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Studies in di- and sesterterpendoid synthesis Romero Martínez Del Sobral, Miguel Angel 1990

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STUDIES IN DI- AND SESTERTERPENOID SYNTHESIS by MIGUEL ANGEL ROMERO MARTINEZ DEL SOBRAL B.Sc, National University of M6xico, 1984 M.Sc, National University of Mexico, 1986 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 August 1990 © Miguel Angel Romero Martinez del Sobral 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 of CMBM/^J^ Y The University of British Columbia Vancouver, Canada Date 2$ ~/WC-OST^ /<J<tO DE-6 (2/88) ABSTRACT Stereoselective 9-step conversions of the ketone 17 into the tricyclic ketone 31 via two similar synthetic pathways are described. The highly stereoselective steps involved in the preparation of 31 were: a) the Lewis acid-catalyzed reaction of the silyl enol ethers SO and 60 with the ethylene ketal of 3-buten-2-one to produce the diketones 37 and 39, respectively, b) the hydrogenation of the enone 32 to give the ketone 56, and c) the Birch reduction of the enone 61 to give 31. Compound 31 contains the correct relative configuration at each of the corresponding chiral centers present in the target molecule 16 and, therefore, appears to be an ideal intermediate for a projected total synthesis of (±)-16 (initially believed to be the sesterterpenoid suvanine). A 15-step total synthesis of the antimicrobial diterpene (±)-8-isocyano-10(14)-amphlilectadiene (23) from the intermediate 24 is described. The key steps in the synthesis of (±)-23 involved the stereoselective Birch reduction of 24, the epimerization of the aldehyde 91 to the corresponding a-formyl isomer, and the degradation of the carboxylic acid function of 95 to an isonitrile group. The last part of the synthetic work described in this thesis resulted in a 15-step conversion of the ketone 17 into the tricyclic ketone 164. Of particular note in this sequence of reactions are: a) the palladium(0)-catalyzed coupling reaction of the enol triflate 143 with lithium cyanide to produce the nitrile 144, b) the stereoselective alkylation of 144 to give compound 148, and c) the stereoselective Birch reduction of the enone 163 to produce 164. The methodology employed in the construction of the tricyclic intermediate 164 contributes to the development of a general route towards the synthesis of the spongiane diterpenes 18-22. ii 0SiMe3 0SiMe3 NH 2 HN-^NMe, OHC MOMO OTBDMS 143 R= OTf 144 R=CN 148 OTBDMS HO 20 R=H 21 R= Ac 22 iii TABLE OF CONTENTS Page ABSTRACT ii TABLE OF CONTENTS iv LIST OF TABLES viii LIST OF FIGURES ix LIST OF ABBREVIATIONS x ACKNOWLEDGEMENTS xiii INTRODUCTION 1 1 5 5 7 8 iv I. General. n . Objectives. Ua. Synthesis of suvanine. lib. Synthesis of spongiadiols. He. Synthesis of (±)-8-isocyano-10,14-amphilectadiene. DISCUSSION i n . Regarding an approach to the total synthesis of "(±)-suvanine" (16). HJa. Isolation and structural elucidation of suvanine. IUb. Retrosynthetic analysis. IJIc. Methylenecyclohexane annulation leading to 17. IUd. Synthesis of the ketone 36. Preparation of the alcohols 44-47. Die. Alkylation of the ketone 36. Preparation of the ketones 48 and 49. inf. Preparation of the silyl enol ether 50. Synthesis of the diketone 37. Dig. Preparation of the enone 32. Synthesis of the ketone 56 and determination of its relative configuration. DIh. Preparation of the ketone 31. IDi. Synthesis of the ketone 31 via the "gem-dimethyl route." Preparation of the ketone 38. IHj. Alkylation of the ketone 38. Preparation of the ketones 58 and 59. DDc. Preparation of the silyl enol ether 60. Preparation of the diketone 39. DD. Preparation of the enone 61. Synthesis of me ketone 31 and determination of its relative configuration. Dim. Conclusions. IV. Total synthesis of (±)-8-isocyano-10,14-amphilectadiene (23). IVa. Compounds structurally related to the parent hydrocarbon amphilectane 25. IVb. Isolation and structural elucidation of 8-isocyano-10,14-arnphilectadiene (23). 46 IVc. Retrosynthetic analysis. 48 IVd. Preparation of the keto ester 24. 49 IVe. Initial attempt to synthesize the keto ester 76. 50 IVf. Synthesis of the keto ester 76. Alternative synthetic plan. 54 IVg. Preparation of the compounds 88 and 89. 55 IVh. Preparation of the compounds 90,91 and 92. 57 IVi. Preparation of the compounds 76 and 93. 59 IVj. Preparation of the compounds 75 and 94. 61 IVk. Preparation of the carboxylic acid 95. 64 IVI. Model studies for the degradation of the carboxyl group of 95 to the isonitrile function of 23. Preparation of the compounds 96,99,104, and 105. 65 rVm. Synthesis of (±)-8-isocyano-10,14-amphilectadiene (23). Preparation of the carbamate 111. 70 IVn. Conclusion. 77 V. Development of a general synthetic approach to the spongiadiols, a group of natural products belonging to the "spongian" family of diterpenoids. 78 Va. Previous syntheses of furanoditerpenoids possessing the "spongian" carbon skeleton. 78 Vb. Retrosynthetic analysis. 80 Vc. Initial attempt to establish a synthetic sequence. Preparation of the ketals 137-139. 84 Vd. Preparation of the ketals 140-142. 87 vi Ve. Preparation of the enol triflate 143 and its Pd(0)-catalyzed coupling with lithium cyanide. Preparation of the a,f3-unsaturated nitrile 144. 90 Vf. Preparation of the nitrile 148. 92 Vg. Reduction of the nitrile 148. Preparation of compounds 149 and 150. 94 Vh. Preparation of the keto alcohol 151 and the ketone 152. 95 Vi. Preparation of the ketones 153 and 154. 97 Vj. Preparation of the compounds 155,156, and 157. 99 Vk. Preparation of compound 163. 103 VI. Preparation of the ketone 164. 103 Vm. Conclusion. 107 EXPERIMENTAL 109-178 VI. General. 109 VU. Solvents and reagents. Ill REFERENCES 179 vii LIST OF TABLES *H nmr spectral data for natural (-)-8-isocyano-10,14-amphilectadiene ((-)-23) and synthetic (±)-8-isocyano-10,14-amphilectadiene ((±)-23). 1 3 C nmr spectral data for natural (-)-8-isocyano-10,14-amphilectadiene ((-)-23) and synthetic (±)-8-isocyano-10,14-amphilectadiene ((±)-23). viii LIST OF FIGURES Figure Page 1 The *H nmr spectrum (400 MHz) of compound 56. 32 2 The *H nmr spectrum (400 MHz) of compound 31. 33 3 The XH nmr spectrum (300 MHz) of natural 8-isocyano-10,14-amphilectadiene. 75 4 The J H nmr spectrum (400 MHz) of synthetic (±)-8-isccyano-1044-amphilectadiene. 75 5 The ! H nmr spectrum (400 MHz) of compound 148. 93 6 The *H nmr spectrum (400 MHz) of compound 164. 105 ix LIST OF ABBREVIATIONS Ac acetyl aq aqueous Bn benzyl br broad Bu butyl cat catalytic COSY correlated spectroscopy m-CPBA meta-chloroperoxvbenzoic acid A heat d doublet DIBAL diisobutylaluminum hydride DMAP 4-N,N-dimemylammopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide equiv equivalent(s) Et ethyl g gram(s) gem geminal glc gas-liquid chromatography h hour(s) HMPA hexamethylphosphoramide X Hz - hertz ir - infrared K - ketal function LD A - lithium diisopropylamide m - multiplet M - molar Me - methyl mg - milligram(s) MHz - megahertz min - minute(s) mmol - millimole(s) mp - melting point mol - mole(s) MOM - methoxymethyl Ms - methanesulfonyl nmr - nuclear magnetic resonance nOe - nuclear Overhauser enhancement PCC - pyridinium chlorochromate Ph - phenyl Pr - propyl Pyr - pyridine q - quartet rt - room temperature s - singlet sec - secondary t - triplet xi ten - tertiary TBDMS - tert-buWldimethvlsUvl TfO - trifluoromethanesulfonate Tf2NPh - N-phenyltrifuorometh THF - tetrahydrofuran tic - thin layer chromatography TMS - trimethylsilyl p-TsO - para-toluenesulfonate Ts - para-toluenefulfonyl v - volume w - weight w1 / 2 - peak width at half height It - reflux xii ACKNOWLEDGEMENTS I am deeply grateful to my research supervisor, Professor Edward Piers, for his guidance and patience, as well as for the outstanding example I believe he sets as an educator and as a scientist. It has indeed been a privilege and a pleasure to work with him as a member of his research group. Special thanks are also due to my parents and to Adri, Alex, Betty-Anne, Francisco K.B., Francisco L.T., Fraser, Fung, Giri, Jacques, Johanne, John, Keith, Miguel G., Montse, Philip, Pierre, Renata, Renato, Richard, Romano, Tim, Veljko (1 d4...), Veranja, and Wendy. The efficient recording of the spectral data by the staff of the nuclear magnetic resonance, mass spectrometry, and elemental analyses laboratories is gratefully acknowledged. Thanks are also extended to Richard Tillyer for his time spent on my behalf at the nmr spectrometer. Furthermore, Professor Raymond Andersen, Dr. Veranja Karunaratne, Betty-Anne Story, and Dr. Romano Andrade are thanked for proofreading this thesis. Financial asistance from the University of British Columbia in the form of a University Graduate Fellowship and from the Killam Foundation for a Predoctoral Fellowship is also acknowledged. xiii INTRODUCTION I. General Marine organisms are the source of a large number of diverse organic compounds. During the last decade scientists have become increasingly aware of the importance of marine natural products. This awareness has given rise to multidisciplinary efforts to discover and study marine natural products with interesting structural and biological properties. Microorganisms, algae, fish, sponges, molluscs, and coelenterates are some examples of marine organisms that have been studied as sources of natural products.1 Marine natural products are of importance to humankind because they play a significant role in maintaining an equilibrium in marine ecosystems and they often exhibit interesting pharmacological properties. For this reason, chemical ecology and pharmacological studies using marine natural products have been increasing rapidly in nature and extent.1 However, many aspects of these natural compounds, such as their biological function and potential applications, are yet to be discovered. From a synthetic organic chemist's point of view, the unusual, synthetically challenging, and aesthetically pleasing structures that natural products of marine origin exhibit, offer an incentive to attempt their synthesis. More importantly, perhaps, the syntheses of natural products often allow the confirmation of original structural assignments, prove the efficiency of new synthetic methods, or test the viability of a -1-synthetic plan. Furthermore, the synthesis of natural products provides an opportunity to discover reactions which can be relevant to chemical theory or useful in the development of new synthetic methods. Unfortunately, the amount of material isolated from natural sources is sometimes limited and, thus, amounts sufficient for extensive biological tests are not available. Chemical synthesis has the potential to provide the necessary amounts of the natural products, or their analogues, for this purpose. Some of the most interesting marine natural products that have been isolated so far are produced by sponges. It is believed that some of these substances act as chemical defence agents against predators, thus facilitating the survival of these fragile and physically unprotected organisms.10 Among the many types of organic substances that have been isolated from sponges are alkaloids, acetylenic compounds, fatty acids, halogenated compounds, macrolides, polyethers, and terpenoids. In the brief discussion given below, the structural diversity of some natural products isolated from sponges will be illustrated. At least one synthesis has been reported for each of the examples mentioned. (+)-Okadaic acid (1), one of the most complex polyether metabolites isolated from marine sources is the causative toxin of diarrhetic shellfish poisoning in Europe.2 -2-Compound 1 was isolated from the sponge Halichondria okadai and from the dinoflagellate Procentrum lima. However, the latter is believed to be the progenitor of okadaic acid.3 A total synthesis of this structurally interesting compound by Isobe and coworkers has been reported in a series of papers.4a_e Kcrotoxinin (2), a known toxin isolated from terrestrial organisms, was isolated from the sponge Spirastrella inconstans.5 Corey and Pearce6a and Niwa et al.6b have synthesized this compound. The antimicrobial sesterterpenoid palauolide (3), which inhibits the growth of Bacillus subtilis and Staphylococcus aureus, has been isolated from at least three different species of sponges collected from Palau, Western Caroline Islands.7 Piers and Wai8 carried out a synthesis of (±)-3 via a 17-step sequence of reactions, starting from 3,6-dimethyl-2-cyclohexen-l-one. Two syntheses of (+)-euryfuran (4),9 a compound isolated from the sponges Euryspongia10 and Dysidea herbacea,11 led to the assignment of its absolute configuration. -3-Isoagatholactone (6) and compounds 7-10, which are metabolites of Spongia officinalis,12 all bear the 'spongian' carbon skeleton 5. Compounds 613a~c and S-IO13^ 14 were synthesized by three research groups. 10 R!=CH2OAc, R2=H The largest group of naturally occurring isocyanides are produced by marine organisms. More than twenty such derivatives are currently known.15 The isocyanides are often found as members of triads with the corresponding isothiocyanates and formamides. The structurally unusual compounds (+)-axamide-l (11), (+)-axisonitrile-l (12), and (+)-axisothiocyanate-l (13) were isolated from the sponge Axinella cannabina.16 A total synthesis of (±)-ll, (±)-12 and their corresponding C 1 0 epimers was carried out by Piers et al.17 (+)-7,20-Diisocyanoadociane (14) was isolated from a sponge of the species Amphimedon1* and was synthesized by Corey and Magriotis,19 thus allowing the assignment of its absolute configuration. (-)-8,15-Diisocyano-ll(20)-amphilectene (15) -4-is a structurally related diisocyano derivative isolated from the sponge Hymeniacidon amphilecta.20 A 20-step stereocontrolled synthesis of (±)-15 was recendy completed by Piers and Llinas-Brunet.21 n . Objectives LXa. Synthesis of suvanine NMe2 16 Suvanine is a tricyclic sesterterpenoid isolated from sponges collected at Suva Harbor, Fiji Island, and Palau. Although it was initially thought that the sponges from which suvanine was isolated belonged to the genus Ircinia,22* a reexamination indicated that they belong to the genus Coscinoderma.22*3 Primarily on the basis of an analysis of the spectral data, suvanine was initially assigned the structure 16.22a Suvanine is toxic to goldfish at 10 ng/mL,22a for this reason, it has been suggested that this substance plays a chemical defensive role for the sponges from which it is isolated. The initially proposed structure of suvanine (16) is particularly interesting because it contains an uncommon arrangement of functional groups (a guanidinium bisulfate and a furan ring), and because it presents novel and synthetically challenging stereochemical features (a cis-svn-trans fused ABC ring system, five contiguous chiral centers, and an axially oriented side chain bound to C1 4). The structurally and pharmacologically interesting features of suvanine made it an attractive and challenging target for synthesis. This motivated us to attempt a stereocontrolled total synthesis of (±)-16. The cis AB ring junction of 16 was a structural characteristic that suggested the use of compound 17 as a starting material. O 17 The ketone 17, a useful and versatile synthetic intermediate, had been prepared previously in our laboratory via an efficient annulation reaction sequence.23 -6-Ub. Synthesis of spongiadiols Many diterpenes with the 'spongian' carbon skeleton 5 have been isolated from various sponges and nudibranchs. Spongiadiol (18), spongiadiol diacetate (19), epispongiadiol (20), epispongiadiol diacetate (21) and isospongiadiol (22) are furanoditerpenoids in which carbon atoms 2, 3 and 19 are oxygenated. This oxygenation pattern is different from that of the majority of the other members of the spongian family of diterpenoids.24 The diterpenoids 18-2225a~d are produced by sponges of the genus Spongia which have been collected from places like Chub Cay, Bahamas25*1 and the Great Barrier Reef, Australia.258 The spongiadiols exhibit antiviral and cytotoxic properties.250''1 For example, an extract from a Caribbean sponge, Spongia sp., containing compounds 18,20 and 22, exhibited activity against Herpes simplex virus, type 1 (HSV-1), and P388 murine leukemia cells.25d -7-The pharmacological properties of the spongiadiols, as well as their structurally interesting functional group distribution, led us to attempt the development of a general synthetic approach to (some of) these substances. In this work, as in the case of the planned synthesis of (±)-16, we envisaged that the ketone 17 would be a suitable starting material. lie. Synthesis of (±)-8-isocyano-10,14-amphilectadiene 19 23 24 25 The diterpene 8-isocyano-10,14-amphilectadiene (23), a compound that inhibits the growth of the microorganisms Staphylococcus aureus and Bacillus subtilis, was isolated from the Palauan sponge Halichondria sp.26 The isonitrile 23 contains the same 'amphilectane' carbon skeleton 25 as 8,15-diisocyano-ll(20)-amphilectene (15), a natural product referred to previously (see p.5). The fact that 23 exhibits a synthetically challenging structure (it presents an array of seven contiguous chiral centers), and is also an antimicrobial substance, made it a tempting objective for a total synthesis. Since a total synthesis of (±)-15 had been completed in our laboratory 2 1 it was envisaged that (±)-23 could be synthesized from the enone 24, a precursor used in the synthesis of the diisocyanide (±)-15. -8-Thus, the objectives of the work described in this thesis were as follows: 1) to develop a general approach to the synthesis of the series of 'spongian' diterpenes (±)-18-22; 2) to synthesize the diterpene isonitrile (±)-23; and 3) to synthesize the sesterterpene (±)-16. It should be noted at the outset, however, that the last objective was not achieved. While we were at an advanced stage of our synthesis of (±)-16, a publication appeared2215 which showed that the initial structural assignment for suvanine was incorrect. Further details will be given in the forthcoming discussion. -9-DISCUSSION m. Regarding an approach to the total synthesis of "(±)-suvanine" (16) ITJa. Isolation and structural elucidation of suvanine N M e 2 16 In 1983, Crews and coworkers228 isolated a new sesterterpene from the dichloromethane extract of a previously undescribed sponge collected in Suva Harbor, Fiji Island. At that time the sponge was believed to belong to the genus Ircinia, but later it was shown to belong to the genus Coscinoderma.22** This new compound, named -10-suvanine, is thought to be a defensive substance for the sponge, as suggested by its toxicity to goldfish (10 u.g/mL). The amorphous solid (mp 218°C) isolated from the sponge extract exhibited [a]D +9.5° and ir (KBr) 3400, 3240, 1640 cm-1. The presence of a guanidine group was suggested by the following data: uv 210 nm (€ 10 500, 0.01 N NaOH in absolute EtOH) and 200 nm (€ 13 000 in MeOH) (the uv of guanidine hydrochloride is 212 nm (e 790, aqueous EtOH), the € increases to >10 000 when the guanidine group is conjugated to a C=0 or C^). 2 2 * Elemental analysis established the formula ( ^ ^ 4 5 ^ 0 ^ 8 0 4 for suvanine. The authors were not able to corroborate this formula by mass spectrometry since the highest m/z cluster appeared at 371 and 370 (by chemical ionization field desorption mass spectrometry). The high resolution mass spectrum exhibited peaks at 371.2920 and 370.2843, corresponding to formulae of C25H39O2 (calcd. 371.2952) and C25H 3 80 2 (calcd. 370.2873). The authors explained the conflicting mass spectral evidence by stating that "A possible rationalization could be OH - displacement of the guanidinium ion subunit under thermal or electron impact conditions."228 The 1 3 C nmr spectral evidence showed that only one oxygen (furan ring) could be located (8 142.9 d, 138.8 d, 124.9 s and 111.0 d). Surprisingly, the remaining nmr spectral evidence (*H nmr, 1 3 C nmr, and *H homonuclear correlation spectroscopy (COSY) nmr spectrum) for suvanine seemed to be in accord with the structure 16, which was initially assigned to the natural product. The nmr data (!H nmr, *H nOe difference spectra, and a ! H- 1 3 C heteronuclear COSY nmr spectrum) for the ozonolysis degradation product of suvanine also seemed to be consistent with its proposed structure 26. In 1988, Crews and coworkers221' reported that 27 is the correct structure of suvanine. The authors realized that the previously reported structure (16) was incorrect when the pyridinium salt of suvanine was fortuitously isolated after treating suvanine with acetic anhydride in pyridine. This experiment, according to the authors, indicated -11-0S03 26 27 that "...suvanine might be a dimethyl guanidinium salt of an enol sulfate rather than the sulfate salt of a dimethyl guanidinium enamine."22b It also became evident that the structure 16 was incorrect when additional 1 H- 1 3 C COSY nmr data were interpreted. The apparently contradictory mass spectral results published in the earlier paper22*1 were 27a 27b m/z 370 Scheme 1 now explained by ascribing the m/z 370 fragment 27b to a fragmentation of 27a in which cleavage of an O-S bond takes place (Scheme 1). A reinterpretation of the nmr spectral data published initially, plus additional two-dimensional nmr data ^H-^C COSY nmr spectrum), indicated that suvanine possesses an AS trans, BC cis ring stereochemistry. The stereochemical assignments were confirmed by an X-ray analysis -12-of a degradation product derived from ozonolysis of (±)-suvanine, followed by lithium aluminum hydride reduction of the resultant keto ester 28. It is interesting to note that the ozonolysis product which was used to prepare the X-ray sample was the keto ester 28, a compound that was not mentioned in the initial publication.22* When the work described in this thesis was initiated, the correct structure of suvanine (27) had not yet been published and, therefore, we began with an attempt to synthesize (±)-16. However, when the correct structure of suvanine (27) was reported,22b we decided to conclude this phase of our work. This decision was taken because the proposed synthetic plan for (±)-16 was not applicable to the synthesis of (±)-27. Furthermore, the structural characteristics of 27 are not as novel as those of compound 16, since many natural products exist which have an AB trans ring junction and a related carbon skeleton.2780 Consequently, it was decided not to pursue the synthesis of (±)-27. This section of the thesis will describe the work done on the synthesis of (±)-16 to the stage reached when the correct structure of suvanine (27) was published. O 28 A-13-nib. Retrosynthetic analysis Scheme 2 A crucial problem that must be addressed in any plan to synthesize (±)-16 is the stereoselective introduction of the correct relative configuration at each of the five contiguous chiral centers. Our retrosynthetic analysis (Scheme 2) was based on the proposal that compound 16 could be prepared from the keto ester 29, a compound that would be generated by the disconnection ( A ) of the target molecule, along with the appropriate functional group interconversions. Examination of molecular models suggested that a suitable nucleophile (synthetically equivalent to the synthon28a 30) would add to the B carbon of the enone function in 29 from the (sterically less hindered) p (top) face of the molecule. It was envisaged that compound 29 could readily be synthesized from the ketone 31. Compound 31 could, in turn, be prepared from the enone 32 via a sequence of reactions involving dissolving metal reduction of its enone function and hydrogenolysis of the cyclopropane ring. It was expected29a,f that the -14-dissolving metal reduction step would lead to the more stable system in which rings B and C are trans-fused. Structure 32 suggested the use of a Robinson annulation transform280 (disconnection (B)), which would lead to the ketone 33. Finally, it seemed likely that 33 could be prepared by cyclopropanation and alkylation of the ketone 17, the starting material for the synthesis. It was expected that the key synthetic reaction (i.e., the alkylation of the enolate anion prepared from 33) in the sequence 33 -* 32 would occur in a stereoselective manner. In relation to this point, it has been suggested that stereoelectronic control is not as important as steric hindrance (when the latter is present) in determining the direction of attack of electrophiles on ketone enolate anions.290 It is also believed that the transition state geometries (six membered rings) in enolate alkylations are reactant-like, thus resembling more closely the geometry of the planar enolate anion.29e Thus, a molecular model of the more stable conformer of the enolate (R= counterion) or enol (R= H) 34 shows quite clearly that attack of electrophiles should occur preferentially from the (sterically less hindered) P (convex) face via the conformer 34b (Scheme 3). On the other hand, conformer 34a (which seems to be less stable than 34b due to a severe steric interaction between a C-ll methylene hydrogen and the C-7 pseudoaxial hydrogen) would present steric hindrance to incoming electrophiles from both the a and the (5 face of the enol(ate). Thus, it was predicted that reaction of 34 with electrophiles should occur via a transition state that might be represented by 34c (Scheme 3). Examination of molecular models seems to indicate that the effect of the OR 34 -15-34c 35c Scheme 3 cyclopropane ring on the relative stabilities of the two chair-like conformers 34a and 34b would be different from that of the corresponding gem-dimethyl moiety in conformers 35a and 35b (Scheme 3). The position of the equilibrium 35a^35b was not easy to predict. However, in this case it also seemed likely that the transition state geometry for the alkylation would be analogous to 34c (i.e., 35c), since both faces of the enolate double bond in 35a are sterically hindered. To what degree these conformational effects would affect the stereoselectivities of the reactions to be used in constructing ring C was not easy to predict. Thus, an investigation of this point was pursued to determine the comparative efficiencies of the two alternative synthetic routes A and B shown in Scheme 4. -16-o Scheme 4 HJc. Methvlenecyclohexane annulation leading to 17 Scheme 5 -17-In 1984, a new methylenecyclohexane annulation sequence based on the concept of "bifunctional conjunctive reagents"30 was developed in our laboratory. This sequence proved to be useful, for example, in the preparation of the bicyclic ketone 1723 (Scheme 5), which contains adequate functional and stereochemical features that would enable its eventual transformation to (±)-16, the initially proposed structure for suvanine. The Grignard reagent 40 is a bifunctional reagent prepared by transmetallation23 of 5-chloro-2-(trimethylstannyl)-l-pentene31 with methyllithium in THF at -78°C, followed by addition of anhydrous magnesium bromide-etherate.32 The reagent 40 underwent conjugate addition to the enone 4133 under the conditions shown in Scheme 5, to provide 42/43, a mixture of epimers. Cyclization of the mixture (crude or purified) by treatment with potassium hydride in THF provided exclusively the desired cis-fused annulated product 17, in yields ranging from 78 to 90 %. Hid. Synthesis of the ketone 36. Preparation of the alcohols 44-47. 