 1.06, 1.08 and 6.85 ppm; irradiation of the singlet resonating at 5 1.06 ppm led to enhancement of the signals resonating at 5 0.92, 2.14 and 6.85 ppm; irradiation of the singlet resonating at 5 1.08 ppm led to enhancement of the signals resonating at 5 0.92 and 2.50 ppm; irradiation of the signal resonating at  8 2.14 ppm led to enhancement of the signals resonating at 5 1.06 and 2.64 ppm; irradiation of the signal resonating at 5 2.22 ppm led to enhancement of the signals resonating at 5 2.50 and 2.64 ppm; irradiation of the signal resonating at 5 2.50 ppm led to enhancement of the signals resonating at 8 1.08 and 2.22 ppm; irradiation of the signals resonating at 6 2.64 ppm led to enhancement of the signals resonating at 6 2.14 and 2.22 ppm. 3.16. 3,4,4aa,5,6,7,8,8a-Octahydro-5,5,80-trimethy1-2-oxo-la (2'-hydroxy iso-butyl)-naphthalene (210). OH  210  Cerium chloride heptahydrate (1.405 g, 3.77 mmol) was dried at 140 ° C for 2 hours under high vacuum, then cooled to room temperature. Anhydrous THE (20 ml)  120 was added and the suspension was stirred for 1 hour at room temperature, then cooled to -78 ° C and methyllithium (3.14 ml, 3.77 mmol) was added and stirred for 1 hour (-78 ° C). Keto ester 201 (952.8 mg, 3.427 mmol) in anhydrous THE (25 ml) was added to the suspension and stirred at that temperature for 1 hour. The reaction was quenched with saturated ammonium chloride solution (40 ml) at -78 ° C. The mixture was allowed to warm to room temperature, and the aqueous layer was extracted with EtOAc (300 ml). The combined organic layers were dried, filtered and concentrated in vacuo. Chromatographic purification of the crude product eluting with EtOAc/hexanes 1:4 gave hydroxy ketone 210 (199.2 mg, 22 %) as a white solid and starting keto ester 201 (281.5 mg, 29 %). Hydroxy ketone 210: mp 70-70.5° C (EtOAc); IR (KBr) v max : 3380, 3034, 2966, 1674, 1630 cm -1 ; 1 H nmr (benzene-d6) 8: 0.64 (3H, s), 0.74 (3H, s), 0.88 (3H, s), 1.23 (6H, s), 0.70-1.60 (7H, m), 1.71 (1H, d, J= 14 Hz), 1.91 (1H, br s), 2.15 (111, br d,  J= 8 Hz), 2.61 (1H, br s), 5.91 (1H, m), 6.30 (1H, br d, J = 10 Hz); 13 C nmr (benzened6) 8: 18.36, 19.00, 21.64, 22.49, 29.64, 31.28, 32.26, 32.33, 34.61, 37.90, 40.96, 48.54, 57.44, 70.42, 119.41, 148.18, 204.89; UV (methanol) X max (log e): 235 (3.8); MS m/z: 264 (M+, 24.3), 249 (84.6), 246 (66.0), 231 (100); HRMS calcd. for CrH2802: 264.2089; found: 264.2086; Anal. calcd. for C17H2802: C 77.24, H 10.66; found: C 77.36, H 10.59.  121 3.17. 3,4,4aa,5,6,7,8,8a-Octahydro-5,5,84-trimethy1-2-oxo-1anaphthalene acetic acid ethyl ester (205).  it/ COOEt  205  A hydrogenation vessel containing a suspension of enone 201 (2.106 g, 7.6 mmol) and 10% palladium on charcoal (210 mg) in EtOAc (100 ml) was purged three times with hydrogen at a pressure of 15 psi. The vessel was then pressurized to 40 psi with hydrogen and shaked for 20 minutes at room temperature. A sample taken for analytical TLC (EtOAc/hexanes 1:4) indicated the reaction was complete. The mixture was filtered through Celite 545 and the flask and Celite were washed with EtOAc (175 ml). The solution was concentrated in vacuo to yield 2.500 g of crude product. Chromatographic purification using EtOAc/hexanes 1:4 as eluent gave keto ester 205 (2.110 g, 100 %) as a colourless oil. [a]D = -34.8 ° (c= 1.00); IR (neat) V max : 2943, 1732 cm-1 ; 1 H nmr 8: 0.87 (3H, s), 0.98 (3H, s), 0.99 (3H, s), 1.24 (3H, t, J= 8 Hz, CH3-CH2), 1.10-1.70 (8H, m), 1.95 (1H, m), 2.30-2.75 (5H, m), 4.11 (2H, q, J= 8 Hz, CH3-CH,,); 13 C nmr 8: 14.08, 18.52, 21.55, 22.01, 23.33, 33.30 (x2), 33.44, 36.37, 38.54, 40.08, 42.15, 44.94, 60.38, 60.86, 171.72, 213.04; MS m/z: 280 (M+, 1.4), 262 (3.6), 247 (6.3), 232 (30.1), 109 (100); HRMS calcd. for C17H2803: 280.2038; found: 280.2044; Anal. calcd. for C17H2803: C 72.83, H 10.06; found: C 72.68, H 9.99.  122 3.18. 3,4,4aa,5,6,7,8,8a-Octahydro-5,5,8a0-trimethyl-2-oxo-1 f3naphthalene acetic acid ethyl ester (211).  211  Method A A solution of keto ester 205 (57 mg, 0.20 mmol) in absolute ethanol (6 ml) was added to a solution of potassium metal (5 mg, 0.13 mmol) in absolute ethanol (3 ml). The reaction mixture was stirred at room temperature for 90 minutes, then refluxed for 1 hour. After cooling to room temperature, saturated ammonium chloride solution (15 ml) was added and extracted with diethyl ether (40 m1). The combined organic layers were dried, filtered and concentrated in vacuo. Chromatographic purification of the residue using EtOAc/petroleum ether 1:4 as eluent, afforded keto ester 211 (25.4 mg, 45 %) as a colourless oil that solidified upon standing, mp 78-78.5° C (EtOAc); IR (KBr) v max : 2923, 1733, 1723 cm -1 ; 1 H nmr 8: 0.74 (3H, s), 0.86 (3H, s), 0.98 (3H, s), 1.26 (3H, t,  J= 7 Hz, CH3-CH2), 1.20-1.30 (1H, m), 1.40-1.70 (7H, m), 2.08 (11-1, m), 2.19 (1H, dd, J= 16, 3 Hz), 2.35-2.50 (2H, m), 2.60-2.80 (2H, m), 4.12 (2H, dq, J= 7, 2 Hz, CH3-CH,,); 13 C nmr 8: 14.16, 14.91, 18.84, 21.68, 23.48, 27.72, 33.48, 33.60, 39.06, 41.36, 41.56, 41.80, 53.76, 59.79, 60.45, 173.49, 211.07; MS m/z: 280 (Mt, 2.2), 262 (5.5), 247 (10.5), 219 (24.6), 109 (100); HRMS calcd. for C17H2803: 280.2039; found: 280.2039; Anal. calcd.for C17H2803: C 72.83, H 10.06; found: C 73.00, H 10.11.  123 Method B To a solution of keto ester 205 (98 mg, 0.35 mmol) in anhydrous THE (12m1), potassium ethoxide (88.2 mg, 1.05 mmol) was added. The mixture was heated at reflux for 2 hours, cooled to room temperature and saturated ammonium chloride solution (15 ml) was added. The aqueous layer was extracted with diethyl ether (40 ml). The combined organic layers were dried, filtered and concentrated in vacuo. Chromatographic purification of the residue eluting with Et0Acipetroleum ether 1:4 mixture gave keto ester 211 (48 mg, 49 %) as a colourless oil that solidified upon standing. 3.19. 1,2,3,4,4aa,5,6,7,8,8a-Decahydro-5,5,80-trimethy1-2,2ethylenedioxy-la-naphthalene acetic acid ethyl ester (215) and 1,2,3,4,4acc,5,6,7,8,8a-decahydro-5,5,84-trimethyl-2,2ethylenedioxy-113-naphthalene acetic acid ethyl ester (216). COOEt^ COOEt  11!^  215  ^  11  216  Method A A solution of keto ester 205 (133.2 mg, 0.5 mmol), p-toluenesulfonic acid (3.8 mg, 2.10 -2 mmol) and ethylene glycol (0.159 ml, 2.8 mmol) in anhydrous benzene (7 ml), was heated at reflux with azeotropic removal of water. The reaction was monitored by GC and showed 90 % conversion after 6 hours. The reaction mixture was then cooled to room temperature, diluted with benzene (20 ml), washed with saturated sodium  124 bicarbonate solution (10 ml), water (10 ml), dried, filtered and concentrated in vacuo. The resulting oil was purified by column chromatography using EtOAc/hexanes 1:4 as eluent. The silica gel was treated with a mixture of EtOAc/hexanes/Et3N in a ratio of 1 : 4 : 4.10 -2 , prior to use. Purification yielded ketal 215 (71.4 mg, 46 %) as a colourless oil that solidified upon standing, ketal 216 (46.3 mg, 29 %) as a colourless oil and starting keto ester 205 (13 mg, 10 %). A longer reflux (19 hours) proved to increase the ratio of ketal 216 (61 % by GC), lowering the ratio of ketal 215 to 11 % (by GC). Ketal 215: mp 42 ° C; [a]D = -7.7 ° (c= 1.00); IR (CHC13) Vm ax : 2946, 1735 cm -1 ; 1H  nmr 5: 0.82 (3H, s, C4-(3CH3), 0.87 (3H, s, C4-aCH3), 0.90-1.18 (2H, m), 1.19  (3H, s, C10-CH3), 1.27 (3H, t, .1= 7 Hz, CX3-CH2), 1.30-1.40 (2H, m), 1.50-1.70 (7H, m), 2.08 (1H, ddd, J= 5, 5, 2 Hz, C9-H), 2.47 (2H, dd, J= 5, 3.6 Hz, Cl 1-2H), 3.80 (2H, dt, J= 6.5, 3 Hz), 3.98 (2H, m), 4.14 (2H, dq, J= 7, 1 Hz, CH3-CH,); 13 C nmr 8: 14.20, 18.51, 20.13, 21.74, 22.23, 32.69, 33.03, 33.42, 33.59, 37.01, 38.08, 42.22, 46.59, 50.30, 60.25, 63.34, 64.46, 111.04, 174.21; MS m/z: 324 (M+, 29), 309 (6.4), 279 (18.8), 99 (100); HRMS calcd. for C19H3204: 324.2302; found: 324.2293; Anal calcd. for C19H3204: C 70.35, H 9.93; found: C 70.50, H 10.04. 1H  nmr nOe difference experiment: irradiation of the singlet resonating at  8 0.82 ppm led to enhancement of the signal resonating at 5 1.19 ppm; irradiation of the singlet resonating at 8 0.87 ppm affected the multiplet resonating at 8 1.60 ppm; irradiation of the singlet resonating at 8 1.19 ppm led to enhancement of the signals resonating at 5 0.82 and 2.08 ppm; irradiation of the signal resonating at 8 2.08 ppm led to enhancement of the signals resonating at 61.19 and 2.47 ppm.  