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Studies toward total syntheses of drimane type antifeedants from thujone Gao, Zhenyong 1989

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STUDIES TOWARD T O T A L SYNTHESES OF DRJMANE TYPE ANTTFEEDANTS FROM THUJONE By Zhenyong Gao B.ScBeijing Teachers* Institute, 1982 M.Eng., Beijing Institute of Light Industry, 1984 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in T H E F A C U L T Y OF GRADUATE STUDIES Department of Chemistry We accept this thesis as conforming to the required standard T H E UNIVERSITY OF BRITISH COLUMBIA May 1989 ©Zhenyong Gao 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. Department The University of British Columbia Vancouver, Canada DE-6 (2/88) ii ABSTRACT This thesis concerns studies directed towards a total synthesis of the drimane type dialdehyde 9_0_ from thujone 42. The naturally occurring drimane dialdehydes have potent antifeedant activity. Development of a versatile synthesis of the drimane type dialdehydes from thujone was the main objective of this research. The decalone 80 was considered an efficient intermediate leading to the drimane dialdehydes. Much work was devoted to develop syntheses of such C7-decalones from thujone 47. The previously known enone 4&, obtained in an efficient manner from thujone 42, is subjected to reduction via catalytic or Birch reduction to afford, in quantitative yield, the cis -fused ketone 62. Deoxygenation of the ketone 62. by Wolff-Kishner reduction afforded 22 in excellent yield. Detailed studies had shown that ozone selectively reacted at the activated tertiary carbon of the isopropyl side chain in molecules such as 22. Thus, the tricyclic alkane 22 was converted to the tertiary alcohol 21 by ozonation. The alcohol 22 was then elaborated to the key intermediate £Q_ via cyclopropane ring opening, free radical rearrangement and ozonation. The stereochemistry of the various products £2,22,22 and f£Q_ with respect to the A/B fusion was established through correlation with the absolute structure and stereochemistry of the diketone 66 the latter being one of the ozonation products of ketone 62. Diketone 6^ was subjected to X-ray diffraction analysis. The drimane skeleton was then constructed via formylation of £0. to j&l and the latter converted to 82, via reaction with phenylselenyl chloride followed by oxidative elimination of the resultant product. Conjugate addition of cyanide to the unsaturated keto-aldehyde 82 afforded 81. The latter was converted into the unsaturated aldehyde 135_ via reduction of its (n-butylthio)methylene derivative, followed by borohydride reduction and mild hydrolysis. Protection of the aldehyde group in 85 gave 86 and the nitrile group in the latter was then reduced to give 88. The latter was then hydrolyzed to the drimane dialdehyde 9Q. The synthesis of 9_Q was accomplished in sixteen steps with an overall yield of 4% from thujone 47, thereby iii indicating that the individual steps in the sequence proceed in excellent yield. The biological activity of compound 2Q will be evaluated. Approaches towards a total synthesis of the natural drimane polygodial 1 are also shown. M 90 iv Table of Contents Title page i Abstract ii Table of Contents iv List of Figures vi List of Schemes vii List of Abbreviations viii Acknowledgements x 1. Introduction 1 1.1. Antifeedants 1 1.2. Drimane type antifeedants 2 1.3. Review of total syntheses of polygodial and warburganal 3 1.4. Object of our research 11 2. Result and discussion 13 2.1. Approaches to the synthesis of the drimane type antifeedants from thujone . 13 2.1.1. First approach 13 2.1.2. Second approach 16 2.2. Outline of the present work 18 2.2.1. Studies of the stereochemistry of ketone 62 and reduction to 72 .... 21 2.2.2. Hydroxylation via ozonation 31 2.2.3. Synthesis of decalone 8J) 34 2.2.4. Synthesis of drimane dialdehyde 9.0 37 2.3. Approach to the natural drimane antifeedants .' 43 2.4. Conclusion 45 3. Experimental 47 3.1. General 47 3.2. (56)-4aJ0!3-(nmethyl-7a4sopropyl-tricyclo[4.4.05'10.07.9]-dec-3-one 62 . 49 3.3. (5B)-4a40!3-dmethyl-3-(l,3-dioxolan-2-yl)-7a-isopropyl-tricyclo[4.4.05.l0.o7,9].decane 49 3.4. (5B)-4,4,10!3-trimethyl-7a-isopropyl-tricyclo[4.4.05'10.07.9]dec-3-one 91, (5B)-2,4,4>10P-tetramethyl-7a-isopropyl-tricyclo[«9]-dec-3-one 98. 50 3.5. (56)-4a,10P-dimethyl-7a-isopropyl-tricyclo[4.4.05'10.07.9]-dec-3-tosylhydrazone 92 52 3.6. (56)-4a,10i3-dimethyl-7a4sopropyl-tricyclo[]-decane22 ... 52 3.7. (5p)-4cx, 10P-d^ methyl-7a-isopropinol-tricyclo[4.4.05>10.07»9]-decane Z3_ (5P)-7a-acetyl-4a,10*3-oimethyl-tricyclo[,9].decane 74 54 3.8. (5|3)-4a, 10(j-dimethyl-3-(l ,3-dioxolan-2-yl)-7a-isopropinol-tricyclo V [4.4.05.i0.o7,9]-decane 69, (5p)-7a-acetyl-4a,10!3-dimethyl-3-(l,3-dioxolan-2-yl)-tricyclo[]-decane 20. 56 3.9. (5!3)-4a,10!3-dimethyl-7a-(l'-hydroxye%l)-tricyclo[4.4.05.^  -decane 7_5 57 3.10. (5P)-8-chloromethyl-4a,9|j-dimethyl-7a-isopropylidene-bicyclo []-nonane 7_6_ 58 3.11. (5p>4a, 10p-dimethyl-7-isopropylidene-bicyclo[]-decane 78 .... 59 3.12. (5(3)-4a,10!3-dimethyl-octahydro-7-(6H)-naphthalenone 80 60 3.13. 9-cyano-4,lOp-dimethyl-7-isopropyl-1,8,9,10-tetrahydro-3-(2H)-naphthalenone 59. 61 3.14. 9-cyano-4,10!3-cumethyl-7-isopro^  naphthalenone 60. 62 3.15. 4,10!3-dimethyl-3-hydroxy-7-isopropenyl-1,2,3,8,9,10-hexahydro-naphthalene 54. 63 3.16. 7-acetyl-4,10!3-dimemyl-3-hydroxy-l,2,3,8,9,10-hexahydro-naphthalene 55_ 64 3.17. 4a, 10|3-dimethyl-cis-perhydro-7-oxonaphthalene-8-carboxaldehyde M. 65 3.18. 4a,10P-dimethyl-l,2,3,4,5|3,6,7,10-octahy(ko-7-oxonaphthalene-8-carboxaldehyde 82. 66 3.19. 4a,10|3-dimethyl-8-(hydroxymethylene)-cis-perhydro-7-oxonaphthalene-9-carbonitrile £3. 67 3.20. 8-[(bulylthio)methylene]-4a,8a|3-dimethyl-cis-perhydro-7 oxonaphthalene-9-carbonitrile 84 68 3.21. 4a,10p-cumethyl-8-formyl-l,2,3,4,5!3,6,9,10-octahy^ naphthalene-9-carbonitrile 85. 69 3.22. 4a,10(j-dimethyl-8-(l,3-dioxolan-2-yl)-l,2,3,4,5p,6,9,10-cctahydro-naphthalene-9-carbonitrile 86,4a,10|3-dimethyl-8- (l,3-dioxolan-2-yl)-1,2,3,4,513,8,9,10-octahydro-naphthalene-9- carbonitrile 81 70 3.23. 4a, 10!3-dimethyl-8-(l ,3-dioxolan-2-yl)-l ,2,3,4,5j3,6,9,10-octahydro-naphthalene-9-carboxaldehyde 88 71 3.24. 4a,10p-dimethyl-l,2,3,4,5!3,6,9,10-octahydro-naphthalene-9,8-dicaboxaldehyde 90. 72 References 74 vi List of Figures Figure 1: The chemistry of thujone 12 Figure 2: lH NMR decoupling experiments on &2. 23 Figure 3: NOE difference experiments on £2. 24 Figure 4: X-ray diffraction analysis of 6_6_. 25 Figure 5: NOE difference experiments on 86. 41 Figure 6: NOE difference experiments on £0. 43 vii List of Schemes Scheme 1 4 Scheme 2 5 Scheme 3 6 Scheme 4 7 Scheme 5 8 Scheme 6 : 9 Scheme 7 10 Scheme 8 13 Scheme 9 14 Scheme 10 16 Scheme 11 17 Scheme 12 19 Scheme 13 20 Scheme 14 21 Scheme 15 27 Scheme 16 28 Scheme 17 31 Scheme 18 32 Scheme 19 34 Scheme 20 36 Scheme 21 42 Scheme 22 44 Scheme 23 44 List of Abbreviations AD3N azobisisobutyronitrile br broad m-CPBA meta-chloroperbenzoic acid d doublet DCC dicyclohexyl carbodiimide dd doublet of doublets ddd doublet of doublets of doublets DDQ dichlorodicyanobenzoquinone DEG diethylene glycol DMAD dimethyl acetylene-dicarboxylate DMS dimethyl sulfide DMSO dimethyl sulfoxide dt doublet of triplets DIBAH di-wo-butylaluminum hydride ether diethyl ether GLC gas liquid chromatography h heptet h hour(s) HMPT hexamethyl phosphoric triamide IR infrared IDA lithium diisopropylarnide LHMDS lithium hexamethyldisilazamide m multiplet max. maxima min minute(s) IX MS NBS NMR NOE PCC pet. ether ph q R.T s t temp TBTH tic THF tosyl UV v/v W-K-H mass spectroscopy N-bromosuccinimide nuclear magnetic resonance nuclear Overhauser effect pyridinium chlorochromate petroleum ether (bp 35-60°C) phenyl quartet room temperature singlet triplet temperature tri-n-butyltin hydride thin layer chromatography tetrahydrofuran /?ara-toluenesulfonyl ultraviolet ratio in volume Huang Minlong modification of Wolff-Kishner reaction A C K N O W L E D G E M E N T S x I wish to express my sincere appreciation to Professor James P. Kutney for the opportunity to pursue this project and for his guidance and valuable advice, both during the progress of this research and in the preparation of this thesis. I am indebted to Dr. Krystyna Piotrowska for her valuable discussions and constructive suggestions concerning the progress of this research. The technical expertise of the staff in the NMR, mass spectroscopy, and microanalytical service laboratories as well as X-ray diffraction service laboratory are gratefully acknowledged. Thanks also due to the members (both past and present) of Dr. Kutney's research group whose enlightening discussions and friendships have made the past two and half years a time to remember. 1 INTRODUCTION 1.1 Antifeedants An antifeedant has been defined, by Munakata1 as a chemical which inhibits feeding but does not kill the the insect direcdy, the insect often remaining near the treated plant material and possibly dying through starvation. It is not, however, identical with an olfactory repellent which is usually a volatile compound which repels the insect before it starts to eat As we know, insecticides, together with herbicides, are currently the most important chemicals used in the protection of food and other crops. Insecticides can be divided into true insecticides and indirectly acting insecticides. Most insecticides used today belong to the first group, e.g. synthetic organic chlorinated compounds, organophosphines and so on. The indirectly acting group consists of repellents, attractants, pheromones, insect growth regulators, and antifeedants. Although the first group are effective, relatively cheap and easy to use, many of these compounds are quite toxic to vertebrates, fish or beneficial lower forms of life. Some are extremely persistent in the environment and many accumulate in animals.Some pest insects have become resistant, requiring highly and possibly phytotoxic dosages and many agents are non-selective thereby toxic to beneficial insects2. Therefore, many efforts have been devoted to the group of "indirecdy acting" insecticides which lack these disadvantages. These compounds are of natural origin, more easily degradable, and furthermore, it is unlikely that they will accumulate and pollute the environment. It is also expected that, in general, such specific compounds will be less toxic to human beings than many of the synthetic pesticides and useful insects will not be disturbed. 1.2 Drimane type antifeedants The naturally occurring antifeedants can be divided according to their general chemical nature, e.g. as alkaloids, terpenes, flavonoids, carbohydrates and others. Our attention will be focussed on the natural sesquiterpenoid dialdehydes within the drimane series, which have relatively simple structures and known strong antifeedant activity. The specific compounds are polygodial I3, warburganal 24 and cinnamodial 25 , 6, since these exhibit strong antifeedant activity. An analogous set of functionalities is found in the rearranged drimane muzigodial 4.7,8 which also exhibits strong antifeedant activity. A common structural feature in these drimanes is the presence of a A7>8-ene-ll,12B-dialdehyde functionality and, with the exception of polygodial, a 9a-hydroxy group. Interestingly, Kubo and Ganjian9 reported that these four insect antifeedants 1-4 taste very hot (spicy) to humans.They suggested that the 96-aldehyde combined with the enal moiety is responsible for the hot taste, which is associated with its antifeedant activity. Based on these structural features, several other synthesized analogues have been investigated for their biological activity10. 