98% Sodium borohydride reduction of the ketone 17 (methanol, -20°C, 1.6 h) afforded a 9:1 (glc analysis) mixture of the epimeric alcohols 44 and 45, in 98 % yield (equation 1). A pure sample of each of the isomeric alcohols 44and 45 was obtained by column -18-chromatography of the mixture on silica gel. The ir spectrum of 44 (the major isomer) exhibited absorptions at 3385, 3067, 1646 and 1082 cm"1 indicating the presence of an alcohol function and an exocyclic methylene group. The 1 H nmr spectrum of 44 exhibited multiplets at 8 4.69-4.66 and 4.66-4.63 due to the olefinic protons and a doublet of doublets at 8 3.32 (J= 13,5 Hz) due to the (axial) proton on C-9 (suvanine numbering system). The relative stereochemistry of 44 was determined by correlation (ir, EIMS, and *H nmr spectrum) - with a sample obtained by hydrolysis of its corresponding MOM-ether derivative. The relative stereochemistry and conformation of this derivative was determined by F. Fleming34 in our laboratories. The alcohol 45 exhibited ir absorptions at 3389, 3067, 1646 and 1050 cm"1, confirming the presence of hydroxyl and exocyclic methylene functions. The  lH nmr spectrum of 45 showed two singlets at 8 4.68 and 4.66 due to the olefinic protons and a broad singlet at 8 3.50 (w1/2=12 Hz, this signal changed to w1/2=10 Hz upon addition of D20) due to the (equatorial35) proton on C-9. These data indicate that 44 and 45 exist primarily in the conformations 44a and 45a, respectively. The mixture of alcohols 44 and 45 was subjected to a cyclopropanation reaction using diethylzinc/methylene iodide36*-0- (equation 2). The reagent used is a convenient alternative to the widely used Simmons-Smith reagent (zinc-copper couple/methylene iodide).36e Thus, reaction of the mixture of alcohols 44/45 with the Et2Zn/CH2l2 reagent -19-in a refluxing 5:1 mixture of toluene and methylene chloride gave a chromatographically separable 9:1 mixture of the epimeric alcohols 46 and 47, respectively. The ir spectrum OH OH OH Et2Zn,CH2I2. toluene/CH2ci2, (2) 46 9:1 47 44/45 80% of 46 exhibited absorptions at 3382 and 1050 cm-1 due to the alcohol function. The *H nmr spectrum of 46 showed a multiplet at 5 3.27, which, upon addition of D 20, was transformed to a doublet of doublets (J= 11,5 Hz). This signal was assigned to the (axial) proton on C-9. The signals due to H3e and H 5 (see the conformational formula 46a) appeared at 5 0.57 (dm, J=12Hz) and 0.47-0.32 (m), respectively. The assignment of these resonances to H 5 and H3e was suggested by their 'abnormal' chemical shifts. The high field chemical shifts exhibited by these protons and by the corresponding protons in most of the cyclopropanated derivatives described in this thesis, suggest that they are being diamagnetically shifted due to the shielding effect of the adjacent cyclopropane ring.37a ,b In this particular case, for example, ring A in compound 46 has a 46a 47a -20-conformation (46a) such that the two equatorial hydrogen atoms H3e and H 5 fall within the shielding zone of the cyclopropyl ring. The particular assignment of the signals for H3e and H 5 in compound 46 was confirmed by the following *H nmr decoupling experiments: irradiation of the broad dd at 5 1.90 (J=12,12 Hz) due to H3a caused the collapse of the signal at 0.57 (dm, J=12Hz) (due to H3e) to a broad singlet; irradiation of the signal at 5 0.57 caused the collapse of the signal at 1.90 due to H3a to a broad doublet (J=12 Hz) and simplified (a w-coupling38 was lost) the multiplet at 0.47-0.32 due to H 5 . The *H nmr spectrum of 47 exhibited a broad singlet at 8 3.35 (w1/2=8 Hz, sharpened upon addition of D20) due to the (equatorial) C-9 proton. Since 47 was epimeric with 46 (at C-9) the conformation of 47 was thus established as 47a. When the cyclopropanation reaction was attempted on the ketone 17, the results were not satisfactory. Side products were formed and a considerable amount of starting material was recovered even when an excess of reagents was employed. However, when the reaction was carried out on the mixture of alcohols 44 and 45, the process was clean and efficient. The fact that a carbonyl group can interfere with the success of the modified Simmons-Smith cyclopropanation has precedent.39 Oxidation of the 9:1 mixture of alcohols 46 and 47 with pyridinium chlorochromate (PCC)40 in dichloromethane (equation 3) gave, in high yield, the ketone 36 as a colorless oil. Compound 36 exhibited, in its ir spectrum, a strong absorption at 1703 cm"1 due to the carbonyl stretching vibration. The *H nmr spectrum of 36 -21-displayed a ddd (J=13,13,6 Hz) at 5 2.58 due to the axial proton at C-8, a dd (J=13,4 Hz) at 8 0.77 due to H 5 and a broad doublet at 8 0.65 (J=13 Hz) due to H3e. Die. Alkylation of the ketone 36. Preparation of the ketones 48 and 49. 48/49 Monoalkylation of the ketone 36 by deprotonation with lithium diisopropylamide (LDA) and addition of methyl iodide gave a mixture of the ketones 48 and 49 in high yield (equation 4). A small amount of this mixture of ketones was epimerized with sodium methoxide in methanol, cleanly affording the ketone 48 (equation 5). The *H nmr spectrum of 48 exhibited a signal at 8 2.68 (ddq, J=13,6,6 Hz) due to the axial proton on C-8 (H8a) (see the conformational formula 48a). The angular and the secondary methyl protons appeared at 8 1.29 and 8 1.00 as a singlet and a doublet (J=6 Hz), respectively. The signals due to H 5 (dd, J=13,4 Hz) and H3e (br d, J=13.5 Hz) appeared at 8 0.75 and 0.66, respectively, suggesting the conformation shown in 48a. In -22-48a order to confirm the proposals regarding the preferred conformation and relative configuration of 48a, the following series of nOe difference experiments were done: irradiation of the signal at 8 0.47-0.41 QHA) caused enhancement of the signals at 1.29 (s, angular methyl protons), 0.66 (br d, J=13.5 Hz, H3e), 0.40-0.32 (m, HB) and 0.21-0.08 (m, He); irradiation of the multiplet at 5 0.40-0.32 (HB) caused enhancement of the signals at 1.29 (s, angular methyl protons), 0.75 (dd, H5), 0.47-0.41 (m, HA) and 8 0.14-0.08 (m, HD). The results of these experiments are summarized by the arrows on the formula 48a. inf. Preparation of the silvl enol ether 50. Synthesis of the diketone 37. Having prepared the ketones 48 and 49, some modifications of the Robinson annulation reaction41a,b were tried for the next stage of the synthesis. The Robinson annulation reaction is a useful procedure for the addition of a six-membered ring to a -23-ketone that has an enolizable hydrogen. The overall process may be illustrated in general terms by the conversion of 51 into 54 (equation 6). Thus, a substrate ketone 52 R' R' R' 51 52 53 54 R,R'=H, alkyl is treated with an enone 51 in the presence of a base. The resultant Michael addition product, the 1,5-diketone 53, undergoes an intramolecular aldol condensation and subsequent dehydration to give the product 54. However, due to side reactions such as polymerization, the use of an enone 51 as the Michael acceptor in the reaction with a specific enolate anion under aprotic conditions is not always successful. Therefore, it is often necessary to use modified reagents and/or a different type of reaction (e.g., an alkylation reaction or a Lewis-acid catalyzed reaction). In order to carry out the desired annulation reaction on the mixture of ketones 48/49, some of the procedures found in the literature were tried (equations 7 to 10). In attempts to alkylate the lithium enolate prepared from the mixture of ketones 48/49 with the ethylene ketal of 4-iodo-2-butanone42 (in the presence of HMPA), only unidentified products and recovered starting material were obtained (equation 7). When the alkylating agent used was l,3-dichloro-2-butene (mixture of isomers, the 'Wichterle reagent') , 4 1 a , b , d a low yield of the (inseparable and slightly impure) mixture of the a-(3-chloro-2-butenyl) ketones 55 was obtained (equation 8). The conditions required to hydrolyze this mixture of vinylic chlorides to the corresponding methyl ketones are quite harsh,41d and resulted in extensive decomposition of the substrate. An acid-catalyzed -24-1) LDA, THF, -78°C -78°C—• 0°C X (7) 1) LDA, THF, -78°C 48/49 > CI -78°C—» rt AcOH, Hg(OAc>2. BF 3 OEt2, rt > or CF3CO2H Hg(OAc)2, rt o , H 2 S 0 4 ( c a t ) , v y 48/49 > " X ( 9) toluene, \ ' N k 1) LDA, THF,-78°C > recovered starting material (10) 2) . -78°C —• 0°C Robinson annulation43 was also attempted (equation 9). However, this procedure led to the formation of intractable material. In a related approach to the construction of ring C, an attempt to alkylate the lithium enolate of the ketone 36 with 4-iodo-l-butene was made, but also proved to be unsuccessful (equation 10). In 1985, Huffman et al. 4 1 f published an efficient variation of the Robinson annulation which, in the initial step, consisted of the Lewis acid catalyzed reaction of silyl enol ethers with vinyl ketones or the ethylene ketal of 3-buten-2-one (a -25-Mukaiyama-type reaction). The reactions are carried out at low temperatures (-80°C to -100°C) in dichloromethane and the Lewis acids used are TiCl4 or mixtures of TiCl 4 and Ti(0-i-Pr)4. These reactions usually afford mixtures of the 1,5-diketone and the corresponding monoketal. Treatment of the crude reaction rnixture with aqueous acid gives the diketone. O OSiMe3 LJ 1) LDA.THF. -78°C-^0°C ^ f ^ T ^ - ^ 2) HMPA, TMSC1,0°C, 1 h (ID 91% H 48/49 50 In order to use this Lewis acid catalyzed method, the TMS enol ether 50 was prepared using a modification of a known literature procedure.44 Thus, HMPA and TMS-C1 were added to a cold (0°C) THF solution of the lithium enolate prepared from the mixture of the ketones 48 and 49. After workup and column chromatography of the crude product, high yields of the TMS enol ether 50 were consistently obtained (equation 11). Conducting this reaction in the absence of HMPA, or employing other procedures described in the literature,45 gave lower yields of the desired product. The ir spectrum of 50 exhibited absorptions at 1673 and 840 cm-1 due to the double bond and the trimethylsilyl group, respectively. The *H nmr spectrum of 50 showed singlets at 8 1.54 Me3SiOv h 5 2T H3e 50a and 0.20, indicating the presence of the vinylic methyl group and the trimethylsilyl group, respectively. A two-proton multiplet at 8 0.62-0.50 was assigned to the equatorial -26-proton at C-3 (H3e) and the proton on C-5 (H5). Thus, the *H nmr data suggests that the TMS enol ether 50 exists primarily in the conformation shown in 50a. The silyl enol ether 50 and the ethylene ketal of 3-buten-2-one (prepared from 3-buten-2-one according to the procedure published by Hahn)46 were added to a cold (-100°C) mixture of TiCl 4 and Ti(0-i-Pr)4 in dichloromethane. The mixture was stirred at -100°C for 1.75 h. Subsequent treatment of the crude product mixture with a 1:1 solution of 10% aqueous hydrochloric acid and THF, followed by chromatography of the material thus obtained, afforded the 1,5-diketone 37 in moderate yield (48%). Additionally, a 12.5:1 (glc analysis) mixture of the ketones 48 and 49 was obtained in 41% yield (equation 12). Analysis of the desired product 37 by glc, indicated the presence of ~3% of another compound, likely the C-8 epimer of 37. Since it was feasible to recycle the mixture of ketones 48/49, and since the reaction had proceeded with high stereoselectivity, we considered this procedure to be satisfactory for our synthetic work. The relative configuration at C-8 of 37 was not known at this stage of our work. However, *H nmr spectroscopy experiments involving a subsequent synthetic intermediate derived from 37 (see Part IUg of this Discussion Section) showed conclusively that this substance possessed the indicated stereochemistry. The ir spectrum of compound 37 exhibited absorptions at 1716 and 1689 cm"1 due to the two l—I (12) 50 37 48/49 -27-carbonyl groups. The *H nmr spectrum of 37 exhibited a three-proton singlet at 8 2.12 due to the methyl ketone moiety, and two broad doublets at 0.75 (J=12 Hz) and 0.64 H3e 37a (J=14 Hz) which could be assigned to the equatorial proton on C-3 and the proton on C-5 (or vice versa). The presence of the latter two signals indicated that compound 37 exists primarily in the conformation 37a. IUg. Preparation of the enone 32. Synthesis of the ketone 56 and determination  of its relative configuration. 37 32 48 Treatment of the diketone 37 with potassium tert-butoxide/tert-butyl alcohol in refluxing benzene gave, after workup and column chromatography of the crude product, the (uv active) enone 32 in 53% yield (equation 13). The ketone 48, obtained as a side product (38% yield) in this reaction, was formed via a retro-Michael process. The ir spectrum of 32 showed absorptions at 1667 and 1592 cm"1 due to the enone carbonyl -28-group and the conjugated carbon-carbon double bond, respectively. The *H nmr spectrum of 32 exhibited a singlet at 5 6.02, due to the vinyl proton. The broad doublet at 8 0.64 (J=14 Hz) and the doublet of doublets at 8 0.59 (J=13,3.5 Hz) were assigned to the equatorial proton at C-3 and the proton at C-5, respectively. The enone 32 was subjected to a dissolving metal reduction29c,f using potassium in ammonia/diethyl ether in the presence of tert-butvl alcohol. After workup and column K/NH 3 /Et 2 0, t-BuOH, tt.30min, then NH4Cl(aq) N + 32 (14) 42% 37% 32 56 chromatography of the crude product mixture, the ketone 56 was obtained in 42% yield, together with a fair amount (37%) of the starting material 32 (equation 14). It has been well established291 that the alkali metal-ammonia reduction of substances possessing the bicyclo[4.4.0]oct-l-en-3-one moiety usually produces the corresponding trans-fused bicyclo[4.4.0]octan-3-ones. Thus, although the reason(s) underlying the stereoselective nature of this process has been the subject of a number of discussions in the literature,29f"h the stereochemistry of the reduction product 56 (equation 14) could be assigned as shown with a good degree of confidence. The catalytic hydrogenation of 32 (palladium-on-charcoal)29d gave the ketone 56 in high yield (equation 15). It is known that heterogeneous catalytic hydrogenations of enones such as 32 proceed via the cis addition of hydrogen to the (sterically) less hindered side of the double bond.29d Examination of a molecular model of 32 shows that in conformer 32a the a. (bottom) face of the enone moiety is hindered by the pseudo axial -29-o o 9 H 2 ,1 atm, Pd-C, EtOAc, rt 97% (15) 32 56 methyl and methylene groups (heavy bonds in formula 32a). Therefore, it seemed highly likely that the reaction would take place from the sterically more open, P (top) face of the molecule to produce 56. The ir spectrum of 56 showed an absorption at 1713 cm"1 due to the carbonyl group. The J H nmr spectrum of 56 (Figure 1, p.32) exhibited signals for the four protons alpha to the ketone function at 8 2.45 (ddd, 1=14,14,7 Hz), 2.42 (ddd, J=14,3,3 Hz), 2.29 (m), and 2.29 (dd, J=14,14 Hz) (H13a, H n e, H13e, and H u a, respectively; see formula 56a). A doublet of doublets at 8 1.28 (J=14,3 Hz) was ascribed to Uga. A broad doublet (J=13 Hz) at 5 0.60 and a doublet of doublets (J=14,4 Hz) at 0.33 were assigned to the equatorial hydrogen atom on C-3 (H3e) and the hydrogen atom on C-5, respectively. The relative stereochemistry and the conformation of 56 were determined by *H nmr homonuclear spin decoupling and 1 H- 1 H nOe difference experiments. Thus, in decoupling experiments, irradiation of the overlapping signals at 8 2.45 (H13a) and 2.42 P 32a -30-17 H3e 14 56a (Hne) simplified the multiplet at 1.70-1.40 (H14e) and caused the collapse of the signals at 1.39 (H14a) to a broad doublet (J=14 Hz) and 1.28 O a^) to a doublet (J=14 Hz); irradiation of the overlapping signals at 8 2.29 (H13e, Hna) simplified the multiplet at 1.70-1.40 (H14e) and caused the collapse of the signals at 1.39 (H14a) to a dd (J=14,14 Hz) and 1.28 (Hga) to a doublet (J=3 Hz); irradiation of the signal at 8 1.28 (Hpa) caused the collapse of the signals at 2.42 (Hne) to a dd (J=14,3 Hz) and 2.29 (Hna) to a doublet (J=14 Hz). In nOe difference experiments, irradiation of the overlapping signals at 8 1.89 (H6a) and 1.84 (H3a) caused enhancement of the signals at 1.47 (dq, J=14,4 Hz, Hge) and 0.60 (br d, J=13 Hz, H3e); irradiation of the signal at 8 1.28 (I^ a) caused enhancement of the signals at 1.09 (s, C 1 7 methyl protons) and 0.33 (dd, J=14,4 Hz, H5); irradiation of the signal at 8 1.20 (C 1 8 methyl protons) caused enhancement of the signals at 2.45 (ddd, 1=14,14,7 Hz, H13a), 2.29 (dd, J=14,14 Hz, Hna), 1.84 (ddd, 14,14,5 Hz, I^ a) and 1.62 (ddd, 1=14,14,5 Hz, H^); irradiation of the signal at 8 0.33 (H5) caused enhancement of the signals at 1.47 (dq, J=14,4 Hz, H e^), 1.28 (dd, J=14,3 Hz, Hpa) and 1.09 (C1 7 methyl protons). The results of these nOe experiments are represented by the arrows in the conformational formulas shown below. -31-o Figure 2. The *H nmr spectrum (CDC13,400 MHz) of compound 31. JHh. Preparation of the ketone 31. Hydrogenation-hydrogenolysis (Adams' catalyst/glacial acetic acid)47 of the enone 32, followed by oxidation (PCC/dichloromethane) of the resultant product mixture, gave a 42% yield of the ketone 31. Some of the tricyclic hydrocarbon 56b (its configuration at C-9 was not determined) was also produced (equation 16). Better results were obtained when the ketone 56 was subjected to the same sequence of reactions (hydrogenolysis and oxidation, equation 17). In this case, the ketone 31 was obtained as the only product in 93% yield. Compound 31 exhibited an ir absorption at -33-o O 1713 cm-1 due to the carbonyl group. The *H nmr spectrum of 31 (Figure 2, p.33) displayed four (three-proton) singlets at 8 1.17, 1.16, 1.08, and 0.92 due to the presence of four methyl groups. On the other hand, the ! H nmr spectrum of compound 56b exhibited four (three-proton) singlets at 8 1.17,1.08,0.97, and 6.88. The synthetic work described above resulted in the 9-step stereoselective conversion of the ketone 17 into the tricyclic ketone 31 in 14% overall yield. Of particular note in this sequence were: (a) the highly stereoselective Mukaiyama-type reaction of the silyl enol ether 50 with the ethylene ketal of 3-buten-2-one to produce 37 (equation 12) and (b) the highly stereoselective hydrogenation of the enone 32 to give the ketone 56 (equation 15). -34-JUL Synthesis of the ketone 31 via the "gem-dimethyl route." Preparation of the  ketone 38. 46 57 Hydrogenolysis of 46 (Adams' catalyst/glacial acetic acid)47 afforded the alcohol 57 in excellent yield (equation 18). The ir spectrum of this compound exhibited absorptions at 3281 and 1042 cm"1 due to the C-OH function and a doublet at 1386 and 1365 cm"1 due to the gem-dimethyl moiety. The *H nmr spectrum of 57 exhibited a doublet of doublets at 8 3.23 (J=13,4 Hz) due to the (axial) proton on C-9. The methyl groups in compound 57 gave rise to three-proton singlets at 8 1.25, 1.15, and 0.86. Based on the coupling constants associated with the C-9 proton, it was possible to infer that 57 exists primarily in the conformation represented by 57a. 98% 57 38 The alcohol 57 was oxidized with PCC in dry dichloromethane40 to give the ketone 38 in high yield (equation 19). The ir spectrum of this material showed an -35-absorption at 1703 cm-1 due to the carbonyl group. The *H nmr spectrum of 38 exhibited three singlets at 8 1.26, 0.97, and 0.85 due to the methyl groups. A comparison of this data with the reported48 chemical shifts for the angular methyl groups in cis-l-decalones (8 1.20-1.05) tentatively suggested the assignment of the signal at 8 1.26 to the angular methyl group on 38. IUj. Alkylation of the ketone 38. Preparation of the ketones 58 and 59. Monoalkylation of the ketone 38 by deprotonation with lithium diisopropylamide (LDA) and addition of methyl iodide gave a 4.2:1 (glc) mixture of the ketones 58 and 59, respectively, in 81% yield (equation 20). The *H nmr spectrum of this mixture indicated that the ratio of the two products was ~5:1. Equilibration of a sample of this mixture of ketones with sodium methoxide in methanol afforded the two substances, 58 and 59, in ratio of 1:6.2 (glc), respectively (equation 21). Column chromatography of this mixture gave a fraction which contained the ketone 59 exclusively, thus allowing its characterization. The ir spectrum of 59 showed an absorption at 1703 cm'1 due to the carbonyl group. The *H nmr spectrum of 59 exhibited a signal at 8 2.87 (ddq, J=14,7,7 Hz) due to the (axial) proton on C-8. A doublet at 8 0.99 (J=7 Hz) was assigned to the secondary methyl group. In order to determine the configuration and the conformation of 59 a series of decoupling experiments was carried out, with the following results. Irradiation of the signal at 8 2.87 (ddq, J=14,7,7 Hz, H8a) caused the collapse of the signals at 2.04 (br ddd, J=14,7,6 Hz, H7e) to a broad dd (J=14,6 Hz), 1.73 (dddd, 1=14,14,14,6 Hz, H7a) to a ddd (J=14,14,6 Hz) and 0.99 (d, J=7 Hz, secondary methyl protons) to a singlet; -36-58/59 4.2:1 (glc) irradiation of the signal at 8 2.04 (br ddd, J=14,7,6 Hz, Hye) caused the collapse of the signals at 2.87 (ddq, J=14,7,7 Hz, H8a) to a dq (J=14,7 Hz) and 1.73 (dddd, J=14,14,14,6 Hz, H7a) to a ddd (J=14,14,6 Hz), simplified the multiplet at 2.26-2.13 (^a) and sharpened the broad doublet (J=6 Hz) at 1.64 (H5); irradiation of the signal at 8 1.73 (dddd, J=14,14,14,6 Hz, H7a) caused the collapse of the signals at 2.87 (ddq, J=14,7,7 Hz, H8a) to a dq (J=7,7 Hz), 2.04 (br ddd, J=14,7,6, H7e) to an unresolved multiplet, and O 58a 59a 1.86 (br dd, J=14,6 Hz, B^t) to a broad doublet (J=14 Hz), and simplified the multiplet at 2.26-2.13 (H6a); irradiation of the signal at 8 1.86 (br dd, J=14,6 Hz, H^) simplified the -37-signals at 2.26-2.13 (m, Hga) and 1.73 (dddd, J=14,14,14,6 Hz, H7a) and caused the collapse of the signal at 2.04 QJT ddd, J=14,7,6 Hzjiye) to a dd (J=14,7 Hz); irradiation of the multiplet at 8 2.26-2.13 (H6a) simplified the signals at 1.86 (Hge), 1.73 (H7a) and 2.04 (H7e), and caused the collapse of the broad doublet at 1.64 (J=6 Hz, H5) to a broad singlet. These results clearly indicated that H 5 (located via the sequence of irradiations mentioned above) has an equatorial orientation with respect to ring B. This orientation was suggested by the w-coupling between H 5 and H7e and also by the magnitude (6 Hz) of the coupling between H 5 and H$a. Furthermore, the absence of coupling of H 5 to Hge suggested that the dihedral angle between the C-H5 and C-Hge bonds was close to 90°. Thus, the preferred conformation of 59 can be represented as 59a. From the *H nmr spectrum of the 4.2:1 (glc) mixture of ketones 58 and 59, it was possible to observe the presence of a signal for the major compound (58) at 8 2.59 (ddq, J=14,7,7 Hz) due to the axial proton on C-8 (H8a). Since 58 was epimeric at C-8 with compound 59, it was inferred that the more stable conformation of 58 is 58a. Examination of molecular models and a qualitative conformational analysis of 58a and 59a does not lead to a definitive statement as to why, upon equilibration (MeONa/MeOH), 59a predominates over 58a (see equation 22). Thus, the conformational analysis of 58a reveals the following 1,3-steric interactions: one CH3-CH3 diaxial, three CH3-H syn-axial, and three CH2-H syn-axial. The corresponding analysis for 59a shows one CH 3-CH 2 diaxial, four CH3-H syn-axial, and one CH3-Csp2 diaxial interaction. It is interesting to compare the results derived from the equilibration of 58 and 59 with those obtained from treatment of mixtures of 48 and 49 with NaOMe in MeOH. As shown above, 59 (see conformer 59a) is more stable than 58 (see conformer 58a). In contrast, equilibration of 48 and 49 leads to the exclusive formation of the epimer 48. The latter observation can be rationalized as follows. A careful examination of -38-58a NaOMe/MeOH (1:6.2) 59a (22) 1,3-diaxial interaction CH3-CH3 CH 3-CH 2 1,3-syn-axial interaction 3xCH 3 -H 3xCH 2-H 4xCH 3 -H l,3-sp2-axial interaction CH3-Csp2 molecular models of conformers 48a and 49a reveals the presence of a severe steric interaction between a C-ll methylene hydrogen and a C-7 (axial) hydrogen in conformer 49a. On the other hand, the C-12/C-13 1,3-diaxial interaction in conformer 48a NaOMe/MeOH > (>99: <1) O (23) 48a 49a (CH2-CH3, see equation 23) appears to be noticeably less severe than the corresponding interaction in conformer 58a (CH3-CH3, see equation 22). It appears that the contribution of these two effects shifts the position of the equilibrium (23) far to the left. -39-ink. Preparation of the silyl enol ether 60. Preparation of the diketone 39. HMPA and cMorotrimethylsilane were added successively to a cold (0°C) THF solution of the lithium enolate prepared from the mixture (4.2:1, glc) of the ketones 58/59. The silyl enol ether 60 was thus produced in 96% yield (equation 24). The ir spectrum of compound 60 exhibited absorptions at 1680 and 843 cm"1 due to the C-C double bond and the trimethylsilyl group, respectively. The *H nmr spectrum of 60 showed singlets at 8 1.50 and 0.20, indicating the presence of the vinylic methyl group and the trimethylsilyl group, respectively. o o OSiMe3 ncy^opirV 1:1,CH2C12> -100°C, 15 min 2) 10% HCl/THF, l : l , r t , l h 45% 39 (25) 24% 58/59 -40-The silyl enol ether 60 and the ethylene ketal of 3-buten-2-one46 were added to a cold (-100°) mixture of TiCl 4 and Ti(0-i-Pr)4 in dichloromethane and the mixture was stirred at -100°C for 15 min. Subsequent treatment of the crude product mixture with a 1:1 solution of 10% aqueous hydrochloric acid and THF, followed by column chromatography of the resultant material, afforded the 1,5-diketone 39 in 45% yield and a ~1:7 mixture of the ketones 58 and 59 in 24% yield (equation 25). In this case, the desired product 39 was completely homogeneous by glc analysis. The diketone 39 exhibited ir absorptions at 1718 and 1688 cm-1 due to the presence of the two carbonyl groups. The *H nmr spectrum of 39 exhibited one proton signals at 8 2.40 (ddd, J=18,10,6 Hz) and 2.22 (ddd, J=18,9,7 Hz) due to the two diastereotopic protons adjacent to the side-chain carbonyl function. A singlet at 8 2.13 could readily be assigned to the methyl group bonded to the carbonyl group. At this stage of the synthesis, the relative configuration of 39 at C-8 was not known. Elucidation of this point had to wait until the conversion of 39 into the previously prepared tricyclic ketone 31 (vide infra) had been completed. UIl. Preparation of the enone 61. Synthesis of the ketone 31 and determination  of its relative configuration. O 5%KOH/MeOH ft.7.5h 13 (26) 71% 39 61 -41-The diketone 39 underwent internal aldol condensation-dehydration in the presence of a 5% solution of potassium hydroxide in methanol (reflux, 7.5 h). After workup and column chromatography of the crude product, the (uv active) enone 61 was obtained in 71% yield (equation 26). Under these conditions, no retro-Michael products were obtained (compare with equation 13). The ir spectrum of 61 showed absorptions due to the a,p-unsaturated carbonyl group and the enone C-C double bond at 1666 and 1587 cm-1, respectively. The *H nmr spectrum of 61 exhibited a singlet at 8 6.08 due to the vinylic proton and two signals at 2.59 (ddd, J=18,15,6 Hz) and 2.37 (ddd, J=l8,6,2 Hz) due to the axial and equatorial protons on C-13, respectively. The enone 61 was subjected to a dissolving metal reduction using potassium in ammonia/diethyl ether in the presence of tert-butyl alcohol.290^ The reaction mixture was refluxed for 1 h. After workup and column chromatography of the product mixture, the ketone 31 was obtained in 62% yield, together with a fair amount (34%) of the recovered starting material 61 (equation 27). The ketone 31, obtained in this way, was physically and spectroscopically indistinguishable from the same compound obtained, as described previously, from 32 and 56 (see equations 16 and 17). Thus, the relative configurations of the diketone 39 and the enone 61 were unambiguously established. -42-Dim. Conclusions The synthetic work described in Sections Hld-IIIh (pp. 18-34) resulted in a stereoselective 9-step conversion of the ketone 17 into the tricyclic ketone 31 (14% overall yield), while that discussed in Sections JHi-im (pp.35-42) performed the same overall conversion 17—*31 (also in 9 steps) in ~10% yield. Thus, there was no significant difference in the overall efficiency of the synthetic pathways A and B (see Scheme 4, p. 17) leading to 31. Compound 31 contains, with the correct relative configurations, four of the five contiguous chiral centers present in the target molecule 16. With respect to sequence B, the stereoselective Mukaiyama reaction leading to 39 (equation 25, p.40) and the highly stereoselective Birch reduction of the enone 61 (equation 27, p.42) are especially noteworthy. Interestingly, the stereochemical outcome of the Mukaiyama reaction was very similar to that of the corresponding reaction (equation 12, p.27) in sequence A. In a different context, it should be mentioned that the reaction conditions that led to the efficient production of the enone 61 (equation 26, p.41) were to have been tried for the conversion of 37 into the enone 32 (see equation 13, p.28). Also, the hydrogenation conditions (as applied to the enone 32; see equation 15, p.30) were to have been tested on the enone 61. However, at this stage of the syntheic work the correct structure of suvanine (27) was reported.220 Consequently, for the reasons explained earlier (see section Hla), we concluded this part of our work. -43-IV. Total synthesis of (±)-8-isocyano-10,14-amphiIectadiene (23) IVa. Compounds structurally related to the parent hydrocarbon amphilectane 25 62 Ri=R2=R3= H 63 Rj= Ac, R2=R3= H 64 R2= Ac, R 1 =R 3= H 65 R3= Ac, Rj=R2= H 66 R= CH=CMe2 69 R 1 = NC, R2= NHCHO 67 R= CH2C(Me)=CH2 15 R 1 =R 2= NC 68 R= CH2C(-NC)Me2 NCI 23 25 The compounds 15 (see p.5), 62-69, and the isonitrile 8-isocyano-10,14-amphilectadiene (23) which