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A new synthesis of enantiomerically pure bicyclic ketones. Total synthesis of the diterpenoids (-)-Kolavenol… Roberge, Jacques Y. 1992

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A NEW SYNTHESIS OF ENANTIOMERICALLY PURE BICYCLIC KETONES.TOTAL SYNTHESIS OF THE DITERPENOIDS(-)-KOLAVENOL AND (-)-AGELASINE BByJACQUES Y. ROBERGEB. Sc. (1985), Universite de SherbrookeM. Sc. (1988), Universite de SherbrookeA THESIS SUBMITTED IN PARTIAL FULFILLMENT OFTHE REQUIREMENTS FOR THE DEGREE OFDOCTOR OF PHILOSOPHYinTHE FACULTY OF GRADUATE STUDIESDEPARTMENT OF CHEMISTRYWe accept this thesis as conformingto the required standardTHE UNIVERSITY OF BRITISH COLUMBIADecember 1992© Jacques Y. Roberge, 1992Department ofThe University of British ColumbiaVancouver, CanadaDateIn presenting this thesis in partial fulfilment of the requirements for an advanceddegree at the University of British Columbia, I agree that the Library shall make itfreely available for reference and study. - I further agree that permission for extensivecopying of this thesis for scholarly purposes may be granted by the head of mydepartment or by his or her representatives. It is understood that copying orpublication of this thesis for financial gain shall not be allowed without my writtenpermission.DE-6 (2/88)iiABSTRACTThis thesis describes the synthesis of a series of enantiomerically pure cis-fused bicyclic trimethylstannyl ketones 124, 132 and 133. The bicyclic ketones wereprepared by means of a methylenecyclohexane, methylenecyclopentane or anethylidenecyclopentane annulation sequence using the bifunctional conjunctivereagents 12, 110 and 115 and the novel, optically active trimethylstannyl enone 64,in which the trimethylstannyl moiety acts as a readily removable "anchoring" group.The trimethylstannyl group has a pronounced effect on the circular dichroism ofthe optically active ketones. A discussion of these effects is presented.A new, general destannylation procedure was developed and used to preparea series of enantiomerically pure bicyclic alcohols 165, 175 and 176 from theketones 124, 132 and 133. The generality of the method was demonstrated with thedestannylation (Li, t-BuOH, NH3) of a series of trimethylstannyl alcohols, ethers andalkenes.The alcohol 165 was used as an intermediate for the total syntheses of theoptically active clerodane diterpenoids (-)-kolavenol (65) and (-)-agelasine B (31).(-)-Kolavenol (65) was prepared in 14 steps and 19.4% overall yield from the enone64. Thus, the alcohol 165 was oxidized and the resulting ketone 47 was converted tothe nitriles 215. The nitriles 215 were stereoselectively alkylated to produce thenitrile 216. Functional group manipulations yielded the iodide 213 via the ether 214.A novel palladium-catalyzed coupling of an organozinc reagent (prepared from 213)with the vinyl iodide 265 produced the ether 282. (-)-Kolavenol (65) was obtained byremoval of the silyl protecting group.(-)-Agelasine B (31) was obtained in three steps from the ether 282. Thus, 282was converted directly into the bromide 300, and the resulting product was alkylatedwith the methyl adenine derivative 301 to give the methoxy-protected adenine_v "'SnMe3- R= H, 132R R = Me, 133CCIMe3Sn1 2CIMe3Sn110RR= H, 175R = Me, 176H OH165OH65OMe___/214iiiderivative 302. A new, mild electrochemical deprotection of 302 was used to prepare(-)-agelasine B (31). This compound was prepared in 16 steps and 5.6% yield fromthe enone 64.A new procedure for the synthesis of compound 233, the enantiomer of theactive component of the commercially useful perfume lonoxide® 251, was discovered.The ether 214 was efficiently converted into 233 using acidic reaction conditions.iv■vTABLE OF CONTENTSPageABSTRACT ^iiTABLE OF CONTENTS ^vLIST OF TABLES^  xviLIST OF FIGURES ^xviiiLIST OF ABBREVIATIONS ^xxACKNOWLEDGEMENTS^  xxvDEDICATION ^xxvi1. INTRODUCTION ^11.1. GENERAL ^11.2. BACKGROUND AND PROPOSAL ^21.2.1. Bifunctional Conjunctive Reagents ^21.2.2. Isolation and Previous Syntheses of Clerodane Diterpenoids ^51.2.3. Retrosynthetic Analysis for the Synthesis of Enantiomerically PureClerodanes ^81.2.4. Chiral "Anchors" ^112. DISCUSSION ^132.1. METHYLENECYCLOHEXANE, METHYLENECYCLOPENTANE AND(Z)-ETHYLIDENECYCLOPENTANE ANNULATION SEQUENCES....^132.1.1. Preparation of (-)-(5R,6R)-3,6-Dimethy1-5-trimethylstanny1-2-cyclohexen-1-one (64) ^132.1.1.1. Preparation of (R)-(-)-5-Methyl-2-cyclohexen-1-one (55) ^132.1.1.2. 1,4-Addition of Trimethylstannyl Nucleophiles to the Enone55 ^182.1.1.3. Oxidation of the Trimethylstannylcyclohexanone 92 ^24viPage2.1.2. 1,4-Additions to (-)-(5R,6R)-3,6-Dimethy1-5-trimethylstanny1-2-cyclohexen-1-one (64) ^262.1.2.1 Conjugate Addition of the 2-(5-Chloro-1-pentenyl) Group^262.1.2.2 Conjugate Addition of the 2-(4-Chloro-1-butenyl) and3-(5-Chloro-2-pentenyl) Groups ^312.1.3. Cyclization of the Trimethylstannyl Chloro Ketones 100, 101, 117and 121 ^362.1.3.1. Cyclization of the Trimethylstannyl Chloro Ketone 100 ^362.1.3.2. Cyclization of the Trimethylstannyl Chloro Ketone 101 ^412.1.3.3. Cyclization of the Trimethylstannyl Chloro Ketone 117 and121 ^452.2. REMOVAL OF THE TRIMETHYLSTANNYL MOIETY ^492.2.1. Previous Destannylation Methods ^492.2.1.1. Oxidation ^492.2.1.2. Carbon-Carbon Bond Formation ^502.2.1.3. Carbon-Carbon Bond Formation-Fragmentation ^512.2.1.4. Replacement of the R3Sn Moiety by an Hydrogen ^522.2.1.5. A Proposal for the Removal of the Trimethylstannyl Group ^532.2.2. Dissolving Metal Reduction of the Bicyclic Trimethylstannyl Ketone124 ^542.2.3. Enantiomeric Purity of the Bicyclic Alcohol 165 ^602.2.4. Dissolving Metal Reduction of the Trimethylstannyl Ketones 132,133 and 102 ^672.2.4.1. Destannylation of Substituted 4-Trimethylstannyl-bicyclo[4.3.0]nonan-2-ones ^672.2.4.2. Trimethylstannyl Cyclohexanone Destannylation ^702.2.5. Dissolving Metal Reduction of Trimethylstannyl Alcohols andEthers ^722.2.5.1. Preparation of the Trimethylstannyl Alcohols 178 and 179 ^72viiPage2.2.5.2. Preparation of the Bicyclic Trimethylstannyl Methyl Ether 184^752.2.5.3. Preparation of the Trimethylstannylcyclohexyl SEM-Ether185 ^772.2.5.4. Destannylation of the Alcohol 178 and the Ether 184 ^782.2.5.5. Destannylation of the Trimethylstannyl Cyclohexanol 179 ^832.2.5.6. Destannylation of the Trimethylstannylcyclohexyl SEM-Ether185 ^852.3. PREPARATION OF trans-FUSED AND cis-FUSED KETONES 17 AND47 ^882.3.1. Oxidation of the Bicyclic Alcohol 165 ^882.4. CIRCULAR DICHROISM ^902.4.1. General ^902.4.2. Circular Dichroism and Structure Relationships: The Octant Rule ^912.4.3. Circular Dichroism Measurements and Absolute Stereochemistryof Ketones ^932.4.3.1. The Circular Dichroism Spectrum of the trans-Fused BicyclicKetone 17 ^932.4.3.2. The Circular Dichroism Spectrum of the cis-Fused BicyclicKetone 47 ^932.4.3.3. The Reported Circular Dichroism of (3-TrimethylstannylCyclohexanones ^962.4.3.4. The Circular Dichroism of P-TrimethylstannylCyclohexanones ^982.4.4. The Circular Dichroism of Enones ^1022.4.4.1. The Circular Dichroism of (-)-(R)-5-methy1-2-cyclohexen-1-one (55) ^1032.4.4.2. The Circular Dichroism of (-)-(5R,6R)-3,6-Dimethy1-5-trimethylstanny1-2-cyclohexen-1-one (64) ^1032.4.5. The Circular Dichroism of MTPA-Esters 171 and 172 ^104VIIIPage2.5. TOTAL SYNTHESIS OF trans-CLERODANE DITERPENOIDS ^1062.5.1. Total Synthesis of (-)-Kolavenol (65) ^1062.5.1.1. Isolation of (-)-Kolavenol (65) ^1062.5.1.2. Previous Total Synthesis of (-)-Kolavenol (65) ^1072.5.1.3. Synthetic Plan ^1082.5.1.4. Synthesis of the (+)-Bicyclic Methoxymethyl Ether 214 ^1112.5.1.5. Preparation of the (-)-Bicyclic Primary Iodide 213 ^1142.5.1.6. Preparation of the Synthetic Equivalent of the Synthons 42and 43 ^1272.5.1.7. Attempted Coupling with the Iodide 213 Acting as anElectrophile ^1302.5.1.8. Coupling with the Iodide 213 Acting as a Precursor of aNucleophilic Reagent ^1342.5.1.9. Preparation of Synthetic (-)-Kolavenol (65) ^1372.5.1.10. Preparation of the Semi-Synthetic (-)-Kolavenol (65) fromNatural (-)-Methyl Kolavenate (33) ^1382.5.1.11. Comparison of the Spectral Data of the Natural, Semi-Synthetic and Synthetic (-)-Kolavenol (65) ^1382.5.2. Synthetic Studies Toward (-)-Agelasine B (31) ^1432.5.2.1. Isolation of (-)-Agelasine B (31) ^1432.5.2.2. Previous Synthesis of (-)-Agelasine B (31) ^1442.5.2.3. Preparation of the Kolavenyl Bromide (300) ^1462.5.2.4. Preparation of the Adenine Derivative 301 ^1472.5.2.5. Preparation of the Methoxy-Protected Adenine Derivative302 and The N6-Alkylated Adenine Derivative 303 ^1482.5.2.6. Reduction of the Methoxy-Protected Adenine Derivative 302with Zinc in Acetic Acid ^150ixPage2.5.2.7. Preparation of the Methoxy-Protected Adenine Derivative313 ^1512.5.2.8. Reduction of the Methoxy-Protected Methyl AdenineDerivative 313 with Zinc in Acetic Acid ^1522.5.2.9. Isolation of Natural (-)-Agelasine B (31) from the CrudeExtract of the Sponge Agelas Species ^1532.5.2.10. Treatment of the Enriched Sample of Natural (-)-Agelasine B(31) with Zinc in Acetic Acid ^1532.5.3. Electrochemical Demethoxylation: Total Synthesis of (-)-AgelasineB (31) ^1542.5.3.1.^Introduction ^1542.5.3.2. Cyclic Voltammetry ^1552.5.3.3. Voltammograms of the Geranyl Derivative 313, the Methoxy-Protected Adenine Derivative 302 and (-)-Agelasine B (31)^1572.5.3.4. Electrolysis of the Methoxy-Protected Adeninium Derivative313 ^1612.5.3.5. Electrolysis of the Methoxy-Protected Adeninium Derivative302 ^1633. CONCLUSION ^1704. EXPERIMENTAL^  1734.1. GENERAL ^1734.1.1. Data Acquisition and Presentation ^1734.1.2. Solvents and Reagents ^1764.2. EXPERIMENTAL PROCEDURES ^1784.2.1. Methylenecyclohexane, Methylenecyclopentane and (Z)-Ethylidenecyclopentane Annulation Sequences ^1784.2.1.1. Preparation of (-)-(R)-5-Methyl-2-cyclohexen-1-one (55) and3-Methyl-2-cyclohexen-1-one (73) ^178A) Preparation of the Silyl Enol Ethers 71 and 72 ^178PageB) Preparation of the a-Seleno Ketones 82, 83, 84 and 85^179C) Preparation of the Cyclohexenones 55 and 73 ^1804.2.1.2. Preparation of (+)-(2R,3R,5S)-2,5-Dimethy1-3-trimethyl-stannylcyclohexan-1-one (92) ^1814.2.1.3. Preparation of (-)-(2S,3R,5S)-2,5-Dimethyl-3-trimethyl-stannylcyclohexan-1-one (93) ^1834.2.1.4. Preparation of (-)-(5R,6R)-3,6-Dimethy1-5-trimethylstanny1-2-cyclohexen-1-one (64) ^184A) Preparation of the Trimethylstannyl Silyl Enol Ether 99 ^184B) Preparation of the Trimethylstannylcyclohexenone 64 ^1854.2.1.5. Preparation of the 5-Chloro-2-trimethylstanny1-1-pentene (12) 1864.2.1.6. Preparation of (+)-(2R,3R,5S)-5-(5-Chloro-2-pent-1-eny1)-2,5-dimethy1-3-trimethylstannylcyclohexanone (100) and(2R,3R,5R)-5-(5-Chloro-2-pent-1-eny1)-2,5-dimethy1-3-trimethylstannylcyclohexanone (101) and (+)-(2R,3R)-2,5,5-Trimethy1-3-trimethylstannylcyclohexanone (102) ^187A) Preparation of the Chloro Ketone 100 ^187B) (+)-(2R,3R)-2,5,5-Trimethyl-3-trimethylstannylcyclohexanone(102) ^189C) Preparation of the Mixture of Chloro Ketones 100 and 101 ^1894.2.1.7. Preparation of (+)-(2R,3R,5S)-5-(5-lodo-2-pent-1-eny1)-2,5-dimethyl-3-trimethylstannylcyclohexanone (126) and(2R,3R,5R)-5-(5-lodo-2-pent-1-eny1)-2,5-dimethyl-3-trimethylstannylcyclohexanone (129) ^191A) Preparation of the lodo Ketone 126 ^191B) Preparation of the Mixture of lodo Ketones 126 and 129^1924.2.1.8. Preparation of (+)-(1R,3R,4R,6R)-3,6-Dimethy1-7-methylene-4-trimethylstannylbicyclo[4.4.0]clecan-2-one (124) and(+)-(1S,3R,4R,6S)-3,6-Dimethy1-7-methylene-4-trimethyl-stannylbicyclo[4.4.0]decan-2-one (130) ^192A) Preparation of the Bicyclic Ketone 124 ^192B) Preparation of the Bicyclic Ketones 124 and 130 ^194xiPage4.2.1.9. Preparation of (+)-(2R,3R,5S)-5-(4-Chloro-2-but-1-eny1)-2,5-dimethy1-3-trimethylstannylcyclohexanone (117) ^1964.2.1.10. Preparation of (Z)-5-Chloro-3-trimethylstannyl-2-pentene(115) ^197A) Preparation of Ethyl (Z)-3-Trimethylstannyl-3-pentenoate^(113) ^197B) Preparation of (Z)-3-Trimethylstannyl-3-penten-1-ol (114) ^198C) Preparation of (Z)-5-Chloro-3-trimethylstannyl-2-pentene^(115) ^1994.2.1.11. Preparation of (+)-(2R,3R,5S)-5-[(Z)-5-Chloro-3-pent-2-eny1]-2,5-dimethy1-3-trimethylstannylcyclohexanone (121) ^1994.2.1.12. Preparation of (+)-(1R,3R,4R,6R)-3,6-Dimethy1-7-methylene-4-trimethylstannylbicyclo[4.3.0]nonan-2-one (132) ^2014.2.1.13. Preparation of (+)-(1R,3R,4R,6R)-3,6-Dimethy1-7-(2)-ethylidene-4-trimethylstannylbicyclo[4.3.0]nonan-2-one(133) ^2024.2.2. Dissolved Metal Reductions of TrimethylstannylcyclohexaneDerivatives ^2044.2.2.1. Preparation of (+)-(1R,2R,3S,6R)-3,6-Dimethy1-7-methylene-bicyclo[4.4.0]decan-2-ol (165) ^2044.2.2.2. Preparation of (-)-(1 R,2S,3R,4R,6R)-3,6-Dimethyl-7-methylene-4-trimethylstannylbicyclo[4.4.0]decan-2-ol (166)^2054.2.2.3. Transformation of the Bicyclic Trimethylstannyl Alcohol 166Into the Bicyclic Alcohol 165 ^2074.2.2.4. Preparation of (-)-(1 R,2R,3S,6R)-3,6-Dimethyl-7-methylene-bicyclo[4.3.0]nonan-2-ol (175) ^2074.2.2.5. Preparation of (-)-(1 R,2R,3S,6R)-3,6-Dimethyl-7-[(Z)-ethylidene]bicyclo[4.3.0]nonan-2-ol (176) ^2084.2.2.6. Preparation of (+)-(1 S,2S)-2,5,5-Trimethylcyclohexanol (177) 2094.2.2.7. Preparation of (-)-(1 R,2R,3R,4R,6R)-3,6-Dimethyl-7-methylene-4-trimethylstannylbicyclo[4.4.0]decan-2-ol (178)^2104.2.2.8. Preparation of (-)-(1 R,2R,3R)-2,5,5-Trimethyl-3-trimethyl-stannylcyclohexanol (179) ^212XIIPage4.2.2.9. Preparation of (+)-(1R,2R,3R,4R,6R)-3,6-Dimethy1-2-methoxy-7-methylene-4-trimethylstannylbicyclo[4.4.0]decane (184)^2134.2.2.10. Preparation of (-)-(1R,2R,3R)-2,5,5-Trimethy1-1-(2'-trimethyl-silylethoxy)methoxy-3-trimethylstannylcyclohexane (185).^2144.2.2.11. Preparation of (-)-(1 R,2S,3S,6S,7R)-3,6,7-Trimethylbicyclo-[4.4.0]decan-2-ol (186) ^2164.2.2.12. Preparation of (+)-(1 R,2S,3S,6R)-3,6-Dimethyl-2-methoxy-7-methylenebicyclo[4.4.0]decane (191) ^2174.2.2.13. Preparation of (+)-(1R,2S)-2,5,5-Trimethylcyclohexan-1-ol(192) ^2184.2.2.14. Preparation of (-)-(1R,2S)-2,5,5-Trimethy1-1-(2-trimethylsilyl-ethoxy)methoxycyclohexane (196) ^2194.2.3. Mosher's Esters ^2204.2.3.1. Preparation of (-)-(1R,2R,3S,6R)-3,6-Dimethy1-7-methylene-bicyclo[4.4.0]clecan-2-y1 (2S)-2-Methoxy-2-pheny1-3,3,3-trifluoropropanoate (171) ^2204.2.3.2. Preparation of (+)-(1R,2R,3S,6R)-3,6-Dimethy1-7-methylene-bicyclo[4.4.0]decan-2-y1(2R)-2-Methoxy-2-pheny1-3,3,3-trifluoropropanoate (172) ^2224.2.4. Total Synthesis of (-)-Kolavenol (65) ^2244.2.4.1. Preparation of (-)-(1R,3S,6R)-3,6-Dimethy1-7-methylene-bicyclo[4.4.0]clecan-2-one (47) ^2244.2.4.2. Preparation of (+)-(1S,3R,6R)-3,6-Dimethy1-7-methylene-bicyclo[4.4.0]decan-2-one (17) ^2254.2.4.3. Preparation of (1 R,2S,3R,6R)- and (1 R,2R,3R,6R)-2-Cyano-3,6-dimethyl-7-methylenebicyclo[4.4.0]decane (215) ^2264.2.4.4. Preparation of (+)-(1S,2R,3R,6R)-2-Cyano-3,6-dimethy1-2-(3,5-dioxahexyl)-7-methylenebicyclo[4.4.0]decane (216)...^2284.2.4.5. Preparation of (+)-(1S,2R,3R,6R)-3,6-Dimethy1-2-(3,5-dioxahexyl)-2-methanoy1-7-methylenebicyclo[4.4.0]decane(218) ^2294.2.4.6. Preparation of (+)-(1 R,2S,3R,6R)-2-(3,5-Dioxahexyl)-7-methylene-2,3,6-trimethylbicyclo[4.4.0]decane (214) ^230XI IIPage4.2.4.7. Preparation of (1 R,2S,3R,6R)-2-(2-Hydroxyethyl)-7-methylene-2,3,6-trimethylbicyclo[4.4.0]decane (232),(-)-(1R,6R,7S,8R)-7-(2-Hydroxyethyl)-1,2,7,8-tetramethyl-bicyclo[4.4.0]dec-2-ene (231), the Acetals 253-255 and(-)-(1 R,5S,6R,9S)-5 ,6 .10.10-Tetramethy1-2-oxa-t ricyclo [7.4 .0 .0 1,5]tridecane (233) ^232A) Preparation of the Mixture of Alcohols 231 and 232 ^232B) Preparation of the Acetals 253-255 ^233C) Preparation of the Alcohol 231 ^234D) Preparation of the Ether 233 ^2354.2.4.8. Preparation of (-)-(1R,6R,7S,8R)-7-(2-lodoethyl)-1,2,7,8-tetramethylbicyclo[4.4.0]dec-2-ene (213) ^2384.2.4.9. Preparation of (E)-3-Trimethylstanny1-2-buten-1-ol (261) ^239A) Preparation of Ethyl (E)- and (Z)-3-Trimethylstanny1-2-butenoate (259 and 260) ^239B) Preparation of (E)-3-Trimethylstanny1-2-buten-1-01 (261) ^2404.2.4.10. Preparation of (E)-1-(tert-Butyldimethylsilyloxy)-3-trimethyl-stanny1-2-butene (262) and (E)-1-(Tri-[iso-propyl]silyloxy)-3-trimethylstannyl-2-butene (263) ^241A) Preparation of the TBDMS-Ether 262 ^241B) Preparation of the TIPS-Ether 263 ^2424.2.4.11. Preparation of (E)-1-(tert-Butyldimethylsilyloxy)-3-iodo-2-butene (264) and (E)-3-lodo-1-(tri-[iso-propyl]silyloxy)-2-butene (265)  243A) Preparation of the TBDMS-Iodide 264 ^243B) Preparation of the TIPS-Iodide 265 ^2444.2.4.12. Preparation of (1R,6R,7S,8R)-7-Ethy1-1,2,7,8-tetramethyl-bicyclo[4.4.0]dec-2-ene (283), the Dimer 284 and(-)-(1R,6R,7S,8R)-7-(3-Methy1-5-(tri-jiso-propylisilyloxy)-3-(E-penteny1)}-1,2,7,8-tetramethylbicyclo[4.4.0jdec-2-ene(282) ^245A) Copper(I) Catalyzed Vinylmagnesium-alkyl Iodide Coupling.^245xivPageB) Palladium-catalyzed Alkylzinc-vinyl Iodide Coupling ^2484.2.4.13. Preparation of (-)-(1 R,6R,7S,8R)-7-[3-Methyl-5-hydroxy-3-(E-penteny1)]-1,2,7,8-tetramethylbicyclo[4.4.0]dec-2-ene(65) [(-)-Kolavenol]  249A) Synthetic (-)-Kolavenol (65) ^249B) Semi Synthetic (-)-Kolavenol (65) ^2504.2.5. Total Synthesis of (-)-Agelasine B (31) ^2524.2.5.1. Preparation of 6-Methoxyamino-9-methylpurine (N6-Methoxy-9-methyladenine 301) ^252A) Preparation of 6-Aminopurine N 1 -Oxide (Adenine N 1 Oxide307) ^252B) Preparation of M-Methoxy-6-aminopurinium Iodide(N 1 -Methoxyadeninium Iodide 308) ^253C) Preparation of M-Methoxy Adenine Derivative 309 ^253D) Preparation of N 1 -Methoxy-9-methyl Adeninium IodideDerivative 310 ^254E) Preparation of 6-Methoxyamino-9-methyl Adenine Derivative301 ^2554.2.5.2. Preparation of Geranyl Bromide (312), 7-Gerany1-6-methoxy-amino-9-methyl Adeninium Bromide Derivative 313 and6-(Geranylmethoxyamino)-9-methyl Adenine Derivative 314 256A) Preparation of Geranyl Bromide (312) ^256B) Reaction of 6-Methoxyamino-9-methyl Adenine Derivative301 with Geranyl Bromide (312) ^2564.2.5.3. Preparation of Kolavenyl Bromide 300, (-)-7-Kolavenyl-N6-methoxy-9-methyl Adeninium Bromide Derivative 302 and(-)-N6-Kolavenyl-N6-methoxy-9-methyl Adenine Derivative303^  258A) Preparation of Kolavenyl Bromide (300) ^258B) Reaction of 6-Methoxyamino-9-methyl Adenine Derivative301 with Kolavenyl Bromide (300) ^259XVPage4.2.5.4. Isolation of Natural (-)-Agelasine B (31) from an Extract of aPapua-New Guinea Sponge Agelas species (Likely Agelasnakamurai) ^2614.2.5.5. Cyclo-voltammetric Studies of 7-Geranyl-N6-methoxy-9-methyl Adeninium Bromide Derivative 313, (-)-7-Kolavenyl-N6-methoxy-9-methyl Adeninium Bromide Derivative 302and (-)-Agelasine B (31) ^264A) Cyclic Voltammogram of 7-Geranyl-N6-methoxy-9-methylAdeninium Bromide Derivative 313 ^265B) Cyclic Voltammogram of (-)-7-Kolavenyl-N6-methoxy-9-methylAdeninium Bromide Derivative 302 ^265C) Cyclic Voltammogram of Natural (-)-Agelasine B (31) ^2654.2.5.6. Electrochemical Reduction of 7-Geranyl-N 6-methoxy-9-methylAdeninium Bromide Derivative 313 and (-)-7-Kolavenyl-N6-methoxy-9-methyl Adeninium Bromide Derivative 302  266A) Preparation of 7-Geranyl-9-methyl Adeninium ChlorideDerivative 315 ^266B) Preparation of Synthetic (-)-Agelasine B (31) ^269REFERENCES^  272xviLIST OF TABLESTable^ Page^2.1^The 400 MHz 1 H NMR and COSY Data for the Cyclohexanone92 ^212.2 The 400 MHz 1 H NMR and 200 MHz COSY Data for the Cyclo-hexanone 93 ^232.3 The 400 MHz 1 H, 75 MHz 13C, APT and HSC NMR ExperimentsData for the Cyclohexenone 64 in C6D6 ^262.4 The 400 MHz 1 H NMR and 200 MHz COSY Data for the ChloroKetone 100 ^302.5 The 400 MHz 1 H, 75 MHz 13C, APT and HSC NMR ExperimentsData for the Bicyclic Ketone 124 in C6D6 ^39^2.6^The 400 MHz 1 H NMR and COSY Data for the Bicyclic Ketone 124in C6D6 ^402.7 The 400 MHz 1 H, 75 MHz 13C, and HSC NMR Experiments Datafor the Bicyclic Ketone 130 ^432.8 The 400 MHz 1 H NMR and 200 MHz COSY Data for the BicyclicKetone 130 ^442.9^The 400 MHz 1 H NMR and COSY Data for the Bicyclic Alcohol 165 582.10 The 400 MHz 1 H NMR and 200 MHz COSY Data for the BicyclicTrimethylstannyl Alcohol 166 ^592.11 The 400 MHz 1 H NMR and COSY Data for the Bicyclic MTPA-Ester171 ^632.12 400 MHz 1 H NMR Chemical Shift Difference Between the Esters171 and 172 ^642.13 13C NMR Chemical Shift Difference Between the Esters 171 and172 ^642.14 The 400 MHz 1 H NMR and 200 MHz COSY Data for the BicyclicAlcohol 176 ^692.15 The 400 MHz 1 H NMR and 200 MHz COSY Data for theCyclohexanol 177 ^712.16 The 400 MHz 1 H NMR and 200 MHz COSY Data for the BicyclicTrimethylstannyl Alcohol 178 ^74xviiTable^ Page2.17 The 400 MHz 1 H NMR and 200 MHz COSY Data for the Ether 184^762.18 The 400 MHz 1 H NMR and 200 MHz COSY Data for the SaturatedBicyclic Alcohol 186 ^792.19 The 400 MHz 1 H NMR and COSY Data for the Bicyclic UnsaturatedEther 191 ^832.20 The 400 MHz 1 H NMR and 200 MHz COSY Data for the CyclohexylAlcohol 192 ^852.21 The 400 MHz 1 H NMR and 200 MHz COSY Data for the CyclohexylSEM-Ether 196 ^862.22 Circular Dichroism of J3-Trimethylstannyl Cyclohexanones ^1002.23^Specific Ellipticity and Circular Dichroism of the MTPA-Esters 171,172 and 202 ^1052.24 Assignment of the NMR Data for the Tricyclic Ether 233 ^1182.25 Comparison of Selected 13C NMR Signals of trans- and cis-Decalins Related to the Ether 233 ^1212.26 Comparison of the Reported Spectral Data of Ether 251 with theData of Ether 233 ^1242.27 Comparison of the Reported Spectral Data for (-)-Kolavenol withthat of the Synthetic and Semi-Synthetic (-)-Kolavenol (65) ^1422.28 Comparison of the Reported Spectral Data for (-)-Agelasine B (31)and the Spectral Data for the Synthetic with Natural (-)-Agelasine B(31) 1644.1^The 400 MHz 1 H NMR and COSY Data for the Tricyclic Ether 233^2364.2^Assignment of the NMR Data for the Geranyl Methyl AdeniniumDerivative 313 ^268FigureLIST OF FIGURESxviiiPage2.1 NOE's of Compound 92^ 212.2 NOE's of Compound 100 312.3 NOE's of Compound 124^ 412.4 NOE's of Compound 130 452.5 NOE's of Compound 132^ 472.6 NOE's of Compound 133 482.7 NOE's of Compound 186^ 802.8 Tridimensional Representation of the Octants of a Cyclohexanone 922.9 Bidimensional Representation of the Rear Octants of aCyclohexanone^ 922.10 Representation of the Rear Octants of the Ketone 17^ 932.11 Representation of the Rear Octants of the Ketone 47^ 942.12 Circular Dichroism Spectra of the trans-Fused and cis-FusedKetones 17 and 47 (amplitude X 10) in CHCI3^ 952.13 Representation of the Rear Octants of the Conformer 197a^ 972.14 Representation of the Rear Octants of the Conformer 197b^ 972.15 Representation of the Rear Octants of the Ketones 199 and 200^ 982.16 Circular Dichroism Spectrum of the Trimethystannyl Ketone 92 inMethanol^ 1012.17 Helicity Rule and Rear Octants Representations for Enones^ 1022.18 Rear Octants Representation for the Enones 55^ 1032.19 Rear Octants Representation for the Enones 64 1032.20 Representation of the Steric Hindrance of the Aldehyde 218^ 1132.21 500 MHz 1 H NMR Spectrum of Compound 233 in CDCI3^ 1192.22 NOE's of the TIPS-Ether 282^ 134FigurexixPage2.23 400 MHz 1 H NMR Spectrum of the Synthetic (-)-Kolavenol (65) inCDC13-D20^ 1402.24 400 MHz 1 H NMR Spectrum of the Semi-synthetic (-)-Kolavenol(65) in CDC13-D20^ 1412.25 Cyclic Voltammetry: Apparatus and Voltammograms^ 1572.26 Voltammogram of Compound 313^ 1582.27 Voltammogram of Compound 302 1602.28 Voltammogram of (-)-Agelasine B (31)^ 1612.29 Electrochemical Mercury Cell (Actual Size) 1622.30 400 MHz 1 H NMR Spectrum of the Synthetic (-)-Agelasine B (31). 1662.31 400 MHz 1 H NMR Spectrum of the Natural (-)-Agelasine B (31)^ 1672.32 100 MHz 1 H NMR Spectrum of Tokoroyama's Synthetic(-)-Agelasine^B^(31) 1682.33 100 MHz 1 H NMR Spectrum of Tokoroyama's Natural(-)-Agelasine B^(31) 169LIST OF ABBREVIATIONA^ ampereA angstromAc^ acetyl or acetateAIBN 2,2'-azobis(2-methylpropionitrile)anal.^ analysisAPT attached proton testATPase^adenosinetriphosphataseax axialbr^ broadBu -^butylc^-^concentration in g/100 mLC coulombcal^ caloriecalcd calculatedCD^ circular dichroismCOSY correlated spectroscopyd^ doublet2D two dimensionaldag^ decagramdba dibenzilideneacetoneDCIMS^desorption chemical ionization mass spectroscopyDDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinonedec^ decompositionDMA N,N-dimethylacetamideDME^ 1,2-dimethoxyethaneXXxxiDMF^ N,N-dimethylformamideDMPU dimethylpropylureaDMSO^dimethylsulfoxidee electronE^ electromotive forceE entgegened.^ editionEd., Eds. editor, editorse. g.^ for exampleeq equatorialequiv^-^equivalentEt ethyleV^ electronvoltFABMS fast atom bombardment mass spectroscopyFT^ Fourier transformGLC gas liquid chromatographyh^ hourh Planck constanthex^ hexanesHMBC heteronuclear multiple bond connectivityHMPA^hexamethylphosphoramideHMQC heteronuclear multiple quantum coherenceHPLC^high pressure liquid chromatographyHRMS high resolution mass spectroscopyHSC^ heteronuclear shift correlationi iso or currenti. e.^ that isIR infrarednj^ n bond(s) coupling constants in Hertzlit. literatureLR^ long rangeLRMS low resolution mass spectroscopyLTMP^ lithium tetramethylpiperidinem multipletm^ metaM metalmCPBA^m-chloroperbenzoic acidMe methylmin^ minutemp -^melting pointMs^ methanesulfonylMTPA -^methoxytrifluoromethylphenylacetyl or acetatemult.^-^multiplicityNMR nuclear magnetic resonanceNOE^-^nuclear Overhauser effectORD optical rotatory dispersionp^ paraPh phenylpH^ hydrogen ion concentrationPMA phosphomolybdic acidppm^ parts per millionPr propylq^ quartetR rectusre^ stereochemical descriptors singlet or secondS^ sinistersi stereochemical descriptorSEM^ 2-trimethylsilylethoxymethylt triplett^ tertiaryTBDMS^tert-butyldimethylsilylTh thienylTHE^ tetrahydrofuranTIPS triisopropylsilylTLC^ thin layer chromatographyTMP tetramethylpiperidineTMSCI^Trimethylsilyl chlorideTosMIC (paratolysufonyl)methyl isocyanidep-Ts^ para-toluenesulfonyluv ultravioletv^ veryV volt-ve^ negativew weakw1 /2^ peak width at half height (frequency)Z zusammena^ 1,2 relative position[ a ID or Xt specific rotation at the sodium D line (589.3 nm) or at thewavelength X and at the temperature t [in (deg•cm2  jdagNI^-^ellipticityxxivi V iXt^-^specific ellipticity at the wavelength A. at at the temperature tfin (deg•cm 2 ),dag jP^1,3 relative position8 -^chemical shift in parts per million from TMSA^ heat or refluxAS chemical shift differenceAe^ circular dichroism in L•mol -1 •cm -1AG° free energy differencee^ molar absorptivity in L•mol -1 •cm -1Y 1,4 relative positionX1/2^ peak width at half height (wavelength)v frequency#^-^numbert transition state•^ coordination or complexXXVACKNOWLEDGEMENTSI would like to acknowledge the contributions to this thesis by my researchsupervisor, Dr. Edward Piers. His excellent teaching, extensive knowledge and highstandards imparted to me the science of organic chemistry in its best form. It was bothan honor and a privilege to work with him for the last four years. His perseverance atcorrecting my "frenglish" during the preparation of this manuscript is alsoacknowledged. Merci very much Ed!Thanks to the present and past members of the Piers group for creating anexcellent research atmosphere, as well as a friendly and stimulating environment. Thefriendships and the memories of this enjoyable and challenging period of my life willnot be forgotten.The professional work of the technical staff of the NMR, mass spectrometry andelemental analyses laboratories is gratefully acknowledged. Thanks are alsoextended to the personnel of the glass, mechanical and electronics shops for theirable technical contributions to my work. The loan of the electrochemical equipment byDrs. C. Orvig, P. Legzdins and D. Dolphin is acknowledged. I thank Dr. Martha Klinefor teaching me how to use the cyclic voltammetry apparatus. The work of theproofreaders of this thesis, Dr. M.D. Fryzuk, Dr. Christine Rogers, Dr. Livain Breau, andDr. Han Yongxin, was very much appreciated.Financial assistance both from the University of British Columbia in the form of aUniversity Graduate Fellowship and from "le Fonds pour la Formation de Chercheurset l'Aide a la Recherche du Quebec" (FCAR) is gratefully acknowledged.I would like to thank my family and friends for their support during my studies.I express my gratitude to the residents of 4636 West 12th for housing me when theworkers started to fall through the ceiling of my apartment. Finally, I would like toexpress my gratitude to Jana Pika "yetemilio" for outstanding scientific and non-scientific support in my last year of studies at UBC.xxv iA la mèrnoire de mon pére."I may, I might, I mustIf you will tell me why the fenAppears impassable, I thenWill tell you why I think that ICan get across it if I try."Marianne Moore (1887-1972)1. INTRODUCTION1.1. GENERALSince WOhler's serendipitous synthesis of urea from ammonium cyanate in1828, organic synthesis has progressed enormously in transforming simple rawmaterials into compounds of elaborated structures. 