3 1.3 Review of total syntheses of polygodial and warburganal As was mentioned in the last section, natural antifeedants are of potential value in new biorational methods of insect control. Therefore much effort has been devoted to developing total syntheses of these compounds since, in most cases, only minute amounts of material can be obtained from natural sources. Syntheses of the drimanes 1 to 4 have exploited a variety of methods, which can be roughly divided into two parts: first, constructing an appropriately functionalized decalin ring system, and then introducing the sensitive hydroxy-ene-dialdehyde function into ring B. The most commonly used decalin ring systems are the epimeric esters 5_, the diene diester 6_, the decalones 2 and 8 shown below: 2 8 Several efficient synthetic routes to polygodial and warburganal are now presented. The starting diester 6 was obtained in independent studies by Tanis and Nakanishi1 1 (83% yield) and Howell et al12 (94% yield). Both studies involved the Diels-Alder reaction of l,3,3-trimethyl-2-vinyl-l-cyclohexene 9_ and dimethyl acetylene-dicarboxylate (DMAD). The efficient Tanis route afforded (±)-polygodial 1 and (±)-warbuganal 2, but the Howell synthetic route was shorter and of higher yield. It is therefore in Scheme 1. The diester 6 was reductively rearranged 9_ DMAD COOMe COOMe Pd/C H2X COOMe COOMe LiAfflU CH2OH CH2OH 1 Ac20 2Se02 3K2CO3 DMSO (C0C1)2 CHO CHO CH2OH ",»OH CH2OH DMSO (CF3CO)20 CHO Scheme 1 using palladium on carbon and an acid catalyst directly to a trans-fused drimane system 10 in 80% yield. Reduction of this diester gave diol 11 and the latter served as the pivotal starting material for several sesquiterpene natural product syntheses. Oxidation of this diol 11 provided (±)-polygodial in 95% yield by using the method developed by Omura and Swem13. The triol 12 was obtained from diol JJ, via acetylation followed by allylic oxidation with selenium dioxide and then cleavage of the resultant acetate groups. The direct oxidation of triol 12 is accomplished in 45% yield by using a modified Swern oxidation14'15. Scheme 2 Another synthesis of (±)-polygodial 1 starting from bicyclofarnesic acid 14, the latter being obtained by cyclization of monocyclofarnesic acid 13, has been developed by Kato et a/ 1 ( \ (Scheme 2) Esterification of 14 and oxidation of the ester with singlet oxygen produced the allylic alcohol 15 in a modest yield of 33%. Treatment of the alcohol 15 with acid gave drimenin 16, which was converted into cinnamolide 17 via reduction and reoxidation. Saponification of lactone 17 and treatment of the resulting sodium salt simultaneously with acid and diazomethane gave a mixture of 18 and 17, which could then be separated. Oxidation of the alcohol 18 into the corresponding aldehyde and protection of the latter gave the acetal 19. Reduction of the ester function in 19 followed by oxidation provided the monoacetal 20 6 which could be hydrolyzed to (±)-polygodial 1. The total synthesis of polygodial 1 in this sequence was completed with a fairly poor yield. Scheme 317 illustrates a much more desirable route to I and obviously would provide an alternative route from 14 since drimenol 21 is readily available via hydride reduction of 14. SeQ2 (MeOPh)2SeO Scheme 3 Oxidation of 21 with pyridinium chlorochromate in dichloromethane, followed by protection of the resultant aldehyde, gave 22. Allylic oxidation of the latter using selenium dioxide and bis (4-methoxyphenyl) selenoxide as co-oxidant afforded 23_ in 45% yield, which upon acid treatment afforded polygodial 1 in an overall yield of 30%. The classical acid-catalyzed cyclization of methyl farnesoate 24 produced methyl 9-epibicyclofarnesate 25 and the latter was used as the starting material for the first synthesis of (±)-warburganal18.(Scheme 4) Selenium dioxide oxidation of 25 gave a mixture from which the aldehyde ester 26 was obtained in 61% yield. Protection of the aldehyde function, followed by reduction of the ester function and oxidation of the resulting alcohol with Collins reagent (chromium trioxide-pyridine complex in dichloromethane), gave the aldehyde 28. The enolate derived from 28. by treatment of 28_ with one equivalent of lithium hexamethyldisilazamide (LHMDS) was oxidized with MoOs-hexamethyl phosphoric triamide (HMPT) complex to give the hydroxylated aldehyde in a low 24% yield. Hydrolysis of the dioxolane group in compound 2& provided (+)-warburganal 2. 2 (±)-warburganal In 1980, 5,5,8a-tomethyl-fratts-l-decalone 7 was introduced as a starting material for the synthesis of warburganal 2. Kende and Blacklock19 reported the synthesis outlined in Scheme 5. Decalone 7 was converted into the selectively protected unsaturated ketone 29 via formylation, dehydrogenation with dichlorodicyanobenzoquinone (DDQ) and reaction with 8 ethylene glycol. Addition of [memoxy(trimemylsUyl)-memyl]limivim gave a diastereoisomeric mixture of alcohols 30, which underwent elimination of trimethylsilanol to afford a 1:3 mixture of the (E)-isomer 11 and (Z)-isomer 12 respectively. Epoxidation of H with m-chloroperbenzoic acid (m-CPBA) gave exclusively the a-epoxide 31 which could be hydrolyzed under mild acid conditions to (±)-warburganal 2. Epoxidation of 12 gave a 4:1 mixture of the 6- and a-epoxides 34 and 15, respectively, and these could be hydrolyzed to a mixture of (±)-warburganal and (±)-epiwarburganal. o a t , 11 H H 3 0 + Scheme 5 9 At the same time, another approach to (+)-warburganal 2 was completed by Goldsmith and Kezar20. (Scheme 6) Formylation of the decalone 7, followed by a selenation procedure gave the unsaturated keto-aldehyde 36 in a high yield (91%). Selective protection of the aldehyde group in compound 36 and addition of methyllithium gave the tertiary alcohol 32, which was then dehydrated using the Burgess reagent21 to 38. Osmylation of diene 38 gave diol 39, and further oxidation of 39 with dicyclohexylcarbodiimide (DCC) in DMSO, followed by hydrolysis of the acetal, afforded (±)-warburganal in 15% overall yield. In yet another approach, Jansen et afi2 introduced decalone 8, which has the carbonyl group at position C7, as a starting material. The carbonyl function is ideally located for the introduction of the other necessary functional groups, and thus provided a very efficient route to polygodial and warburganal. (Scheme 7) (±)-polygodial (±)-warburganal The drimane skeleton was constructed via formylation of 8 and conjugate addition of cyanide to the unsaturated keto-aldehyde 40. The resultant keto-aldehyde 41 was converted into the unsaturated aldehyde 42 via reduction of its (n-butylthio)methylene derivative, followed by borohydride reduction and mild hydrolysis. Protection of the aldehyde group in 42 gave 43 and the nitrile group in the latter was then reduced by diisobutylaluminium hydride (DD3AH) to give 44. The axial aldehyde group in 44 was epimerized to its equatorial epimer 45 with the help of potassium tert-butoxide in tert-butanol. (±)-Polygodial was then readily available after hydrolysis of 45_. According to the work of Tanis and Nakanishi11, the enolate of compound 45_, derived from lithium diisopropylamide (LDA), was easily deprotonated and subsequently oxidized with MoOs-hexamethyl phosphoric triamide (HMPT) complex (see Scheme 4) to 46,, which was then hydrolyzed to (±)-warburganal. In summary, the above discussion provides some of the highlights in the synthetic studies leading to the drimane antifeedants. Other studies are detailed in an excellent recent review23. 1.4 Object of our research The monoterpene thujone 42 is the major component of the Western red cedar (Thuja pUcata) leaf oil. A considerable amount of synthetic work utilizing thujone as a chiral synthon has been completed in our group during the past few years. These studies have shown that thujone 42 can be a viable chiral synthon for synthesizing a variety of natural products and biologically important molecules.( See Figure l )2 4 Since the structures and activities of these insect antifeedants are now known, our goal was to develop general synthetic routes to many of these drimanes from thujone 47.The synthetic strategies would be applicable to not only the natural products but would also provide simple structural analogues. It would be possible to then study these compounds at a molecular level and to define the structure and the stereochemistry responsible for the important biological activity. From Figure 1, the chiral sesquiterpene 52, available from thujone 42, has the desired decalin ring skeleton. If the C7-isopropyl group could be converted into the 7-decalone system, similar in structure to the racemic structure 8 employed by Jansen (Scheme 7), an attractive route to the chiral polygodial family is near in hand. Studies in this direction are presented in the next section. 12 pyrethoid insecticide analogues F igure 1 1 3 2 Results and Discussion 2.1 Approaches to the synthesis of the drimane type antifeedants from thujone. 2.1.1 First approach The initial approach was based on the previously known sequence developed in Dr. Kutney's group. (See Scheme 8) Schenne 8 Robinson annelation of thujone 47 with ethyl vinyl ketone (EVK) and cyclization of the resultant intermediate, proceeds stereospecifically to afford the tricyclic enone 48. This enone 48 was converted to 50 via ketalization to 49, followed by treatment of 49 with potassium permanganate in basic solution. Treatment of 50 with aqueous hydrobromic acid gave the bromo-dienone 51 2 5 . The overall yield of 51 from the readily available thujone 47 is 25%, so that the various reactions proceed in excellent yields. The present research extends from the bromide 5_L £See Scheme 9) Scheme 9 The syntheses of 52 and 5_3_ were established in our group several years ago25*26. Reduction of 51 with excess of tri-n-butyltin hydride (TBTH) in benzene gave (+)-6-cyperone 52 in 79% yield. The latter was then converted to 51 in 54% yield by initial treatment of 52 with N-bromosuccinimide (NBS) in water and THF (1:1 v/v) followed by reaction of the resultant bromohydrin in refluxing benzene containing a catalytic amount of p-toluenesulfonic acid. Reduction of the carbonyl group of 51 was considered necessary at this stage. This product 54, as a mixture of C3-alcohols, was treated with a mixture of osmium tetroxide and sodium periodate at ambient temperature to afford the dienone 55 in 70% yield. The parallel study starting from 51 provided the alternative series of compounds (Scheme 9) possessing the C9-cyano group. In this study, the conversion of 51 to 5£ was accomplished by treatment of 51 with potassium cyanide in DMSO. The cyano group could serve as the aldehyde function, as required for the polygodial series. The overall yield from 51 to 60 was 38%, so that again, the individual conversions in this sequence proceeded in good yield. At this point in the study, the unsaturated ketone 55 thus obtained, could be converted to the desired trans A/B fused system by catalytic reduction of the olefinic double bonds. The resultant product could be elaborated to the required C7-decalone 5£. by Baeyer-Villiger reaction, followed by saponification and oxidation as shown in Scheme 9. However this consideration was abandoned when a more efficient method to these compounds was developed. 