was the objective of our synthetic effort, are diterpenoids isolated from marine sources that bear the amphilectane carbon skeleton of the parent hydrocarbon 25. Thus, it is pertinent to discuss briefly some aspects of the work related -44-to the isolation and structural elucidation of compounds 15 and 62-69, as well as to the total synthesis of 62 (vide infra). The pseudopterosins A-D 4 9 (62-65) have been isolated from the Caribbean sea whip Pseudopterogorgia elisabethae and show antiinflammatory and analgesic activities. The structure of pseudopterosin C (64) was determined by X-ray crystallography. The identification of the pentose portion of 64 as 3-0-acetyl-(3-xylopyranose allowed the assignment of its absolute configuration. On the other hand, the structures of pseudopterosins A, B, and D (62, 63, and 65) were established on the basis of spectral analyses.49 Scheme 6 A total synthesis of (-)-pseudopterosin A (62) has been carried out by Broka et ah50 (see Scheme 6). Thus, a 19-step sequence starting from (S)-(-)-limonene led to the epoxide 70. Subjection of 70 to an intramolecular Friedel-Crafts alkylation, followed by benzylation of the phenolic hydroxyl group, gave 71, which possesses the tricyclic part of the basic arnphilectane skeleton. The alcohol 71 was transformed (in 8 steps) to the -45-intermediate 72. Finally, glycosidation of 72 was followed by deacetylation and cleavage of the benzyl unit with lithium in ammonia to give the desired natural product 62. The isonitriles 66-68 were isolated from an Adocia sp. sponge by Kazlauskas et al.51 The structure of 66 was determined by X-ray diffraction analysis, whereas the structures of 67 and 68 were proposed on the basis of a comparison of their spectra with those of compound 66. The diterpenoid isonitriles 69 and 15 were isolated from the Caribbean sponge Hymeniacidon amphilecta by Faulkner and coworkers.20 A single crystal X-ray diffraction analysis allowed the structural determination of the diisocyanide 15, a compound which exhibited antibiotic activity against Staphylococcus aureus. Bacillus subtilis and Candida albicans. A total synthesis of (±)-15 has been completed by Piers and Llinas-Brunet21 The synthesis of compound 24 (see pp.8,9), a key intermediate in their synthesis of (±)-15, is discussed in section IVd of this thesis since it is directiy related to our total synthesis of (±)-23. IVb. Isolation and structural elucidation of 8-isocvano-10,14-amphilectadiene (23) In 1987, Faulkner and coworkers26 reported the isolation of three new diterpene isonitriles from the hexane extract of the Palauan sponge Halichondria sp., namely, 7-isocyano-l-cycloamphilectene (73), 7-isocyano-ll-cycloamphilectene (74), and (-)-8-isocyano-10,14-amphilectadiene (23). Compound 23 bears the parent "amphilectane" skeleton 25, was the minor constituent of the hexane extract (0.066% of dry weight) of the sponge, and decomposed slowly on storage at -20°C. Compound 23 also exhibited antimicrobial activity by inhibiting Staphilococcus aureus and Bacillus -46-H 19 subtilis at 5 ug/disk in the standard disk assay.26 The structures of 73 and 74 were (kterrnined by Faulkner and coworkers26 using a combination of spectral and X-ray analyses, whereas that of 23 was determined primarily on the basis of spectral data. Compound 23 (isolated as an oil) exhibited [a]D -79.8° (c=2.0, CHC13) and an ir (CHC13) absorption at 2130 cm1. The J H nmr spectrum of 23 exhibited signals at 8 1.66 (d, 3H, J=l Hz), 1.57 (d, 3H, J=l Hz), and 5.15 (br d, 1H, J=7 Hz) due to the isobutenyl group. The signal at 8 5.15 was coupled to a signal at 8 2.24 (m, 1H, J=12,12,7,4 Hz), which was assigned to the axial proton on C-l. The two doublets at 8 0.88 (d, 3H, J=3.6 Hz) and 1.02 (d, 3H, J=6 Hz) were assigned to the secondary methyl groups. The 1 3 C nmr spectrum of 23 showed signals at 8 154.5 (br s) and 63.3 far s), due to the tertiary isonitrile function and signals at 8 137.6 (s), 133.4 (d), 126.6 (s), and 118.8 (d) due to two carbon-carbon double bonds. Furthermore, *H COSY and decoupling experiments allowed the establishment of the relative stereochemistry at C-l, C-12, and C-13. On the other hand, since the (C-3)-(C-8) stereochemistry is identical in all other amphilectenes, Faulkner and coworkers26 assigned the relative stereochemistry of 23 as 15*,3S*,4i?*,75*,8i?*,125*,135*. -47-IVc. Retrosynthetic analysis 23 75 76 24 The strategy for the construction of 8-isocyano-10,14-amphilectadiene (23) was based on the recognition that the keto ester 24 (previously prepared in our laboratories)21 would serve as a suitable starting material. Thus, a comparison of structures 23 and 24 shows that it was necessary to degrade the ester function of 24 to an isonitrile and to elaborate the protected alcohol moiety into an isobutenyl group. In addition, the correct relative stereochemistry for three contiguous chiral centers (at C-l, C-12 and C-13) had to be established. The transformation of the ester function to an isonitrile was left for the last steps of the synthesis, since it is known that 23 decomposes slowly at -20°C 2 6 and that the isonitrile function could give rise to side-reactions during certain synthetic manipulations.52 Furthermore, it was envisaged that the ester diene 75 could readily be synthesized from the ketone 76 using, for example, the Pd(0)-catalyzed coupling of a regioselectively generated enol triflate with tetramethyltin.53a'c Finally, it seemed likely that 76 could be prepared by transforming the siloxymethyl fragment in 24 to an axially oriented formyl group. Epimerization of the latter compound to give the (presumably more stable) aldehyde with an equatorially oriented formyl group would then be followed by its eventual transformation into the required isobutenyl moiety via Wittig-type methodology. -48-IVd. Preparation of the keto ester 24 The keto ester 24 (Scheme 7) was prepared according to the sequence developed in our laboratories by Piers and Llinas-Brunet21 en route to their synthesis of the diterpenoid (±)-8,15-diisocyano-ll(20)-amphilectene (15). Thus, stereoselective alkylation54 of the potassium enolate of 2-(methoxycarbonyl)-3-methylcyclohexanone (77) with (E)-1 -(rm-butvldimethylsUoxv)-6^ iodo-3-(trimethvlstannvl)-2-hexe gave the keto ester 78. An efficient 'one pot' sequence (formation of the enol triflate of 78,56c followed by an intramolecular Pd(0)-catalyzed coupling reaction55*57) afforded the diene 79 with complete retention of the exocyclic double bond stereochemistry. OR Scheme 7. Reagents and conditions: R=Si(f-Bu)Me2, E=C02Me; (a) KH, PhMe; (£)-l-(tert-butyldimethoxysUoxy)-fo ft, 48 h; -49-(b) LiN(i-Pr2), THF, -48°C, 1 h; PhN(S02CF3)2, rt, 30 min; (Ph3P)4Pd (0.07 equiv), ft, overnight; (c) propenal, PhH, ft, 20h; NaOMe, MeOH; (d) NaBH4, MeOH; (e) /?-MeC6H4S02Cl, pyridme,p-(N,N-dimemylammo)pyridine, CH2CI2; (f) LiEt3BH, THF, rt, 3 h; NaOH, H2O2, THF; (g) CX)3-3,5-dimethylpyrazole, CH2C12,0°C, 1.5 h. A regioselective Diels-Alder reaction of 79 with propenal gave a mixture of four of the eight possible stereoisomers. Upon subjecting the crude mixture to epimerization with sodium methoxide in methanol (affording two isomeric aldehydes), followed by column chromatography, the desired isomer (80) was isolated in 58% yield. The structure of 80 was assigned on the basis of previous work on the Diels-Alder reactions of dienes structurally similar to 79.55 The transformation of 80 into 81 was effected via sodium borohydride reduction, p-toluenesulfonation of the resulting primary alcohol, and reductive displacement of the /j-toluenesulfonate with lithium triethylborohydride.58 Finally, 24 was prepared via the allylic oxidation of 81 with (M)3-3,5-climethylpyrazole.59 IVe. Initial attempt to synthesize the keto ester 76 Following our retrosynthetic analysis (section IVc of this Discussion), the ketone 82 was prepared by a dissolving metal reduction of 24 with sodium in ammonia in the presence of tert-butyl alcohol290-* (Scheme 8). Workup and column chromatography of the product thus obtained gave the keto ester 8260 in 86% yield. -50-Scheme 8. Reagents and conditions: R= Si(f-Bu)Me2, E= C02Me; (a) Na, f-BuOH, NH 3 , ft, 40 min; (b) n-Bu4NF, THF, rt, 2.5 h; (c) PCC, NaOAc, CH2C12, 45 min; (d) NaOMe, MeOH, rt, overnight. The ir spectrum of 82 showed strong absorptions at 1724 and 1707 cm"1 due to the ester and ketone carbonyl groups, respectively. The  lH nmr of 82 (see formula 82a) exhibited a one-proton multiplet at 5 2.53 due to H^, a dd (J=13,4 Hz) at 2.32 due to H1 2a, a dddd (J=13,3,3,3 Hz) at 2.08 due to H5e, a ddd (J=13.5,3,3 Hz) at 1.88 due to H2e, a one-proton dddd (J=l 1,11,11,3 Hz) at 1.74 due to H4a, a dd (J=13,ll Hz) at 1.56 due to H1 3a, a three-proton multiplet at 1.47-1.32 due to Hga, H6e, and H5a, and a ddd (1=13.5,13.5,3.5 Hz) at 1.12 due to H2a. In *H nmr homonuclear decoupling experiments (see formula 82a), irradiation of the signal at 5 1.12 (H2a) simplified the multiplet at 2.53 (Hje) and caused the collapse of the signal at 1.88 (H2e) to a broad singlet; irradiation of the signal at 8 1.88 -51-\ 82a (H2e) simplified the multiplet at 2.53 (H1e) and transformed the signal at 1.12 (H2a) into a doublet of doublets, (J=l3.5,3.5 Hz); irradiation of the signal at 8 2.08 (H5e) simplified the multiplet at 1.47-1.32 Q^a, H e^, H5a) and caused the collapse of the signal at 1.74 (H4a) to a ddd (7=11,11,11 Hz); irradiation of the signal at 8 2.32 (H12a) simplified the multiplet at 2.53 (H^) and caused the collapse of the signal at 1.56 QH13a) to a doublet (J =11 Hz). Based on the arguments given in sections nib and JUg of this Discussion, it was expected that the alkali metal-ammonia reduction of 24 would give the product in which the six-membered rings are trans-fused. The *H nmr spectral data discussed above strongly supported this assumption. Thus, the J values (13,11 Hz) associated with the coupling between H 1 3a and H 1 2a and between H 1 3a and IL^ a, respectively, indicates that H 1 3a is trans and diaxial to both H 1 2a and H a^. Furthermore, the value of IH1-H12 (4 Hz) is consistent with an equatorial (H1e)-axial (H12a) relationship. Thus, the stereochemistry of the reduction product 82 can be assigned with confidence. In the next step, treatment of 82 with a solution of tetra-w-butylammonium -52-fluoride in THF gave the unstable hemiketal 83 as a colorless oil. The ir spectrum of 83 (crude product) exhibited absorptions at 3402 due to the O-H function and 1723 cm"1 due to the methyl ester function. The ! H nmr spectrum of 83 (crude product) exhibited two (one-proton) multiplets at 8 4.00 (dd, J=8,8 Hz) and 8 3.77 (dd, J=10,8 Hz) due to the C-14 methylene protons and a complex multiplet at 8 3.05-2.94 probably due to H^. Oxidation of the crude compound 83 (PCC, NaOAc, CH2C12, rt). followed by workup and chromatography of the material thus obtained, gave the keto aldehyde 84 in 46% yield (from 82). The ir spectrum of this compound exhibited an absorption at 1723 cm"1 due to the carbonyl groups. The  lH nmr spectrum of 84 exhibited a broad singlet at 8 9.61 due to the formyl group proton, a multiplet at 8 3.38-3.32 due to H ^ , a doublet of doublets at 8 2.40 (J=12,4 Hz) (partially overlapped by a multiplet at 8 2.47-2.35) due to H1 2a, and a ddd at 8 2.10 (J=14,3,3 Hz) due to H2e. In decoupling experiments, irradiation of the multiplet at 8 3.38-3.32 (H^) sharpened the singlet at 8 9.61 (formyl group proton), and caused the collapse of the signals at 8 2.40 (H12a) to a doublet (J=12 Hz) and 8 2.10 (H2e) to a dd (J=14,3 Hz). Also, a dd (J=14,14 Hz) at 8 1.40 (due to H2a) then stood out from the complex signals in the region 8 1.60-1.24. With the hope of obtaining the keto aldehyde 85, possesing the equatorially oriented CHO group, the aldehyde 84 was subjected to epimerization with sodium methoxide in methanol (room temperature, overnight). However, after chromatography of the crude product on silica gel, a mixture (~1:1 by *H nmr analysis) of the epimeric aldehydes 84 and 85 was obtained in low yield along with a considerable amount of unidentified side-products. The ! H nmr spectrum of the crude mixture obtained after workup clearly exhibited a doublet at 8 9.74 (J=2 Hz) and a broad singlet at 9.61 due to the formyl protons of 85 and 84, respectively. Also, three-proton singlets at 8 3.78 and 3.72 were observed and assigned to the methyl ester protons of 85 and 84, respectively. -53-Treatment of the aldehyde 86, an intermediate in the Piers-Llinas-Brunet synthesis of the diterpenoid 15,21 with sodium methoxide-methanol under conditions very similar to those described above, produced the C-l epimer 87 in excellent yield (equation 28). This result suggests that the impediment for the complete epimerization 86 87 of 84 is not steric in nature. Perhaps an unfavorable dipole-dipole repulsion between the equatorial CHO group and the C-ll carbonyl group in 85 destabilizes this epimer. In any case, due to the unsatisfactory result of this experiment, a different approach (described in the next section) for the preparation of 76 from the intermediate 24 was undertaken. IVf. Synthesis of the keto ester 76. Alternative synthetic plan In light of the failure to epimerize efficiently the aldehyde 84, an alternative approach to the preparation of a compound with the desired configuration at C-l, was undertaken. Thus, it seemed likely that the presence of an axial substituent on C-ll would cause a 1,3-diaxial interaction with the axial formyl group on C-l, leading the latter to adopt the preferred equatorial orientation under epimerization conditions -54-111 / E E 82 R= TBDMS 88 R=TBDMS, R'= H 89 R= TBDMS, R'= MOM 90 R= H, R'= MOM R'O E 92 R'=MOM 91 R'=MOM E= C02Me Scheme 9 (Scheme 9). Our plan consisted of performing a stereoselective reduction of 82, followed by conversion of the resultant alcohol 88 into the methoxymethyl (MOM) ether 89. A chemoselective cleavage of the silyl ether function in 89 and subsequent oxidation of the resultant primary alcohol 90 would give the aldehyde 91. Finally, 91 would (presumably) be easily epimerized to the aldehyde 92 under basic conditions, thus establishing the correct stereochemistry at C-l (Scheme 9). IVg. Preparation of the compounds 88 and 89 It is well known618"4 that the reduction of cyclohexanones with sterically demanding hydride reducing agents normally produces a predominance of the corresponding axial alcohol. In this regard, the tri-sec-butylborohydrides61d are especially effective and, therefore, were considered as the reagents of choice for the stereoselective reduction of the keto ester 82. -55-Reduction of the keto ester 82 with lithium tti-sec-butylborohydride ("L-Selectride®")61d in THF at -78°C afforded, after workup and chromatography, the alcohol 88 in 98% yield (equation 29). The *H nmr spectrum of 88 exhibited a triplet OTBDMS OTBDMS (J=2.5 Hz, D 20 exchanged) at 5 5.26 due to the alcohol function, a broad singlet (w1/2=7.5 Hz) at 3.91 due to the equatorial proton H ne, and a dd (J=l 1.5,11.5 Hz) at 1.66 due to H1 3a. Therefore, as indicated by the w 1 / 2 value of 7.5 Hz for H n e, 3 5 the reduction had taken place with the desired stereoselectivity, giving the axially oriented OH function in compound 88. When the alcohol 88 was treated with chloromethyl methyl ether in the presence of N,N-dusopropylemylamine and a catalytic amount of DMAP,6 2 the ester acetal 89 was obtained in 96% yield after workup and column chromatography (equation 30). The *H nmr spectrum of 89 exhibited singlets at 8 4.65 (2H) and 3.39 (3H), respectively, due to the five protons associated with the methoxymethyl group. Singlets at 8 3.72 (1H, w1/2=7.5 Hz), 3.66 (3H), 0.90 (9H), 0.03 (3H), and 0.02 (3H) were assigned to H ue, the carbomethoxy protons, and the tert-butyldimethylsilyl protons, respectively. -56-OTBDMS OTBDMS HO Me02C | MOM-Cl, DMAP ( c a t ) , (»-Pr)2NEt,MeCN,tt.5h XL .o Me02C (30) 96% 88 89 IVh. Preparation of the compounds 90,91 and 92 OTBDMS OH n-Bu4NF, THF, rt, 5 h 96% (3D Cleavage of the tert-butyldimethylsilyl ether function in 89 was carried out by employing the conditions reported by Corey and Venkateswarlu63, namely, with -57-tetra-w-butvlammonium fluoride in THF at room temperature. After workup and column chromatography of the crude product on silica gel, the alcohol 90 was obtained in 96% yield (equation 31). The ir spectrum of 90 exhibited absorptions at 3417 and 1723 cm"1 due to the hydroxyl and methyl ester functions, respectively. The *H nmr spectrum of 90 showed a multiplet at 8 4.73-4.67 due to the CH3O-CH2-O- protons. The one-proton multiplets at 8 3.86 (transformed to a dd, J=12,6 Hz when D 20 was added) and 3.59 (ddd, J=12,7,4 Hz; transformed to a dd, J=12,4 Hz when D 20 was added) were assigned to the diastereotopic C H 2 O H protons. Moreover, the triplet (J=7 Hz) at 8 3.20 disappeared when D 20 was added and was thus assigned to the hydroxyl proton. OH H ^ 92 The alcohol 90 was oxidized with PCC in the presence of sodium acetate to give the crude aldehyde 91 (equation 32). The ! H nmr spectrum of the crude product 91 exhibited a doublet at 8 10.00 (J=6 Hz) due to the formyl group proton and a one-proton multiplet at 2.39-2.32 due to H^. In a *H nmr decoupling experiment, irradiation of the -58-doublet at 6 10.00 simplified the signal at 2.39-2.32 to a multiplet with w1/2=8 Hz. This experiment thus indicated that the Hje proton is equatorial.35 The crude aldehyde (91) was subjected to epimerization with sodium methoxide in methanol at room temperature. Glc analysis of the reaction mixture showed that no starting material remained after 6.5 h. After workup and chromatography of the crude product, the aldehyde 92 was isolated in 74% yield (from 90, see equations 32 and 33). The ir spectrum of 92 showed an absorption at 1724 cm"1 due to the aldehyde and ester functions. The ! H nmr spectrum of 92 exhibited a doublet (J=3.5 Hz) at 5 9.58 due to the formyl group proton, a dddd (J=12,l 1.5,3.5,3.5 Hz) at 2.67 due to H ^ , and a dd (J=10,3.5 Hz) at 1.73 due to H2e (this proton is not coupled to H3a). In a decoupling experiment, irradiation of the signal at 8 9.58 transformed the multiplet at 2.67 (H^) into a ddd (J=12,11.5,3-5 Hz). The two large coupling constants associated with the signal due to Hxa indicated that this proton is axially oriented and that, therefore, the CHO function had the desired equatorial orientation. In a second decoupling experiment, irradiation of the signal at 8 2.67 (Hxa) caused, inter alia, collapse of the doublet at 9.58 (CHO) to a singlet and the dd at 1.73 (H2e) to a doublet (J=10 Hz). The : H nmr data summarized above showed clearly that the desired epimerization reaction (at C-l) had taken place. rVi. Preparation of the compounds 76 and 93 Wittig olefination of the aldehyde 92 using conditions similar to those reported by Christenson and Willis64 (isopropylidenetriphenylphosphorane in DMSO) gave, after workup and chromatography of the crude product on silica gel, the ester alkene 93 in fair -59-92 93 -(67-93%) to good yields (equation 34). In spite of the inconsistent yields and the occasional presence of inseparable impurities in the product, the reaction conditions used were far superior when compared to other alternatives that were also tested.65a,b The *H nmr spectrum of 93 exhibited a broad doublet (J=10 Hz) at 8 4.89 due to the olefinic proton, a multiplet at 2.45-2.23 due to Hja, and two (three-proton) doublets (J=l Hz) at 1.66 and 1.59 due to the vinyl methyl groups. In a decoupling experiment, irradiation of the doublet at 8 4.89 (vinyl proton) simplified the multiplet at 2.45-2.23 (Hja) and caused the collapse of the doublets at 1.66 and 1.59 (vinyl methyl groups) to the corresponding singlets. The cleavage of MOM ethers usually requires strongly acidic conditions (for example HCl/MeOH,668 PhSH/BF3.OEt266b) which may restrict their utilization in organic synthesis. However, Y. Guindon et al. 6 6 c have found that MOM, MEM ((2-methoxyethoxy)methyl), and MTM ((methylthio)methyl) ethers can be cleaved at -78°C by Me2BBr (under milder conditions) to give, after aqueous workup, the parent alcohols in excellent yield. Cleavage of the MOM-ether function in 93 with dimethylboron bromide in dichloromethane at low temperature (-78°C)6 6 c was followed by immediate oxidation -60-(PCC-sodium acetate) of the resultant (unstable) crude alcohol (equation 35). Column chromatography of the crude product on silica gel and recrystallization (pentane-Et20) of the solid thus obtained afforded the keto ester 76 in good yield (85% from 93). However, significant amounts of unidentified side products were produced if the acetal cleavage reaction was allowed to proceed for more than 20 min. The ir spectrum of the keto ester 76 showed two strong absorptions at 1724 and 1717 cm"1 due to the ester and ketone carbonyl groups, respectively. The ! H nmr spectrum of 76 exhibited a doublet of multiplets (J=9 Hz) at 5 4.67 due to the vinylic proton, a one-proton dd (J=l 1.5,10 Hz) at 2.27 due to H1 2a, two (three-proton) doublets at 1.73 (J=1.5 Hz) and 1.62 (J=l Hz) due to the vinyl methyl groups, and a one-proton dd at 1.17 (J=12.5,l 1.5 Hz) due to H1 3a. rVi. Preparation of the compounds 75 and 94 Two methods56a,b for the preparation of enol trifluoromethanesulfonates (enol triflates) were known before their synthesis via the trapping of regioselectively generated enolate anions with N-phenyltriiQuoromethanesulfonimide (Tf2NPh) was devised by -61-o 1 h, then HMPA, Tf2NPh, -48°C, 15 min, LDA,THF,-48°C CF 3S0 20 H H 14 10 (36) Me02C | —*rt,30min Me02C | 76 94 (67%, based on recovered starting; material) McMurry. The most common was the reaction of trifluoromethanesulfonic anhydride (triflic anhydride) with ketones in the presence of a mild nonnucleophilic base.56a This method normally leads to the production of the thermodynamically more stable product (that with the more substituted double bond). The second method consisted of trapping enolate anions with triflic anhydride.5615 However, the more reactive enolates (for example, those produced from monoketones) have the tendency to undergo C-sulfonation56d under these conditions. However, with McMurry's N-phenyltriflimide reagent it is possible to trap a variety of enolates generated in a number of ways to provide (in a more versatile way) the corresponding enol triflates. Using a modification of the procedure published by McMurry,56c the keto ester 76 was deprotonated with LDA in THF and the solution of the resultant enolate anion was treated sequentially with HMPA and Tf2NPh. After workup and column chromatography of the crude product on silica gel, the enol triflate 94 was obtained in 52% yield (67% based on recovered starting material, see equation 36). The ir spectrum of 94 showed strong absorptions at 1728 and 1207 cm"1 due to the ester and sulfonate -62-(symmetric stretching vibration of S02) groups, respectively. The *H nmr spectrum of 94 exhibited broad doublets at 8 5.73 (J=7 Hz) and 5.04 (J=8 Hz) due to H 1 0 and H 1 4 , respectively. With the enol triflate 94 in hand, we proceeded to carry out a coupling reaction with lithium dimethylcuprate67 (Gilman's cuprate) under the conditions reported by Ireland et al.68 Thus, treatment of compound 94 with a freshly prepared solution of lithium dimethylcuprate in dry ether at -10°C, followed by workup and chromatography (silica gel) of the material thus obtained, provided the ester diene 75 in 92% yield (equation 37). The *H nmr spectrum of 75 exhibited a one-proton multiplet at 8 5.39-5.34 due to H 1 0 , a one-proton doublet of multiplets (J=9 Hz) at 5.09 due to H 1 4 , and three (three-proton) doublets at 1.63, 1.56, and 1.60 (all with J=l Hz) due to the vinylic methyl groups. Thus, it was clear that the desired coupling process had taken place. -63-IVk. Preparation of the carboxylic acid 95 It was anticipated that the ester 75 would be relatively unreactive under normal saponification conditions due to steric hindrance towards acyl oxygen cleavage. Therefore, the benzeneselenide induced SN2 cleavage reaction69 was chosen in order to transform 75 into the desired carboxylic acid 95. This was considered as an optimum 75 95 alternative since in sterically hindered methyl esters the methyl carbon is less hindered than the carbonyl carbon. In the event, conversion of the ester diene 75 into the acid 95 was efficiently carried out by refluxing a solution of 75 and the highly nucleophilic sodium benzeneselenide in THF-HMPA69 for 54 h (equation 38). After workup, column chromatography and recrystallization (pentane-Et20) of the product, the carboxylic acid 95 was obtained in 85% yield. The ir spectrum of this material exhibited a broad absorption at 3280-2380 and a strong absorption at 1687 cm"1, both due to the carboxyl function. The : H nmr spectrum of 95 exhibited the following characteristic signals: a multiplet at 5 5.45-5.36 due to H 1 0 , a doublet of multiplets (J=9 Hz) at 5.10 due to H 1 4 , a -64-Hoa 95a doublet of doublets (J=17,6 Hz) at 2.80 due to K^e, a multiplet at 2.21-2.10 due to Hja, a broad doublet (J=17 Hz) at 1.71 due to H a^, and two (three-proton) doublets (J=l Hz each) at 1.64 and 1.56 due to the isobutenyl methyl groups. In ! H nmr homonuclear decoupling experiments, irradiation of the signal at 8 5.45-5.36 (H10) caused the collapse of the signal at 2.80 (Hoe) to a doublet (J=17 Hz) and sharpened the doublet at 1.71 (Hoa); irradiation of the signal at 8 5.10 (H14) caused the collapse of the signal at 2.21-2.10 (Hxa) to a ddd (J=10.5,10.5,4 Hz) and changed the doublets at 1.64 and 1.56 (J=l Hz each, isobutenyl methyl groups) to singlets. IV1. Model studies for the degradation of the carboxyl group of 95 to the  isonitrile function of 23. Preparation of the compounds 96,99,104, and 105 A model study was undertaken to optimize the conditions for the efficient conversion of the carboxylic acid 95 to the target compound 23. The carboxylic acid 96 was chosen as a suitable model since its structure resembled that of the "lower part" of structure 95 and furthermore its precursor (compound 97)70a was readily available. Previous work done in our laboratories7015 using the model compound 98 for the -65-COOH 97 98 preparation of its corresponding isonitrile showed that the sequence of transformations: acid (98) —* acid chloride —» acyl azide —> isocyanate, was not efficient. Therefore, an alternative route (as set out below) was implemented for the model compound 96. Catalytic hydrogenation29d of 97 (Pd-C, 10% Pd content) in ethyl acetate afforded the carboxylic acid 96 in 95% yield, after workup and recrystallization (petroleum ether-Et20) of the crude product (Scheme 10). The ir spectrum of 96 showed absorptions at 3400-2400,1695 and 936 cm"1 due to the carboxyl function. Treatment of 96 with diphenylphosphorazidate (DPPA) and triethylamine in toluene at 80°C for 2 h (formation of the isocyanate)71 was followed by the addition of 2-(trimethylsilyl)ethanol.72 After 1.5 h (80°C), additional amounts of 2-(trimethylsilyl)ethanol and triethylamine were added and the mixture was stirred at 80°C for 36 h. Workup and column chromatography of the crude product afforded the carbamate 99 in 79% yield (Scheme 10). The ir spectrum of 99 exhibited absorptions at 3456 due to the N-H stretching vibration, 1729 due to the carbonyl group ("amide I -66-H H H ^ v L ^ X . H2.Pd-C.latm. r^P^I ( P h O ^ O ^ . f ^ P ^ l ^ ^ T ^ AcOEt,3h Et 3N. toluene. 