1 The synthesis of the most toxicnon-proteinic compound palytoxin (1) by Kishi and coworkers, 2 for example,demonstrates the power of contemporary organic chemistry. This progress, however,does not mean that organic synthesis has become a "mature science". In fact, a lot ofprogress can still be made in all fields of synthesis to improve the selectivity, thesimplicity and the efficiency of a given synthesis. 3,4 The explosive increase in thenumber of reactions and methods in recent history has made it necessary for syntheticorganic chemists to move from the initial intuitive planning of the synthesis of a singletarget compound to a systematized retrosynthetic analysis of the general synthesis of agroup of compounds. For his contribution in this area of organic chemistry, Corey wasawarded the 1990 Nobel Prize for Chemistry, primarily for the elaboration of the theoryand the methodology of organic synthesis. 5,6The development of new reactions relies less on serendipity than on thecreativity of the researchers. The new catalytic asymmetric cis dihydroxylation ofalkenes by Sharpless and coworkers 7 is a good example of this kind of progress. It ishoped that the work presented in this thesis will make a contribution to thedevelopment of new reactions and new general synthetic methods.1, Me110H^HO"^'OHOHOHHO,^„ OH0^0 Me OH Me HO)L s..,1-..'^....„..,_,,,, .,- sA,0*^OHOHOHOH0^,/0OH^OH'OH1 OHSOH21.2. BACKGROUND AND PROPOSAL1.2.1. Bifunctional Conjunctive ReagentsAn ideal synthesis is one that starts from inexpensive and simple materials andgives quantitative yield of the desired product with complete control of all thestereogenic centers, in a single operation. We are still far from this ideal, althoughmuch has been done to get closer to this ultimate goal. The use of organic reagentsthat possess more than one reactive site allows for the rapid synthesis of complexstructures. Reagents having two reactive sites are called bifunctional conjunctivereagents 8 or multiple coupling reagents. 9 Schematically, the use of bifunctionalconjunctive reagents can be illustrated by examining the synthons 2-4 (Scheme1.1). These synthons can be simple or complex, having a variety of functionality aswell as different chain lengths.3Synthon 2 with two acceptor sites 8 1 ° can act as an electrophile in a reactionwith substrate 5 to give 6. The adduct 6 can also be obtained by nucleophilic attack ofthe donor site d of synthon 3 on an electrophilic center of the substrate 5. Generalintermediate 7 should be available from attack of a nucleophilic substrate 5 on theacceptor site a of synthon 3 or by a nucleophilic attack of the donor site d of synthon 4on an electrophilic center of the substrate 5. The adduct 6 can be intramolecularlycyclized by a nucleophilic reaction of the "S" portion of the species with the acceptorsite a to give 8. Alternatively, 7 can be cyclized to give 8 by having the donor site dattack the "S" portion of the synthon 7.The acceptor and donor groups have to be selected carefully to avoid unwantedside reactions. It is sometimes necessary to have one of the reactive sites of thesynthons (2-4) in a "masked" state to avoid undesired reactions (decomposition,polymerization or self-condensation). A very efficient transformation can be achievedwhen the reactivity of the functionalized sites of the bifunctional synthons and thesubstrate are well "tuned". Under these circumstances, the "product" 8 can beobtained in one operation from a combination of one of the synthons 2-4 and thesubstrate 5 without having to isolate the intermediates 6 or 7.a(r. a2a3d 657d^Scheme 1.1Our research group has been involved for a number of years in the design ofnew bifunctional conjunctive reagents and their use in natural products syntheses. 11The total synthesis of (±)-palauolide (9) (Scheme 1.2), a marine natural product, byMe 3SnCu•SMe 211CI 0d^a CIM12 M = SnMe313 M = Li14 M = MgBrCI101514CuBr•SMe 2 KOt-Bu: 9 HO O 0Scheme 1.2BF3.0Et2 : 1 74Piers and Wai 12 demonstrates the effectiveness of a bifunctional conjunctive reagentin synthesis. The synthesis starts with the regioselective addition oftrimethylstannylcopper(I) dimethyl sulfide complex (11) to 5-chloro-1-pentyne (10) togive bifunctional reagent 12, where the 2-position is the donor site (d) and the5-position is the acceptor site (a). Transmetallation of the trimethylstannyl function of12 to give the lithio species 13 can be effected using methyllithium at lowtemperature. Reagent 13 can be transmetallated with magnesium bromide to give theorganomagnesium species 14. The second transmetallation was necessary toproduce a more stable, softer nucleophilic reagent. Addition of the organomagnesiumreagent 14 to the enone 15 was effected in the presence of copper(I) bromidedimethyl sulfide complex and boron trifluoride etherate to give the adduct 16. Betteryields of the cyclized product 17 were obtained when the intermediate 16 wasisolated and then cyclized rather than using a direct cyclization method.Intramolecular cyclization was accomplished with potassium tert-butoxide to give thebicyclic ketone 17. The decalin carbon unit of (±)-palauolide (9) is easily recognizedin the ketone 17. By varying the substrates and the conjunctive bifunctional reagentsemployed, many natural products have been successfully prepared in our group. Areview of these syntheses is beyond the scope of the thesis and the examples can befound in the literature. 1351.2.2. Isolation and Previous Syntheses of Clerodanes DiterpenoidsNature has provided us with a multitude of compounds that save or ease the lifeof millions of people every day. Thanks to progress in chromatography and inspectroscopy, natural product chemists have become very efficient at isolating andcharacterizing even minor metabolites from biological sources. These improvementsare useful because they allow the natural products chemist to collect only a fewspecimens of a species in order to find and to characterize new compounds. It is oftenthe case, however, that not enough product can be isolated to properly test for thebiological activity or even for complete determination of the stereochemistry of thecompound. 14 Also, even if the molecule is relatively abundant in a species, a largedemand for a useful compound can endanger the existence of the species. 15 The totalsynthesis of a natural product is therefore sometimes necessary to confirm thestructure of the natural product, to produce biologically-active synthetic products inconvenient amounts and to create new, useful molecules. These new compoundsmay be helpful against affliction or they may be useful as probes to learn more aboutthe mechanisms of life. 16Our group has been working on the synthesis of natural products of theclerodane family. The clerodanes are a large family of diterpenoids having the carbonskeleton 18 (equation 1.1). Biosynthetically they are believed to be derived from theindicated rearrangements of the labdane diterpenoid skeleton 19. The clerodanescan be divided into two subgroups, the cis- and trans-clerodanes, according to the twodifferent configurational arrangements of the decalin ring junction between C-5 andC-10. The main interest in the clerodanes resides in their biological activities. Theyshow antimicrobial, antitumoral, cholagogic, cardiotonic, coronadilating and pesticidalactivity. 17 Some of them are also known antifeedants. 17 A large number of clerodaneshave been isolated and only a few representative newly-isolated clerodanes are listed171 1^16^151320^11 12^141918clerodane skeleton186here: trans-clerodanes: (+)-cornutin A (20), 1 8 ( - )-y-methoxybutenolide (21), 19grandifolide A (22), 20 and (-)-(5R,8R,9S,10R)-12-exo-ent-3,13(16)-clerodien-15-oicacid (23); 21 cis-clerodanes: the (+)-epoxide 24, 22 (-)-Iinguifolide (25), 23stevisalicinone (26), 24 and (-)-ageline B (27). 2519^18labdane skeleton1928^29 Me00C 3 OAc 31COOH7A number of clerodanes have already been synthesized by our group and byothers, and many approaches have been studied. A review of the syntheses and thesynthetic approaches to the antifeedant clerodanes up to 1986 has alreadyappeared, 26 and a retrosynthetic analysis of a few representative syntheses ofclerodanes has been done by Fleming. 27 All the reported total syntheses ofclerodanes completed to date are listed here: trans-clerodanes: (±)-annonene (28), 28(±)-avarol (29), 29 (±)-ajugarin IV (30), 30 (-)-agelasine B (31),31 (±)-ajugarin I (32), 32(±)-palauolide (9),33 (-)-methyl kolavenate (33), 34 (±)-maingayic acid (34), 35(±)-isolinaridiol (35) and (±)-isolinaridiol diacetate (36), 13b (±)-cascarillone (37), 36(±)-stephalic acid (38) ;13h cis-clerodanes: (±)-linaridial (39); 37 (±)-1 5,1 6-epoxy-cis-cleroda-3,1 3(1 6),1 4-triene (40). 35,3881.2.3. Retrosynthetic Analysis for the Synthesis of Enantiomerically PureClerodanesThe biological activity of a given compound is often different from that of thecorresponding enantiomer. In a racemic mixture, the best one can hope is that theenantiomer of a compound will be inactive. Unfortunately often this is not the case,and the wrong enantiomer might even have toxic effects. 39 Our previously-reportedsyntheses of natural products using bifunctional conjunctive reagents having led toracemic products, we set a goal to devise a general synthetic plan to prepareenantiomerically-pure compounds belonging to the cis- and trans-clerodane familiesof diterpenoids.Retrosynthetically, the bond between C-12 and C-13 of 18 (Scheme 1.3) canbe cleaved to give the synthons 42 (nucleophilic) or 43 (electrophilic) and the synthon41 in which moiety X is a functional group that can either be converted into a leavinggroup or can be employed to make the carbon 12 nucleophilic. Disconnection of thestructure 41 between C-9 and C-11 leads to the synthon 44 having a carbanion-stabilizing group E (nitrile, carbonyl) and the synthon 45 (L = leaving group). Synthon44 can be seen as being derived from ketone 46 using an appropriate transform. Forthe synthesis of many trans-clerodanes, the trans-ketone 17 is the synthetic equivalentof ketone 46. The exo-methylene function of ketone 17 can be used as a handle tofunctionalize at positions 1 to 4 and 18 of the clerodane skeleton. Previous work in ourlaboratory 12 has shown that trans-ketone 17 can be easily derived from the cis-ketone947 by isomerization. Therefore, the cis-ketone 47 was identified as our keyintermediate in our synthetic strategy for the synthesis of both cis- and trans-clerodanediterpenoids. Because the cis-ketone 47 is readily epimerized, it was necessary totake measures to preserve the stereochemical integrity of the centers 8 and 10 incases where cis-clerodanes were the desired targets. It was felt that this could beachieved by having a removable or transformable "anchoring group" "A" at C-7, withthe configuration defined as shown in synthon 48.We reasoned that the anchor "A" would fulfill three major functions. First, theketone 48 (conformation 49) should be the major product under acid- or base-promoted equilibrating conditions, provided that the group "A" is sufficiently bulky.Each of the isomers 50 and 51 would be disfavored by the severe 1,3-diaxialinteraction between the angular methyl and the "A" group. A methylenecyclohexaneannulation 40 transform related to the ketone 48 would give the bifunctional conjunctivesynthon 53 and the optically-active chiron 41 52. Since it is known 42 that thestereochemical orientation of a 1,4-addition to an enone of the type 52 is controlled bythe presence of a bulky group in the 5 position of 52, the second role of the group "A"is to direct the addition of the synthon 53 to the re-side of carbon 3 in 52. Enone 52can be synthetically derived from ketone 54, where the anchor "A" serves its last rolein preserving the chirality originally present in enone 55. The known enone 55 isreadily available from the ketone 56. The enantiomer of 56, the (S)-(-)-3-methyl-cyclohexanone (57) is also readily available,43 so that it is possible to access bothenantiomeric series of clerodanes using this strategy. In addition, a synthetically-useful chiral anchor "A" should be characterized by the following criteria: it should beeasily introduced, stable to moist air, heat, and to mild acids and bases, and it shouldbe easy to replace by hydrogen, or to convert into another functional group.ti0541818 4145\^/d42or\^/a4320 E44a/) d +5357 56 55 18 17I II4610Scheme 1.3Me3Sis'6058RMgXCuBr•Me2S61CuCl2DMF0Me3Si59 Me3SiMe3Si6263(+)-a-curcumeneScheme 1.4Kinetic resolution111.2.4. Chiral "Anchors"A search of the literature revealed that the trimethylsilyl group has been used asa chiral anchor for the synthesis of natural products. 44 5-Trimethylsilylcyclohex-2-en-1-one (58) (Scheme 1.4) was kinetically resolved to give (R)-(-)-5-trimethylsilyl-cyclohex-2-en-1-one (59) and (S)-(+)-5-trimethylsilylcyclohex-2-en-1-one (60). 45Copper(I)-catalyzed addition of an organomagnesium reagent to enone 59 gave theketone 61 with high stereoselectivity. The silyl group could be removed with copper(II)chloride in hot DMF to give the chiral cyclohexenone 62. The ketone 61 (R = para-tolyl) has been used for the synthesis of (+)-a-curcumene (63).The trimethylsilyl group fulfills most of the requirement of a synthetically usefulanchoring group. It is relatively easy to introduce and is stable to moist air, heat andmild acids and bases. The major drawback of the trimethylsilyl anchor is that therelatively strong carbon-silicon bond [-'305 kJ/mol (-73 kcal/mol)] 46 makes it difficult toremove the anchor in the presence of sensitive functional groups.56OH--0.--■—•111.,--lb..--II..-II.-z 6531^Scheme 1.512Based on our experience, we envisaged that the trimethylstannyl group(Me3Sn) 47 would be able to fulfill all the requirements for a synthetically usefulanchoring group. Trimethylstannyl compounds are easily prepared by conjugateaddition of a suitable organocuprate to a,13-unsaturated ketones. They are "stable" 48and the weak C-Sn bond [-188 kJ/mol (-45 kcal/mo1)146 should allow the replacementof the Me3Sn group by an hydrogen or its transformation into another functional group.This thesis describes the preparation of the optically active trimethylstannyl-cyclohexenone 64 (Scheme 1.5) from the ketone 56 and demonstrates the use ofenone 64 as a substrate in methylenecyclohexane, methylenecyclopentane, and(Z)-ethylidenecyclopentane annulation sequences. The successful syntheses of(-)-kolavenol (65) and (-)-agelasine B (31), two representative, enantiomerically puretrans-clerodanes, are presented to illustrate the synthetic utility of the trimethylstannylgroup as an effective anchoring group.2. DISCUSSION2.1. METHYLENECYCLOHEXANE, METHYLENECYCLOPENTANE AND(Z)-ETHYLIDENECYCLOPENTANE ANNULATION SEQUENCES2.1.1. Preparation of (-)-(5R,6R)-3,6-dimethy1-5-trimethylstanny1-2-cyclohexen-1-one (64)The early stage of our work was aimed at the preparation of the cyclohexenone64, comprising a trimethylstannyl anchoring group, starting from the known(R)-(-)-5-methyl-2-cyclohexen-1-one 55. 49 In order to prepare enough of the keyintermediate 64 and to submit it to a variety of annulation sequences, we needed toaccess cyclohexenone 55 in large quantities. The optically active enone 55 has beenused before in synthesis [(+)-luciduline, 50 (-)-ptilocaulin51 and (-)-calcimycin52j and inchiroptical studies53,54,55 by other researchers. Approaches to enone 55 aresummarized in Scheme 2.1, and will be described in the following paragraphs.13552.1.1.1. Preparation of (R)-(-)-5-Methyl-2-cyclohexen-1-one (55) Allinger and Riew54 have prepared enone 55 from (+)-pulegone (66) (A,Scheme 2.1) using a lengthy and low-yielding procedure. Pulegone (66) wastreated with aqueous acid to give the retroaldol product 56 in 66% yield. Ketone 56was a-brominated to yield the bromoketone 67 (21%). Ketalization of bromoketone1 467 followed by elimination of HBr from bromoketal 68 gave the unsaturated ketal 69in 65% overall yield. Finally, hydrolysis of the ketal function gave the enone 55 in 9%overall yield from pulegone. Alternatively, bromoketone 67 was transformed into theunsaturated semicarbazone 70 and enone 55 was obtained in 9% overall yield afterhydrolysis.Friedrich and Lutz49 have prepared the enone 55 using a photosensitizedoxidation of the mixture of silyl enol ethers 71 and 72 (B, Scheme 2.1). Theirsynthesis was shorter and their overall yield (43%) was better than that obtained byAllinger and Riew. Because the enol formation with i-Pr2NLi was not highlyregioselective, 3-methyl-2-cyclohexen-1-one (73) was obtained in 22% yield inaddition to the desired enone 55. Oppolzer and Petrzilka 5° have trapped the lithiumenolate of ketone 56 with diphenyl disulfide (C, Scheme 2.1). The formation of a 2:1mixture of unspecified diastereomers 74 was observed. Oppolzer and Petrzilka didnot observe any of the isomeric sulfides (sulfenylation at the C-2 position of ketone56). 56 Oxidation of the thioethers 74 and thermolysis of the resulting sulfoxide gaveenone 55 in a 43% overall yield. Caine and coworkers56 have added sodiumthiophenolate to a mixture of the known pulegone epoxides 75 to obtain a mixture ofsulfides 74 (unknown ratio) (D, Scheme 2.1). Oxidation of the sulfide moieties and asubsequent elimination reaction gave the enone 55 in 49% overall yield. Djerassiand coworkers55 have prepared enone 55 in 13% overall yield from the ketone 56 byheating the bromoketone 67 in the presence of lithium carbonate and lithium bromidein DMF (E, Scheme 2.1).These approaches to enone 55 have the disadvantage of low yield and/or longreaction sequences, which make the procedures unsuitable for large scalepreparations. We therefore decided to develop an alternative synthesis of enone 55,which will be described in the following pages.E;7^55m (13%)a) H30+ , 66% b) Br2 , H2O, 21% c) (HOCH2 )2 , p-TsOH, 92% d) NaOH, Me0H,71% e) H30+ , 96% f) NH2NHCONH 2 , AcOH, 65% g) i-Pr2NLi, THF; TMSCIh) hu, 02, Rose Bengal, THF i) i-Pr2NLi, THF; PhSSPh j) m-CPBA, CCI4 ; Ak) H202 , NaOH I) PhSNa, THF m) Li2CO3 , LiBr, DMF, A.Scheme 2.115C^ Pd(OAc)2, 076OSiMe3t,,(LPd(OAc)2, CH 3CNor 00, CH3CN16We had first planned to use the Saegusa oxidation of the silyl enol ether 71 toprepare enone 55. 57 In this method, the silyl enol ether 76 (equation 2.1) is reactedeither with palladium(II) acetate in acetonitrile or with palladium(II) acetate and1,4-benzoquinone in acetonitrile. The corresponding enone 77 is usually obtained inhigh yield along with a small amount of ketone resulting from hydrolysis of the silylenol ether.The selective formation of the silyl enol ether 71 over 72 would result in a betteryield of the desired Saegusa oxidation product. Addition of the ketone 56 to a solutionof i-Pr2NLi and then quenching with TMSCI gives a mixture of distal (71) and proximal(72) enol ethers in a typical ratio of 2-3:1. 56 A modification of the procedure reportedby Corey and Gross58 for the formation of silyl enol ethers was attempted to obtain amore favorable ratio of isomers. Thus, ketone 56 was added to a cold (-78 °C)solution of TMSCI (5 equiv) and i-Pr2NLi (1.1 equiv) to give a quantitative yield of amixture of the silyl enol ethers 71 and 72, in a slightly improved ratio of 2.5:1.Substitution of the more sterically demanding lithium 2,2,6,6-tetramethylpiperidide(LiTMP) for i-Pr2NLi improved the ratio of 71:72 to 5.7:1 (93% yield). The lattermixture of enol ethers was subjected to the Pd(II) oxidation. A number of solvents andsolvent mixtures (acetonitrile, acetonitrile-benzene, acetonitrile-THF) and oxidants(palladium(II) acetate, a mixture of palladium(II) acetate and 1,4-benzoquinone) wereinvestigated, but all reaction conditions were unsuccessful. Even under optimumconditions (palladium(II) acetate, acetonitrile), only 12% of the enone 55 wasobtained, along with 18% of m-cresol as a major side product. In view of thesedifficulties, alternative oxidation procedures were explored.OM[B] ArSeX41( CI(78 79^[Ox/SePh8017Fleming and Paterson59 have used 2,3-dichloro-5,6-dicyano-1,4-benzoquinone(DDQ) in benzene to oxidize silyl enol ethers into enones. This approach was appliedin an attempt to convert a mixture of the enol ethers 71 and 72 into the enones 55 and73. Many reaction conditions [i. e. 2,4,6-trimethylpyridine, DDQ, benzene, 12-18% of55; 2,4,6-trimethylpyridine, DDQ, dichloromethane, reflux, -7% of 55; 2,4,6-trimethylpyridine, DDQ, acetonitrile -20 °C60 , 0% of 55] were tried with little success.This synthetic strategy was abandoned and we turned to alternative procedures toprepare enone 55.The elimination of a seleninic acid from a keto a-selenoxide has been reportedto be an efficient and mild way to prepare enones. 61 Since the reaction conditions forthe oxidation of the selenide and the elimination reaction are much milder than thosenecessary to effect the same overall conversion with a sulfide, a better yield of enone55 than that obtained by Oppolzer and Petrzilka and by Caine and coworkers wasexpected. The methods involves the trapping of the enolate, the enol, the enol ether orthe enol acetate 79 of a ketone 78 (Scheme 2.2) (M = Li, H, alkyl or trialkylsilyl, orAc) with an appropriate arylselenenyl reagent to give the a-selenoketone 80. Theselenide can be oxidized to the selenoxide 81 with variety of oxidants (Nalati, 03,H202, peracids). The selenoxide 81 is not usually isolated, since elimination normallytakes place in situ to give the enone 77.O Scheme 2.2+PhSe71+ 7 2 PhSeBr018The addition of a THE solution of phenyl selenenyl bromide 62 (prepared in situfrom diphenyl diselenide and bromine) to a mixture of enol ethers 71 and 72 in cold(-78 °C) ether (Et20), gave a quantitative yield of a complex mixture of selenides82-85 (equation 2.2). This mixture was oxidized with hydrogen peroxide 63,64 to givethe enone 55 ([ a ]p30 -86.9°, c = 2.6 in chloroform {lit. 50 , -90.1° c = 2.55 in chloroform))in 68% yield, accompanied by -20% of the enone 73. The spectral data of enone 55were in agreement with those reported in the literature. 50 Having established animproved route to prepare enone 55, we turned our attention to the 1,4-addition of thetrimethylstannyl group to this enone.SePhH202 55 + 7368% -20%82: a + 83:^84: a + 85: 13^ (2.2)2.1.1.2. 1.4-Addition of Trimethylstannyl Nucleophiles to the Enone 55 The 1,4-addition of a trimethylstannyl nucleophile to the enone 55, followed bytrapping 65 of the resultant enolate 90 with iodomethane, should afford directly thesynthetic equivalent of synthon 54 ("A" = Me3Sn), (2R,3R,5S)-2,5-dimethy1-3-trimethylstannylcyclohexanone (91) (Scheme 2.3). The attack of the Me3Sn groupon enone 55 was expected to occur axially from the side opposite to the methyl groupfor stereoelectronic66 reasons to give the enolate 90. Studies on 1,4-addition ofnucleophiles on cyclohexenones have shown that those reactions, when kineticallycontrolled, are subject to stereoelectronic effects. The 1,4-addition occurs withstereoelectronic control when the a-orbital of the bond being made is aligned with then-orbitals of the resulting enolate. The axial attack is favored because it goes throughthe more stable chair-like enolate intermediate 90 rather than the boat-like enolateintermediate 91. Subsequent trapping of the enolate 90 with iodomethane shouldtake place to give the ketone 92 with the methyl group on C-2 trans to the55Me3Sn"Me—nMe19trimethylstannyl moiety. For steric reasons, the alkylating agent approaches from theside opposite the bulky Me3Sn group, and for stereoelectronic 67 reasons, thealkylation takes place via a more stable chair-like transition state with the methyl groupbecoming attached in an axial orientation.Me3 SnLi6Me3Sn'^ 8orMe(Me3SnCuCN)Li^0^8 7or [Me3SnCu(2-Th)CN]Li 288or(Me3SnCuSPh)Li89OMelHMPAMe3Sn K k N'c,,,-_^Me —I _90+0+94-Scheme 2.3SnMe3We first tried the 1,4-addition-trapping procedure with trimethylstannyllithium 68(86). A mixture of the ketones 92, 93 and two other compounds having the proposedstructures 94 and 95 was obtained in 78% yield. The ratio of the ketone 92 to theother three side products was 7:2 as determined by GLC. The pure ketone 92([ a ]c, 28 +134.1°, c = 1.022 in Me0H) 68 was obtained by flash chromatographywhile 93 was obtained in a pure form via the epimerization of 92 (vide infra). Theketones 94 and 95 were not isolated and their presence in the mixture was suspected20on the basis of the GLC analysis. The use of the cyanocuprate 87 7° or the higherorder (2-thienyl)(cyano)cuprate 88 71 gave the same products in a ratio of 92:8[92:(93+94+95)] in 58% and 70% yield, respectively. The best results were obtainedwhen (trimethylstannyl)(phenylthio)cuprate 89 7° was used. Thus, addition of enone55 to a cold THE solution of lithium (trimethylstannyl)(phenylthio)cuprate (-20 °C, 1 h),followed by the trapping of the resulting enolate with iodomethane dissolved in THF-HMPA (hexamethylphosphoric triamide) (-78 °C, 30 min, -20 °C, 40 min) gave amixture of ketones 92, 93, 94 and 95 in a ratio of 97:3 [92:(93+94+95) asdetermined by GLC] in 78% yield.The IR spectrum of ketone 92 exhibits absorptions at 1708, 768 and 526 cm -1 ,indicating the presence of a six-membered cyclic ketone and a trimethylstannylgroup. 72 The 1 H NMR spectrum of 92 could be fully assigned using decoupling and1 H- 1 H homonuclear correlation 2D-NMR (COSY) experiments. 73 The COSYhomonuclear correlations are listed in Table 2.1. The results of the nuclearOverhauser enhancement difference experiments (NOE) 74 on 92 supported thepredicted stereochemical outcome of the 1,4-addition-trapping procedure. The resultsare summarized on Figure 2.1 and the enhancements are represented with arrows.The beginning of the arrows represent the irradiated signals while the tips are directedtowards the enhanced signals. Irradiation of the signal due to Me-8 (8 0.97) led to theenhancement of the signals corresponding to hydrogens 3, 4e, 5 and 6e; irradiation ofthe signal due to H-3 led to the enhancement of the resonances due to Me-7 andMe-8. Enhancement of the signal due to H-4e could not be seen because of theproximity of its chemical shift with that of irradiated signal H-3. None of the otherproducts (93 to 95) could show all of these enhancements. The 13C NMR spectrum ofthe ketone 92 could be assigned with the help of the carbon-tin couplings 75 and anAPT experiment.76H-5H-4e Me-7H-6eH-6aH-4a SnMe3 H-2Figure 2.1 NOE's of Compound 92Table 2.1: The 400 MHz 1 H NMR and COSY Data for the Cyclohexanone 92Assignment(H-X)1H NMR8 ppm (mutt., # of H, J (Hz))COSY Correlation(H-X)Me3Sn 0.11 (s, 9H, 2J sn-H = 52) _Me-8 0.97 (d, 3H, 7) 4a (LR)a, 5, 6a (LR)Me-7 1.02 (d, 3H, 6.5) 2, 3 (LR)3 1.62 (ddd, 1H, 12, 12, 3.5) Me-7 (LR), 4e, 4a, 24e 1.71 (dddd, 1H, 14, 3.5, 3.5, 2) 3, 4a, 6e (LR), 54a 2.01 (ddd, 1H, 14, 12, 4) 3, 4e, 5, Me-8 (LR)6e 2.17 (ddd, 1H, 13, 3.5, 2) 4e (LR), 5, 6a2, 5 2.41-2.51 (m, 2H) Me-8, Me-7, 3, 4e, 4a, 6e, 6a6a 2.57 (dd, 1H, 13, 6) Me-8 (LR), 6e, 5a (LR) = Long range or "W" coupling.Further confirmation of the stereochemistry of the ketone 92 was obtained afterepimerization of the methyl group in the 2 position (Me-7) by using equilibratingconditions (sodium methoxide in methanol at room temperature). Taking into accountthe conformational free energy difference (-AG°) 77 of a methyl group (1.74 kcal/mol2122[7.3 kJ/mol]) and the trimethylstannyl moiety (1.0 kcal/mol [4.2 kJ/mol]), 78 one shouldexpect ketones 92 and 93 to equilibrate to a mixture in a ratio of approximately of1:3.5 (-AG° -0.74 [3.1 kJ/mol]). Molecular mechanics 79 calculations predicted a ratio of1:5.5 (-AG° -1.02 [4.3 kJ/mol]). Experimentally, the ketones 92 and 93 had reachedan equilibrium ratio of 1:1.1 after 92 had been treated with NaOMe in Me0H for 24 h atroom temperature. However, only 68% of the material was recovered due todecomposition of the product or the starting material. The equilibrium ratio suggeststhat there might be a stabilizing interaction between the carbonyl and thetrimethylstannyl group that favors the Me3Sn being in the equatorial orientation morethan is predicted from the conformational free-energy difference alone. Hudec 53 andKitching and coworkers8° had also observed that the preference for an equatoriallyoriented trimethylstannyl group of trans-5-methyl-3-trimethystannylcyclohexanone wasgreater than expected on the basis of the value of -AG°. Hudec's explanation for thispreference will be discussed later in the circular dichroism section (see section 2.4.3).Ketones 92 and 93 were separated by flash chromatography to give the pure ketone93 in 14% yield ([ a ]D25 -44.1 ° , c = 0.935 in Me0H).The IR spectrum of ketone 93 exhibits absorptions at 1712, 769 and 524 cm -1 ,indicating the presence of a six-membered cyclic ketone and a trimethylstannyl group.The 1 H NMR spectrum could be assigned with the assistance of decoupling andCOSY experiments. The COSY homonuclear correlations are shown in Table 2.2.23H-6eH-4e H_3H-4a Me-8^H-6aH-2H-5^„„ ,SnMe3 Me-793Table 2.2: The 400 MHz 1 H NMR and 200 MHz COSY Data for the Cyclohexanone93Assignment(H-X)1H NMR6 ppm (mutt., # of H, J (Hz))COSY Correlation(H-X)Me3Sn 0.11 (s, 9H, 2J sn-H = 52) ----Me-8 1.01 (d, 3H, 6) 5Me-7 1.04(d, 3H, 6, 4JSn-H = 4) 25 1.75-1.85 (m, 1H) Me-8, 4e, 4a, 6a,6e4a 1.85 (ddd, 1H, 12.5, 12, 5) 3, 4e, 56a 1.97 (ddd, 1H, 13, 12.5, 1) 5, 6e3, 4ea 2.00-2.05 (m, 2H) 2,4a, 56e 2.40 (ddd, 1H, 13, 4, 2 ) 5, 6a2 2.77 (dqd, 1H, 6.5, 6, 1, 3J sn-H = 132) Me-7, 3a overlapping signals.The stereochemical assignments of 92 and 93 are further confirmed bycomparing their 13C NMR spectral and chiroptical data. 69 1-1Lidec63 and Kitching andcoworkers 81 have observed that 13C NMR chemical shifts for axially orientedtrimethylstannyl groups are deshielded relative to those of equatorially orientedgroups. For example, the 13C NMR signal for the axial Me3Sn group of 3a-trimethyl-stannylcholestane 96 appears at 6 -9.3 while the equatorial Me3Sn group of313-trimethylstannylcholestane 97 give rise to a 13C NMR signal at 8 -12.1. TheMe3Sn groups of ketones 92 and 93 produce 13C NMR resonances at 8 -10.13 and8 -8.80 respectively. The results of these experiments, supports that the Me3Sn groupis equatorially oriented in ketone 92 and axially oriented in ketone 93.246 -12.1^".Me3Sn s976-9.3Me3Sn 9 6The values associated with carbon-tin coupling constants also provides usefulinformation about the stereochemistry of 92 and 93. The two- and three-bond Sn-Ccouplings have been reported to follow a Karplus-type equation. 