2.1.2 Second approach 61 R=H 62 R=CH3 65 R=H 6£ R=CH3 + 6J. R=H 64 R=CH3 S©Ja©ani© 10 In 1981, Dr. Piotrowska* involved in steroid syntheses in Dr.Kutney's group, found that ozone selectively reacted at the tertiary carbon of the isopropyl side chain of compounds such as the sesquiterpene analogue 61. In her study, compounds 63 and 65 were obtained from the so called "dry ozonation"27 of compound 61 at -78°C. It was only a preliminary investigation, but such a novel reaction was worthy of further study in our program. The initial results established that the ratio of the tertiary alcohol 63 with respect to methyl ketone 65 was 2:1 (Scheme 10). A more detailed study of this interesting ozonation reaction was undertaken by Y. H. Chen in our research group. In ethyl acetate as the solvent and employing a low *: Personal communication from Dr. K. Piotrowska. 17 temperature for the ozonation reaction (-40°C), it was possible to convert SL in an overall 70% yield, to a mixture of the tertiary alcohol £4 and methyl ketone 6^ in a 2:1 ratio respectively. Subsequent treatment of M with concentrated hydrochloric acid afforded the five-membered ring system SL* shown in Scheme 10. With this data on hand, it was of interest to evaluate this approach for our purpose. The available tricyclic intermediate 68, obtained from ketalization of &l, was chosen and similar ozonization conditions indeed afforded a 1:1 ratio of the alcohol 6.2 and methyl ketone 7_Q (68%) (Scheme 11). Treatment of 6_9_ with concentrated hydrochloric acid gave the five-membered ring compound ^ .Purification of SL was difficult due to its instability to column *: Personal communication from Y. H. Chen. chromatography (silica gel and alumina) so the crude product was treated directly with tri-n-butyltin hydride (TBTH) in refluxing benzene to afford the rearranged six-membered ring alkene 21. The mechanism concerning the rearrangement will be discussed later. The overall yield from the alcohol 6J? to the final product 21 was consistently in the 40-46% range. 2.2 Outline of the present work. In summary, the above studies appeared well suited for our objective to provide a versatile synthetic route for a family of chiral polygodial analogues. An outline of the presently completed study is provided in Scheme 12 and 13. Details of the various reactions are given in the following sections. 1 H m 21 In summary, the ds-decalone analogue 80 was synthesized in seven steps from 48 in 27% overall yield and was then converted to the drimane-type dialdehyde 9_Q in eight steps with an overall yield of 27%. The stereochemistry of the various compounds was established through correlation with the absolute structure of diketone 66 (Scheme 10), the latter being obtained by X-ray analysis. 2.2.1 Studies of the stereochemistry of tricyclic ketone £2. and reduction to 7_2 Scheme 14 The starting material, tricyclic enone 4JL. was prepared in a large quantity via the previously published procedure25 involving Robinson annelation of thujone 4 2 with ethyl vinyl ketone (Scheme 12). Catalytic hydrogenation of 4&, using Pd/C as a catalyst in ethanol, afforded the A/B cis fused product 62 in quantitative yield. The stereochemistry of @2 at C4 22 and C5 was first investigated by a detailed proton NMR study. The C4 and C5 methine protons appeared as multiplets at 2.59 and 1.70 ppm respectively, while the C4 methyl group revealed a doublet at 0.94 ppm. These assignments were established from the following decoupling studies. There are three multiplets, each integrating for one proton, resonating at 2.15, 2.42 and 2.59 ppm in the spectrum. On the basis of their chemical shifts, they must be attached to C2 and C4. Irradiation of the signal at 2.59 ppm resulted in the three-proton doublet at 0.94 ppm, to collapse into a singlet (Figure 2b), thereby implying that the multiplet at 2.59 ppm was due to the proton at C4, and the doublet at 0.94 ppm was, in turn, due to the C14 methyl group. Conversely, irradiation of the signal at 0.94 ppm changed the splitting pattern at 2.59 ppm from a multiplet to a poorly resolved doublet (Figure 2c). Also as a result of irradiation of the C4 proton signal at 2.59 ppm, the multiplet at 1.70 ppm, integrating for one proton, became a doublet of doublets, thereby allowing assignment of the multiplet at 1.70 ppm to be that of the C5 proton. The C15 methyl signal was then easily recognized at 1.23 ppm since it is the only three proton singlet in the spectrum, (see Figure 2) Having located these key protons in the NMR spectrum, we started to investigate the stereochemistry at C4 and C5 by a Nuclear Overhauser Effect (NOE) difference experiment. The NOE data have considerable potential in the elucidation of configuration at specific centers in organic molecules. The maximum value that the Overhauser effect can have is determined by the nature of the nuclear species involved, and it is proportional to 1/r6, where r is the distance between the nuclei concerned. Therefore NOE data are obtained for nuclei in dose proximity. Examination of a molecular model of £2 showed that the distances between the C14 methyl group and the C5 proton, and also the C15 methyl group and the C5 proton are small if these nuclei are on the same side of the molecule. Therefore irradiation of the p" oriented C15 methyl or C14 methyl signals should enable determination of the configurations at C4 and C5. U14-Uri3 15 9 C4-H 2.59 C5-H if 1.70" 0.94 ^-NMR (400 MHz, C D C I 3 ) of tricyclic ketone 62 a) normal 400 MHz spectrum. b) homonuclear spin decoupling at 2.59 ppm. c) homonuclear spin decoupling at 0.94 ppm Figure 2 C 1 5 - C H 3 CI4-CH3 2.59 , 1.70 1.23 0.94 Nuclear Overhauser difference experiments on the tricyclic ketone £2 ' a) off resonance spectrum b) irradiation at 1.23 ppm c) irradiation at 0.94 ppm Figure 3 X-ray diffraction analysis of diketone 6j§ Figure 4 26 Irradiation at 1.23 ppm (C15 methyl) resulted in the enhancement of the multiplet at 2.59 ppm due to the C4 proton, but revealed no effect on the multiplet at 1.70 ppm due to the C5 proton (Figure 3b). Irradiation at 0.94 ppm (C14 methyl) gave only a very small enhancement at 1.70 ppm (Figure 3c). These observations indicated that the C4 proton is on the same side as the C15 methyl group, namely, the C14 methyl group is cc-oriented, however the nature of the ring A/B fusion (cis or trans) remained unclear. (See Figure 3) In order to settle this question and to allow assignments in subsequent synthetic intermediates, as outlined in Schemes 12 and 13, a suitable crystalline compound for X-ray analysis was required. The tosylhydrazone 22 failed to yield suitable crystals. Fortunately, the compound 6Ji obtained from ozonolysis of £2, provided satisfactory crystals upon recrystallization from hexanes. The subsequent X-ray analysis of £6 clearly revealed the C14a-methyl orientation and cis A/B ring fusion as shown in Scheme 14 and Figure 4. As a result, it is possible to assign cis A/B ring fusion in all compounds arising from 6J2. At this stage we investigated whether we could develop a trans A/B fused system via reduction of compound 48. The classical Birch reduction of a,6-unsaturated ketones involves transfer of electrons with the formation of a carbanion species which leads, after suitable work up, to a saturated ketone28. A detailed study on the Birch reduction of a,(j-unsaturated ketone was published by Stork. In his publication29 Stork indicated "that the saturated ketone formed by such a reduction is not simply the more stable of the two isomers at the (j-carbon. The energies of the stereoelectronically allowed transition states, rather than those reduction products, determine the stereochemistry of the latter". In this postulate, Stork argues that transition states such as 93A and 93B (Scheme 15) are involved and 93A would be favored since a maximum overlap of the p-orbitals occurs. On this basis, an octalone system, upon Birch reduction, is expected to yield the A/B trans fused system. Another study by Djerassi, Stork et al30 showed that the reduction of 9j6 indeed afforded the A/B trans fused compound 22. This result indicates that the a-isopropyl group at C7, which is axially oriented in a conformation similar to 93A. would be expected to provide some steric hindrance to approach Scheme I S 2 8 If we consider our study involving the Birch reduction of 48, the favored transition state, according the Stork hypothesis, would be 94A. In fact, the result obtained was the cw-fused system 95B and this would require the less favored transition state 94B. It was clear that our system does not follow the Stork hypothesis. In another study, it was shown that small variations in the translcis product ratio were observed when methyl substituents were at the angular position and at various positions on ring B of the parent octalone, and it was suggested by Robinson31 that the stereoselectivity of the reduction might be explained by assuming that the |3-carbon atom is trigonal in the transition state for protonation. Substituents were considered to influence the reduction stereochemistry by causing small changes in the position of the equilibrium involving the two half-chair conformations, 93C and 93D. of ring A of the species undregoing protonation. Applying this hypothesis to compound 48_, and assuming a 6,6-fused ring system, the thermodynamically stable intermediate 94C should be also greatly preferred in the protonation process. (See Scheme 16) yfo-93C 93D 94C 94D Scheme 16 29 Various laboratories have studied the Birch reduction of 6,5-fused compounds (See Table 1) and their results are summarized in a review article by Caine32. It is clear that in these instances a mixture of cis and trans fused products, with the cis isomer predominating, is obtained. Reactant Reaction conditions Product 90 : 10 18% 55% Table 1: Birch reduction of 6,5-fused bicyclic a,|3-unsaturated ketones. Based on various postulates and experimental results as shown above, it appears more appropriate to consider compound 48 as a 6,5-fused system. In our study, however, the cis-fused product was exclusive and no trans-fused system could be detected. At this stage, it was considered necessary to get rid of the carbonyl group of 62, so that the products from ozonolysis could be efficiently used in later stages of the synthetic route. The first approach involved conversion of ketone 62 to the tosylhydrazone 92 in 97% yield, 3 0 followed by reduction to the corresponding methylene derivative with sodium borohydride or catechoborane (Scheme 14). The results are listed in Table 2. Although the results were reasonably satisfactory, high cost of catecholborane and more difficult handling conditions particularly in scale-up encouraged us to evaluate the classical Huang Minlong modification of the Wolff-Kishner reaction (W-K-H). Thus ketone £2 was treated with hydrazine and potassium hydroxide in the high boiling point solvent, (Methylene glycol (DEG), to give the desired hydrocarbon 22. The IR spectrum of this compound indicated the absence of the carbonyl group absorption. The yields were consistently high (85%-89%) and were independent of the scale of the