Ketal 216: [a]D = +8.3 ° (c= 1.00); IR (neat) V max : 2946, 1736 cm -1 ; 1 H nmr 5:  0.83 (3H, s), 0.87 (3H, s), 0.89 (3H, s), 1.25 (3H, t, .T= 7.5 Hz, 013-CH2), 1.00-1.21 (2H, m), 1.30-1.50 (5H, m), 1.55-1.65 (3H, m), 1.91 (1H, dd, J= 3, 9 Hz), 2.15 (2H,  125 m), 2.29 (1H, dd, J= 17, 9 Hz), 3.73-3.88 (2H, m), 3.92-4.16 (4H, m); 13 C nmr 8: 14.25, 14.73, 18.56, 19.69, 21.68, 28.83, 33.24, 33.60, 35.76, 38.47, 39.26, 41.80, 53.99, 54.92, 60.07, 63.24, 65.00, 110.50, 174.69; MS m/z: 324 (Mt, 19.3), 309 (3.4), 279 (9.2), 99 (100); HRMS calcd. for C19H3204: 324.2302; found: 324.2308; Anal. calcd. for C19H3204: C 70.35, H 9.93; found: C 70.43, H 9.87. Method B To a solution of trimethylsilyl inflate (30^0.15 mmol) in anhydrous methylene chloride (1 ml) at -78 ° C, was added 1,2-bis(trimethylsilyloxy)ethane (0.42 ml, 1.7 mmol). A solution of keto ester 205 (434.6 mg, 1.55 mmol) in anhydrous methylene chloride (5 ml) was added to the reaction and the mixture was warmed to 0 ° C and stirred for 2 hours; the reaction was monitored by GC. (Strict anhydrous conditions were required, traces of moisture were found to lower the yield of ketal 215 to 44 %, increasing the presence of ketal 216 up to 30 % ). The reaction was quenched with dry pyridine (0.35 ml), poured into saturated sodium bicarbonate solution (10 ml) and extracted with diethyl ether (50 ml). The combined organic layers were washed with 10 % copper sulfate solution (30 nil), water, dried, filtered and concentrated in vacuo. Bulb to bulb distillation of the crude product gave 482 mg of a colourless oil (bp 118° C at 9 mm Hg). GC analysis of the oil showed a 93 : 5 : 2 mixture of products, being the minor compounds ketal 216 and starting keto ester 205, respectively, and ketal 215 being the major one. The mixture was not further purified. Method C A solution of triflic acid (17.4 gl, 0.2 mmol) in anhydrous THF (2.4 ml) was cooled to -78 ° C, 1,2-bis(trimethylsilyloxy)ethane (0.48 ml, 1.9 mmol) was added to the solution with temperature maintained at -78 ° C. A solution of keto ester 205 (276.1 mg, 1.0 mmol) in anhydrous THF (12.2 ml) was added and the reaction mixture was stirred at  126 0 ° C. After 14 hours GC analysis showed a mixture of 215 : 216 : 205 in a 8 : 1 : 1 ratio. The reaction was quenched with dry pyridine (150 ill), poured into saturated sodium bicarbonate solution (10 ml) and extracted with diethyl ether (50 ml). The combined organic layers were washed with 10% copper sulfate solution (20 ml), water (20 ml), dried, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel treated with EtOAc/hexanes/Et3N in a 1 : 4 : 4.10 -2 ratio prior to use, and eluted with EtOAc/hexanes 1:4, affording ketal 215 (214.4 mg, 67 %), ketal 216 (27.1 mg, 8 %) and starting keto ester 205 ( 27.0 mg, 10 %).  3.20. 1,2,3,4,4aa,5,6,7,8,8a-Decahydro-2,2-ethylenedioxy-loc(2chydroxyethylen)-5,5,8a13-trimethylnaphthalene (217). 12  11^s"--- OH  217  To a solution of ketal 215 (621.9 mg, 1.9 mmol) in anhydrous diethyl ether (50 ml) was added LAH (218 mg, 5.7 mmol). The suspension was stirred at room temperature. After 10 minutes analytical TLC (EtOAc/hexanes 1:1) showed reaction completion. Water (10 ml) was slowly added to the reaction mixture and stirred for 5 minutes, then 15 % sodium hydroxide solution (10 ml) was added and stirred for 5 minutes more. The mixture was then filtered and the filtrate was washed with diethyl ether (50 ml). The aqueous layer was extracted with diethyl ether (60 m1). The combined organic layers were washed with water (60 ml), dried over anhydrous Na2SO4, filtered and  127 concentrated in vacuo. The residue was chromatographed on silica gel treated with EtOAc/hexanes/Et3N in a 1 : 1 : 2.10 -2 ratio prior to use, and eluted with EtOAc/hexanes 1:1, affording hydroxy ketal 217 (537.8 mg, 100 %) as a colourless oil. [a] ; = -7.5 ° (c= 1.00); IR (neat) V ma x : 3300, 2947 cm -1 ; 1 H nmr 5: 0.83 (311, s), 0.88 (3H, s),  1.00-1.15 (211, m), 1.17 (3H, s), 1.25 (1H, m), 1.35-1.71 (10H, m), 1.82 (1H, m, C11-HA), 2.02 (11-1, m, C11-HB), 3.49 (1H, m, C12-HA), 3.68 (1H, m, C12-HB), 3.85 (2H, m), 3.98 (2H, m);  13 C  nmr 5: 16.46, 20.13, 21.52, 22.71, 30.95, 32.88, 32.96,  33.36, 36.09, 38.90, 42.31, 46.29, 52.72, 63.09, 64.46, 64.63, 112.32; MS m/z: 282 (M+, 2.4), 267 (0.3), 252 (0.2), 99 (100); HRMS calcd. for C17H3003: 282.2195; found: 282.2195; Anal. calcd. for C17H3003: C 72.31, H 10.70; found: C 72.41, 11 10.75. 1 H nmr decoupling experiment: irradiation of the signal resonating at 5 3.49 ppm  affected the multiplets resonating at 6 1.82, 2.02 and 3.68 ppm; irradiation of the signal resonating at 5 3.68 ppm affected the multiplets resonating at 5 1.82, 2.02 and 3.49 ppm. 3.21. 1,2,3,4,4aa,5,6,7,8,8a-Decahydro-2,2-ethylenedioxy-la-(2%0benzyl ethyl)-5,5,84-trimethylnaphthalene (218). 12 112,:;Ph  218 Method A Sodium hydride, 60 % dispersion in parafin oil (9.2 mg, 0.23 mmol), was weighed, and washed three times with anhydrous THE (9 ml), under argon atmosphere.  128 Anhydrous THF (3 ml) was added. A solution of hydroxy ketal 217 (58.7 mg, 0.21 mmol) in anhydrous THF (10 ml) was added dropwise with good stirring. Sodium iodide (3.3 mg, 0.02 mmol) and potassium carbonate (55 mg, 0.40 mmol) were added to the suspension, then benzyl chloride (25.3 0.22 mmol) was added. The reaction mixture was heated at reflux for 12 hours. After cooling the reaction to room temperature, water (5 ml) was added slowly. The aqueous layer was extracted with diethyl ether (15 ml). The combined organic layers were washed with water (5 ml), dried, filtered and concentrated in vacuo. The residue was chromatographed on silica gel treated with EtOAc/hexanes/Et3N 1 : 9 : 1.10 -2 ratio prior to use, and eluted with EtOAc/hexanes 1:9, affording hydroxy benzyl ketal 218 (52.8 mg, 68 %) as a colourless oil and starting hydroxy ketal 217 (12.8 mg). Hydroxy benzyl ketal 218: oc2 = +0.95 ° (c= 1.00); IR (neat) V max : 2946 cm -1 ; 1 H nmr 8: 0.82 (3H, s), 0.87 (3H, s), 1.06 (3H, m), 1.15 (3H, s), 1.35-1.80 (11H, m),  3.44 (2H, m), 3.80 (2H, m), 3.92 (21-1, m), 4.52 (2H, d, J= 3 Hz, CH2-Ph), 7.25 (1H, m), 7.32 (4H, m); 13 C nmr 8: 16.46, 20.13, 21.53, 22.67, 27.94, 32.87, 33.23, 33.36, 36.38, 38.66, 42.21, 46.19, 51.11, 63.25, 64.36, 71.98, 72.59, 112.15, 127.37, 127.59 (x2), 128.26 (x2), 138.75; MS m/z: 372 (M+, 25.7), 357 (2.1), 281 (42.1), 99 (100); HRMS calcd. for C24H3603: 372.2666; found: 372.2665; Anal. calcd. for C24H3603: C 77.39, H 9.73; found: C 77.32, H 9.67.  Method B Sodium hydride, 80 % dispersion in parafin oil (169 mg, 5.63 mmol), was weighed, and washed three times with anhydrous THF (15 ml), under argon atmosphere. Anhydrous THF (24 ml) was added. A solution of hydroxy ketal 217 (529.5 mg, 1.88 mmol) in anhydrous THF (35 ml) was added dropwise with good stirring. Benzyl bromide (0.67 ml, 5.63 mmol) and tetrabutylammonium iodide (67.6 mg, 0.18 mmol) were added to the suspension. The reaction mixture was refluxed for 22 hours, and  129 monitored by analytical TLC (EtOAc/hexanes 1:4). After reaction completion, it was cooled to room temperature and water (10 ml) was added slowly. The aqueous layer was extracted with diethyl ether (30 ml). The combined organic layers were washed with water (30 ml), dried, filtered and concentrated in vacuo. The residue was chromatographed on silica gel treated with EtOAc/hexanes/Et3N 1 : 9 : 1.10 -2 ratio prior to use, and eluted with EtOAc/hexanes 1:9, affording hydroxy benzyl ketal 218 (684.7 mg, 98 %) as a colourless oil.  3.22. 3,4,4aa,5,6,7,8,8a-Octahydro-la(2'-0-benzyl ethyl)-5,5,841trimethylnaphthalen-2(1H)-one (219). 