82 For example, thecisoid 3 J sn-C of 7-norbornyltrimethylstannane (98) is 11.9 Hz while the transoidcoupling is 67.5 Hz. We observed that the coupling constants 3J Sn-C between theMe3Sn and Me-7 groups in compounds 92 and 93 were 60 Hz (transoid) and 20 Hz(cisoid), respectively. With the relative stereochemistry of 92 firmly established, thenext step of the synthetic sequence was the regioselective introduction of a carbon-carbon double bond to obtain the desired trimethylstannylcyclohexenone 64.706SnMe38 11.9 (cisoicl)(transoid) 8 67.5982.1.1.3. Oxidation of the Trimethylstannylcyclohexanone 92The silyl enol ether 99 (equation 2.3) was prepared in quantitative yield fromthe ketone 92 following the procedure of Fleming and Paterson. 59 The silyl enol ether99 was oxidized with DDQ and collidine (2,4,6-trimethylpyridine) in benzene to givethe desired enone 64 ([ a ]D 29 -45.2°, c = 1.072 in Me0H) in 57% overall yield from theketone 92. Attempts were made to improve the yield of the oxidation step by varyingthe reaction conditions. No product at all was obtained when acetonitrile was used as''SnMe36 4^(2.3)25the solvent. 60 Variation in the base 83 from collidine to 2,6-di-tert-butylpyridine (50%yield) or to bis(trimethylsilyl)trifluoroacetamide 84 (45%) also did not improve the yield.Alternatively, selenoxide formation and elimination of selenenic acid gave the sameoverall yield of the enone 64 as the DDQ oxidation, but the former procedure was lessconvenient.0^ OSiMe31) i-Pr2NLi, THE DDQcollidine''SnMe3 benzene9992''''SnMe32) TMSCIThe IR spectrum of the cyclohexenone 64 exhibits absorptions at 1669, 768and 526 cm -1 , indicating the presence of a six-membered cyclic enone and atrimethyistannyl group. The 1 H NMR spectrum was fully assigned when the spectrumwas taken using C6D6 as a solvent, which gave better dispersion of the signals thanCDCI3. The 13C NMR spectrum was assigned with the assistance of the APT and theheteronuclear 1 H- 13C shift correlation experiments (HSC). 85 The heteronuclear C-Hcorrelations obtained from the HSC experiment are displayed in Table 2.3. The H-Hcoupling constants of H-5 (12, 9 and 6 Hz) and the 3J c_sn coupling constant of Me-8(23 Hz, which is correlated to a 50° dihedral angle between the Me3Sn and the methylgroups using Kitching and coworkers' Karplus equation") confirm the trans-arrangement of the methyl and the trimethyistannyl groups.26H-5Me-7H-4e^\ H-2OMe-8Me3Sn IH-4a^H-66 4Table 2.3: The 400 MHz 1 H, 75 MHz 13C, APT and HSC NMR Experiments Data forthe Cyclohexenone 64 in C6D6Assignment(C-X)13C and APT6 ppm (APTa, J sn_c (Hz))81H NMR and HSC 1 H- 13C Shift Correlationsppm (mutt., # of H, J (Hz), Assignment [H-X])Me3Sn -10.36 (-ve, 340) 0.03 (s, 9H, 2J sn-H = 52, Me3Sn)Me-8 16.54 (-ve, 23) 1.21 (d, 3H, 7, Me-8)Me-7 23.81 (-ve, 6) 1.45 (s, 3H, Me-7)5 28.87 (-ye, 400) 1.34 (ddd, 1H, 12, 9, 6, H-5)4 35.10 (11) 1.90-2.00 (m, 2H, 4a, 4e)6 43.87 (-ye, 16) 2.17-2.26 (m, 1H, H-6)2 125.95 (-ve, 9) 5.96 (br s, 1H, H-2)3 162.62 ^b1 202.18 ^ba -ye is reported when a negative peak is observed. The absence of -ve indicates a positive signal.b No correlationWith the synthesis of the enone 64 established, the scope and limitations of thetrimethylstannyl moiety as an anchoring group in methylenecyclohexane andmethylenecyclopentane annulation sequences could be investigated.2.1.2. 1,4-Additions to (-)-(5R,6R)-3,6-Dimethy1-5-trimethylstanny1-2-cyclohexen-1-one (64)2.1.2.1 Conjugate Addition of the 2-(5-Chloro-1-pentenyl) Group The reactivity of the trimethylstannylcyclohexenone 64 was first tested with theaddition of the synthetic equivalent of synthon 53 (see Scheme 1.3). The known 87Grignard reagent 14 was prepared from the 5-chloro-2-trimethylstannyl-1-penteneMeLiSnMe3 -78 °C, THFCI 064CuBr•SMe 2(0.05 equiv)CI 014BF3.0Et2(1.1 equiv )-78 °C, THF90%'''SnMe3100 ^ 101CI13CI12CIMgBr2.0Et2THF, -78 °C^,MgBr_^I1) CuCN•2(LiCI)2) 64, TMSCI (5 equiv)3) BF3.0Et2 (1.1 equiv)-78 °C, THF86%Scheme 2.413 100  +27(12, Scheme 2.4) by transmetallation with methyllithium (small excess) followed by asubsequent transmetallation with magnesium bromide. Reagent 14 was added to theenone 64 in the presence of a catalytic amount of copper(I) bromide-dimethyl sulfidecomplex and boron trifluoride etherate. Work-up and purification of the crude materialgave a mixture of the chloro ketones 100 and 101 varying in ratios from -4:1 to 5.3:1by 1 H NMR. The combined yield of 100 and 101 was -90%. These ketones couldnot be separated by flash chromatography 88 on silica gel. Evidence for the structuralassignment of epimer 101 was obtained from the 1 H NMR spectrum of the mixture andfrom the spectral properties of the products obtained after cyclization of the mixture ofchloro ketones (see section 2.1.3.2).28Stereochemically pure chloro ketone 100 was eventually obtained by using acyanocuprate reagent instead of a Grignard reagent. Thus, transmetallation ofvinyllithium 13 with THF-soluble lithium chloride•copper(I) cyanide 89 at -78 °C gavethe corresponding cyanocuprate. A mixture of the enone 64 and TMSCI90 was addedto the cyanocuprate solution, followed by boron trifluoride etherate. 91 The chloroketone 100 was obtained as a single epimer ([ a ]D29 +86.4°, c = 1.10 in Me0H),along with a small amount (-4%) of the trimethylstannyl ketone 102 ([ a ] D 26+134.0°, c = 1.008 in Me0H).The trimethylstannylcyclohexanone 102 92 was isolated in all cases where acyanocuprate was used, even when the vinylstannane 12 was used in excess relativeto the methyllithium in the transmetallation step. This result suggests that vinyllithium13 and Me4Sn are in equilibrium with methyllithium and vinylstannane 12 (equation2.4). Further support for the existence of such an equilibrium was obtained whenbutyllithium was added to vinylstannane 12 at -78 °C in THF to give, upon work-upwith H2O, a mixture of 5-chloro-1-butene 103 and a small amount of 2-(butyldimethyl-stanny1)-5-chloro-1-pentene 104 and 5-chloro-2-(dibutylmethylstannyI)-1-pentene105 (equation 2.5). The mixture of chloro vinylstannanes 104 and 105 was identifiedby a combination of 1 H NMR and mass spectroscopy.+^MeLi^—^Me4Sn +Me3Sn'2^ Li 1 3^(2.4)CI^ CI12^+ BuLi 1) THF, -78 °C+Bu3 _n MenSnn = 2 104n = 1 105 (2.5)2) H2O10329The reagents TMSCI and boron trifluoride etherate were both required to obtainhigh chemical yields. The vinyl cyanocuprate derived from the vinyllithium 13 reactedvery slowly to give low yield when added to enone 64 in the absence of borontrifluoride etherate. The low yield was probably due to the decomposition of thecuprate; however, the epimeric selectivity of the addition was complete. With borontrifluoride etherate as the sole additive, the reaction proceeded rapidly, with anidentical stereoselectivity but the yields were lower (65%).The IR spectrum of the chloro trimethylstannylcyclohexanone 100 indicated thepresence of a six-membered cyclic ketone (1708 cm -1 ), a double bond (1637 cm -1 )and a trimethylstannyl group (768 and 526 cm -1 ). The 1 H NMR spectrum of 100 wasassigned using homonuclear correlations (COSY) and NOE experiments. The COSYcorrelations are listed in Table 2.4. The results of the NOE difference experiments of100 supported the predicted stereochemical outcome of an axial 1,4-addition to theenone 64 based on stereoelectronic arguments (see section 2.1.1.2). The attackoccurred axially on the side opposite to the trimethylstannyl moiety. The results of theNOE experiments are summarized on Figure 2.2. Irradiation of the signal due to H-3led to enhancement of the resonances attributed to Me-7, H-4e, H-3' and H-1'a(5 4.96) (100a); irradiation of the signal due to H-4a led to enhancement of thesignals corresponding to Me-8, H-4e, H-2 and H-6a (100b) and irradiation of thesignal due to H-1'a led to enhancement of the signals assigned to H-3, H-6e and H-1'b(100c). The reciprocal enhancement between H-1'a and H-3 and the couplingsconstants of the latter hydrogen (J=14, 13, 2.5 Hz) clearly demonstrate the trans-trans arrangement between the chloropentene, trimethylstannyl and Me-7 moieties of100.H-1'bIH -6aH-2H-4a 100Table 2.4: The 400 MHz 1 H NMR and 200 MHz COSY Data for the Chloro Ketone100Assignment(H-X)1H NMR6 ppm (mutt., # of H, J (Hz))COSY Correlation(H-X)Me3Sn 0.10 (s, 9H, 2JSn-H = 52) --Me-7 0.96 (d, 3H, 6.5) 2Me-8 1.11 (s, 3H) ----3 1.26 (ddd, 1H, 14, 13, 2.5, 2J sn_H = 45) 2, 4a, 4e4a 1.63 (dd, 1H, 14, 14, 3,-/ Sn-H = 21) 3, 4e4' 1.87-1.98 (m, 2H) 3', 5'3', 4e 2.03-2.13 (m, 3H) 1'a, 1'b, 3, 4', 4a, 6e (LR)a2, 6a 2.17-2.30 (m, 2H) 3, 6e, Me-7,6e 2.73 (dd, 1H, 14, 3) 4e (LR), 6a5' 3.55 (m, 2H) 4'l'b 4.88 (br s, 1H) 1'a, 3'1'a 4.96 (s, 1H) l'b, 3'a (LR) = Long range or "W" coupling.30SnMe3100aSnMe3 100cFigure 2.2 NOE's of Compound 10031The 13C NMR spectrum of the chloro trimethylstannylcyclohexanone 100 couldbe assigned using the values of the Sn-C coupling constants and an APT experiment.A coupling constant of 11 Hz (3J Sn-C) was observed between the Me3Sn group andMe-7, indicating a cisoid arrangement between the methyl and trimethylstannyl groupsas discussed previously (see structure 98, section 2.1.1.2).Having demonstrated that a 2-(5-chloro-1-pentenyl) moiety can be stereo-selectively and efficiently added to enone 64, we explored the possibility of adding, ina conjugate sense, other bifunctional reagents to this substrate.2.1.2.2 Conjugate Addition of the 2-(4-Chloro-1-butenyl) and 3-(5-Chloro-2-pentenyl) Groups The methylenecyclopentane annulation sequence is also potentially useful forthe synthesis of natural products. For example, the rearranged clerodane 60-hydroxy-incana-pteroniolide (106) 93 could be synthetically derived from the methylene-cyclopentane annulation product 107 (equation 2.6). Compound 107 could besynthetically derived from the 3-methylcyclohexanone 57 (the enantiomer of 56) usingthe methodology discussed in the preceding pages.32 ^> ^>5 7(2.6)1 0 6The first part of the methylene- and (Z)-ethylidenecyclopentane annulationsequences, the 1,4-addition of the substituted vinyl moieties to the enone 64, wereinitially explored with reagents derived from 4-chloro-2-trimethylstannyl-1-butene(110)94 and (Z)-5-chloro-3-trimethylstannyl-2-pentene (115)13d,95 (Scheme 2.5).The chloro butene 110 was prepared in two steps from 3-pentyn-1-ol (108)(equation 2.7). Addition of trimethylstannylcopper(I)-dimethyl sulfide to 3-pentyn-1-01(108) produced the trimethylstannyl alcohol 109 which was subsequently convertedto the chloride 110 by reaction with triphenylphosphine and triethylamine in carbontetrachloride. (Z)-5-Chloro-3-trimethylstannyl-2-pentene (115) (Scheme 2.5) wasprepared from ethyl 2-pentynoate (111). Addition of lithium (trimethylstanny1)-(phenylthio)copper(I) (89) to the alkynoate 111 gave the (E)-trimethylstannyl ester112. 96 Stereoselective deconjugation of the (E)-trimethylstannyl ester 112 withi-Pr2NLi followed by protonation with acetic acid yielded the (Z)-trimethylstannyl ester113. The (Z)-trimethylstannyl ester 113 was reduced with lithium aluminum hydridein ether to give the (Z)-trimethylstannyl alcohol 114. Finally, the latter compound 114was converted into (Z)-5-chloro-3-trimethylstannyl-2-pentene (115) using triphenyl-phosphine and triethylamine in carbon tetrachloride. The overall yield from ethyl2-pentynoate (111) was 46% and the spectral data of (Z)-5-chloro-3-trimethylstanny1-2-pentene (115) were consistent with those previously reported.13c1,96OH Ph3 P, Et3 NA ,CCI4 Me3Sn70%^110  (2 . 7)Me3Sn10933Me3 SnCu•SMe2OH^11^)^THF, Me0H10 8 -78 °C, 69%^COOEt111Me3 SnCu(SPh)Li^\8 9^ 1) i-Pr2NLi,THF, -78 °C'...„\  COOEt ^THF, Me0H Me3Sn ^2) AcOH, THF, -98 °C-78 °C, 83%^1 1 2 82%Me3Sn114OH LiAIH4I^COOEtEther, -20 °C Me3Sn73%^113Scheme 2.5The 1,4-addition of the Grignard reagent 116, prepared by the transmetallationof 4-chloro-2-trimethylstannyl-1-butene (110), to enone 64 (Scheme 2.6) producedthe trimethylstannyl cyclohexanone 102 (-5% yield) and an inseparable mixture (byflash chromatography) of chloro ketones 117 and 118 97 in a ratio of 6.7:1 (by 1 HNMR). The combined yield of 117 and 118 was 55% (73% yield based on recoveredstarting enone 64). Eventually, the chloro ketone 117 ([ a 11)25 +87.7°, c . 1.212 inMe0H) was prepared, free of the epimer 118, in 69% yield (76% yield based onrecovered starting enone 64), through the 1,4-addition of the cyanocuprate 119 toenone 64 in the presence of TMSCI and boron trifluoride etherate. Thetrimethylstannyl cyclohexanone 102 was also obtained in 10% yield."'SnMe3- 117+ 0^+ 102 (-5%)CICI341) MeLi, THF1 1 0 ^2) MgBr2.0Et2 BrMg-78 °C, THF 1 1 664CuBr•SMe20.05 equivBF3.0Et21.1 equivTHF, -78 °C55%110^ [Li(CN)Cu2) CuCN•2(LiCI)-78 °C, THF^1 1 964, TMSCI2.5 equiv1) MeLi, THF117  + 102(-10%)BF3.0Et21.1 equivTHF, -78 °CScheme 2.6 69%The HRMS (M -F-Me) 99 and the elemental analysis were consistent with theproposed molecular formula for the chioro ketone 117 and the spectral data (IR,1 H NMR, 13C NMR, and circular dichroism) were similar to those obtained for thechioro ketone 100. Those similarities simplified the assignment of all the signals inthe 1 H NMR and 13C NMR spectra of 117.The 1,4-addition of the organomagnesium species 120 (equation 2.8) to enone64 gave the chloro ketone 121 ([ a )D 25 +116.2°, c = 1.036 in Me0H) and some ofthe starting enone 64. 99 The yield was 65% (84% yield based on recovered enone64). The more hindered nature of reagent 120 is probably responsible for thecomplete stereoselectivity of the addition. The same stereoselectivity was alsoobtained with the corresponding cyanocuprate 122 but the addition was sluggish andthe yield was low (16% after 2 h at -78 °C, 70% yield based on recovered startingenone 64). It is interesting to note that in contrast to our previous results, none of thetrimethylstannylcyclohexanone 102 was isolated. This observation can beunderstood if we consider the equilibrium between the lithio species 123 (equation2.9) and the trimethylstannyl species 115. Relief of A( 1,3 ) strainl 00 in 115 by''''SnMe31 21^(2.8)35replacement of the bulky trimethylstannyl group by the relatively small lithium ion willcause the equilibrium to shift completely to the right.1) MeLi, THE115 ^2) Mg Br2.0Et2-78 °C, THE[^CIiBrMg12064, CuBr•SMe20.05 equivBF3.0Et2 1.1 equivTHF, -78 °C65%[ Li(CN)C122CIu +^MeLi Me4Sn +CILi^(2.9 )1 2 3^k4 .uiMe3Sn11 5The IR spectrum of chloro ketone 121 exhibits absorptions at 1707, 1640, 773and 525 cm -1 , indicating the presence of a six-membered cyclic ketone, a double bondand a trimethylstannyl group. The 1 H NMR and 13C NMR spectra were very similar tothose of 100 and 117 and indeed could be assigned with the aid of comparisons withthe spectra of the previously prepared trimethylstannylcyclohexanone 102 and thechloro ketones 100 and 117. The presence of signals due to the olefinic proton(8 5.38 q, 1H, J. 7.5 Hz) and the vinylic methyl group (6 1.75 d, 3H, J. 7.5 Hz) wereconsistent with the structural formula 121. 69In summary, we have described thus far a somewhat improved procedure toprepare the previously reported enone 55 and have shown how this substance can beconverted efficiently and stereoselectively into the ketone 92. This ketone was thentransformed to the enone 64 by use of straightforward chemistry. The compatibility ofthe Me3Sn function with cuprate additions to the enone 64 was demonstrated with thesuccessful, stereoselective preparation of the chloro ketones 100, 117 and 121. The055CI 0CI09 2 '''SnMe30"'SnMe3^'''SnMe3100 _ 1 1 7"'SnMe364036next section of this thesis will consist of a description of the exploration of the reactionconditions required for the cyclization of these ketones.2.1.3. Cyclization of the Trimethylstannyl Chloro Ketones 100, 101, 117and 1212.1.3.1. Cyclization of the Trimethylstannyl Chloro Ketone 100The results of our initial attempts to cyclize the chioro ketone 100 weredisappointing. Both reported cyclization conditions 12 using potassium hydride in THFat room temperature or potassium tert-butoxide and 2 - methyl-2-propanol in THF gavecomplex mixtures of ketones. No product could be detected when i-Pr2NLi was usedas a base in THF. Small amounts (8 to 47% yield) of the desired cyclized bicyclicketone 124 were obtained with potassium hexamethyldisilazide (125) in THF at roomtemperature (equation 2.10). The low yields thus obtained are probably due to theelimination of the trimethylstannyl moiety under the basic conditions. The presence ofnew olefinic signals in the 1 H NMR spectrum of the crude reaction mixture providedevidence for this proposal. Better results were obtained by replacing the chloride witha better leaving group (e.g. iodide), thus allowing the cyclization to occur at lowertemperatures even when using a less readily-equilibrated, more tightly bondedcounterion (lithium instead of potassium).CI 0 37(Me3Si)2NK 125, THF8-47%INalAcetone95% (2.10)Thus, the chloro ketone 100 was treated with sodium iodide in refluxingacetone for 10 h (Finkelstein reaction) to give the iodo ketone 126 in 95% yield(equation 2.10). The spectral data of this material was consistent with the proposedstructure 126. The 1 H and 13C NMR signals for the iodomethylene group of 126appeared at 6 3.23 and 6 6.93, respectively, while the equivalent resonances forchloromethylene moiety of 100 appeared at 8 3.55 and 6 52.68, respectively.The iodo ketone 126 was added to a cold (-78 °C) solution of i-Pr2NLi in THF,and the resulting solution of the lithium enolate was rapidly warmed to 35 °C to givethe bicyclic ketone 124 ([ a ]p28 +109.0°, c = 1.014 in Me0H) in 93% yield (equation2.11). The lithium enolate of 126 is expected to cyclize faster via the transition state127 (leading to the cis-fused product 124) than via the transition state 128 (leading toa trans-product) for the following reasons: (1) the better antiperiplanar alignment ofthe orbitals of the enolate with the antibonding orbital of the carbon-iodide bond and(2) the fact that the boat-like transition state 128, necessary in order to maintain aneffective orbital overlap through the cyclization, would suffer from angle strain as wellas steric interactions involving the methyl group in the 5-position and theiodomethylene moiety.V-^ -I1) i-Pr2NLi, THE-78 °CI'SnMe31 26^2) -78°C to 35 °C93%The IR spectrum of the bicyclic ketone 124 exhibits absorptions at 1702, 1636,772 and 527 cm -1 , indicating the presence of a six-membered cyclic ketone, anexocyclic carbon-carbon double bond and a trimethylstannyl group. A combination of1 H NMR, 1 H decoupling, NOE, COSY, 13C NMR, APT and HSC experiments was usedto determine the structure of the bicyclic ketone 124. The HSC heteronuclearcorrelations and the APT experiment results (Table 2.5) and the COSY homonuclearcorrelations (Table 2.6) were used to establish the carbon-hydrogen connectivities.The relative and absolute configurations were established on the basis of NOEexperiments, coupling constants and chiroptical properties.693839Me-110 H-3H-9aH-4^SnMe3H-10e—H-1H-9eH-8eH-13b IH-8aH 5a/H-10a H-5eIH-13a Me-12124Table 2.5: The 400 MHz 1 H, 75 MHz 13C, APT and HSC NMR Experiments Data forthe Bicyclic Ketone 124 in C6D6Assignment(C-X)13C and APT6 ppm (APTa, .-I sn-c (Hz))1H NMR and HSC 1 H- 13C Shift Correlations5 ppm (mutt., # of H, J (Hz), Assignment [H-X])Me3Sn -10.34 (-ye, 315) 0.05 (s, 9H, 2JSn-H = 51, Me3Sn)Me-11 16.37 (-ve, 15) 1.04 (d, 3H, 6.5, Me-11)10 21.87 1.40 (dddd, 1H, 14, 14, 5, 5, 10a)and 2.12-2.30 (10e)b9 23.75 1.50-1.60 (m, 1H, 9a), and2.12-2.30 (9e)b4 29.24 (-ve, 382) 1.81 (ddd, 1H, 14, 14, 2.5, 2J sn-H = 43, H-4)Me-12 30.39 (-ve) 1.07 (s, 3H, Me-12)8 33.10 2.00-2.10 (8a)c and2.12-2.30 (8e)b5 41.55 (13) 3,1 Sn-H = 24, 5a)1.55 (dd, 1H, 14, 14,and 2.00-2.10 (5e)c3 48.12 (-ve, 15) 2.00-2.10 (H-3)c6 48.46 ^d1 56.06 (-ye, 3) 1.95 (d, 1H, 5, H-1)13 107.78 4.58 (br s, 1H, 13a) and4.78 (br s, 1H, 13b)7 150.76 ^d2 209.92 ^da -ve is reported when a negative peak is observed. The absence of -ve indicates positive APT signal.b Signals unresolved (8e, 9e and 10e)c Signals unresolved (H-3, 5e and 8a)d^No correlation40Table 2.6: The 400 MHz 1 H NMR and COSY Data for the Bicyclic Ketone 124 inC6D6Assignment(H-X)1H NMR5 ppm (mutt., # of H, J (Hz))COSY Correlation(H-X)Me3Sn 0.05 (s, 9H, 2Jsn_H = 51) ^aMe-11 1.04 (d, 3H, 6.5) 3Me-12 1.07 (s, 3H) ^a10a 1.40 (dddd, 1H, 14, 14, 5, 5) 1, 9a, 9e, 10e9a 1.50-1.60 (m, 1H) 8a, 8e, 9e, 10a, 10e5a 1.55 (dd, 1H, 14, 14, 3J sn_H = 24) 4, 5e4 1.81 (ddd, 1H, 14, 14, 2.5, 2J sn-H = 43) 3, 5a, 5e1 1.95 (d, 1H, 5) 10a35e8a2.00-2.10 (m, 3H)4, Me-115a8e, 9a, 9e8e9 e10e2.12-2.30 (m, 3H)8a, 9a, 13a (LR)b, 13b (LR)b10a13a 4.58 (br s, 1H) 8e (LR)b, 13b13b 4.78 (br s, 1H) 8e (LR)b, 13aa No correlation.b (LR) = Long range coupling.Simultaneous irradiation of the signals due to Me-11 and Me-12 produced aNOE enhancement of the signals attributed to H-1, H-3 and H-4, H-5e, and H-8a (see124a, Figure 2.3). The signal of Me-12 was irradiated and the enhancements arerepresented on structure 124b. No enhancement of the signal assigned to H-10acould be observed in either of these experiments. Irradiation of the signalcorresponding to H-4 (see 124c) enhanced the signals due to Me-11 and the olefinichydrogen (H-13a). Finally, irradiation of the signal due to H-1 (124d) led toenhancement of the signals attributed to H-5a, H-10a, H-10e and Me-12. Theproximity of the signals assigned to H-3 to the irradiated resonance due to H-1Me-11nH-3H-4 SnMe3—H-1H-5eMe-12 31 24aMe-110H-4^SnMe3H-8a0 Me-11SnMe3—H-1H-5aH-5eMe-121 24bMe-11H-8a41(AS = -0.05) precluded the observation of an enhancement of the H-3 signal. Theresults shown on structures 124a and 124c are in agreement with the cis-cisarrangement on the cyclohexanone ring of the alkene moiety, H-4, and Me-11. The cisring junction of the decalin skeleton was confirmed by the reciprocal enhancement ofthe signals due to Me-12 and H-1 (see 124b and 124d).H-10e1H-10aSnMe3—H-1H-5a^H-13a Me-12^Me-12124c 124dFigure 2.3 NOE's of Compound 1242.1.3.2. Cyclization of the Trimethylstannyl Chloro Ketone 101 The structure of the chloro ketone 101 obtained by the addition of the Grignardreagent 14 to the enone 64 (see Scheme 2.4), could be inferred from a series ofchemical manipulations. Thus, the mixture of chlorides 100 and 101 (in a ratio of5.3:1 by 1 H NMR) was treated with sodium iodide in refluxing acetone to give aninseparable mixture of the iodo ketones 126 and 129 in quantitative yield(Scheme 2.7). This mixture was then cyclized with i-Pr2NLi in THE as described10 0 + 101 ^(5.3:1)NalAcetone100%124  +42earlier to give, after a series of four careful separations by flash chromatography, thebicyclic ketone 124 (68%), a mixture of the bicyclic ketones 124 and 130 (7%) andpure bicyclic ketone 130 (8%) ([ a ]r) 25 +209.0°, c = 0.900 in Me0H). The cis-decalin 130 would be expected to be the kinetic product of the cyclization, since thetransition state 131 would be predicted to be more stable than alternativearrangements for reasons similar to those described previously in connection with thecyclization of 126.I01 2 6 +""''SnMe3129i-Pr2NLi, THE-78 °C[Me Me SnLi+ -0 -•tScheme 2.7The IR spectrum of the bicyclic ketone 130 exhibited absorptions that indicatedthe presence of a six-membered cyclic ketone (1698 cm -1 ), an exocyclic carbon-carbon double bond (1632 cm -1 ), and a trimethylstannyl group (769 and 527 cm -1 ).A combination of 1 H NMR, selective decoupling, NOE, COSY, 13C NMR, and HSCexperiments were used to determine the structure of the bicyclic ketone 130. TheHSC heteronuclear correlations (Table 2.7) and the COSY homonuclear correlations(Table 2.8) were used to established the carbon and hydrogen connectivities. Thestereochemistry of 130 was established by a combination of the NOE experiments, thecoupling constants and the chiroptical properties.69H-4Me- 2 Me-11H-8eH-9e^130Table 2.7: The 400 MHz 1 H, 75 MHz 13C, and HSC NMR Experiments Data for theBicyclic Ketone 130Assignment(C-X)130 NMR8 ppm (,./ Sn-C (Hz))1H NMR and HSC 1 H- 13C Shift Correlations8 ppm (mult., # of H, J (Hz), Assignment [H-X])Me3Sn -10.13 (315) 0.11 (s, 9H, 2JSn-H = 52, Me3Sn)Me-11 15.53 (15) 0.99 (d, 3H, 6.5, Me-11)Me-12 24.09 1.10 (s, 3H, Me-12)9 27.15 1.30 (ddddd, 1H, 14, 14, 13, 4, 4, 9a) and1.84-1.91 (m, 1H, 9e)10 27.73 1.62-1.69 (m, 1H, 10e) and1.83 (m, 1H, 10a)4 29.57 (390) 1.57 (ddd, 1H, 14, 13, 4, H-4)8 32.78 2.23 (dm, 1H, 14, 8e) and2.37-2.45 (m, 1H, 8a)a5 36.19 (12) 1.18 (ddd, 1H, 14, 4, 1.5, 5e) and2.43 (dd, 1H, 14, 14, 5a)a3 42.62 (19) 2.65 (dq, 1H, 13, 6.5, H-3)6 45.23 (65) ^b1 60.11 2.14 (ddd, 1H, 13, 4, 1.5, H-1)13 107.69 4.71 (br s, 1H, 13b) and4.73(br s, 1H, 13a)7 153.63 ^b2 216.30 ba Overlapping signals (5a and 8a).b No correlation4344Table 2.8: The 400 MHz 1 H NMR and 200 MHz COSY Data for the Bicyclic Ketone130Assignment(H-X)1H NMR8 ppm (mult., # of H, J (Hz))COSY Correlation(H-X)Me3Sn 0.11 (s, 9H, 2J sn-H = 52, Me3Sn) aMe 110.99 (d, 3H, 6.5, Me-11)3Me-121.10 (s, 3H, Me-12) ^a5e1.18 (ddd, 1H, 14, 4, 1.5)4, 5a9a1.30 (ddddd, 1H, 14, 14, 13, 4, 4)1 (LR)b, 8a, 8e, 9e, 10a, 10e41.57 (ddd, 1H, 14, 13, 4)3, 5a, 5e10e1.62-1.69 (m, 1H)1, 9a, 9e, 10a10a1.83 (m, 1H)1, 9a, 9e, 10e9e1.84-1.91 (m, 1H)8a, 8e, 9a, 10a, 10e12.14 (ddd, 1H, 13, 4, 1.5)9a (LR)b, 10a, 10e8e2.23 (dm, 1H, 14)8a, 9a,9e8a2.37-2.45 (m, 1H)8e, 9a,9e, 13a (LR)b, 13b (LR)b5a2.43 (dd, 1H, 14, 14)4, 5e32.65 (dq, 1H, 13, 6.5)4, Me-1113b4.71 (br s, 1H)8a (LR)b, 13a13a 4.73 (br s, 1H) 8a (LR)b, 13ba No correlation.b (LR) = Long range coupling or U coupling..Selective decoupling of the 1 H NMR signal due to Me-11 (8 0.99) of compound130 resulted in a doublet at 8 2.65 (H-3, J = 13 Hz). Irradiation of H-3 produced adoublet of doublets at 8 1.57 (H-4, J = 14, 4 Hz) and a singlet for Me-11. Finally,irradiation of the signal due to H-4 gave a doublet of doublets at 8 1.18 (H-5e, J 14,1.5 Hz), a doublet at 8 1.43 (H-5a, J = 14 Hz) and a quartet at 8 2.65 (H-3, J = 6.5 Hz),thus establishing the Me-11, H-3, H-4, H-5e, H-5a spin system and their relativeorientations using the values of their coupling constants. The 1,3-diaxial relationshipbetween H-4 and Me-12 and the cis ring junction of the decalin skeleton wasconfirmed by the NOE experiments. Thus irradiation of the signal due to H-4 led to the45enhancement of the signals due to Me-11, Me-12 and H-5e (see 130a, Figure 2.4)and irradiation of the signal due to Me-12 led to the enhancement of signals due toH-4, H-1 and H-13a 101 (130b). The elucidation of the structure of compound 130therefore confirmed our proposed structure for the chloro ketone 101. With thestructure of 124 and 130 established, we investigated the annulation sequences ofthe chloro ketones 117 and 121.Figure 2.4 NOE's of Compound 1302.1.3.3. Cyclization of the Trimethylstannyl Chloro Ketones 117 and 121 The chloro ketones 117 and 121, having one less carbon in the alkenyl sidechain than the chloro ketone 100, were expected to cyclize faster than 100. Also,examination of molecular models indicated that the transition state for the cyclization ofthe enolates of 117 and 121 should involve less angle strain and steric interactionsthan in the transition state 127, again due to the shorter carbon chain. We werepleased to find that the chloro ketones 117 and 121 readily cyclized upon treatmentwith i-Pr2NLi, followed by warming to 45 °C. The bicyclic ketone 132 ([ a ] D 26+76.7°, c = 1.14 in Me0H) (equation 2.12) was obtained in 88% yield while thebicyclic ketone 133 ([ a ] [3,26 +77.10, c = 0.978 in Me0H) (equation 2.13) wasobtained in 83% yield.46CI 1) i-Pr2 NLi, THE-78 °C, 1 h-^''''SnMe3 2) -78°C to 45 °C 1 1 7^45 min, 88°/0."'SnMe313 2^(2.12)1) i-Pr2NLi, THE-78 °C, 1 h"'SnMe3 2) -78°C to 45 °C1 21^45 min, 83%CI"'SnMe3(2.13)133Me-100H-8aH-8eH-3SnMe3—H-1H 5aH-9eH-4H- 19a^H-5eH-12a Me-11132H-12bThe IR spectrum of bicyclic ketone 132 exhibits absorptions at 1687, 1652, 765and 522 cm -1 , indicating the presence of a six-membered cyclic ketone, an exocycliccarbon-carbon double bond and a trimethylstannyl group. A combination of 1 H NMR,NOE, 130 NMR and APT experiments and comparison with the spectra of 124 and130 were used to confirm the structure of the bicyclic ketone 132. The 130 NMRspectra could be assigned by a combination of the Sn-C coupling constants, thechemical shifts and the APT experiment. The stereochemistry of 132 was establishedwith the assistance of the NOE experiments, the coupling constants and the chiropticalproperties. 