reaction (Table 2). In summary, this latter procedure was employed for all future studies. Method Time (h) Yield Comments Sodium Borohydride33 12 58% lower yield, easy to handle, not feasible for large quantity Catecho-borane34 3 75% fairly high yield, anhydrous conditions, not feasible for large quantity .expensive. W-K-H3^ 8 87% high yield, low cost, can handle large quantity Table 2: Reduction of 62 2.2.2 Hydroxylation via ozonation Schema© 17 It is known that ozone reacts slowly with saturated hydrocarbons with oxygen insertion into the C-H bond. Insertion occurs preferentially at the tertiary carbon atoms, resulting in alcohols and ketones. This type of reaction had been little used until 1975 when Cohen et al reported27 the dry ozonation method for hydroxylation of saturated compounds. The main idea was to use silica gel as the reaction matrix based on the fact that silica gel absorbs ozone efficiently at low temperature (its concentration being about 4.5% by weight at -78°C). In practice, the silica gel is preabsorbed with the organic substrate, cooled to -78°C and then saturated with ozone; it is then allowed to warm slowly to room temperature and the product is eluted in the normal fashion. It has also been observed36 that ozone cleaves not only C-H bonds, but also C-CH3 bonds, which occurs by a direct insertion of ozone into these bonds (Scheme 18). ? -C-H 0 3 O a I H' oxygen insertion (hydroxylation) -C-OH -C-CH3 H H O" 1 n - C j j O ^ - O - O - C H a H / C = 0 ozone insertion (Cleavage) As mentioned earlier, Dr. Piotrowska in our laboratory had made preliminary study of this reaction, and a more detailed study was now undertaken. Application of this dry ozonation procedure to ketal 6J8. afforded 60% of alcohol 6J2 and a small amount of ketone 2Q. However, application of this technique to our synthesis presented difficulties: the progress of this reaction was not easily monitored, and there were technical limitations to the scale of the experiment. However, these difficulties can be overcome by the use of a solvent37, although ozone is only slightly soluble in organic solvents (about 0.1-0.3% by weight at -78°C)38 and reaction time may be longer. To perform the reaction, all the compounds under study were dissolved in ethyl acetate and a stream of ozone was then passed through the solution at -40°± 10°C for 8-10 hours. The reaction was quenched by dimethyl sulfide (DMS). The expected alcohol and ketone products were separated by silica gel chromatography. In this manner, the tricyclic alkane 22 afforded a mixture of the alcohol 7_3_ and ketone 74 in a 1:1 ratio (overall yield 66-70%). The IR spectra indicated the presence of hydroxyl group in 73 and carbonyl absorption in 24, and while *H-NMR spectra showed that the two doublets at 8=0.89 and 0.96ppm in the starting material 22 (C12 and C13 methyl groups), had collapsed to two 33 singlets at 8=1.18 and 1.27ppm in 73 and one singlet at 8=2.03ppm in 74. If the temperature of the ozonation process was raised to 0°C, many products were observed even after a short time of reaction (30 minutes). The reaction was very slow when conducted below -50° C, for example, at -60 to -70C, only 10% of substrate was converted after 18 hours. Compounds 9_1 and 9.8 were also investigated for comparison. The results and conditions are listed in Table 3. Substrate time(h) temp(°C) conversion(%) yield(%) alcohol/ketone 68 6 -40 75 68 1/1 61 8 -40 100 45 1/1 22 1 0 70 side products 22 8 -40 70 66-75 1.2/1 62 10 -40 100 67 2.4/1 21 3 0 100 89* 1.5/1* 98 3 0 100 79* 1.4/1* *: Relative percentage of area in glc. Table 3: Ozonation results of several compounds From the above studies, it was concluded that: a) higher yields of products are generally obtained when a molecule has a minimum number of tertiary carbon atoms, b) the distribution of alcohol vs ketone is not controllable by the reaction temperature and time, c) a carbonyl or a ketal group at ring A does not improve the yield, but it does shorten the reaction time. The separated ketone 24 was reduced to alcohol 7_5_ in 93% yield with NaBrL^ and this product, together with alcohol 23_, provide a convenient family of cyclopropylcarbinols which can undergo an important cyclopropane ring opening reaction discussed in the next section. 34 2.2.3 Synthesis of decalone &Q m J E H 1 OH 73 99 CN 100 In Scheme 8, presented earlier, cyclopropyl ring opening was achieved in a manner to that studied by Julia et al39 while in Schemes 10 and 11, an alternate ring opening reaction was observed. It was therefore appropriate to treat the cyclopropylcarbinols 23 and 25 obtained above, with concentrated hydrochloric acid at both 0°C and room temperature for 2 hours, in order obtain chlorides 7_6_ and 22 respectively (Scheme 12). The IR spectra of these products indicated the absence of hydroxyl groups. The parent mass of 7j6 at 240 (m/z) is consistent with the molecular formula CisH2535Cl and at 242 (m/z) for the natural 37C1 isomer (Ci5rl2537Cl). The iH-NMR spectra of these compounds were consistent with the five-membered ring structure shown in 16 (Scheme 19) Thus the spectrum revealed a typical ABX coupling system, that is, two well resolved doublet of doublets at 8=3.45ppm (lH,dd,J=ll,4Hz) and 5=3.61ppm (lH,dd,J=ll,8Hz) consistent with methylene protons on a carbon atom attached to the chlorine. Purification of this mixture of chlorides was not successful because these compounds are extremely unstable to both silica gel and alumina chromatography. Even a rapid filtration of the reaction mixture through a short silica gel column results in a partial decomposition. Actually, we found that it was convenient to carry the reaction mixture directly into the next step of the sequence. In related studies, involving an attempted conversion of 22 with 48% hydrobromic acid to the corresponding five-membered ring bromide (76. replaced Cl by Br), a more complex mixture of products, as determined by glc, and conjugated diene products (UV absorption) were noted. At this stage, consideration of the ring opening of 26 and 22 to a six-membered ring B, for example to compound 22, was considered since subsequent displacement of chloride by cyanide would allow convenient entry into the C9-aldehyde series, (see Schemes 9 and 13). McCormick et a/40>41 reported a high yielding, stereoselective conversion of secondary and tertiary cyclopropylcarbinols into homoallylic bromides or iodides by treatment with magnesium bromide or iodide in refluxing anhydrous ether. In this study, they also reported in another publication42 that a combination of magnesium halide and zinc halide provided a striking increase in both reaction rate and regioselectivity in conversions involving a bicyclic system. On this basis, alcohol 22 was treated with one molar equivalent of magnesium bromide together with one molar equivalent of zinc bromide in refluxing anhydrous ether. However, incomplete conversion of substrate to the five-membered ring product was observed. In another study, a mixture of zinc bromide and aqueous hydrobromic acid43 was utilized to promote this transformation, but with similar results to those noted above. The crude product 26 was treated with excess tri-n-butyltin hydride (TBTH) initiated by azobisisobutyronitrile (AIBN) in refluxing toluene for 8 hours to afford the rearranged six-membered ring product 28, the overall yield from 23 to 28 was 52-56%. The crude chloride 77 was converted to 22 in the same conditions described above (the overall yield from 25 to 36 79 was 53%). The six-membered ring structure of 7j£ was supported by the !H-NMR spectra. There are four methyl signals in the spectra at 6=0.88 ppm (3H,d,J=6.6, C4-CH3), 0.94 ppm (3H,s, CIO-CH3), 1.655 ppm (3H,s, CII-CH3) and 1.660 ppm (3H,s, CII-CH3) which are consistent with the structure of 7J£. If B ring was five-membered one more methyl signal,a doublet, would be observed. There is little doubt that the above conversion of 26 to 7_8_ involves a radical process. Thus homolytic fission of the C-halogen bond, initiated by the tri-n-butyltin radical, generates intermediate 101. Rearrangement of 1Q1 as shown in Scheme 20 affords 102, which is finally converted to 78/79. It is logical to assume that the rearrangement, 101—>102. could involve a concerted 1,2-shift although mechanistic studies were not performed here. R-X + (n-C4H9)3Sn- R- + (n-C4H9)3Sn-X R- + (n-C4H9)3SnH R-H + (n-C4H9)3Sn-X=Halide 76 R=CH3 77 R=H 101 102 78 R=CH3 22 R=H Sclh©m© 2<D 3 7 In our initial studies with TBTH and the chlorides 7J> and 22, refluxing benzene was utilized as the reaction medium. In this case, a 50% yield of 28 or 22 was obtained in a 24 h reaction time. Subsequent studies in refluxing toluene increased the yield (generally 52-56%) and reduced the reaction time to 8 hours. With the alkenes 2S and 22 in hand, the important intermediate decalone £0. was readily available. Alkene 2& or 22 (or the mixture) was treated with ozone at -60°C (chloroform/dry ice) for 20 minutes. After decomposition of the resultant intermediate ozonide under reductive conditions employing dimethyl sulfide (DMS) at higher temperature44, decalone 80 was obtained in 90-93% yield. The IR spectrum of the product showed a carbonyl absorption at 1705 cm_1and the ^ -NMR spectrum indicated disappearance of the methyl proton singlets at 8=1.655 and 1.660 ppm normally due to the unsaturated side chain in the substrate 28. 2.2.4 Synthesis of drimane dialdehyde 9_0 (see Scheme 13) CHO CHO 2Q As shown in Scheme 7, the C8-aldehyde function of 40 was introduced via formylation of decalone 8 with ethyl formate and sodium hydride in ether at room temperature. When we applied the same condition to decalone 80, no reaction was observed at room temperature over a 24 hour period and a similar result was observed at elevated temperature. It was clear that stronger base such as KH or CsH45 was required. 38 Gas evolution readily commenced when substrate 80 was added to a suspension of potassium hydride in THF at room temperature and upon addition of ethyl formate, formylation occurred in 20 minutes. The product, isolated in 89% yield, was the C8 formyl compound 8_1. (See Table 4). It should be noted, as shown in Table 4, that THF is a superior solvent to ether in this process. Entry Base Solvent Temperature Yield Time 1 NaH ether R.T. or Reflux — 24h 2 NaH THF R.T. or Reflux — 24h 3 KH ether R.T. 81% 30min 4 KH THF R.T. 89% 20min Table 4: Formylation of 80 Compound 81 is easily purified through a silica gel column or by extraction with potassium hydroxide solution, but somewhat unstable even when stored at 0°C. Consequently it was best to perform the next reaction without delay. This compound showed in the IR spectrum a weak absorption for the OH (enolic) function and a strong carbonyl absorption. The olefinic bond in 82 was introduced via a selenylation-deselenylation reaction with 81. Liotta et al reported46 that the rate of selenation with PhSeCl/pyridine can be roughly correlated with the percent enolic character of the starting B-dicarbonyl compound. When the substrate in question exists to a substantial extent in its enol form, selenation is instantaneous at room temperature. In our case, compound 81 exists entirely in the enol form as supported by two singlets shown in the *H-NMR spectrum at 8=8.56 and 14.29ppm. Compound 8J. was therefore readily converted to the corresponding unsaturated derivative 82 by a) selenation using a 1:1 complex of phenylselenenyl chloride/pyridine and b) in situ oxidation with 30% H2O2. The isolated yield of 82 was 86%. The UV spectrum showed the conjugated 3 9 absorption at 238 nm, the IR spectrum indicated the conjugated C=0 absorption at 1680 cm - 1 and the !H-NMR spectrum revealed the olefinic proton at 5=7.45 ppm as well as the aldehyde proton at 8=10.09 ppm. The resultant keto aldehyde 82 smoothly underwent a conjugate addition with cyanide to give 9-nitrile 83. The crude product was purified by extraction with potassium hydroxide solution, then acidification, extraction again with organic solvent. Further purification with column chromatography on either silica gel or alumina was not successful since all the crude product would be consumed on the column. The crude product showed the cyano group absorption at 2236 cm - 1 in IR spectrum, and iJI-NMR spectrum gave singlets at 8=4.01, 8.98 and 15.04ppm supporting the structure of 83.. The stereochemistry at C9 was not clear, although it could be assumed that the nitrile group was (3-oriented. The conversion of the formyl ketone moiety in 83 into the a.P-unsaturated aldehyde 85 was performed via the following two steps. 