80°C; > ^ N ^ TMSCCH^OH ^ ^ 97 96 95% , 99 0 79% l)»-Bu4NF.THF, 55°C.3h H H *" 2)CH 3C02CHO. Ph3P.CCl4.Et3N. do <- CD Et20, rt, 2 h CH2a2< N C HN-CHO 105 76% 104 92% Scheme 10 band"), and at 1504 cm'1 due to the N-H bending vibration ("amide II band"). The 1 H nmr spectrum of 99 displayed a broad singlet at 8 4.37 due to the carbamate (N-H) proton, a triplet (J=8 Hz) at 4.12 due to protons on the methylene group adjacent to the carbamate function (-CH2-02C-NH-), and a singlet at 0.04 due to the trimethylsilyl group. The conversion of the acid 96 into the carbamate 99 described above involves a reaction protocol that is simpler and less laborious than the classical procedure. Presumably the first intermediate formed in the reaction is the mixed anhydride 100, followed by the formation of the carboxylic acid azide 10171 (as illustrated in Scheme 11). Under the reaction conditions 101 undergoes a Curtius rearrangement to form the isocyanate 102, which is finally allowed to react with 2-trimethylsilylethanol72 to form the carbamate 103. -67-o II o o (PhO)2P-N3,Et3N, II || R-C02H > R-C-0-P(0Ph)2 + N3" + Et3NH+ PhMe.A 100 o R= alkyl, aryl - + R-C-N-NsN + Et3NH+ (PhO^PO^ 101 ° M^SiCCH^OH, R-NH-C-0(CH2)2SiMe3 < R-N=C=0 + N 2 103 Et3N, PhMe, A 102 Scheme 11 The carbamate 99 (Scheme 10) was cleaved with tetra-n-butvlammonium fluoride in warm THF. 7 2 The resultant amine (crude product) was treated immediately with acetic formic anhydride73 in diethyl ether. After workup and recrystallization (petroleum ether-Et20) of the crude product, the formamide 104 was obtained in 92% yield. The ir spectrum of 104 showed absorptions at 3304 due to the N-H stretching vibration, 3060 due to the first overtone of the N-H in plane bending vibration (at 1529 cm"1), and 1662 cm"1 due to the carbonyl stretching vibration. The *H nmr spectrum of 104 suggested the presence of a mixture (~1:1) of cisoid and transoid rotamers. The one-proton doublets at 6 8.21 (J=1.5 Hz) and 8.16 (J=13 Hz) were readily assigned to the formyl group proton of the cisoid and transoid rotamers, respectively. Treatment of the formamide 104 with triphenylphosphine, triemylamine and carbon tetrachloride in dichloromethane74 for 2 h at 60°C was followed by addition of an extra amount of carbon tetrachloride. The reaction mixture was stirred at 60°C for a -68-further 2 h. After workup, column chromatography on silica gel of the crude product, and recrystallization (pentane-Et20) of the solid thus obtained, the isonitrile 105 was obtained in 76% yeld (Scheme 10). The ir spectrum of 105 displayed an absorption at 2119 cm"1 due to the isonitrile function (in comparison, aliphatic nitriles absorb in the region 2260-2240 cm'1). The ! H nmr of 105 exhibited eight- and nine-proton multiplets at 5 1.90-1.59 and 1.52-1.10, respectively. Ph3P + CC14 -> [Ph3PCl]+ CC13-106 O II H-C-NH-R OPPh3+ Cl-I -> H-C=N-R + HCC13 107 R= alkyl, aryl EfeN Et3NH+Cl" +ON-R <r 109 + c i -H-ON-R + Ph3P=0 108 Scheme 12 The dehydration reaction involved in the conversion of the formamide 104 into the isonitrile 105 is believed to be a stepwise process, illustrated generally in Scheme 12.74 Thus, the salt 106 formed initially from Ph3P and CC14, reacts with the formamide (general formula R-NHCHO) to give the intermediate 107 and CHC13. Elimination of the elements of triphenylphosphine oxide from 107 followed by triethylamine-promoted removal of HC1 from the resultant intermediate 108, would give the isonitrile 109. Deuterium labelling experiments showed that the proton on the chloroform that is produced comes exclusively from the N-H moiety.74 -69-Noteworthily, in the work described above (Scheme 10), the carboxylic acid 96 was transformed into the isonitrile 105 using a five-step sequence of reactions with an overall yield of 52%. This model study served as an informative prelude to the subsequent successful conversions of the dicarboxylic acid 110 and the monocarboxylic acid 95 into the amphilectane diterpenoids 1521 (see p.5) and 23 (vide infra), respectively. IVm. Synthesis of (±)-8-isocvano-10.14-amphilectadiene (23). Preparation of the  carbamate 111 95 111 -70-Having completed successfully the model study for the degradation of a tertiary carboxyl function to the corresponding isonitrile group, we proceeded to attempt the corresponding sequence of reactions on the carboxylic acid 95. Towards this end, a stirred solution of the acid 95 in dry toluene was treated sequentially with triethylamine and diphenylphosphorazidate.71 The resulting solution was stirred at 80°C for 23 h and then 2-(trimethylsilyl)ethanol72 and triethylamine were added. After the mixture had been stirred at 90°C for 24 h, additional amounts of 2-(trimethylsilyl)ethanol and triethylamine were added and the solution was stirred for a further 24 h at 90°C. Workup and column chromatography (silica gel) of the crude product thus obtained afforded the carbamate 111 in 96% yield (equation 39). The ir spectrum of 111 exhibited absorptions at 3446, 1736, and 1508 cm"1 due to the carbamate function. The J H nmr spectrum of 111 displayed a broad doublet (J=5 Hz) at 5 5.34 due to H 1 0 , a dm (J=9 Hz) at 5.11 due to H 1 4 , a broad singlet at 4.27 due to the N-H proton, a two-proton multiplet at 4.13-4.02 due to the -CH2-0(CO)- protons, and a nine-proton singlet at 0.03 due to the trimethylsilyl protons. The next step in the sequence involved treatment of 111 with tetra-zi-butylammonium fluoride in warm THF 7 2 for 2 h. Workup was followed by -71-treatment of the crude oil thus obtained with a solution of acetic formic anhydride in dry ether.73 The reaction mixture was stirred at room temperature for 2 h. After workup, the crude oil was dissolved in dry dichloromethane. Triphenylphosphine, carbon tetrachloride, and triethylamine74 were added to the solution and the mixture was stirred at 55°C for 1 h (see equation 40). Workup and column chromatography of the mixture on silica gel afforded the isonitrile (±)-23 in 80% yield (from the carbamate 111) as a white solid, mp 79-81°C (recrystallization from pentane-E^O). The ir spectrum of synthetic (±)-8-isocyano-10,14-amphilectadiene ((±)-23) exhibited an absorption at 2126 cm"1 due to the isonitrile function. The *H nmr (400 MHz) spectrum of (±)-23 exhibited a multiplet (w1y2=ll Hz) at 8 5.26 due to H 1 0 , a doublet of multiplets (J=9 Hz) at 5.15 due to H 1 4 , a broad dd at 2.45 (J= 17,4.5 Hz) due to Ifys, and a three-proton doublet at 1.69 (]=1 Hz) due to the Cy) methyl protons. The isobutenyl group gave rise to a pair of three-proton doublets at 8 1.66 (J=l Hz) and 1.57 (J=l Hz). The remaining methyl group signals appeared as doublets at 8 1.02 (J=6.5 Hz) and 0.88 (J=6 Hz). The spectral data derived from our synthetic (±)-23 was in accord with the data reported by Faulkner and coworkers26 (1H, 1 3 C nmr, and high resolution EIMS) for natural (-)-8-isocyano-10,14-amphilectadiene (23). For comparison purposes the *H and 1 3 C nmr spectral data reported for the natural material and those derived from our synthetic material are compiled in Tables 1 and 2, respectively. Furthermore, a direct comparison of the *H nmr (300 MHz) spectrum of natural (-)-2375 and the *H nmr (400 MHz) spectrum of synthetic (±)-23 was possible (see Figures 3 and 4). -72-Table 1: *H nmr spectral data for natural (-)-8-isocyanc~10,14-amphilectadiene ((-)-23) and synthetic (±)-8-isocyano-10,14-amphilectadiene ((±)-23) Reported data: *H nmr (CDC13, 360 MHz) 8 5.26 (m, 1H, w1 /2=ll Hz, H1 0), 5.15 (br d, 1H, J=9 Hz, H1 4), 2.45 (br dd, 1H, J=17,4.4 Hz, Hg), 2.24 (m, 1H, J=12,12,7,4 Hz, H a^), 2.04 (m, 1H, H12a), 2.0 (m, 2H), 1.69 (d, 3H, J=0.9 Hz, C20 methyl protons), 1.66 (d, 3H, J=1.0 Hz), 1.57 (d, 3H, J=l.l Hz), 1.02 (d, 3H, J=6 Hz), 0.88 (d, 3H, J=6.3 Hz). Our data: ! H nmr (CDC13, 400 MHz) 8 5.26 (m, 1H, w1/2=ll Hz, H 1 0), 5.15 (dm, 1H, J=9 Hz, H1 4), 2.45 (br dd, 1H, J=17, 4.5 Hz, Hge), 2.31-2.19 (m, 1H, H^), 2.12-1.92 (m, 3H), 1.69 (d, 3H, J=l Hz, C20 methyl protons), 1.66 (d, 3H, J=l Hz, isopropylidene methyl protons), 1.57 (d, 3H, J=l Hz, isopropylidene methyl protons), 1.02 (d, 3H, J=6.5 Hz, methyl protons), 0.88 (d, 3H, J=6 Hz, methyl protons). -73-Table 2: 1 3 C nmr spectral data for natural (-)-8-isocyano-10,14-amphilectadiene ((-)-23) and synthetic (±)-8-isocyano-10,14-amphilectadiene ((±)-23) Reported data: 1 3 C nmr (CDC13, 50.3 MHz) 8 15.4 (q), 17.6 (q), 19.6 (q), 25.1 (q), 25.7 (q), 29.2 (t), 29.8 (t), 37.2 (d), 37.9 (t), 40.6 (d), 41.4 (d), 42.1 (d), 43.5 (t), 44.8 (d), 49.6 (d), 63.3 (br s), 118.8 (d), 126.6 (s), 133.4 (d), 137.6 (s), 154.5 (br s). Our data: 1 3 C nmr (75.3 MHz, CDC13, proton decoupled) 8 15.4, 17.5, 19.5, 25.1, 25.7, 29.1, 28.8, 37.2, 37.9, 40.6, 41.4, 42.1, 43.5, 44.8, 49.5, 63.2 (t, Jc.i4N=4.5 Hz), 118.8,126.7,133.4,137.6,154.4 (t, Ic_i4N=4.5 Hz). -74-, i, , , , —, 5 3 2 1 Oppm Figure 4: The *H nmr (CDC13,400 MHz) spectrum of synthetic (±)-8-isocyano-10,14-amphilectadiene -75-OTBDMS OTBDMS (b) (-*8), (c) (^89), (d) (^ 90) E=C02Me E I 88 R^TBDMS, R2=OH 89 R^TBDMS, R2=MOM 90 R!=OH, R2=MOM OHC (g) R,0 E § E I 76 (j)(-94), (k)(-*75) 93 E I 92 (1)(^ 95), (m)(->lll) (n),(o),(p) 94 R3=OTf 75 R3=Me R 4 = 95 R4=C02H 111 R4=NHC02(CH2)2TMS NC 23 Scheme 13 Reagents and conditions: (a) Na, NH3, f-BuOH, ft, 40 min; isoprene, NH4Cl(aq),(83%); (b) L-Selectride®, THF, -78°C, 3h; 0°C, lh; NaOH(aq)10%, H2O2(aq)30%, 5h, (98%); -76-(c) M0M-C1, DMAP, (/-Pr)2NEt, MeCN, ft, 5h, (96%); (d) n-Bu4NF, THF, rt, 5h, (96%); (e) PCC, NaOAc, CH2C12, rt, 2h; (f) NaOMe, MeOH, rt, 6.5h (74% from 30); (g) Ph3P=CMe2, DMSO, rt, 2h, ~(67-93%); (h) Me2BBr, CH2C12, -78°C, 20 min; NaHC0 3 ( a q ) -THF; (i) PCC, NaOAc, CH2C12, rt, 2h, (85% from 33); (j) LDA, THF, -48°C, lh; HMPA, Tf2NPh, -48°C, 15 min; rt, 30 min, (67%); (k) Me2CuLi(10 equiv), Et 2 0, -10°C, 2h, (92%); (1) PhSeNa, THF, HMPA, ft, 54h, (85%); (m) (PhO)2P(0)N3, Et3N, toluene, 80°C, 23h; TMS(CH2)2OH, Et3N, 90°C, 48h, (96%); (n) /1-BU4NF, THF, 55°C, 2h; (o) CH 3 C0 2 CHO, Et 20, rt, 2h; (p) Ph3P, CCI4, Et3N, CH2C12, 55°C, lh (80% from 37). IVn. Conclusion The work summarized in sections rVf-IVm constitutes the successful (15 step) total synthesis of (±)-8-isocyano-10,14-amphilectadiene ((±)-23) from the intermediate 24 in ~18% overall yield (Scheme 13). To our knowledge, this is the first total synthesis of this biologically and structurally interesting natural product. -77-V. Development of a general synthetic approach to the spongiadiols, a group of natural products belonging to the "spongian" family of diterpenoids. Va. Previous syntheses of furanoditerpenoids possessing the "spongian" carbon  skeleton In 1981 E.A. Ruveda and coworkers1315 synthesized e/ir-12a-hydroxyspongia-13(16),14-diene (112), an intermediate which bears the basic carbon skeleton of spongiadiol (18) and the related furanoid diterpenes 19-22 (see p.7). The authors prepared compound 112 using the readily available methyl isocopalate (113)76 as starting material (Scheme 14). Thus, the diene 114, obtained by conversion of the methoxycarbonyl moiety in 113 into an exocyclic double bond, was subjected to photooxygenation77 to yield the diene 115. Diels-Alder addition of singlet oxygen to compound 115 gave the cyclic peroxide 116 in low yield. Treatment of 116 with ferrous sulfate in aqueous tetrahydrofuran gave the target compound 112 in 75% yield (see Scheme 14). -78-Scheme 14 In a related approach to the synthesis of (±)-12a-hydroxyspongia-13(16),14-diene ((±)-112), Nakano and Hernandez130 used (±)-labda-8(20),13-dien-15-oic acid (117) as a starting material (Scheme 15). Thus, cyclization of 117 was followed by methylation of the carboxyl group to give (±)-113. Photooxygenation of (±)-113 gave a low yield of the allylic alcohol 118 together with other side products. Subsequent epoxidation of 118 and treatment of the resulting product with lithium diisopropylamide led to the butenolide 119. Subsequent reduction of 119 with DIBAL gave the furanoditerpenoid (±)-112 in 19% yield along with some starting material (119). Since it is relevant for the construction of ring D of the spongiadiols, it should be pointed out that Minato and Nagasaki78 have obtained higher yields for the DIBAL reduction-dehydration of 3,4-disubstituted and 3-substituted butenolides to the corresponding furans. -79-Scheme 15 In relation to the transformation of 113 into 118 (see Scheme 15), it should be mentioned that E.A. Ruveda and coworkers13*1 have also synthesized compound 118 from 113 in 60% overall yield using a different approach (see Scheme 16). Scheme 16 Vb. Retrosynthetic analysis Our retrosynthetic analysis (Scheme 17) was based on the proposal that the spongiadiols 18-22 could be prepared from the common intermediate 121 via suitable -80-Spongiadiols RO y \ H OR 18 19 R = H R= Ac Ro^ y ^ i OR O H 20 R = H 21 R= Ac 22 OR' I K OR' OR' 122 R'= protecting group; K= ketal function K O 05 NC * H ^ 125 ° 126 17 Scheme 17 functionalization of the double bond in ring A. It was envisaged that the furan ring in compound 121 could be introduced by appropriate use of the ketone function in 122. A number of methods (apart from the ones mentioned in section Va of this thesis) have been reported79 for the construction of 3,4-fused furans from ketones. Of particular interest is the method published by Price and Schore80a (see example in Scheme 18). This sequence has been used successfully in a natural product synthesis,80b and seems to -81-be one of the best methods available (in terms of the number of steps and yield) for the preparation of 2,3-fused furans from six-membered cyclic ketones . In the next retrosynthetic step (Scheme 17), a 1,3-carbonyl transposition81 of the ketone 122 would lead to the intermediate 123. The ketone 123 could in turn be prepared from the bicyclic ketone 124 via a stereoselective Robinson annulation-Birch reduction sequence. With respect to the Michael addition step in the Robinson annulation, it seemed reasonable to predict that attack of electrophiles would occur from the sterically less hindered a face of the enol or enolate anion of 124. ca0 (a) CHOH ( b ) CHSBu11 127 O 128 I O 129 (c) (e) (59% from 129) 132 SBur (d) CHSBu Scheme 18. Reagents and conditions: (a) NaOMe, EtOCHO, THF; (b) /1-C4H9SH, p-TsOH, CfcHfr ft; (c) C H 2 = S M e 2 > D M E > (d) 2 4 h> r o o m temperature; (e) HgS0 4 , Et 20. Following the intramolecular aldol condensation-dehydration of the Michael adduct obtained from 124, a dissolving metal reduction would afford the more stable B-C trans-fused ring system 123 (see sections IUb and JJJg of this Discussion). It was envisaged that compound 124 (Scheme 17) could be prepared from the ketal nitrile 125. This could be achieved, in principle, by a dhsobutylaluminum hydride (DIBAL) reduction of 125, a sodium borohydride reduction of the resulting aldehyde, and then a -82-deprotection-protection sequence to give 124. It was expected that the ketone 126 could be readily transformed into the nitrile 125 via methodology recendy developed in our laboratories. This transformation would involve the palladium (O)-catalyzed coupling of the enol triflate 133 (prepared from 126) with lithium cyanide82 to give the a,P-unsaturated nitrile 134 (see Scheme 19). The next step would consist of the site-selective methylation of the conjugated enolate of 134, namely 135, to give the nitrile 125. It was expected that this alkylation would proceed via the stereoselective attack of the electrophile from the sterically less hindered a face of the conjugated anion 135 (Scheme 19). Attack of the mcoming electrophile from the P face of the enolate would be hindered by the angular methyl group as shown in formula 135. Scheme 19 Finally, the trans-fused keto ketal 126 was to be prepared from the readily available cis-fused ketone 1723 (see section Die of this thesis) via a sequence of reactions which would involve conversion of the carbonyl group into a ketal function, oxidative cleavage of the exocyclic double bond, and base-catalyzed epimerization of the ketone 136 thus obtained. It was expected, on the basis of a qualitative conformational analysis -83-and an examination of molecular models, that the equilibrium in this base-catalyzed epimerization (see equation 41) would lie in favor of the trans-fused keto ketal 126 (represented by formula 126a). B / B H ^ 126a 1,3-syn-axial 1 x CH3-H 3 x CH3-H interaction 2 x O-H 3 x O-H 3 x CH2-H 1,3-CH3-Csp2-syn-axial interaction l x C ^ - C ^ lxCH 3 -C s p 2 gauche 2xCH 3-0 ! x C £ 3 ' 2 interaction 1 x CH2-0 1 * CH2-0 (41) Vc. Initial attempt to establish a synthetic sequence. Preparation of the ketals  137-139 O 17 In order to gain access to the ketal alkene 137, a stirred mixture of the ketone 17P ethylene glycol, a small amount of silica gel containing 5% p-toluenesulfonic acid (p-TsOH),83 and benzene was refluxed under a Dean-Stark water trap for 2.5 h. Workup -84-and column chromatography of the material thus obtained afforded the ketal alkene 137 in 84% yield (equation 42). The ir spectrum of 137 did not exhibit a carbonyl stretching absorption; however, it did show absorptions at 3067 and 1650 cm"1 due to the exocyclic double bond. The *H nmr spectrum of compound 137 displayed a two-proton multiplet at 8 4.66-4.60 due to the exocyclic methylene protons, a four-proton multiplet at 4.03-3.87 due to the ketal protons, and a singlet at 0.88 due to the angular methyl group protons. Following the method described by Sharpless and coworkers84, the ketal alkene 137 was subjected to an oxidative cleavage of the exocyclic double bond using Ru02 (7 mol %)-NaI04 in a mixed solvent system containing carbon tetrachloride, acetonitrile, and water. After the mixture had been stirred vigorously at room temperature for 2h, glc analysis of the organic phase showed a substantial amount of remaining starting material. Therefore, additional amounts of the solvent mixture and ruthenium (IV) oxide were added and vigorous stirring was continued for 3 h. Column chromatography (silica gel) of the material obtained after workup, afforded the keto ketal 138 in 51% yield (equation 43). The ir spectrum of 138 showed an absorption at 1712 cm"1 due to the newly formed carbonyl group. The J H nmr spectrum of this compound exhibited a four-proton multiplet at 8 4.02-3.87 due to the ketal protons and a ddd at 2.49 (J=13,12,7 Hz), most likely due to H3a. The available spectral data did not allow an unambiguous assignment -85-for the conformation of 138, however, it seemed reasonable to assume (on the basis of a qualitative conformational analysis) that the preferred conformation for 138 would be represented by formula 138a (see equation 44). In order to prepare the desired trans-fused bicyclic ketone 139, the keto ketal 138 was subjected to epimerization with sodium methoxide in methanol at room temperature for 24 h. After workup, gas-liquid chromatographic analysis of the crude mixture showed the presence of the starting material (138) and the desired product (139) in a ratio of ~1:4.8, respectively. This mixture of ketones proved to be difficult to separate by column chromatography; however, it was possible to isolate 139 in pure form in 66% yield after chromatography and recrystallization (pentane-Et20) of the material thus obtained. The remaining material (26%) consisted of a 1:1 mixture of 138 and 139 (equation 45). The difficulties encountered with the purification of 139 and the low product yield obtained in the oxidative cleavage of the exocyclic olefin in 137 led us to try a -86-different approach. Thus, it was hoped that the use of the 2,2-dimethyl-l,3-propanediol ketal of 17, and related intermediates, would allow their facile purification since it has been our observation that such ketals are often easily crystallized. Furthermore, we expected to have better yields in the transformation of the exocyclic double bond to the corresponding ketone function by means of an ozonolysis reaction.85 The results of these modifications are described in the following Section. Vd. Preparation of the ketals 140-142 17 140 68% In order to protect the ketone function of compound 17, a solution of 17, 2,2-dimethyl-l,3-propanediol, and p-TsOH in dry benzene was refluxed for 2 h under a Dean-Stark water trap. Workup, column chromatography of the crude product on silica gel, and recrystallization (pentane) of the material thus obtained afforded the ketal alkene 140 in 68% yield (equation 46). The ir spectrum of 140 exhibited absorptions at 1650 and 1106 cm"1 due to the exocyclic double bond and the ketal function, respectively. The *H nmr spectrum of 140 showed a two-proton multiplet at 8 4.69-4.59 due to the exocyclic methylene protons. The methylene protons of the ketal function gave rise to two (one-proton) doublets (J=12 Hz) at 8 3.70 and 3.64 and two (one-proton) doublet of doublets (J=12,3 Hz) at 3.32 and 3.27. The expected singlets for the protons due to the three methyl groups appeared at 8 1.19,1.08, and 0.71. -87-Apart from the major product 140, an inseparable mixture (4.6:1, glc analysis) of two other products was also isolated after column chromatography. On the basis of 140a spectral data, it was concluded that the major component of the mixture was the ketal alkene 140a. The structure of the minor compound is still unknown to us. The ir spectrum of the mixture did not exhibit absorptions due to the C-H stretching vibration for the exocyclic methylene group. However, the presence of the ketal function was indicated by a strong absorption at 1109 cm"1. The J H nmr spectrum of the mixture showed signals due to the ketal methylene protons at 8 3.72 (d, J=ll Hz), 3.57 (d, J=ll Hz), 3.36 (dd, J=ll,3 Hz), and 3.29 (dd, J=ll,3 Hz) and a broad singlet due to the vinyl methyl group at 8 1.62. No signals at lower field than 8 3.72 were observed and it was therefore clear that the compounds did not possess olefinic protons. With the ketal alkene 140 in hand we proceeded to carry out the oxidative cleavage of the exocyclic double bond. Thus, ozonolysis85 of 140 -88-(mcMoromethane-methanol solution, -78°C), followed by reduction of the intermediate with dimethyl sulfide (equation 47), gave, after workup, column chromatography of the crude product, and recrystallization (pentane-Et20), the keto ketal 141 in 80% yield. The ir spectrum of this product exhibited a carbonyl stretching absorption band at 1710 cm*1. The XH nmr spectrum of 141 showed a two-proton broad doublet (J=ll Hz) at 8 3.64 and a two-proton multiplet at 3.35-3.24 due to the ketal methylene protons. The three singlets at 8 1.16,1.11, and 0.90 were assigned to the methyl group protons. 141 142 89% The keto ketal 141 was subjected to epimerization by treatment with sodium methoxide in methanol at 45°C for 2.5 h. Workup and column chromatography of the material thus obtained afforded the keto ketal 142 in 89% yield. Some starting material (10%) was also recovered (see equation 48). It should be noted that the mixture of ketones 142 and 141 was easy to separate by column chromatography, as opposed to the case of the mixture of ketones 138 and 139 referred to (Section Vc of this Discussion). Furthermore, the ratio of trans- to cis-fused product was improved from ~4.8:1 (for the keto ketals 139 and 138) to -9:1 (for the keto ketals 142 and 141). The ir spectrum of compound 142 showed an absorption due to the carbonyl group at 1713 cm"1. The *H nmr of this material exhibited three (three-proton) singlets at 8 1.20, 0.85, and 0.73 due to the tertiary methyl groups. -89-Ve. Prepararion of the enol triflate 143 and its Pd(0)-catalyzed coupling with  hthium cyanide. Preparation of the a.B-unsaturated nitrile 144 In 1989, Piers and Fleming82 reported a novel reaction in which enol trifluoromethanesulphonates (enol triflates) underwent efficient coupling with lithium cyanide in the presence of catalytic amounts of 12-crown-4 and tetrakis(triphenylphosphine)palladium(0). This reaction, which is analogous to the nickel(O)- or palladium(0)-catalyzed coupling reactions of alkenyl halides with potassium cyanide,86a"c allows the site-selective conversion of unsymmetrically substituted ketones into a,|3-unsaturated nitriles (scheme 20). This coupling process has O OTf CN 145 146 147 Scheme 20 been used successfully in the total synthesis of the trans-clerodane diterpenoid (±)-stephalic acid.87 The method mentioned above seemed to be perfectly suited for the eventual construction of the hydroxymethyl moiety attached to ring A of the spongiadiols (see the retrosynthetic analysis in section Vb of this Discussion). Thus, selective deprotonation of the keto ketal 142 with LDA at -78°C and reaction of the resultant enolate anion with N-phenyltrifluoromethanesulfonimide frf2NPh)5 6 c gave, after workup and column chromatography, the enol triflate 143 in 89% yield (equation 49). This material, even -90-after recrystallization from pentane-Et20, was occasionally contaminated with traces of Tf2NPh. However, this impurity did not affect the outcome of the subsequent coupling 142 143 reactions. The ir spectrum of compound 143 showed an absorption band at 1211 cm"1 due to the sulfonate function (symmetric stretching vibration of the S02 group). The  lH nmr spectrum of this material exhibited a one-proton multiplet at 8 5.68-5.62 due to the vinyl proton and three singlets at 1.14,0.93, and 0.71 due to the methyl group protons. Clean and efficient conversion of 143 into the a,p-unsaturated nitrile 144 was accomplished by treating the enol triflate 143 with LiCN, (Ph3P)4Pd, and 12-crown-4 in benzene at room temperature (equation 50). Column chromatography and recrystallization (pentane-E^O) of the crude reaction product afforded the -91-a,P-unsaturated nitrile 144 in 91% yield. The ir spectrum of the nitrile 144 showed an absorption at 2209 cm"1 due to the nitrile function. The XH nmr spectrum of 144 displayed a one-proton multiplet at 8 6.60-6.53 due to the vinyl proton, and exhibited the usual signals due to the ketal function and the three tertiary methyl groups. The next step in the sequence was the stereoselective deconjugative alkylation of the a.fJ-unsaturated nitrile 144. Towards this end, deprotonation (LDA, THF, -78°C) of 144 was followed by addition of dry HMPA and an excess of methyl iodide (equation 51). Workup and column chromatography on silica gel of the product thus obtained, afforded exclusively the P/y-unsaturated nitrile 148 as a white crystalline solid (recrystallized from hexane-Et20) in 96% yield. The ir spectrum of the nitrile 148 displayed an absorption at 2229 cm"1 due to the nitrile function. The J H nmr spectrum of 148 (Figure 5) showed two (one-proton) multiplets at 8 5.92-5.85 and 5.49-5.42 due to the vinylic protons H 2 and H 3 , respectively, a broad doublet (J=18 Hz) at 2.73 due to H ^ , and a doublet of doublets (J=18,6 Hz) at 2.00 due to Hxe. In -H nmr decoupling experiments, irradiation of the signal at 8 5.49-5.42 (H3) simplified the multiplet at -92-CN 5.92-5.85 ( H 2 ) and sharpened the doublet at 2.73 (Hia); irradiation of the signal at 5 5.92-5.85 ( H 2 ) simplified the multiplet at 5.49-5.42 (H3) and caused the collapse of the doublet of doublets at 2.00 (H,e) to a doublet (J=18 Hz) (see formula 148a). The stereochemical outcome of this highly stereoselective reaction was not rigorously established. However, based on the argument given in the retrosynthetic analysis discussion (section Vb and Scheme 19), we were confident that the relative configuration of the newly formed center (C-4) was as shown in formula 148a. Figure 5. The *H nmr spectrum (CDC13,400 MHz) of compound 148. -93-Vg. Reduction of the nitrile 148. Preparation of compounds 149 and 150 DffiAL, CH2Cl2' rt, 30 min; NaHC03 ( a q ) (52) OHC 97% 148 149 Reduction of the nitrile 148 was efficiently accomplished using dusobutylaluminum hydride (DIBAL)88 (equation 52). Column chromatography on silica gel of the material obtained after workup gave the aldehyde 149 in 97% yield. The ir spectrum of this material showed a strong absorption at 1718 cm"1 due to the aldehyde carbonyl group. The ! H nmr spectrum of 149 exhibited a one-proton singlet at 8 9.76 due to the formyl proton, a one-proton multiplet at 5.34 due to H 3 , and a doublet of doublets (J=10,2 Hz) at 5.34 due to H 2 . 