69The results of the NOE experiments unambiguously established the cis-ringjunction of 132. Thus, irradiation of the signal due to Me-11 (see 132a, Figure 2.5)Me-10—H-1Me-10SnMe3H-5aH-5a.el. 0/0/ H-9a H-5e2%1.5%H-12a Me-111% J132aSnMe33 0/02°/09% 0H-81------Me-10H-5e 4%Me-11132cFigure 2.5 NOE's of Compound 132SnMe3H-5eMe-11132b47led to the enhancement of the signals due to H-9a, H-5a, H-5e, H-1 (8 2.42, dd, J. 6,5 Hz) and H-12a. Irradiation of the signal due to H-4 (132b) led to the enhancementof the signals due to Me-10, H-5e and H-8a. Finally, irradiation of the signal due toH-5a (132c) led only to the enhancement of the signal due to Me-11. Theenhancement of H-5e could not be seen in the last experiment because its chemicalshift was too close to that of the irradiated signal (M = 0.16).The IR spectrum of the bicyclic ketone 133 shows absorptions that can beassigned to a six-membered cyclic ketone (1687 cm -1 ) and a trimethylstannyl group(767 and 527 cm -1 ). A combination of 1 H NMR, NOE and 13C NMR experiments andcomparison with the spectra of 124, 130 and 132 were used to determine thestructure of the bicyclic ketone 133. The 13C NMR spectra could be assigned with theassistance of the Sn-C couplings constants, the chemical shifts and the APTexperiment. The stereochemistry of 133 was established with the NOE experiments,the couplings constants and the chiroptical properties.69H-8e^ H-5aIH-9a H-5eMe-13 Me-11133H-12Me-10SnMe3—H-13%H-5aH-5e 2°1.5%Me-13 Me-111%^....) 133aMe-104% H-5eMe-13 Me-11133b48Me-100 H-3H-8a^H-4^SnMe3H-9e—H-1The results of the NOE experiments established the cis-ring junction of thebicyclic ketone 133. Irradiation of the signal due to Me-11 (see 133a, Figure 2.6)led to enhancement of the signals assigned to Me-13, H-5a, H-1 (5 2.30, d, J = 5 Hz)and H-5e. Irradiation of the signal due to H-5e (133b) led to the enhancement of theresonances attributed to Me-11, Me-13 and H-5a.Figure 2.6 NOE's of Compound 133The preceding work has demonstrated the feasibility of carrying out themethylenecyclopentane, (Z)-ethylidenecyclopentane and methylenecyclohexaneannulation sequences on the enantiomerically pure trimethylstannylcyclohexenone64 and the usefulness of the Me3Sn group as an anchor to direct and maintain thestereochemistry of the cyclized products. The next objective of the project was toremove the trimethylstannyl anchor, and the results of this portion of the research willbe described in the following pages.2.2. REMOVAL OF THE TRIMETHYLSTANNYL MOIETY2.2.1. Previous Destannylation MethodsA search of the chemical literature indicated that there were several methodsreported to remove a trialkylstannyl moiety. These methods were rarely general andworked only on a few specific substrates. The known destannylation methods can bedivided in four classes: oxidation, carbon-carbon bond formation, a combination ofcarbon-carbon bond formation and fragmentation, and replacement of the R3S nmoiety by an hydrogen. Examples of each type are presented next.2.2.1.1. Oxidation Still68 has shown that the tetraalkylstannyl moiety can be oxidized to a carbonylgroup in the presence of chromium trioxide. The synthesis of dihydrojasmone (138)illustrates this oxidation (Scheme 2.8). The 1,4-addition of trimethylstannyllithium to2-cyclopenten-1-one (134), followed by trapping of the resulting enolate withiodopentane, gave the stannyl ketone 135. Reaction of methyllithium with thecarbonyl moiety produced the tertiary alcohol 136, which was directly oxidized into thehydroxy ketone 137. The alcohol was then dehydrated to provide dihydrojasmone(138) in an overall yield of 71% from 135. The destannylation method is limited bothby the requirement of having a tertiary alcohol in the position y to the Me3Sn moiety,and by the necessity of using a large excess of chromium trioxide in order to get goodreaction yields. Nevertheless, this type of oxidation might provide access to highlyoxidized members of the clerodane family like the (+)-epoxide 24, for example.4950MeLiMe 3SnLiTHE-N H3C511 11 1, -33 °C90%^1 35  SnMe3Ether, -78 °C1 3 4CrO3Pyrid neNaOH71%Scheme 2.82.2.1.2. Carbon-Carbon Bond Formation Examples of the use of a simultaneous destannylation-carbon bond formationare more common than the oxidation of the trialkylstannyl moiety. Kadow andJohnson 102 have prepared the bicyclo[3.1.0]hexane 141 in 62% overall yield from thetributylstannyl ketone 139 following the procedure outlined in equation 2.14. The1,2-addition product 140 was dehydrated with thionyl chloride in pyridine, triggeringdestannylation and cyclopropanation to give 141. The reaction produced cyclopropylcompounds in good yield only when a good carbocation-stabilizing moiety was on thecarbon adjacent to the tertiary alcohol.0S1 3 9 nBu 3 Ph OH°SnBu3140SOCl2Pyridine62%PhPhLi1 41^(2.14)In a series of publications, Macdonald and coworkers 103 have explored theintramolecular destannylation-cyclization of primary alkyistannyl enones, ketones andalkenes. The method is exemplified by equation 2.15. The ketone 142 is cyclized inthe presence of diethylaluminum chloride to give the tertiary alcohol 143 in 91% yield.51Although a high yield has been reported for a few specific cases, this method oftenresults in formation of a terminal alkene as the major product by elimination of theMe3Sn moiety, especially for the formation of rings larger than 5 carbon atoms. Forexample, ketone 144 (equation 2.16) gave the alkene 145 in 90% yield using acidicconditions identical with those in equation 2.15.Et2AICI (2.5 equiv)CH 2Cl2 , 0 °C, 91%SnMe3 Et2AICI (2.5 equiv)CH2Cl2 , 0 °C, 90%OH143 ^(2.15)oOH1 45^(2.16)rSnMe31422.2.1.3. Carbon-Carbon Bond Formation-Fragmentation Posner and coworkers 104 have used a "one-pot" annulation sequence involvingan oxidative destannylation to prepare macrolides. The total synthesis ofphorocantholide I (151) (Scheme 2.9), a natural 10-membered ring lactone isolatedfrom an insect secretion, illustrates the procedure. Thus, tributylstannyllithium wasconjugatively added to the cyclohexenone 146, and the resulting enolate was trappedwith the iodide 147 to give the ketone 148. The ethoxyethyl protective group wascleaved with aqueous ammonium chloride to give the hemiketal 149. The crudehemiketal was oxidized with lead tetraacetate to yield the macrolide 150. Finally,Wilkinson hydrogenation of 150 produced the natural product 151 in 27% overallyield.52.••"'^H2, CIRh(PPh 3 )3---‘1-VAS1 4 9 nBu3(Ac0)3 Ir;--\) o//P13(0A04n!rt•-,1 4 61) Bu3SnLi H30+•./15127% overall Scheme 2.9 - 150 ^-85%+ Bu 3 Snl1520 IBu3SnHAIBNSnBu3 A, C6H601 5 4^(2 . 17 )Similarly Baldwin and coworkers 105 have prepared 10-membered rings by afree radical-promoted cyclization-destannylation method. For example, the iodide152 (equation 2.17) was cyclized with tributyltin hydride and AIBN in benzene to givethe radical intermediate 153, which then fragmented in situ to propagate the radicalchain and produce the 10-membered ketone 154 in 85% yield.2.2.1.4. Replacement of the RaSn Moiety by an Hydrogen To the best of our knowledge only two direct methods exist for the replacementof the R3Sn moiety of a tetraalkylstannane by an hydrogen. Except for a few specificexamples, the yields of the reactions were generally low because of the very harshconditions used. Olszowy and Kitching 106 have destannylated the triisopropyl-stannane 155 (equation 2.18) by treatment with deuterated trifluoroacetic acid indioxane at 100 °C for 10 days! The deuterated cyclohexane 156 was obtained in only30% yield.53CF3COODDioxanei-Pr3Sn100 °C, 10 days30% 156155 (2.18)BuLi(2 equiv)-78 °CD2078%158 ^ 1 5 9^(2.19)DHONewman-Evans and Carpenter107 have successfully destannylated 2-hydroxy-5-tributylstannylbicyclo[2.1.1]hexane 157 (equation 2.19) by the addition of butyl-lithium at -78 °C followed by deuteration with D20 to give the alcohol 159 in 78%yield. A high yield for the reaction has been reported only when the orientation of thetrialkystannyl and hydroxyl groups are syn as shown in structure 157. The authorssuggested that this arrangement allowed the negative charge on the carbon atom tobe stabilized by an intramolecular complexation of the lithium counterions with theoxygen anion as depicted in intermediate 158.2.2.1.5. A Proposal for the Removal of the Trimethylstannyl Group With the exception of Still's oxidation method, none of the known procedures forremoval of a Me3Sn group would be useful to access the clerodane skeleton using ashort reaction sequence. A new destannylation method needed to be developed toachieve our goal. It was proposed that a dissolving metal reduction in either ammoniaor amine solvents should result in transfer of an electron to the polarizable tin atom,with the eventual formation of a carbanion. Protonation of the latter species wouldprovide the product where the Me3Sn function is replaced by a hydrogen. Thisproposal is represented in Scheme 2.10. Single electron transfer 108 to 160 wouldgive the radical 161 and trimethylstannylmetal. This radical could accept another16154electron from a second metal atom to form the carbanion 162, which could then eitherabstract a proton from the solvent or another proton source to produce 163, thedesired destannylated product. We set out to verify that this hypothesis could beapplied to the destannylation of (3-trimethylstannyl ketone substrates.(-1/ThrSnMe3160+ MSnMe31 6 3HProtonsourceScheme 2.10r\- H—XM+1622.2.2. Dissolving Metal Reduction of the Bicyclic TrimethylstannylKetone 124Dissolving metal reduction of a carbonyl group with calcium metal in ammoniais a well known method. Wen had previously reported the reduction of the bicyclicketone 17 to the alcohol 164 (equation 2.20) using this method. We thus proposed touse these conditions to accomplished the desired destannylation.1) Ca, NH3 , -33 °C2) EtOH75% 1) Ca (4.8 equiv)NH3 , Ether 5:1,„,SnMe2) EtOH (20 equiv)1 2 4^3 -33 °C9°/0OHH3.:1 6 6 "'SnMe26% (2.21)+55Using reaction conditions reported by Wai (see equation 2.20), the reduction ofthe bicyclic ketone 124 with calcium in ammonia (equation 2.21) was attempted. Thedesired bicyclic alcohol 165 ([ a ] D24 +37.0°, c = 0.892 in chloroform) was isolatedin 9% yield, along with a 26% yield of the bicyclic trimethyistannyl alcohol 166(I a hp25 -9.52°, c = 1.505 in chloroform). After a series of experiments, effectiveconditions for the reduction of 124 to 165 were found. Thus, a THF solution of2-methyl-2-propanol and 124 (equation 2.22) was added to a cold (-78 °C) deep bluesolution of lithium in ammonia to produce the alcohol 165 in 89% yield. 11 °1) Li (10 equiv)NH3 , THF 6:1t-BuOH (20 equiv)OHH E2) NH4CI-78 °C, 89%The reaction conditions were varied in order to learn about the mechanism ofthe reduction. By using only 2.2 equivalents of electrons from the metal in thereduction process, only one of the functional groups (ketone or Me3Sn) should bereduced if there is a significant difference in their reduction rate. In the event,reduction of 124 using 2.2 equivalents of lithium in ammonia gave compounds 124,165 and 166 in isolated yields of 18%, 31% and 43%, respectively (equation 2.23).The yield of the bicyclic trimethyistannyl alcohol 166 based on the recovered ketone1 24 was 52%. The use of calcium metal gave slightly different results. With1.1 equivalents of calcium, we isolated 31% of 124, only 12% of 165, and 42% of thebicyclic trimethyistannyl alcohol 166 (61% yield based on recovered 124). The lower16531%12%16643%42% (2.23)56reactivity of calcium in the reduction process probably accounts for the greater relativeamount of 166 formed during the reduction. 1081) MetalOH^OHNH3 , THF 2:1^1:1 = H .t-BuOH (5 equiv)124  +"'SnMe3 -78 to -33 °C1 24^2) NH4C1Metal = Li (2.2 equiv): 18%Metal = Ca (1.1 equiv): 31%'''SnMe3The bicyclic trimethylstannyl alcohol 166 was converted to the bicyclic alcohol165 in 94% yield using a procedure identical to that described in equation 2.22. Inone experiment, the reduction of the ketone 124 with lithium in ammonia in thepresence of 2-methyl-2-propanol was quenched with water a minute after the additionof the ketone. From the resulting mixture we isolated a small amount of a ketone thatwas assigned the structure 17 on the basis of the comparison of its 1 H NMR spectrumwith that of Wai. 111 It was concluded from the results of the dissolving metal reductionsof 124 that the rate of reduction of the carbonyl group is only marginally faster than thereduction of the trimethylstannyl moiety.17The IR spectrum of the bicyclic alcohol 165 exhibits absorptions at 3280, 1637,and 1021 cm -1 , indicating the presence of a hydroxyl group and an exocyclic carbon-carbon double bond. A combination of 1 H NMR, selective decoupling, COSY,13C NMR and APT experiments was used to confirm the structure of the bicyclicalcohol 165.Me-11OHH-2^H-3H-9a^H-4a^H-4eH-10e—H-1H-9eH-8eIH-13b^H-10 H-5eH-8a^H-13a Me-12165H-5a57Selective decoupling of the signal at 6 1.01 (Me-11) simplified the signal due toH-3 at -8 1.40. The same signal at -8 1.4 (H-3) was simplified along with theappearance of a broad singlet at 6 1.37 (H-1) and a singlet at 5 1.25 (OH) when thesignal at 6 3.15 (H-2) was irradiated. The values of the coupling constants of thesignal at 8 3.15 (H-2) after D20 exchange (J = 10, 10 Hz) suggested that H-1 and H-3are both trans-diaxial to H-2. The homonuclear correlation data (COSY experiment)for the bicyclic alcohol 165 are listed in Table 2.9. The assignment of H-13a andH-13b were based on a comparison of the 1 H NMR spectrum of 165 with that of 124.The 13C NMR spectrum was tentatively assigned on the basis of a combination of thechemical shifts and an APT experiment.58Table 2.9: The 400 MHz 1 H NMR and COSY Data for the Bicyclic Alcohol 165Assignment(H-X)1H NMR8 ppm (mutt., # of H, J (Hz))COSY Correlation(H-X)Me-11 1.01 (d, 3H, 7) 2 (LR)a, 3Me-12 1.15 (s, 3H) bOH 1.25 (d, 1H, 6)c 2134a, 4e5a9a, 9e1.20-1.60 (m, 7H)2, 10a, 10eMe-11, 25e8a, 8e10a 1.70- 1.82 (m, 1H) 1, 8a (LR)a, 9a, 9e, 10e5e10e1.98-2.07 (m, 2H) 4a, 4e, 5a1, 8e(LR)a, 9a, 9e, 10a8e 2.18 (br d, 1H, 13.5) 8a, 9a, 9e, 10e(LR)a8a 2.35-2.45 (m, 1H) 8e, 9a, 9e, 10a(LR)a, 13a and 13b(LR)a2 3.15 (ddd, 1H, 10, 10, 6)d Me-11 (LR)a, OH, 1, 313a 4.60 (dd, 1H, 1.5, 1.5) 8a (LR)a, 13b13b 4.79 (dd, 1H, 1.5, 1.5) 8a (LR)a, 13aa (LR) = Long range coupling.b No correlation.c Exchanges with D20.d Becomes dd, J= 10, 10 Hz, with D20.The IR spectrum of the bicyclic trimethylstannyl alcohol 166 exhibitedabsorptions assigned to a hydroxyl group (3290 and 1018 cm -1 ), an exocyclic carbon-carbon double bond (1637 cm -1 ) and a trimethylstannyl groups (764 and 523 cm -1 ).A combination of 1 H NMR, selective decoupling, COSY, 13C NMR, APT experimentsand comparison with the spectral data of 124 and 165 were used to confirm thestructure of the bicyclic trimethylstannyl alcohol 166.The 1 H NMR spectrum of 166 was very similar to that of 165. The couplingconstants of the signal at 8 3.16 (H-2) after D20 exchange (J = 10, 10 Hz) suggestedthat H-1 and H-3 are both trans-diaxial to H-2. The homonuclear correlations (COSYexperiment) are listed in Table 2.10. The 13C NMR spectrum of the alcohol 166 wasMe-11OHH3H-9a^H-4^SnMe3H-10eH-2H-9eH-8eH-13bH-81H-10 H-5eH-13aMe -1216659tentatively assigned on the basis of a combination of the chemical shifts and an APTexperiment.-H-1H-5aTable 2.10: The 400 MHz 1 H NMR and 200 MHz COSY Data for the BicyclicTrimethylstannyl Alcohol 166Assignment(H-X)1H NMR8 ppm (mutt., # of H, J (Hz))COSY Correlation(H-X)Me3Sn 0.08 (s, 9H, 2J sn-i-i = 51) ^aMe-11 1.01 (d, 3H, 6) 3Me-12 1.12 (s, 3H) aOH 1.25 (d, 1H, 6)b 21345a1.26-1.50 (m, 4H)2, 10a, 10eMe-11, 25e9a, 9e 1.50-1.60 (m, 2H) 8a, 8e, 10a, 10e10a 1.70- 1.82 (m, 1H) 1, 9a, 9e, 10e10e 2.02 (br d, 1H, 14) 1, 8e(LR)c, 9a, 9e, 10a5e 2.07 (br dd, 1H, 14, 1) 4, 5a8e 2.17 (br d, 1H, 15) 8a, 9a, 9e, 10e(LR)b8a 2.32-2.40 (m, 1H) 8e, 9a, 9e, 13a and 13b(LR)b2 3.16 (ddd, 1H, 10, 10, 6)d OH, 1, 313a 4.51 (dd, 1H, 1.5, 1.5) 8a (LR)b, 13b13b 4.80 (dd, 1H, 1.5, 1.5) 8a (LR)b, 13aa No correlation.b Exchanges with D20.c (LR) = Long range coupling.d Becomes dd, J= 10, 10 Hz, with D20.60With a successful destannylation procedure available we wanted to verify theenantiomeric purity of the bicyclic alcohol 165.2.2.3. Enantiomeric Purity of the Bicyclic Alcohol 165The enantiomeric purity of the bicyclic alcohol 165 was established byesterification with optically active a-methoxy-a-trifluoromethylphenylacetyl chloride.The formation of Mosher's esters is a well established method for the determination ofthe optical purity of secondary alcohols. 112 The esters are prepared by the addition ofa secondary alcohol to a-methoxy-a-trifluoromethylphenylacetyl chloride (MTPA-CI).The diastereomeric purity is easily ascertained by examination of the 1 H, 13C or19F NMR spectra of the resulting ester. The fluorine-19 NMR spectrum is simpler than1 H or 13C NMR spectra (usually a single peak for each enantiomer is observed in19F NMR) and uncongested, making the determination of the enantiomeric purity ofthe alcohol easier to perform. The method is absolute since the optical purity of aproduct can be determined without knowing the optical rotation of the pure product.The sensitivity of the determination of optical purity of an alcohol with Mosher's estersis limited by the sensitivity of the NMR technique used.The (R)-(-)- and (S)-(+)-a-methoxy-a-trifluoromethylphenylacetyl chlorides (168and 170) (equation 2.24) were prepared from the commercially-available (S)-(-)- and(R)-(+)-a-methoxy-a-trifluoromethylphenylacetic acid 113 (167 and 169), respectively,according to the procedure of Mosher and coworkers. 1120F3C,C6H5 '^OHMeO(S)-1670C6H5 e•F3C^OHMeO(R)-169SOCl2^...-NaCI (0.5 equiv)SOC l20F3C,..,^C6H5 '^C lMeO(R)-168OC6H5 ,F3C '^ClMeO(S)-170 (2.24)NaCI (0.5 equiv)061The bicyclic alcohol 165 was treated with the acid chlorides 168 and 170(equation 2.25) separately following the procedure of Dale and Mosher. 114 The crude,isolated product mixture containing the MTPA-esters 171 and 172 was analyzed byNMR spectroscopy. The esters 171 ([ a ] p28 -23.9°, c = 0.463 in chloroform) and172 ([ a ]D 30 +31°, c = 0.503 in chloroform) were purified from their respectivecrude reaction mixtures by chromatography and then characterized. The 1 H NMRspectrum of the crude product containing 171 was compared with the spectrum of thepurified ester 172 and was shown to be completely devoid of the distinct signalsattributed to the enantiomer of 172 thus showing that the alcohol 165 wasenantiomerically pure.1) Pyridine, CCI4rt., 4 days2) Me2 N(CH2 )3NH23) H30+1) Pyridine, CCI 4rt., 4 days2) Me2N(CH 2 )3 NH 23) H30+=171 r,Y6"5Me0 CF31 7 2 (2.25)OHH 0F3C,,+ C6 H 5 ( SCIMeO(R)-1681.4 equiv0165OHHC6 H 5 ,+ F3C '^ClMeO(S)-1701.4 equiv165The IR spectrum of the bicyclic ester 171 exhibits absorptions at 3084, 1734,1638 and 723 cm -1 (3079, 1737, 1637 and 725 for the bicyclic ester 172), indicatingthe presence of an aromatic ring, an ester carbonyl, an exocyclic carbon-carbondouble bond and a trifluoromethyl moiety. A combination of 1 H NMR, COSY (171),13C NMR, 19 F NMR experiments, chiroptical properties, 69 and comparison with thespectral data of 124 and 165 were used to confirm the structure of the bicyclic esters171 and 172.62The homonuclear correlations of the COSY experiments are listed in Table2.11. The assignments for H-13a and H-13b were made by comparison with the1 H NMR spectrum of 124. The 13C NMR spectra of 171 and 172 were tentativelyassigned with the assistance of a combination of the chemical shifts and comparisonwith the spectra of 124, 165 and 166. The characteristic 1 H NMR signals of 171 are:Me-11 doublet at 6 0.86, Me-12 singlet at 6 1.11, MeO unresolved quartet (long rangeH-F coupling) at 6 3.56, olefinic protons H-13a and H-13b at 6 4.62 and 6 4.83, H-2doublet of doublets (J = 10, 10 Hz) at 8 4.95 and the aromatic protons at 6 7.35-7.40and 7.60-7.64. The 1 H and 130 NMR spectra of 171 and 172 are very similar, andthe assignment of the spectra of 172 can be made by comparison with those of 171.The resolved NMR signals of 172 that have a chemical shift difference greater than8 0.02 (in absolute value) as compared with those of 171 (As = 6 172-6 171) arelisted in Table 2.12 ( 1 H NMR) and in Table 2.13 ( 13C NMR). None of the signals of172 were observed in the 1 H and 13C NMR spectra of 171 and vice-versa, in eitherthe crude reaction product mixture or in the purified product, thus establishing theenantiomeric excess for the alcohol 165 at a value of at least 98%. 115The 19 F NMR (188.3 MHz) spectra were recorded for the esters 171 and 172.The spectrum of the (S)-MTPA ester 171 showed a singlet at 6 4.85 (externaltrifluoroacetic acid standard) with satellites due to carbon couplings ( 1 J F-C = 288 Hz,2J F-C = 44 Hz and 3J F-C = 27 Hz) and a small singlet at 6 5.05. The relative intensityof the two signals was determined to be 157:1 (99.4% pure) in the NMR spectrum. Thespectrum of the (R)-MTPA ester 172 showed a singlet at 6 5.02 (external trifluoroaceticacid standard) with 13C satellites couplings of 1 J F-C = 289 Hz, 2J F-C = 44 Hz and3J F-C = 27 Hz and a small singlet at 6 4.85. The relative intensity of the two signalswas 64:1 (98.4% pure). These results clearly show that the bicyclic alcohol 165 isenantiomerically pure (__96`)/0 enantiomeric excess) within the limits of 1 H, 130 and19 F NMR detection.0633 'H-13b 1H-8aH-10 H-5eH-13aMe-121720H-3^H-2^H-3H-9aH-4e H-4a^H-4eH-10e-H-1^ -H-1H-9eH-5a H-8e^ H 5aH-13b 1H-8a171H-4aH-10eTable 2.11: The 400 MHz 1 H NMR and COSY Data for the Bicyclic MTPA-Ester 171Assignment(H-X)1H NMR5 ppm (mutt., # of H, J (Hz))COSY Correlation(H-X)Me-11 0.86 (d, 3H, 7) 3Me-12 1.11 (s, 3H) ^a10e 1.16 (br dd, 10, 3) 1, 8e(LR)b, 9a, 9e, 10a5a 1.20-1.31 (m, 1H) 4a, 4e,5e9e 1.37- 1.45 (m, 1H) 8e, 8a, 9a, 10a, 10e14a,4e9a10a1.50-1.60 (m, 5H)2, 10e3, 5a, 5e8a, 8e, 9e3 1.60-1.72 (m, 1H) Me-11, 2, 4a, 4e5e 2.03 (ddd, 1H, 13, 4, 4) 4a, 4e, 5a8e 2.18 (br dd, 1H, 13, 3) 9a, 9e, 10e(LR)b8a 2.30-2.40 (m, 1H) 9a, 9e, 13a and 13b(LR)bOMe 3.56 (unresolved q, 3H, 5J F_H = 1) ^a13a 4.62 (br s, 1H) 8a(LR)b, 13b13b 4.83 (br s, 1H) 8a(LR)b, 13a2 4.96 (dd, 1H, 10, 10) 1, 3m-, and p-H's 7.35-7.40 (m, 3H) o-H'so-H's 7.60-7.64 (m, 2H) m-, and p-H'sa No correlation.b (LR) = Long range coupling.H-9eH-8eH-9aH-264Table 2.12: 400 MHz 1 H NMR Chemical Shift Difference Between the Esters 171and 172Assignment 1H NMR 171 1H NMR 172 AS (ppm)(H-X) 5 ppm (mutt., # of H, J (Hz)) 8 ppm (mutt., # of H, J (Hz)) 8 172-8 171Me-11 0.86 (d, 3H, 7) 0.77 (d, 3H, 6.5) -0.09Me-12 1.11 (s, 3H) 1.14 (s, 3H) 0.0310e 1.16 (br dd, 10, 3) 1.35 (br d, 13) 0.192 4.96 (dd, 1H, 10, 10) 4.92 (dd, 1H, 10, 10) -0.04Table 2.13: 130 NMR Chemical Shift Difference Between the Esters 171 and 172Assignment(C-X)171(75.3 MHz)5 ppm1 72(125.3 MHz)8 ppmAS (ppm)(8 172-8 171)Me-11 18.98 18.56 -0.4210 21.31 21.53 0.224 21.57 21.79 0.229 29.14 29.08 -0.06Me-12 30.00 30.09 0.098 36.34 36.40 0.063 38.65 38.58 -0.076 41.23 41.30 0.071 48.01 48.15 0.14OMe 55.4155.21 -0.202 79.3079.68 0.3813 108.74108.70 -0.047 149.82149.90 0.08An empirically-derived correlation of configuration with 1 H NMR chemical shiftsfor diastereomeric a-methoxy-a-trifluoromethylphenylacetates has been developed byDale and Mosher. 114 Their empirical correlation is described in Scheme 2.11. They65have made a number of (R)- and (S)-MTPA-esters and have observed that acorrelation can be made between the theoretical conformations 116 173 and 174 andthe NMR chemical shift differences between the substituents L 2 and L3 . Theydiscovered that the NMR signal due to L3 of 173 was consistently observed at lowerfield than that of 174 while the reverse trend was observed for the NMR signals due toL2 of 173 and 174.The results obtained with the MTPA esters 171 and 172 were in agreementwith those predicted by the model of Dale and Mosher (Scheme 2.11). It was foundthat the signal due to Me-11 in 172 was shielded relative to that of 171 (A8 = -0.09),while the signal due to H-10e in 172 was deshielded relative to the correspondingsignal in 171 (AO = +0.19). Examination of the 13 C NMR spectra of 171 and 172revealed the same trend. The signals due to Me-11 and C-3 in 172 were shieldedrelative those of 171 (AS = -0.42 and -0.07, respectively), while the signals due toC-1 and C-10 in 172 were deshielded relative those of 171 (As = +0.14 and +0.22,respectively).Two major objectives of this thesis were realized by the work described in thelast section. The development of a new efficient destannylation method for13-trimethylstannyl ketones set the stage for further works towards the synthesis ofclerodane-type natural products. Furthermore, the fact that the alcohol 165 had beenobtained in enantiomerically pure form confirmed the effectiveness of thetrimethylstannyl moiety as a readily removable "chiral anchor". The next stage of thiswork involved verification of the generality of the destannylation procedure by carryingout this reduction on a number of trimethylstannyl ketones, alcohols and ethers.OF3COF3CAL 8 = i.......j..,_________A8 = -A8 = 8 173 -S 174III I IIA8 = 8 172 - 8 171F3C171Scheme 2.1166,L3^ L3L2 .,", L2 C6H5^0-11°.