1) protection of the aldehyde group of &3_ by n-butylmercaptan, 2) reduction of the carbonyl group of the (n-butylthio)methylene derivative 84 with sodium borohydride,! followed by hydrolysis promoted by mercuric chloride. The overall yield in the conversion 82 85 was 52%. The U V spectrum of 85 showed the conjugated absorption at 224 nm, and the lH NMR spectrum indicated the aldehyde and olefinic protons at 8=7.05,9.5lppm respectively. Protection of the aldehyde group of &5_, so that the nitrile could be reduced to an aldehyde, with ethylene glycol catalyzed by p-toluenesulfonic acid, provided ketal 86 in 71% yield along with the isomeric ketal 87_ in 18% yield. The IR spectra showed no carbonyl group in these products while iH-NMR spectra revealed one olefinic proton at 8=6.05ppm for 86 and two olefinic protons at 8=5.53, 6.62ppm for 87. Since the double bond is expected to move back into conjugation on deprotection of the ketal, compound 87 could be utilized. Examination of the iJI-NMR spectrum of &6 revealed the proton attached to the C9 atom, which carries the cyano group, at 8=2.79ppm (singlet IH). On the basis of its chemical shift, the C10 methyl group was also easily noted at 8=1.24ppm (singlet 3H). Irradiation of the 4 0 CIO methyl proton resonance (8=1.24ppm) resulted in an enhancement of a signal at 8=2.79ppm (C9-H) (Figure 5). From the more stable conformation of 86 (See 86A), it was clear that irradiation of the CIO methyl protons would be expected to provide an enhancement to the C9 axial proton in 86-1 and similarly to the C9 equatorial proton in 86-2. Since the distance between these protons and the corresponding methyl protons should be similar in the two possible isomers (86-1 and 86-2). In conclusion, NOE experiment cannot clearly establish the stereochemistry at C9. R 2 Nitrile 86 was reduced to the corresponding aldehyde 88 with DIBAH at -60°C to -50°C in three hours (85% yield). This reduction was done at this temperature, because at the lower temperature of -78°C, the reaction would not proceed to completion, whilst at room temperature, a low yield of aldehyde was obtained. Nitrile 87 was reduced to aldehyde 88 with DIBAH at -78°C for two hours. C10-CH 3 J J C9-H "2.79" Nuclear Overhauser difference experiments on nitrile 86. (400 MHz, CDCI3) a) off resonance spectrum b) irradiation at 1.24 ppm 1.24 Figure 5 42 We surprisingly found that nitrile 84 was resistant to DIBAH reduction. When excess DIBAH was added to £4. only alcohol 103 was found even after 12 hours at room temperature.(see Scheme 21). Schema© 21 With 88 and 89 in hand, we were ready to perform the final steps of the sequence. Ketal 88 was hydrolyzed in an acetone/water mixture with an acid (p-toluenesulfonic acid) catalyst at room temperature for three hours to give our target compound 90 in 93% yield. As we expected, hydrolysis of 89 provided the same compound 90 in 77% yield (overall from 87). The IR spectrum of this compound showed a saturated aldehyde at 1718 cm-1 and a conjugated aldehyde at 1665 cm-1, and the iH-NMR spectrum revealed the two aldehyde protons at 5=9.44 and 9.79ppm. Another NOE difference experiment was applied to 90 as shown in Figure 6. Irradiation at the CIO methyl protons resonance at 5=1.26ppm (3H,s) resulted in an enhancement of the C9 proton at S=3.33ppm (lH,d,J=3) and C9 aldehyde proton at 5=9.79ppm (lH,d,J=3). Similar arguments concerning NOE results and stereochemistry at C9, to those presented above for 86, apply in this case and therefore NOE data cannot establish the C9 configuration in the final product 90. However it should be noted that the acidic treatment in the conversions, 88->9_Q and 89->90 may well provide the C9 a-orientation for the aldehyde function. In the latter case, this functionality is in a more favored equatorial orientation. 43 C9-H 1 CHO CD C10-CH3 H 2Q JL C9-H =flr 3.33 1.26 Nuclear Overhauser difference experiments on drimane dialdehyde 2Q (400 MHz, CDCI3) a) off resonance spectrum b) irradiation at 1.50 ppm Figure 6 2.3 Approach to the natural drimane antifeedants As was seen in Section 1.2, the naturally occurring drimane antifeedants have a trans A/B ring fusion coupled with the functional groups in ring B and gm-dimethyl group in ring A. An approach to a trans decalone with a gem-dimethyl group in ring A, which will eventually lead to the natural drimane antifeedants, is now presented. From our previous work, the enone 4j£ could not be converted to a trans A/B ring juncture by either catalytic hydrogenation or the Birch reduction (Section 2.2.1 and Scheme 14). As mentioned earlier, the 6,5-fused system plays an important part in formation of the cis A/B fusion, it was therefore decided to study molecules of the 6,6-fused system. Reductive alkylation of the 44 trienone 5_3_, available from Scheme 9, did not give the desired diene 106 (Scheme 22). However, an efficient sequence has been developed by Scheme 22 Dr. Cheng* based on a large amount of work in the model studies (Scheme 23). This study will provide a novel entry to the natural products of the polygodial family. Scheme 23 *: Personal communication with Dr. K. P. N. Cheng. Alkylation of 52 with methyl iodide and sodium methoxide in DMSO provided the dienes 105 and 106 in a 2:1 ratio. The former was then readily epimerized to 106 via catalysis with iodine in refluxing hexane. The diene 106 could be converted to the trans A/B fused compound 109 by reduction followed by selective ozonation of the more active exocyclic double bond of diene IQ2 to give enone 1QJ£. Finally the latter could be elaborated to the chiral trans decalone 109 by Birch reduction. The chiral decalone 109 can be easily converted to the chiral natural products polygodial and warburganal by performing the procedures described in Scheme 7 and 13. 2.4 CONCLUSION Polygodial 1 exhibits a number of interesting biological properties, including a marked antifeedant activity against insects, and tastes very hot to humans. However, in spite of various efforts made in recent years, the biochemical mechanism for these activities still remains obscure. D' Ischia et al47 have suggested that the biological activity of polygodial is related to its ability to react with amino groups. Based on this hypothesis and experiments, epi-polygodial 110 and the cis -fused isomer 111 were observed non-active9<47, but the cis-fused dialdehyde 112 was found active to some insects 4 8. The newly synthesized drimane dialdehyde 90 possesses the following structural features: a cis A/B ring junction, one methyl group in ring A and the required dialdehyde functionality in ring B. Detailed evaluation of its biological activity will reveal whether this thujone-derived intermediate, with only one methyl group in ring A, will possess this important activity. This result could lead to a new family of antifeedants from the readily available and inexpensive thujone. Regardless, the above studies have provided considerable chemistry relating to the synthesis of the drimane type dialdehydes both in the natural and unnatural series. It is clear that the information derived can be extended to other terpenoid synthesis. 4 7 3. Experimental 3.1 General Unless otherwise specified, all reagents were supplied by the Aldrich Chemical Company and used without further purification. Petroleum ether refers to the fraction boiling in the range 30-60°C. Anhydrous tetrahydrofuran (THF), diethyl ether and toluene were purified by distillation from a mixture of the solvent with sodium and benzophenone. Anhydrous benzene was obtained by distillation from a mixture of benzene and calcium hydride and dry methanol from a mixture with magnesium and iodine. Ozone was produced by a Welsbach Ozonator. The compounds were characterized by their melting points on a Nalge melting point apparatus and are uncorrected. The infrared spectra were recorded on Perkin-Elmer 71 OB and 1710 (Fourier Transform I.R.) spectrometers either in chloroform solution (using sodium chloride cells of 0.1mm path length) or as a neat liquid film (using sodium chloride plate). The ultraviolet spectra were recorded on a Cary 15 spectrometer in 1cm quartz cells, the extinction coefficients (log £max.) being given in parentheses, and the wavelength(s) of the maxima in nanometers. The mass spectra were recorded on AEI-MS-9 Qow resolution) or KRATOS-MS-50 (high resolution) spectrometers. The *H NMR spectra were recorded on either Bruker WH-400 or Varian XL-300 spectrometers and the chemical shifts are reported in ppm relative to tetramethylsilane (internal standard). The optical rotations were recorded on a Perkin-Elmer 141 automatic polarimeter in a 10 cm cell at ambient temperature using the solvent and concentrations (g/lOOml) indicated in parentheses following the recorded rotation values. The elemental analyses were determined by combustion analysis by Mr. P. Borda, Microanalytical Laboratory, The University of British Columbia. The X-ray diffraction analysis was performed by Dr. S. Rettig on a RIGAKU AFC6 diffractometer. Column chromatography was performed using 230-400 mesh silica gel supplied by E . Merck Co. Unless otherwise stated, all reactions 48 were monitored by thin layer chromatography (TLC) analyses, which were carried out on commercial aluminium-backed silica gel plates (Merck art 5554). Visualization was accomplished with ultraviolet light and/or by spraying with 5% ammonium molybdate-10% aqueous sulfuric acid, followed by heating. Gas-liquid chromatography (GLC) was performed on a Hewlett Packard model 5890 gas chromatograph, using a flame ionization detector and a 25m x 0.21mm fused silica capillary column coated with DB1701. It is important to note that the numbering system employed for the compounds prepared conforms with that used for the natural drimane sesquiterpenoids. This is done in order to allow facile comparison with compounds within the drimane family. However the corresponding names according to IUPAC system are shown in parentheses. 