149 150 -94-Reduction of the aldehyde 149 with sodium borohydride in dry methanol at -10°C proceeded cleanly (equation 53). Workup and solvent removal (vacuum pump) from the material thus obtained gave the alcohol 150 in 96% yield as a colorless oil that was homogeneous by tic and glc analyses. The ir spectrum of this material showed an absorption at 3350 cm"1 due to the OH function. The J H nmr spectrum of 150 confirmed the presence of the hydroxymethyl moiety by exhibiting two (one-proton) doublets (J=ll Hz) at 8 3.62 and 3.49, and a broad singlet (D20 exchanged) at 1.54. Vh. Preparation of the keto alcohol 151 and the ketone 152 150 151 To a stirred solution of the alcohol 150 in acetone was added hydrochloric acid (10% aqueous solution). The reaction mixture was stirred at room temperature for 1 h. Workup and column chromatography on silica gel of the material thus obtained, afforded the keto alcohol 151 in 98% yield (equation 54). The ir spectrum of 151 exhibited an O-H stretching absorption at 3453 cm"1 and a carbonyl absorption at 1704 cm1. In the ! H nmr spectrum of 151, the vinyl protons appeared at 8 5.74 and 5.54 (ddd, H 2 , J=10,6,2 Hz and dd, H 3 , J=10,3 Hz, respectively). Other resonances exhibited were: two -95-(one-proton) doublet of doublets (J=ll,6 Hz each) at 8 3.74 and 3.70 due to the methylene protons of the hydroxymethyl moiety (each of these signals collapsed to a doublet (J=ll Hz) when D 20 was added), a ddd (7=14,14,7 Hz) at 2.60 due to H8a (see formula 151a), a broad doublet (7=18 Hz) at 2.38 due to H^, a dddd (J=14,2,2,2 Hz) at 2.29 due to H8e, a one-proton multiplet at 2.18-2.08 due to H T C , a doublet of doublets at 1.99 (J=18,6 Hz) due to Hje, a one proton dddd (J=12,12,12,4 Hz) at 1.74 due to Hga, and a one-proton multiplet at 1.63-1.47 due to H7a. In *H nmr proton decoupling experiments, irradiation of the signal at 8 5.74 (H^ simplified the signal at 5.54 (H3) to a doublet (J=3 Hz), the broad doublet at 2.38 (Hja) was sharpened and the dd at 1.99 (Hje) collapsed to a doublet (J=18 Hz); irradiation of the signal at 8 2.60 (H8a) simplified the signals at 2.29 (H8e, to an unresolved multiplet), 2.18-2.08 (H7e) and 1.63-1.47 (H7a); irradiation of the signal at 5 2.18-2.08 (H7e) simplified the signals at 2.60 (H8a), 2.29 (H8e, collapsed to a doublet of multiplets, J=14 Hz), 1.74 (Hga, collapsed to a ddd, J=12,12,12 Hz), and 1.63-1.47 (H7a). Conversion of the keto alcohol 151 into its tert-butvldimethylsilvl (TBDMS) ether was accomplished using a slight modification of a literature procedure89 (equation 55). Thus, to a cold (-78°C) solution of 151, 4-N,N-dimethylammopyridine (DMAP), and triethylamine in dry dichloromethane was added tert-butyldimethylsilyl-trifluoromethanesulfonate (TBDMS-OTf). The mixture was stirred at -78°C for 30 min. H8e 151a Hxa H 2 -96-o o TBDMS-OTf, DMAP, Et 3 N, CH 2C1 2. -78°C.30min 93% (55) OH OTBDMS 151 152 Workup and column chromatography (silica gel) of the mixture thus obtained afforded the ketone 152 in 93% yield. When the reaction was carried out with TBDMS-C1 instead of TBDMS-OTf (under conditions identical with those described above) or with TBDMS-C1 and imidazole in DMF, 6 3 the yields of 152 were lower. The ir spectrum of the ketone 152 exhibited a strong absorption at 1710 cm"1 due to the carbonyl function. The ! H nmr spectrum of 152 displayed two one-proton doublets (J=10 Hz each) at 8 3.60 and 3.56 due to the methylene protons in the -CH2-0(TBDMS) moiety. The nine-proton singlet at 8 0.91 and the three-proton singlets at 0.04 and 0.03 were assigned to the tert-butyldimethylsilyl group protons. Vi. Preparation of the ketones 153 and 154 O O H8a H8e OTBDMS OTBDMS 153 154 -97-Monoalkylation of the ketone 152 proceeded cleanly. Thus, deprotonation (LDA, THF) of 152 and methylation (methyl iodide) of the resultant enolate anion gave two products. After workup and column chromatography on silica gel, two fractions were obtained. The first fraction consisted of a mixture of the epimers 153 and 154 in 57% yield. The second fraction contained exclusively the ketone 153 in 39% yield. The mixture of epimers obtained from the first fraction was subjected to epimerization (sodium methoxide in methanol). After workup and column chromatography on silica gel, the ketone 154 was obtained as the only product in 88% yield. The *H nmr spectrum of compound 153 exhibited a one-proton doublet of quartets (J=8,8 Hz) at 8 2.64 due to the equatorial proton H8e and a doublet (J=8 Hz) at 1.13 due to the secondary methyl group protons. On the other hand, the *H nmr spectrum of 154 displayed a one-proton ddq (J=12,6,6 Hz) at 8 2.68 due to the axial proton H8a and a doublet (J=6 Hz) at 1.00 due to the secondary methyl group protons. Certainly, it would have been possible to carry out the next transformation (vide infra) using a mixture of the ketones 153 and 154. However, it was desired to confirm the reproducibility of the alkylation reaction on a larger scale, as well as to have increased amounts of pure 154. Furthermore, it was found that it was easier to separate traces of dialkylated product and/or starting material from 154, obtained after epimerization, than from the mixture of 153 and 154 obtained after the alkylation of 152. -98-Thus, the alkylation-epimerization steps were carried out sequentially, using conditions very similar to those outlined above. In this way, 154 was produced from 152 in 81% overall yield (equation 56). Vj. Preparation of compounds 155,156, and 157 O OTMS OTBDMS 2)HMPA,TMS-C1, 0°C,40min 1) LDA.THF, -78°C-+0°C 93% (57) OTBDMS 154 155 The synthesis of the diketone 157 involved the Lewis acid-promoted Michael-type addition of the enol silyl ether 155 onto the ethylene ketal of 3-buten-2-one. Therefore, the trimethylsilyl enol ether 155 was first prepared using a modification of a known literature procedure.44 Thus, to a cold (0°C) solution of the lithium enolate of 154 in dry THF were added HMPA and TMS-C1 and the reaction mixture was stirred at 0°C for 40 min. Following workup, column chromatography on silica gel of the crude product afforded the silyl enol ether 155 in 93% yield (equation 57). The ir spectrum of 155 exhibited characteristic absorptions at 1676 and 842 cm"1 due to the enol ether double bond and the trimethylsilyl group, respectively. The *H nmr spectrum of 155 showed a three-proton singlet at 8 1.54 due to the vinylic methyl group and two (nine-proton) singlets at 0.91 and 0.22 due to the tert-butyl and trimethylsilyl group protons, respectively. The Michael-type addition step of the six-membered ring annulation sequence was carried out by adding the ethylene ketal of 3-buten-2-one (prepared from -99-OTMS I 1 O > II (58) OTBDMS TiCty Ti(OPr/)4 (1.5:1), CH2a2- - 7 8 ° c . OTBDMS OTBDMS +153/154 10 min 11% 155 156 -5% 157 14% 3-buten-2-one according to the procedure published by Hahn)46 to a cold (-78°C) mixture of TiCl 4 and Ti(OPT,)4 in dry dichloromethane. After the mixture had been stirred at -78°C for 5 min, a solution of the trimethylsilyl enol ether 155 in dry dichloromethane was added and the reaction mixture was stirred for a further 10 min period. After workup, thin layer chromatographic analysis of the crude product mixture showed the presence of four compounds and a considerable amount of intractable "baseline" material. Column chromatography of this mixture afforded the desired diketone 157 in 14% yield, the epimeric (and somewhat impure, 90% by glc analysis) diketone 156 in ~5% yield, and the ketones 153 and 154 in 6 and 5% yield, respectively (equation 58). When a Michael addition was attempted under conditions very similar to those described above, except for the use of TBDMS-OTf as Lewis acid, a large number of (polar) unidentified compounds were produced. Another attempt to prepare the Michael adduct 157 by slowly adding 3-buten-2-one to a cold (-10°C) ethereal solution of the mixture 153/154 in the presence of a catalytic amount of sodium ethoxide90 also failed. In this case, only the ketone 154 was recovered. The ir spectrum of 157 exhibited two strong absorptions at 1718 and 1695 cm"1 due to the two carbonyl functions. The  lH nmr spectrum of 157 exhibited a three-proton singlet at 6 2.16 due to the methyl ketone moiety. The three (nine-, three-, and -100-three-proton) singlets which appeared at 5 0.91, 0.04, and 0.03, respectively, were assigned to the tert-butyldimethylsilyl protecting group. The remaining methyl group signals appeared as three-proton singlets at 5 1.19,1.18, and 1.08. The ir spectrum of the (somewhat impure) diketone 156 exhibited two strong absorptions at 1719 and 1694 cm"1 due to the two carbonyl groups. The *H nmr of this material displayed a singlet at 8 2.14 due to the methyl ketone moiety. Three singlets appeared at 8 0.91, 0.04, and 0.03 and were assigned to the tert-butylsilyl protecting group. The remaining methyl group signals appeared as singlets at 8 1.13, 1.07, and 0.99. Examination of molecular models indicates that electrophilic attack on the enol ether 155 would occur preferentially from the a (less hindered) side of the molecule. However, the relative configurations at C-8 of compounds 156 and 157 were not known with certainty at this stage of our work. Later, *H nmr spectroscopy experiments involving a synthetic intermediate derived from 157 (see Part Vm of this Discussion Section) showed conclusively that the diketone 157 possessed the indicated stereochemistry. Nevertheless, at this point, it was decided that any further attempts to produce 157 in a more efficient way would be carried out after the relative stereochemisty of this product had been confirmed. Thus, the next two synthetic steps were carried out with the available material (vide infra). In spite of having obtained a low yield of 157, the stereochemical outcome of the reaction suggested that other approaches to its construction could be promising. An example of such approach would be the reaction of the lithium enolate of 154 (represented by formula 154a in Scheme 22) with the Michael acceptor 3-triethylsilyl-3-buten-2-one under aprotic conditions. The previous success of this reaction is illustrated by the preparation of the bicyclo[4.4.0]oct-l-en-3-one 160 from the lithium enolate 158 (see Scheme 21).91 Another possibility would be the reaction of the -101-OLi O SiEt, -78°C-»rt 158 159 160 80% overall Scheme 21 lithium enolate 154a with (E)-4-(phenylsulphonyl)-3-buten-2-one411 to produce the enone 161 (Scheme 22). Chemoselective reduction of the conjugated carbon-carbon O O PhS02 OLi THF, -20°C 154a OTBDMS OTBDMS Scheme 22 double bond in adduct 161 to give 162, followed by an aldol condensation-dehydration sequence of reactions would produce the desired enone 163. -102-Vk. Preparation of compound 163 O H 1 3a O H13e KOH, MeOH, U,1.5h (59) 78% OTBDMS OTBDMS 157 163 Treatment of the diketone 157 with a 5% solution of potassium hydroxide in refluxing methanol gave, after workup and column chromatography of the crude product, the enone 163 in 78% yield (equation 59). The ir spectrum of the enone 163 exhibited absorptions at 1671 and 1617 cm"1 due to the enone function. The : H nmr spectrum of 163 displayed a broad singlet at 5 5.85 due to the vinyl proton H n . A ddd (J=18,15,5 Hz) at 5 2.58 and a broad doublet (J=18 Hz) at 2.38 could be assigned to H 1 3a and H13e, respectively. VI. Preparation of the ketone 164 The next step in the synthetic sequence required the stereoselective generation of the BIC trans-fused ring junction to produce the ketone 164. The enone 163 was subjected to a dissolving metal reduction using sodium in ammonia-diethyl ether in the presence of tert-butyl alcohol (equation 60). The reaction mixture was refluxed for 40 min. After workup and column chromatography of the product mixture, the ketone 164 was obtained in 94% yield. The relative stereochemistry of this product was established -103-o o 163 164 on the basis of *H nmr experiments (vide infra). The ir spectrum of compound 164 showed a strong absorption at 1711 cm"1 due to the carbonyl group. The 1 H nmr spectrum of 164 (Figure 6) exhibited a dd (7=11,2 Hz) at 8 5.60 and a ddd (J=l 1,6,2 Hz) at 5.49 due to the vinyl protons H 3 and H 2 , respectively (see formula 164a). Two (one-proton) doublets (J=10 Hz each) appeared at 8 3.60 and 3.49 and were assigned to the methylene protons of the -CH2-OTBDMS moiety. A ddd (J=16,16,6 Hz) at 8 2.46 was ascribed to H 1 3a and the three-proton multiplet at 2.34-2.25 was assigned to protons H n a, H ne, and H13e. A one-proton broad doublet (J=18 Hz) at 8 1.27 was assigned to H 5 . The one-proton doublet of doublets (J=18,6 Hz) at 8 1.90 was assigned to the pseudo-equatorial proton H^. From the four-proton multiplet at 8 1.66-1.38, three protons were assigned to Hja, H1 4a, and H14e. The three-proton singlets at 8 1.14, 1.05, and 0.89 were assigned to the C-17, C-18, and C 2 0 methyl group protons, respectively. The nine-proton singlet at 8 0.90 and the three-proton singlets at 0.03 and 0.02 were due to the tert-butyldimethylsilyl group. -104-fi 1 1 r 3 2 1 Oppm Figure 6. The *H nmr spectrum (CDC13,400 MHz) of compound 164. In *H nmr decoupling experiments (see formula 164a), irradiation of the signal at 5 1.90 (Hje) simplified the signals at 5.49 ( H 2 ) and the four-proton multiplet at 1.66-1.38 (due to the decoupling of Hja); irradiation of the signal at 8 2.46 (H13a) simplified the three-proton multiplet at 2.34-2.25 (due to the decoupling of H13e) and the four-proton multiplet at 1.66-1.38 (due to the decoupling of H1 4e and H14a). The following nOe difference experiments corroborated the proposed structure for 164. Thus, irradiation of the signal at 8 1.90 (H:e) caused enhancement of the signals -105-enhancement of the signals at 3.60 (doublet, J=10 Hz, C 1 9 methylene proton), 2.34-2.25 (multiplet, Hna), 1.90 (dd, J=18,6 Hz, Hje) and the singlets at 1.14 (C 1 7 methyl protons), 0.03 and 0.02 (both signals due to protons on the methyl groups bonded to Si); irradiation of the signal at 8 1.05 (C 1 8 methyl protons) caused enhancement of the signals at 1.27 (dd, J=13,3 Hz, H 5 ; in this case the signal does not appear as a broad doublet but as a sharp dd), 3.49 (doublet, J=10 Hz, C 1 9 methylene proton) and 5.60 (dd, J=ll,2 Hz, H3). These nOe experiments are summarized by the arrows shown in the conformational formula 164b (vide supra). -106-The spectral data discussed above confirmed the expected stereochemical outcome for the Birch reduction of the enone 163 (see Section mg of this Discussion). That is, the B and C rings of 164 are indeed, as expected, trans-fused. This stereochemistry was indicated by the nuclear Overhauser enhancement of the signals due to H n a and H n e upon irradiation of the signals due to C-20 and Hje, respectively. From an examination of molecular models it appears that these enhancements would be very unlikely in the case of the corresponding BIC cis-fused ring system. On the other hand, the (expected) relative configuration at C-8 was confirmed by the nuclear Overhauser enhancement of the C-17 methyl group signal upon irradiation of the C-20 methyl group signal. Finally, the relative stereochemistry at C-4 was established on the basis of the nuclear Overhauser enhancement of the signal due to H 5 upon irradiation of the signal due to the C-18 methyl group. It should be noted that the relative stereochemistry at C-4 cannot be established on the basis of the enhancement of the C-19 methylene proton signal upon the simultaneous iiTadiation of the signals due to the C-20 methyl group (8 0.89) and the f-butyl group (8 0.90) (see arrows with a broken line in formula 164b). Vm. Conclusion The synthetic work described above resulted in a fifteen-step conversion of the ketone 17 into the tricyclic ketone 164 in 3 % overall yield. The palladium(0)-catalyzed coupling reaction to produce the nitrile 144 (equation 50, p.91), the stereoselective alkylation to produce compound 148 (equation 51, p.92), and the stereoselective reduction of the enone 163 (equation 60, p. 104) were key steps in our sequence. On the other hand, the synthesis of the Michael adduct 157 from the silyl enol ether 155 -107-(equation 58, p. 100) leaves much to be desired. A much needed improvement in the yield of this step would substantially increase the efficiency of our synthetic route. To this end some suggestions have been made in section Vj of this Discussion. However, due to time constraints, none of these were attempted. Another point worth considering in future work is the potential utility of an intermediate such as 150 (see p.94) as a suitable model for the functionalization of ring A. In conclusion, the methodology employed in the construction of the tricyclic intermediate 164 allowed for the stereoselective construction, with the correct relative configuration, of five of the six chiral centers present in the spongiadiols. Therefore, this appears to be a viable general route towards the total synthesis of the spongiadiol family of di terpenoids. -108-EXPERIMENTAL VI. General Proton nuclear magnetic resonance (*H nmr) spectra were recorded on a Bruker model WH 400 spectrometer using deuteriochloroform as the solvent and tetramethylsilane (TMS) as an internal standard. In some cases in which trialkylsilyl groups were present, the resonance positions were determined relative to the chloroform signal (8 7.25).92 Signal positions are given in parts per million (8) from TMS. The multiplicity, number of protons, coupling constants, and assignments (where possible) are indicated in parentheses. Abbreviations used are: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; w1/2, peak width at half height. In cases where a proton is coupled with the same coupling constant to two, three, four or five protons which are chemically and magnetically non-equivalent the designations dd, ddd, dddd and dddt are used instead of using t, q, quintet, and sextet respectively. For compounds exhibiting AB and ABX type spin systems the quoted values for chemical shifts and coupling constants are measured as if they were first order systems, although these values only approximate the real values.93 Decoupling experiments refer to ^ - - H spin decoupling experiments. Carbon nuclear magnetic resonance (1 3C nmr) spectra were recorded on a Varian model XL 300 spectrometer at 75.3 MHz using deuteriochloroform as the solvent and TMS as the internal standard. Signal positions are given in parts per million (8) from TMS. Infrared (ir) spectra were obtained on liquid films or using KBr pellets, employing a Perkin-Elmer model 1710 FT spectrophotometer. Low resolution mass -109-spectra (low res. ms) were recorded on a AEIMS9/DS55SM (1964, In-House 1980) or on a Kratos MS50/DS55SM (1974) spectrometer. High resolution mass spectra (used whenever Exact Mass is quoted) were recorded on a Kratos/AEl MS 50 or MS 902 spectrometer. All compounds which were characterized by high resolution mass measurements were homogeneous by glc and tic analyses. Microanalyses were performed by Mr. P. Borda, Microanalytical Laboratory, University of British Columbia. Gas-liquid chromatography (glc) was performed on either a Hewlett-Packard model 5880 or model 5890 capillary gas chromatograph, both using a flame ionization detector and a 25 m x 0.21 mm fused silica column coated with cross-linked SE-54. Thin layer chromatography (tic) was performed on commercially available aluminum backed silica gel plates (E. Merck, type 5554). Visualization was accomplished with iodine vapor, ultraviolet light or a 5 % solution of ammonium molybdate in 10 % aqueous sulfuric acid (w/v). Column chromatography (flash type94) was done on 230-400 mesh silica gel (E. Merck, silica gel 60). Melting points (uncorrected) were measured on a Fischer-Johns melting point apparatus. Distillation temperatures (uncorrected) are indicated as air-bath temperatures of Kugelrohr (bulb-to-bulb) distillations. Unless otherwise stated, all reactions were carried out under an atmosphere of dry argon, with dry solvents and in oven or flame-dried glassware. Concentration or removal of the solvent under reduced pressure (water aspirator) refer to solvent removal via a Biichi rotary evaporator at 15 Torr. Cold temperatures were maintained by the use of the following baths: acetone/ice (-10°C), aqueous calcium chloride/C02 (-20 to -40°C),95 acetone/C02 (-78°C), liquid nitrogen/dry methanol (-100°C). All temperatures are recorded in degrees Celsius (°C). -110-VTI. Solvents and reagents Petroleum ether refers to a hydrocarbon mixture with b.p. 30-60°C. Ether refers to diethyl ether. Tetrahydrofuran, ether, and benzene were distilled from sodium benzophenone ketyl. Dichloromethane and carbon tetrachloride were distilled from phosphorus pentoxide. Iodomethane was passed through a short column (Pasteur pipette) of basic alumina (activity I) before use. Dtisopropylamine, triethylamine, hexamethylphosphoramide, dimethyl sulfoxide, and acetonitrile were distilled from calcium hydride and stored over activated 4A molecular sieves. Ethanol and methanol were distilled from magnesium. tert-Butyl alcohol was distilled and dried over activated powdered 3A molecular sieves. Dimethylformamide was dried over activated 4A molecular sieves and distilled before use. Trimethylsilyl chloride was dried by refluxing over calcium hydride and was distilled before use. Solutions of methyllithium in ether (low halide content) and methyllithium-lithium bromide complex in ether, were obtained from Aldrich Chemical Co., Inc. and were standardized using the procedure of Kofron and Baclawski.96 Lithium diisopropylamide (LDA) was prepared by the addition of a solution of methyllithium-lithium bromide complex (1.0 equiv.) in ether to a solution of diisopropylamine (1.05 equiv.) in anhydrous tetrahydrofuran at -78°C. The resulting colorless or slightly yellow solution was stirred at 0°C for 10 min before being used. Diphenyl phosphorazidate was prepared as described by Yamada and coworkers.71 Formic acetic anhydride was prepared as described by Huffman.73 Copper(I) bromide-dimethyl sulfide complex was prepared by the method described by Wuts.97 -Ill-Triphenylphosphine was purified by recrystallization from methanol-ethyl acetate. All other reagents were commercially available and were utilized without further purification. Preparation of the alcohols 44 and 45 OH OH 44 To a cold (-20°C), stirred solution-suspension of sodium borohydride (0.420 g, 11.100 mmol) in dry methanol (27 mL) was added a solution of the ketone 1723 (1.750 g, 9.830 mmol) in dry methanol (10 mL). The reaction mixture was stirred at -20°C for 100 min. A saturated aqueous solution of ammonium chloride (10 mL) was added slowly and the mixture was allowed to warm to room temperature. The methanol was removed under reduced pressure and brine (20 mL) was added to the residue. The mixture was extracted with dichloromethane (3x50 mL). The combined extract was dried (MgS04) and the solvent was removed under reduced pressure. The resulting crude product was purified by column chromatography on silica gel (130 g, 9:1 petroleum ether-ethyl acetate). Distillation (air-bath temperature 70-75°C/0.4 Torr) of the oil thus obtained provided 1.750 g (98 %) of the alcohols 44/45 (9:1 mixture of epimers by glc analysis). -112-When the same experiment was carried out on a different scale it was possible to isolate a pure sample of each of the isomeric alcohols 44 and 45. Compound 44 exhibited on ir (film): 3385, 3067, 1646, 1082 cm'1;  lH nmr (400 MHz) 8 4.69-4.66 (m, 1H, vinyl proton), 4.66-4.63 (m, 1H, vinyl proton), 3.32 (dd, 1H, J=13,5 Hz, CH-OH), 2.22 (td, 1H, J=13,5 Hz), 2.10 (dd, 1H, J=13,5 Hz), 1.87 (dd, 1H, J=13,4 Hz), 1.83-1.22 (m, 11H, simplified upon addition of D20), 1.04 (s, 3H, methyl protons). Exact Mass. calcd. for C 1 2 H 2 0 O: 180.1514; found: 180.1512. The rninor isomer 45 exhibited on ir (film): 3389, 3067,1646,1050 cm"1; *H nmr (400 MHz) 8 4.68 (s, 1H, vinyl proton), 4.66 (s, 1H, vinyl proton), 3.50 (br s, 1H, CH-OH), 2.31-2.16 (m, 2H), 2.07 (dt, 1H, J=13,5 Hz),, 1.92-1.34 (m, 10H), 0.99 (s, 3H, methyl protons), 1.05-0.95 (m, 1H). Exact Mass. calcd. for C 1 2 H 2 0 O: 180.1514; found: 180.1507. Preparation of the alcohols 46 and 47 The mixture of alcohols 44/45 was dissolved in dry dichloromethane (5 mL) and dry air was slowly passed through the stirred solution at room temperature. Diiodomethane (3 mL, 37.200 mmol) was added and then a 1.6 M solution of diethylzinc in toluene (24 mL, 38.400 mmol) was added over a period of 15 min. (Explosion Hazard: The air current should never be introduced after the reagents have been mixed together under an inert atmosphere). The resulting solution was refluxed for 2.5 h under an atmosphere of dry air. The mixture was allowed to cool to room temperature and 10 % hydrochloric acid (20 mL) was added. The phases were separated and the aqueous layer was extracted with E^O (2x50 mL). The combined extract was -113-46a OH 47 washed with a saturated aqueous solution of ammonium chloride (1x10 mL) and brine (2x10 mL) and then was dried (K2CO3) and concentrated. Column chromatography of the residual material on silica gel (120 g, 9:1 petroleum ether-ethyl acetate) and distillation (air-bath temperature 79-84°C/0.8 Torr) of each of the products thus obtained afforded 1.350 g (72 % from the alcohols 44/45) of the alcohol 46 and 0.150 g (8 % from the alcohols 44/45) of the alcohol 47. The alcohol 46 exhibited ir (film): 3382, 3065, 1050 cm"1; ! H nmr (400 MHz) 8 3.27 (m, 1H, CH-OH, D 20 addition transforms the signal to a dd, J=ll,5 Hz), 1.90 (br dd, 1H, J=12,12 Hz, H a^), 1.80-1.13 (m, 11H), 1.30 (s, 1H, -OH, D 20 exchanged), 1.24 (s, 3H, methyl protons), 0.57 (dm, 1H, J=12 Hz, H e^), 0.47-0.32 (m, 3H, two cyclopropyl protons, Hs), 0.11-0.00 (m, 2H, cyclopropyl protons). In decoupling experiments, irradiation of the signal at 8 1.90 (H3a) caused the collapse of the signal at 8 0.57 (H3e) to a broad singlet; irradiation of the signal at 8 0.57 (H3e) caused the collapse of the signal at 1.90 (H3a) to a broad doublet (J=12 Hz) and simplified the multiplet at 8 0.47-0.32 (H5). Exact Mass calcd. for C 1 3 H 2 2 0: 194.1671; -114-found: 194.1671. The alcohol 47 showed ir (film): 3434, 3067, 1067 cm"1; J H nmr (400 MHz) 6 3.35 (br s, 1H, w1/2=8 Hz, sharpened upon addition of D20), 1.98-1.40 (m, 11H), 1.43 (br s, 1H, -OH, D 20 exchanged), 1.18 (s, 3H, methyl protons), 0.72 (dd, 1H, J=13,5 Hz), 0.56 (dm, 1H, J=13 Hz), 0.42-0.30 (m, 2H, cyclopropyl protons), 0.12-0.04 (m, 2H, cyclopropyl protons). ExaclMass calcd. for C^H^O: 194.1671; found: 194.1664. Preparation of the ketone 36 To a stirred slurry (room temperature) of pyridinium chlorochromate (3.000 g, 13.917 mmol) and 4 A molecular sieves (0.900 g) in dry dichloromethane (38 mL) was added a solution of a 9:1 mixture of the epimeric alcohols 46 and 47 (1.500 g, 7.730 mmol) in dry dichloromethane (8 mL). The reaction mixture was stirred at room temperature for 85 min. Diethyl ether (30 mL) was added and the mixture was filtered through a column of Florisil (30 g, elution with Et20). Concentration of the eluate and distillation (air-bath temperature 65-70°C/0.8 Torr) of the remaining oil gave 1.350 g (91 %) of the tricyclic ketone 36 which exhibited ir (film): 3068, 1703, 1374 cm"1; ! H nmr (400 MHz) 8 2.58 (ddd, 1H, J=13,13,6 Hz, Hga), 2.25 (dm, 1H, J=13 Hz), 2.14-1.95 (m, 3H), 1.90 (ddd, 1H, 1=11,11,5 Hz), 1.78-1.42 (m, 4H), 1.29 (s, 3H, methyl protons), 1.23 (br d, 1H, J=13 Hz), 0.77 (dd, 1H, J=13,4 Hz, H-5?), 0.65 (br d, 1H, J=13 Hz, H e^?), O 36 -115-0.49-0.32 (m, 2H, cyclopropyl protons), 0.25-0.08 (m, 2H, cyclopropyl protons). Exact  Mass calcd. for C13H20 :192.1515; found: 192.1513. Preparation of the ketones 48 and 49 To a cold (-78°C), stirred solution of LDA (1.660 mmol) in dry T H F (7.4 mL) was added a solution of the ketone 36 (0.290 g, 1.510 mmol) in dry THF (1.5 mL, washing with 1.5 mL of THF). The solution was stirred at -78°C for 15 min and at 0°C for 20 min. Methyl iodide (1 mL, 16.060 mmol) was added rapidly and the reaction mixture was stirred at 0°C for 45 min. Water (5 mL), a 5 % aqueous solution of sodium thiosulfate (5 mL) and Et20 (5 mL) were added. The phases were separated and the aqueous layer was extracted with Et20 (3x20 mL). The combined extract was washed with brine (2x10 mL) and dried (MgS04). Removal of the solvent under reduced pressure gave an oil that was shown (glc) to consist of two products in a ratio of 1.3:1 . -116-Subjection of this mixture to column chromatography on silica gel (30 g, 98:2 petroleum ether-ethyl acetate), followed by distillation (air-bath temperature 70-75°C/l Torr) of the oil thus obtained, furnished 0.297 g (95 %) of a mixture of ketones 48 and 49 as a colorless oil, which exhibited ir (film): 3068, 1703, 1374 cm"1; ! H nmr (400 MHz) (selected signals) 8 2.68, 2.63-2.52 (ddq, m, 1H total, ratio of signals ~1.3:1, J=13,6,6 Hz), 1.29, 1.22 (s, s, 3H total, ratio of signals ~1.3:1), 1.03, 1.00 (d, d, 3H total, ratio of signals ~1:1.3, J=6 Hz in each case), 0.66, 0.60 (br d, br d, 1H total, ratio of signals ~1.3:1, J=13.5 Hz in each case), 0.48-0.33 (m, 2H, cyclopropyl protons), 0.23-0.08 (m, 2H, cyclopropyl protons). Exact Mass calcd. for C14H220: 206.1671; found 206.1678. A solution of the epimeric mixture of ketones 48 and 49 (0.020 g, 0.097 mmol) in a 0.4 M solution of sodium methoxide in methanol (1 mL) was stirred overnight at room temperature. The solvent was removed under reduced pressure and a saturated aqueous solution of ammonium chloride (1 mL) and Et20 (1 mL) were added. The layers were separated and the aqueous phase was extracted with Et20 (2x2 mL). The combined extract was washed with brine (1x2 mL) and dried (MgS04). Removal of the solvent under reduced pressure gave an oil that was shown (glc) to consist nearly exclusively of the ketone 48. Column chromatography (silica gel, 2 g, 98:2 petroleum ether-ethyl acetate) of the oil thus obtained afforded 0.019 g (95 %) of the ketone 48 after removal of traces of solvent (vacuum pump). This compound exhibited ir (film): 3068, 1703, 1375 cm4; ! H nmr (400 MHz) 8 2.68 (ddq, 1H, J=13,6,6 Hz, Hga), 2.15 (dddd, 1H, 1=13,13,13,3.5 Hz), 2.08-1.98 (m, 2H), 1.93 (ddd, 1H, J=13,13,4.5 Hz), 1.77-1.54 (m, 3H), 1.35-1.15 (m, 2H), 1.29 (s, 3H, angular methyl protons), 1.00 (d, 3H, J=6 Hz, secondary methyl protons), 0.75 (dd, 1H, J=13,4 