______c■ View Me0■'''•^<^HH^>---,. r,7 \or3%..,(S)^ 174"Li"R R = H, 132R = Me, 133OH1:1RR= H, 175, 75%R = Me, 176, 66% (2.26)672.2.4. Dissolving Metal Reduction of the Trimethylstannyl Ketones 132,133 and 1022.2.4.1. Destannylation of Substituted 4-Trimethylstannylbicyclo[4.3.0]nonan-2-onesThe bicyclic trimethylstannyl ketones 132 and 133 were converted separatelyinto the bicyclic alcohols 175 ([ a ]D 23 -72.4°, c = 0.716 in chloroform) and 176([ a ]D 23 -35.2°, c = 0.995 in chloroform) (equation 2.26) in 75% and 66% yield,respectively, using a procedure identical with that described for the transformation ofthe bicyclic ketone 124 into the bicyclic alcohol 165.The IR spectrum of the bicyclic alcohol 175 exhibits absorptions at 3264, 1654,and 1033 cm -1 , indicating the presence of a hydroxyl group and an exocyclic carbon-carbon double bond. A combination of 1 H NMR, 13 C NMR, APT experiments andcomparison with the spectra of 132, 165 and 166 were used to confirm the structureof the bicyclic alcohol 175.The 1 H NMR spectrum was tentatively assigned from the chemical shifts andcomparison with previous spectra. The characteristic 1 H NMR resonances for 175 aredue to the Me-10 doublet at 8 0.95, the Me-11 singlet at 60.98, a D20 exchangeablehydroxyl proton at 6 1.31, the H-2 doublet of doublet of doublets (becomes dd withH-8e H 5aMe-10OHH-2^H-3H-8aH-4a^H-4eH-9e—H-1H-12bH-9a H-5eH-12a Me-1117568D20, J = 10, 10 Hz) at 8 2.65 and the two broad olefinic signals for H-12a and H-12b at8 4.67 and 8 4.90. The coupling constants of the signal due to H-2 after D20exchange (J = 10, 10 Hz) suggested that the structure and conformation of 175 is asshown below. The chemical shifts and an APT experiment were used to tentativelyassign the 13C NMR spectrum of 175.The IR spectrum of the bicyclic alcohol 176 exhibited absorptions due to thepresence of a hydroxyl group (3326 and 1015 cm -1 ) and an exocyclic carbon-carbondouble bond (1655 cm -1 ). A combination of 1 H NMR, COSY, 13 C NMR, APTexperiments and comparison with the spectra of 132, 133, 165 and 166 were usedto confirm the structure of bicyclic alcohol 176. The homonuclear correlations (COSY)are listed in Table 2.14.69Me-10OHH-2^H-3H-4a^H-4eH-9e-H-1H-5aH-8eH-8aIH-9a H-5eMe-13 Me-11176H-12Table 2.14: The 400 MHz 1 H NMR and 200 MHz COSY Data for the Bicyclic Alcohol176Assignment(H-X)1H NMR6 ppm (mutt., # of H, J (Hz))COSY Correlation(H-X)Me-10 0.98 (d, 3H, 6.5) 34a 1.00-1.10 (m, 1H) 3, 4e, 5a, 5eMe-11 1.07 (s, 3H) a34e5a1.25-1.40 (m, 3H)Me-10, 2, 4a5eOH 1.31 (d, 1H, J= 6 Hz)b 21 1.50 (ddd, 1H, 13, 7, 3.5) 2, 9a, 9eMe-13 1.62 (ddd, 3H, 7, 2, 2) 8a and 8e (LR)c, 129a, 9e 1.70-1.85(m, 2H) 1, 8a, 8e5e 2.30 (ddd, 1H, 14, 3, 3) 4a, 4e, 5a8a, 8e 2.37-2.45 (m, 2H) Me-13(LR)b, 9a, 9e2 2.77 (ddd, 1H, J = 10,10, 6)d OH, 1, 312 5.25 (br q, 1H, 7) Me-13, 8a, 8e(LR)Ca No correlation.b Exchanges with D20.c (LR) = Long range coupling.d Becomes dd, J = 10, 10 Hz, with D20.The 1 H NMR spectrum of 176 was tentatively assigned from the chemical shiftsand the homonuclear correlations. The coupling constants of the signal due to H-2,„,SnMe3102OH"Li" 66%(2.27)70after D20 exchange (J = 10, 10 Hz) indicated to us that the conformation of the alcohol176 is as shown on the previous page. The 13C NMR spectrum was tentativelyassigned with the assistance of the chemical shifts and an APT experiment.2.2.4.2. Trimethylstannyl Cyclohexanone Destannylation The trimethylstannyl cyclohexanone 102 was converted into the cyclohexanol177 ([ a ]o24 +27.6°, c = 1.125 in chloroform) (equation 2.27) in 66% yield using aprocedure identical with that described for the transformation of the bicyclic ketone124 into the bicyclic alcohol 165.The IR spectrum of cyclohexanol 177 showed absorptions assigned to ahydroxyl group (3351 and 1029 cm -1 ) and a gem-dimethyl 117 moiety (1387 and1365 cm -1 ). A combination of 1 H NMR, selective decoupling (in CDCI3 and D20),COSY, 13C NMR, APT experiments, and comparison with the spectra of 102, 165 and166 were used to confirm the structure of cyclohexanol 177. The homonuclearcorrelations are listed in Table 2.15.71Me-9^H-1H-3a H-6eMe-8 OHH-4e^ Me-7H-3eH-6H-4a 17 7 H-2Table 2.15: The 400 MHz 1 H NMR and 200 MHz COSY Data for the Cyclohexanol177Assignment(H-X)1H NMR6 ppm (mutt., # of H, J (Hz))COSY Correlation(H-X)Me-9 0.90 (s, 3H) 4a(LR)a, 6a(LR)aMe-8 0.94 (s, 3H) 4e(LR)a, 6e(LR)aMe-7 1.02 (d, 3H, 6) 23a 1.00-1.05 (m, 1H) 2, 3e, 4a, 4e6a 1.10 (dd, 1H, 10, 12.5) Me-9(LR)a, 1, 6e24a1.15-1.25 (m, 2H) Me-7, 1, 3a, 3eMe-9(LR)a, 4eOH 1.27 (d, 1H, 5)b 13e 1.28-1.33 (m, 1H) 2, 3a, 4e, 4a4e 1.52-1.57 (m, 1 H) Me-8(LR)a, 3a, 3e, 4a6e 1.67 (ddd, 1H, 12.5, 4, 2.5) Me-8(LR)a, 1, 6a1 3.30 (m, 1H, w112c = 26)d OH, 2, 6a, 6ea (LR) = Long range coupling.b Exchanges with D20.c^W1/2 is the width at half height of the signal in Hz.d W1/2 becomes 22 Hz with D20.Selective decoupling (mixture of CDCI3 and D20) of the signals of the alcohol177 at 8 1.67 (H-6e) simplified the signals for H-6a at 6 1.10 (d, J = 10 Hz) and H-1at 8 3.30 (br dd, J= 10, 10 Hz), thus confirming the trans, trans-arrangement of H-6a,H-1 and H-2. Irradiation of the signal at 6 3.30 (H-1) produced a doublet at 6 1.10(H-6a, J = 12.5 Hz), doublet of doublets at 8 1.67 (H-6e, J = 12.5, 2.5 Hz) andsimplified the signal at 8 1.15-1.25 (H-2). The 13 C NMR spectrum of 177 wastentatively assigned by comparison with the spectra of 102, 165 and 166 and by useof an APT experiment.""'SnMe312402.2.5. Dissolving Metal Reduction of Trimethylstannyl Alcohols andEthers2.2.5.1. Preparation of the Trimethylstannyl Alcohols 178 and 179The trimethylstannyl alcohols 178 and 179 were prepared by i-Bu2A1Hreduction of the corresponding trimethylstannyl ketones 124 and 102. Thus,treatment of the ketone 1 24 with i-Bu2AIH produced the bicyclic alcohol 178([ a ]D 24 -68.6°, c = 1.138 in chloroform) in 96% yield (equation 2.28), while thereduction of 102 gave the alcohol 179 ([ a ]D28 _55.0 ° , c = 1.008 in Me0H) in 90%yield. The bulky reducing agent approached the carbonyl moiety selectively from theless hindered face of each of the substrates 124 and 102 (si-face), as illustrated inScheme 2.12. Attack on the si-face of the carbonyl moieties (transition states 180and 182) suffers from less steric hindrance than the attack on the re-face (transitionstates 181 and 183), thus favoring the formation of products with an axial hydroxylgroup.721) i-Bu2AIH (3 equiv)-78 °C —> 25 °C2) NH4CI, H2O96%1) i-Bu2AIH (3 equiv)-78 °C --> 25 °C2) NH4CI, H2O90%,,17 9 SnMe3 (2.28)H OH"'SnMe3178OH73R i , R2 =^4,,,R 1 = Me, R2 = Hssss2AIR2.--H'si-sideScheme 2.12SnMe3181183SnMe3re-sideR 1AR –H"...I, 2-^ •• R2• , -.0180182H-2 Me-11HOH-9aH-4H-10e^H-3SnMe3—H-1H 5aH-9eH-8eH-13bH-8aH-10a 1+5eH-13a me-12178The IR spectrum of the alcohol 178 exhibits absorptions at 3558, 1632, 1081,764, 523 cm -1 , indicating the presence of a hydroxyl group, an exocyclic carbon-carbon double bond and a trimethylstannyl moiety. A combination of 1 H NMR, COSY,13C NMR, APT experiments and comparison with the spectral data of 162 and 163were used to confirm the structure of 178. The homonuclear correlations are listed inTable 2.16.74Table 2.16: The 400 MHz 1 H NMR and 200 MHz COSY Data for the BicyclicTrimethylstannyl Alcohol 178Assignment(H-X)1H NMR8 ppm (mutt., # of H, J (Hz))COSY Correlation(H-X)Me3Sn 0.10 (s, 9H, 2J sn-H = 52) ^aMe-11 0.91 (d, 3H, 6.5) 3Me-12 1.10 (s, 3H) ^a5a 1.32 (dd, 1H, 15, 14, 3J sn_H = 14) 4, 5e1 1.45 (br d, 1H, 5.5) 2, 10a, 10e4 1.55 (ddd, 1H, 14, 14, 2.5, 2J sn-H = 53) 3, 5a, 5e39a10e1.60-1.75 (m, 3H)Me-11, 2, 48a, 8e, 9e, 10a1OH 1.71 (d, 1H, 12)b 210a 2.03-2.16 (m, 1H) 1, 9a, 9e, 10e5e8e9e2.17-2.33 (m, 3H)4, 5a8a, 9a10a, 10e8a 2.40-2.53 (m, 1H) 8e, 9a, 9e, 13a and 13b(LR)C2 3.55 (ddd, 1H, 12, 2.5, 2.5)d OH, 1, 313a 4.76 (br s, 1H) 8a(LR)C, 13b13b 4.83 (br s, 1H) 8a(LR)d, 13aa No correlation.b Exchanges with D20.c (LR) = Long range coupling.d Becomes br s with D20.The 1 H NMR spectrum of 178 had many similarities to that of 166. The doubletof doublet of doublets at 8 3.55 (H-2) (J = 12, 2.5, 2.5 Hz) collapsed to a broad singletafter D20 exchange, thus establishing that H-1 and H-3 are both cis to H-2. The130 NMR spectrum of 178 was tentatively assigned by comparison with the spectra of165 and 166 and with the aid of an APT experiment.The trimethylstannyl cyclohexanol 179 exhibited IR absorptions attributed to ahydroxyl group (3482 and 1071 cm -1 ) and gem-dimethyl (1386 and 1363 cm -1 ) andtrimethylstannyl (763 and 523 cm -1 ) moieties. A combination of 1 H and 13C NMRMe-9 H-3 H-6e0HMe-8H-4eH-6aSnMe3H-4aH -21 7 9H-1Me-775(C6D6), APT experiments and comparison with the spectral data of 177, 165, 166and 178 were used to confirm the structure of the alcohol 179.The width at half height (8 Hz) of the signal due to H-1 suggested a cis,cis-arrangement of the hydrogens H-2, H-1 and H-6a. The 13 C NMR spectrum wastentatively assigned by comparison with the spectra of 177, 165, 166 and 178 andwith the aid of an APT experiment.2.2.5.2. Preparation of the Bicyclic Trimethylstannyl Methyl Ether 184 The potassium salt of the bicyclic alcohol 178 was treated with iodomethane inDMF to give the ether 184 ([ a ]p24 +3.90, c = 0.98 in chloroform) (equation 2.29)in 91% yield. 1181781) KH (3 equiv)DMSO (1 equiv)DMF, 25 °C2) Mel (10 equiv)0 °C --> 25 °C91%184^(2.29)The IR spectrum of the bicyclic ether 184 exhibits absorptions at 1640, 1461,1093, 764 and 523 cm -1 , indicating the presence of an ether function, an exocycliccarbon-carbon double bond and a trimethylstannyl moiety. A combination of 1 H NMR,selective decoupling, COSY, 13C NMR, APT experiments and comparison with thespectral data of 165, 166 and 178 were used to confirm the structure of the ether184. The homonuclear correlations are listed in Table 2.17.Me-11H-2MeOH-9aH-4H-10eH3SnMe3-H-1H-5aH-9eH-8e^H-13b,^H-10-H-8a^H-13aMe-12184Table 2.17: The 400 MHz 1 H NMR and 200 MHz COSY Data for the Ether 184Assignment(H-X)1H NMR5 ppm (mutt., # of H, J (Hz))COSY Correlation(H-X)Me3Sn 0.05 (s, 9H, 2Jsn-H = 51) ^aMe-11 0.96 (d, 3H, 6.5) 3Me-12 1.06 (s, 3H) ^a5a 1.21 (dd, 1H, 15, 14, 3J sn-H = 14) 4, 5e1 1.45 (br dd, 1H, 2.5, 2.5) 2, 10a, 10e349a10e1.52-1.80 (m, 4H)Me-11, 25a, 5e8a, 8e, 9e, 10a19e10a1.90-2.12 (m, 2H) 8a, 8e, 9a, 10e15e8e2.15-2.25 (m, 2H) 4, 5a8a, 9a, 9e8a 2.42 (ddddd, 1H, 15, 12.5, 6, 2.5, 2.5) 8e, 9a, 9e, 13a and 13b(LR)b2 3.12 (dd, 1H, 3.5, 2.5, 4J sn-H = 18) 1, 3MeO 3.38 (s, 3H) ^a13a 4.55 (br s, 1H) 8a(LR)b, 13b13b 4.68 (br s, 1H) 8a(LR)b, 13aa No correlation.b (LR) = Long range coupling.76SEM-CI (3 equiv)i-Pr2NEt (5 equiv)001SiMe32'^I.-88% 185 "'SnMe3(2.30)C H2Cl277The main differences between the 1 H NMR spectrum of 184 and that of 178was the absence of the hydroxyl signal, the upfield shift of the signal due to H-2 to5 3.12 from 5 3.55, and the appearance of the methoxy singlet at 5 3.38. Theassignments of the 1 H NMR spectrum were confirmed by selective decouplingexperiments of the signals due to Me-11, H-5a, H-8a, and H-2, respectively. The13C NMR spectrum of 184 was tentatively assigned by comparison with the spectra of165 and 178, and with the aid of an APT experiment.2.2.5.3. Preparation of the Trimethylstannylcyclohexyl SEM-Ether 185Following a procedure reported by Lipshutz and Pegram, 119 the trimethylstannylalcohol 179 was treated with (2-trimethylsilylethoxy)methyl chloride (SEM-CI) anddiisopropylethylamine to give the SEM-protected product 185 ([ a ]D 28 -68.9°,c = 1.008 in Me0H) (equation 2.30) in 88% yield.OHThe IR spectrum of the SEM-ether 185 indicated absorptions due to gem-dimethyl (1459 and 1364 cm -1 ), ether (1101 cm -1 ), trimethylsilyl (1250 and836 cm -1 ) 129 and trimethylstannyl (764 and 523 cm -1 ) moieties. A combination of 1 H,13C, APT NMR experiments (all in C6D6) and comparison with the spectral data of102, 179 and 184 were used to corroborate the structure of the SEM-ether 185.The main differences between the 1 H NMR spectra of 185 and 179 was theabsence of a signal due to a hydroxyl proton and the appearance of the signals due tothe SEM moiety [5 0.03 (Me3Si), 5 0.99 (H-2'), 5 3.62-3.70 (H-1, H-1'), and 5 4.59 and4.76 (two d, OCH2O)] in the spectrum of 185. The 13C NMR spectrum was tentativelyassigned by comparison with the spectra of 102, 179 and 184 and with theassistance of an APT experiment.782.2.5.4. Destannylation of the Alcohol 178 and the Ether 184When the trimethylstannyl alcohol 178 was treated with lithium in ammoniausing conditions identical with those described for the transformation of 124 to 165,none of the expected bicyclic alcohol 187 was produced. The only product obtained(91% yield) was assigned the structure 186  ([ a ]D 25 -13.9°, c = 0.985 inchloroform) (equation 2.31), based on the following spectral data. 186178(2.31)The IR spectrum of the saturated bicyclic alcohol 186 exhibits absorptions at3515 and 1013 cm -1 , indicating the presence of a hydroxyl moiety. A combination of1 H NMR, selective decoupling, NOE, COSY, 13 0 NMR , APT experiments andcomparison with the spectral data of 124, 178 and 184 were used to confirm thestructure of the saturated bicyclic alcohol 186. The homonuclear correlations arelisted in Table 2.18.The absence of signals due to olefinic protons in the 1 H NMR spectrum and thepresence of a second methyl doublet at higher field indicated that the carbon—carbondouble bond in 178 had been reduced in addition to the carbon—tin bond.Me-11H-2HOH-4aH-7 H-10eH3H-4e—H-1H-5aH-9eH-8e1Me-13H-10 H-5eH-8a^Me-12186H-9aTable 2.18: The 400 MHz 1 H NMR and 200 MHz COSY Data for the SaturatedBicyclic Alcohol 186Assignment(H-X)1H NMR8 ppm (mult., # of H, J (Hz))COSY Correlation(H-X)Me-13 0.74 (d, 3H, 7) 7Me-12 0.83 (s, 3H) 7(LR)aMe-11 0.94 (d, 3H, 6) 35a 0.98 (ddd, 1H, 13.5, 13, 3) 4a, 4e, 5e131.13-1.26 (m, 2H) 2, 10a,10eMe-11, 4a, 4eOH 1.30 (d, 1H, 4.5)b 28a 1.35 (dddd, 1H, 13, 13, 13, 4.5) 7, 8e, 9a, 9e4a, 4e8e9a10a1.40-1.55 (m, 5H)3, 5a, 5e7, 8a, 9e10e15e79e10e1.83-2.13 (m, 4H)4a, 4e, 5aMe-12(LR)a, Me-13, 8a8e, 9a, 10a12 3.73 (br s, 1H)b OH, 1, 3a (LR) = Long range coupling.b Exchanges with D20.c Almost no change with D20.79/^rMe-11)H-2HOH-4a^H-4eH-5aMe-11HOH-8ee-13^H-5e me -13^H-5eMe-12186cH-8a3Me-12186aHO—H-1H-5ee-13^rH-8a^Me-12"■____.--A86bMe-13^ e-13186f^<---- 186eMe-12 Me-12Figure 2.7 NOE's of Compound 186Me-11H-3H-4e—H-1..)H-5aHOMe-13 H-5eMe-12186d80The results of the NOE experiments confirmed the proposed structure for 186,and the enhancements are summarized in Figure 2.7. Most importantly, irradiationof the signal assigned to Me-13 enhanced the resonances due to H-8a and H-8e, aphenomenon which could only happen if Me-13 is in the equatorial orientation (see186a). The 13C NMR spectrum was tentatively assigned by comparison with thespectra of 124,178 and 184 and with the aid of an APT experiment.Me-11It is known that isolated double bonds can be reduced by dissolving metals inthe presence of a good proton source at higher temperatures. When the reducedunsaturation is part of a methylenecyclohexane ring, it would be expected that theresulting methyl group would occupy the more stable, normally equatorial,orientation. 121 For example, Wai 121 reported that reduction of the phosphorodiamidate188 (Scheme 2.13) with lithium in diethylamine in the presence of0ii(Me2N)2P 0—%188812-methyl-2-propanol at 0 °C gave a 1:1 mixture of the desired alkene 189 and thesaturated compound 190. When the temperature was decreased to -10 °C, the ratioof 189:190 was 2:1. Complete chemoselectivity was finally obtained at -20 °C in theabsence of 2-methyl-2-propanol.OCH2OMeOCH2OMeLi, EtNH 2t-BuOH0 °C, 10 minOCH2OMeLi, EtN H2^190t-BuOH188^ 189:190 2:1-10 °C, 5 minLi, EtN H2188 ^ 189-20 °C, 10 minScheme 2.13In our case, the ease of reduction of the carbon-carbon double bond of thebicyclic alcohol 178 is probably due to the proximity of the hydroxyl group to thedouble bond which could increase the rate of reduction by intramolecularprotonation, 122 thus permitting the reduction to occur even at -78 °C. Support for thishypothesis was obtained by destannylation of the methyl ether 184, which was treatedunder conditions identical with those used for 178. Thus, the expected unsaturatedether 191 ([ a } D 24 ÷4.40, c = 0.69 in chloroform) was obtained in 52% yield(equation 2.32).SnMe.82OMe^ OMe"Li"52%1 91^(2.32)H-2 Me-11MeOH-9aH-4aH-10eH-3H-4e—H-1H 5aH-9eH-8e /H-10a H-5eIH-13a Me-12191H-13b IH-8aThe IR spectrum of the unsaturated ether 191 exhibited absorptions attributedto an ether function (1461 and 1101 cm -1 ) and an exocyclic carbon-carbon doublebond (1640 cm -1 ). A combination of 1 H NMR, selective decoupling, COSY, 13C NMR,APT experiments and comparison with the spectral data of 124, 178, 184 and 186were used to confirm the structure of the unsaturated ether 191. The homonuclearcorrelations are listed in Table 2.19.83Table 2.19: The 400 MHz 1 H NMR and COSY Data for the Bicyclic UnsaturatedEther 191Assignment(H-X)1H NMRS ppm (mutt., # of H, J (Hz))COSY Correlation(H-X)Me-11 0.97 (d, 3H, 7) 35a 0.90-1.08 (m, 1 H) 4a, 4e, 5eMe-12 1.13 (s, 3H) ^a9a 1.35-1.45 (m, 1H) 8a, 8e, 9e, 10a, 10e14a, 4e10a1.45-1.62 (m, 4H)2, 10e3, 5a, 5e9a, 9e3 1.75-1.85 (m, 1H) Me-11, 2, 4a, 4e9e10e1.85-2.02 (m, 2H) 8a, 8e, 9a, 10a15e 2.06 (ddd, 1H, 14.5, 7.5, 4) 4a, 4e, 5a8e 2.18-2.26 (m, 1H) 8a, 9a, 9e8a 2.29-2.38 (m, 1H) 8e, 9a, 9e, 13a and 13b(LR)b2 3.29-3.38 (m, 1H) 1, 3OMe 3.33 (s, 3H) ^a13a, 13b 4.67 (s, 2H) 8a(LR)ba No correlation.b (LR) = Long range coupling.Selective decoupling experiments involving signals due to Me-11, H-5a, H-3,H-5e and H-2 confirmed the 1 H NMR assignments of 191. The 13C NMR spectrumwas tentatively assigned by comparison with the spectra of 124, 178, 184 and 186and with the assistance of an APT experiment.2.2.5.5. Destannylation of the Trimethylstannyl Cyclohexanol 179Treatment of the alcohol 179 with lithium in ammonia, using conditionsidentical with those described for the transformation of 124 to 165, produced thecyclohexanol 192 ([ a )D 25 +2.6°, c = 1.080 in chloroform) (equation 2.33) in 70%yield. Preparation of the enantiomer of 192 (i. e. 195) has been reported byOH OH"Li"70%(2.33)Beauveriasulfurescens10 days47%OH=.•1 9520% (2.34)++19333%Me-9H-3a H-6eoMe-8H-4eIH-3e H-6 H-2H-4a192H-1Me-784Kergomard and coworkers. 123 It was prepared in 20% yield along with the ketone 194by microbiological reduction (Beauveria sulfurescens) of 2,5,5-trimethylcyclohex-2-en-1-one 1 93 (equation 2.34). The optical rotation of 1 95 was [ a ]578 25 -11°,c = 0.027 in chloroform. 123 The alcohol 192 had the same magnitude of rotation withthe opposite sign ([ a ]578 25 +11°, c = 0.040 in chloroform), 124 thus supporting ourassignment.The IR spectrum of the cyclohexanol 192 exhibits absorptions at 3367, 1387,1366 and 1068 cm -1 , indicating the presence of a hydroxyl group and a gem-dimethylmoiety. A combination of 1 H NMR, COSY, 13 C NMR, APT experiments andcomparison with the spectral data of 102, 177 and 179 were used to establish thestructure of cyclohexyl alcohol 192. The homonuclear correlations of 192 are listed inTable 2.20.(2.35)19685Table 2.20: The 400 MHz 1 H NMR and 200 MHz COSY Data for the CyclohexylAlcohol 192Assignment(H-X)1H NMR (400 MHz)8 ppm (mult., # of H, J (Hz))COSY Correlation(H-X)Me-8a 0.97 (s, 3H) bMe-7 0.93 (d, 3H, 7) 2Me-9a 0.99 (s, 3H) b4a 1.07-1.15 (m, 1H) 3a, 3e, 4eOH 1.21 (d, 1H, 4.5)c 13a, 3e4e6a, 6e1.33-1.60 (m, 5H)2, 4a12 1.82 (m, 1H) Me-7, 3a, 3e1 3.88 (dddd, 7, 4.5, 4, 4, 1H)d OH, 6a, 6ea Me-8 and Me-9 can be interchanged.b No correlation.C Exchanged with D20.d Becomes ddd, J = 7, 4, 4 Hz with D20.The examination of the 1 H NMR spectrum of 192 (with D20) revealed that H-1had the expected equatorial orientation. The 13 C NMR spectrum was tentativelyassigned by comparison with the spectra of 102, 177 and 179 and with the aid of anAPT experiment.2.2.5.6. Destannylation of the Trimethylstannylcyclohexyl SEM-Ether 185 Reaction of the SEM-ether 185 with lithium in ammonia under conditionsidentical with those described for the transformation of 124 to 165 provided thecyclohexyl SEM-ether 196 ([ a ]D 25 -4.8°, c = 1.005 in chloroform) (equation 2.35)in 85% yield.cl.SiMe3SiMe3"Li" 85%i •Me-9^0/-■oStMe3H-3a H-6e^2'Me-8H-4eIAH-3e H-6H-4a^H-2196H-1Me-786The SEM-ether 1 96 displayed IR absorptions due to a gem-dimethylfunction(1462 and 1366 cm -1 ), an ether group (1103 cm -1 ) and a trimethylsilyl moiety(1250 and 836 cm -1 ). A combination of 1 H NMR, COSY, 13C NMR, APT experimentsand comparison with the spectral data of 102, 179 and 185 were used to confirm thestructure of 196. The homonuclear correlations are listed in Table 2.21.Table 2.21: The 400 MHz 1 H NMR and 200 MHz COSY Data for the CyclohexylSEM-Ether 196Assignment(H-X)1H NMR (400 MHz)5 ppm (mult., # of H, J (Hz))COSY Correlation(H-X)Me3Si 0.01 (s, 9H) bMe-8a 0.89 (s, 3H) bMe-7 0.90 (d, 3H, 7) 22' 0.90-0.95 (m, 2H) 1'Me-9a 0.95 (s, 3H) b4a 1.03-1.12 (m, 1H) 3a, 3e, 4e6e 1.25 (dd, 1H, 13.5, 4) 6a, 13a 1.35 (ddd, 1H, 13.5, 10, 4) 2, 3e, 4a, 4e3e4e6a1.40-1.56 (m, 3H)2, 3a, 4a1, 6e2 1.83-1.93 (m, 1H) Me-7, 3a, 3e1' 3.58-3.67 (m, 2H) 2'1 3.74 (ddd, 8, 4, 4, 1H) 6a, 6eOCH2O 4.62-4.70 (two d, 8, 1H) ba Me-8 and Me-9 can be interchanged.b No correlation.87The 13C NMR spectrum of 196 was tentatively assigned by comparison withthe spectra of 102, 177, 179 and 185 and with the assistance of an APT experiment.The generality of the dissolved metal destannylation reaction was successfullydemonstrated in this last section. Trimethylstannyl compounds containing alkene,carbonyl, hydroxy, methyl ether and SEM-ether functions have been efficientlydestannylated. Having disclosed both the usefulness and the generality of the use ofthe trimethylstannyl anchor for the formation of enantiomerically-pure compounds, weset out to prepare the synthetically useful bicyclic trans-fused and cis-fused bicyclicketones 17 and 47, respectively.(2.36).H OH^Pr4N+Ru04- (0.05 equiv)NMO (1.5 equiv)4 A Molecular sievesCH 2Cl2 , 50 min, 96%^4 7882.3. PREPARATION OF trans-FUSED AND cis-FUSED KETONES 17 AND472.3.1. Oxidation of the Bicyclic Alcohol 165Following a procedure reported by Ley and coworkers, 125 the bicyclic alcohol165 was oxidized to the cis-fused ketone 47 ([ a 1D 25 -32.6°, c = 1.175 inchloroform) (equation 2.36) with N-methylmorpholine N-oxide (NMO) in the presenceof a catalytic amount of tetrapropylammonium perruthenate (TPAP). The product 47was obtained in 96% yield, free of any detectable amount of isomers resulting fromepimerization.A combination of IR, 1 H NMR, 13C NMR, APT experiments and comparison withthe spectral data of the racemic ketone 47 reported by Wai 126 was used to confirm thestructure of the optically active ketone 47. 69The spectral data of the enantiomerically pure bicyclic ketone 47 wereconsistent with those reported by Wai. 127 The 13C NMR spectrum was tentativelyassigned by comparison with the spectra of 124 and 165 and with the assistance ofan APT experiment.Following a procedure of Wai, 127 the ketone 47 was treated with potassium tert-butoxide in 2-methyl-2-propanol to give a mixture (73% yield) of the trans-fused ketone17 and the cis-fused ketone 47, in a ratio of 94:6, respectively, as established by1 H NMR spectroscopy (equation 2.37). The two ketones were separated by means ofradial chromatography.128t-BuOK (2 equiv)4706:9417^(2.37)89t-BuOH, 48 h73% A combination of IR, 1 H NMR, 13C NMR, and APT experiments was used toconfirm the structure of the trans-fused ketone 17. 69 The spectral data of the bicyclicketone 17 agreed very well with those reported by Wai. 127 The 13C NMR spectrumwas tentatively assigned by comparison with the spectra of 124, 165 and 47 and withthe assistance of an APT experiment.The next step in this research program was to demonstrate the synthetic utility ofthe enantiomerically pure ketones 17 and 47 for the synthesis of trans- and cis-clerodane diterpenoids. Before discussing the syntheses, we will discuss andsummarize the circular dichroism (CD) spectra of the CD-active compounds obtainedin the course of our work.902.4. CIRCULAR DICHROISM2.4.1. GeneralCircular dichroism (CD) is a powerful chiroptical method that can, if usedproperly, give valuable information about the absolute configuration of a compound orits conformation. The subject of CD has been reviewed, 129 and therefore only thebasic principles will be described.A circular dichroism spectrum is the plot of the difference in absorption by achromophore of left and right polarized electromagnetic radiation versus thewavelength of the radiation. A non-zero signal is observed when the chromophore islocated in an asymmetric environment, and such a chromophore is called achirophore. This phenomenon of differential absorption is also called a Cotton effect,and was first observed in optical rotatory dispersion (ORD) spectra. The CD spectrumof a chirophoric compound will have the same magnitude but the opposite sign to thatof its enantiomer. The most studied chirophores by CD are carbonyl groups, probablybecause they absorb in an accessible wavelength range, 13° and because of theirwidespread occurrence in natural products. The absolute stereochemistry of newcarbonyl compounds can be assigned with a very good level of certainty on the basisof the comparison of their CD data with the data available in the voluminous literatureon the subject. 131A set of empirical rules has been developed for the determination of theabsolute stereochemistry of ketones, enones and esters. 131 The rules were firstdeveloped to predict accurately the absolute stereochemistry of cyclohexanonederivatives. The analysis of the CD spectra of the ketones 17 and 47 will serve toillustrate the use of the octant rule for the confirmation of absolute stereochemistry.912.4.2. Circular Dichroism and Structure Relationships: The Octant RuleThe octants are divisions of the space around the ir-orbitals of the carbonylmoiety based both on experimental results and theoretical considerations of theinteraction of polarized electromagnetic radiation with the charge distribution of theinteracting orbitals. The octants for a cyclohexanone derivative are shown in Figure2.8. The carbonyl group is centered along the z axis where the x and y axesintersect. The C1, C2 and C6 carbon atoms of the cyclohexanone lie in the yz plane,while C3, C4 and C5 sit above the yz plane. When one or more of the hydrogensattached to C2, C3, C5 or C6 are replaced by a substituent that creates an asymmetricmolecule, the octant rule is stated as: "The sign of the 300-nm Cotton effect for chiralketones is positive if the bulk of the dissymmetric environment of the carbonylchromophore lies in the far lower right or far upper left octants, and negative if in the farlower left and far upper right octants."132 Since the front four octants are almost neveroccupied, the octant rule can be redrawn as in Figure 2.9. The point of view is nowalong the z-axis through the carbonyl group. The orientations of the substituents onthe cyclohexanone are indicated with the markers ax (axial orientation) andeq (equatorial orientation). The substituents on the x and y axes (C2-eq, C4-ax,C4-eq and C6-eq) are generally considered to make no contribution to the Cottoneffect.92xFigure 2.8 Tridimensional Representation of the Octants of a Cyclohexanone^ ax^ax Cleq 5 • 3 eqax6^1^2^eq     eq yax axLa ciFigure 2.9 Bidimensional Representation of the Rear Octants of a CyclohexanoneExceptions to the octant rule are known. 133 Normally a substituent contributesto the Cotton effect in a manner that is in a direct relationship to the sign of the octantwhere the substituent is located. Such a substituent is called consignate. Somesubstituents, such as fluorine and Me3N -F, show antioctant behavior and are thereforecalled dissignate.17932.4.3. Circular Dichroism Measurements and Absolute Stereochemistryof Ketones2.4.3.1. The Circular Dichroism Spectrum of the trans-Fused Bicyclic Ketone 17Redrawing of the trans-fused ketone 17 according to the rules of the simplifiedoctant (Figure 2.10), one can predict that the sign of the Cotton effect should bepositive, since the bulk of the molecule lies in a positive octant. Experimentally, theCD absorption of 17 measured in chloroform was in good agreement with thisprediction. The specific ellipticity, ['P ]299.525 , was measured to be +5194 (DE . +3.0)for the ketone 17. 