49 3.2 (5B)-4a,10p-dimethyl.7a.is6propyl.tricyclo[4.4.05»l0.o7,9].dec.3. one 62 {(6B)-lfi,5a-dimethyl-8a-isopropyl-tricycIo[ 8» 1 0]-dec-4-one £ 2 . } A mixture of tricyclic enone 4 8 2 2 (8.00 g, 36.7 mmol), potassium hydroxide (lg, 17.8 mmol) and 10% palladium on active charcoal (2 g) in ethanol (800 ml) was hydrogenated at room temperature and atmospheric pressure. Hydrogen absorption ceased after 3.5 hours. The mixture was filtered through a celite plug and the filtrate evaporated. Water (100 ml) was added to the residue, the mixture was extracted with methylene chloride (2x100 ml) and dried over sodium sulfate. Evaporation of the solvent at reduced pressure afforded the saturated ketone 62 as a colorless oil (7.99 g, 99%). The physical properties of QZ are as follows: IR v max- (neat): 2942, 2846 (C-H, St.), 1702 (C=0, st.) cm"1. 1H-NMR (400 MHz,CDCl 3 ) 8: 0.20(lH,dd,J=9,4, C8-H), 0.43(lH,dd,J=6,4, C8-H), 0.85(3H,d,J=8, CII-CH3), 0.91(3H,d,J=8, CII-CH3), 0.94(3H,d,J=7, C4-CH 3 ) , 1.18(lH,t,J=11.2), 1.23(3H,s, CIO-CH3), 1.33(lH,h,J=8, C l l - H ) , 1.61-1.83(5H,m), 2.15(lH,m, C2-H), 2.42(lH,m, C2-H), 2.59QH, m, C4-H). MS m/z: 220(M+), 205,177,136,124,105, 93, 86, 82, 67, 55,41. High resolution mass measurement: calculated for C 1 5 H 2 4 O : 220.1821; found: 220.1815. Elemental analysis: calculated for C 1 5 H 2 4 O : C 81.76, H 10.98; found: C 81.67, H 11.00. 3.3 (5B)-4a,10p-dimethyI-3-(l,3-dioxoIan-2-yI)-7a-isopropyI-tricyclo[>9]-decane 6JJ 50 {(6n)-lp,5a-dimethyl-4-(l,3-dioxolan-2-yl)-8a-isopropyI-tricyclo['10]-decane £8.1 61 A solution of ketone £2 (3.53 g, 16 mmol), ethylene glycol (2.1 g, 33.9 mmol) and p-toluenesulfonic acid (50mg, 0.26 mmol) in benzene (70 ml) was heated at reflux with a Dean-Stark apparatus for 4 hours. The solution was cooled and ether (100 ml) was added. The solution was washed with saturated aqueous sodium bicarbonate (50 ml) and water (2x50 ml), then dried over sodium sulfate. The solvent was evaporated. The residue was filtered through a short column of silica gel using a solvent of ether/pet ether (1:9 v/v). The solvent was evaporated to give the pure ketal 61 (3.67 g, 87%) as a colorless oil. The physical properties of 61 are as follows: IR v m ax. (neat): 2940,2855 (C-H St.), 1110 (C-0 SL) cm-1. !H-NMR (400 MHz, CDC1 3) 8: 0.10(lH,ddJ=8,4.8, C8-H), 0.37(lH,dd,J=4.8,3.8, C8-H), 0.84(3H,d,J=7.2, CII-CH3), 0.88(3H,d,J=7.2, CII-CH3), 0.98(3H,d,J=7.2,C4-C H 3 ) , 1.00(3H,s, CIO-CH3), 1.02-1.97(10H,m), 3.97-4.00(4H,m). MS m/z: 264(M+), 249,235, 221,99. 3.4 (5B)-4,4,10P-trimethyl-7a-isopropyl-tricydo[4.4.05»10.07.9]dec-3-one 91 (5B)-2,4,4,10p-tetramethyI-7a-isopropyI-tricyclo[4.4.05»10.07»9]-dec-3-one 21 {(6fi)-lB,5,5-trimethyI-8a-isopropyl-tricyclo[»10]dec-4-one 21 (6B)-lB,3,5,5-tetramethyl-8a-isopropyl-tricyclo[»10]-dec-4-one 211 21 91 A solution of enone 48 (1.1 g, 5 mmol) in dry T H F (13 ml) was added dropwise to a solution of lithium (0.09g, 13 mmol) in liquid ammonia (38 ml) (purified by distillation from lithium). After addition was complete the blue solution was stirred for 10 minutes, then dry THF (40 ml) was added. Removal of ammonia was completed by heating under reflux and, after allowing the mixture to cool (argon protection), methyl iodide (7.5 g, 52.8 mmol) was added and the mixture was heated at reflux for 1 hour. After stirring at room temperature for 5 hours, the mixture was poured into water and extracted with ether (3x50 ml). The ethereal solution was washed with brine and dried over magnesium sulfate. Column chromatography on silica gel using 5% ether/pet. ether gave the desired ketone 21 (0.632 g, 54%) as a colorless oil plus compound 21 (0.470 g, 40%). The physical properties of 21 are as follows: IR v max. (neat): 2940, 2850 (C-H St.), 1700 (C=0 st.) cnr 1-1H-NMR (400MHz, CDC1 3) 5: 0.18(lH,ddJ=8,4.8, C8-H), 0.39(lH,dd,J=4.8,4, C8-H), 0.84(3H,d,J=6.4, CII-CH3), 0.86(lH,m), 0.90(3H,d,J=6.4, CII-CH3), 0.96(3H,s, CIO-CH3), 1.22(3H,s, C4-CH 3 ) , 1.32(3H,s, C4-CH 3 ) , 1.28-1.38(2H,m), 1.47(lH,dd,J=12,7.6), 1.72(lH,ddJ=12,7.2), 1.83(2H,m), 2.13(lH,m, C2-H), 2.70(lH,m, C2-H). MS m/z: 234(M+), 219, 201,191,105, 96, 81,49, 55,43. The physical properties of 2E are as follows: IR v max. (neat): 2925, 2850 (C-H st,), 1695 (C=0 st) cm-*. 5 2 1H -NMR (400MHz, C D C I 3 ) 8: 0.14(lH,ddJ=8,4.8, C8-H), 0.41(lH,dd,J=4.8,4, C8-H), 0.83(3H,d,J=5.6, C2-CH 3), 0.88(3H,d,J=6.8, C I I - C H 3 ) , 0.95(3H,s, C10-CH 3), 0.98(3H,d,J=6.8, CII-CH3), 1.06-1.80(7H,m), 2.91(lH,m, C2-H). MS m/z: 248(M+), 233, 205, 149, 136,123,114, 107, 96, 81,71, 55,41. 3.5 (5B).4a,10!3-dimethyl-7a-isopropyI.tricyclo[4.4.05,i0.o7,9]. (iec.3-tosylhydrazone £2 {(6B)-lB,5a-dimethyl-8a-isopropyl- t r icycIo[ 8 » 1 0 ]-dec-4-tosylhydrazone 92) A solution of tricyclic ketone 62 (19.655 g, 89.1 mmol) in benzene (1500 ml) with p-toluenesulfonyl hydrazide (17.425 g, 93.7 mmol) and boron trifluoride etherate (1 ml) was stirred under argon at room temperature for 6 hours. The benzene was evaporated under reduced pressure. The residue was diluted with water (500 ml) and extracted with ether (2x500 ml). The extracts were dried over sodium sulfate and the solvent was evaporated. Recrystallization from ether/pet ether gave hydrazone 22 as white crystals (33.53 g, 97%). Mp: 88.5-89.5°C Elemental analysis: calculated for C22H32N2O2S: C 68.00, H 8.30, N 7.21; found: C 68.16, H 8.43, N 7.25. 22 3.6 (5B)-4a,10p-dimethyl-7a-isopropyl-tricycIo[4.4.0 5» 1 0 .0 7» 9]-decane 12 {(6B)-l!3,5a-dimethyl-8a-isopropyl-tricyclo[ 8» 1 0]-decane 121 53 3.6.1 Method A To a solution of tosylhydrazone 22 (6.20 g, 15.9 mmol) in methanol (200ml) was added sodium borohydride (11.3 g, 339 mmol) in small portions during one hour and the resulting mixture was heated under reflux for an additional 8 hours. The solvent was removed under reduced pressure. The residue was dissolved in ether and the ethereal solution was washed with water, 10% sodium carbonate solution, IN hydrochloric acid and water, then dried over sodium sulfate. The solvent was removed under reduced pressure. Chromatography of the residue on a silica gel column using petroleum ether as eluant gave 22 (1-90 g, 58%) as a colorless oil. 3.6.2 Method B To a solution of tosylhydrazone 22 (20.45 g, 52.7 mmol) in chloroform (100 ml) at -15°C under argon, catecholborane (6.31 ml, 58 mmol) was added and the hydroboration was allowed to proceed at -10°C for one hour. Sodium acetate trihydrate (20.1 g, 155 mmol) was then added, and the reaction mixture was brought to a gentle reflux for 3 hours, cooled to room temperature, and filtered. The solid material on the filter was washed with chloroform (50 ml), and the combined filtrates were evaporated under reduced pressure. The remaining oil was purified by chromatography on a silica gel column with hexanes as eluant to afford 22 (8.14 g, 75%) as a colorless oil. 54 3.6.3 Method C A mixture of the carbonyl substrate 62 (30 g, 136.4 mmol) and hydrazine (21.8 g, 681.8 mmol) in diethylene glycol (300 ml) was heated from 100-130°C for 1.5 hours (water and excess hydrazine were distilled). After cooling, potassium hydroxide (45.8 g, 818.4 mmol) was added to the reaction mixture and heating was continued at 200-210°C for 6 hours. The cooled reaction mixture was added to water (300 ml), extracted with ether (2x250 ml), washed with brine and dried over sodium sulfate. The solvent was removed and the residue was purified on a silica gel column using pet. ether as eluant to give the ketone-free compound 22 (24.5 g, 87%) as a colorless oil. The physical characteristics of 22 are as follows: IR v m a x . (neat): 3035, 2995, 2925,2860 (C-H St.), 1470,1385 (C-H bend) cm'l iH-NMR (400 MHz, CDCI3) 6: 0.07(lH,dd,J=8,5, C8-H), 0.40(lH,dd,J=10,5, C8-H), 0.81(3H,d,J=6.8, C4-CH 3 ) , 0.89(3H,d,J=6.6, CII-CH3), 0.96(3H,d,J=6.6, C l l -CH3), 0.95(3H,s, CIO-CH3), 1.10-1.63(12H,m). MS m/z: 206(M+), 191,163,123, 110,95, 81, 55. High resolution mass measurement: calculated for Ci 5H26: 206.2034; found: 206.2033. -Elemental analysis: calculated for C15H26: C 87.30, H 12.70; found: C 87.24, H 12.75. 3.7 (5p)-4a,10p-dimethyl-7a-isopropinol-tricyclo[4.4.05»10.07»9]-decane U (5p)-7a-acetyl-4a,10P-dimethyI-tricyclo[4.4.05'10.07»9]-decane 24 {(6P)-lB,5a-dimethyl-8a-isopropinol-tricyclo[ 8» 1 0]-decane u (6P)-8a-acetyl-lp,5a-dimethyI-tricyclo[]-decane 21) 5 5 Ozone was bubbled through a solution of22 (24 g, 116.5 mmol) in ethyl acetate (500 ml) containing sodium bicarbonate (9.8 g) at -40°C (acetonitrile/dry ice bath) for eight hours. The excess ozone was removed under a stream of argon and then dimethyl sulfide (5 ml) was added to the solution. The reaction mixture was allowed to warm to room temperature and stirred for one hour. Filtration and concentration, followed by flash chromatography on a silica gel column (hexanes-ethyl acetate as eluant, 17:3, v/v) provided alcohol 22 (10 g, 38.7%) and ketone 14 (7.7 g, 32.3%) and starting material 22 (6.9 g, 28.7%). The total yield was 71% based on the recovered starting material. The physical properties of 23. are as follows: IR v max.(neat): 3405 (O-H, St.), 3050, 2903, 2850 (C-H st), 1140 (C-O St.) cm"1. *H-NMR (400 MHz, CDC13) 5: 0.43(lH,dd,J=5.2,4.4, C8-H), 0.48(lH,dd,J=5.8,4.4, C8-H), 0.83(3H,d,J=6.4, C4-CH 3 ) , 0.98(3H,s, CIO-CH3), 1.18(3H,s, CII-CH3), 1.27(3H,s, CII-CH3), 1.00-1.51(10H,m), 1.62(lH,br, O-H), 1.75(lH,t,J=12) MS m/z: 204(M+-H2O), 189, 161, 133, 119, 105, 95, 91, 81, 67, 59, 55, 41, 32. High resolution mass measurement: calculated for C15H260:222.1984; found: 222.1982. Elemental analysis: calculated for C15H26O: C 81.02, H 11.78; found: C 80.80, H 11.53. The physical properties of 24 are as follows: IR v max. (neat): 3000, 2925,2859(C-H st), 1680(C=O st) cm"1. *H-NMR (400 MHz CDCI3) 6: 0.86(3H,dJ=6.4, C4-CH 3 ) , 1.03(3H,s, CIO-CH3), 1.04-1.73(12H,m), 2.03(3H,s, CII-CH3), 2.10(lH,tJ=12). MS m/z: 206(M+), 191,177,163, 95, 81,43. High resolution mass measurement for C14H22O: 206.1671; found: 206.1662. 5 6 Elemental analysis: calculated for C14H22O: C 81.50, H 10.75; found: C 81.56, H 10.90. 3.8 (5p)-4a,10P-dimethyl-3-(l,3-dioxolan-2-yI)-7a-isopropinoI-tricyclo[4.4.0540.o7,9].decane and (5P)-7a-acetyI-4a,10p-dimethyl-3-(l,3-dioxolan-2-yI)-tricycIo[4.4.0 5» I 0 .0 7» 9]-decane 2SL {(6p)-ll3,5a-dimethyI-4-(l,3-dioxolan-2-yl)-8a-isopropinoI-tricyclo[ 8» 1 0]-decane £2. and (6B)-8a-acetyl-ip,5a-dimethyI-4-(l,3-dioxolan-2-yl)-tricyclo[>10]-decane 2JU 61 2Q £2 Compounds £2 and 7_Q_ were prepared as described for 73 and 74. Thus compound 6j£ (190 mg/200 ml ethyl acetate) gave £2 (46 mg, 22.8%) and 7_Q_ (50 mg, 26.3%) and starting material (48 mg, 25.2%). The physical properties of £2 are as follows: IR v max.(neat): 3601 (O-H St.), 2950, 2875 (C-H St.), 1110 (C-O st.) cm"1. ] H - N M R (400 MHz, CDCI3) 5: 0.38(lH,ddJ=5.2,4, C8-H), 0.43(lH,dd,J=8.8,4, C8-H), 0.84(3H,d,J=7, C4-CH 3 ) , 1.03(3H,s, CIO-CH3), 1.19(3H,s, CII-CH3), 1.27(3H,s, CII-CH3), 1.30-1.67(8H,m), 1.95(lH,m), 2.17(lH,m), 3.80-3.99(4H,m). 1 3 C - N M R (75MHz, CDCI3) 6: 7.727, 11.856, 21.610,27.582, 27.630, 28.461, 31.000, 33.237, 33.989, 34.525, 35.742, 39.135, 45.868, 64.052, 65.593, 70.756, 111.217. MS m/z: 280(M+), 262, 247, 99, 59, 55, 41. The physical properties of ZQ are as follows: 57 IR v max.(neat): 2953, 2882 (C-H st), 1684 (C=0 st), 1102 (C-0 st) cnr* 1H-NMR (300MHz, CDC1 3) 6: 0.89(3H,d,J=7.5, C4-CH 3 ) , 1.01(lH,m), 1.07(3H,s, CIO-CH3), 1.26-1.83(8H,m), 1.96(lH,m), 2.10(3H,s, CII-CH3), 2.56(lH,t,J=13.5), 3.80-3.99(4H,m). MS m/z: 264(M+), 221,179,99, 55,43. 