12 110z:^  Ph  219  Method A To a solution of hydroxy benzyl ketal 218 (683 mg, 1.83 mmol) in acetone (20 ml), 1M HC1 (5.5 ml) was added. The reaction mixture was stirred at room temperature. After 1 hour, analytical TLC (EtOAc/hexanes 1:4) showed reaction completion. Saturated sodium bicarbonate solution (20 ml) was added and the solution was extracted with diethyl ether (80 ml). The combined organic layers were washed with water (30 ml), dried, filtered and concentrated in vacuo. Chromatographic purification of the crude product using EtOAc/hexanes 1:4 as eluent, gave hydroxy benzyl ketone 219 (584 mg, 97 %) as a colourless oil. [a] g = -27.6 ° (c= 1.00); IR (neat) Vmax: 2947,  130 1708 cm -1 ; 1 H nmr 8: 0.86 (3H, s), 0.94 (3H, s), 0.95 (3H, s), 1.05-1.25 (2H, m), 1.40-1.70 (6H, m), 1.80-1.95 (3H, m), 2.02 (1H, m), 2.27 (1H, m), 2.54 (1H, m), 3.30 (1H, m), 3.42 (1H, m), 4.42 (2H, s), 7.32 (5H, m). 13 C nmr 8: 18.61, 21.78, 22.07, 23.48, 27.73, 33.29, 33.46, 36.93, 38.50, 40.02, 42.34, 44.80, 62.22, 68.85, 73.26, 127.57, 127.78 (x2), 128.33 (x2), 138.20, 215.00; MS m/z: 328 (M+, 1.6), 313 (2.1), 269 (8.3), 221 (11.4), 206 (10.7), 91 (100); HRMS calcd. for C22H3202: 328.2402; found: 328.2396; Anal. calcd. for C22H3202: C 80.45, H 9.81; found: C 80.40, H 9.79. Method B To a solution of ketal 215 (3.95 g, 12.2 mmol) in anhydrous diethyl ether (120 ml), LAH (1.39 g, 36.6 mmol) was added and the solution was stirred at room temperature for 10 minutes. Water (50 ml) was added slowly and stirred for 5 minutes, then 15 % sodium hydroxide solution (30 ml) was added and stirred for 5 more minutes. The mixture was filtered and the filtrate was washed with diethyl ether (150 ml). The aqueous layer was extracted with diethyl ether (200 ml). The combined organic layers were washed with water (150 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield 3.60 g of crude hydroxy ketal 217, this was dissolved in anhydrous THF  (100 ml) and added to a solution of sodium hydride (80 % dispersion in parafin oil) (1.10 g, 36.6 mmol) in anhydrous THF (22 ml). Benzyl bromide (4.35 ml, 36.6 mmol) and tetrabutylammonium iodide (439 mg, 1.2 mmol) were added to the suspension. The reaction mixture was heated at reflux for 22 hours. After cooling to room temperature, water (70 ml) was added slowly. The aqueous layer was extracted with diethyl ether (250 m1). The combined organic layers were washed with water (100 m1), dried, filtered and concentrated in vacuo. The residue was dissolved in acetone (122 ml) and 1M HC1 (37 ml) was added. The reaction was stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution (130 ml) was added and the solution was extracted with diethyl ether (500 ml). The combined organic layers were washed with water (200 ml),  131 dried, filtered and concentrated in vacuo. Chromatographic purification of the residue using EtOAc/hexanes 1:4 as eluent afforded hydroxy benzyl ketone 219 (3.50 g, 87 % from 215 over 3 steps) as a colourless oil. 3.23. 1,2,3,4,4aa,5,6,7,8,8a-Decahydro-la-(2'-0-benzyl ethyl)-2a,5,5, 80-tetramethylnaphthalen-213-ol (220). 12 11^Ph  H  220  Method A To a solution of hydroxy benzyl ketone 219 (44.5 mg, 0.13 mmol) in anhydrous diethyl ether (10 ml), methylmagnesium iodide (70 gl, 0.21 mmol) was added. The mixture was refluxed for 5 hours, then cooled to room temperature and saturated ammonium chloride solution (6 ml) added. The aqueous layer was extracted with diethyl ether (30 ml). The combined organic layers were washed with water (20 ml), dried, filtered and concentrated in vacuo. Chromatographic purification of the residue eluting with EtOAc/hexanes 1:6, afforded starting ketone 219 (32.0 mg, 72 %) as well as alcohol 220 (6.9 mg, 15 %) as a white solid, mp 85-86 ° C (EtOAc); [a] ii = -12.1 ° (c= 1.00); IR (KBr) V max : 3397, 2946 cm -1 ; 1 H nmr 8: 0.83 (3H, s), 0.86 (3H, s), 1.02 (2H, m), 1.14 (2H,  m), 1.25 (3H, s), 1.27 (3H, s), 1.35-1.60 (9H, m), 1.70 (1H, m), 1.87 (1H, m, Cl 1-H), 3.40 (2H, dd, J= 8, 8 Hz, C12-2H), 4.52 (2H, s, CH2-Ph), 7.26 (1H, m), 7.36 (4H, m); 13 C  nmr 8: 18.33, 18.76, 21.38, 24.65, 29.44, 31.15, 32.89, 33.30, 36.18, 36.97,  132 38.71, 42.20, 46.63, 55.38, 72.12, 72.96, 75.08, 127.54, 127.58 (x2), 128.37 (x2), 138.50; MS m/z: 344 (M+, 0.5), 329 (0.7), 253 (2.3), 91 (100); HRMS calcd. for C23H3602: 344.2715; found: 344.2706; Anal. calcd. for C23H3602: C 80.19, H 10.52;  found: C 80.00, H 10.45. 1 H nmr decoupling experiment: irradiation of the doublet of doublets resonating at  8 3.40 ppm affected the signals resonating at 8 1.40 and 1.86 ppm.  Method B Cerium chloride heptahydrate (652.0 mg, 1.75 mmol) was dried at 140 ° C for 2 hours under high vacuum, then cooled to room temperature. Anhydrous THF (11 ml) was added and the suspension was stirred for 1 hour at room temperature, then cooled to -78 ° C and methyllithium (1.25 ml, 1.75 mmol) was added and stirred for 1 hour (-78 ° C). Hydroxy benzyl ketone 219 (441.4 mg, 1.34 mmol) in anhydrous THF (14 ml) was added to the suspension. After the addition was completed the syringe was rinsed into the reaction with anhydrous THF (2 ml). Analytical TLC (EtOAc/hexanes 1:6) showed reaction completion after 10 minutes. The reaction was quenched with saturated ammonium chloride solution (20 ml) at -78 ° C. The mixture was allowed to warm to room temperature, and the aqueous layer was extracted with EtOAc (100 ml). The combined organic layers were dried, filtered and concentrated in vacuo. Chromatographic purification of the crude product eluting with EtOAc/hexanes 1:6 gave alcohol 220 (458.5 mg, 100 %) as a white solid.  133 3.24. 1,2,3,4,4aa,5,6,7,8,8a-Decahydro-la-(2'-hydroxyethyl)2a,5,5,84-Tetramethylnaphthalen-20-ol (221).  221 A suspension of alcohol 220 (114.4 mg, 0.33 mmol) and 10 % palladium on charcoal (117.2 mg) in absolute EtOH (20 ml), was purged three times with hydrogen at a pressure of 15 psi in a hydrogenation vessel. The pressure was increased to 20 psi of hydrogen and the vessel was shaken for 10 minutes at room temperature. A sample taken for analytical TLC (EtOAc/hexanes 1:1) showed reaction completion. The suspension was filtered through Celite 545. The flask and Celite were washed with EtOH (60 ml). Concentration in vacuo afforded diol 221 (95.5 mg) as a white solid; mp 145.5-146 ° C (EtOAc); foe = -22.7 ° (c= 1.00). IR (KBr) V max : 3315, 2947 cm -1 ; 1 H nmr 8: 0.84 (311, s), 0.85 (1H, m, C9-H), 0.88 (3H, s), 0.98-1.20 (4H, m), 1.27 (3H, s), 1.29 (3H, s), 1.30-1.75 (10H, m), 1.84 (1H, m, Cl 1-H), 3.57 (2H, dd, J= 8, 8 Hz, C12-2H); 13 C nmr  8: 18.31, 18.72, 21.35, 24.65, 31.15, 32.48, 32.88, 33.28, 36.28, 36.97,  38.65, 42.22, 46.71, 55.15, 64.50, 75.03; MS m/z: 254 (M+, 4.9), 239 (27.1), 236 (50.9), 221 (100); HRMS calcd. for CI6H3002: 254.2246; found: 254.2242; Anal. calcd. for C16H3002: C 75.55, H 11.88; found: C 75.50, H 11.79. 1 H nmr decoupling experiment: irradiation of the signal resonating at  6 3.57 ppm  simplified the multiplet resonating at 6 1.34 ppm to a doublet of doublets with coupling constant values of 3 and 13 Hz, and simplified the multiplet resonating at 8 1.84 ppm to a doublet of doublets with coupling constant values of 4 and 13 Hz.  134  3.2 5. 1,2,313,3a,4,5,5aa,6,7,8,9,9a-Dodecahydro-30,6,6,90tetramethylnaphtho[2,1-b]furan epi-Ambrox (3).  3 Method A p-Toluenesulfonic acid (33 mg, 0.17 mmol) was added to a suspension of diol 221 (337 mg, 1.33 mmol) in nitromethane (30 ml). The reaction mixture was heated to 80° C (oil bath temperature) for 30 minutes. After cooling to room temperature, it was diluted with diethyl ether (50 ml) and washed with saturated sodium bicarbonate solution (25 ml). The organic layer was dried, filtered and concentrated in vacuo. Chromatographic purification of the crude product eluting with EtOAc/hexanes 1:4 mixture, yielded (-)-epi-Ambrox (3) (261.5 mg, 83 %) as a colourless oil that solidified upon standing, and a mixture of primary alcohols 222 (33.8 mg, 11 %). (-)-epi-Ambrox (3); mp.30.5-31° C; [a]D = -6.1° (c= 1.00); IR (CHC13) vmax:  2938 cm -1 ; 1 H nmr 8: 0.82 (3H, s), 0.90 (3H, s), 1.11 (3H, s), 1.10-1.30 (4H, m), 1.38 (3H, s), 1.42 (2H, m), 1.54-1.70 (6H, m), 1.93 (1H, m, C11-HA), 2.05 (1H, m, C11-HB), 3.78 (1H, dd, J= 9, 8 Hz, C12-HA), 3.86 (1H, ddd, J= 9, 9, 3 Hz, C12-HB); 13 C nmr 6: 18.50, 20.41, 21.75, 22.82, 27.70, 28.84, 32.92, 33.57, 35.77, 36.02,  38.67, 42.31, 46.71, 59.00, 64.07, 80.83; MS m/z: 236 (Mt, 14.8), 221 (67.5), 203 (3.4), 137 (100); HRMS calcd. for C16H280: 236.2140; found: 236.2138; Anal. calcd. for C16H280: C 81.30, H 11.93; found: C 81.19, H 12.00.  