Hz, H^, 0.66 (br d, 1H, J=13.5 Hz, Hge), 0.47-0.41 (m, 1H, H^), 0.40-0.32 (m, 1H, l y , 0.21-0.08 (m, 2H, He, Ho). In a decoupling experiment, irradiation of the signal at 6 1.00 (secondary methyl protons) caused the collapse of the signal at 8 2.68 (H8a) to a dd (J=13,6 Hz). In nOe difference -117-experiments, irradiation of the signal at 8 0.47-0.41 (HA) caused enhancement of the signals at 8 1.29 (s, angular methyl protons), 8 0.66 (br d, J=13.5 Hz, H3e), 8 0.40-0.32 (m, HB) and 8 0.21-0.08 (m, He); irradiation of the multiplet at 8 0.40-0.32 (HB) caused enhancement of the signals at 8 1.29 (s, angular methyl protons), 8 0.75 (dd, H5), 8 0.47-0.41 (m, HA) and 8 0.14-0.08 (m, HD). Exact Mass calcd. for C 1 4 H 2 2 0: 206.1671; found 206.1678. Preparation of the silyl enol ether 50 OTBDMS To a cold (-78°C), stirred solution of LDA (5.335 mmol) in dry THF (36 mL) was added a solution of a ~1.3:1 mixture of the ketones 48 and 49 (1.000 g, 4.850 mmol) in 5 mL of dry THF and the solution was stirred for 20 min. The solution was warmed to 0°C and stirred for 20 min. Hexamethylphosphoramide (0.86 mL, 4.850 mmol) and cMorotrimethylsilane (0.10 mL, 5.820 mmol) were added successively. After the reaction mixture had been stirred at 0°C for 1 h, 1,1,1,3,3,3-hexamethyldisilazane (0.5 mL) was added and the solvent was removed under reduced pressure. Pentane (50 mL) was added to the residue and after the mixture had been stirred for a few seconds, the solution was decanted. To the residue was added saturated aqueous sodium bicarbonate (20 mL) and the mixture was extracted with pentane (2x20 mL). The combined extract -118-was mixed with the previously decanted solution, the solution was washed with brine (3x40 mL), dried (MgS04) and the solvent was removed under reduced pressure. The crude material was purified by column chromatography (silica gel, 130 g, 95:5 pentane-triethylamine). Removal of the volatile material (vacuum pump) from the appropriate fractions gave 1.282 g (91 %) of the silyl enol ether 50 as a colorless oil that exhibited ir (film): 3067, 1673, 1189, 840 cm"1; *H nmr (400 MHz) 5 2.15-1.70 (m, 4H), 1.65-1.40 (m, 5H), 1.54 (s, 3H, vinyl methyl protons), 1.19 (s, 3H, methyl protons), 0.62-0.50 (m, 2H), 0.45-0.30 (m, 2H, cyclopropyl protons), 0.20 (s, 9H, -SKCH^), 0.16-0.04 (m, 2H, cyclopropyl protons). Exact Mass calcd. for C 1 7H 3 0O 2Si: 278.2065; found: 278.2067. Preparation of the diketone 37 To a cold (-78°C), stirred solution of freshly distilled TiCl4 (0.05 mL, 0.397 mmol) in dry dichloromethane (0.4 mL) was added freshly distilled Ti(OPr-i)4 (0.075 mL, 0.270 mmol). The mixture was stirred at -78°C for 5 min and then was cooled to -100°C. A solution of the ethylene ketal of 3-buten-2-one46 (0.10 mL, 1.100 mmol) and the silyl enol ether 50 (0.095 g, 0.342 mmol) in dry dichloromethane (1.5 mL) was added. The mixture was stirred at -100°C for 1.75 h. After the reaction mixture had H3e 37 -119-been treated with water (2 mL), dichloromethane was added (2 mL) and the mixture was allowed to warm to room temperature. The layers were separated and the aqueous phase was extracted with dichloromethane (2x10 mL). The combined extract was washed with brine (2x4 mL) and the solvent was removed under reduced pressure. The residual material thus obtained was dissolved in 8 mL of a 1:1 solution of THF and 10 % hydrochloric acid and the mixture was stirred at room temperature for 1 h. A saturated aqueous solution of sodium bicarbonate was added slowly until the solution reached pH 7. The mixture was extracted with Et20 (3x25 mL). The combined extract was washed with brine (1x20 mL) and dried (MgS04). The solvent was removed under reduced pressure and the crude oil thus obtained was purified by column chromatography (silica gel, 10 g, 95:5 petroleum ether-ethyl acetate). Collection of the appropriate fractions and removal of traces of solvent (vacuum pump) from one of the oils thus obtained gave 0.028 g (41 %) of a 12.5:1 mixture (glc analysis) of the ketones 48 and 49. Distillation (air- bath temperature 120-130°C/0.4 Torr) of an oil obtained from other fractions gave the diketone 37 (0.045 g, 48 %) as a colorless oil. Glc analysis of this material showed that it was contaminated with ~3 % of another compound, likely the C8-epimer of 37. This material exhibited ir (film): 3066, 1716, 1689, 1371 cm"1; *H nmr (400 MHz) 5 2.40-2.20 (m, 2H), 2.20-2.00 (m, 1H), 2.12 (s, 3H, -(CO-CHj), 1.99-1.83 (m, 2H), 1.82-1.40 (m, 5H), 1.34 (br d, 1H, J=12 Hz), 1.30-1.15 (m, 1H), 1.27 (s, 3H, methyl protons), 1.19 (s, 3H, methyl protons), 0.75 (br d, 1H, J=12 Hz, Hs?), 0.64 (br d, 1H, J=14Hz, H e^?), 0.47-0.33 (m, 2H, cyclopropyl protons), 0.27-0.10 (m, 2H, cyclopropyl protons). Exact Mass calcd. for C ^ H ^ : 276.2090; found: 276.2090. -120-Preparation of the enone 32 O 32 To a solution of the diketone 37 (0.600 g, 2.174 mmol) in 70 mL of dry benzene were added potassium tert-butoxide (0.150 g, 1.300 mmol) and teat-butyl alcohol (1 mL, 10.70 mmol). The reaction mixture was refluxed under a Dean-Stark water trap for 2 h. The solution was allowed to cool to room temperature and a saturated aqueous solution of ammonium chloride (25 mL) was added. The layers were separated and the aqueous phase was extracted with a 1:1 solution of petroleum ether-ethyl acetate (2x30 mL). The combined extract was washed with brine (1x20 mL) and dried (MgS04). The solvent was removed under reduced pressure and the crude product thus obtained was purified by column chromatography (silica gel, 50 g, 95:5 petroleum ether-ethyl acetate). Solvent removal (water aspirator, then vacuum pump) from the appropriate fractions gave 0.170 g (38 %) of the ketone 48. Removal of the solvent from the fractions containing the major product, followed by distillation (air-bath temperature 124-129°C/0.5 Torr), gave 0.305 g (53 %) of the enone 32 as a colorless oil. This material exhibited ir (film): 3062, 1667, 1592, 1374 cm'1; *H nmr (400 MHz) 8 6.02 (s, 1H, vinyl proton), 2.59 (ddd, 1H, J=18,14,5 Hz), 2.37 (ddd, 1H, J=18,5,2), 2.08 (dddd, 1H, J=13,13,13,3 Hz), 2.01-1.79 (m, 3H), 1.76-1.38 (m, 5H), 1.38 (br s, 6H, methyl -121-protons), 1.31 (ddd, 1H, J=13,13,3.5 Hz), 1.12 (br d, 1H, J=14 Hz), 0.64 (br d, 1H, J=14 Hz, H e^), 0.59 (dd, 1H, J=13,3.5 Hz, Hj), 0.55-0.47 (m, 1H, cyclopropyl proton), 0.45-0.36 (m, 1H, cyclopropyl proton), 0.25-0.10 (m, 2H, cyclopropyl protons). Exact  Mass calcd. for C18H260:258.1983; found: 258.1989. Preparation of the ketone 56 17 7 56 56a Procedure a. To a cold (-78°C), stirred solution of potassium (0.035 g, 0.895 mmol) in ammonia (5 mL, freshly distilled from sodium) was added a solution of the enone 32 (0.019 g, 0.074 mmol) and tert-butyl alcohol (6uL, 0.059 mmol) in dry Et20 (0.5 mL). The reaction mixture was refluxed for 30 min. A saturated aqueous solution of ammonium chloride (1 mL) was added and the ammonia was removed using a warm water bath (~45°C). Diethyl ether (5 mL) and water (3 mL) were added to the residue and the layers were separated. The aqueous phase was extracted with Et20 (2x10 mL). The combined extract was dried (MgS04) and concentrated. The crude product thus obtained was purified by column chromatography on silica gel (0.85 g, Pasteur pipette, 95:5 petroleum ether-ethyl acetate). Removal of traces of solvent from each of the oils -122-thus obtained gave 0.007 g (37 %) of the enone 32 as an oil and 0.008 g (42 %) of the desired ketone 56 as a white crystalline solid, mp 99-100°C (recrystallization from pentane). Procedure b. To a solution (room temperature) of the enone 32 (0.185 g, 0.717 mmol) in ethyl acetate (10 mL) was added palladium on activated carbon (0.018 g, 10 % palladium content). The mixture was stirred under hydrogen gas (1 atm) for 7 h. The mixture was filtered through a plug of Florisil (2 g, elution with ethyl acetate) and the solvent was removed under reduced pressure. After removal of traces of solvent (vacuum pump) from the resulting oil and recrystallization from pentane, 0.180 (97 %) of the ketone 56 was obtained as a white crystalline solid, mp 99-100°C. This material exhibited ir (KBr): 3065, 1713, 1386 cm'1; *H nmr (400 MHz) 8 2.45 (ddd, 1H, J=14,14,7 Hz, H13a), 2.42 (ddd, 1H, J=14,3,3 Hz, Hne), 2.29 (dd, 1H, J=14,14 Hz, Hna), 2.29 (m, 1H, H13e), 1.89 (dddd, 1H, J=14,14,14, 3.5 Hz, H a^), 1.84 (ddd, 1H, J=13,13,3 Hz, IL^ a), 1.70-1.40 (m, 6H), 1.39 (ddd, 1H, J=14,14,5 Hz, H14a), 1.28 (dd, 1H, J=14,3 Hz, Hoa), 1.20 (s, 3H, C 1 8 methyl protons), 1.12 (br d, 1H, J=14 Hz, Hje?), 1.09 (s, 3H, C 1 7 methyl protons), 0.60 (br d, 1H, J=13 Hz, FLje), 0.48-0.41 (m, 1H, cyclopropyl proton), 0.41-0.33 (m, 1H, cyclopropyl proton), 0.33 (dd, 1H, J=14,4 Hz, Hs), 0.16-0.06 (m, 2H, cyclopropyl protons). In decoupling experiments, irradiation of the overlapping signals at 8 2.45 (H13a) and 2.42 (Hne) simplified the multiplet at 8 1.70-1.40 (H14e) and caused the collapse of the signals at 8 1.39 (H14a) to a broad doublet (J=14 Hz) and 8 1.28 (Hoa) to a doublet (J=14 Hz); irradiation of the overlapping signals at 8 2.29 (H13e, Hjja) simplified the multiplet at 8 1.70-1.40 (H14e) and caused the collapse of the signals at 8 1.39 (H14a) to a dd (J=14,14 Hz) and 8 1.28 (Hoa) to a doublet (J=3 Hz); irradiation of the signal at 8 1.28 (Hoa) caused the collapse of the signals at 8 2.42 (Hne) to a dd (J=14,3 Hz) and 8 2.29 (Hna) to a doublet (J=14 Hz). In nOe difference experiments, irradiation of the overlapping signals at 8 1.89 (H^ a) and 8 -123-1.84 (H3a) caused enhancement of the signals at 8 1.47 (dq, J=14,4 Hz, H6e) and 8 0.60 (br d, J=13 Hz, H3e); irradiation of the signal at 8 1.28 (Hga) caused enhancement of the signals at 8 1.09 (s, C 1 7 methyl protons) and 8 0.33 (dd, J=14,4 Hz, H5); irradiation of the signal at 8 1.20 (C 1 8 methyl protons) caused enchancement of the signals at 8 2.45 (ddd, J=14,14,7 Hz, H13a), 8 2.29 (dd, J=14,14 Hz, Hna), 8 1.84 (ddd, 14,14,5 Hz, rl^ a) and 8 1.62 (ddd, J=14,14,5 Hz, Hxa?); irradiation of the signal at 8 0.33 (H5) caused enhancement of the signals at 8 1.47 (dq, J=14,4 Hz, H6e), 8 1.28 (dd, J=14,3 Hz, Hoa) and 8 1.09 (C 1 7 methyl protons). Exact Mass calcd. for C^H^O: 260.2140; found: 260.2138. Preparation of the alcohol 57 OH To a stirred solution (room temperature) of the alcohol 46 (0.317 g, 1.634 mmol) in glacial acetic acid (5 mL) was added platinum(TV) oxide (0.037 g, 0.163 mmol). The mixture was stirred under hydrogen gas (1 atm) for 2.5 h. The mixture was filtered through a plug of Florisil (6 g, elution with ethyl acetate) and the eluate was neutralized by adding slowly a saturated aqueous solution of sodium bicarbonate (~10 mL) and enough solid potassium carbonate to bring the aqueous phase to pH 7. The layers were separated and the aqueous phase was extracted with ethyl acetate (2x10 mL). The combined extract was washed with brine (1x10 mL) and dried (MgS04). The solvent -124-was removed under reduced pressure, affording 0.297 g (93 %) of the alcohol 57 as a white solid exhibiting mp 91-93°C (recrystallization from pentane); ir (KBr): 3281, 1386, 1365, 1042 cm"1; *H nmr (400 MHz) 6 3.23 (dd, 1H, J=13,4 Hz, CH-OH), 1.77-1.35 (m, 8H), 1.34-1.13 (m, 2H), 1.25 (s, 3H, methyl protons), 1.15 (s, 3H, methyl protons), 1.04 (br dd, 1H, J=12,5 Hz), 0.86 (s, 3H, methyl protons). Exact Mass calcd. for C13H240: 196.1827; found: 196.1827. Preparation of the ketone 38 O To a stirred slurry (room temperature) of pyridinium chlorochromate (0.400 g, 1.836 mmol) in dry dichloromethane (10 mL) was added a solution of the alcohol 57 (0.200 g, 1.020 mmol) in dry dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 2 h. Diethyl ether (5 mL) was added and the resultant suspension was filtered through a column of Florisil (8 g, elution with Et20). Removal of the solvent from the eluate, followed by distillation (air-bath temperature 70-75°C/l Torr) of the residual oil, gave 0.195 g (98 %) of the ketone 38 as a colorless oil that exhibited ir (film): 1703, 1387, 1366 cm"1; -H nmr (400 MHz) 8 2.70-2.56 (m, 1H), 2.35-2.20 (m, 2H), 2.19-2.00 (m, 2H), 2.00-1.80 (m, 2H), 1.65-1.45 (m, 2H), 1.44-1.25 (m, 3H), 1.26 (s, 3H, methyl protons), 1.18 (ddd, 1H, J=12,3 Hz), 0.97 (s, 3H, methyl -125-protons), 0.87 (ddd, 1H, J=13,13,5 Hz), 0.85 (s, 3H, methyl protons). Exact Mass calcd. forC 1 3H 2 20: 194.1670; found: 194.1664. Preparation of the ketones 58 and 59 O 59 59a To a cold (-78°C), stirred solution of LDA (2.268 mmol) in dry THF (15 mL) was added a solution of the ketone 38 (0.400 g, 2.062 mmol) in dry THF (1 mL, washing with 1 mL of THF). The solution was stirred at -78°C for 20 min and at 0°C for 20 rnin. Methyl iodide (2 mL, 32.120 mmol) was added rapidly and the reaction mixture was stirred at room temperature for 1 h. Water (10 mL), a 5 % aqueous solution of sodium -126-thiosulfate (8 mL) and EtzO (10 mL) were added. The phases were separated and the aqueous layer was extracted with Et 20 (3x40 mL). The combined extract was washed with brine (2x30 mL) and dried (MgS04). Removal of the solvent under reduced pressure gave an oil that was shown (glc) to consist of two products in a ratio of 4.2:1. Subjection of this mixture to column chromatography on silica gel (40 g, 98:2 petroleum ether-ethyl acetate), followed by distillation (air-bath temperature 70-75°C/l Torr) of the oil thus obtained, furnished 0.346 g (81 %) of a mixture of ketones 58 (major compound) and 59 as a colorless oil exhibiting ir (film): 1702, 1390, 1377 cm"1; ! H nmr (400 MHz) 5 2.87, 2.59 (ddq, ddq, 1H total, ratio of signals ~1:5, J=14,7,7 Hz in each case, Hga), 1.29, 1.28 (s, s, 3H total, ratio of signals ~5:1, met hyl protons),0 1.08, 0.95, 0.87, 0.78 (s, s, s, s, 6H total, ratio of signals ~5:1:5:1, methyl protons); 1.03, 0.99 (d, d, 3H total, ratio of signals ~5:1, J=7 Hz in each case, C23 methyl protons). Exact Mass calcd. for C 1 4H240: 208.1827; found: 208.1819. A solution of the epimeric mixture of ketones 58 and 59 (0.005 g, 0.024 mmol) in a 0.2 M solution of sodium methoxide in methanol (1 mL) was stirred for 1.75 h at room temperature. The solvent was removed under reduced pressure. Dichloromethane (1 mL), water (1 mL) and a saturated aqueous solution of ammonium chloride (1 mL) were added and the layers were separated. The aqueous phase was extracted with dichloromethane (2x3 mL). The combined extract was washed with brine (1x3 mL) and dried (MgS04). Removal of the solvent under reduced pressure gave an oil which was shown to consist (glc) of the ketones 59 and 58 in a ratio of 6.2:1. Column chromatography (silica gel, 0.85 g, Pasteur pipette, 98:2 petroleum ether-ethyl acetate) of the oil thus obtained enabled the collection of a fraction which contained the ketone 59 exclusively (glc analysis). Solvent removal from this fraction and distillation of the oil thus obtained (air-bath temperature 70-75°C/l Torr) afforded a sample (homogeneous by tic and glc analyses) of the ketone 59 which exhibited ir (film): 1703, 1378, 1366 cm-1; -127-*H nmr (400 MHz) 8 2.87 (ddq, 1H, J=14,7,7 Hz, Hga), 2.29 (br d, 1H, J=13 Hz), 2.26-2.13 (m, 1H, Hga), 2.04 (br ddd, 1H, J=14,7,6, H7e), 1.86 (br dd, 1H, J=14,6 Hz, Hge), 1.73 (dddd, 1H, J=14,14,14,6Hz,H7a),1.64 (brd, 1H, J=6Hz, H5), 1.59 (dddt, 1H, 1=13,13,13,6 Hz, H3J, 1.36 (dddt, 1H, J=13,4,4,4 Hz, I^ e), 1.33-1.25 (m, 1H), 1.28 (s, 3H, methyl protons), 1.16 (ddd, 1H, J=13,13,4 Hz), 0.99 (d, 3H, J=7 Hz, secondary methyl protons), 0.95 (s, 3H, methyl protons), 0.85 (ddd, 1H, J=13,13,4 Hz), 0.78 (s, 3H, methyl protons). In decoupling experiments, irradiation of the signal at 8 2.87 (H8a) caused the collapse of the signals at 8 2.04 (H7e) to a broad dd (J=14,6 Hz), 8 1.73 (H7a) to a ddd (J=14,14,6 Hz) and 8 0.99 (secondary methyl protons) to a singlet; irradiation of the signal at 8 2.04 (H7e) caused the collapse of the signals at 8 2.87 (H8a) to a dq (J=14,7 Hz) and 8 1.73 (H7a) to a ddd (J=14,14,6 Hz), simplified the multiplet at 8 2.26-2.13 (Hga) and sharpened the broad doublet at 8 1.64 (H5); irradiation of the signal at 8 1.73 (H7a) caused the collapse of the signals at 8 2.87 (H8a) to a dq (J=7,7 Hz), 8 2.04 (H7e) to an unresolved multiplet and 8 1.86 (H^ e) to a broad doublet (J=14 Hz), and simplified the multiplet at 8 2.26-2.13 (Hga); irradiation of the signal at 8 1.86 (H6e) simplified the signals at 8 2.26-2.13 (H^ a) and 8 1.73 QH7a) and caused the collapse of the signal at 8 2.04 (H7e) to a dd (J=14,7 Hz); irradiation of the multiplet at 8 2.26-2.13 (Hga) simplified the signals at 8 1.86 (Hge), 8 1.73 (H7a) and 8 2.04 (H^), and caused the collapse of the broad doublet at 8 1.64 (H5) to a broad singlet. Exact Mass calcd. for C^H^O: 208.1827; found: 208.1819. Preparation of the silvl enol ether 60 To a cold (-78°C), stirred solution of LDA (1.724 mmol) in dry THF (11.7 mL) was added a solution of the ketones 58 and 59 (0.326 g, 1.567 mmol, 4.2:1 mixture of -128-OTBDMS 60 epimers) in 2 mL of dry THF and the solution was stirred for 30 min. The solution was warmed to 0°C and stirred for 15 min. Hexamethylphosphoramide (0.29 mL, 1.595 mmol) and freshly distilled cMorotrimethylsilane (0.23 mL, 1.812 mmol) were added successively. After the reaction mixture had been stirred at 0°C for 20 min, 1,1,1,3,3,3-hexamethyldisilazane (0.25 mL) was added and the solvent was removed under reduced pressure. Pentane (50 mL) was added to the residue and after the mixture had been stirred for a few seconds, the solution was decanted. To the residue was added saturated aqueous sodium bicarbonate (20 mL) and the mixture was extracted with pentane (2x20 mL). The combined extract was mixed with the previously decanted solution. The solution was washed with brine (3x10 mL), dried (MgS04) and the solvent was removed under reduced pressure. The crude material was purified by column chromatography (silica gel, 25 g, 95:5 pentane-triemylamine). Removal of the volatile material (vacuum pump) from the appropriate fractions gave 0.420 g (96 %) of the silyl enol ether 60 as a colorless oil. This material exhibited ir (film): 1680, 1253, 1190, 843 cm1; *H nmr (400 MHz) 8 2.15-1.96 (m, 2H), 1.96-1.80 (m, 2H), 1.70-1.58 (m, 1H), 1.50 (s, 3H, vinyl methyl protons), 1.45-1.03 (m, 6H), 1.13 (s, 3H, methyl protons), 1.00 (s, 3H, methyl protons), 0.94 (s, 3H, methyl protons), 0.20 (s, 9H, -SKCH^). Exact  Mass calcd. for C 1 7H 3 2OSi: 280.2222; found: 280.2220. -129-Preparation of the diketone 39 To a stirred solution (room temperature) of freshly distilled TiCl4 (0.18 mL, 1.630 mmol) in dry dichloromethane (12 mL) was added freshly distilled Ti(OPr-i)4 (0.49 mL, 1.630 mmol). The mixture was stirred at room temperature for 3 min and then was cooled to -100°C. A solution of the ethylene ketal of 3-buten-2-one46 (0.44 mL, 4.840 mmol) and the silyl enol ether 60 (0.415 g, 1.482 mmol) in dry dichloromethane (3.3 mL) was added. The mixture was stirred at -100°C for 15 min. After the reaction mixture had been treated with water (20 mL), dichloromethane (10 mL) was added and the mixture was allowed to warm to room temperature. The layers were separated and the aqueous phase was extracted with dichloromethane (2x50 mL). The combined extract was washed with brine (1x20 mL) and the solvent was removed under reduced pressure. The residual material thus obtained was dissolved in 35 mL of a 1:1 solution of THF and 10 % hydrochloric acid and the mixture was stirred at room temperature for 1 h. A saturated aqueous solution of sodium bicarbonate was added slowly until the aqueous phase was neutral, The mixture was extracted with E^O (3x30 mL). The combined extract was washed with brine (1x20 mL) and dried (MgS04). The solvent was removed under reduced pressure and the crude oil thus obtained was purified by column chromatography (silica gel, 30 g, 9:1 petroleum ether-ethyl acetate). Collection -130-of the appropriate fractions and removal of traces of solvent (vacuum pump) from the oil thus obtained gave 0.073 g (24 %) of a ~1:7 mixture of the ketones 58 and 59. Distillation (air-bath temperature 120- 130°C/0.4 Torr) of an oil obtained from other fractions gave (0.186 g, 45 %) of the diketone 39 as a colorless oil. This material exhibited ir (film): 1718, 1688, 1367 cm'1; ! H nmr (400 MHz) 8 2.40 (ddd, 1H, J=18,10,6 Hz, -CH2-(CO)-), 2.22 (ddd, 1H, J=18,9,7 Hz, -CH^CO)-), 2.13 (s, 3H, -(CCO-CH3), 2.18-1.65 (m, 7H), 1.58-1.35 (m, 3H), 1.35-1.25 (m, 1H), 1.28 (s, 3H, methyl protons), 1.25-1.15 (m, 1H), 1.15-1.00 (m, 1H), 1.07 (s, 3H, methyl protons), 1.04 (s, 3H, methyl protons), 0.89 (s, 3H, methyl protons). Exact Mass calcd. for C 1 8 H 3 0 O2: 278.2246; found: 278.2247. Preparation of the enone 61 61 The diketone 39 (0.015 g, 0.054 mmol) was dissolved in 1 mL of a 5 % solution of potassium hydroxide in methanol and the reaction mixture was refluxed for 7.5 h. The solution was allowed to cool to room temperature and was neutralized with a 10 % solution of hydrochloric acid. The aqueous phase was extracted with Et20 (3x5 mL). -131-The combined extract was washed with brine (1x5 mL) and dried (MgS04). The solvent was removed under reduced pressure and the crude product thus obtained was purified by column chromatography (silica gel, 0.85 g, Pasteur pipette, 9:1 petroleum ether-ethyl acetate). Solvent removal under reduced pressure and distillation (air-bath temperature 120-125°C/0.1 Torr) of the oil thus obtained, afforded 0.01 g (71 %) of the enone 61 as a colorless oil, which exhibited ir (film): 3057, 1666,1587, 1377 cm"1; *H nmr (400 MHz) 8 6.08 (s, 1H, vinyl proton), 2.59 (ddd, 1H, J=18,15,6 Hz, H13a), 2.37 (ddd, 1H, J=18,6,2 Hz, H13e), 1.90-1.55 (m, 7H), 1.50-1.20 (m, 5H), 1.39 (s, 3H, methyl protons), 1.33 (s, 3H, methyl protons), 1.23 (s, 3H, methyl protons), 1.13 (br d, 1H, J=12 Hz), 0.97 (s, 3H, methyl protons). Exact Mass calcd. for C 1 8 H 2 8 0: 260.2140; found: 260.2139. Preparation of the ketone 31 Procedure a. To a cold (-78°C), stirred solution of potassium (0.144 g, 3.690 mmol) in ammonia (8 mL, freshly distilled from sodium) was added a solution of the enone 61 (0.032 g, 0.123 mmol) and tert-butyl alcohol (23uL, 0.246 mmol) in dry Et20 (0.5 mL). The reaction mixture was refluxed for 1 h. Isoprene was added until the blue -132-color of the solution disappeared. The ammonia was removed using a stream of argon. Diethyl ether (10 mL) and a saturated aqueous solution of ammonium chloride (5 mL) were added to the residue and the layers were separated. The aqueous phase was extracted with E^O (3x10 mL). The combined extract was washed with brine (1x10 mL), dried (MgSO^ and concentrated. The crude product thus obtained was purified by column chromatography on silica gel (3 g, 95:5 petroleum ether-ethyl acetate). Removal of traces of solvent (vacuum pump) from the materials thus obtained gave 0.011 g (34 %) of the enone 61 as an oil and 0.020 g (62 %) of the desired ketone 31 as a white crystalline solid, mp 80- 81°C (recrystallization from petroleum ether). Procedure b. To a stirred solution (room temperature) of the ketone 56 (0.017 g, 0.065 mmol) in glacial acetic acid (2 mL) was added platinum (TV) oxide (0.002 g, 0.009 mmol). The mixture was stirred under hydrogen gas (1 arm) for 2 h. The mixture was filtered through a plug of Florisil (0.6 g, Pasteur pipette, elution with ethyl acetate) and the eluate was neutralized by adding slowly a saturated aqueous solution of sodium bicarbonate (~3 mL) and enough solid potassium carbonate to bring the aqueous phase to pH 7. The layers were separated and the aqueous phase was extracted with ethyl acetate (3x5 mL). The combined extract was washed with brine (1x5 mL) and dried (MgS04). The solvent was removed under reduced pressure and the residual material was dissolved in dry dichloromethane (0.5 mL). The solution was added (room temperature) to a stirred slurry of pyridinium chlorochromate (0.028 g, 0.131 mmol) in dry dichloromethane (1.5 mL). The reaction mixture was stirred for 1 h. Diethyl ether (3 mL) was added and the mixture was filtered through a plug of Florisil (~0.6 g, elution with Et20). Removal of the solvent under reduced pressure and column chromatography of the residual oil thus obtained (silica gel, 0.85 g, Pasteur pipette, 95:5 petroleum ether-ethyl acetate), afforded 0.016 g (93 %) of the ketone 31 as a crystalline solid, mp 80-81°C (recrystallization from petroleum ether). This material (which was identical -133-with the main product obtained from procedure a) exhibited ir (KBr): 1713, 1389 cm"1; *H nmr (400 MHz) 8 2.50-2.38 (m, 2H, H1 3a, Hne), 2.29 (dddd, 1H, J=15,5,2,2 Hz, H13e), 2.25 (dd, 1H, J=15,15 Hz, Hna), 1.70-0.98 (m, 14H), 1.17 (s, 3H, methyl protons), 1.16 (s, 3H, methyl protons), 1.08 (s, 3H, methyl protons), 0.92 (s, 3H, methyl protons). Exact Mass calcd. for C18H30 :262.2297; found 262.2299. -134-Preparation of the acid 96 H C0 2H 96 To a stirred solution of the acid 9770a (0.125 g, 0.694 mmol) in ethyl acetate (3 mL) was added palladium on activated carbon (0.010 g, 10 % palladium content) at room temperature. The mixture was stirred under hydrogen gas (1 atm) for 3 h. The mixture was filtered through a plug of Florisil (2 g, elution with ethyl acetate) and the solvent was removed under reduced pressure from the filtrate. After removal of traces of solvent (vacuum pump), 0.120 g (95 %) of the saturated acid 96 was obtained as a white solid, mp 128-131°C (petroleum ether-ethyl acetate); ir (KBr): 3024, 1695, 936 cm"1; *H nmr (400 MHz) 6 2.09 (br d, 2H, J=12 Hz), 1.93-1.68 (m, 4H), 1.67-1.54 (m, 2H), 1.45-1.10 (m, 9H). Exact Mass calcd. for C n H 1 8 0 2 : 182.1307; found: 182.1306. Preparation of the carbamate 99 H -135-To a stirred (room temperature) solution of the acid 96 (0.078 g, 0.429 mmol) in toluene (0.3 mL) were added diphenylphosphorazidate71 (120 uL, 0.600 mmol) and triethylamine (62 uL, 0.443 mmol). The solution was stirred at 80°C for 2 h and then 2-(trimethylsilyl)ethanol (0.30 mL, 2.10 mmol) was added. After the mixture had been stirred for 1.5 h, additional 2-(trimethylsilyl) ethanol (0.20 mL, 1.4 mmol) and triethylamine (62 uL, 0.443 mmol) were added. The reaction mixture was stirred at 80°C for 36 h. The solvent was removed under reduced pressure (water aspirator, then vacuum pump) and E^O (3 mL) was added to the residue. The resultant solution was filtered through a plug of silica gel (10 g, elution with Et20). The eluate was concentrated and the crude product was purified by column chromatography on silica gel (100 g, 98:2 petroleum ether-Et20). Traces of solvent were removed (vacuum pump) from the material thus obtained, affording 0.100 g (79 %) of the carbamate 99 as a colorless oil. This compound exhibited ir (film): 3456, 1729, 1504 cm"1; lH nmr (400 MHz) 8 4.37 (br s, 1H, w1/2=12 Hz, -NH-(CO)O-), 4.12 (t, 2H, J=8 Hz, -0-CH2-CH2-), 2.50 (br d, 2H, J=14 Hz), 1.70 (br d, 2H, J=14 Hz), 1.65-1.21 (m, 9H), 1.15 (ddd, 2H, J=12,12,3 Hz), 1.05-0.94 (m, 4H), 0.04 (s, 9H, methyl protons). Exact Mass calcd. for C 1 6H 3 1N0 2Si: 297.2124; found: 297.2122. Preparation of the formamide 104 H HN-CHO 104 -136-To a stirred solution (room temperature) of the carbamate 99 (0.055 g, 0.185 mmol) in dry THF (1.7 mL) was added a 1 M solution of tetra-n-butvlammonium fluoride in THF (0.70 mL, OJOmmol). The solution was stirred at 55°C for 3 h. The solvent was removed under reduced pressure and petroleum ether (30 mL) and a 4:1 solution (30 mL) of saturated aqueous ammonium chloride and concentrated ammonium hydroxide were added to the residue. The phases were separated and the aqueous phase was extracted with petroleum ether (2x30 mL). The combined extract was washed successively with an aqueous solution of saturated ammonium chloride (1x30 mL) and brine (2x30 mL). The solution was dried (MgSO^ and the solvent was removed under reduced pressure (water aspirator, then vacuum pump). The crude oil thus obtained was dissolved in dry Et20 (1.5 mL) and formic acetic anhydride73 (0.2 mL, 0.19 mmol) was added. The solution was stirred at room temperature for 2 h. Water (2 mL) and Et20 (5 mL) were added and the phases were separated. The aqueous phase was extracted with Et20 (2x3 mL) and the combined extract was washed with brine (1x5 mL) and dried (MgS04). Removal of the solvent under reduced pressure and recrystallization (petroleum ether-Et20) of the material thus obtained gave 0.031 g (92 % from the carbamate 99) of the formamide 104 as a white solid, mp 140-143°C; ir (KBr): 3304, 3060, 1662, 1529 cm"1; *H nmr (400 MHz) 8 8.21 (d, 0.5 H, J=1.5 Hz, -CHO), 8.16 (d, 0.5H, J=13 Hz, -CHO), 6.08 (br s, 0.5H, -NH-CHO), 5.01 (br s, 0.5H, -NH-CHO), 3.01 (br t, 1H, J=8 Hz), 2.65 (br d, 1H, J=14 HZ), 1.85 (br d, 1H, J=14 Hz), 1.81-1.65 (br t, 2H, J=14 Hz), 1.60-1.49 (m, 2H), 1.49-1.02 (m, 10H). Exact Mass calcd. for C n H 1 