3.9 (5p)-4a,10p-dimethyl.7a-(l'-hydroxy ethyl)-tricyclo[4.4.0MO.o7.9]. decane 25. {(6R).lp,5a-dimethyI-8a-(l'-hydroxy ethyl)-tricyclo[°]-decane 75) 74 25 To a solution of ketone 24 (5.2 g, 25 mmol) in methanol (70 ml) was added sodium borohydride (0.58 g, 15 mmol) at 0°C. The reaction mixture was stirred at 0°C for 20 minutes, then the methanol was evaporated. Ether was added to the residue and the solution was washed with water and brine. The solvent was removed under reduced pressure and the residue was purified by chromatography on a silica gel column (ether-pet/ether as eluant, 1:1, v/v) to afford alcohol 25 (4.8 g, 93%) as a colorless oil. The physical properties of 25 are as follows: IR v max. (neat): 3325(0-H, st), 3050, 2900(C-H, st), 1100(C-O, st) cm"1 1H-NMR (300 MHz, CDCI3) 8: 0.24(lH,dd,J=9,4.8, C8-H), 0.56(lH,dd,J=6,4.8, C8-H), 0.82(3H,d,J=6.6, C4-CH 3 ) , 0.98(3H,s, CIO-CH3), 1.21(3H,d,J=6.6, CII-CH3), 0.88-1.67(llH,m), 1.72(lH,t,J=11.4), 3.42(lH,q,J=6.6, C l l - H ) . 5 8 MS m/z: 208(M+), 190(M+-H2O), 175,164, 149, 135, 123, 95, 81, 67, 55, 43. High resolution mass measurement for C 1 4 H 2 4 O : 208.1827; found: 208.1829. Elemental analysis: calculated for C14H24O: C 80.71, H 11.61; found: C 80.50, H 11.54. 3.10 (5{5)-8-chloromethyl-4a,9f3-diinethyl-7a-isopropylidene-bicyclo[4.3.0 5» 9]-nonane 2SL {(6P)-9-chloromethyl-lC,5a-dimethyl-8a-isopropylidene-bicyclo[4.3.0]-nonane 76) 11 26 R=CH 3 25. 22 R=H Compound H (6.08 g, 27.4 mmol) was dissolved in dichloromethane (150 ml) and added to ice cold concentrated hydrochloric acid (150 ml). The mixture was stirred rapidly at 0°C for two hours. The mixture was poured into water (200 ml), and the aqueous layer was extracted with dichloromethane (3x70 ml). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution (2x70 ml), dried over sodium sulfate, and the solvent was evaporated. The yellow oil was carried over to next step without purification. The physical characteristics of 26 are as follows: IR v max- (neat): 2905,2850 (C-H St.), 1654 (C=C St.), 718 (C-Cl st) cm"1. *H-NMR (400 MHz, CDCI3) 6: 0.87(3H,d, J=7, C4-CH 3 ) , 1.14(3H,s, C9-CH 3 ) , 1.65(3H,s, C11-CH 3 ) , 1.73(3H,s, C11-CH 3 ), 0.89-1.59(7H,m), 1.90(lH,m), 2.11(2H,d,br,J=10, C6-H), 2.50(lH,m,br, C8-H), 3.45(lH,dd,J=ll,4, C10-H), 3.61(lH,dd,J=ll,8, C10-H). 5 9 MS m/z: 242/240(M+), 227/225, 204, 197, 189, 147, 133, 119, 105, 95, 91, 83, 79, 61, 55,41. High resolution mass measurement: calculated for Ci5H2535Cl: 240.1656; found: 240.1650. Compound 22 was prepared from 25 as described for 26- The crude oil product was carried over to next step without purification. 3.11 (5P)-4a,10P-dimethyl-7-isopropylidene-bicycIo[4.4.05»10]-decane IS {(6P)-lB,5a-dimethyl-8-isopropylidene-bicyclo[4.4.0]-decane 78) H R 2& R=CH3 22 R=H TBTH <AIBN toluene i H 26 R=CH3 22 R=H To a solution of crude 26 from 3.10 in dry toluene (250 ml) under argon was added tri-n-butyltin hydride (11.9 g, 41.1 mmol). AIBN (300 mg, 1.9 mmol) was then added and the reaction mixture was heated at reflux under argon for two hours. A further portion of AIBN (300mg) was added and the reaction maintained at gentle reflux for an additional 6 hours. The solvent was evaporated and the residue chromatographed on silica gel with hexanes to give 28. (3.16 g, 56% calculated from 22) as a colorless oil. The physical properties of 2S are as follows: IR v max. (neat): 2920 (C-H St.), 1660 (C=C st) cm"1. 6 0 1H-NMR (400 MHz, CDCI3) 8: 0.88(3H,d,J=6.6, C4-CH 3 ) , 0.94(3H,s, CIO-CH3), l.ll-1.62(10H,m), 1.65(3H,s, CII-CH3), 1.66(3H,s, C11-CH 3), 1.83-1.98(2H,m), 2.41 (2H,m). MS m/z: 206(M+), 191,163,109, 95, 81, 67,55,41. High resolution mass measurement: calculated for C15H26: 206.2034; found: 206.2037. Elemental analysis: calculated for C15H26: C 87.30, H 12.70; found: C 87.05, H 12.60. Compound 22 was prepared from 22 as described for 2&. The total yield from 25. to 22 was 53%. The physical characteristics of 22 are as follows: IR v max. (neat): 2950, 2930, 2859 (C-H st.), 1660 (C=C St.), 829 (C-H bend) cm-1. Partial iH-NMR (1:1 Cll-isomers) (300 MHz, CDCI3) 8: 0.83,0.87(3H,two sets,d,J=6, C4-CH3), 0.95(3H, two sets.s, CIO-CH3), 1.56(3H,two sets,d,J=4.2, C l l -CH3), 5.13(lH,two sets,m,Cll-H). MS m/z: 192(M+), 177, 163, 109, 95, 81, 67, 55,41. High resolution mass measurement for C14H24: 192.1878; found: 192.1870. 3.12 (Sp)-4a,10!3-dimethyl-octahydro-7-(6H)-naphthaIenone 8J& {(8ap)-4ap,8a-dimethyl-octahydro-2-(lH)-naphthalenone Ml H R 28 R=CH3 H 22 R=H Ozone was bubbled through a solution of 28 (2.30 g, 11.2 mmol) in ethyl acetate (70 ml) at -60°C. After 20 minutes, the system was flushed with argon until no blue color in the 61 solution, and dimethyl sulfide (1.12 ml, 15.2 mmol) was added. The solution was then allowed to warm up slowly to 0°C in one hour, then stirred at ice bath temperature for one hour, finally at room temperature for one hour.The solvent was removed and residue was purified by flash chromatography (ether/pet ether, 2:8, v/v) to give decalone £Q_ (1.83 g, 91%) as a colorless oil. 79 provided 80 in the same way to give a yield of 90%. The physical properties of JH are as follows: [ a ] D 8 = + 1 2 . 9 ° (0.940, methanol). IR v max. (neat): 2900, 2845 (C-H St.), 1705 (C=0 st.) cm-l. 1H-NMR (300 MHz, CDC1 3) 5: 0.80(3H,dJ=7, C4-CH 3 ) , 1.05(3H,s, CIO-CH3), 1.06-2.03(10H,m), 2.12-2.56(4H,m). MS m/z: 180(M+), 123, 109,95, 81, 69, 55,41. High resolution mass measurement for C12H20O: 180.1514; found 180.1514. Elemental analysis: calculated for C12H20O: C 79.94, H 11.18; found: C 80.00, H 11.30. 3.13 9-cyano-4,10p-dimethyl-7-isopropyI-l,8,9,10-tetrahydro-3-(2H)-naphthalenone 59 {5-cyano-l,4aP-dimethyl-7-isopropyl-4,4a,5,6-tetrahydro-2-(3H)-naphthalenone 59) Bromo-dienone 5_122 (1.00 g, 3.4 mmol) was added to a stirred mixture of potassium cyanide (0.241 g, 3.7 mmol) in dimethyl sulfoxide (10 ml) at 110°C. The mixture was heated at 110-120°C for 17 hours. The reaction mixture was cooled, diluted with water (400 ml), and 6 2 extracted with ether (3x100 ml). The ether extract was washed with 6N hydrochloric acid and water, and dried over sodium sulfate. After removal of the solvent, the residue was purified by silica gel chromatography to give yellow crystals(0.478 g, 59%). The physical properties of 52 are as follows: mp: 94.5-95.50C U V Xmax. (CH3OH): 295 nm. IR vmax. (CHCI3): 2955, 2930(C-H st), 2240(C=N st), 1655(C=0 st), 1620,1590(C=C st.) cm- 1. *H-NMR (300 MHz, CDCI3) 8: 1.14(3H,d,J=6.6, CII-CH3), 1.17(3H,dJ=6.6, C l l -CH3), 1.18(3H,s, CIO-CH3), 1.75(lH,m), 1.90(3H,s, C4-CH 3 ) , 2.37-2.69(6H,m), 2.79(lH,dd,J=6,l, C9-H), 6.44(lH,s, C6-H). 1 3 C - N M R (75MHz, CDCI3) 8: 10.434, 20.684, 21.145, 21.294, 27.191, 33.432, 35.747, 35.827, 38.350, 118.901, 120.229, 129.919, 129.978, 149.480, 150.247, 197.586. MS m/z: 243(M+), 228, 215, 200, 188, 172, 91, 77,43. 3.14 9-cyano-4,10(3-dimethyl-7-isopropenyl-l,8,9,10-tetrahydro-3-(2H)-naphthalenone 60 {5-cyano-l,4aP-dimethyl-7-isopropenyl-4,4a,5,6-tetrahydro-2-(3H)-naphthalenone 60) 1) To a solution of cyano-dienone 52 (0.516 g, 2.12 mmol) in T H F and water (50 ml, 1:1 v/v) was added N-bromosuccinimide (2 g, 11.3 mmol) and the mixture was stirred for 22 hours. The reaction mixture was diluted with water (100 ml) and extracted with ether (2x100 CN C N 6 3 ml). The organic layer was washed with water, dried over sodium sulfate and the solvent was removed. 2) To this residue in dry toluene (20 ml) was added 2^-dimethyl-l,3-propanediol (1.3 g, 12.5 mmol) and p-toluenesulfonic acid (5 mg) and the reaction was heated at reflux under argon for 30 minutes. It was then cooled, diluted with water (50 ml) and extracted with ether (3x50 ml). The combined organic extracts were washed with water (2x50 ml), dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (ether/pet ether, 4:6, v/v) to give a colorless oil (0.326 g, 64%). The physical characteristics of 6j} are as follows: U V W . (CH 3OH): 313 nm. IR Vmax . (neat): 2925(C-H St.), 2245(ON St.), 1650(C=O st), 1665, 1620, 1595(C=C 1H-NMR (300MHz, CDCI3) 8: 1.22(3H,s, C10-CH 3), 1.80(2H,m), 1.96(3H,s, C4-CH3), 2.05(3H,s, CII-CH3), 2.40-2.70(4H,m), 2.63(lH,dd,J=6,l, C9-H), 5.23(lH,s, C13-H), 5.28(lH,s, C13-H), 6.73(lH,s, C6-H). MS m/z: 241(M+), 226, 213,198,115, 56,43. 3.15 4,10j3-dimethyl-3-hydroxy-7-isopropenyl-l,2,3,8,9,10-hexahydro-naphthalene 54 {l,4aP-dimethyl-2-hydroxy-7-isopropenyl-2,3,4,4a,5,6-hexahydro-naphthalene 54) To a mixture of 53_23 (0.216 g, 1 mmol) in methanol (5 ml) and a methanol solution of cerium chloride heptahydrate (0.4 M , 2.5 ml) was added sodium borohydride (0.038 g, 1 mmol) over 1 minute and the reaction stirred for 10 minutes. Water (50 ml) was added to the st.) cm - 1 . 6 4 mixture, and the mixture was extracted with ether (3x30 ml). The organic extracts were washed with water (30 ml) and dried over sodium sulfate. Evaporation of the solvent and purification of the residue on a silica gel column (ether/pet ether, 5:5, v/v) gave alcohol 54 (0.169 g, 81%) as a colorless oil. The physical properties of 54 are as follows: IR Vmax. (neat): 3320(O-H st), 2905(C-H st), 1649,1610,1585(C=C st) cm-l. !H-NMR (400 MHz, CDC1 3) 6: 1.02(3H,s, CIO-CH3), 1.35-1.58(5H,m), 1.72-1.82(2H,m), 1.86(3H,s, C4 -CH 3 ) , 1.99(3H,s, CII-CH3), 2.05-2.13(2H,m), 4.15(lH,t,J=8, C3-H), 4.96(lH,s, C13-H), 5.15(lH,s, C13-H), 6.74(lH,s, C6-H). MS m/z: 218(M+), 203, 185, 177, 157,143, 129,115, 105, 91, 84,77, 55, 51.. 3.16 7-acetyl-4,10p-dimethyl-3-hydroxy-l,2,3,8,9,10-hexahydro-naphthalene 55 {7-acetyl-l,4aJj-dimethyI-2-hydroxy-2,3,4,4a,5,6-hexahydro-naphthalene 551 To a suspension of osmium tetraoxide (6.6 mg, 0.026 mmol) and sodium periodate (0.397 g, 1.85 mmol) in ether and water (3.2 ml, 1:1 v/v) was added 54 (0.188 g, 0.86 mmol) and the mixture was stirred vigorously for 75 hours at ambient temperature. The reaction mixture was filtered through a celite pad and the precipitate was washed thoroughly with ether. The combined ether layers were washed with excess 10% sodium sulfide solution, the aqueous layer containing a black precipitate was filtered and the filtrate was extracted with ether. The combined ether layers were washed with brine, dried over magnesium sulfate and 65 concentrated. The residue was purified on a silica gel column (ether/pet ether, 4:6, v/v) to give a colorless oil (0.133 g, 70%). The physical properties of 55 are as follows: U V Amax. (CH 3OH): 293 nm. 1H-NMR (300 MHz, CDCI3) 8: 0.99(3H,s, C10-CH3), 1.22-1.55(5H,m), 1.75-1.88(2H,m), 1.95(3H,s, C4-CH3), 2.11(2H,m), 2.38(3H,s, CII-CH3), 2.50(2H,m), 4.18(lH,br, C3-H), 7.17(lH,s, C6-H). MS m/z: 220(M+), 205,177,91,43. 3.17 4a,10(j-dimethyI-cis-perhydro-7-oxonaphthaIene-8-carboxaIdehyde {5a,8a|3-dimethyl-cis-perhydro-3-oxonaphthalene-2-carboxaldehyde S I ) H The formylation of £Q was performed by suspending potassium hydride (1.33 g, 33.3 mmol) in dry THF (120 ml). To this suspension was added a mixture of 8J) (6.00 g, 33.3 mmol) and ethyl formate (5.00 g, 66.6 mmol) in dry T H F (10 ml) over 5 niinutes. After stirring at room temperature for 20 minutes, the solvent was evaporated and ether (100 ml) was added to the residue. The ethereal solution was extracted twice with 4N potassium hydroxide (50 ml). The combined alkaline solution was acidified with concentrated hydrochloric acid and extracted with ether. The ethereal solution was washed with brine and dried. Evaporation of ether gave &I (6.17 g, 89%) as a light yellow liquid. The physical properties of 8J. are as follows: [a]g=0.575, (1.980, methanol). IR vmax.