135 1H  nmr decoupling experiment: irradiation of the signal resonating at 8 3.78 ppm  affected the signals resonating at 8 1.93, 2.05 and 3.86 ppm; irradiation of the signal resonating at 8 3.86 ppm affected the signals resonating at 8 1.93, 2.05 and 3.78 ppm. Method B Cerium chloride heptahydrate (1.45 g, 3.90 mmol) was dried at 140° C for 2 hours under high vacuum, then cooled to room temperature. Anhydrous THF (16 ml) was added and the suspension was stirred for 1 hour at room temperature, then cooled to -78° C. Methyllithium (2.9 ml, 3.90 mmoles) was added and stirred for 1 hour at -78° C. Hydroxy benzyl ketone 219 (640 mg, 1.95 mmol) in anhydrous THF (20 ml) was added dropwise to the suspension. After 10 minutes, analytical TLC (EtOAc/hexanes 1:6) showed reaction completion. Saturated ammonium chloride solution (30 ml) was added. The mixture was allowed to warm to room temperature, and the aqueous layer was extracted with EtOAc (150 ml). The combined organic layers were dried, filtered and concentrated in vacuo. The residue was dissolved in absolute ethanol (20 ml) in a hydrogenation vessel. 10 % Palladium in charcoal (670 mg) was added and the vessel was purged 3 times with hydrogen at 15 psi, then shaken for 10 minutes at a hydrogen pressure of 20 psi, at room temperature. The suspension was filtered through Celite 545 using a water aspirator. The flask and Celite were washed with ethanol (60 ml). Concentration in vacuo yielded 565 mg of an oil. Nitromethane (44 ml) was added to the crude product, then p-toluenesulfonic acid (49 mg, 0.26 mmol) was added, and the mixture was heated to 80° C (oil bath temperature) for 30 minutes. After cooling to room temperature, the reaction mixture was diluted with diethyl ether (100 ml). The organic layer was washed with saturated sodium bicarbonate solution (50 ml), dried, filtered and concentrated in vacuo. Chromatographic purification of the residue, eluting EtOAc/hexanes 1:4, yielded (-)-epi-Ambrox (3) (371 mg, 80 % from 219; 3 steps) as a colourless oil that solidified in vacuo, and 50 mg (11 %) mixture of primary alcohols (222).  136  3.26. 1,2,3,4,4aa,5,6,7,8,8a-Decahydro-2,2-ethylenedioxy-113-(2'hydroxyethylen)-5,5,8a0-trimethylnaphthalene (223). 12  223  To a solution of ketal 216 (428 mg, 1.32 mmol) in anhydrous diethyl ether (40 ml), LAH (150 mg, 3.95 mmol) was added. The suspension was stirred at room temperature. After 10 minutes, analytical TLC (EtOAc/hexanes 1:1) showed reaction completion. Water (5 ml) was added and stirred for 5 minutes, then 15 % sodium hydroxide solution (5 ml) was added and stirred for 5 minutes more. The mixture was filtered and the filtrate was washed with diethyl ether (50 ml). The aqueous layer was extracted with diethyl ether (50 ml). The combined organic layers were washed with water (50 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The remaining oil was chromatographed on silica gel treated with EtOAc/hexanes/Et3N in a 1 : 1 : 2.10 -2 ratio, prior to use, and eluted with EtOAc/hexanes 1:1 to yield hydroxy ketal 223 (342.7 mg, 92 %) as a white solid, mp 69-70° C.(EtOAc); [a] D = +9.3°  (c= 1.00, EtOH); IR (KBr) V max : 3228, 2916 cm -1 ; 1 H nmr (acetone-d6) 8: 0.84 (3H, s), 0.90 (6H, s), 0.90-1.00 (4H, m), 1.15-1.65 (8H, m), 1.73 (1H, m), 1.94 (1H, ddd,  J= 12, 4, 4 Hz), 2.82 (111, br s, 0-H), 3.50 (2H, m), 3.80 (1H, dd, J= 8, 8 Hz), 3.90 (1H, m), 4.00 (2H, m); 13 C nmr (acetone d6) 8: 15.02, 19.17, 20.56, 22.04, 28.04, 33.81, 33.91, 36.60, 39.74, 39.82, 42.73, 55.02, 55.98, 63.94, 64.40, 65.73, 111.68;  137 MS m/z: 282 (M+, 0.1), 264 (0.5), 249 (1.1), 220 (15.6), 205 (100); HRMS calcd.for C17H3003: 282.2195; found: 282.2189; Anal. calcd. for C17H3003: C 72.31, H 10.70; found: C 72.52, H 10.85. 3.27. 1,2,3,4,4aa,5,6,7,8,8a-decahydro-2,2-ethylenedioxy-lp(2'-0benzyl ethyl)-5,5,84-trimethylnaphthalene (224). 12  224  Sodium hydride, 80 % dispersion in parafin oil (108.8 mg, 3.62 mmol) was weighed and washed three times with anhydrous THE (15 ml), under argon atmosphere. Anhydrous THE (15 ml) was added. A solution of hydroxy ketal 223 (340 mg, 1.20 mmol) in anhydrous THE (23 ml) was added dropwise with good stirring. Benzyl bromide (0.43 ml, 3.62 mmol) and tetrabutylammonium iodide (43.5 mg, 0.12 mmol) were added to the suspension. The reaction mixture was heated at reflux. After 22 hours, TLC (EtOAc/hexanes 1:4) showed reaction completion. The reaction was cooled to room temperature and water (7 ml) was added slowly. The aqueous layer was extracted with diethyl ether (25 ml). The combined organic layers were washed with water (25 ml), dried over anhydrous Na2S 04, filtered and concentrated in vacuo. The residue was chromatographed on silica gel treated with EtOAc/hexanes/Et3N 1 : 9 : 1.10 -2 , prior to use, and eluted with EtOAc/hexanes 1:9, affording hydroxy benzyl ketal 224 (412.2 mg, 92 %) as a white solid, mp 85-86° C (EtOAc); [a] il = +22.9° (c= 1.00); IR (KBr)  138 V max : 2910 cm -1 ; 1 H nmr 8: 0.82 (3H, s), 0.88 (3H, s), 0.90 (3H, s), 0.90-0.96 (2H, m), 1.15 (1H, ddd, J= 13, 13, 5 Hz), 1.25-1.80 (10H, m), 1.90 (1H, ddd, J= 10, 3, 3 Hz), 3.40 (1H, m, C12-HA), 3.60 (1H, m, C12-Hg), 3.75 (111, dd, J= 4, 4 Hz), 3.86 (1H, ddd, J= 7, 7, 5 Hz), 3.96 (1H, ddd, J= 7, 7, 7 Hz), 4.03 (1H, m), 4.50 (21-1, d, J= 3 Hz, CH2-Ph), 7.27 (1H, m), 7.34 (4H, m);  13 C  nmr 5: 14.43,  18.50, 19.80, 21.68, 24.01, 33.22, 33.58, 36.09, 39.02, 39.17, 41.98, 53.84, 55.23, 63.28, 65.09, 72.39, 72.62, 111.35, 127.31, 127.54(x2), 128.24(x2), 138.90; MS m/z: 372 (Mt, 1.2), 357 (0.3), 281 (5.3) 205 (13.9), 99 (100); HRMS calcd. for C24H3603: 372.2664; found: 372.2656; Anal. calcd. for C24H3603: C 77.39, H 9.73; found: C 77.47, H 9.68. 3.28. 3,4,4aa,5,6,7,8,8a-Octahydro-10(2%0-benzyl ethyl)-5,5,80trimethyl-l-naphthalene (225). 12  225  Method A To a solution of hydroxy benzyl ketal 224 (411 mg, 1.1 mmol) in acetone (40 ml), 1M HC1 (3.3 ml) was added. The reaction mixture was stirred at room temperature for 4 hours. Saturated sodium bicarbonate solution (20 ml) was added slowly, and the solution was extracted with diethyl ether (200 ml). The combined organic layers were washed with water (100 ml), dried and concentrated in vacuo. Chromatographic  139 purification of the residue eluting with EtOAc/hexanes 1:4, afforded hydroxy benzyl ketone 225 (346.7 mg, 96 %) as a colourless oil. [a] i = -19.6° (c= 1.00); IR (neat) V max : 2947, 1709 cm -1 ; 1 H nmr 5: 0.73 (3H, s), 0.86 (3H, s), 0.97 (3H, s), 1.15-1.30 (3H, m), 1.40-1.90 (6H, m), 2.04 (2H, m), 2.28 (2H, m), 2.41 (1H, ddd, J= 12, 5, 2 Hz), 3.29 (1H, ddd, J= 10, 9, 6 Hz, C12-HA), 3.53 (1H, m, C12-HB), 4.42 (1H, d, J= 12 Hz, CHA-Ph), 4.49 (1H, d, J= 12 Hz, CHB-Ph), 7.32 (5H, m); 13 C nmr 5: 14.67, 18.96, 21.63, 22.00, 23.93, 33.46, 33.65, 39.11, 41.88, 42.30, 42.41, 54.13, 60.06, 69.51, 72.60, 127.39, 127.54 (x2), 128.27 (x2), 138.68, 212.03; MS m/z: 328 (M+, 2.7), 313 (2.5), 269 (10.3), 237 (62.6), 221 (8.9), 179 (88.9), 91 (100); HRMS calcd. for C22H3202: 328.2402; found: 328.2398; Anal. calcd. for C22H3202: C 80.45, H 9.81;  found: C 80.54, H 9.81.  Method B To a solution of hydroxy benzyl ketone 219 (546.0 mg, 1.66 mmol) in THF/Me0H 1:1 (20 ml), sodium methoxide (270.0 mg, 5.00 mmol) was added and the solution was heated at reflux for 22 hours. After cooling to room temperature, saturated ammonium chloride solution (15 ml) was added and the mixture was extracted with diethyl ether (150 ml). The combined organic layers were washed with water (75 ml), dried, filtered and concentrated in vacuo. Chromatographic purification of the residue eluting with EtOAc/hexanes 1:4, afforded hydroxy benzyl ketone 225 (487.6 mg, 89 %) as a colourless oil and starting ketone 219 ( 52.3 mg, 10 %).  140 3.2 9. 1,2,3,4,4aa,5,6,7,8,8a-Decahydro-113-(2'-0-benzylethyl)-2a,5,5, 843-tetramethylnaphthalen-213-ol (226). 