134,135 The CD spectrum of the ketone 17 is shown in Figure 2.12. LIU Me•^I LaI 0 Me--La QFigure 2.10 Representation of the Rear Octants of the Ketone 172.4.3.2. The Circular Dichroism Spectrum of the cis-Fused Bicyclic Ketone 47The octant rule prediction for the bicyclic ketone 47 is complicated by theexistence of two possible chair-chair conformations 47a and 47b (equation 2.38).Both conformations must be examined to determine their relative populations, andthus their contributions to the Cotton effect. The conformation 47a, with two sp3 -sp3 ,two gauche sp2 -sp3 and one sp2 -sp2 carbon-carbon interactions (2 x 0.9 + -3 x 0.5kcal/mol 136 = -3.3 kcal/mol [13.8 kJ/mol]), is more stable than the conformation 47bwith one gauche sp 2-sp3 , three gauche sp3-sp3 and one 1 ,3-diaxial Me-CH2 (spa-spa)carbon-carbon interactions (-0.5 + 3 x 0.9 + 3.7 kcal/mol = -6.9 kcal/mol [28.9 kJ/mol]).IMe 047 b^(2.38)94With a free energy difference (AG°) calculated to be approximately 3.6 kcal/mol[15.1 kJ/mol], conformer 47a should be the major contributor to the Cotton effect.Thus, the sign of the Cotton effect was predicted to be negative, as shown in Figure2.11. In accordance with the prediction, the CD of 47 in chloroform was found to be[ Ill ]302.8 25 = -477.1 (Os = -0.28). The CD spectra of the ketone 47 is shown inFigure 2.12. The amplitude of the specific ellipticity of the ketone 47 was multipliedby a factor of ten (10) for better comparison with that of the ketone 17.a Me=u aFigure 2.11 Representation of the Rear Octants of the Ketone 47-5.000E+03  """" 111 cm.".h: 335.025 C230.0 WL [nm]CD X 10 cis Ketone c..1.175 CHC136.000E+03•••47CD trans Ketone c.01.38 CHC13 1mm 256.7:Conditions of Memory 7File :Date : 11-02-92Data : [ik]Scan : WLBand width :1.0 nmResponse2 secWavelength range :335.0 - 195.OnmStep resolution :0.1nm/dataScan speed :20nm/minAccumulation :^1No. Wavelength Value1 292.60 nm 5.176E+032 299.50 nm 5.249E+033 294.00 nm -4.679E+034 302.70 nm -4.771E+03Figure 2.12 Circular Dichroism Spectra of the trans-Fused and cis-Fused Ketones 17 and 47 (amplitude X 10) in CHCI3962.4.3.3. The Reported Circular Dichroism of 13-Trimethylstannyl Cyclohexanones Hudec reported the first CD spectra of cyclic p-trimethylstannyl ketones. 53Hudec prepared (3R,5S)-5-methyl-3-trimethylstannylcylohexanone (197) [from(-)-(R)-5-methyl-2-cyclohexen-1-one (55)] and (1R,5R,6S)-6-methy1-5-trimethylstannyl-bicyclo[4.4.0]decan-3-one (199) {from (1 R,6R)-6-methylbicyclo[4.4.0]dec-4-en-3-one(198)1 (equation 2.39), and then studied the CD spectra of those compounds.Me3SnLi, Cul THF55Me3SnLi, CulTHF198^199  SnMe3Two major CD absorption bands were observed for the ketones 197 and 199.A strong absorption at 294-298 nm, and a weaker one of opposite sign, at 220-229 nm were supposedly due to a n->n* transition. Because the symmetry of thetransitions are opposite (n a -W at -225 nm, n s ---)n* at -296 nm), the signs of theirrespective Cotton effects are also opposite. Hudec assumed that ketone 197 existsmainly in the conformation 197a and not 197b. He predicted that the sign of theCotton effect would be positive since the bulk of the molecule (Me3Sn moiety) was in apositive octant (Figure 2.13). Kitching and coworkers have shown," using C-Sncoupling constants and by LiAIH4 reduction, that the ketone 197 actually exists as amixture of the conformers 197a and 197b in a 3:2 ratio. Thus, the conformation197b, having a negative Cotton effect (because the Me3Sn group occupies anegative octant) (Figure 2.14) should decrease the value of the specific ellipticity of197. The observed specific ellipticity of ketone 197 was positive at 298 nm and(2.39)97negative at 220 nm thus confirming Hudec's prediction. Surprisingly, the Cottoneffects were quite strong {[ IP ]298 = +7813 (Ac = +6.51) and [ `11 ]220 = -10873 (Ac =-9.06)}. This observation was more fully understood by the study of the CD spectrumof the ketone 199.IZIMe3Sn ^a LaMe^I^Me3Sn0ciFigure 2.13 Representation of the Rear Octants of the Conformer 197aLa^caSnMe3Me•---0 --•Figure 2.14 Representation of the Rear Octants of the Conformer 197bThe ketone 199 (R = Me3Sn) was predicted to have a positive Cotton effectbecause the Me3Sn moiety, the most polarizable group on 199, lies in a positiveoctant (Figure 2.15). 137 The experimental results were not in agreement with thosepredicted: the specific ellipticities were [ 'P ]294 = -1504 (Ac = -1.50) and ['P ]229 =+552 (Ac = +0.55). The structurally related ketone 200 (with R = H) had a slightlysmaller Cotton effect than 199 VP ]289 = - 2461, Ac = -1.24). Hudec concluded fromthese results, and from his previous results with nitrogen derivatives, that the 13-trimethylstannyl moiety on a cyclohexanone is strongly consignate when equatorially-oriented and weakly dissignate when axially-oriented. This conclusion explains whythe Cotton effect of the trimethylstannyl cyclohexanone 197 is relatively strong, sinceboth conformers might be contributing, in a positive sense, to the Cotton effect.a98Hudec explained the unusual consignate-dissignate behavior of the trimethylstannylmoiety by the existence of a strong through-bond coupling of the carbon-tin a-bondorbital with the ir-orbitals of the carbonyl group. Our results from conformationally andstereochemically less ambiguous models support Hudec's reports on the stronglyconsignate equatorial and weakly dissignate axial CD behavior of the Me3Sn group in3-trimethylstannyl cyclo—hexanones.0R = Me3Sn 199La^ca^R = H^200Figure 2.15 Representation of the Rear Octants of the Ketones 199 and 2002.4.3.4. The Circular Dichroism of p-Trimethylstannyl CyclohexanonesThe CD measurements of the p-trimethylstannyl cyclohexanones preparedduring the studies described in this thesis are listed in Table 2.22. The CD spectrumof the trimethylstannyl cyclohexanone 92 is representative of the CD spectra of thetrimethylstannyl ketones obtained during the work presented in this thesis and thespectrum is shown in Figure 2.16. As in Hudec's pioneering work, two Cotton effectsof opposite sign were observed in all cases; a positive low energy transition at 298-308 nm and a negative higher energy transition at 221-236 nm. The value of the longwave circular dicroism (As) of the substrates with an equatorially-orientedtrimethylstannyl moiety is strong, with values ranging from +12.84 to +16.48. Thecircular dicroisms of the ketones 92 and 102 (+15.79 and +16.48) demonstrates, assuggested by Hudec, that the equatorially-oriented trimethylstannyl group is stronglyconsignate. The comparatively low intensity of AE of 197 (+6.51) can be accounted forsince 40% of its ellipticity contribution comes from the conformation 197b, with aweakly dissignate axial trimethylstannyl group.SnMe3Me Me Me0^093 201Me3Sn Me99The circular dicroism of the conformationally unambiguous ketone 93 (seediscussion in section 2.1.1.2) is +0.85 (Table 2.22) while the circular dichroism of thecorresponding ketone 201 with the Me3Sn moiety replaced by a hydrogen is +0.62. 138Because the value of the circular dichroism of the ketone 93 is greater than that ofketone 201, the weakly dissignate character of the axial trimethylstannyl moiety asstated by Hudec is confirmed.The circular dicroism of each of the ketones 100, 126, 117 and 121 (Table2.22) is smaller than that of either 92 and 102. This result can be explained by thenegative contribution to the Cotton effect of the halo alkene side chain, which probablyresides in a negative octant. When the steric bulk of the alkene side chain is reduced(removal of a halogen atom), as in the cyclized products 124, 132 and 133, themagnitude of the circular dicroisms are increased. The ketone 130, with bothnegatively and positively contributing side chains, has a stronger Cotton effect than thecorresponding cyclized ketone 124 (AE= +16.08 vs. +15.04).The intensities of the high energy transitions varied more than those of the lowenergy transitions. This variability of the short wave values may be attributed to thefact that in this area of the spectrum, there is a high level of noise due to the UVabsorption of the substrates and the solvent (e.g. see the increase in absorbance inthe region of 220-225 nm of the ketone 92 in Figure 2.16).RMeRear OctantsRepresentationSubstituentsStructure #[ IP lx(se)LongWavea[ Ili lx(AE)ShortWavebStructureLa : Me LaMe3Sn—t ■ 1 R----Me I 0Lal ^C3+18030(+15.79)+17950(+16.48)X0CI^/ RMe3Sn i t • Me--Me 1 0---0-O  Dn = 2, X = CI, R = H100n = 2, X = I, R = H1 26n = 1, X = CI, R = H117n = 1, X = CI, R =Me121+10820(+12.84)+9034(+13.22)+11630(+13.30)+11310(+13.42)Ren = 2, R = H124n=1,R=H1 32n = 1, R = Me1 331 30 +14946(+16.08)Li^: SnMe3Met ■^ i La--- 1^0^Me--Ej^1^L:193MeR = H: 92R = Me: 102-6789(-5.95)-7454(-6.84)-2666(-3.16)-8814(-12.90)-6780(-7.76)-7568(-8.98)+13980(+15.04)+14980(+15.48)+13329(+14.34)-9123(-9.82)-6307(-6.52)-4821(-5.19)-8015(-8.60)+973(+0.85)-2127(-1.86)100Table 2.22: Circular Dichroism of p-Trimethylstannyl Cyclohexanonesa The exact value of the wavelength of the absorption maxima is in the Experimental Section. Theabsorption maxima ranged between 298-308 nm.b The exact value of the wavelength of the absorption maxima is in the Experimental Section. Theabsorption maxima ranged between 221-236 nm.Conditions of Memory 4File :Date : 11-02-92Data :Scan : WLBand width :1.0 nmResponse^•2 secWavelength range :340.0 - 225.OnmStep resolution :0.1nm/dataScan speed :20nm/minAccumulation :1.900E+04cid-7.000E+036.000E+00^. r.V' ■ VIIAbs0 . 000E+00 11111111111111 1 11111111141111111111141111,111111111111111111111101No. Wavelenath Value 1^232.60 nm -6.789E+032^299.70 nm^1.803E+04225.0^ WL[nm]4: ^ CD Me3Sn Ketone c■1.022 1mm Me0H 28 C340.0Figure 2.16 Circular Dichroism Spectrum of the Trimethylstannyl Ketone 92 in Methanol1022.4.4. The Circular Dichroism of EnonesRules have been derived to infer the absolute stereochemistry of a,(3-unsaturated ketones from the sign of their Cotton effect. 131 The application of theserules is complicated by the difficulty in assessing the precise conformation of enones,the weakness of the carbonyl nic* absorption (normally between 320-350 nm), thefact that the CD curve often shows vibrational fine structure and is sometimes of abisignate form. 139 A modified octant rule can be applied to the CD spectra of simpleenones, and it is based on the helicity of the enones. An optically active enone havingthe helicity illustrated in (A) (Figure 2.17) is expected to have a positive Cotton effectfor the n—>n* absorption at 320-350 nm. The helicity rule representation (A) for anenone in a half-chair conformation can be translated into the octant representation (B).The sign of the 320-350 nm transition is fixed by the antioctant behavior (dissignate)of the double bond. The enantiomeric relationship is illustrated by (C) and (D).(+) Cotton0 CIA (—) CottonCFigure 2.17 Helicity Rule and Rear Octants Representations for EnonesMe551032.4.4.1. The Circular Dichroism of (-)-(R)-5-methyl-2-cyclohexen-1-one (55) A bisignate CD curve was observed for the enone 55 for the n--nc* transitionwith specific ellipticities values of -428 at 353 nm (Ae = -0.14) and +377 at 316 nm(De = +0.13). A negative Cotton effect could be inferred by the application of themodified octant rule to the half-chair conformation 55 (Figure 2.18). Theexperimental results are therefore consistent with the predicted absolute configuration.Figure 2.18 Rear Octants Representation for the Enone 552.4.4.2. The Circular Dichroism of (-)-(5R. 6R)-3.6-Dimethy1-5-trimethylstanny1-2- cyclohexen-1-one (64) Analysis of the CD spectrum of the trimethylstannyl cyclohexenone 64 bymeans of the modified octant rule (Figure 2.19) predicts a positive Cotton effectbecause the dissignate double bond is present in the negative octant. Theexperimental value of the specific ellipticity of 64 was positive as expected, but wasunusually large ([ 11-1 ]29330 = +2365, Ac = +2.06). The magnitude of the measuredellipticity probably results from the contribution of the dissignate enone double bondand the strongly consignate contribution of the trimethylstannyl moiety to the Cottoneffect.11Me3Sn--- Me---4----6^ Me3Sn 6 4^MeLa : aFigure 2.19 Rear Octants Representation for the Enone 6402.4.5. The Circular Dichroism of the MTPA-Esters 171 and 172The CD spectrum of methyl (S)-2-methoxy-2-phenyl-3,3,3-trifluoropropanoate(202) has been studied by Djerassi and coworkers. 140 It was found that the specificellipticity (or AO values were very dependant on solvent and temperature, while thewavelength of the absorption varied only slightly. The sign of the Cotton effect wasindependent of the measurement conditions. The transitions between 253-280 nmwere assigned to the phenyl ring, and the transition at 230-250 nm was attributed tothe ester carbonyl.C F3Me0 z C H----...40.0° 6 5(S)Me00202The specific ellipticities of the MTPA-esters are listed in Table 2.23. The signand the amplitude of the Cotton effects of the bicyclic ester 171 correlate well withthose of the methyl ester 202.An almost enantiomeric relationship is observed between the sign of the Cottoneffects of the methyl ester 202 and the bicyclic ester 172 (Table 2.23). Thewavelength of absorption due to the carbonyl moiety of 172 is longer than expectedand the value of the circular dicroism is weaker than expected. It is obvious that thecontribution of the asymmetric bicyclic moiety to the Cotton effect of the carbonyl groupis responsible for this observed difference.104P6H5Me0 .' CF3(R)0172105Table 2.23: Specific Ellipticity and Circular Dichroism of the MTPA-Esters 171, 172and 202Estern—m.Absorption[Structure Phenyl Ring AbsorptionT 1233 =-1867aAs = -2.32[ T1256 =+235As = +0.29[ T1263 =+400As = +0.50[ q' 1269 =+307AC = +0.38CF3Me0 = C----..;•••• H6 5(S)Me00202[ T1230 =-2981bAs = -2.24[ q' 1256 =+161CAs = +0.12[ q' 1261 =+268bAs = +0.20[ q' 1269 =+157cAs = +0.12[ T1240 =+585aAE = +0.73[ T1256 =-139AE = -0.17[ T1262 =-241As = -0.30[ T1269 =-155As = -0.19.a Measured in chloroform at 29 °C.b Measured in cyclohexane at 20 °C.c Extrapolated from the CD curve of 202 in ether:isopentane:ethanol (5:5:2). See Figure 5 in ref 140The circular dichroism studies of our trimethylstannyl ketones providedconfirmation, with unambiguous models, of Hudec's report of the consignate-dissignate behavior of the trimethylstannyl moiety in f3 - trimethylstannyl-cyclohexanones. The CD results also provided supplementary evidence for thestereochemical assignments of the substances prepared during the course of ourC OX >_/,/--OX203 204.•OH(2.40)106work. The following sections of this thesis will describe the use of the optically active,stereodefined bicyclic ketones 17 and 47 as precursors for the total syntheses of thetrans-clerodane diterpenoids (-)-kolavenol (65) and (-)-agelasine B (31).2.5. TOTAL SYNTHESIS OF trans-CLERODANE DITERPENOIDS2.5.1. Total Synthesis of (-)-Kolavenol (65)2.5.1.1. Isolation of (-)-Kolavenol (65) (-)-Kolavenol (65) (equation 2.40) was isolated by Misra and coworkers 141 fromthe oleoresin of an Asian plant called Hardwickia pinata Roxb. The structure and theabsolute stereochemistry of 65 were elucidated by means of spectroscopic methods( 1 H NMR, IR, MS) and chemical degradations and correlations. 142 It was postulatedthat kolavenol is biosynthetically related to the geranylgeraniol precursor 203 (X =P2063- ) by rearrangement of the cation 204 (equation 2.40). Compound 65 wasshown by Hubert and Wiemer143 to repel the leafcutter ant Atta cephalotes.1072.5.1.2. Previous Total Synthesis of (-)-Kolavenol (65) (-)-Kolavenol (65) has been prepared by the reduction of (-)-methyl kolavenate(33) (equation 2.41) 141 which is available from the esterified extracts of the roots of theSolidago species. 144 A formal total synthesis of (-)-kolavenol (65) has been done byTokoroyama and coworkers who have synthesized (-)-methyl kolavenate (33)according to Scheme 2.14. 34Tokoroyama's synthesis started with Ender's asymmetric alkylation of the(S)-hydrazone 205 to produce the enone 206 (Scheme 2.14). Methyllithium wasadded to the enone 206, and the tertiary alcohol intermediate was oxidized to yieldthe transposed enone 207. Compound 207 was converted into the bicyclic enone208 using a previously reported sequence of reactions. 34 The cyano alcohol 209was prepared from 208 in 83% overall yield by means of a stereoselectivehydrocyanation followed by reduction of the carbonyl moiety with L-Selectride®(LiB[CH(Me)C2H5j3H). At this point, all the chiral centers necessary to construct theclerodane carbon skeleton had been introduced with the required stereochemistry.The vinyl moiety of 209 was elaborated by a hydroboration reaction to install therequired primary hydroxyl group. The resulting primary alcohol function wasconverted into the corresponding pivaloate and then the secondary alcohol wasdehydrated with phosphorus oxychloride to give the bicyclic pivaloate 210. The nitrilegroup was reduced (i-Bu2AIH) to the imine with simultaneous removal of the pivaloate.108After acid hydrolysis of the imine, the resulting aldehyde was further reduced underWolff-Kishner conditions to produce the angular quaternary methyl group. The primaryalcohol was transformed into a mesylate and then displaced with bromide ion to givethe primary bromide 211. The alkylation of the bromide 211 with lithium acetylide-ethylene diamine complex gave the acetylene derivative 212 in 71% yield. Finally,Negishi's zirconium-catalyzed carboalumination, followed by the trapping of theorganoaluminum intermediate with methyl chloroformate, produced the desired(-)-methyl kolavenate (33) in 31% yield.2.5.1.3. Synthetic Plan As described in Scheme 1.3, it was planned to produce the clerodaneskeleton 18 through the coupling of substances equivalent to synthons such as 42 or43 with an intermediate of the type 41 (Scheme 2.15). A synthetic equivalent of 41is the bicyclic primary iodide 213, since the iodide can be displaced by a nucleophile(like 42) or can be subjected to a lithium-iodine exchange to give an alkyllithiumspecies suitable for addition to an electrophile (like 43). The bicyclic iodide 213 couldbe prepared from the bicyclic methoxymethyl ether 214 by means of functional groupmanipulations. The preparation of the racemic bicyclic methoxymethyl ether 214 hadbeen reported previously by Piers and Wai.13b109..• 1) MeLi, ether2) PCC, CH2Cl2206 2071) i-Pr2NLi, THF2) p-MeC6 H4S03 MeOMe^3) Mel, pentane4) 2 M HCI205..... 1) Me2CHCMe2BH2 , THF2) H202 , NaOHCN^3) t-BuCOCI, pyridine4) POCI32091) CH2=CHMgBr•(Bu 3P•Cul)4 , THF2) CH2O3) MeS02C1, Et3N, CH2Cl24) EtCOCH2COOMe, NaOMe, C6H6208^5) 2 M HCI, Me0H,1) Et2AICN, C6H 6 , MeC6H62) LiB[CH(Me)C2H5 ]3H, THF^  HO'3) H202 , NaOH, 83%B1) i-Bu2AIH, MeC6 H62) AcOH, H2O3) NH2NH2 , KOH, (HOCH2 )2 4) MeS02C1, Et3N, CH2Cl25) LiBr, THF210LiC --- CH . (H2NCF1 2)2Me2SO71%1) ZrCl2 (i-C5H5 )2 , Me3AI2) CICOOMe, 31%Scheme 2.14+\^/d4 2^or/4 341Scheme 2.15110The racemic bicyclic ether 214 was synthesized from the trans-fused bicyclicketone 17 in six steps and in an overall yield of 28% (Scheme 2.16). 13b Theconversion of the ketone 17 to the mixture of nitriles 215 (85:15 a-CN:(3-CN) waseffected by reaction of 17 with the potassium anion of (p-tolylsulfonyl)methylisocyanide in 2-methyl-2-propanol and HMPA. 12 The mixture 215 was deprotonatedwith i-Pr2NLi and the resultant anion was alkylated with 2-iodo-1-methoxymethoxyethane to produce exclusively the nitrile 216 (steric approach control). 13b Therequired quaternary methyl group was prepared by a stepwise reduction of the nitrilemoiety. The nitrile 216 was first transformed to the an aldehyde by reaction withi-Bu2AIH and hydrolysis of the resulting imine. The aldehyde was then reduced withLiAIH4 and the alcohol was converted to a phosphorodiamidate. The ether 214 wasfinally obtained by reduction of the amidate with lithium in methylamine.p-TosCH2NC, t-BuOKt-BuOH , HMPA40-55 °C, 3 days64%0MeNC,216,,OMe0--.'1) i-Bu2AIH, DME, 60 °C, 6 h2) AcOH, H2O, THF, 10 h, 92%3) LiAIH4 , Et20, 95%4) BuLi, DME, (Me 2NCH2 )25) Cl2PONMe2 , 12 h; Me2 NH, 63%6) Li, MeNH2 , -20 °C, 10 min, 80%Scheme 2.162.5.1.4. Synthesis of the (+)-Bicyclic Methoxymethyl Ether 214The optically active bicyclic methoxymethyl ether 214 was prepared in foursteps from the cis-fused ketone 47 using a sequence of reactions significantlymodified from that reported by Piers and Wai. 13b Because the reaction conditionsused to convert the ketone 17 into the nitrile 215 (Scheme 2.16) were similar tothose used to isomerize the ketone 47 into the ketone 17 (see equation 2.37), it wasdecided to convert 47 directly into the mixture of nitriles 215 (equation 2.42). It wasalso discovered that use of N,N-dimethylpropyl urea (DMPU) in place of the more toxicHMPA improved the yield of the reaction from 64% to 82%.CNp-TosCH2 NC, t-BuOKt-BuOH, DMPU215a-CN:13-CN85:15^(2.42)40-55 °C, 4 days4 7^82%111CN215i-Pr2 NLiICH2CH2OCH2OMeTHF, HMPA99%2 1 4-217OMe0—/AcOH, H2OTHF, 12 h89%OMeO^____/u(2.43)Fic,„218112The identity of the mixture 215 was confirmed by comparison of the spectraldata of the nitriles (IR, 1 H NMR, HRMS) with the reported data, 145 and by TLC and GLCcomparison with an authentic sample of the racemic 215. The ratio of a- and 13-nitrileswas determined by GLC and 1 H NMR spectroscopy.The mixture of nitriles 215 was not separated but was alkylated, following theprocedure described by Wai, 145 with 2-iodo-1-methoxymethoxy ethane to produce thebicyclic ether 21 6 ([ a I D 25 +56.9°, c = 1.06 in chloroform) in 94% yield (seeScheme 2.16, vide supra). The spectral data of the ether 216 (IR, 1 H NMR, FIRMS)was in agreement with that reported by Wai. The main features of the 13 0 NMRspectrum were the signals assigned to the methoxy group (-ve, 6 55.37), the acetalmethylene (6 95.50), the exocyclic carbon-carbon double bond (6 157.85 and8 104.18) and the nitrile moiety (6 122.32).The bicyclic nitrile 216 was reduced with i-Bu2AIH to afford the aldehyde 218in 89% yield after the hydrolysis of the imine 217 (equation 2.43). 146 It was found thatthe yield of the aldehyde 218 was greatly reduced if the pH was too low during thehydrolysis of the aluminium salts. It was also observed that the aldehyde 218 wasvery unstable in chloroform that had not been filtered through flame-dried basicalumina. This acid lability of the aldehyde 218 and the imine 217 was subsequentlyfound to be a general property of the trans-clerodanes, and will be discussed later.i-Bu2AIH, DME216 ^ 50-60 °C, 6 hThe spectral data obtained for the aldehyde 218 was consistent with thepreviously reported data. 147 The 13C NMR spectrum was recorded and showedcharacteristic signals for the methoxy group (8 55.16), acetal methylene (8 96.35),113exocyclic carbon-carbon double bond (5 103.84 and 6 158.32) and aldehyde moiety(6 206.52). The specific rotation ([ a ]D 25 ) of the aldehyde 218 was +69.2°,c = 1.035 in chloroform, and a positive Cotton effect was observed at 311 nm(['P ]311 25 = +854, De = +0.76). It is difficult to produce an octant representation of thealdehyde 218 that leads to an acceptable rationale for the sign of the Cotton effect.It was proposed that the deoxygenation of the aldehyde 218 to the desiredbicyclic methoxymethyl ether 214 could be effected directly using either a Wolff-Kishner 148 or a Huang-Minlon 149 deoxygenation reaction. Our first attempts to form thehydrazone using the Huang-Minlon reaction conditions were unsuccessful. Weattributed this failure to the very hindered nature of the aldehyde moiety (see Figure2.20). Eventually, the hydrazone 219 was prepared by heating the aldehyde 218with anhydrous hydrazine in anhydrous diethylene glycol (equation 2.44). 150[DANGER, hot anhydrous hydrazine might detonate on exposure to oxygen.] Theexcess hydrazine and the water produced by the reaction were removed by distillation,and the resulting hydrazone was then converted to the deoxygenated ether 214([ a ]D 25 +75.7°, c = 1.165 in chloroform) under the Huang-Minlon reactionconditions.OMeFigure 2.20 Representation of the Steric Hindrance of the Aldehyde 218214OMe___/(2.44)H 2NNH 2(HOCH2CH2 )20218 ^120-140 °C7hH2N,NI'0 ___/0MeKOHoo''^230 °C1.5 h219 ^82%114The spectral data of the (+)-bicyclic methoxymethyl ether 214 was in agreementwith that reported by Wai 151 The following characteristic 130 NMR signals for the ether214 were recorded: methoxy group (8 55.05), acetal methylene (8 96.38) andexocyclic carbon-carbon double bond (8 102.75 and 8 160.35).The (+)-bicyclic methoxymethyl ether 214 could thus be obtained optically pure,using our improved procedure, in four steps and in an overall yield of 56%. Our nextgoal towards the total synthesis of (-)-kolavenol (65) was the preparation of theprimary iodide 213.2.5.1.5. Preparation of the (-)-Bicyclic Primary Iodide 213 The first step in the preparation of the iodide 213 was the removal of themethoxymethyl group from the ether 214 using dimethylboron bromide. A discussionof the deprotection mechanism at this point will simplify the interpretation of our results.Guindon and coworkers 152 have proposed the mechanism illustrated in Scheme2.17 for the hydrolysis of methoxymethyl ethers with dimethylboron bromide. The firststep of the deprotection is believed to be the complexation of the Lewis acid Me2BBrwith the oxygen atoms of the ether 220 to produce the complex 221. The reactioncan then proceed following either pathway (A) or (B). Route (A) should lead to theoxonium salt 224 and the boron ether 225 via the complex 222. The oxonium salt224 is probably in equilibrium with the bromomethyl ether 226; however, eithercompound should yield the free alcohol 227 and HBr upon treatment with water.Similarly, pathway (B) would produce the boron ether 229 and the oxonium salt 228via the complex 223. Reaction of the ether 229 and the bromomethyl ether 230 with[A '0--1+^Br"224I LMe2BOMe+2251Br-R0–BMe2229[OMe.1228i115water would give the same products as those produced in path (A). Guindon andcoworkers have observed the bromomethyl ether 226 by 1 H NMR spectroscopy, andthey also succeeded in trapping 226 with nucleophiles (e. g. 226 + Me0H —> 220).From the ratio of the free alcohol to the trapped ether, they have established that thepreference for the pathway (A) over (B) for a primary methoxymethyl ether is on theorder of 25:1. 152R CD40Me220Me2BBrR„^Me-0„+ ,0B ss Br-Me/ Me2211=1^ -FMe ^R^+ MeSD CC^ 'Clif _O., .._-.•Me" \ Br- b\ Br-Mee Me Me"222^ 223R'O . Br226Me0H220MeBr^C)230H2O .,R27OH + HBr + CH 2O + Me0H + CH4 + H3B032Scheme 2.17,OMe0---•1) Me2BBr, CH2Cl2-78 °C, 6 h2) NaHCO3 , H2OTHF, 82% 2 31^2 3 2^(2.45)..... s 214OH^OH116Using Guindon's procedure, Wai observed that the methoxymethyl moiety of theether 214 could be hydrolyzed along with the isomerization of the exo-methylenemoiety to give the alcohol 231 in high yield, free of the alcohol 232 (equation 2.45). 153The isomerization of the carbon-carbon double bond was probably catalyzed by thepresence of traces of HBr in the dimethylboron bromide or by the HBr produced by thehydrolysis of the excess Me2BBr. 154Our attempts to reproduce Wai's results with the optically-active ether 214 wereunsuccessful. Treatment of the (+)-bicyclic methoxymethyl ether 214 withdimethylboron bromide in cold (-78°C) dichloromethane, followed by a work-up in thepresence of base produced a colorless oil that turned black and released white fumesif left for too long (-1 h) at room temperature before chromatography. None of thedesired alcohol was isolated from the black mixture; however a small amount of a lesspolar compound was observed. The same non-polar compound was isolated in 69%yield when we attempted to remove the methoxymethyl ether protecting group of 214by heating it at 50 °C in aqueous HCI-THF for 20 h. 155 The structure 233 wasproposed for this non-polar product on the basis of the spectral data analysis and waslatter confirmed by comparison with results from the literature.31211H-3b,H-12a^0Me-17 H-13e1H-11eH-12eH-3a11-4b:H-6—H-4aMe-15H-7eH-8a117IR absorptions at 1386 and 1365 cm -1 indicated the presence of a gem-dimethylmoiety, while absorptions at 1064 and 912 cm -1 were consistent with the presence of atetrahydrofuran ring. 156 The molecular formula of compound 233 was found to beCi6H280 from the interpretation of the HRMS (calcd 236.2140, found 236.2147) andthe elemental analysis (calcd C 81.29%, H 11.94%, found C 81.00%, H 12.10%).The 1 H NMR spectrum (Figure 2.21) displayed 3 methyl singlets (5 0.81, 0.87 and0.92), 1 methyl doublet that was assigned to Me-15 (5 0.81 J = 6 Hz), and twodoublet of doublet of doublets assigned to H-3a and H-3b (5 3.71, J.3, 8.5, 10 Hzand 5 3.82, J. 8.5, 8.5, 8.5 Hz).The 13C NMR spectrum of 233 displayed 16 distinct signals in agreement withthe proposed molecular formula (Table 2.24). The signals were divided into fourgroups based on the interpretation of the APT and the HMQC 157 experiments. Thesignals of four methyl moieties were found and among them, the 13C NMR signal at5 17.44 was assigned to Me-15 from analysis of the HMQC experiment. Sevenmethylenic carbons were identified, with the 13 C NMR resonance at 5 62.44 assignedto C-3 on the basis of the HMQC experiment and the chemical shift. Two methinesand three quaternary carbons were also observed. The 13C NMR signal at 5 85.10was attributed to C-1 on the basis of its chemical shift.Me-16 H-13a H-8e Me-14H-11a^H-9^H-7a233118Table 2.24: Assignment of the NMR Data for the Tricyclic Ether 233Assignment(C-X)a13C Spectrum8 (APT)HMQC1H NMR Correlations8 (mult., # of H, J (Hz),Assignment)Long Range1H-13C HMBC158CorrelationsC-XMe-14 13.47(-ve) 0.81 (s, 3H, Me-14) 1, 4, 5, 6Me-15 17.44(-ve) 0.81 (d, 3H, 6, Me-15) 5, 6, 712 18.44 1.30-1.40 (m, 3H, H-12e) 1, 10, 11, 131.70 (ddddd, 1H, 3, 3.5, 13, 13, 13,H-12a)8 22.10 1.30-1.40 (m, 3H, H-8a) 1, 6, 7, 9, 101.41-1.51 (m, 3H, H-8e)Me-17 22.37(-ve) 0.94 (s, 3H, Me-17) Me-16, 9, 10, 117 31.28b 1.00-1.20 (m, 4H, H-7a) 6, 8, 91.41-1.51 (m, 3H, H-7e)13 31.42b 1.00-1.20 (m, 4H, H-13e) 9, 11, 121.52-1.65 (m, 2H, H-13a)Me-16 32.27(-ve) 0.87 (s, 3H, Me-16) Me-17, 9, 10, 1110 34.09 ^c c4 35.37 1.52-1.65 (m, 2H, H-4b) 1, 3, 5, 6, Me-141.77 (ddd, 1H, 3, 8.5, 12.5, H-4a)6 35.46(-ve) 1.41-1.51 (m, 3H, H-6) 4, 5, 7, Me-14, Me-151 1 42.70 1.00-1.20 (m, 4H, H-11 a) 9, 10, 12, 13, Me-16,1.30-1.40 (m, 2H, H-11e) Me-175 47.03 ^c c9 47.91(-ve) 1.00-1.20 (m, 4H, H-9) 7, 8, 10, 13, Me-16,Me-173 62.44 3.71 (ddd, 1H, 3, 8.5, 10, H-3b) 1, 4, 53.82 (ddd, 1H, 8.5, 8.5, 8.5, H-3a)1 85.10 ^c ca The table reads from left to right. The assignment and the chemical shifts of the 13C NMR spectrum(with the results of the APT experiments in brackets) are in the first and second columns, respectively.The third column shows the 1 H NMR signal(s) which correlates with the carbon of the first two columns,as obtained from the HMQC experiment (1 bond correlation). The last column lists the carbons whichcorrelate with the 1 H NMR signal(s) of the third column as obtained from the HMBC experiment (2 and 3bonds correlation).b The assignment can be interchanged.c No correlation.