9 NO: 181.1467; found: 181.1472. -137-Preparation of the isonitrile 105 H NC 105 To a stirred solution (room temperature) of the formamide 104 (0.020 g, 0.110 mmol) in dry dichloromethane (0.5 mL) were added triphenylphosphine (0.040 g, 0.153 mmol), CC14 (12 uL, 0.113 mmol) and triemylamine (20 uL, 0.143 mmol). The reaction mixture was stirred at 60°C for 2 h . An additional amount of CC14 (12 uL) was added and stirring was continued for 2 h. The reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The solid residue thus obtained was washed several times with a 97:3 pentane-Et2C* solution. The combined washings were concentrated and the crude product was purified by column chromatography (silica gel, 10 g, 99:1 pentane-Et20). Recrystallization (pentane-Et20) of the material thus obtained afforded 0.0136 g (76 %) of the isonitrile 105 as a white solid, mp 33-35°C; ir (KBr): 2119, 1450 cm"1; J H nmr (400 MHz) 6 1.90-1.59 (m, 8H), 1.52-1.10 (m,9H). Exact Mass calcd. for C n H 1 7 N : 163.1361; found: 163.1356. Preparation of the ketone 82 A solution of the enone 2421 (0.0350 g, 0.083 mmol) and tert-butyl alcohol (17 uL, 0.180 mmol) in dry Et20 (0.8 mL) was added via cannulation to a stirred solution of sodium (0.029 g, 1.261 mmol) in ammonia (3 mL, freshly distilled from sodium). The -138-\ OTBDMS SiO O Me02C | H5e O 82 82a reaction mixture was refluxed for 40 min. Isoprene was added dropwise until the blue color of the solution disappeared. A saturated solution of aqueous ammonium chloride (10 mL) and Et20 (5 mL) were added successively. While the resultant mixture was stirred for 4 h, it was warmed occasionally with a water bath (~45°C) and Et20 was added occasionally. The layers were separated and the aqueous phase was extracted with Et20 (2x10 mL). The combined extract was dried (MgS04) and concentrated. The crude product was purified by column chromatography on silica gel (20 g, 9:1 petroleum ether-Et20), affording 0.0300 g (86 %) of the ketone 82 as a white solid, mp 79-81°C (recrystallization from pentane); ir (film): 1724,1707, 838, 776 cm"1; *H nmr (400 MHz) 8 3.68 (s, 3H, -OCH3), 3.65 (dd, 1H, J=10,5.5 Hz, -CH2-OSiMe2Bu-t), 3.60 (dd, 1H, J=10,10 Hz, -CH2-OSiMe2Bu-t), 2.62 (ddd, 1H, J =13.5,8,3.5 Hz), 2.53 (m, 1H, H e^), 2.50-2.35 (m, 2H), 2.32 (dd, 1H, J=13,4 Hz, H12a), 2.08 (dddd, 1H, J =13,3,3,3 Hz, g^ e), 1.88 (ddd, 1H, J=13.5,3,3 Hz, H e^), 1.74 (dddd, 1H, J =11,11,11,3 Hz, I^ a), 1.56 (dd, 1H, J=13,ll Hz, H13a), 1.52 (m, 1H), 1.47-1.32 (m, 3H, H a^, H e^, H a^), 1.28 (m, 1H), 1.12 (ddd, 1H, J =13.5,13.5, 3.5 Hz, H2a), 1.00-0.79 (m, 1H), 0.95 (d, 3H, J=6 Hz, methyl protons), 0.90 (d, 3H, J =6 Hz, methyl protons), 0.89 (s, 9H, t-butyl protons), 0.05 (s, 3H, methyl protons), 0.03 (s, 3H, methyl protons). In decoupling experiments, -139-irradiation of the signal at 8 1.12 (H2a) simplified the multiplet at 8 2.53 (r^ e) and caused the collapse of the signal at 8 1.88 (H2e) to a broad singlet; irradiation of the signal at 8 1.88 (H2e) simplified the multiplet at 8 2.53 (Hje) and caused the collapse of the signal at 8 1.12 (H2a) to a d of d, (J=13.5,3.5 Hz); irradiation of the signal at 8 2.08 (H5e) simplified the multiplet at 8 1.47-1.32 (H6a, H6e, H5a) and caused the collapse of the signal at 8 1.74 (H4a) to a ddd (£=11,11,11 Hz); irradiation of the signal at 8 2.32 (H12a) simplified the multiplet at 8 2.53 (H^) and caused the collapse of the signal at 8 1.56 (H13a) to a doublet (J =11 Hz). Exact Mass calcd. for C^E^oC^Si (M+-Me): 407.2618; found: 407.2610. Preparation of the alcohol 88 OTBDMS Me02C | 88 To a cold (-78°C), stirred solution of the ketone 82 (0.06 g, 0.142 mmol) in dry THF (3.30 mL) was added a 1.0 M solution of lithium oi-sec-butylborohydride in THF (0.20 mL, 0.200 mmol). The solution was stirred for 3 h at -78°C and for 1 h at 0°C. A 10 % aqueous solution of sodium hydroxide (0.5 mL) and a 30 % aqueous solution of hydrogen peroxide (0.33 mL) were added and the mixture was stirred at room -140-temperature for 5 h. Water (20 mL) and diethyl ether (20 mL) were added and the layers were separated. The aqueous phase was extracted with Et20 (3x25 mL) and the combined extract was washed successively with a 5 % aqueous solution of sodium bisulfite (1x20 mL) and brine (2x20 mL). The extract was dried (MgS04) and concentrated. Column chromatography of the crude product on silica gel (10 g, 9:1 pentane-Et20) and removal of traces of solvent (vacuum pump) from the material thus obtained, afforded 0.059 g (98 %) of the alcohol 88 as a colorless oil. This product exhibited ir (film): 3453, 1724,1256,1170, 1072 cm'1; ! H nmr (400 MHz) 8 5.26 (t, 1H, J=2.5 Hz, -OH, D 20 exchanged), 4.10 (dd, 1H, J=9.5,ll Hz, -CH^-OSiMe^u-t), 3.91 (br s, 1H, w1/2=7.5 Hz, H ne, sharpened when D 20 is added), 3.66 (s, 3H, -(CO^CH^), 3.49 (br d, 1H, J=ll Hz, -CH2-OSiMe2Bu-t), 2.16 (ddd, 1H, J=13,3.5,3.5 Hz), 2.00-1.86 (m, 3H), 8.20 (m, 1H), 1.66 (dd, 1H, J=11.5,11.5 Hz, H13a), 1.81-1.10 (m, 8H), 0.96 (d, 3H, J=7 Hz, methyl protons), 0.89 (s, 9H, t-butyl protons), 0.93-0.80 (m, 2H), 0.84 (unresolved d, 3H, methyl protons), 0.10 (s, 3H, methyl protons), 0.09 (s, 3H, methyl protons). Exact Mass calcd. for C ^ ^ ^ S i (M+-H20): 406.2903; found: 406.2903. Preparation of the ester acetal 89 OTBDMS -141-To a stirred solution (room temperature) of the alcohol 88 (0.279 g, 0.596 mmol) in dry acetonitrile (7.1 mL) were added successively N,N-diisopropylethylamine (0.47 mL, 2.70 mmol), 4-N,N-(iimethylammopyridine (0.003 g, 0.025 mmol) and chloromethyl methyl ether (0.20 mL, 2.60 mmoL). The mixture was refluxed for 5 h and then was allowed to cool to room temperature. The solvent was removed under reduced pressure. Diethyl ether (40 mL) and a saturated aqueous solution of sodium bicarbonate (20 mL) were added to the crude product The layers were separated and the aqueous phase was extracted with EtzO (2x40 mL). The combined extract was washed with brine (2x40 mL) and dried (MgS04). Removal of the solvent and column chromatography of the crude oil thus obtained (silica gel, 45 g, 9:1 pentane-Et20) gave 0.295 g (96 %) of the ester acetal 89 as a colorless oil, after removal of traces of solvent (vacuum pump). This compound exhibited ir (film) 1724, 1082, 1045 cm'1; *H nmr (400 MHz) 5 4.65 (s, 2H, -O-CH^-OMe), 3.87 (dd, 1H, J=10.5, 5.5 Hz, -CH -^OSiMe^ Bu-t), 3.72 (br s, 1H, w1/2=7.5 Hz, Hne), 3.66 (s, 3H, -(CCOOCHg), 3.61 (dd, 1H, J=10.5,10.5 Hz, -CH2-OSiMe2Bu-t), 3.39 (s, 3H, -0-CH2-OCH3), 2.18 (m, 1H), 2.05-1.6 (m, 5H), 1.58-1.10 (m, 8H), 0.93 (d, 3H, J=6.5 Hz, methyl protons), 0.90 (s, 9H, t-butyl protons), 0.86 (d, 3H, J=6.5 Hz, methyl protons), 1.07-0.80 (m, 2H), 0.03 (s, 3H, methyl protons), 0.02 (s, 3H, methyl protons). Exact Mass calcd. for C24H4304Si (M^C^O): 423.2931; found: 423.2932. -142-Preparation of the alcohol 90 OH Me02C I 90 To the ester acetal 89 (0.085 g, 0.182 mmol) was added a 1 M solution of tetra-K-butylammonium fluoride in THF (2.44 mL, 2.44 mmol). The solution was stirred at room temperature for 5 h. A saturated aqueous solution of sodium bicarbonate (10 mL) was added and the resultant mixture was extracted with Et20 (3x20 mL). The combined extract was washed with brine (2x20 mL) and dried (MgS04). Removal of the solvent under reduced pressure and column chromatography of the crude product (silica gel, 14 g, 7:3 Et20-petroleum ether) afforded, after removal of traces of solvent (vacuum pump) from the oil thus obtained, 0.062 g (96 %) of the alcohol 90 as a colorless oil. This compound exhibited ir (film): 3417, 1723, 1039 cm4; *H nmr (400 MHz) 8 4.73-4.67 (m, 2H, -O-CH^-OMe), 3.92-3.81 (m, 1H, -CH2-OH, transformed to a dd, J=12,6 Hz when D 20 was added), 3.88 (br s, 1H, Hne), 3.68 (, 3H, -(CO)OCH3), 3.59 (ddd, 1H, J=12,7,4 Hz, -CH2-OH, transformed to a dd, J =12,4 Hz when D 20 was added), 3.44 (s, 3H, -O^-Oai , ) , 3.20 (t, 1H, J=7 Hz, -OH, D 20 exchanged), 2.24-2.15 (m, 1H), 2.09 (ddd, 1H, J=13,6,3 Hz), 2.04-1.94 (m, 2H), 1.92-1.71 (m, 2H), 1.71-1.15 (m, 9H), 0.95 (d, 3H, J=7 Hz, methyl protons), 1.01-0.82 (m, 1H), 0.85 (d, 3H, J=6 Hz, methyl protons). Exact Mass calcd. for C ^ q ^ O s : 354.2406; found: 354.2408. -143-Preparation of the aldehyde 92 Me02C | 92 To a stirred slurry of pyridinium chlorochromate (0.280 g, 1.300 mmol) and sodium acetate (0.028 g, 0.619 mmol) in dry dichloromethane (9 mL) (room temperature) was added a solution of the alcohol 90 (0.218 g, 0.619 mmol) in dry dichloromethane (2 mL). The reaction mixture was stirred for 2 h at room temperature. Dry Et20 (10 mL) was added and the mixture was filtered through a column of Florisil (20 g, elution with Et20). The solvent was removed from the eluate under reduced pressure and the crude product was dissolved in dry methanol (3.5 mL). A 0.20 M solution of sodium methoxide in methanol (0.3 mL) was added and the solution was stirred at room temperature for 6.5 h. The solvent was removed under reduced pressure and Et20 (30 mL) and a saturated aqueous solution of ammonium chloride (10 mL) were added to the residue. The aqueous phase was extracted with Et20 (2x30 mL) and the combined extract was washed with brine (1x30 mL) and dried (MgS04). The solvent was removed under reduced pressure and the crude product thus obtained was purified by column chromatography on silica gel (35 g, 7:3 petroleum ether-Et20). Collection of the appropriate fractions, concentration and removal of traces of solvent (vacuum pump) -144-afforded 0.161 g (74 %) of the aldehyde 92 as a colorless oil exhibiting ir (film): 2704, 1724, 1377,1042 cm"1; *H nmr (400 MHz) 8 9.58 (d, 1H, J=3.5 Hz, -CHO), 4.65 (d, 1H, J=7 Hz, -O-CTb-OMe), 4.56 (d, 1H, J =7 Hz, -O-CH^-OMe), 3.69 (br s, 4H, -(CO)OCH3, Hne), 3.37 (s, 3H, -CH2-OCH3), 2.67 (dddd, 1H, J=12, 11.5,3.5,3.5 Hz, Hja), 2.28 (m, 1H), 2.10-1.85 (m, 3H), 1.73 (dd, 1H, J=10,3.5 Hz, H2e), 1.60-1.02 (m, 9H), 0.94 (d, 3H, J=6 Hz, methyl protons), 0.91 (d, 3H, J=7 Hz, methyl protons), 1.00-0.81 (m, 1H). In decoupling experiments, irradiation of the signal at 8 9.58 (formyl group proton) caused the collapse of the dddd at 8 2.67 (Hxa) to a ddd (J=12,l 1.5,3.5 Hz); irradiation of the signal at 8 2.67 (TH^ a) caused the collapse of the doublet at 8 9.58 (formyl group proton) to a singlet, simplified the multiplets at 8 2.10-1.85 (H12a ?) and 8 1.60-1.02 (H2a ?), and changed the dd at 8 1.73 (H2e) to a doublet (J=10 Hz). Exact  Mass calcd. for C 1 9 H 2 8 0 4 (M+-CH40): 320.1987; found: 320.1990. Preparation of the ester alkene 93 Sodium hydride (0.021 g, 80 % dispersion in oil, 0.700 mmol) was placed in a flame dried, three-necked flask equipped with a reflux condenser and was washed with Me02C | 93 -145-pentane (3x0.5 mL). The system was alternately evacuated (vacuum pump) and filled with argon (3 times). Freshly distilled dimethyl sulfoxide (7 mL) was introduced and the stirred mixture was heated at 70°C until evolution of hydrogen ceased. The transparent solution thus obtained was allowed to cool to room temperature. Isopropyltriphenylphosphonium bromide (0.278 g, 0.720 mmol, recrystallized from pentane- dichloromethane and dried overnight, (vacuum pump)) was added in small portions through the top of the condenser. A current of argon was introduced via a needle inserted through a septum on the flask while the phosphonium bromide was being added. The dark red solution obtained after the addition was stirred at room temperature for 15 min. A solution of the aldehyde 92 (0.062 g, 0.164 mmol) in dry dimethyl sulfoxide (2 mL) was added using a cannula. The reaction mixture was stirred for 2 h at room temperature. Water (40 mL) was added and the mixture was extracted with 1:1 pentane-Et20 (2x40 mL). Solid NaCl was added to the aqueous phase which was then extracted with 1:1 pentane-Et20 (1x40 mL) and pentane (1x40 mL). The combined extract was washed with water (5x20 mL) and brine (2x20 mL), was dried (MgS04) and then was concentrated. The crude product thus obtained was purified by column chromatography on silica gel (10 g, 92:8 petroleum ether-EtzO). Collection of the appropriate fractions, concentration and removal of traces of solvent (vacuum pump) gave 0.062 g (~93 %, small amount of Et20 present) of the ester alkene 93 as a colorless oil exhibiting ir (film): 1725,1376,1171,1147,1045 cm"1; *H nmr (400 MHz) 5 4.89 (br d, 1H, J=10 Hz, vinyl proton), 4.63 (d, 1H, J=6 Hz, 0-CH2-OMe), 4.53 (d, 1H, J=6 Hz, -O-CH^-OMe), 3.57 (s, 3H, -(CO)-OCH3), 3.65 (br s, 1H, w1/2=8 Hz, Hne), 3.35 (s, 3H, -CH2-OCH3), 2.45-2.33 (m, 1H, Hja), 2.32 -2.24 (m, 1H), 2.05-1.80 (m, 4H), 1.66 (d, 3H, J=l Hz, isopropylidene methyl protons), 1.59 (d, 3H, J=l Hz, isopropylidene methyl protons), 1.58-1.10 (m, 9H), 0.98-0.80 (m, 1H), 0.90 (d, 3H, J=7 Hz, methyl protons), 0.86 (d, 3H, J=7 Hz, methyl protons). In a decoupling experiment irradiation of the -146-doublet at 8 4.89 (vinyl proton) simplified the multiplet at 5 2.45-2.23 (H^) and caused the collapse of the doublets at 8 1.66 and 8 1.59 (isopropylidene methyl protons) to the corresponding singlets. Exact Mass calcd. for C^I^gC^: 378.2770; found: 378.2765. Preparation of the keto ester 76 To a cold (-78°C), stirred solution of the ester alkene 93 (0.062 g, 0.164 mmol) in dry dichloromethane (1.5 mL) was added a 1.3 M solution of dimethylboron bromide (0.195 mmol) in dry dichloromethane (0.15 mL). After the solution had been stirred at -78°C for 20 min, THF (2.1 mL) and a saturated aqueous solution of sodium bicarbonate (1 mL) were added simultaneously. The mixture was warmed to room temperature. Brine (5 mL) and Et20 (5 mL) were added, the phases were separated and the aqueous phase was extracted with Et20 (2x5 mL). The combined extract was washed with brine (1x5 mL) and dried (MgS04). The solvent was removed under reduced pressure (water aspirator, then vacuum pump) and the crude product was dissolved in dry dichloromethane (1 mL). This solution was added using a cannula (washing with 0.5 mL of dry dichloromethane) to a stirred slurry of pyridinium chlorochromate (0.095 g, 0.440 Me02C | 76 -147-mmol) and anhydrous sodium acetate (0.012 g, 0.146 mmol) in dry dichloromethane (2 mL). The mixture was stirred at room temperature for 2 h. Diethyl ether (3 mL) was added and the resultant suspension was filtered through a column of Florisil (10 g, elution with Et20). Removal of the solvent from the eluate gave a crude product that was purified by column chromatography (silica gel, 11 g, 9:1 pentane-Et20). Removal of traces of solvent (vacuum pump) from the material thus obtained afforded 0.046 g (85 %) of keto ester 76 as a white solid, mp 91-93°C (recrystallization from pentane-Et20); ir (KBr) 1724, 1717, 1375 car1; ! H nmr (400 MHz) 8 4.67 (dm, 1H, J=9 Hz, H1 4), 3.77 (s, 3H, -C02CH3), 2.82 (ddd, 1H, J=13.5,6,3 Hz), 2.65-2.54 (m, 1H), 2.48 (ddd, 1H, J =13.5,13.5,6 Hz), 2.33-2.23 (m, 1H), 2.27 (dd, 1H, J=l 1.5,10 Hz, H12a), 1.06 (dq, 1H, J=13.5,3.5 Hz), 1.96 (m, 1H), 1.73 (d, 3H, J=1.5 Hz, isopropylidene methyl protons), 1.62 (d, 3H, J=l Hz, isopropylidene methyl protons), 1.57-1.24 (m, 7H), 1.17 (dd, 1H, J=12.5,11.5 Hz, H13a), 0.93 (d, 3H, J =7 Hz, methyl protons), 0.88 (d, 3H, J=6 Hz, methyl protons), 0.97-0.78 (m, 1H). Exact Mass calcd. for C^^Og: 332.2351; found: 332.2344. Preparation of the enol triflate 94 Me02C | 94 -148-To a cold (-48°C), stirred solution of LDA (0.561 mmol) in dry THF (1.1 mL) was added a solution of the keto ester 76 (0.046 g, 0.139 mmol) in dry THF (0.5 mL, washing with 0.5 mL of dry THF). The solution was stirred for 1 h. A solution of hexamethylphosphoramide (25uL, 0.138 mmol) and N-phenyltrifluoromethane-sulfonimide (0.150 g, 0.420 mmol) in dry THF (0.5 mL) was added. The reaction mixture was stirred for 15 min, was allowed to warm to room temperature, and then was stirred for an additional 30 min. The solution was poured into a vigorously stirred saturated aqueous solution of sodium bicarbonate (15 mL). The mixture was extracted with pentane (3x20 mL) and the combined extract was washed with brine (2x10 mL) and dried (MgS04). The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel (8 g, pentane, then 97:3 pentane-Et20). After removal of traces of solvent from each fraction, 0.01 g of the starting material was recovered and 0.0335 g (67 %, based on recovered starting material) of the enol triflate 94 was obtained as a colorless oil. The enol triflate 94 exhibited ir (film): 1728, 1207 cm"1; ^-nmr (400 MHz) 5 5.73 (br d, 1H, J=7 Hz, H1 0), 5.04 (br d, 1H, J =8 Hz, H1 4), 3.64 (s, 3H, -(COOCHg), 3.03 (dd, 1H, J=18,7 Hz), 2.25-2.38 (m, 2H), 2.10 (m, 1H), 1.83 (m, 1H), 1.66 (d, 3H, J=l Hz, isopropylidene methyl protons), 1.57 (d, 3H, J=l Hz, isopropylidene methyl protons), 0.90 (d, 3H, J=7 Hz, methyl protons), 0.88 (d, 3H, J=6 Hz, methyl protons); Exact Mass calcd. for C22 H3i F305 S : 464.1844; found: 464.1852. Preparation of the ester diene 75 A solution of the enol triflate 94 (0.066 g, 0.142 mmol) in dry Et20 (0.5 mL, washing with 0.5 mL of Et20) was added to a cold (-10°C) solution of Me2CuLi68 (1.422 -149-Me02C I 75 mmol) in Et20 (4 mL). The reaction mixture was stirred at -10°C for 2 h. A saturated aqueous solution of ammonium chloride-ammonium hydroxide (pH=8, 10 mL) was added and stirring was continued for 1 h. The mixture was extracted with Et20 (3x20 mL). The combined extract was washed with brine (1x20 mL) and dried (MgS04). The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel (11 g, 97:3 pentane-Et20). Removal of traces of solvent (vacuum pump) from the material thus obtained gave 0.043 g (92 %) of the ester diene 75 as a colorless oil, which exhibited ir (film): 1726, 1456, 1381 cm-1; *H nmr (400 MHz) 5 5.39-5.34 (m, 1H, H 1 0), 5.09 (dm, 1H, J=9 Hz, H1 4), 3.62 (s, 3H, -(CO)OCH3), 2.83 (br dd, 1H, J=17,6 Hz), 2.14 (ddd, 1H, 1=10.5,10,5 Hz), 2.04-0.95 (m, 1H), 1.84 (br dd, 1H, J=10.5,10.5 Hz), 1.75-1.48 (m, 2H), 1.63 (d, 3H, J=l Hz, isopropylidene methyl protons), 1.60 (br d, 3H, J=l Hz, vinylic methyl protons), 1.56 (d, 3H, J=l Hz, isopropylidene methyl protons), 1.48-1.34 (m, 3H), 1.18 (dd, 1H, J=10.5,10.5 Hz, H13a), 1.14-0.80 (m, 4H), 0.88 (d, 3H, J=6 Hz, methyl protons), 0.84 (d, 3H, J=6.5 Hz, methyl protons). Exact Mass calcd for C22H3402: 330.2559; found: 330.2561. -150-Preparation of the acid 95 95 95a An 80 % dispersion of sodium hydride (0.05 g, 1.67 mmol) in mineral oil was washed with dry THF (3x1 mL). To this material was added dry THF (2.5 mL). The stirred mixture was cooled to at 0°C, and then benzeneselenol (0.17 mL, 1.600 mmol) and hexamethylphosphoramide (0.565 mL, 3.250 mmol) were added. The resulting orange colored solution was transferred by cannulation to a flask equipped with a reflux condenser. To this solution (room temperature) was added a solution of the ester diene 75 (0.05 g, 0.150 mmol) in dry THF (2x0.5 mL). The mixture was refluxed for 54 h, cooled to room temperature, and the solvent was removed under reduced pressure. To the residual material thus obtained were added slowly water (2 mL) and a 10 % solution of hydrochloric acid (2 mL). The mixture was extracted with Et20 (5x15 mL). The combined extract was washed with water (5x20 mL) and brine (5x20 mL). The solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel, 8 g; 4:1, then 3:2 hexane-Et20). After removal of traces of solvent (vacuum pump) from the material thus obtained, 0.0405 g (85 %) of the acid 95 was obtained as a white solid, mp 174-176°C (recrystallization from pentane-Et20); ir (KBr): 3280-2380 (br), 1687, 1444, 1277 cm"1; *H nmr (400 MHz) 8 5.45-5.36 (m, 1H, -151-H1 0), 5.10 (dm, 1H, J=9 Hz, H 1 4), 2.80 (dd, 1H, J=17,6 Hz, H e^), 2.21-2.10 (m, 1H, H a^), 2.10-2.01 (m, 1H), 1.95 (br dd, 1H, J=10.5,10.5 Hz, H12a), 1.71 (br d, lh, J=17 Hz, H<,a), 1.64 (d, 3H, J=l Hz, isopropylidene methyl protons), 1.63 (d, 3H, J=l Hz, methyl protons), 1.56 (d, 3H, J=l Hz, isopropylidene methyl protons), 1.21 (dd, 1H, J=10.5,10.5 Hz, H13a), 1.14-1.00 (m, 1H), 0.93 (d, 3H, J=6.5 Hz, methyl protons), 0.87 (d, 3H, J=6.5 Hz, methyl protons). In decoupling experiments, irradiation of the signal at 8 5.45-5.36 (H10) caused the collapse of the signal at 8 2.80 (Hoe) to a doublet (J=17 Hz) and sharpened the doublet at 8 1.71 (Hoa); irradiation of the signal at 8 5.10 (H14) caused the collapse of the signal at 8 2.21-2.10 (Hxa) to a ddd (1=10.5,10.5,4 Hz) and changed each of the doublets at 8 1.64 and 1.56 (isopropylidene methyl protons) to a singlet. Exact  Mass calcd. for C 2 i H 3 2 0 2 : 316.2403; found: 316.2403. Preparation of the carbamate 111 To a stirred solution (room temperature) of the acid 95 (0.019 g, 0.06 mmol) in dry toluene (0.3 mL) were added triethylamine (14 uL, 0.100 mmol) and diphenylphosphoryl azide (14 uL, 0.070 mmol). The solution was stirred at 80°C for 23 -152-h and then 2-(trimethylsilyl)ethanol (0.100 mL, 0.700 mmol) and triethylamine (0.100 mL, 0.720 mmol) were added. After the mixture had been stirred at 90°C for 24 h, additional 2-(trimethylsilyl)ethanol (0.100 mL) and triethylamine (0.100 mL) were added. The reaction mixture was stirred at 90°C for 24 h. The solvent was removed under reduced pressure (water aspirator, then vacuum pump) and E^O (3 mL) was added to the residue. The resultant solution was filtered through a plug of silica gel (2 g, elution with Et20). The eluate was concentrated and the crude product was purified by column chromatography on silica gel (20 g, 95:5 pentane-Et20). After removal of traces of solvent (vacuum pump) from the oil thus obtained, 0.025 g (96 %) of the carbamate 111 was obtained as a colorless oil. This compound exhibited ir (film): 3446, 3035, 1736, 1508, 1250, 1224 cm1; *H nmr (400 MHz) 8 5.34 (br d, 1H, J=5 Hz, H1 0), 5.11 (dm, 1H, J=9 Hz, H1 4), 4.27 (br s, 1H, wiy2=4 Hz, -(CO)-NH-), 4.13-4.02 (m, 2H, -(CO)0-CH2-), 3^ 68 (br d, 1H, J=16 Hz, H e^), 2.30-2.20 (m, 1H), 2.00 (dddd, 1H, 1=13,4,4,4 Hz), 1.81 (br dd, 1H, J=10,10 Hz, H12a), 1.73 (br d, 1H, J=16 Hz, Hoa), 1.68-1.64 (m, 6H, isopropylidene methyl protons, C20 methyl protons), 1.58 (d, 3H, J=l Hz, isopropylidene methyl protons), 1.55-1.10 (m, 8H), 1.00-0.85 (m, 2H), 0.96 (d, 3H, J=7 Hz, methyl protons), 0.88 (d, 3H, J=7 Hz, methyl protons), 0.80-0.70 (m, 1H), 0.03 (s, 9H, methyl protons). Exact Mass calcd. for C 2 6H 4 5N0 2Si: 431.3219; found: 431.3228. Preparation of (±)-8-isocvano-10,14-amphilectadiene ((±)-23) To a stirred solution (room temperature) of the carbamate 111 (0.020 g, 0.046 mmol) in dry THF (0.9 mL) was added a 1 M solution of tetra-n-butylammonium fluoride in THF (0.38 mL, 0.38 mmol). The solution was stirred at 55°C for 2 h. The -153-23 solvent was removed under reduced pressure and pentane (6 mL) and a 4:1 solution of saturated aqueous ammonium chloride and 30 % aqueous ammonium hydroxide (3.6 mL) were added to the residue. The phases were separated and the aqueous phase was extracted with pentane (2x6 mL). The combined extract was dried (MgSO^ and the solvent was removed under reduced pressure (water aspirator, then vacuum pump). The crude oil thus obtained was dissolved in Et20 (0.9 mL) and formic acetic anhydride73 (75 uL, 0.57 mmol) was added. The solution was stirred at room temperature for 2 h. Water (3 mL) and Et20 (5 mL) were added and the phases were separated. The aqueous phase was extracted with Et20 (2x6 mL) and the combined extract was washed with brine (1x3 mL) and dried (MgS04). The solvent was removed under reduced pressure (water aspirator, then vacuum pump). The crude oil thus obtained was dissolved (room temperature) in dry dichloromethane (0.4 mL) and triphenylphosphine (0.032 g, 0.122 mmol), CC14 (11 uL, 0.104 mmol) and triethylamine (43 uL, 0.308 mmol) were added. The mixture was stirred at 55°C for 1 h. The solvent was removed under reduced pressure and the residual material was washed several times with a 97:3 pentane-Et20 solution. The combined washings were concentrated and the crude product was purified by column chromatography (silica gel, 5 g, initial elution with pentane, then the polarity -154-of the eluate was increased gradually to 97:3 pentane-Et20). Collection and concentration of the appropriate fractions gave 0.011 g (80 % from the carbamate 111) of the isonitrile (±)-23 as a white solid that exhibited mp 79-81°C (recrystallization from pentane-Et20). This compound exhibited ir (KBr): 2126, 1447, 1379 cm4; ! H nmr (400 MHz) 8 5.26 (m, 1H, w1/2=ll Hz, H1 0), 5.15 (dm, 1H, J=9 Hz, H 1 4), 2.45 (br dd, 1H, J=17, 4.5 Hz, Hoe), 2.31-2.19 (m, 1H), 2.12-1.92 (m, 3H), 1.69 (d, 3H, J=l Hz, C 2 0 methyl protons), 1.66 (d, 3H, J=l Hz, isopropylidene methyl protons), 1.57 (d, 3H, J=l Hz, isopropylidene methyl protons), 1.02 (d, 3H, J=6.5 Hz, methyl protons), 0.88 (d, 3H, J=6 Hz, methyl protons). The *H nmr spectrum of this material was identical with that of natural 8-isocyano-10,14-amphilectadiene 2326; 1 3 C nmr (75.3MHz, CDC13, proton decoupled) 8 15.4, 17.5, 19.5, 25.1, 25.7, 29.1, 28.8, 37.2, 37.9, 40.6, 41.4, 42.1, 43.5, 44.8, 49.5, 63.2 (t, Jc uN=4.5 Hz), 118.8, 126.7, 133.4, 137.6, 154.4 (t, Ic.uN=4.5 Hz). These chemical shifts agree well with those published26 for natural 8-isocyano-10,14-amphilectadiene. Exact Mass calcd. for C ^ ^ N : 297.2457; found: 297.2461. -155-Preparation of the ketal alkene 137 H 137 To a solution of the ketone 1723 (0.115 g, 0.646 mmol) in 2.6 mL of dry benzene was added 0.043 mL (0.775 mmol) of ethylene glycol, and 10 mg of silica gel containing 5% p-toluenesulfonic acid. The mixture was refluxed for 2.5 h under a Dean-Stark water trap. After the mixture had been cooled to room temperature, the solvent was removed under reduced pressure and the remaining crude material was subjected to column chromatography on silica gel (10 g, elution with 95:5 petroleum ether-E^O). Collection and concentration of the appropriate fractions, followed by removal of traces of solvent (vacuum pump) afforded 0.121 g (84%) of the ketal alkene 137 as a colorless oil which exhibited ir (film): 3067, 1650, 1092 cm"1; *H nmr (400 MHz) 8 4.66-4.60 (m,2H,C=CH2), 4.03-3.87 (m, 4H, ketal protons ), 2.32-2.17 (m, 2H), 2.07 (dd, 1H, J=14,4 Hz), 1.90-1.47 (m, 6H), 1.43 (brd, 1H, J= 14Hz), 1.38-1.17 (m, 3H), 0.88 (s, 3H, methyl protons). Exact Mass calcd. for C14H2202:222.1620; found: 222.1617. Preparation of the keto ketal 138 To a mixture of the ketal alkene 137 (0.074 g, 0.333 mmol), CC14 (2 mL), acetonitrile (2 mL), water (3 mL) and sodium periodate (0.300 g, 1.403 mmol) was added ruthenium (IV) oxide (0.003 g, 6.8 mol %). The mixture was stirred vigorously at -156-o 138 room temperature for 2 h. Gas-liquid chromatographic analysis of the organic phase at this stage showed that almost half of the starting material had not reacted. Therefore 1.5 mL of water, 1 mL of CC14, 1 mL of acetonitrile and 0.003 g of Ru02 were added and vigorous stirring was continued for 3 h. Gas-liquid chromatographic analysis showed that no starting material was present in the reaction mixture. Dichloromethane (10 mL) was added and the phases were separated. The aqueous phase was extracted with dichloromethane (3x10 mL) and the combined extract was dried (MgS04) and concentrated. The residue was diluted with 20 mL of Et20 and the resultant mixture was filtered through a celite pad. Concentration of the filtrate gave a crude product which was purified by column chromatography on silica gel (10 g, 4:1 petroleum ether-Et20). Removal of traces of solvent (vacuum pump) from the oil thus obtained gave 0.038 g (51 %) of the ketone 138 as a colorless oil. This material was homogeneous by tic and glc analyses and exhibited ir (film): 1712,1089 cm"1; lH nmr (400 MHz) 6 4.02-3.87 (m, 4H, ketal protons ), 2.49 (ddd, 1H, 1=13,12,7 Hz), 2.36 (dd, 1H, J=12,5 Hz), 2.25-2.19 (m, 1H), 2.11 (ddd, 1H, 1=14,14,5 Hz), 2.04-1.94 (m, 1H), 1.92-1.69 (m, 4H), 1.67-1.50 (m, 4H), 0.95 (s, 3H, methyl protons). Exact Mass calcd. for C 1 4 H 2 0 O 3 : 224.1412; found: 222.1414. -157-Preparation of the keto ketal 139 The ketone 138 (0.038 g, 0.170 mmol) was dissolved in 1 mL of a 0.17 M solution of sodium methoxide in methanol. The solution was stirred at room temperature for 24 h. The solvent was removed under reduced pressure. Water (5 mL) and dichloromethane (5 mL) were added to the residue and the phases were separated. The aqueous phase was extracted with dichloromethane (3x5 mL) and the combined extract was dried (MgS04). Gas-liquid chromatographic analysis of this solution showed the presence of the starting material and the desired product 139 in a ratio of about 1:4.8, respectively. Removal of the solvent and subjection of the crude product to column chromatography (silica gel, 4g, 4:1 petroleum ether-E^O) gave 0.025 g (66%) of the pure keto ketal 139 after having removed traces of solvent (vacuum pump). This material exhibited mp 72-73°C (recrystallization from pentane-E^O). Combination of the remaining column fractions and the mother liquors from the recrystallization afforded 0.01 g of a 1:1 mixture of the product 139 and the starting material 138. The keto ketal 139 showed ir (KBr): 1705, 1084 cm"1; *H nmr (400 MHz) 8 4.06-3.90 (m, 4H, ketal protons), 2.64 (dd, 1H, J= 12,3 Hz), 2.34-2.25 (m, 2H), 2.05-1.92 (m, 2H), 1.90-1.76 (m, 1H), 1.74-1.50 (m, 5H), 1.49-1.39 (m, 2H), 0.92 (s, 3H, methyl protons). Exact Mass calcd. for Q4H20O3: 224.1413; found: 224.1417. -158-Preparation of the ketal alkene 140 140 A stirred solution of the keto alkene 1723 (0.588 g, 3.303 mmol), 2,2-dimethyl-l,3-propanediol (0.515 g, 4.945 mmol) and p-toluenesulfonic acid (5 mg, 0.026 mmol) in 13.6 mL of dry benzene was refluxed for 2 h under a Dean-Stark water trap. The solvent was removed under reduced pressure and the residue was subjected to column chromatography on silica gel (60 g, 98:2 pentane-E^O). Collection and concentration of the appropriate fractions gave 0.596 g (68 %) of ketal alkene 140 as a white solid, which showed mp 76-77°C (recrystallization from pentane). This material exhibited ir (KBr): 3067, 1650, 1106 cm"1; *H nmr (400 MHz) 6 4.69-4.59 (m, 2H, C=CH2), 3.70 (d, 1H, J=12 Hz, ketal proton), 3.64 (d, 1H, J=12 Hz, ketal proton), 3.32 (dd, 1H, J=12,3 Hz, ketal proton), 3.27 (dd, 1H, J=12,3 Hz, ketal proton), 2.55 (br d, 1H, J=12 Hz), 2.30-2.18 (m, 2H), 2.05 (br dd, 1H, J=13,4 Hz), 1.87-1.69 (m, 2H), 1.68-1.49 (m, 3H), 1.48- 1.21 (m, 4H), 1.19 (s, 3H, methyl protons), 1.08 (s, 3H, methyl protons), 0.71 (s, 3H, methyl protons). Exact Mass calcd for CnH^C^ : 264.2089; found: 264.2089. An inseparable mixture of two other products (0.216 g, 4.6:1 glc ratio) was also isolated as a colorless oil after removal of traces of solvent (vacuum pump). The major component was presumed to be the ketal alkene 140a on the basis of the spectral -159-data obtained from this mixture: ir (film): 1472, 1394, 1109 cm"1; *H nmr (400 MHz) 8 3.72 (d, J=ll Hz, ketal proton), 3.57 (d, J=ll Hz, ketal proton), 3.36 (dd, J—11, 3 Hz, ketal proton), 3.29 (dd, J=ll,3 Hz, ketal proton), 2.60 (br d, J=14 Hz), 2.54 (br d, J=14 Hz), 1.82 (br d, J=17 Hz), 1.62 (br s, 3H, vinylic methyl protons), 1.44 (ddd, J=12,12,4 Hz), 1.18 (s, methyl protons), 1.13 (s, methyl protons), 0.70 (s, methyl protons). Preparation of the keto ketal 141 O 141 Ozone was bubbled into a cold (-78°C), stirred solution of the ketal alkene 140 (1.000 g, 3.788 mmol) in 150 mL of 2:1 dichloromethahe-methanol until a pale blue tint appeared. The solution was purged with argon for 10 min while it was allowed to warm to room temperature. Dimethyl sulfide (3 mL) was added and the solution was stirred for 24 h at room temperature. Most of the solvent was evaporated in a stream of argon and the remainder was removed under reduced pressure. The residual material was taken up in 200 mL of Et20 and the solution was washed successively with water (lx 50 mL) and brine (2x50 mL). The organic phase was dried (MgSO^ and the solvent was removed under reduced pressure. Column chromatography of the crude product (silica gel, 70 g, 4:1 pentane^O) gave 0.804 g (80 %) of the keto ketal 141 as a white -160-crystalline solid that showed mp 104-105°C (recrystallization from pentane- E^O); ir (KBr): 1710, 1106 cm"1; *H nmr (400 MHz) 8 3.64 (br d, 2H, J=ll Hz, ketal protons), 3.35-3.24 (m, 2H, ketal protons), 2.50-2.39 (m, 1H), 2.35 (dd, 1H, J=10,5 Hz), 2.23-2.12 (m, 3H), 2.12-2.01 (m, 1H), 1.92-1.69 (m, 3H), 1.68-1.35 (m, 4H), 1.16 (s, 3H, methyl protons), 1.11 (s, 3H, methyl protons), 0.90 (s, 3H, methyl protons). Anal, calcd. for C 1 6 H 2 6 0 3 : C 72.14, H 9.84; found; C 72.44, H 9.91. Exact Mass calcd. 