12  226 Cerium Chloride heptahydrate (720.0 mg, 1.93 mmol) was dried at 140° C under high vacuum for a period of 2 hours, then cooled to room temperature. Anhydrous THF (12 ml) was added, and the suspension was stirred at room temperature for 1 hour, then cooled to -78° C and methyllithium (1.38 ml, 1.93 mmol) was added. The mixture was stirred at -78° C for 1 hour. A solution of hydroxy benzyl ketone 225 (487.6 mg, 1.49 mmol) in anhydrous THF (15 ml) was added dropwise to the suspension, with maintaince of the temperature. After 10 minutes, a sample taken for analytical TLC (EtOAc/hexanes 1:4) showed reaction completion. Saturated ammonium chloride solution (15 ml) was added to the reaction mixture, and the temperature was allowed to rise to 25° C. The aqueous layer was extracted EtOAc (80 ml). The combined organic layers were washed with water (40 ml), dried, filtered and concentrated in vacuo. Chromatographic purification of the residue with EtOAc/hexanes 1:4, afforded hydroxy benzyl alcohol 226 (502.8 mg, 98 %) as a white solid, mp 88.5-89° C (EtOAc/hexane); [a] ; = +10.8°  (c= 1.00); IR (KBr) V m a x : 3479, 2910 cm -1 ; 1 H nmr 8: 0.83 (3H, s), 0.86 (3H, s), 0.70-0.90 (2H, m), 0.97 (3H, s), 1.10 (3H, s), 1.20-1.80 (13H, m), 3.44 (2H, m), 4.50 (2H, s), 7.27 (1H, m), 7.33 (4H, m); 13 C nmr 8: 15.07, 18.13, 18.30, 21.64, 25.28, 30.68, 33.25, 33.42, 38.63, 39.22, 41.98, 42.18, 54.91, 55.89, 72.42, 72.73, 72.89,  141 127.43, 127.48 (x2), 128.31 (x2),138.63; CI MS m/z: 345 (M++1), 326 (0.2), 311 (0.2), 267 (0.2), 235 (10.3), 218 (34.2), 91 (100); Anal. calcd. for C23H3602: C 80.19, H 10.52; found: C 80.40, H 10.58.  3.30. 1,2,3,4,4aa,5,6,7,8,8a-Decahydro-113-(2'-hydroxyethyl)2a,5,5,84-tetramethylnaphthalen-213-ol (90).  90 A suspension of hydroxy benzyl alcohol 226 (502.8 mg, 1.46 mmol) and 10% Palladium on charcoal (500.6 mg) in absolute ethanol (15 ml) was purged three times with hydrogen at 15 psi. The hydrogen pressure was then increased to 20 psi and the vessel was shaken for 10 minutes. Sample taken for analytical TLC (EtOAc/hexanes 1:1) showed reaction completion. The suspension was then filtered through Celite 545. The vessel and the Celite were washed with ethanol (50 ml). Concentration in vacuo and chromatographic purification of the residue, using diethyl ether/hexanes 5:1 as eluent, afforded diol 90 (370.0 mg, 100 %) as a white solid, mp 168-170° C (EtOAc);  [ot]D = +15.7° (c=1.00, ethanol); IR (KBr) V max : 3358, 3322, 2925 cm -1 ; 1 H nmr 8: 0.83 (3H, s), 0.87 (3H, s), 0.80-0.90 (2H, m), 0.98 (3H, s), 1.14 (3H, s), 1.30-1.80 (14H, m), 3.56-3.68 (2H, m, C12-2H); 13 C nmr 8: 15.13, 18.13, 18.30, 21.64, 28.66, 30.68, 33.27, 33.42, 38.52, 39.33, 41.96, 42.25, 54.65, 55.88, 64.94, 72.91; MS m/z: 254 (M+, 1.2), 236 (6.7), 221 (11.2), 43 (100); HRMS calcd. for C16H3002: 254.2247;  142 found: 254.2254; Anal. calcd. for C16H3002: C 75.55, H 11.88; found: C 75.58, H 11.80. 3.31. 1,2,30,3a,4,5,5aa,6,7,8,9,9a-Dodecahydro-3a13,6,6,9a0tetramethylnaphtho[2,1-b]furan Ambrox® (2).  2  To a suspension of diol 90 (370 mg, 1.46 mmol) in nitromethane (29 ml), p-toluenesulfonic acid (11.6 mg, 6.10 -2 mmol) was added. The reaction mixture was heated to 80° C (oil bath temperature) for 30 minutes with good stirring. It was then cooled to room temperature and diluted with diethyl ether (60 ml). The organic layer was washed with saturated sodium bicarbonate solution (40 ml), dried and concentrated in vacuo. Chromatographic purification of the residue eluting with EtOAc/hexanes 1:4, gave pure (-)-Ambrox® (2) (261.4 mg, 76%) as a white solid as well as a mixture of primary alcohols (73.7 mg, 21 %). (-)-Ambrox ® (2): mp 76-77° C (EtOH); [a]t5 = -24.1° (c= 1.00); IR (KBr) Vmax: 2936 cm-1 ; 1 H nmr 8: 0.84 (3H, s), 0.85 (3H, s), 0.88 (3H, s), 1.09 (3H, s), 0.90-1.80 (13H, m), 1.95 (111, ddd, .1= 12, 2, 2 Hz), 3.83 (1H, dd, J= 16, 7 Hz, C12-HA), 3.93  (1H, m, C12-HB); 13 C nmr 8: 15.04, 18.41, 20.66, 21.14 (x2), 22.64, 33.07, 33.58, 36.20, 39.76, 39.97, 42.45, 57.27, 60.13, 64.98, 79.92; MS m/z: 236 (M+, 3.9), 221  143 (100), 203 (2.3); HRMS calcd. for C16H280: 236.2140; found: 236.2133; Anal. calcd. for C16H280: C 81.30, H 11.93; found: C 81.22, H 12.00.  ^^  144 BIBLIOGRAPHY  1.  a) R. I. Zalewsky and J. J. Skolik, eds., Natural Products Chemistry 1984, Studies in Organic Chemistry 20, Elsevier Science Publishers B. V., 1985. b) E. J. Ariens; W. Soudijn, and P. B. M. W. Timmermans, Stereochemistry and Biological Activity of Drugs, Blackwell Scientific, Palo Alto, CA, 1983.  2.  a) E. J. Ariens, J. S. Van Rensen, and W. 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Rev. 58, 2037 (1988). 118. D. D. Perrin, W. L. Armarego, and D. R. Perrin, Purification of laboratory Chemicals, 2nd Edition, Pergamon Press, 1980.  150  151  Appendix 1.^X-ray Structure report on ketodiol 135. A. Crystal Data Empirical Formula^  C 15 H 24 0 3  Formula Weight^  252.35  Crystal Color, Habit^  colorless, needle  Crystal Dimensions (mm)^0.100 X 0.120 X 0.450 Crystal System^  orthorhombic  No. Reflections Used for Unit Cell Determination (29 range) ^25 ( 46.0 - 73.3°) Omega Scan Peak Width at Half-height^ Lattice Parameters:  0.38  a^ 12.654 (2)A ^  b = 23.239 (1)A ^ c = 9.526 (1)A V = 2801.3 (6)A 3 Space Group^  P2 1 2 1 2 1 (#19)  Z value^  8  D  1.197 g/cm 3  calc^ ^ F 000  6.16 cm -1  ^  P (CuEm  1104  )  B. Intensity Measurements  Diffractometer^  Rigaku AFC6S  Radiation^  CuKm (X = 1.54178 A)  Temperature^  21°C  Take-off Angle^  6.0°  Detector Aperture^  6.0 mm horizontal 6.0 mm vertical  Crystal to Detector Distance^285 mm  152 Scan Type^  w-28  Scan Rate^  16.0°/min (in omega) (8 rescans)  Scan Width^  (1.00 + 0.20 tan8)°  28  155.1°  max^  No. of Reflections Measured^Total: 3307 Corrections  Lorentz-polarization Absorption (trans. factors: 0.90 - 1.00) Secondary Extinction (coefficient:^0.89467E-05) C. Structure Solution and Refinement  Structure Solution Refinement  ^  ^  Function Minimized  ^  Least-squares Weights p-factor  ^  ^  Anomalous Dispersion  ^  Direct Methods Full-matrix least-squares Z w (IFol - IFc1) 4Fo 2 /a 2 (Fo 2 ) 0.03  All non-hydrogen atoms  No.^Observations^(I>3.00a(I)) No. Variables Reflection/Parameter Ratio  2028 360 5.63  Residuals:^R; Rw  0.037; 0.043  Goodness of Fit Indicator  1.54  Max Shift/Error in Final Cycle  0.07  Maximum Peak in Final Diff. Map Minimum Peak in Final Diff. Map  2  0.13 e/A 3 -0.11 e - /A 3  153  H23A  54  C6 1  11 H8A  a'  - olt  H18A  H16A 116  H2A^C12  03A  Fig 28 Single crystal X-ray structure of ketodiol 135 (PLUTO drawing).*  The numbering of carbon atoms here, is different from that used in the Discussion (Section 2.).  154  Fig. 29 The unit cell structure of ketodiol 135 (packing diagram).  155  Table 5 Final atomic coordinates (fractional) and B eq (A) of ketodiol 135. atom  x  B eg  y  O(1A)  0.2048(2)  -0.0216(1)  0.1720(4)  7.9(2)  0(2A)  0.4635(2)  0.1126(1)  0.0336(3)  4.7(1)  0(3A)  0.4637(2)  0.1143(1)  0.3041(3)  5.1(1)  C(1A)  0.4413(8)  -0.0530(4)  0.058(1)  4.2(4)  C(1A')  0.4446(7)  -0.0432(4)  -0.028(1)  4.9(4)  C(2A)  0.3275(8)  -0.0527(4)  0.007(1)  5.2(5)  C(2A')  0.3674(8)  -0.0597(4)  0.082(1)  5.5(5)  C(3A)  0.2805(3)  -0.0109(2)  0.0993(5)  5.8(2)  C(4A)  0.3156(3)  0.0487(2)  0.0637(4)  4.6(2)  C(5A)  0.4357(3)  0.0573(1)  0.0853(4)  3.7(1)  C(6A)  0.4670(2)  0.0579(1)  0.2440(4)  3.8(1)  C(7A)  0.5732(3)  0.0292(1)  0.2566(4)  4.1(2)  C(8A)  0.6559(3)  0.0537(1)  0.1616(4)  4.6(2)  C(9A)  0.5954(3)  0.0016(1)  0.1177(4)  4.3(2)  C(10A)  0.5044(3)  0.0088(1)  0.0181(4)  4.7(2)  C(11A)  0.6085(3)  0.0037(2)  0.3953(5)  5.7(2)  C(12A)  0.6223(4)  0.0499(2)  0.5071(5)  7.7(3)  C(13A)  0.5359(4)  -0.0437(2)  0.4451(6)  8.9(3)  C(14A)  0.2493(3)  0.0945(2)  0.1365(5)  6.4(2)  C(15A)  0.5423(4)  0.0231(2)  -0.1284(5)  8.4(3)  0(18)  0.1689(2)  0.2937(1)  0.8138(3)  6.8(2)  0(28)  0.4195(2)  0.1474(1)  0.7468(3)  4.2(1)  0(3B)  0.3258(2)  0.1638(1)  0.5083(3)  4.7(1)  C(1B)  0.4544(3)  0.2979(2)  0.8506(5)  6.1(2)  156 Table 5 Final atomic coordinates (fractional) and B eg (A) of ketodiol 135. (cont)  atom  x  y  z  B eq  C(2B)  0.3483(4)  0.3236(2)  0.8177(5)  6.5(2)  C(3B)  0.2613(3)  0.2797(2)  0.8228(4)  4.8(2)  C(4B)  0.2958(3)  0.2178(1)  0.8326(4)  4.0(2)  C(5B)  0.3883(2)  0.2058(1)  0.7305(3)  3.5(1)  C(6B)  0.3530(2)  0.2164(1)  0.5748(3)  3.4(1)  C(7B)  0.4388(2)  0.2505(1)  0.5017(4)  3.8(1)  C(8B)  0.5448(3)  0.2215(2)  0.5071(4)  4.6(2)  C(9B)  0.5175(3)  0.2664(1)  0.6126(4)  4.4(2)  C(10B)  0.4860(3)  0.2463(1)  0.7585(4)  4.2(2)  C(11B)  0.4129(3)  0.2890(2)  0.3781(4)  4.7(2)  C(12B)  0.3300(3)  0.3343(2)  0.4122(5)  5.6(2)  C(13B)  0.3816(4)  0.2549(2)  0.2495(5)  7.1(2)  C(14B)  0.2035(3)  0.1769(2)  0.8127(4)  4.9(2)  C(15B)  0.5778(3)  0.2161(2)  0.8321(4)  5.7(2)  157 Table 6 Hydrogen atom coordinates (fractional) and Biso (A2) of ketodiol 135.  