%av9voL____ k......)^k."'".."...-•••■•■I1.4 1.3 1.1I^i1.2 I^I^1^11.0 0.9 0.81.51.8iPPRT1.7 1.6i233Ak^fit1/41 I I I IPPR 3.9 3.8 3.7 3.6H2OiFigure 2.21 500 MHz 1 H NMR Spectrum of Compound 233 in CDCI3120A series of selective homonuclear decouplings of the ether 233 in relation to theHMQC data provided evidence for the assignment of a few more 13C NMR signals(Table 2.24). Thus, irradiation of the signal at 6 3.82 and 3.71 induced amodification of the signals at 5 1.77 and 1.52-1.65. The two latter signals wereassigned to H-4 and consequently, the 13C NMR signal for C-4 was observed at635.37. Decoupling of the signals due to Me-15 simplified the resonance due to H-6at 6 1.41-1.51 resulting in the assignment of the 13C NMR signal at 8 35.46 to C-6.The other methine carbon signal at 8 47.91 was assigned to C-9 by default and theattached hydrogen was found at 5 1.00-1.20.Analysis of the spectral data provided the correlation of each 13C NMR signalwith its respective attached proton(s). The connectivity of the carbons was establishedwith the help of an HMBC experiment (Table 2.24). The doublet at 6 0.81 ( 1 H NMR)was correlated to a quaternary carbon at 8 47.03 (C-5), a methylene carbon at5 31.28 (C-7) (or 5 31.42, C-13) and the methine due to C-6, thus confirming the initialassignment of C-6. The remaining quaternary carbon signal (at 6 34.09) wasassigned to C-10. The methyl singlet at 5 0.81 ( 1 H NMR) showed correlations withC-1, C-4, C-5 and C-6 thus providing enough evidence to assign the methyl singlet at8 0.81 to Me-14. The methyls at 6 0.87 and 0.94 ( 1 H NMR) both correlated to C-10,C-9 and the methylene carbon at 8 42.70 (C-11). The methyl at 5 0.87 ( 1 H NMR) hadan HMBC correlation with the carbon at 8 22.37, which also had an HMQC correlationwith the methyl at 8 0.94 ( 1 H NMR), thus establishing the gem-dimethyl relationship ofthese two groups. The hydrogen at 8 1.70 ( 1 H NMR) correlated (HMBC) with C-11and a carbon at 6 31.42 (C-13). This hydrogen showed NOE enhancement giving adoublet of doublet of doublet of doublet of doublets (ddddd, J . 3, 3.5, 13, 13, 13 Hz)when the signal at 8 0.94 was irradiated. The signal at 6 1.70 was assigned to H-12a(233) on the basis of the observed coupling constants since no other hydrogen of 233can have three large (13 Hz) and two small (3 and 3.5 Hz) coupling constants. Thepreceding NOE enhancement was also used to distinguished between C-16 and C-1716^R1210^89 17 234: R, R' = Me235: R = Me, R' = H236: R = H, R' = Me237: R, R' = H%•••,0/ R'11238: R, R' = Me239: R = Me, 11 1 = H240: R = H, RI = Me241: R, R' = H233121since only the axial methyl will be close enough to H-12a to show an enhancement.At this point, the 13C NMR spectrum of 233 was confidently assigned (C-8 wasassigned by default) and its 13C NMR chemical shift data was compared with a seriesof reported examples to determine whether the ring junction was cis or trans.The 13 C NMR spectra of trans-fused compounds 234-241 159 and the cis-fused compounds 242-246 160 were assigned and reported in the literature. Theaverage chemical shifts of the signals assigned to C-7-13 and C-16 and C-17 for boththe trans and cis compounds are compared with the assigned 130 NMR signals for theether 233 in Table 2.25.Table 2.25: Comparison of Selected 13C NMR Signals of trans- and cis-DecalinsRelated to the Ether 233C-X13C NMR Chemical Shifts (8)Trans (234-241) I^233 Cis (242-246)Range^MeanI^Range I^Mean7 33.2-39.9 36.4 31.3 33.0-43.1 37.18 17.6-21.0 19.4 22.1 21.7-24.4 23.1*9 54.3-54.9 *54.4 *47.9 46.7-53.2 *50.310 33.0-33.3 33.1 34.1 33.8-34.1 34.0*11 42.4-42.5 *42.5 *42.7 35.2-36.2 *35.612 18.4-18.7 18.6 18.4 18.6-19.2 19.0*13 42.1-42.9 *42.7 *31.4 26.7-34.0 *30.2Me-16 33.1-33.5 33.3 32.27 32.2-33.7 32.9 'Me-17 21.1-21.6 *21.4 *22.4 31.0-31.5 *31.3OH-H+H233Scheme 2.18122There is a significant difference between the chemical shifts of the trans- andcis-fused models at the carbon centers marked with a star (*) in Table 2.25. Two ofthese pairs (C-9 and C-13) were rejected because, in compound 233, these centerswere close to the tetrahydrofuran ring oxygen and thus were not similar enough to becompared with those of the set of known compounds we had. However, the measuredchemical shifts of C-11 and Me-17 of 233 (8 42.7 and 22.4 respectively) had almostthe same values as those of the corresponding carbons in the models compounds ofthe trans series. On this basis, the ring junction of the ether 233 was assigned thetrans stereochemistry.It may be proposed that 233 is formed from the acid-catalyzed rearrangementof the alcohol 231 or 232 (Scheme 2.18). Protonation of the double bond of 231 or232 would lead to the same tertiary carbocation 247. Rearrangement of thiscarbocation would produce the decalin 248 with a tetrasubstituted double bond. Thisbond can be protonated and the new tertiary carbocation trapped with the alcoholoxygen acting as an internal nucleophilic terminator 161 to produce 233.+250 249/."- OH,OH^KG-23MeC 6 H5reflux1.5 hotherproducts(2.46)251____/COOMess252123A Chemical Abstract Service Structure Search® resulted in the discovery of aRussian patent by Vlad and coworkers 162 for the preparation and use of compound249 as a less expensive substitute for whale's ambergris in the perfume industry(equation 2.46). This ether was prepared in 24% yield by the dehydration ofbicyclohomofarnesane-8a,12-diol 250 catalyzed by the acidic ion exchange resinKG-23. The same workers later reported the preparation of 251 under the samereaction conditions. 163 The spectral data reported for 251 were identical with those of249 reported in the previous patent. Vlad and coworkers corrected their previousassignment of the ether 249 by a chemical correlation to the previously known ester252. The spectral data for the ether 233 is compared with those for the ether 251 inTable 2.26, and from this comparison it can be concluded that the ether prepared bytreatment of 214 with aqueous acid (vide supra) is enantiomeric with the ether 251.124Table 2.26: Comparison of the Reported Spectral Data of Ether 251 with the Data ofEther 233Data Ether233Ether251IR1386 13831365 13681039 10441023 10301 H NMRCCI40.80, s, Me 0.80, s, Me0.81, d, J = 6 Hz, Me 0.82, d, J = 6 Hz, Me0.86, s, Me 0.87, s, Me0.91, s, Me 0.92, s, Me3.66, ddd, J = 3, 8.5, 10 Hz, OCH23.72, m, OCH23.76, ddd, J = 8.5, 8.5, 8.5 Hz, OCH2LRMS M-1-(236), 6% M-1-(236), 11%Analysiscalcd. for C16H280C 81.29%, H 11.94%C 81.00%, H 12.10% C 81.36%, H 12.05%I a lD -36.3° (25 °C) +39.1° (18°C)Concentration g/100 mLin chloroform1.77 6.3The cleavage of the ether 214 with dimethylboron bromide, using theprocedure of Wai, 164 was repeated and the crude product was immediately subjectedto column chromatography on silica gel. The major homogeneous fraction appearedto be unstable on TLC. The resulting oil was distilled (Kugelrohr), yielding a mixture ofthe alcohols 231 and 232 165 and a non-polar still-pot residue (see equation 2.45).The latter material, the amount of which was dependent on the work-up procedureused, was purified by flash chromatography. The molecular formula of the acquiredmaterial was found to be C33H5602 by HRMS (calcd: 484.4280, found: 484.4276)and elemental analysis (calcd: C 81.76%, H 11.64%, found: C 81.92%, H 11.72%).The analysis of the IR spectrum indicated the presence of a carbon-carbon doublebond (1636 cm -1 ) and an ether moiety (1109, 1080,1038 and 891 cm -1 ). The 1 H NMRspectrum displayed three dioxomethylene singlets at 5 4.55, 4.57 and 4.60, showingthat the residue was not homogeneous. With the exception of the dioxomethylene256 L\-exo257 A-endo (2.47)O'\CH2255O—CH2Br—HBr231and^+232 253-255125singlets and the presence of a broad multiplet at 5 3.30-3.50, the 1 H NMR spectrum ofthe mixture was very similar to that of the mixture of alcohols 231 and 232. Thus, thestructures 253-255 were proposed on the basis of the spectral data for the non-polarresidue. The formaldehyde acetals 253-255 were probably formed by the reaction ofthe deprotected, partially-isomerized alcohol mixture 231 and 232 with some non-hydrolyzed bromomethylene derivatives 256 or 257 (equation 2.47) (see 226 to 220Scheme 2.17, vide supra). The observation that the bromomethylene compounds256 and 257 were not hydrolyzed during work-up with aqueous sodium bicarbonate-THF and chromatography was very surprising, since, according to Guindon andcoworkers, no bromomethylene substances should be left after the aqueous work-up 0 66 The mixture of formaldehyde acetals 253-255 was converted into a1:1 mixture of the alcohols 231 and 232 in 84% yield using the reaction conditionsdescribed in equation 2.48 (DME is the acronym of 1,2-dimethoxyethane).126OH 1) Me2BBr (4 equiv)CH2Cl2 , -78 °C, 2 h25 3-25 52) NaOH (6 M), H 2ODME, 1 day84% 231 A-exo232 A-endo (2.48)Attempts to minimize the formation of side products during the hydrolysis of themethoxymethyl ether moiety of 214 led to an effective procedure. Thus, treatment of214 with dimethylboron bromide in dichloromethane at -78 °C produced a 1:4 mixtureof the alcohols 231 and 232 in 86% yield, after careful work-up with sodiumcarbonate and sodium bicarbonate in aqueous DME (equation 2.49). The spectraldata of the mixture of alcohols 231 and 232 were compared with those obtained byWai and were found to be acceptable. 1670 --1 zOMe1) Me2BBr (3 equiv)CH2Cl2 , -78 °C, 4.5 h 231 A-exo232 L-endo2) Na2CO3-NaHCO3H2O-DME, 6 h86%214(2.49)The exocyclic carbon-carbon double bond of the remaining amount of 231 inthe mixture of alcohols 231 and 232 was isomerized by treatment of the mixture withanhydrous p-Ts0H in dry chloroform. The material obtained, in 93% yield, consistedof a mixture of the alcohols 231 and 232, in ratios varying from 1:52 to 1:107, asdetermined by integration of 1 H NMR spectra. The observed ratios of exo- and endo-cyclic carbon-carbon double bonds is consistent with the expected ratio calculated 79from the difference in energy between the two isomers 231  and 2 3 2(AG° = -2 kcal/mol [8.4 kJ/mon). The specific rotation ([ a jo 25 ) of the mixture ofalcohols 231 and 232 (ratio 1:107) was -48.7° (c = 1.04 chloroform).(2.50)12 (2.4 equiv)(C 6 H 5 )3P (2.5 equiv)imidazole (2.5 equiv)CH 2Cl2 , 0-25 °C, 1 day90%127The alcohol 232 was converted into the iodide 213 using a modification of theprocedure developed by Garregg and Samuelsson. 168 Thus, the iodide 213([ a ]p 25 -45.7°, c = 1.75 in chloroform) was obtained in 90% yield after stirring asolution of the alcohol 232 with a mixture of iodine, triphenylphosphine and imidazole(equation 2.50).Absorptions for the primary iodide moiety of compound 213 were observed inthe IR spectrum at 1158 and 530 cm -1 . A characteristic upfield signal for theiodomethylene group was observed at 6 1.09 in the 13C NMR spectrum of compound213. The 1 H NMR spectrum of 213 was characterized by the presence of two methylsinglets (8 0.70, 6 0.97), a methyl doublet (8 0.82, J. 6 Hz), a methyl doublet of doubletof doublets (8 1.56, J = 1.5, 1.5, 1.5 Hz), two iodomethylene hydrogen signals (ddd,1H, 6 3.02, J = 5.5, 9, 12.5 Hz and ddd, 1H, 8 3.11, J = 5, 9, 12.5 Hz) and a broadolefinic singlet (1H, 8 5.18). The iodide 213 was free of the isomeric exo-olefinproduct since no other olefinic signals were observed in the 1 H NMR spectrum.Having devised an efficient route for the preparation of the iodide 213 we set out toprepare the synthetic equivalents of the donor synthon 42 and the acceptor synthon43 (see Scheme 2.15).2.5.1.6. Preparation of the Synthetic Equivalent of the Synthons 42 and 43The vinyl iodides 264 or 265 (Scheme 2.19) can be viewed as being thesynthetic equivalents of both synthons 42 and 43. Thus, lithium-iodine exchange,effected by treatment of 264 and 265 with an alkyllithium reagent, would produce thecorresponding nucleophilic vinyllithium species. Alternatively, 264 and 265 could beMe3Sn)262: R = TBDMS, 99%263: R = TIPS, 96%imidazoleCH2Cl2-/---ORI264: R = TBDMS, 95%265: R = TIPS, 92%Scheme 2.19/—ORTBDMSCI or TIPSCICOOEt----*/^+Me3Sn25979% i-Bu2AIH(3 equiv), Et20-78 °C --->0 °C97%)Me3Sn^\ COOEt260>____7-0HMe3Sn 261^\^/d 42or^a /43 COOEt(Me3SnCuCN)Li (87)(1.3 equiv)258^EtOH (1.3 equiv)THF, -78 °C128coupled directly with a suitable nucleophilic organometallic reagent. The vinyl iodides264 and 265 were easily prepared in four steps from ethyl 2-butynoate (258).The first step in the synthesis was the 1,4-addition of the (trimethylstannyI)-(cyano)cuprate 87 7° to the butynoate 258 in the presence of ethanol (Scheme2.19). 169 The E-trimethylstannyl ester 259 was obtained in 79% yield, along with asmall amount of the Z-trimethylstannyl ester 260. 170The IR spectrum of the E-ester 259 displayed absorptions for the ester carbonyl(1715 cm -1 ), carbon-carbon double bond (1604 cm -1 ) and trimethylstannyl moiety(772 and 530 cm -1 ). Similar absorptions were observed for the Z-isomer 260.Characteristic 1 H NMR signals for the E-ester 259 were observed at 8 0.17 (s, Me3Sn)and at 8 5.97 (q, J = 2 Hz, 3 J Sn-H = 74 Hz) while those of the Z-ester 260 wereobserved at 8 0.19 (s, Me3Sn) and at 8 6.40 (q, J = 2 Hz, 3J Sn-H = 117 Hz). Thestereochemical assignments of E-ester 259 and Z-ester 260 were obtained from the3 J Sn-H coupling constants between the tin atoms (average of 117Sn and 119 Sncouplings) and the olefinic protons. The 3 J Sn-H coupling for an olefinic proton trans to129a trimethylstannyl group is in the range 87-139 Hz while the cis arrangement givescoupling in the range 47-74 Hz. 171The E-ester 259 was reduced with i-Bu2AIH and the resulting alcohol 261 wasallowed to react with either tert-butyldimethylsilyl chloride (TBDMSCI) 172 or triiso-propylsilyl chloride (TIPSCI) 173 to give the TBDMS-ether 262 or the TIPS-ether 263.The ethers 262 and 263 were each treated with iodine 174 to give the iodides 264 and265 in 94% and 88% overall yield from the alcohol 261, respectively. The spectraldata (IR, 1 H NMR, 13C NMR, APT, LRMS and HRMS) and the elemental analyseswere consistent with the structures proposed for compounds 261-265.The alcohol 261 had characteristic IR absorptions at 3303 and 1006 cm -1(hydroxyl group) and at 768 and 526 cm -1 (Me3Sn moiety). The 1 H NMR spectrumdisplayed an olefinic signal as a quartet of triplets at 5 5.78 (1 H, J = 2, 6.5 Hz) with tin-hydrogen coupling of 76 Hz, indicating that this hydrogen was cis to thetrimethylstannyl group.The silyl ethers 262 and 263 had characteristic absorptions for thetrimethylstannyl (775, 528 and 766, 528 cm -1 , respectively) and trialkylsilyl groups(1256, 838 and 1256, 883 cm -1 , respectively). The 1 H NMR spectra of 262 and 263displayed expected resonances for the olefinic hydrogens (5 5.68, qt, 1H, J. 2,6.5 Hz, 3 J Sn-H = 76 Hz and 5 5.69, qt, 1 H, J.2, 6.5 Hz, 3 J sn-H = 76 Hz,respectively).The IR spectra of the vinyl iodides 264 and 265 exhibited signals at 1639 and1640 cm -1 (C—C double bond, respectively) and 1257, 838 cm -1 and 1255, 883 cm -1(trialkylsilyl group, respectively). The olefinic signals for the iodides 264 and 265were observed at 8 6.28 (qt, 1H, J=2, 6.5 Hz) and 8 6.31 (qt, 1H, J=2, 6.5 Hz) intheir respective 1 H NMR spectra.With the vinylic iodides 264 and 265 and the vinylstannyl compounds 262 and263 in hand, investigations into the coupling of these substances with the iodide 213were carried out.1302.5.1.7. Attempted Coupling with the Iodide 213 Acting as an Electrophile It was initially planned to carry out the transmetallation of the trimethyistannylether 262 with methyllithium and to use the resulting vinyllithium species 266 todisplace the primary iodide function in compound 213 (equation 2.51). 175 Modelstudies for the coupling reaction were made with the ether 262 and the primary iodide267. No significant amount of the coupled product 268 was obtained from thereaction of the vinyllithium 266 with the iodide 267, and neither of the startingmaterials were recovered./-0TBDMS^MeLiMe3Sn^ THF262 [) /-0TBDMS1Li266266 +I^THE or2^Ether orXC67 THF-HMPAThe vinyl iodide 264 was treated with tert-butyllithium and coupling of theresultant lithium species with 267 in THE-HMPA was attempted (equation 2.52).Again, the reaction did not give any of the desired product 268. It was suspected thatthe failure of the coupling reaction was due to an unsuccessful lithiation step. Thishypothesis was tested by trapping the product of the lithium-halogen exchange withTMSCI to give a mixture of compounds in only -25% yield after addition of pentaneand filtration through Florisil® (equation 2.53). Analysis of the product by 1 H NMRspectroscopy showed that a mixture of the silylated compounds 269 and 270 andsmaller amounts of the compounds 271 and 272 were obtained. Compound 270 ispossibly formed by a lithium halogen exchange of 264 and a TBDMS hydrogenabstraction with the alkyllithium (t-BuLi or the vinyl lithium species) followed by thetrapping of the corresponding dianion with TMSCI. The vinyl hydrogen in compounds271 and 272 may be introduced by intermolecular proton abstraction (of the TBDMSgroup hydrogen) or by protonation with traces of moisture. Crich and Ritchie 176 have131reported that a methyl group attached to a silicon atom can be lithiated with tert-butyllithium. For example, compound 273 gives a mixture of the sulfides 274 and275 upon treatment with tert-butyllithium and diphenyl disulfide (equation 2.54). Toavoid this side reaction, the TIPS-ether 265 was used for the coupling, since isopropylgroups are not as readily metallated with tert-butyllithium as compared to the methylmoiety of the TBDMS group of 264. When the TIPS-ether 265 was treated with tert-butyllithium and the resulting vinyllithium species 276 was trapped with TMSCI, thevinyl silane 277 was obtained in 75% yield (equation 2.55).>c>\^z—OTBDMS 1) t-BuLi k2 equiv, THE^/-0TBDMSI /^2) 267, THF-HMPA264 2 68^(2.52)/-0TBDMSMe3Si 26 9I/----0 ^Me3Si 270^SiMe3_ 1) t-BuLi 2 equiv, THE264 ^2) TMSCI 4 equiv /--OTBDMS+H271\>_,,,,,--0 Z..^H 272^SiMe3(2.53)SI iPhS---^'0+ RO„,A0RORO„, ,o■■RO^SPh274R = TBDMS 275^(2.54)1) t-BuLi2) PhSSPhRO) 7--OTIPS t-BuLi^7-0TIPS^TMSCI^) y—OTIPSMe3Si 277^(2.55)I 265^THF, -78 °C LI 276^75 %0 Me0LiCuOMe278 0 0280(2.56)132The use of cuprates rather than vinyllithium reagents has been reported to effectcoupling with alkyl iodides. In the course of the synthesis of maytansine, for example,Corey and coworkers 177 have coupled the cuprate 278 with the benzylic iodide 279to give compound 280 in 90% yield (equation 2.56). It was hoped that similarmethodology could be applied to the primary iodide 213, although it must be pointedout that 213 is not as reactive as Corey's benzylic iodide 279.CI MeCI COOMe^MeO^NCOOMeN,Me -78 to -25 °C90%The vinyllithium species 276 (equation 2.55, vide supra) was used to preparenucleophilic reagents that were coupled with the iodide 213. The results of theattempted coupling of 213 with higher order cyano cuprates [obtained by adding twoequivalents of 276 to CuCN or one equivalent of 276 to (2-thienyl)Cu(CN)Li (88)]were not encouraging. Alternatively, the coupling reaction was attempted with theGrignard reagent 281 in the presence of a copper(I) catalyst (CuCN or Cul) 178 (seeequation 2.57) but the yields of the desired product were unacceptable. The bestresults were obtained when the Grignard reagent 281 was added in an inversefashion 179 to a mixture of the iodide 213, tributylphosphine, tributylphosphine-copper(1) iodide complex 180 and HMPA in THF. A mixture of non-polar products andthe pure, desired TIPS-ether of (-)-kolavenol 282 (45% yield) ([ a ]D25 -39.7°,c = 1.60 in chloroform) were obtained after work up and purification (equation 2.57).The non-polar mixture was purified by TLC grade chromatography and was found toconsist of recovered starting iodide 213 (70% of the non-polar mixture by GLC) andsmaller amounts of the olefin 283 and the dimer 284.213Bu3P 0.7 equivBu3P•Cul 0.5 equivHMPA 5 equivTHF, 7 °C to 25 °C16^1s OTIPS133z—OTIPS 1) t-BuLi 7.1 equiv, THE^_/--OTIPS2 6 5^2) MgBr2.0Et2 3.5 equiv BrMg3.5 equiv -78 °C to 25 °C^2 81+ + 213(2.57)Key IR absorptions for the TIPS ether 282 were observed at 1669 cm -1 (carbon-carbon double bond) and at 1257 and 883 cm -1 (triisopropylsilyl group). Five signalsdue to methyl groups were observed in the 1 H NMR spectra of 282: three singlets at8 0.71, 8 0.99 and 6 1.61 (Me-20, 19 and 16, respectively), a doublet at 8 0.80(J = 6.5 Hz, Me-17) and a doublet of doublets at 8 1.59 (J = 1.5, 2 Hz, Me-18). Thesignals due to the isopropyl groups and the methylene-15 (Figure 2.22) wereobserved between 8 1.00-1.20 (21H, m) and at 8 4.25 (d, J . 6 Hz), respectively.Two olefinic protons were detected at 8 5.20 (br s, H-3) and 8 5.31 (qt, J = 1.5, 6 Hz,H-14). The stereochemistry of olefinic chain of 282 was confirmed by the use of NOEdifference experiments (Figure 2.22). Irradiation of the signal due to Me-18 led tothe enhancement of the signal due to H-3 (a). Reciprocal enhancements wereobserved between the resonances assigned to Me-16 and the methylene-15 (1N-->c)and the latter methylene and H-14 (th->e).134(c b,e"--\ 15Me-16^OTIPScl)) eH-14H-3 11# 101110Mel 20Me-17 Me-18^Me-19Figure 2.22 NOE's of the TIPS-Ether 282The alkene 282 exhibited an IR absorption due to a carbon-carbon doublebond at 1663 cm -1 . The characteristic 1 H NMR signals were: two methyl singlets(8 0.68, Me-20 and 60.98, Me-19), a methyl triplet (6 0.69, J = 8.5 Hz, Me-12), amethyl doublet (6 0.75, J = 6.5 Hz, Me-17), a methyl doublet of doublets (6 1.55, J = 2,2.5 Hz, Me-18) and an olefinic hydrogen (br m, 65.19, H-3). The 13C NMR spectrumindicated the presence of 16 carbons which is in agreement with the assignedstructure.The IR and 1 H NMR spectra of the dimer 284 were similar to those of 283. Themajor difference was the absence of the methyl triplet. The 130 NMR spectrumdisplayed only 16 resonances but the HRMS was consistent with a dimeric compound.Although the copper-catalyzed Grignard coupling gave the desired product, thelow yield of the reaction along with problems in the scaling up the reaction promptedus to use another approach to the synthesis of (-)-kolavenol (65).2.5.1.8. Coupling with the Iodide 213 Acting as a Precursor of a Nucleophilic ReagentTokoroyama and coworkers 181 have reported the total synthesis of (±)-ageline A(285), a marine natural product extracted from sponges of the genus Age/as, using aPd(0)-catalyzed coupling of the organozinc reagent 286 with the vinyl bromide 287a135(equation 2.58). The coupled product 289 was obtained in 66% yield usingPdC12dppf 182 (288) as the source of palladium(0). The resulting compound 289 wassubsequently converted into (±)-ageline A (285).ZnBrBr^ sCoC6 H5Cp--H6 5` /CIPdP/ SCI\-C6H52 8 8 C6H5286CD287THE(2.58)An approach similar to that of Tokoroyama was envisaged for the coupling ofthe primary iodide 213 with vinyl iodide 265. The formation of the zinc reagents frombutyl iodide 290 and the iodide 267 was studied initially. Knochel and coworkers 183have used the reaction of primary iodides with activated zinc (Zn dust, BrCH2CH2Br,TMSCI, THF) ("Zn", 291) to prepare organozinc reagents. This method was applied tothe iodides 290 and 267 (equation 2.59). We observed no formation of homocoupledproducts as described by Knochel and coworkers 183 but a variable amount of iodidewas converted to the corresponding alkane. Better results were obtained using a136stepwise procedure. Thus, lithium-iodide exchange 184 of the iodides 290 or 267 witht-BuLi in ether-hexane 185 followed by addition of zinc bromide prepared in situ withzinc dust and dibromoethane in THE gave the desired zinc reagents 294 and 295(equation 2.60).Bul290 I267++"Zn"291"Zn"291 BuZnI292ZnIX-2-9/3 (2.59)1) t-BuLiEther-Pentane^BuZnBr290 ^ 2942672) ZnBr21) t-BuLiEther-PentaneZnBr295 (2.60)2) ZnBr2The same palladium(0) catalyst as the one used by Tokoroyama, PdCl2dppf(288) (equation 2.58), was tested to couple the organozinc species 293 with theiodide 265 but none of the desired product was obtained. With palladium(0) bis-(dibenzylidene)acetone [Pd(dba)2} 186 and triphenylphosphine 187 the coupled productwas obtained in yields up to 60%. The best yield was attained using Pd(dba)2 andtriphenylarsine. 188 Triphenylarsine has been found to be the ligand of choice forpalladium(0) catalyzed coupling reactions. It was found to increase the rate of theStine coupling of vinylstannane compounds with vinyl iodides by a factor of 100-1000compared to the rates measured with phosphine ligands like triphenylphosphine. 188The faster reaction rates can be attributed to the lower dissociation energy oftriphenylarsine from the palladium(0) compared with that of triphenylphosphine.The zinc reagent 296 was prepared as shown in equation 2.61. The solution ofthis reagent was then carefully transferred to a solution/suspension of Pd(dba)2 and137triphenylarsine in THF. The iodide 265 was added immediately and the mixture wasstirred overnight. The TIPS-ether 282 was obtained in 77% yield. Also isolated weresmall amounts of the alkane 283 and the dimer 284. The next step of the projectedwork was the conversion of 282 into (-)-kolavenol (65).I ZnBr1) t-BuLi 2.3 equivether-hexane, -78 °C2) ZnBr2 2 equivTHF, -78 °C to 25°C1) Pd(dba)2 0.03 equiv(C6 H5 )3As 0.12 equivTHF2)) /--OTIPSI 265 1.5 equiv21 h(2.61)2.5.1.9. Preparation of Synthetic (-)-Kolavenol (65) Synthetic (-)-kolavenol (65) was produced in 96% yield by cleavage of the silylether linkage 282 with tetrabutylammonium fluoride 189 (equation 2.62). The spectraldata of this material was in agreement with that reported for natural (-)-kolavenol (65)(see section 2.5.1.11).142OTIPSBu4NF 2.5 equivTHF, 2 h96%COOMei-Bu2AIH 4 equiv, ether-78 °C ---> 25 °C, 2 h47%2.5.1.10. Preparation of the Semi-Synthetic (-)-Kolavenol (65) from Natural (-)-MethylKolavenate (33) A small sample of (-)-methyl kolavenate (33) (4.7 mg, from esterified naturalkolavenic acid) was obtained from Dr. Tokoroyama. 