266.1885; found: 266.1886. Preparation of the keto ketal 142 O 142 A solution of the keto ketal 141 (1.000 g, 3.759 mmol) in 25 mL of a 0.174 M solution of sodium methoxide in methanol was stirred at 45°C for 2.5 h. The solvent was removed under reduced pressure. Water (20 mL) and Et20 (20 mL) were added and the phases were separated. The aqueous phase was extracted with Et20 (3x30 mL) and the combined extract was washed with brine (1x20 mL), dried (MgSO^ and concentrated. Column chromatography of the residual material on silica gel (100 g, elution with 5:1 pentane- Et^), followed by removal of traces of solvent (vacuum pump) gave 0.100 g of recovered starting material 141 and 0.888 g (89 %) of the keto ketal 142 as a colorless oil -161-which showed ir (film): 1713, 1111 cm'1; XH nmr (400 MHz) 8 3.70 (d, 1H, J=12 Hz, ketal proton), 3.66 (d, 1H, J=12 Hz, ketal proton), 3.37 (dd, 1H, J=12,3 Hz, ketal proton), 3.29 (dd, 1H, J=12,3 Hz, ketal proton), 2.70 (dd, 1H, J=13,3 Hz), 2.53 (br d, 1H, J=ll Hz), 2.34-2.24 (m, 3H), 2.06-1.95 (m, 1H), 1.91-1.74 (m, 2H), 1.66-1.50 (m, 2H), 1.50-1.17 (m, 3H), 1.20 (s, 3H, methyl protons), 0.85 (s, 3H, methyl protons), 0.73 (s, 3H, methyl protons). Exact Mass calcd for C^gH^C :^ 266.1885; found: 266.1886. Preparation of the enol triflate 143 To a cold (-78°C) solution of lithium diisopropylamide (LDA) (3.672 mmol) in 10.1 mL of dry THF was added, via cannulation, a solution of the ketone 142 (0.888 g, 3.338 mmol) in 4 mL of dry THF. The solution was stirred for 30 min and then was warmed to 0°C for 5 min. After the reaction mixture had been recooled to -78°C, solid N-phenyltrifluoromethanesiuTonimide (1.310g, 3.667 mmol) was added. The solution was allowed to warm to room temperature and was stirred for 1 h. The reaction mixture was filtered through a plug of silica gel (20 g, elution with Et20). Removal of the solvent from the filtrate gave a yellow oil. Upon careful purification of this material by column chromatography (silica gel, 80 g, 95:5,then 9:1 and finally 5:1 pentane-Et20), CF 3S0 20 143 -162-1.184 g (89 %) of the enol triflate 143 was obtained as a white solid. This material, even after recrystallization from pentane-Et20, was contaminated with traces of N-phenyltrifluoromethanesulfonimide. However, this impurity did not affect the outcome of the next reaction. The (slightly impure) enol triflate 143 showed ir (KBr): 1417, 1211, 1113 cm"1; lH nmr (400 MHz) 6 5.68-5.62 (m, 1H, vinyl proton), 3.69 (d, 1H, J=ll Hz, ketal proton), 3.63 (d, 1H, J=ll Hz, ketal proton), 3.37-3.26 (m, 2H, ketal protons), 2.92-2.83 (m, 1H), 2.58 (br d, 1H, J=12 Hz), 2.30-2.10 (m, 2H), 1.94-1.78 (m, 2H), 1.75 (br d, 1H, J=9 Hz), 1.72-1.65 m, 1H), 1.46-1.28 (m, 3H), 1.14 (s, 3H, methyl protons), 0.93 (s, 3H, methyl protons), 0.71 (s, 3H, methyl protons). Exact Mass calcd. for C17H25F305S: 398.1374; found: 398.1383. Preparation of the nitrile 144 To a mixture of dry LiCN (0.106 g, 3.212 mmol) (previously dried under vacuum (pump) at 45°C for 2 h), (Ph3P)4Pd (0.176 g, 0.152 mmol) and 12-crown-4 (20 uL, 0.124 mmol) was added a solution of the enol triflate 143 (0.544 g, 1.367 mmol) in 8 mL of dry benzene and the resultant mixture was stirred at room temperature for 2.5 h. Water (4 mL) was added, the phases were separated and the aqueous layer was extracted with CN 144 -163-Et20 (3x50 mL). The combined extract was dried (MgSO^ and the resulting solution was passed through a plug of Florisil (5 g, elution with EtaO). Removal of the solvent under reduced pressure and chromatographic purification of the residual material (silica gel, 50 g, 9:1 pentane-Et^ O), afforded 0.344 g (91 %) of the nitrile 144 as a white crystalline solid. This material showed mp 123-124°C (recrystallization from pentane-Et20); ir (KBr): 3036, 2209, 1626, 1110, 1092 cm'1; *H nmr (400 MHz) 8 6.60-6.53 (m, 1H, vinyl proton), 3.70 (d, 1H, J=ll Hz, ketal proton), 3.64 (d, 1H, J=ll Hz, ketal proton), 3.35-3.25 (m, 2H, ketal protons), 2.66-2.50 (m, 2H), 2.35-2.10 (m, 2H), 1.97-1.80 (m, 3H), 1.75-1.65 (m, 1H), 1.50-1.31 (m, 3H), 1.14 (s, 3H, methyl protons), 0.85 (s, 3H, methyl protons), 0.71 (s, 3H, methyl protons). Anal, calcd. for C17H25O2: C 74.14, H 9.15, N 5.09; found: C 73.95, H 9.09 , N 5.10. Exact Mass calcd. 275.1885; found: 275.1891. Preparation of the nitrile 148 To a solution of LDA (1.877 mmol) in 6.25 mL of dry THF at -78°C was added a solution of the nitrile 144 (0.344 g, 1.251 mmol) in 3 mL of dry THF. The reaction mixture was stirred for 15 min at -78°C and for 5 min at 0°C and then was recooled to 148 148a -164--78°C. Dry HMPA (0.22 mL, 1.27 mmol) and an excess of methyl iodide (0.5 mL, 8.0 mmol) were added successively and the reaction mixture was warmed to 0°C and stirred for 30 min. Aqueous sodium thiosulfate (5 % solution, 10 mL) and brine (15 mL) were added and the mixture was extracted with Et20 (3x50 mL). The combined extract was washed with brine and dried (MgS04). Removal of the solvent under reduced pressure, followed by column chromatography of the residual material (silica gel, 20 g, 5:1 hexane-Et20) gave 0.348 g (96 %) of the nitrile 148 as a white crystalline solid. This material showed mp 115-116°C (recrystallization from hexane-E^O); ir (KBr): 3027, 2229, 1113 cm'1; ! H nmr (400 MHz) 8 5.92-5.85 (m, 1H, H )^, 5.49-5.42 (m, 1H, H3), 3.71 (d, 1H, J=12 Hz, ketal proton), 3.63 (d, 1H, J=12 Hz, ketal proton), 3.35-3.27 (m, 2H, ketal protons), 2.73 (br d, 1H, J=18 Hz, H a^), 2.60-2.53 (m, 1H), 2.00(dd, 1H, J=18,6 Hz, Hje), 1.82-1.64 (m, 5H), 1.42 (s, 3H, methyl protons), 1.45-1.30 (m, 1H), 1.15 (s, 3H, methyl protons), 1.14 (s, 3H, methyl protons), 0.71 (s, 3H, methyl protons). In decoupling experiments (see formula 148a), irradiation of the signal at 8 5.49-5.42 (H3) simplified the multiplet at 5.92-5.85 (H^ and sharpened the doublet at 2.73 (Hja); irradiation of the signal at 8 5.92-5.85 (H2) simplified the multiplet at 5.49-5.42 (H3) and caused the collapse of the doublet of doublets at 2.00 (H^) to a doublet (J=18 Hz). Anal, calcd. for C 1 8 H 2 7 N0 2 : C 74.69, H 9.41, N 4.84; found: C 74.82, H 9.37, N 4.72. Exact Mass calcd. 289.2042; found: 289.2042. Preparation of the aldehyde 149 To a solution of the nitrile 148 (0.292 g, 1.010 mmol) in dry dichloromethane (13.4 mL) was added a hexane solution of dusobutylaluminum hydride (1.140 mmol). The solution was stirred at room temperature for 30 min. Water (20 drops) and saturated -165-H3 \ OHC 149 aqueous sodium bicarbonate (30 drops) were added and the mixture was stirred vigorously for 5 rnin. Diethyl ether (20 mL) was added and stirring was continued for 5 min. Enough MgS04 was then added to absorb the water. The mixture was filtered through a plug of Florisil (3 g, elution with E^O). Removal of the solvent from the eluate and column chromatography of the residue on silica gel (15 g, 17:3 hexane-E^O) gave 0.287 g (97 %) of the aldehyde 149 as a colorless oil after the last traces of solvent had been removed under reduced pressure (vacuum pump). This compound showed ir (film): 3015, 2718,1718,1113 cm"1; J H nmr (400 MHz) 8 9.76 (s, 1H, -CHO), 5.99-5.91 (m, 1H, H 3 ) , 5.34 (dd, 1H, J=10,2 Hz, H 2 ) , 3.70 (d, 1H, J=ll Hz, ketal proton), 3.62 (d, 1H, J=ll Hz, ketal proton), 3.37-3.25 (m, 2H, ketal protons), 2.80 (br d, 1H, J=19 Hz), 2.55 (br d, 1H, J=12 Hz), 2.07-1.95 (m, 2H), 1.80- 1.71 (m, 1H), 1.68-1.60 (m, 1H), 1.45-1.10 (m, 3H), 1.17 (s, 3H, methyl protons), 1.13 (s, 3H, methyl protons), 1.01 (s, 3H, methyl protons), 0.71 (s, 3H, methyl protons). Exact Mass calcd. for C1 8H2803: 292.2038; found: 292.2032. Preparation of the alcohol 150 To a cold (-10°C), stirred solution of the aldehyde 149 (0.287 g, 0.983 mmol) in -166-9.8 mL of dry methanol was added sodium borohydride (0.019 g, 0.502 mmol) and the mixture was stirred at -10°C for 20 min. Water (1 mL) and a saturated aqueous solution of ammonium chloride (2 mL) were added and the reaction mixture was allowed to warm to room temperature. The methanol was removed under reduced pressure and brine (15 mL) was added to the residue. The mixture was extracted with dichloromethane (3x25 mL). The combined extract was washed with brine (1x25 mL) and dried (MgS04). Solvent removal under reduced pressure (water aspirator, then vacuum pump) gave 0.276 (96 %) of the alcohol 150 as colorless oil which was homogeneous by tic and glc analyses. This material showed ir (film): 3350, 3012, 1112 cm'1; *H nmr (400 MHz) 8 5.74 (ddd, 1H, J=10, 6, 3 Hz, H2), 5.49 (dd, 1H, J=10,3 Hz, H3), 3.70 (d, 1H, J=ll Hz, ketal proton), 3.67 (d, 1H, J=ll Hz, ketal proton), 3.62 (d, 1H, J=ll Hz, CH2OH), 3.49 (d, 1H, J=ll Hz, C H 2 O H ) , 3.33 (dd, 1H, J=ll,4 Hz, ketal proton), 3.28 (dd, 1H, J=ll,14 Hz, ketal proton), 2.71 (br d, 1H, J=18 Hz), 2.56-2.48 (m, 1H), 1.97-1.86 (m, 2H), 1.70-1.53 (m, 2H), 1.54 (br s, 1H, D 20 exchanged, -CH2-OH), 1.40-1.08 (m, 5H), 1.16 (s, 3H, methyl protons), 1.05 (s, 3H, methyl protons), 1.03 (s, 3H, methyl protons), 0.70 (s, 3H, methyl protons). Exact Mass calcd. for C 1 8 H 3 0 O 3 : 294.2194; found: 294.2194. -167-Preparation of the keto alcohol 151 O H8a H6a OH H8e Hi* H 2 H 3 OH 151 151a To a stirred solution of the alcohol 150 (0.276 g, 0.939 mmol) in acetone (34 mL) was added a 10 % solution of aqueous hydrochloric acid (0.48 mL). The reaction mixture was stirred at room temperature for 1 h. A saturated aqueous solution of sodium bicarbonate (0.5 mL) was added and the acetone was removed under reduced pressure. The residual material was taken up in dichloromethane (80 mL) and brine was added. The phases were separated and the aqueous layer was extracted with dichlorometane (20 mL). The combined extract was dried (MgS04) and the solvent was removed under reduced pressure. The crude material obtained was purified by column chromatography on silica gel (20 g, 3:1 Et20- pentane). Distillation (air-bath temperature 160-170°C / 0.1 Torr) of the material thus obtained provided 0.192 g (98 %) of the keto alcohol 151 as a colorless oil, which exhibited ir (film): 3453, 3022, 1704 cm"1; *H nmr (400 MHz) 8 5.74 (ddd, 1H, J=10,6,2 Hz, H )^, 5.54 (dd, 1H, J=10,3 Hz, H3), 3.74 (dd, 1H, J=ll,6 Hz, -CH2-OH), 3.60 (dd, 1H, J=ll,6 Hz, -CH^-OH), 2.60 (ddd, 1H, J=14,14,7 Hz, Hga), 2.38 (br d, 1H, J=18 Hz, H a^), 2.29 (dddd, 1H, 1=14,2,2,2 Hz, Hge), 2.18-2.08 (m, 1H, H7e), 1.99 (dd, 1H, J=18,6 Hz, H e^), 1.91 (br d, 1H, J=13 Hz), 1.74 (dddd, 1H, J=12,12,12,4 Hz, H a^), 1.66 (dd, 1H, J=13,3 Hz), 1.63-1.47 (m, 1H, H7a), 1.31 (t, 1H, J=6 Hz, -168-CH2-OH, D 20 exchanged, also the signals at 8 3.74 and 3.60 collapsed, each to a doublet of J=ll Hz), 1.20 (s, 3H, methyl protons), 1.09 (s, 3H, methyl protons). In decoupling experiments (see formula 151a), irradiation of the signal at 8 5.74 ( H 2 ) simplified the signal at 5.54 (H3) to a doublet (J=3 Hz), the broad doublet at 2.38 (H^) is sharpened and the dd at 1.99 (H^) collapsed to a doublet (J=18 Hz); irradiation of the signal at 8 2.60 (H8a) simplified the signals at 2.29 (H8e), 2.18-2.08 (H^) and 1.63-1.47 (H7a); irradiation of the signal at 8 2.18-2.08 (Bye) simplified the signals at 2.60 (H8a), 2.29 (H8e), 1.74 (Hga, collapsed to a ddd, J=12,12,12 Hz) and 1.63-1.47 (H7a). Exact Mass calcd. for C13H20O2:208.1464; found: 208.1466. Preparation of the ketone 152 Hie o To a cold (-78°C) solution of the keto alcohol 151 (0.076 g, 0.365 mmol), 4-N,N-dimethylaminopyridine (0.0045 g, 0.037 mmol) and trietliylamine (0.076 mL, 0.545 mmol) in dry dichloromethane (3.5 mL) was added tert-butyldimethylsilyl-trifluoromethanesulfonate (0.092 mL, 0.401 mmol). The solution was stirred for 30 min and then a saturated aqueous solution of sodium bicarbonate (5 mL) and Et20 (10 mL) were added. The mixture was allowed to warm to room temperature and the phases were separated. The aqueous phase was extracted with Et20 (2x20 mL). The combined -169-extract was washed with brine (1x20 mL) and dried (MgS04). Removal of the solvent, followed by column chromatography of the residue on silica gel (10 g, 95:5 pentane-Et20) and further removal of traces of solvent (vacuum pump) from the oils thus obtained gave 0.1095 g (93 %) of the ketone 152 as a colorless oil Compound 152 exhibited ir (film): 3019,1710,1084, 852, 838 cm"1; ! H nmr (400 MHz) 8 5.63 (ddd, 1H, J=10,6,2 Hz, H 2 ) , 5.52 (dd, 1H, J=10,3 Hz, H 3 ) , 3.60 (d, 1H, J=10 Hz, -ak-OSiMe^Bu-t), 3.56 (d, 1H, J=10 Hz, -CH -^OSiMeaBu-t), 2.59 (ddd, 1H, J=14.14,7 Hz), 2.34 (br d, 1H, J=18 Hz, H a^), 2.28 (dq, 1H, J=14,2 Hz), 2.15-2.06 (m, 1H), 1.96 (dd, 1H, J=18,6 Hz^e), 1.91 (br d, 1H, J=14 Hz), 1.71 (dddd, 1H, J=13,13,13,4 Hz), 1.61 (dd, 1H, J=13,3 Hz), 1.58-1.43 (m, 1H), 1.18 (s, 3H, methyl protons), 1.04 (s, 3H, methyl protons), 0.91 (s, 9H, t-butyl protons), 0.04 (s, 3H, methyl protons), 0.03 (s, 3H, methyl protons). Exact Mass calcd. for C^H^C^Si (M+-t-Bu): 265.1624; found: 265.1624; low resolution chemical ionization mass spectrum: M+=322. Preparation of the ketones 153 and 154 TBDMSO TBDMSO t K A 153 1 5 4 To a cold (-78°C) stirred solution of LDA (0.046 mmol) in 0.23 mL of dry THF was added a solution of the ketone 152 (0.0135 g, 0.0415 mmol) in 0.25 mL of dry THF. -170-The solution was stirred at -78°C for 10 min and at 0°C for 10 min and then was recooled to -78°C. An excess of methyl iodide (~ 0.1 mL) was added and the reaction mixture was stirred at room temperature for 1 h. Water (1 mL), a 5% solution of aqueous sodium thiosulfate (1 mL) and ether (3 mL) were added. The phases were separated and the aqueous layer was extracted with Et20 (2x5 mL). The combined extract was washed with brine (1x3 mL) and dried (MgSCvt). Analysis of the solution by tic showed the presence of two compounds. Solvent removal under reduced pressure and column chromatography of the residue on silica gel (Pasteur pipette, 0.86 g, 95:5 pentane-Et20) gave two fractions. The first fraction provided 8 mg (57 %) of a mixture of epimers 153 and 154 (tic analysis). The second fraction consisted of 5.5 mg (39 %) of pure 153. Traces of solvent were removed (vacuum pump) from both fractions. The 8 mg mixture of epimers was dissolved in 0.5 mL of a 0.174 M solution of freshly prepared sodium methoxide in methanol and the solution was stirred at room temperature for 1 h. A saturated aqueous solution of ammonium chloride (2 drops) was added and the methanol was removed under reduced pressure. Brine (3 mL) and Et20 (5 mL) were added to the residue and the phases were separated. The aqueous phase was extracted twice with Et20 (1x3 mL). The combined extract was dried (MgSO^ and concentrated. The crude material thus obtained was purified as described above to afford 7 mg (88 %) of the pure epimer 154. The alkylation-epimerization sequence was carried out using conditions very similar to those outlined above, but on a larger scale. Thus, the ketone 152 (0.258 g, 0.801 mmol) gave the ketone 154 (0.219 g, 0.651 mmol) in 81 % yield. Compound 153 showed ir (film): 3023, 1708, 1083, 838 cm"1; XH nmr (400 MHz) 8 5.64-5.53 (m, 2H, vinyl protons), 3.60 (d, 1H, J=10 Hz, -O^-OSiM^Bu-t), 3.55 (d, 1H, J=10 Hz, -CH -^OSiMeaBu-t), 2.64 (dq, 1H, J=8,8 Hz, Hge), 2.13 (dd, 1H, J=18, 5 Hz, H e^), 2.05 (br d, 1H, J=18 Hz, H a^), 1.98-1.85 (m, 2H), 1.78-1.64 (m, 1H), 1.64-1.54 -171-(m, 1H), 1.16 (s, 3H, methyl protons), 1.13 (d, 3H, J=8 Hz, methyl protons), 1.09 (s, 3H, methyl protons), 0.91 (s, 9H, t-butyl protons), 0.03 (s, 3H, methyl protons), 0.02 (s, 3H, methyl protons). Exact Mass calcd. for C 1 9H3 30 2Si (M+-Me): 321.2249; found: 321.2254; low resolution chemical ionization mass spectrum: M+=336. Compound 154 showed ir (film): 3023, 1708, 1091, 838 cm'1; ! H nmr (400 MHz) 8 5.64 (ddd, 1H, J=10,7,2 Hz, H )^, 5.52 (dd, 1H, J=10,3 Hz, ft,), 3.61 (d, 1H, J=10 Hz, -CH2-OSiMe2Bu-t), 3.57 (d, 1H, J=10 Hz, -CHjrOSiMe^u-t), 2.68 (ddq, 1H, J=12,6,6 Hz, Hga), 2.39 (br d, 1H, J=18 Hz, H a^), 2.16-2.07 (m, 1H), 1.94-1.86 (m, 1H), 1.93 (dd, 1H, J=18,7 Hz, Hje), 1.79 (dddd, 1H, 1=13,13,13,4 Hz), 1.59 (dd, 1H, J=13,4 Hz), 1.30-1.15 (m, 1H), 1.17 (s, 3H, methyl protons), 1.03 (s, 3H, methyl protons), 1.00 (d, 3H, J=6 Hz, methyl protons), 0.91 (s, 9H, t-butyl protons), 0.04 (s, 3H, methyl protons), 0.03 (s, 3H, methyl protons). Exact Mass calcd. for C 1 9H3 3 0 2 Si (M+-Me): 321.2249; found: 321.2257; low resolution chemical ionization mass spectrum: M+=336. Preparation of the silvl enol ether 155 To a cold (-78°C) stirred solution of LDA (0.724 mmol) in 4.8 mL of dry THF was added a solution of the ketone 154 (0.219 g, 0.652 mmol) in 1.5 mL of dry THF and the solution was stirred for 30 min. The solution was warmed to 0°C and dry OTMS TBDMSO 155 -172-hexamethylphosphoraniide (0.127 mL, 0.724 mmol) and cMorotrimethylsilane (0.370 mL, 2.915 mmol) were added successively. After the reaction mixture had been stirred at 0°C for 40 min, 1,1,1,3,3,3-hexamethyldisilazane (0.8 mL) was added and the solvent was removed under reduced pressure. Pentane (50 mL) was added to the residue and after the mixture had been stirred for a few seconds, the solution was decanted. To the residue was added saturated aqueous sodium bicarbonate (10 mL) and the mixture was extracted with pentane (2x10 mL). The combined extract was mixed with the previously decanted solution, the solution was washed with brine (3x30 mL), dried (MgS04) and the solvent was removed under reduced pressure. The crude material was purified by column chromatography (silica gel, 22 g, 93:5:2 pentane-E^O-triethylamine). Removal of the volatile material (vacuum pump) from the appropriate fractions gave 0.248 g (93 %) of the silyl enol ether 155, a colorless oil that exhibited ir (film): 3024, 1676, 1091, 842 cm1; *H nmr (400 MHz) 8 5.64-5.57 (m, 2H, vinyl protons), 3.66 (d, 1H, J=10 Hz, -CH2-OSiMe2Bu-t), 3.48 (d, 1H, J=10 H^-Qk-OSiMeiBu-t), 2.11-1.95 (m, 2H), 1.90 (d, 1H, J=18 Hz, H a^), 1.80-1.72 (m, 1H), 1.59-1.52 (m, 1H), 1.54 (s, 3H, methyl protons), 1.42-1.15 (m, 2H), 1.05 (s, 3H, methyl protons), 1.03 (s, 3H, methyl protons), 0.91 (s, 9H, t-butyl protons), 0.22 (s, 9H, methyl protons), 0.03 (s, 6H, methyl protons). Exact Mass calcd. for C ^ H ^ C ^ : 408.2880; found: 408.2877. Preparation of the diketone 157 To a cold (-78°C), stirred solution of freshly distilled TiCl 4 (0.02 mL, 0.162 mmol) in dry dichloromethane (0.86 mL) was added freshly distilled Ti(OPr-i)4 (0.03 mL, 0.108 mmol). The mixture was stirred at -78°C for 5 min and then a solution of methyl vinyl ketone ethylene ketal (0.03 mL, 0.33 mmol) in dichloromethane (0.16 mL) -173-was added, and the mixture was stirred for 5 min. A solution of the trimethylsilyl enol ether 155 (0.044 g, 0.108 mmol) in dichloromethane (0.16 mL) was added, and the reaction mixture was stirred for 10 min. After the reaction mixture had been treated with 5% aqueous K 2 C0 3 (0.5 mL), Et20 (5 mL) was added and the mixture was allowed to warm to room temperature. Vigorous stirring was continued for 5 min and then MgS04 was added to eliminate the water. The slurry was filtered through a plug of Florisil (Pasteur pipette) and the collected material was rinsed several times with E^O. The solvent was removed from the filtrate under reduced pressure. Thin layer chromatographic analysis of the crude product showed the presence of four compounds and a considerable amount of "baseline" material. Column chromatography of this mixture (silica gel, 5g, 7:3 pentane-Et20) followed by removal of traces of solvent (vacuum pump) from each of the fractions gave 0.0025 g (6 %) of the ketone 153, 0.0020 g (5 %) of the ketone 154, 0.0020 g (~5 %) of the (somewhat impure) diketone 156, and 0.0060 g (14 %) of the desired diketone 157, all as colorless oils. The diketone 157 exhibited ir (film): 3022, 1718, 1695, 1086, 854, 838 cm'1; ! H nmr (400 MHz) 8 5.59 (ddd, 1H, J=10,6,2 Hz, H^, 5.54 (dd, 1H, J=10,3 Hz, H3), 3.61 (d, 1H, J=10 Hz, -CHa-OSiMe^u-t), 3.57 (d, 1H, J=10 Hz, -CH^- OSiMe^u-t), 2.46-2.29 (m, 2H), 2.22 (dd, 1H, J=18,6 Hz, Hje), 2.16 (s, 3H, R-(CO)CH,), 2.04 (br d, 1H, J=18 Hz, H a^), 2.00-1.91 (m, 1H), 1.91-1.83 (m, 1H), 1.80 (dddd, 1H, J=14,14,14,4 Hz), 1.69 (ddd, 1H, -174-J=15,4,4 Hz), 1.64-1.48 (m, 2H), 1.25-1.13 (m, 1H), 1.19 (s, 3H, methyl protons), 1.18 (s, 3H, methyl protons), 1.08 (s, 3H, methyl protons), 0.91 (s, 9H, t-butyl protons), 0.04 (s, 3H, methyl protons), 0.03 (s, 3H, methyl protons). Exact Mass calcd. for C20H33O3S1 (M+-t-Bu): 349.2199; found: 349.2203; low resolution chemical ionization mass spectrum: M+= 406. The (somewhat impure, 90% glc) diketone 156 exhibited ir (film): 3018, 1719, 1694,1087, 838 cm4; *H nmr (400 MHz) 8 5.68- 5.52 (m, 2H, H 2H 3), 3.63 (d, 1H, J=10 Hz, -Qk-OSiMeaBu-t), 3.54 (d, 1H, J=10 Hz, -CH -^OSiMeiBu-t), 2.60-2.47 (m, 2H), 2.14 (s, 3H, -(COJCHj), 2.08 (br d, 1H, J=18 Hz), 1.13 (s, 3H, methyl protons), 1.07 (s, 3H, methyl protons), 0.99 (s, 3H, methyl protons), 0.91 (s, 9H, t-butyl protons), 0.04 (s, 3H, methyl protons), 0.03 (s, 3H, methyl protons). Exact Mass calcd. for C^^C^Si: 406.2903; found: 406.2900. Preparation of the enone 163 TBDMSO 163 The diketone 157 (0.006 g, 0.015 mmol) was dissolved in 0.13 mL of a 5 % solution of potassium hydroxide in methanol and the solution was refluxed for 1.5 h. -175-Brine (2 mL) and a 10% solution of hydrochloric acid (3 drops) were added. The mixture was extracted with E^O (3x2 mL) and the combined extract was dried (MgS04). The solvent was removed under reduced pressure and the crude product was purified by chromatography on silica gel (Pasteur pipette, 0.86 g, 7:3 pentane-E^O). Concentration and removal of traces of solvent (vacuum pump) from the resultant oil gave 0.0045 g (78 %) of the enone 163 as a colorless oil exhibiting ir (film): 3028, 1671, 1617,1078, 838 cm"1; J H nmr (400 MHz) 8 5.85 (br s, 1H, H n ) , 5.65-5.65 (m, 2H, vinyl protons), 3.62 (d, 1H, J=10 Hz, -qH -^OSiMejBu-t), 3.53 (d, 1H, J=10 Hz, -CH -^OSiMe^ Bu-t), 2.58 (ddd, 1H, 1=18,15,5 Hz, H13a), 2.38 (br d, 1H, J=18 Hz, H13e), 2.21 (dd, 1H, J=18,5 Hz, H e^), 2.09 (br d, 1H, J=18 Hz, H^), 1.88 (ddd, 1H, J=15,15,4 Hz), 1.82-1.62 (m, 5H), 1.49 (br d, 1H, J=13 Hz), 1.40-1.30 (m, 1H), 1.35 (s, 3H, methyl protons), 1.21 (s, 3H, methyl protons), 1.06 (s, 3H, methyl protons), 0.90 (s, 9H, t-butyl protons), 0.04 (s, 3H, methyl protons), 0.03 (s, 3H, methyl protons). Exact Mass calcd. for C24H4o02Si: 388.2798; found: 388.2789. Preparation of the ketone 164 -176-To a cold (-78°C), stirred solution of sodium (0.004 g, 0.174 mmol) in ammonia (2 mL) (freshly distilled from sodium) was added a solution of enone 163 (0.004 g, 0.010 mmol) and tert-butvl alcohol (2 uL, 0.021 mmol) in E^O (0.1 mL). The solution was refluxed for 40 min and then was treated successively with isoprene, a saturated aqueous solution of ammonium chloride (2 mL), and Et^ O (2 mL). While the resulting mixture was stirred for 2 h, it was warmed occasionally with a water bath to eliminate the ammonia. Brine (2 mL) and Et20 (2 mL) were added to the residual material and the phases were separated. The aqueous phase was extracted with Et20 (2x3 mL). The combined extract was dried (MgS04) and the solvent was removed under reduced pressure. Chromatography of the crude product thus obtained (silica gel, Pasteur pipette, 0.86 g, 7:3 pentane-Et20) gave 0.0038 g (94 %) of ketone 164 as a white crystalline solid, which exhibited mp 99-101°C (recrystallization from pentane-Et20). This compound exhibited ir (KBr):3069, 1711, 1472, 854, 836 cm'1; *H nmr (400 MHz) 5 5.60 (dd, 1H, J=ll,2 Hz, H,), 5.49 (ddd, 1H, J=l 1,6,2 Hz, H^, 3.60 (d, 1H, J=10 Hz, CH^-OSiM^Bu-t), 3.49 (d, 1H, J=10 Hz, -CH2-OSiMe2Bu-t), 2.46 (ddd, 1H, J=16,16,6 Hz, H13a), 2.34-2.25 (m, H n a, H ne, H13e), 1.90 (dd, 1H, J=18,6 Hz, H e^), 1.76-1.67 (m, 2H), 1.66-1.38 (m, 4H), 1.37-1.29 (m, 1H), 1.27 (brd, 1H, J=13 Hz, Hj), 1.18 (dd, 1H, J=13,4 Hz), 1.14 (s, 3H, C 1 7 methyl protons), 1.05 (s, 3H, C 1 8 methyl protons), 0.90 (s, 9H, t-butyl protons), 0.89 (s, 3H, C^ o methyl protons), 0.03 (s, 3H, methyl protons), 0.02 (s, 3H, methyl protons). In decoupling experiments (see formula 164a), irradiation of the signal at 6 1.90 (Hje) simplified the signals at 5.49 (H2) and at 1.66-1.38 (H a^); irradiation of the signal at 8 2.46 (H13a) simplified the signals at 2.34-2.25 (H13e) and at 1.66- 1.38 (H14e, H14a). In nOe difference experiments, irradiation of the signal at 5 1.90 (H^ e) caused enhancement of the signals at 5.49 (ddd, J=16,6,2 Hz, gy, 2.34-2.25 (multiplet, Hne) and 1.60 (broad doublet, J=18 Hz, H a^); irradiation at 8 0.89 (C^ methyl protons, tert-butyl protons) caused enhancement of the signals at 3.60 (doublet, -177-J=10 Hz, C 1 9 methylene proton), 2.34-2.25 (multiplet, Hna), 1.90 (dd, J=18,6 Hz, H^ e) and the singlets at 1.14 (C 1 7 methyl protons), 0.03 and 0.02 (protons on the methyl groups bonded to Si); irradiation of the signal at 8 1.05 (C 1 8 methyl protons) caused enhancement of the signals at 1.27 (dd, J=13,3 Hz, Hs), 3.49 (doublet, J=10 Hz, C 1 9 methylene proton) and 5.60 (dd, J=ll,2 Hz, H3). 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