B.is°  atom  x  y  H(1A)  0.451(4)  0.116(2)  -0.065(5)  9(1)  H(2A)  0.486(4)  0.134(2)  0.243(5)  7(1)  H(3A)  0.4420  -0.0582  0.1600  5.1  H(3A')  0.4939  -0.0750  -0.0444  5.8  H(4A)  0.4787  -0.0851  0.0133  5.1  H(4A')  0.4069  -0.0346  -0.1158  5.8  H(5A)  0.3225  -0.0408  -0.0911  6.2  H(5A')  0.3329  -0.0958  0.0549  6.7  H(6A)  0.2945  -0.0906  0.0186  6.2  H(6A')  0.4046  -0.0650  0.1711  6.7  H(7A)  0.3029  0.0535  -0.0372  5.5  H(8A)  0.4157  0.0341  0.2946  4.6  'H(9A)  0.6437  0.0905  0.1144  5.5  H(10A)  0.7308  0.0503  0.1866  5.5  H(11A)  0.6325  -0.0354  0.1177  5.1  H(12A)  0.6781  -0.0136  0.3797  6.9  H(13A)  0.6483  0.0322  0.5939  9.2  H(14A)  0.6733  0.0786  0.4743  9.2  H(15A)  0.5542  0.0685  0.5251  9.2  H(16A)  0.4646  -0.0282  0.4591  10.6  H(17A)  0.5336  -0.0744  0.3745  10.6  H(18A)  0.5623  -0.0593  0.5340  10.6  H(19A)  0.2752  0.1328  0.1104  7.7  H(20A)  0.1753  0.0905  0.1077  7.7  158 Table 6 Hydrogen atom coordinates (fractional) and Biso (A2 ) of ketodiol 135. (cont) atom  x  Y  z  B.iso  H(21A)  0.2547  0.0896  0.2385  7.7  H(22A)  0.5872  -0.0081  -0.1633  10.1  H(23A)  0.4813  0.0278  -0.1907  10.1  H(24A)  0.5830  0.0590  -0.1261  10.1  H(1B)  0.382(3)  0.129(1)  0.688(4)  4.3(9)  H(28)  0.381(3)  0.153(1)  0.445(4)  5(1)  H(38)  0.5079  0.3279  0.8387  7.3  H(48)  0.4536  0.2851  0.9486  7.3  H(5B)  0.3330  0.3539  0.8864  7.8  H(6B)  0.3506  0.3403  0.7233  7.8  H(78)  0.3227  0.2118  0.9280  4.8  H(8B)  0.2894  0.2405  0.5771  4.1  H(98)  0.5501  0.1811  0.5356  5.5  H(108)  0.5977  0.2296  0.4345  5.5  H(11B)  0.5525  0.3039  0.6045  5.2  H(12B)  0.4780  0.3098  0.3542  5.6  H(13B)  0.3555  0.3588  0.4888  6.7  H(14B)  0.3168  0.3580  0.3289  6.7  H(15B)  0.2644  0.3153  0.4408  6.7  H(16B)  0.3150  0.2346  0.2677  8.5  H(17B)  0.3724  0.2810  0.1697  8.5  H(188)  0.4370  0.2268  0.2276  8.5  H(19B)  0.1509  0.1836  0.8863  5.9  H(20B)  0.1714  0.1835  0.7205  5.9  159 Table 6 Hydrogen atom coordinates (fractional) and Bi so (A2 ) of ketodiol 135. (cont) atom  x  Y  z  Biso  H(21B)  0.2288  0.1371  0.8185  5.9  H(22B)  0.5559  0.2044  0.9266  6.9  H(23B)  0.5985  0.1820  0.7782  6.9  H(24B)  0.6380  0.2425  0.8389  6.9  160 Table7Bondlenghts(A)ofketodio1135 with estimated standard deviations in parentheses. atom  distance  atom  atom  distance  atom  0(1A)  C(3A)  1.209(4)  C(11A) C(13A)  0(2A)  C(5A)  1.419(4)  1(1B)  C(3B)  1.218(4)  0(3A)  C(6A)  1.432(4)  0(28)  C(5B)  1.422(4)  C(1A)  C(2A)  1.52(1)  0(38)  C(6B)  1.420(4)  C(1A)  C(10A)  1.69(1)  C(18)  C(2B)  1.503(6)  C(1A') C(2A')  1.48(1)  C(1B)  C(10B)  1.539(5)  C(1A') C(10A)  1.49(1)  C(2B)  C(3B)  1.501(5)  C(3A)  1.44(1)  C(3B)  C(4B)  1.506(5)  C(2A') C(3A)  1.59(1)  C(4B)  C(58)  1.547(4)  C(2A)  1.512(6)  C(3A)  C(4A)  1.494(5)  C(4B)  C(148)  1.518(5)  C(4A)  C(5A)  1.546(5)  C(5B)  C(6B)  1.568(5)  C(4A)  C(14A)  1.522(5)  C(5B)  C(10B)  1.577(4)  C(5A)  C(6A)  1.563(5)  C(6B)  C(7B)  1.514(4)  C(5A)  C(10A)  1.562(5)  C(7B)  C(8B)  1.502(4)  C(6A)  C(7A)  1.505(4)  C(7B)  C(9B)  1.498(5)  C(7A)  C(8A)  1.496(5)  C(7B)  C(11B)  1.516(5)  C(7A)  C(9A)  1.499(5)  C(8B)  C(9B)  1.490(5)  C(7A)  C(11A)  1.516(5)  C(98)  C(10B)  1.520(5)  C(8A)  C(9A)  1.493(5)  C(10B) C(15B)  1.528(5)  C(9A)  C(10A)  1.501(5)  C(11B) C(12B)  1.520(5)  C(10A) C(15A)  1.513(6)  C(11B) C(13B)  1.513(6)  C(11A) C(12A)  1.521(7)  161 Table 8 Bond angles (deg) of ketodiol 135 with estimated standard deviations in parentheses. angle  angle  atom  atom  atom  C(10A)  112.0(7)  C(9A)  C(7A)  C(11A)  123.1(3)  C(2A') C(1A') C(10A)  109.5(8)  C(7A)  C(8A)  C(9A)  60.2(2)  C(3A)  101.6(7)  C(7A)  C(9A)  C(8A)  60.0(2)  C(1A') C(2A') C(3A)  110.2(7)  C(7A)  C(9A)  C(10A)  111.5(3)  C(10A)  118.7(3)  atom  atom  atom  C(2A)  C(1A)  C(1A)  C(2A)  0(1A)  C(3A)  C(2A)  122.4(5)  C(8A)  C(9A)  0(1A)  C(3A)  C(2A')  117.4(5)  C(1A)  C(10A) C(5A)  105.0(4)  0(1A)  C(3A)  C(4A)  123.9(4)  C(1A)  C(10A) C(9A)  97.2(4)  C(2A)  C(3A)  C(4A)  111.5(5)  C(1A)  C(10A) C(15A)  C(2A') C(3A)  C(4A)  115.7(5)  C(1A') C(10A) C(5A)  115.1(4)  C(3A)  C(4A)  C(SA)  112.4(3)  C(1A') C(10A) C(9A)  119.1(5)  C(3A)  C(4A)  C(14A)  112.3(3)  C(1A') C(10A) C(15A)  C(5A)  C(4A)  C(14A)  113.0(3)  C(5A)  C(10A) C(9A)  104.4(3)  0(2A)  C(5A)  C(4A)  108.3(3)  C(5A)  C(10A) C(15A)  113.3(3)  0(2A)  C(5A)  C(6A)  105.4(3)  C(9A)  C(10A) C(15A)  111.3(3)  0(2A)  C(5A)  C(10A)  111.9(3)  C(7A)  C(11A) C(12A)  111.6(3)  C(4A)  C(5A)  C(6A)  112.3(3)  C(7A)  C(11A) C(13A)  112.3(4)  C(4A)  C(5A)  C(10A)  113.5(3)  C(12A) C(11A) C(13A)  111.4(4)  C(6A)  C(5A)  C(10A)  105.1(3)  C(2B)  C(1B)  C(10B)  115.1(3)  0(3A)  C(6A)  C(SA)  112.8(3)  C(1B)  C(2B)  C(3B)  112.2(3)  0(3A)  C(6A)  C(7A)  113.6(3)  0(1B)  C(3B)  C(2B)  121.3(4)  C(5A)  C(6A)  C(7A)  107.5(3)  0(18)  C(3B)  C(4B)  122.6(4)  C(6A)  C(7A)  C(8A)  114.1(3)  C(2B)  C(3B)  C(4B)  116.0(3)  C(6A)  C(7A)  C(9A)  106.7(3)  C(3B)  C(4B)  C(5B)  110.6(3)  C(6A)  C(7A)  C(11A)  120.4(3)  C(3B)  C(4B)  C(1413)  111.6(3)  C(8A)  C(7A)  C(9A)  59.8(2)  C(58)  C(4B)  C(14B)  113.0(3)  C(8A)  C(7A)  C(11A)  118.0(3)  0(2B)  C(5B)  C(4B)  108.3(3)  123.1(4)  93.7(5)  162 Table 8 Bond angles (deg) of ketodiol 135 with estimated standard deviations in parentheses.  (cont) atom  atom  atom  atom^angle^atom^atom  0(2B)  C(5B)  C(6B)^109.5(2)^C(12B)^C(11B) C(13B)  0(2B)  C(58)  C(10B)^109.4(3)  C(4B)  C(5B)  C(6B)^110.6(3)  C(4B)  C(5B)  C(10B)^112.3(3)  C(6B)  C(5B)  C(10B)^106.8(3)  0(3B)  C(6B)  C(5B)^110.8(3)  0(38)  C(6B)  C(7B)^114.8(3)  C(5B)  C(6B)  C(7B)^108.3(3)  C(6B)  C(7B)  C(8B)^113.0(3)  C(6B)  C(7B)  C(9B)^106.4(3)  C(6B)  C(7B)  C(11B)^120.8(3)  C(8B)  C(7B)  C(9B)^59.6(2)  C(8B)  C(7B)  C(11B)^119.0(3)  C(9B)  C(7B)  C(11B)^123.0(3)  C(7B)  C(8B)  C(9B)^60.1(2)  C(7B)  C(9B)  C(8B)^60.3(2)  C(7B)  C(9B)  C(10B)^113.2(3)  C(8B)  C(9B)  C(10B)^117.5(3)  C(1B)  C(10B) C(5B)^110.9(3)  C(1B)  C(10B) C(9B)^110.5(3)  C(1B)  C(10B) C(15B)^107.1(3)  C(5B)  C(10B) C(9B)^103.6(3)  C(5B)  C(10B) C(15B)^113.6(3)  C(9B)  C(10B) C(15B)^111.2(3)  C(7B)  C(11B) C(12B)^113.1(3)  C(7B)  C(11B) C(13B)^112.0(3)  angle 110.8(3)  163 Table 9 Torsional or conformational angles (deg) of ketodiol 135. (1)^(2)^(3)^(4)^angle^(1)^(2)^(3)^(4)  angle  O(1A)C(3A)C(2A)C(1A) -123.9(6)  C(1A'C(10AC(9A)C(8A)  179.0(5)  0(1A)C(3A)C(2A'C(1A'  170.5(6)  C(2A)C(1A)C(10AC(5A)  56.2(8)  0(1A)C(3A)C(4A)C(5A)  132.3(4)  C(2A)C(1A)C(10AC(9A)  163.3(7)  O(1A)C(3A)C(4A)C(14A  3.5(6)  C(2A)C(1A)C(10AC(15A  -75.3(8)  0(2A)C(5A)C(4A)C(3A)  173.3(3)  C(2A)C(3A)C(4A)C(5A)  -64.0(6)  0(2A)C(5A)C(4A)C(14A  -58.3(4)  C(2A)C(3A)C(4A)C(14A  167.2(5)  0(2A)C(5A)C(6A)0(3A)  28.0(4)  C(2A'C(1A'C(10AC(5A)  -44(1)  0(2A)C(5A)C(6A)C(7A)  -97.9(3)  C(2A'C(1A'C(10AC(9A)  80.8(8)  0(2A)C(5A)C(10AC(1A) -165.9(4)  C(2A'C(1A'C(10AC(15A -162.3(7)  0(2A)C(5A)C(10AC(1A'  -135.2(5)  C(2A'C(3A)C(4A)C(5A)  0(2A)C(5A)C(10AC(9A)  92.3(3)  0(2A)C(5A)C(10AC(15A  -29.0(4)  C(3A)C(2A)C(1A)C(10A  -69.4(8)  0(3A)C(6A)C(5A)C(4A)  -89.8(3)  C(3A)C(2A'C(1A'C(10A  65(1)  0(3A)C(6A)C(5A)C(10A  146.4(3)  C(3A)C(4A)C(5A)C(6A)  -70.8(4)  O(3A)C(6A)C(7A)C(8A)  -72.7(4)  C(3A)C(4A)C(5A)C(10A  48.3(4)  0(3A)C(6A)C(7A)C(9A) -136.5(3)  C(4A)C(5A)C(6A)C(7A)  144.3(3)  -27.6(7)  C(2A'C(3A)C(4A)C(14A -156.4(6)  0(3A)C(6A)C(7A)C(11A  76.5(4)  C(4A)C(5A)C(10AC(9A) -144.7(3)  C(1A)C(2A)C(3A)C(4A)  72.1(8)  C(4A)C(5A)C(10AC(15A  94.0(4)  C(1A)C(10AC(5A)C(4A)  -42.9(5)  C(5A)C(6A)C(7A)C(8A)  52.7(4)  C(1A)C(10AC(5A)C(6A)  80.2(4)  C(5A)C(6A)C(7A)C(9A)  -11.1(3)  C(1A)C(10AC(9A)C(7A)  -92.0(4)  C(5A)C(6A)C(7A)C(11A -158.0(3)  C(1A)C(10AC(9A)C(8A) -158.6(4)  C(5A)C(10AC(9A)C(7A)  15.7(4)  C(1A'C(2A'C(3A)C(4A)  -28(1)  C(5A)C(10AC(9A)C(8A)  -50.9(4)  C(1A'C(10AC(5A)C(4A)  -12.2(6)  C(6A)C(5A)C(4A)C(14A  57.7(4)  C(1A'C(10AC(5A)C(6A)  110.9(5)  C(6A)C(5A)C(10AC(9A)  -21.5(3)  C(1A'C(10AC(9A)C(7A) -114.4(6)  C(6A)C(5A)C(10AC(15A -142.8(3)  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.  