(rieat): 3350(br,O-H st), 2920,2850(C-H st), 1650(00 st), 1600(C=C st) cnr*. 1H-NMR (400 MHz, CDCI3) 8: 0.85(3H,d,J=6.4, C4 -CH 3 ) , 1.09(3H,s, CIO-CH3), 0.88-1.63(8H,m), 2.05(2H,dJ=14.8, C9-H), 2.28(2H,dd,J=8,4, C6-H), 8.56(lH,s, olefin-H), 14.29(lH,br,s, 0-H). MS m/z: 208(M+), 190,178,110,95. High resolution mass measurement: calculated for C13H20O2: 208.1463; found: 208.1462. 3.18 4a,10P-dimethyl-l,2,3,4,5P,6,7,10-octahydro-7-oxonaphthaIene-8-carboaldehyde 22 {5a,8aP-dimethyI-3,4,4aP,5,6,7,8,8a-octahydro-3-oxonaphthalene-2-carboaIdehyde 82, I H fil 82 To an ice cooled solution of benzene selenenyl chloride (5.68 g, 29.7 mmol) in dichloromethane (300 ml) were added pyridine (2.58 g, 32.6 mmol) and 81 (6.17 g, 29.7 mmol) in dichloromethane (25 ml). The reaction mixture was stirred for 1 hour and washed with 4N hydrochloric acid (25 ml) and brine (25 ml). The dichloromethane solution was cooled to 0°C, 30% hydrogen peroxide (4.5 ml) was added in three portions with intervals of 20 minutes, and the reaction was stirred at 0°C for another 30 rninutes. the solvent was then evaporated and the residue was purified by column chromatography on silica gel using pet ether/ether (4:1 v/v) as eluant to give J52 (5.26 g, 86%) as a colorless oil. The physical properties of 82 are as follow. [a;£ 0 =96.16°, (1.016, methanol). U V Xmax =238, (3.836). IR Vmax. (neat): 2920, 2856(C-H St.), 1680(C=O st), 1617(C=C st) cm-1. 1H-NMR (400 MHz, CDC1 3) 8: 0.91(3H,d,J=6.8, C4-CH 3 ) , 1.21(3H,s, CIO-CH3), 1.07-2.05(8H,m), 2.42(2H,m, C6-H), 7.45(lH,s, C9-H), 10.09(lH,s, aldehyde-H). MS m/z: 206(M+), 191,178,110, 95. High resolution mass measurement: calculated for C13H18O2: 206.1307; found: 206.1303. Elemental analysis: calculated for Ci 3 Hi802: C 75.67, H 8.79; found: C 75.55, H 8.94. 3.19 4a,10|3-dimethyl-8-(hydroxymethylene)-cis-perhydro-7-oxonaphthalene-9-carbonitriIe SI. {5a,8aJ3-dimethyl-2-(hydroxymethyIene)-cis-perhydro-3-oxonaphthalene-l-carbonitrile g3J CN H £ 2 £ 2 To a solution of £2 (3.00 g, 14.6 mmol) in dioxane (43 ml) and water (4.3 ml) was added a solution of potassium cyanide (0.9-19 g, 14.6 mmol) in dioxane (4.3 ml) and water (1 ml). The reaction mixture was stirred at room temperature for 30 minutes, and then the dioxane was evaporated. The residue was treated with 4N potassium hydroxide (20 ml) and extracted with ether. The basic solution was acidified with concentrated hydrochloric acid (5 ml) and washed with ether. The ethereal solution was washed with brine and dried. The ether was evaporated to give crude 83 (2.41 g,71%) as a yellow oil. The physical characteristics of £ 2 are as follows: IR v m ax. (neat): 3621(0-H St.), 3019, 2964, 2933(C-H St.), 2236(ON St.), 1220(C-O st.) cm-1. 6 8 1H - N M R (400MHz, C D C I 3 ) 6 : 0.91(3H,d,J=5.2, C4-CH 3 ) , 1.15(3H,s, C I O -CH3) , 1.22-2.00(8H,m), 2.53(lH,d,J=20, C6-H), 2.56(lH,dd,J=20,4.6, C6 - H ) . 4.01(lH,s, C 9 -H), 8.98(lH,s, olefin-H), 15.04(lH,s, O-H). MS m/z: 233(M+), 215,206,178, 110, 95, 81,77, 67,53,41. High resolution mass measurement: calculated for C14H19NO2:233.1415; found: 233.1415. 3.20 8-[(butylthio)methylene]-4a,8aP-dimethyl-cis-perhydro-7-oxonaphthaIene-9-carbonitrile 84. {2-[(butylthio)methyIene]-5a,10P-dimethyl-cis-perhydro-3-oxonaphthalene-l-carbonitrile £4} A solution of £3. (2.41 g, 10.4 mmol), 1-butanethiol (1.0 ml) and p-toluenesulfonic acid (14 mg) in dry benzene (60 ml) was refluxed for 3 hours in a Dean-Stark apparatus. After cooling, the reaction mixture was washed with saturated sodium bicarbonate solution (10 ml), water (10 ml) and brine (10 ml) and dried. The benzene was evaporated and the residue was purified by column chromatography on silica gel using ether/pet. ether (3:7 v/v) as eluant to give compound £ 4 (2.77 g, 88%) as white crystals. The physical properties of £ 4 are as follows: mp=85-86°C. IR Vmax. (CHC13): 2990, 2950, 2933, 2852(C-H st), 2220(ON St.), 1660(C=O St.), 1545(C=C st.) cm- 1. iH-NMR (400 MHz, C D C I 3 ) 8: 0.85(3H,d,J=6.4, C4-CH 3 ) , 0.95(3H,t,J=8), 1.38(3H,s, C I O -CH3 ) , 1.02-2.25(12H,m), 2.32(lH,dd,J=20,10, C6 - H ) , 6 9 2.43(lH,dd,J=20,8, C6-H), 2.94(2H,t,J=8.4,S-CH2), 3.37(lH,s, C9-H), 7.89(lH,s, olefin-H). MS m/z: 305(M+), 248,217,109, 89, 67,55,44. High resolution mass measurement: calculated for CigH27NOS: 305.1805; found: 305.1809. Elemental analysis: calculated for C18H27NOS: C 70.77, H 8.91, N 4.59, S 10.50; found: C 70.63, H 8.72, N 4.41, S 10.39. 3.21 4a,10p-dimethyl-8-formyl-l,2,3,4,5p,6,9,10-octahydro-naphthalene-9-carbonitrile fi5_. {5a,8ap-dimethyI-2-formyl-l,4,4ap,5,6,7,8,8a-octahydro-naphthalene-l-carbonitrile S5J To a solution of 84 (1.623 g, 5.3 mmol) in methanol (15 ml) was added sodium borohydride (62 mg, 1.6 mmol) at 0°C. The reaction mixture was stirred for 15 minutes, and then the methanol was evaporated Ether was added to the residue, and the solution was washed with water and brine. The ether was evaporated and the residue was dissolved in methanol (25 ml). Mercuric chloride (2.44 g, 9.0 mmol) and 4N hydrochloric acid (7.5 ml) were added to this solution. The reaction mixture was stirred at room temperature for 16 hours and then filtered. The methanol was evaporated, and ether (100 ml) was added. The ethereal solution was washed with saturated sodium bicarbonate solution with brine and dried. The ether was evaporated and the residue was purified by column chromatography on silica gel using ether/pet. ether (3:7 v/v). as eluant to give 8_5_ (0.712 g, 84%) as white crystals. The physical properties of 8_5_ are as follows: H 84 7 0 mp=103-104.5°C. [a]D5=149.8, (0.990, methanol). U V X m a x =224, (4.129). IR vmax. (CHC13): 2915, 2850(C-H st), 2220(C=N st), 1683(C=0 st), 1659(C=C st), 1H - N M R (400 MHz, C D C I 3 ) 8: 0.91(3H,d,J=5.2, C4-CH 3 ) , 1.36(3H,s, C10-CH 3 ), 1.05-2.13(8H,m), 2.31(lH,ddd,J=20.4,9.2,3.5, C6-H), 2.45(lH,ddd,J=20.4,7.6,4, C6-H), 3.30(lH,s, C 9 - H ) , 7.05(lH,dd,J=4,3.5, C7-H), 9.51(lH,s, aldehyde-H). MS m/z: 217(M+), 200,190,146,110,105,95, 81,77, 55,41. High resolution mass measurement for C14H19NO: 217.1471; found: 217.1469. 3.22 4a,10J3-dimethyl-8-(l,3-dioxoIan-2.yl)-l,2,3,4,5J3,6,9,10-octahydro-naphthalene-9-carbonitrile fi£ 4a,10p-dimethyI-8-(l ,3-dioxolan.2-yl)- l ,2,3,4,5p,8,9,10-octahydro-naphthaIene-9-carbonitrile 87 {5a,8ap-dimethyI-2-(l,3-dioxoIan-2-yl)-l,4,4ap,5,6,7,8,8a-octahydro-naphthalene-l-carbonitrile 86 5oc,8ap-dimethyl-2-(l ,3-dioxolan-2-yl)-l ,2,4aP,5,6,7,8,8a-octahydro-naphthalene-l-carbonitrile S2J = H = H = H £ 5 81 A solution of 8J. (712 mg, 3.3 mmol), ethylene glycol (0.83 ml), and p-toluenesulfonic acid (5 mg) in benzene (9 ml) was refluxed for 3 hours in a Dean-Stark apparatus. The reaction mixture was cooled, ether (50 ml) was added, and the solution was washed with saturated sodium bicarbonate solution and dried. The solvent was evaporated and the residue was purified by column chromatography on silica gel using ether/pet. ether (3:7 v/v) as eluant to give £ £ (615 mg, 71%) and fil (156 mg, 18%). The physical properties of £6 are as follows: [a]J,5=109.6o, (0.920, methanol). IR Vmax. (neat): 2950, 2900(C-H st), 2220(ON st), 1680(C=C st) cm- 1. iH-NMR (400 MHz, CDCI3) 8: 0.79(3H,dJ=7, C4-CH 3 ) , 1.24(3H,s, CIO-CH3), 0.85-2.14(10H,m), 2.79(lH,s, C9-H), 3.85-4.04(4H,m), 5.19(lH,s, C8-CH), 6.05(lH,dd,J=4,3.5, C7-H). MS m/z: 261 (M+), 246, 221,138,110, 95, 86,73, 55, 41. High resolution mass measurement for C16H23NO2:261.1729; found: 261.1724. Elemental analysis: calculated for C16H23NO2: C 73.53, H 8.87, N 5.36; found: C 73.31, H 8.98, N 5.36. iH-NMR of fil (400 MHz, CDCI3) 8: 0.84(3H,dJ=7, C4-CH 3 ) , 1.30(3H,s, C10-C H 3 ) , 1.19-2.32(9H,m), 2.85(lH,d,J=4.4, C9-H), 3.83-4.05(4H,m), 5.14(lH,d,J=6, C8-H), 5.53(lH,dd,J=10,2, olefin-H), 6.02(lH,dd,J=10,2, olefm-H). 3.23 4a,10!3-dimethyl-8-(l,3-dioxolan-2-yl)-l,2,3,4,5p,6,9,10-octahydro-naphthalene-9-carboxaldehyde 88. {5a,8ap-dimethyl-2-(l,3-dioxolan-2-yI)-l,4,4ap,5,6,7,8,8a-octahydro-naphthalene-l-carboxaldehyde gfi} CN CHO £6 ££ A solution of £ 6 (250 mg, 0.96 mmol) in dry toluene (19 ml) was cooled to -60°C under argon, and a solution of dmoburylaluminium hydride (1.0M, hexane solution) (1.80 ml) was 72 added. The reaction mixture was stirred at -60°C for 3 hours and then poured into saturated ammonium chloride solution (15 ml). The layers were separated and the aqueous was extracted 5 times with ether (100 ml). The combined organic solutions were dried, and the solvent was evaporated. The residue was purified by column chromatography on silica gel using ether/pet ether (3:7 v/v) as eluant to give (215 mg, 85%) as a colorless oil. The physical characteristics of £& are as follows: [a]o=311°, (0.820, methanol). IR Vmax. (neat): 2900, 2835(C-H St.), 2690(C-H st. aldehydic), 1705(C=O St.), 1655(C=C st.) cm"1. iH-NMR (400 MHz, CDC1 3) 8: 0.84(3H,d,J=7, C4-CH 3 ) , 1.10(3H,s, CIO-CH3), 0.93-2.25(10H,m), 2.67(lH,d,J=5, C9-H), 3.80-4.10(4H,m), 5.16(lH,s, C8-CH), 6.20(lH,dd,J=4.4,3.6, C7-H), 9.50(lH,d,J=5, aldehyde-H). MS m/z: 264(M+), 249,235,73, 55,45,41. High resolution mass measurement for C16H24O3: 264.1726; found: 264.1723. Elemental analysis: calculated for C 1 6 H 2 4 O 3 : C 72.70, H 9.15; found: C 73.00, H 9.30. Compound £ 2 (188 mg, 0.72 mmol) in toluene (15 ml) was reduced by DIBAH (toluene solution, 1.5M) (1.3 ml) at -78°C in 2 hours by the above procedure to give £9. The crude product was hydrolyzed in the next reaction without further purification. 3.24 4a,10p-dimethyl-l,2,3,4,5p,6,9,10-octahydro-naphthalene-9,8-dicarboxaldehyde 90. {5a,8ap-dimethyI-l,4,4ap,5,6,7,8,8a-octahydro-naphthalene-l,2-dicarboxaldehyde 9JD A solution of £ £ (92 mg, 0.35 mmol) and p-toluenesulfonic acid (8 mg) in acetone (7 ml) and water (1.7 ml) was stirred for 2 hours at room temperature. The acetone was evaporated, and water/ether were added. The aqueous was extracted with ether, and the combined ethereal solution was washed with saturated sodium bicarbonate solution, with water, and brine and then dried. The ether was evaporated and the residue was chromatographed on silica gel using ether/pet. ether (3:7 v/v) as eluant to give 9_Q (71 mg, 93%) as a colorless oil. The physical properties of 2Q are as follows: [a ] D 6 =393° , (0.700, methanol). U V W . = 2 2 9 , (4.026). IR VmaxXneat): 2920,2860(C-H St.), 2820, 2715(C-H st. aldehydic), 1718(C=0 St.), 1665(C=0 conjugated st,), 1300(C-H bend aldehydic) cm"1. *H-NMR (300 MHz, CDCI3) 8: 0.86(3H,d,J=7. C4-CH 3 ) , 1.26(3H,s, CIO-CH3), 1.05-2.50(10H,m), 3.33(lH,d,J=3, C9-H), 7.09(lH,dd,J=4.3,3.8, C7-H), 9.44(lH,s, C8-aldehyde-H), 9.79(lH,d,J=3, C9-aldehyde-H). MS m/z: 220(M+), 202, 192,177,121, 109, 95, 91, 81,77, 67,55, 41. High resolution mass measurement for C14H20O2:220.1461; found: 220.1462. Elemental analysis: calculated for C14H20O2: C 76.33, H 9.15; found: C 76.38, H 9.20. Crude product of 82 from last step in acetone (15 ml), water (3.6 ml) and IN hydrochloric acid (2 ml) was refluxed for 6 hours to give 9_Q (121 mg, 77% from 87). 74 REFERENCES 1. K. Munakata, Pure. Appl. Chem. 42, 57 (1975). 2. T. A. van Beek and A. de Groot, Terpenoid antifeedants (part I). An overview of terpenoid antifeedants of natural origin. Reel. Trav. Chim. Pays-Bas 105.513 (1986). 3. C. S. Barnes and J. W. Loder, Aust. J. 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