164 Table 9 Torsional or conformational angles (deg) of ketodiol 135.^(cont) (1)^(2)^(3)^(4)  angle  (1)^(2)^(3)^(4)  angle  C(6A)C(7A)C(8A)C(9A)  -95.9(3)  0(2B)C(5B)C(10BC(9B)  105.4(3)  C(6A)C(7A)C(9A)C(8A)  108.6(3)  0(2B)C(5B)C(10BC(15B  -15.4(4)  C(6A)C(7A)C(9A)C(10A  -3.0(4)  0(3B)C(6B)C(5B)C(48)  -98.4(3)  C(6A)C(7A)C(11AC(12A  -64.9(5)  0(3B)C(6B)C(5B)C(10B  139.2(3)  C(6A)C(7A)C(11AC(13A  61.0(5)  0(3B)C(6B)C(7B)C(8B)  -67.6(4)  C(7A)C(6A)C(5A)C(10A  20.5(3)  0(3B)C(6B)C(7B)C(9B) -131.0(3)  C(7A)C(8A)C(9A)C(10A  99.5(3)  0(3B)C(68)C(7B)C(11B  82.4(4)  C(7A)C(9A)C(10AC(15A  138.3(3)  C(1B)C(2B)C(3B)C(4B)  -10.7(5)  C(8A)C(7A)C(9A)C(10A -111.6(3)  C(1B)C(10BC(5B)C(4B)  -15.8(4)  83.2(4)  C(1B)C(10BC(5B)C(6B)  105.5(3)  C(8A)C(7A)C(11AC(12A  C(8A)C(7A)C(11AC(13A -150.9(4)  C(1B)C(10BC(9B)C(7B) -109.2(3)  C(8A)C(9A)C(7A)C(11A -105.6(4)  C(1B)C(10BC(9B)C(8B) -176.7(3)  C(8A)C(9A)C(10AC(15A  71.7(5)  C(2B)C(1B)C(10BC(5B)  -39.8(5)  C(9A)C(7A)C(11AC(12A  153.7(4)  C(2B)C(1B)C(10BC(9B)  74.5(4)  C(9A)C(7A)C(11AC(13A  -80.4(5)  C(2B)C(1B)C(10BC(15B -164.2(4)  C(9A)C(8A)C(7A)C(11A  114.0(3)  C(2B)C(3B)C(4B)C(5B)  C(10AC(5A)C(4A)C(14A  176.8(3)  C(2B)C(3B)C(4B)C(148 -170.5(3)  C(10AC(9A)C(7A)C(11A  142.8(4)  C(3B)C(2B)C(1B)C(10B  55.1(5)  0(18)C(3B)C(2B)C(1B)  172.0(4)  C(3B)C(48)C(5B)C(6B)  -61.7(3)  0(1B)C(3B)C(4B)C(58)  133.4(4)  C(3B)C(4B)C(5B)C(10B  57.5(4)  0(1B)C(3B)C(4B)C(148  6.7(6)  C(4B)C(5B)C(6B)C(7B)  134.9(3)  0(2B)C(5B)C(4B)C(3B)  178.4(3)  C(4B)C(5B)C(10BC(9B) -134.3(3)  °(2B)C(53)C(4B)C(14B  -55.7(4)  C(4B)C(5B)C(10BC(15B  104.9(3)  0(2B)C(5B)C(68)0(3B)  20.8(3)  C(5B)C(6B)C(7B)C(8B)  56.7(4)  0(2B)C(5B)C(6B)C(7B)  -105.9(3)  C(5B)C(6B)C(7B)C(9B)  -6.6(3)  0(2B)C(5B)C(10BC(1B) -136.1(3)  -43.9(4)  C(5B)C(6B)C(7B)C(11B -153.3(3)  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.  165  Table 9 Torsional or conformational angles (deg) of ketodiol 135.  (corn)  (1)^(2)^(3)^(4)^angle^(1)^(2)  (3)^(4)  angle  C(5B)C(10BC(9B)C(7B)^9.6(4) C(5B)C(10BC(9B)C(8B)^-57.9(4) C(6B)C(5B)C(4B)C(14B^64.2(3) C(6B)C(5B)C(10BC(9B)^-13.0(3) C(6B)C(5B)C(10BC(15B -133.8(3) C(6B)C(7B)C(8B)C(9B)^-96.0(3) C(6B)C(7B)C(9B)C(8B)^107.5(3) C(6B)C(7B)C(98)C(10B^-2.1(4) C(6B)C(7B)C(11BC(12B^56.8(4) C(6B)C(7B)C(11BC(13B^-69.3(4) C(7B)C(65)C(5B)C(108^12.5(3) C(7B)C(8B)C(9B)C(108^102.4(3) C(7B)C(9B)C(10BC(15B^131.9(3) C(8B)C(7B)C(9B)C(10B^-109.5(3) C(8B)C(7B)C(11BC(12B^-155.0(3) C(8B)C(7B)C(11BC(138^79.0(4) C(8B)C(9B)C(7B)C(11B^-106.8(4) C(8B)C(9B)C(10BC(15B^64.5(4) C(9B)C(7B)C(11BC(12B^-84.3(4) C(9B)C(7B)C(11BC(13B^149.7(4) C(9B)C(8B)C(7B)C(11B^113.4(4) C(10BC(5B)C(4B)C(14B -176.6(3) C(10BC(9B)C(7B)C(11B^143.7(3)  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.  166  Appendix 2.^X-ray Structure report on racemic alcohol 220. A. Crystal Data Empirical Formula^  C  H 0 23 36 2  Formula Weight^  344.54  Crystal Color, Habit^  colorless, prism  Crystal Dimensions (mm)^0.150 X 0.150 X 0.150 Crystal System^  tetragonal  No. Reflections Used for Unit Cell Determination (2(9 range) ^25 ( 21.3 - 38.3°) Omega Scan Peak Width at Half-height^ Lattice Parameters:  0.08 a =^33.669 (3)A c =^7.51 (1)A V = 8513 (11)A 3  Space Group Z value  I4 1 /a (#88) 16  D  1.075 g/cm 3  calc^ ^ F 000 ^ 41 (CuKa)  3040  4.78 cm -1  B. Intensity Measurements Diffractometer^  Rigaku AFC6S  Radiation^  CuKa (X = 1.54178 A)  Temperature^  21°C  Take-off Angle^  6.0°  Detector Aperture^  6.0 mm horizontal 6.0 mm vertical  Crystal to Detector Distance^285 mm Scan Type^  w-2(9  167 Scan Rate^  8.0°/min (in omega) (8 rescans)  Scan Width^  (0.89 + 0.20 tane)°  29  120.1°  max^  No. of Reflections Measured ^Total: 3589 Unique: 3450 (R int^.029) Lorentz-polarization Absorption (trans. factors: 0.86 - 1.00) Secondary Extinction (coefficient:^0.15536E-05)  Corrections^  C. Structure Solution and Refinement Structure Solution Refinement  ^  ^  Function Minimized  Full-matrix least-squares  ^  Least-squares Weights p-factor  Direct Methods  w (IFol - IFc1)  ^  4Fo 2 /a 2 (Fo 2 )  ^  Anomalous Dispersion  0.01  ^  All non-hydrogen atoms  No. Observations (I>3.00a(I)) ^1344 227 No. Variables^ Reflection/Parameter Ratio^5.92 Residuals: R; R w^0.050; 0.049 Goodness of Fit Indicator  2  ^  Max Shift/Error in Final Cycle  2.54  ^  0.14  Maximum Peak in Final Diff. Map^0.19 e/A! Minimum Peak in Final Diff. Map^-0.15 e - /A J  168  H3  H23  Fig 30 Single crystal X-ray structure of racemic alcohol 220 (PLUTO drawing). *  * The numbering of carbon atoms here, is different from that used in the Discussion (Section 2.).  169  Fig. 31 The unit cell structure of racemic alcohol 220 (packing diagram).  170 Table 10 Final atomic coordinates (fractional) and Beq (A) of racemic alcohol 220. atom  x  y  eq  0.19148(7)  0.5887(4)  5.3(1)  0.0948(1)  0.0862(1)  0.1694(5)  9.1(2)  C(1)  0.0089(1)  0.1045(1)  0.6578(5)  5.0(2)  C(2)  0.0251(1)  0.1314(1)  0.5050(5)  4.3(2)  C(3)  -0.0039(1)  0.1639(1)  0.4445(5)  4.4(2)  C(4)  -0.0438(1)  0.1456(1)  0.3985(6)  6.0(3)  C(5)  -0.0598(1)  0.1185(1)  0.5442(7)  6.9(3)  C(6)  -0.0303(1)  0.0858(1)  0.5941(6)  5.5(3)  C(7)  -0.0479(2)  0.0521(1)  0.7098(7)  7.7(3)  C(8)  -0.0147(2)  0.0223(1)  0.7506(8)  9.3(4)  C(9)  0.0228(2)  0.0403(2)  0.8273(8)  10.3(4)  C(10)  0.0388(1)  0.0712(1)  0.7007(6)  7.6(3)  C(11)  0.0043(1)  0.1292(1)  0.8306(6)  7.3(3)  C(12)  0.0402(1)  0.1071(1)  0.3429(5)  5.2(2)  C(13)  0.0837(2)  0.1114(1)  0.3149(7)  8.1(3)  C(14)  0.0118(1)  0.1890(1)  0.2905(6)  6.3(3)  C(15)  -0.0679(2)  0.0662(1)  0.8835(9)  13.0(5)  C(16)  -0.0795(2)  0.0298(2)  0.601(1)  11.7(4)  C(17)  0.1322(2)  0.0902(2)  0.122(1)  14.8(6)  C(18)  0.1439(2)  0.0613(2)  -0.022(1)  8.5(4)  C(19)  0.1515(2)  0.0705(2)  -0.190(2)  12.8(6)  C(20)  0.1648(3)  0.0426(5)  -0.312(1)  14.8(7)  C(21)  0.1723(4)  0.0064(4)  -0.253(2)  19(1)  C(22)  0.1652(5)  -0.0010(4)  -0.089(3)  26(1)  0(1)  -0.01164(7)  0(2)  171  Table 10 Final atomic coordinates (fractional) and B eq (A) of racemic alcohol 220. (cont) atom^x^y  ^ z^ B  C(23)^0.1514(3)^0.0255(4)  *B  eg  - (8/3)n 2 EEU..a.*a.j *(a..a.j )  ^  eg  0.027(1)^17.9(8)  172 Table 11 Hydrogen atom coordinates (fractional) and Bi so (A2) of racemic alcohol 220. atom  x  Y  z  B.iso  H(1)  0.0105  0.2034  0.6107  6.1  H(2)  0.0483  0.1451  0.5535  5.2  H(3)  -0.0630  0.1670  0.3783  7.2  H(4)  -0.0408  0.1300  0.2891  7.2  H(5)  -0.0654  0.1345  0.6503  8.2  H(6)  -0.0844  0.1061  0.5021  8.2  H(7)  -0.0236  0.0730  0.4808  6.6  H(8)  -0.0250  0.0029  0.8364  11.1  H(9)  -0.0077  0.0087  0.6395  11.1  H(10)  0.0167  0.0528  0.9421  12.3  H(11)  0.0427  0.0194  0.8446  12.3  H(12)  0.0461  0.0579  0.5891  9.1  H(13)  0.0625  0.0831  0.7542  9.1  H(14)  0.0301  0.1406  0.8636  8.7  H(15)  -0.0148  0.1507  0.8107  8.7  H(16)  -0.0052  0.1120  0.9269  8.7  H(17)  0.0341  0.0790  0.3625  6.2  H(18)  0.0264  0.1165  0.2358  6.2  H(19)  0.0980  0.1034  0.4228  9.7  H(20)  0.0901  0.1391  0.2866  9.7  H(21)  0.0364  0.2024  0.3272  7.5  H(22)  0.0172  0.1719  0.1879  7.5  H(23)  -0.0081  0.2090  0.2575  7.5  H(24)  -0.0481  0.0790  0.9598  15.6  H(25)  -0.0890  0.0852  0.8549  15.6  173 Table 11 Hydrogen atom coordinates (fractional) and Biso (A2) of racemic alcohol 220 (cont)  atom  x  y  z  B.3.zo  H(26)  -0.0793  0.0433  0.9459  15.6  H(27)  -0.1009  0.0482  0.5692  14.1  H(28)  -0.0675  0.0191  0.4929  14.1  H(29)  -0.0904  0.0080  0.6728  14.1  H(30)  0.1363  0.1172  0.0776  17.8  H(31)  0.1491  0.0856  0.2261  17.8  H(32)  0.1477  0.0980  -0.2291  15.4  H(33)  0.1685  0.0496  -0.4380  17.8  H(34)  0.1830  -0.0141  -0.3324  22.2  H(35)  0.1703  -0.0280  -0.0458  31.4  H(36)  0.1468  0.0176  0.1509  21.5  174 Table 12 Bond lenghts (A) of racemic alcohol 220 with estimated standard deviations in parentheses. atom  atom  distance  atom  atom  distance  0(1)  C(3)  1.449(4)  C(7)  C(8)  1.533(7)  0(2)  C(13)  1.433(5)  C(7)  C(15)  1.543(7)  0(2)  C(17)  1.315(6)  C(7)  C(16)  1.536(7)  C(1)  C(2)  1.559(5)  C(8)  C(9)  1.514(7)  C(1)  C(6)  1.540(5)  C(9)  C(10)  1.509(7)  C(1)  C(10)  1.542(5)  C(12)  C(13)  1.487(6)  C(1)  C(11)  1.549(5)  C(17)  C(18)  1.506(8)  C(2)  C(3)  1.538(5)  C(18)  C(19)  1.323(9)  C(2)  C(12)  1.550(5)  C(18)  C(23)  1.28(1)  C(3)  C(4)  1.517(5)  C(19)  C(20)  1.39(1)  C(3)  C(14)  1.527(5)  C(20)  C(21)  1.32(1)  C(4)  C(5)  1.524(6)  C(21)  C(22)  1.28(2)  C(5)  C(6)  1.529(6)  C(22)  C(23)  1.33(1)  C(6)  C(7)  1.548(6)  175 Table 13 Bond angles (deg) of racemic alcohol 220 with estimated standard deviations in parentheses. atom  atom  atom  angle  atom  atom  atom  angle  C(13)  0(2)  C(17)  113.5(4)  C(6)  C(7)  C(8)  108.3(4)  C(2)  C(1)  C(6)  108.0(3)  C(6)  C(7)  C(15)  114.5(4)  C(2)  C(1)  C(10)  110.3(4)  C(6)  C(7)  C(16)  109.0(5)  C(2)  C(1)  C(11)  109.9(3)  C(8)  C(7)  C(15)  110.6(5)  C(6)  C(1)  C(10)  109.1(3)  C(8)  C(7)  C(16)  107.0(5)  C(6)  C(1)  C(11)  113.3(3)  C(15)  C(7)  C(16)  107.2(5)  C(10)  C(1)  C(11)  106.3(4)  C(7)  C(8)  C(9)  114.9(5)  C(1)  C(2)  C(3)  114.1(3)  C(8)  C(9)  C(10)  109.5(5)  C(1)  C(2)  C(12)  112.8(3)  C(1)  C(10)  C(9)  113.6(4)  C(3)  C(2)  C(12)  110.6(3)  C(2)  C(12)  C(13)  112.5(4)  0(1)  C(3)  C(2)  110.4(3)  0(2)  C(13)  C(12)  108.0(4)  0(1)  C(3)  C(4)  105.9(3)  0(2)  C(17)  C(18)  112.4(5)  0(1)  C(3)  C(14)  105.9(3)  C(17)  C(18)  C(19)  125.6(9)  C(2)  C(3)  C(4)  109.8(3)  C(17)  C(18)  C(23)  117(1)  C(2)  C(3)  C(14)  113.4(3)  C(19)  C(18)  C(23)  117.1(8)  C(4)  C(3)  C(14)  111.1(3)  C(18)  C(19)  C(20)  122.3(8)  C(3)  C(4)  C(5)  113.2(4)  C(19)  C(20)  C(21)  118(1)  C(4)  C(5)  C(6)  112.1(4)  C(20)  C(21)  C(22)  118(1)  C(1)  C(6)  C(5)  109.8(3)  C(21)  C(22)  C(23)  124(2)  C(1)  C(6)  C(7)  117.0(4)  C(18)  C(23)  C(22)  121(1)  C(5)  C(6)  C(7)  114.7(4)  176 Table 14 Torsional or conformational angles (deg) of racemic alcohol 220. (1)  (2)^(3)^(4)  angle  (1)  63.3(4)  C(1) C(10)C(9)^H(10)  -63  0(1) C(3)^C(2)^C(12) -168.3(3)  C(1) C(10)C(9)^H(11)  177  0(1) C(3)^C(2)^H(2)  -53  C(2) C(1)^C(6)^C(5)  -58.0(4)  0(1) C(3)^C(4)^C(5)  -68.5(4)  C(2) C(1)^C(6)^C(7)  169.1(3)  0(1) C(3)^C(4)^H(3)  52  C(2) C(1)^C(6)^H(7)  54  0(1) C(3)^C(4)^H(4)  171  C(2) C(1)^C(10)C(9)  0(1) C(3)^C(14)H(21)  61  C(2) C(1)^C(10)H(12)  -51  0(1) C(3)^C(14)H(22)  -179  C(2) C(1)^C(10)H(13)  68  0(1) C(3)^C(14)H(23)  -59  C(2) C(1)^C(11)H(14)  -58  0(2) C(13)C(12)C(2)  176.7(3)  C(2) C(1)^C(11)H(15)  62  0(2) C(13)C(12)H(17)  56  C(2) C(1)^C(11)H(16)  -178  0(2) C(13)C(12)H(18)  -63  C(2) C(3)^0(1)^H(1)  65  0(2) C(17)C(18)C(19)  109.2(8)  C(2) C(3)^C(4)^C(5)  50.8(5)  0(2) C(17)C(18)C(23)  -79.0(9)  C(2) C(3)^C(4)^H(3)  171  C(1) C(2)^C(3)^C(4)  -53.1(4)  C(2) C(3)^C(4)^H(4)  -70  C(1) C(2)^C(3)^C(14) -178.0(3)  C(2) C(3)^C(14)H(21)  -61  C(1) C(2)^C(12)C(13) -114.7(4)  C(2) C(3)^C(14)H(22)  59  C(1) C(2)^C(12)H(17)  6  C(2) C(3)^C(14)H(23)  179  C(1) C(2)^C(12)H(18)  125  C(2) C(12)C(13)H(19)  57  C(2) C(12)C(13)H(20)  -64  0(1) C(3)^C(2)^C(1)  C(1) C(6)^C(5)^C(4)  58.7(5)  (2)^(3)^(4)  angle  -171.2(4)  C(1) C(6)^C(5)^H(5)  -62  C(3) C(2)^C(1)^C(6)  C(1) C(6)^C(5)^H(6)  179  C(3) C(2)^C(1)^C(10)  176.2(3)  C(1) C(6)^C(7)^C(8)  -48.4(6)  C(3) C(2)^C(1)^C(11)  -66.9(4)  75.5(6)  C(3) C(2)^C(12)C(13)  116.2(4)  C(1) C(6)^C(7)^C(16) -164.4(4)  C(3) C(2)^C(12)H(17)  -123  C(1) C(10)C(9)^C(8)  C(3) C(2)^C(12)H(18)  -4  C(1) C(6)^C(7)^C(15)  57.4(6)  57.1(4)  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.  177 Table 14 Torsional or conformational angles (deg) of racemic alcohol 220. ^(cons) (1)  (2)  (3)^(4)  angle  (1)  (2)  (3)^(4)  angle  C(3) C(4) C(5)^C(6)  -55.3(5)  C(6) C(5) C(4)^H(4)  65  C(3) C(4) C(5)^H(5)  65  C(6) C(7) C(8)^C(9)  51.9(6)  C(3) C(4) C(5)^H(6)  -176  C(6) C(7) C(8)^H(8)  173  C(4) C(3) 0(1)^H(1)  -176  C(6) C(7) C(8)^H(9)  -69  C(4) C(3) C(2)^C(12)  75.3(4)  C(6) C(7) C(15)H(24)  -63  C(4) C(3) C(2)^H(2)  -170  C(6) C(7) C(15)H(25)  57  C(4) C(3) C(14)H(21)  175  C(6) C(7) C(15)H(26)  177  C(4) C(3) C(14)H(22)  -65  C(6) C(7) C(16)H(27)  -61  C(4) C(3) C(14)H(23)  55  C(6) C(7) C(16)H(28)  59 179  C(4) C(5) C(6)^C(7)  -167.2(4)  C(6) C(7) C(16)H(29)  C(4) C(5) C(6)^H(7)  -53  C(7) C(6) C(1)^C(10)  49.2(5)  C(5) C(4) C(3)^C(14)  177.0(3)  C(7) C(6) C(1)^C(11)  -69.0(5)  C(5) C(6) C(1)^C(10) -177.9(4)  C(7) C(6) C(5)^H(5)  72  C(5) C(6) C(1)^C(11)  C(7) C(6) C(5)^H(6)  -47  -179.1(4)  C(7) C(8) C(9)^C(10)  -57.7(6)  C(5) C(6) C(7)^C(15)  -55.2(7)  C(7) C(8) C(9)^H(10)  62  C(5) C(6) C(7)^C(16)  64.9(5)  C(7) C(8) C(9)^H(11)  -178  C(6) C(1) C(2)^C(12)  -70.1(4)  C(8) C(7) C(6)^H(7)  67  C(6) C(1) C(2)^H(2)  174  C(8) C(7) C(15)H(24)  60  C(6) C(1) C(10)C(9)  -52.8(5)  C(8) C(7) C(15)H(25)  180  C(6) C(1) C(10)H(12)  68  C(8) C(7) C(15)H(26)  -60  C(6) C(1) C(10)H(13)  -173  C(8) C(7) C(16)H(27)  -178  C(6) C(1) C(11)H(14)  -179  C(8) C(7) C(16)H(28)  -58  C(6) C(1) C(11)H(15)  -59  C(8) C(7) C(16)H(29)  62  C(6) C(1) C(11)H(16)  61  C(8) C(9) C(10)H(12)  -63  -176  C(8) C(9) C(10)H(13)  178  C(5) C(6) C(7)^C(8)  C(6) C(5) C(4)^H(3)  64.0(5)  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.  178 Table 14 Torsional or conformational angles (deg) of racemic alcohol 220. ^(cons) (1)^(2)^(3)^(4)  angle  (1)^(2)^(3)^(4)  angle  C(9)^C(8)^C(7)^C(15)  -74.3(6)  C(15)C(7)^C(6)^H(7)  -169  C(9)^C(8)^C(7)^C(16)  169.2(5)  C(15)C(7)^C(8)^H(8)  46  C(9)^C(10)C(1)^C(11)  69.7(5)  C(15)C(7)^C(8)^H(9)  165  C(10)C(1)^C(2)^C(12)  49.0(4)  C(15)C(7)^C(16)H(27)  63  C(10)C(1)^C(2)^H(2)  -67  C(15)C(7)^C(16)H(28)  -177  C(10)C(1)^C(6)^H(7)  -66  C(15)C(7)^C(16)H(29)  -57  C(10)C(1)^C(11)H(14)  61  C(16)C(7)^C(6)^H(7)  -49  C(10)C(1)^C(11)H(15)  -179  C(16)C(7)^C(8)^H(8)  -70  C(10)C(1)^C(11)H(16)  -59  C(16)C(7)^C(8)^H(9)  48  C(10)C(9)^C(8)^H(8)  -178  C(16)C(7)^C(15)H(24)  176  C(10)C(9)^C(8)^H(9)  63  C(16)C(7)^C(15)H(25)  -64  C(11)C(1)^C(2)^C(12)  165.9(3)  C(16)C(7)^C(15)H(26)  56  C(11)C(1)^C(2)^H(2)  50  C(17)0(2)^C(13)H(19)  -66  C(11)C(1)^C(6)^H(7)  176  C(17)O(2)^C(13)H(20)  54  C(11)C(1)^C(10)H(12)  -170  C(17)C(18)C(19)C(20)  175.4(7)  C(11)C(1)^C(10)H(13)  -51  C(17)C(18)C(19)H(32)  -5  C(12)C(2)^C(3)^C(14)  -49.6(4)  C(17)C(18)C(23)C(22)  -174(1)  C(12)C(13)O(2)^C(17)  174.2(6)  C(17)C(18)C(23)H(36)  6  C(13)0(2)^C(17)C(18)  175.8(7)  C(18)C(19)C(20)C(21)  C(13)0(2)^C(17)H(30)  -64  C(18)C(19)C(20)H(33)  C(13)0(2)^C(17)H(31)  55  C(18)C(23)C(22)C(21)  C(13)C(12)C(2)^H(2)  1  C(18)C(23)C(22)H(35)  -180  C(14)C(3)^0(1)^H(1)  -58  C(19)C(18)C(17)H(30)  -11  C(14)C(3)^C(2)^H(2)  65  C(19)C(18)C(17)H(31)  -130  C(14)C(3)^C(4)^H(3)  -62  C(19)C(18)C(23)C(22)  C(14)C(3)^C(4)^H(4)  56  C(19)C(18)C(23)H(36)  -4(2) 176 1(3)  -2(2) 178  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.  179 Table 14 Torsional or conformational angles (deg) of racemic alcohol 220.^(cont) (1)^(2)^(3)^(4)  angle  C(19)C(20)C(21)C(22) C(19)C(20)C(21)H(34)  3(2) -177  (1)^(2)^(3)^(4)  angle  H(11)C(9)^C(10)H(12)  57  H(11)C(9)^C(10)H(13)  -62  C(20)C(19)C(18)C(23)  4(1)  H(17)C(12)C(13)H(19)  -64  C(20)C(21)C(22)C(23)  -1(3)  H(17)C(12)C(13)H(20)  176  C(20)C(21)C(22)H(35)  179  H(18)C(12)C(13)H(19)  177  C(21)C(20)C(19)H(32)  176  H(18)C(12)C(13)H(20)  57  C(21)C(22)C(23)H(36)  -180  H(32)C(19)C(20)H(33)  -4  C(22)C(21)C(20)H(33)  -177  H(33)C(20)C(21)H(34)  3  C(23)C(18)C(17)H(30)  161  H(34)C(21)C(22)H(35)  -1  C(23)C(18)C(17)H(31)  41  H(35)C(22)C(23)H(36)  0  C(23)C(18)C(19)H(32)  -176  C(23)C(22)C(21)H(34)  179  H(2)^C(2)^C(12)H(17)  122  H(2) C(2)^C(12)H(18)  -119  H(3) C(4)^C(5)^H(5)  -55  H(3)^C(4)^C(5)^H(6)  64  H(4)^C(4)^C(5)^H(5)  -174  H(4) C(4)^C(5)^H(6)  -55  H(5) C(5)^C(6)^H(7)  -174  H(6)^C(5)^C(6)^H(7)  67  H(8)^C(8)^C(9)^H(10)  -58  H(8) C(8)^C(9)^H(11)  62  H(9) C(8)^C(9)^H(10)  -177  H(9)^C(8)^C(9)^H(11)  -57  H(10)C(9)^C(10)H(12)  177  H(10)C(9)^C(10)H(13)  58  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.  

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