190 It was reduced with i-Bu2AIH togive (-)-kolavenol (65) in 47% yield (equation 2.63). This semi-synthetic (-)-kolavenoland the synthetic (-)-kolavenol obtained as described above (2.5.1.9) were identical byTLC analysis. A comparison of the spectral data of synthetic, semi-synthetic andnatural (-)-kolavenol (65) is made in section 2.5.1.11.2.5.1.11. Comparison of the Spectral Data of the Natural. Semi-Synthetic andSynthetic ( -)-Kolavenol (65) Comparison of the spectral data of our synthetic kolavenol, the semi-synthetickolavenol derived from methyl kolavenate and the reported data for (-)-kolavenol ispresented in Table 2.27. This comparison confirmed that we had realized the total139synthesis of (-)-kolavenol, in 14 steps and 19.4% overall yield from the optically activetrimethylstannyl cyclohexenone 64. The identity of the synthetic kolavenol can also beconfirmed by the examination of the D20 exchanged 400 MHz 1 H NMR spectra ofsynthetic (Figure 2.23) and semi-synthetic (Figure 2.24) (-)-kolavenol (65).In summary, the synthesis of enantiomerically pure (-)-kolavenol (65) wasaccomplished by means of a novel methylenecyclohexane annulation-destannylationsequence. We also improved on and shortened the procedure of Piers and Wai for thepreparation of the methoxymethyl ether 214. The acid sensitivity of this compoundwas illustrated by its acid-catalyzed rearrangement to give the tricyclic ether 233. Thisacid lability of the trans-clerodane skeleton should be considered when planning thesynthesis of other clerodanes. The elucidation of the structure of the rearrangementproduct 233 was unambiguously accomplished using two dimensional NMRtechniques and NOE experiments. This assignment corrected the erroneouspublished assignment of the structure of the enantiomer of 233. The acid catalyzedrearrangement leading to 233 should be explored to produce the commerciallyimportant perfume lonoxide® 251. Finally, a new efficient palladium-catalyzedcoupling procedure of the zinc reagent 296 with the iodide 265 yielded the protectedprecursor of (-)-kolavenol 282. The next section will be concerned with the use of theTIPS-ether 282 as a precursor for the total synthesis of (-)-agelasine B (31).OHHODt^.--r-^T- r- -T- r-^ T 1 /^I^ 15 . 0 .^4 . 0 2. 0^15PPM^1 H^1 _ 0PPMFigure 2.23 400 MHz H NMR Spectrum of Synthetic (-)-Kolavenol (65) in CDCI3-D20 Figure 2.24 400 MHz 1 H NMR Spectrum of the Semi-synthetic (-)-Kolavenol (65) in CDC13-D20 41.142Table 2.27: Comparison of the Reported Spectral Data for (-)-Kolavenol with that ofthe Synthetic and Semi-Synthetic (-)-Kolavenol (65)Data^II Synthetic^Semi-Synthetic^Reported 140-150 °C/0.1 torr140-150 °C/0.1 torr 140-150 °C/0.03 torra B.P.3333b3319331916651668 166812401241 12421172 11751172IR (neat, cm -1 ) 11331131 113111001100 110010801075 10751000 10061001851 865851797 8007976 0.72 (s, 3H)b,f5 0.70(s, 3H)e 5 0.70(s, 3H)e5 0.79 (d, 3H, 7) 6 0.80 (d, 3H, 7)5 0.79 (d, 3H, 7)5 0.98 (s, 3H)6 0.99 (s, 3H) 6 0.99 (s, 3H)1 H NMR 51.58 (m, 3H) 6 1.55 (d, 3H, 1.5)5 1.58 (m, 3H)5 1.66 (s, 3H,) 5 1.63 (d, 3H, 1)5 1.66 (s, 3H,)5 5.18 (br s, 1H) 5 5.18 (br s, 1H) 5 5.12 (br t, 1H)5 5.30 (t, 1H, 6.5)5 5.38 (br t, 1H, 6.5)65.38 (br t, 1H, 6.5)^h 5 16.0005 15.93g5 16.48 5 16.525 17.995 17.945 18.22 5 18.005 18.405 18.335 19.986 19.905 26.85 6 26.956 27.605 27.476 32.935 32.79130 NMR 5 36.335 36.225 36.925 36.705 36.925 36.815 38.215 38.146 38.675 38.585 46.535 46.395 59.375 59.405 120.44 5 120.455 122.80 5 123.025 140.466 140.805 144.386 144.53LRMS M -I- (290) M±(290)HRMS (290.2610)i 290.2619 290.2602h C20H34ObC20H340Analysis^h -45.7° (4.2, 33 °C)b-57.1° (2.52, 26 °C)d-56.3° (3.55, 25 °C)[ a ]ct (CHU&(c, t)a Reference 141; b Reference 142b; c Reference 191; d Reference 144; e 400 MHz, CDCI3;f 60 MHz, CCI4; g 125.8 MHz, CDCI3; h Not enough material; i 25 MHz, CDCI3;j Calculated value for C2011340.C20 H33 -Cr/- 'N—Me2.5.2. Synthetic Studies Toward (-)-Agelasine B (31)2.5.2.1. Isolation of (-)-Agelasine B (31) (-)-Agelasine B (31) is a structurally unusual marine natural product isolatedfrom the Okinawan sponge Agelas nakamurai Hoshino. 192 This substance possessesa 9-methyl-7-adeninium moiety attached to C-15 of a trans-clerodane diterpenoidskeleton and, interestingly, has been shown to display a variety of biological activities,including antimicrobial activity and inhibitory effects on Na, K-ATPase. 193 In additionto their interesting biological activity, biologists have used the compounds isolatedfrom the Age/as sponges to establish the chemotaxonomy of the otherwise difficult toidentify monogenic 194 family of sponges. 195The first partial structural elucidation of the agelasines was reported by Cullenand Devlin 196 working with an extract from the sponge Age/as dispar Duchessaingand Michelotti. They showed, using spectroscopic techniques and chemicaldegradation, that the agelasines were composed of a diterpenoid skeleton (C20H33)and a 9-methyl-7-adeninium moiety (see 297).H2N \ NN —'297143144The full structural elucidation of agelasine B (31) was accomplished byNakamura and coworkers 192 by use of spectroscopic methods and chemicaldegradation. It was found that agelasine B (31) was sensitive to both strong acids andweak bases. Thus, when agelasine B (31) was treated with HCI in acetic acid 192b therearranged product 298 was obtained in 75% yield (equation 2.64), while treatment ofthe agelasines 297 with aqueous sodium carbonate 196 or aqueous ammoniumhydroxide 25 produced the formamides 299 (equation 2.65). The rearrangement of 31to 298 is another example of the acid sensitivity of the trans-clerodane skeleton.31HCI-CH3COOH70% 297Na2CO3-H 20orCHOC201133 —N HN–MeH 2N--^NN__//(2.65)299NH4OH-H20-Me0H2.5.2.2. Previous Synthesis of (-)-Agelasine B (31) Tokoroyama and coworkers 31 have prepared (-)-agelasine B (31) from(-)-methyl kolavenate (33) obtained from esterification of natural (-)-kolavenic acid(Scheme 2.20). This synthesis constitute a formal total synthesis of (-)-agelasine B(33) since they have already synthesized (-)-kolavenate (33) (see section 2.5.1.2).Reduction of the ester moiety of 33 gave (-)-kolavenol (65), which was converted intothe bromide 300. The bromide was displaced with the known adenine derivative 3011) i-Bu2AIH2) PBr315%145to give the desired methoxy adenine derivative 302 and the hydrobromide adduct303 in a ratio of 4.3:1. The N-methoxy group of 302 was removed using zinc in aceticacid, and the counterion was then exchanged with chloride to give (-)-agelasine B(31)./ NNMe0 = --(/H^ (NNNN-Me301/* MeBr -^DMA, 60 °CN .+ N -(N___^/NMe0 N-2/H^+1) ZnAcOH-H2018 h2) NaCI, H2O78%30264%OMeN NIINNN •HBr\Me3 1Scheme 2.20(2.67)R = Br 300 85%R = OH 65 10%OTIPS1) (C6 H5 )3 PBr2 1.5 equivCH2Cl2 , 1 h2) latrobead® silica filtration2821462.5.2.3. Preparation of the Kolavenyl Bromide (300) It was initially planned to carry out the total synthesis of (-)-agelasine B (31) viaan approach similar to that of reported by Tokoroyama and coworkers. 31 A report byPalomo and coworkers 197 indicated that a silyl ether can be transformed directly intoan alkyl bromide using triphenylphosphine dibromide. For example, the silyl ether304 was converted into the primary bromide 305 in 91% yield using thetriphenylphosphine dibromide reagent (equation 2.66).(C6H5 )3PBr2 2.2 equivTBDMSO(CH2 ) 13CH3 ^  BrCH2(CH2)12CH3304^CH2Cl2, 10 min91% 305^(2.66)Low yields of the bromide 300 were obtained when Palomo's procedure wasapplied to the TIPS-ether 282. It was suspected that the low yields might be due tothe instability of the allylic bromide 300 during chromatography on common (acidic)silica gel. Indeed, compound 300 was obtained in 85% yield when purification of thecrude product was done with neutral silica gel (latrobeads®) (equation 2.67). A smallamount of (-)-kolavenol (65) was isolated as a side product (-10%) in the reaction.147Because of its instability, the bromide 300 was not fully characterized and onlyits 1 H NMR spectrum was recorded. The spectrum of 300 displayed three methylsinglets (6 0.72, 0.98 and 1.71), one methyl doublet (6 0.81, J = 6 Hz) and one methylmultiplet (6 1.58). A doublet was observed at 6 4.00 (2H, J = 8.5 Hz), it was attributedto the hydrogen of the bromomethylene moiety. The signals for the olefinic hydrogensappeared as a broad singlet at 6 5.19 (1H) and a broad triplet at 6 5.50 (1H,J = 8.5 Hz).2.5.2.4. Preparation of the Adenine Derivative 301 The adenine derivative 301 was prepared in five steps from adenine (306)using a previously reported procedure (Scheme 2.21). 198 Adenine (306) wasoxidized with hydrogen peroxide in acetic acid to give the N 1 -oxide 307 (mp 295-300 °C dec, lit. 198 a 297-307 °C dec), which was alkylated with iodomethane toproduce the salt 308 (mp 223-227 °C, lit. 198b 222°C). Compound 308 wasneutralized using an ion exchange resin to afford the methoxyaminopurine 309(mp 250-260 °C dec, lit. 198b 255-257 °C dec), which yielded the quaternaryammonium salt 310 (mp 205-215 °C dec, 1it 198 b 214-215 °C dec) upon treatment withiodomethane. The air-sensitive adenine derivative 301 (mp 230-235 °C dec, iitissc239 °C dec) was obtained by neutralization of the ammonium salt 310, followed by athermal Dimroth rearrangement.22 hI61 0/0MelDMAH N \ 1 „NN--g1 +Me0N'N-03070071488HN / N 9 30 )`/0 H202/F1204.4 equiv27--(4H2N \ N 3N--^CH3COOH2 5 d, 63%306N N-Me IRA-402-HCO3 -_(^H2ON— wN ^MeO^Ni--^2) Reflux, 3 h57%1) Amberlite3014.N + toNJ - N ---/( 9H N-4 NN-'MeO308AmberliteIRA-402HCO3 -H2093%Mel^NN/DMAI^H N /1 p4.5 d^N--/35% med309310Scheme 2.212.5.2.5. Preparation of the Methoxy-Protected Adenine Derivative 302 and The N6-Alkylated Adenine Derivative 303 Kolavenyl bromide (300) was treated with the adenine derivative 301 usingreaction conditions identical to those reported by Tokoroyama and coworkers (seeScheme 2.20). 31 The methoxy adenine derivative 302 ([ a ]o25 -24.4°, c = 1.02in Me0H [lit.31 [ a ]D21 -26.2°, c = 1.00 in MeOH]) and the N 6-alkylated adeninederivative 303 (isolated as the free base) ([ a ]D 25 -38.7°, c = 2.96 in Me0H) wereisolated in 42% and 32% yield, respectively, after purification. The ratio of the isolatedproducts 302 to 303 (1.3:1) was different from that reported by Tokoroyama for thesame reaction (4.4:1!). It had also been reported that the reaction could be performedat room temperature for an extended period of time without loss of selectivity oryields. 31 The alkylation was repeated at room temperature and the products 302 and303 were obtained in 29% and 23%, respectively. Thus, the ratio of the two productswas, again, 1.3:1! The best yields were obtained when kolavenyl bromide 300 was+DMA, 60 °C3hBr30338%(2.68)8' Br -16^15 '/.^Me14^Ni+ 14(17^N___^NI 6' r^2'u_SMe0 —H^301 2 equiv 18 302^OMe/Bu4NI catalytic^52% N^N 2'Nt., IV8' 9 ' \Me149treated with 301 in the presence of a catalytic amount of Bu4Nl (equation 2.68). Theproducts 302 and 303 were obtained in 52% and 38% yields respectively, giving aratio of 1.4:1 of isolated products. The ratio of the crude reaction products 302 to 303as obtained by integration of the 1 H NMR spectrum was even worse at 1.25:1!The reason for the discrepancy between our results and those of Tokoroyama is notclear.Compound 302 exhibited IR absorptions due to the NH group at 3414, 1595and 881 cm -1 , the carbon-carbon and carbon-nitrogen double bonds at 1672 and1556 cm -1 and the N-0 bond at 1058 cm -1 (lit.31 3360, 1670, 1590, 1550, 1050,880 cm -1 ). Analysis of the 1 H NMR spectrum confirmed the formation of 302. Sevenmethyl groups were observed: 5 singlets at 6 0.70, 6 0.98, 6 1.89 (Me-16), 8 3.92(Me-N), and 6 4.04 (Me-0), one doublet at 6 0.78 (J = 6 Hz, Me-17), and one multipletat 6 1.55 (Me-18). The other relevant 1 H NMR signals were: a doublet at 8 5.15 (2H,J . 8 Hz, H's-15), a broad singlet at 8 5.15 (H-3) and a broad triplet at 8 5.43 (J . 8 Hz,H-14) and the signals attributed to the adeninium moiety at 8 7.82 (d, 1H, J = 4 Hz, H-2'[becomes a singlet with D20]) 199 , 8 9.90 (H-8') and 8 10.49 (br s, NH [exchanged with„Br -NN' i\lieN 1) Zn 10 equiv___(/^AcOH-H 20HMe0 N^50 °C, 10 h2) NaCI, H2O302150D2O]) (lit. 31 two singlets at 8 7.97 and 8 9.83, 1H each). The 13C NMR spectrum wasconsistent with the proposed structure. The UV spectrum of 302 had a maximum at294 nm (e 4452, 9.0 x 10 -5 M in Me0H) characteristic of a N-methoxy methyladeninium moiety. 20°The neutral adenine derivative 303 exhibited IR absorptions consistent with thereported data. 31 In contrast to the IR spectrum of 302, no NH absorptions wereobserved. The 1 H NMR spectrum of 303 was differentiated from the spectrum 302 bythe absence of exchangeable protons, and by the more shielded nature of the signalsassigned to Me-16 (A8201 0.11), N-Me (a 0.11), 0-Me (A8 0.12), H's-15 (08 0.38) andH-8' (08 1.42) due to the neutrality of the molecule. The 13C NMR spectrum wasconsistent with the proposed structure. The UV spectrum of 303 had a maximum at278 nm (e 14498, 1.8 x 10 -5 M in Me0H) characteristic of a N-methoxy methyl adeninemoiety. 20°2.5.2.6. Reduction of the Methoxy-Protected Adenine Derivative 302 with Zinc in Acetic Acid The methoxy-protected agelasine B 302 was treated with zinc in acetic acid asdescribed by Tokoroyama and coworkers (equation 2.69). 31 No agelasine B (31) orstarting material were observed in the 1 H NMR spectrum of the crude reaction mixture(equation 2.69). After three unsuccessful attempts, it was decided to investigate thereduction using a less valuable model compound.N \N-Me2) latrobead® silica filtration100%6 31411 0/0—0H1) (C6H5 )3PBr2 1.2 equivCH2Cl2 , 1 h10> 6^N— NMeO' 6 ' N___//^+8^313 ^H38%,N^NMe0^N.2/301 H1.3 equiv10DMA, 55 °C2.5 hOMe1,,,/7—INI...6N' T^I IN8Nt___ N^(2.70)9' \ Me311 312/, MeNO W3 ,1512.5.2.7. Preparation of the Methoxy-Protected Adenine Derivative 313 The geranyl derivative 313 202 was prepared in two steps from geraniol (311)using a procedure similar to that reported by Tokoroyama and coworkers. 31,206Geraniol (311) was treated with triphenylphosphine dibromide to give the knowngeranyl bromide (312). 203 The allyl bromide 312 was treated with the methoxy methyladenine derivative 301 to give the alkylated adenine derivative 313 after purificationby selective precipitation and centrifugation, while the compound 314 was obtainedby chromatography over basic alumina of the material derived from the supernatantsolutions.204The spectral data for the compounds 313 and 314 were consistent with theproposed structures. The assignment of the spectra (IR, 1 H NMR, 13C NMR, LRMS,HRMS and UV205 ) was based on comparison with that of 302 and 303.9^1 7' / C1 -Me/--N + K.H2 N^N4^_S315 ^(2.71)6Br me 1) Zn 10 equiv+ N ^Ac0H-H2050 °C, 10 hN — NMeO'^N-'^2) NaCI, H2O313 ^H 33%1522.5.2.8. Reduction of the Methoxy-Protected Methyl Adenine Derivative 313 with Zincin Acetic Acid Removal of the methoxy protecting group of compound 313 was attemptedusing reaction conditions identical to those reported by Tokoroyama and coworkers(equation 2.71). 206 The desired product 315 (mp 154-157 °C [lit. 31 145-150 °C]) wasobtained in 33% yield after purification of the crude reaction mixture.The IR spectrum of the dialkyl adeninium 315 displayed absorptions assignedto the NH2 group (3322 and 3131 cm -1 ) and to the carbon-nitrogen and carbon-carbon double bonds (1651, 1613 and 1590 cm -1 ). The 1 H NMR spectra exhibitedsignals consistent with the structure 315. The presence of the adeninum moiety wasconfirmed by the occurrence of the signals at 8 4.07 (s, 3H, N-Me), 8 6.78 (br s, 2H,NH2 [exchanged with D20]), 8 8.49 (s, 1H, H-2') and 8 10.95 (s, 1H, H-8' [slowlyexchanged with D20]). 136 The 1 H and 13 C NMR spectra could be assignedcompletely by mean of the off-resonance proton decoupled 13C, APT, HMQC andHMBC NMR experiments. The UV spectrum of 315 was characteristic of a compoundhaving a 7,9-dialkyl adeninium moiety with a maximum at 273 nm (e 6777,2.78 x 10 -4 M in Me0H).237Because the isolated yield of 315 was low it was decided to test the stability of(-)-agelasine B (31) to the zinc in acetic acid reduction procedure. The opportunity todo this test was given to us when Dr. R. Andersen generously gave us a sample of theextract of the sponge Agelas species (probably nakamurai) containing (-)-agelasine B(31).2081532.5.2.9. Isolation of Natural (-)-Agelasine B (31) from the Crude Extract of the Sponge Agelas Species The initial extraction and purification steps of (-)-agelasine B (31) from thesponge Agelas were carried out by Ms. Jana Pika (Ph. D. student withDr. R. Andersen). 209 The purified extract obtained by Ms. Pika was passed through aSepPak® C18 reverse phase chromatographic column and was then further purifiedeither by high pressure liquid chromatography (HPLC) to give a sample of pure(-)-agelasine B (31) or by TLC grade silica chromatography to give a sample enrichedin (-)-agelasine B (31) (>25% of the mixture as established by the integration of the1 H NMR spectrum of the mixture, the remaining 75% was composed of the agelasinesA, C, D and E). The latter sample was used to test the stability of (-)-agelasine B (31)with zinc in acetic acid. The HPLC-purified sample (mp 170-175 °C) exhibitedspectral data consistent to that reported for (-)-agelasine B (31) (lit.31,192b 167-170 °C)(see Table 2.28, vide infra).2.5.2.10. Treatment of the Enriched Sample of Natural (-)-Agelasine B (31) with Zincin Acetic Acid A sample containing (-)-agelasine B (>25% pure, vide supra, 93 mg) wastreated with zinc in acetic acid using reaction conditions similar to those describedpreviously (see equation 2.71). After work-up, no (-)-agelasine B (31) was observedin the 1 H NMR spectrum of the crude reaction mixture. Purification of this material byTLC grade silica chromatography produced only a very small amount of agelasine B.The reason(s) for the failure of effecting reduction of 302 with zinc in acetic acidor for the destruction of (-)-agelasine B (31) under the same conditions are unclear,particularly when one takes into account the reports of Tokoroyama andcoworkers. 31,181,206 In our hands, both processes gave a large number of productsthat differed widely in polarity (TLC analyses). One can speculate that the adeniniummoiety may have been reduced and/or that some of the observed side products mayhave been due to the established rearrangement of the acid sensitive trans-clerodane154skeleton. The difficulties encountered with Tokoroyama's demethoxylation methodprompted the development of another reaction procedure for the demethoxylation ofcompound 302.2.5.3. Electrochemical Demethoxylation: Total Synthesis of(-)-Agelasine B (31)2.5.3.1. Introduction It has been proposed that zinc in acidic solution reduces a substrate by actingas an electron donor (single or two electron donor). 210 The reduction potential of thetransferred electron from the metal to the substrate will often dictate which products areformed in the reaction. The reduction potential has to be sufficiently large in order totransfer electrons to the substrate and produce an anion. The resulting anion israpidly protonated by the acid present in the reaction medium to give the reducedproduct. If the reduction potential is not correctly adjusted, either a reduction does nottake place at all or the reduction products can be further reduced. When the yieldsobtained by reduction with metals in the presence of acids are not acceptable, the onlyway to avoid side product formation is by changing the acid, the acid concentration,the metal or by using an amalgam of different metals in order to adjust the reductionpotential of the transferred electron to the desired level. Optimization is difficult andrequires a large amount of material to do all the trials, because the products have to beisolated in order to obtain the yield of the reactions. Both the adjustment of theelectron transfer potential and the need for a smaller amount of substrate to find theappropriate reaction conditions can be met by the use of an electrochemical process.An example of the electrolysis of a nitrogen-oxygen bond has been reported.Lund and Kwee 211 have demethoxylated 1-methoxybenzotriazole (316) to give thebenzotriazole (317) in an unreported yield (equation 2.72) by means of a reduction ata controlled potential of -0.75 V versus a saturated calomel electrode (SCE) in 1 Naqueous HCI. The reduction of 316 was shown to be a two electron process bypolarography.155OMe1N;NN3 1 6-0.75 V (SCE), HgHN" N1\1 /31 71 N aqueous HCI(2.72)Single electron transfer reactions are easy to control with an electrode since thepotential of the transferred electron can be accurately determined by adjusting thepower supply potential. The number of electrons donated can be measured andcontrolled in a more reliable way than in the case of reduction with metals in thepresence of acids. The major advantage of electrochemistry over metal-acidreductions is that the use of electroanalytical methods (e.g. cyclic voltammetry orpolarography) require only very small amounts of the substrate to rapidly investigateand optimize the reaction conditions. 212 Since cyclic voltammetry was used to solveour synthetic problem, a short discussion of the method will be included.2.5.3.2. Cyclic Voltammetry213Cyclic voltammetry is a relatively simple experiment that can provide valuableinformation about the electrochemical behavior of a compound. This electrochemicaltechnique is similar to linear sweep voltammetry (LSV) where the potential (E)between the electrodes is scanned linearly towards a more negative or positivepotential until a reduction or an oxidation takes place and a current (i) is observed. Incyclic voltammetry, the voltage is scanned towards a preset potential and then back toits initial point. A schematic representation of a voltammograph and the three-electrode electrochemical cell necessary for cyclic voltammetry are shown in (A)(Figure 2.25).156The cell is composed of a work electrode (W) where the reaction of interesttakes place, a counter electrode (C), and a reference electrode (RE) against which thepotential of the working electrode is measured. The electrodes are immersed in asolution of the electroactive substance and a support electrolyte that provides sufficientelectrical conductivity through the solution. The reference electrode is a half-cell thathas a known and constant potential as long as the current going through it isnegligible. The voltammograph generates a triangular potential wave that scansbetween two preset limits and records the current variations between the work and thecounter electrodes. The speed of the scanning can be varied to yield informationabout the kinetics of the electrochemical reaction.The voltammogram (B) (Figure 2.25)214 is typical of a reversible process. Theresulting second half is symmetrical with the first wave. An irreversible process ischaracterized by a returning wave that follows the residual current (C). 215 Anelectrochemical step followed by a chemical step is called an EC process (D), and hasa returning wave showing a non-symmetrical minimum due to the transfer of electronsfrom the newly-formed species. The maximum at high potential of curve (E)represents the point were the solvent or the electrolyte becomes electroactive and getsreduced. The potential at which the current rapidly rises is called the solventdischarge, breakdown or decomposition potential.157VoltammographW = Work electrodeRE = Reference electrodeC = Counter electodeCellCURRENT B ReversibleprocessC Irreversible^D EC processprocess(-E) POTENTIALFigure 2.25 Cyclic Voltammetry: Apparatus and VoltammogramsE SolventdecompositionA Schematic of voltammetric cell.2.5.3.3. Voltammograms of the Geranyl Derivative 313, the Methoxy-Protected Adenine Derivative 302 and (-)-Agelasine B (31) The reduction of the geranyl derivative 313 was investigated under conditionssimilar to those reported for the demethoxylation of 1-methoxybenzotriazole (316)(equation 2.72). Although the choice of a mercury work electrode was suitable for oursubstrates, we could not use aqueous HCI as the reaction medium because it couldtrigger the rearrangement of the trans-clerodane skeleton. Instead, a 0.1 M aqueoussodium acetate buffer solution at a pH of 4.5 was selected. This choice was based onthe availability of the buffer and the necessity of having a mildly acidic reactionmedium for the reduction to take place.The voltammetric measurements were made using a hanging mercury dropelectrode (HMDE) as the work electrode, a platinum wire as the counter electrode, anda Ag/AgCI electrode in a saturated solution of AgCI in saturated aqueous KCI158(separated from the reaction solution by a porous glass [Vicor®]) as the referenceelectrode (E = 0.197 V vs. normal hydrogen electrode NHE, -0.045 V vs. SCE). Thescanning speed was set at 100 mV/s and the reaction solution was purged of oxygenwith dry nitrogen.The voltammogram of the compound 313 (2.5 x 10 -3 M in NaOAc buffer) wasrecorded from 0 to -1.2 V and an expansion of the voltammogram is shown in Figure2.26.216 The resulting curve has the shape typical of an irreversible process with amaximum at -1.06 V (2.4 gA) and a minimum at -1.12 V (2.0 p.A). Solventdecomposition is observed at -1.2 V. Without the substrate, the solvent decompositionis not observed until a potential of at least -1.4 V is reached. The observed differencein the solvent decomposition potential is probably due to the reduction of the solventwith the substrate 313 acting as the catalyst, transferring electrons from the electrodeto the solvent and producing hydrogen gas. This phenomenon is called catalytichydrogen reduction and has been reported by Janik and Elving, 217 who haveobserved the low potential solvent reduction while studying the polarographicbehavior of purines, pyrimidines, pyridine and flavins at pH's more acidic than 5._ BrMeN+ N .987 -< 6 -t 5 —m'i 4 -U332 1 N-Me0'313NN--{/H-1.06 V1L_I-1-1-1-1-1-1-1_-0.9^-1.0^-1.1^-1.2Applied Potential (V)Figure 2.26 Voltammogram of Compound 313159The voltammogram of the methoxy-protected adenine derivative 302 wasrecorded, and showed features similar to those of 313. Two irreversible waves wereseen in the expansion at -1.01 V (1.5 1.tA, 1.3 x 10 -3 M in NaOAc buffer) and -1.18 V(0.7 IA) (Figure 2.27). Solvent decomposition was observed at -1.29 V.Natural agelasine B (31) was also studied by cyclic voltammetry (2.4 x 10 -3 M inNaOAc buffer) (Figure 2.28). A small maximum was observed at -1.02 V althoughthe current was very small at 0.08 p.A. Catalytic hydrogen reduction occurred at -1.2 V.The small maximum at -1.02 V may be due either to the reduction of (-)-agelasine B(31) or to the reduction of a contaminant present in trace amounts.From the results of the voltammograms of compounds 302, 313 and 31, it wasconcluded that the methoxy-protected adeninium derivatives 302 and 313 may bereduced at constant potential of --1 V in the aqueous sodium acetate buffer. Even if areduction wave is observed at -1.02 V for (-)-agelasine B (31), its amplitude is smallenough (32 times smaller than that of compounds 302 and 313) that the methoxyadenine derivative 302 will be reduced faster than the desired demethoxylatedproduct. In all cases the substrates were recovered unchanged from the analytical cellin good yield (70-90%), showing that the buffer is not harmful to the compounds 302,313 and 31. Verification of the electroanalytical predictions based on cyclicvoltammetry was made with the electrolysis of compound 313.Br -/-\ MeN +\N' Me1.6 -f-1.4 -1.2 -1.0 T15- 0.8 T0.6 -0.4 -0.2 T[: I-0.8160302-0.9 -1.0^-1.1^-1.2Applied Potential (V)-1.3Figure 2.27 Voltammogram of Compound 3020.8 1^ 0.6(I') 0.4-C.)0.21616-1-1-1-1-1-1-1-1-1-1-1--0.7^-0.8^-0.9^-1.0^-1.1^-1.2Applied Potential (V)Figure 2.28 Voltammogram of (-)-Agelasine B (31)2.5.3.4. Electrolysis of the Methoxy-Protected Adeninium Derivative 313 The electrochemical reductions were all performed in a mercury electro-chemical cell made by the UBC glass and mechanical shops. The electrochemicalcell used is shown diagrammatically in Figure 2.29. A constant potential of -1.0 Vwas maintained for the duration of the electrolysis, and the amount of current thatpassed through the solution was monitored with an electrometer hooked into avoltage-time integrator made by the UBC electronics shop.The electrolysis of the suspension of the adeninium derivative 313 wasstopped after 1.9 equivalents of electrons had passed through thesolution/suspension. The expected product 315 was obtained in 41% yield (57%based on recovered 313) after exchange of the counterion with chloride ion (equation2.73). The spectral data derived from 315 were identical with those described earlier.The addition of cosolvents to solubilize the adeninium salt 313 [methanol, ethylenecarbonate, poly(dimethylsiloxane)] did not improve the yields of 315.1) Hg, -1.0 VBr me (vs. Ag/AgCI)NaOAc buffer 101.9 equiv of e - \N—//^ 8H^2) NaCI, H2O, 41%9^1 7 , z\CI -me+H2N46 N ___(/(2.73)315Side viewHgRubberseptaTeflon® capRubbersepta CounterelectrodeReferenceelectrodeGlass frit30 mL, 4-5.5 p.mMagneticstir barAg wireTeflon® tubingPyrex®AkV glassPtmeshAg+/AgCI(4M KCI)Vicor®glass4— Pt wire238uglassTeflon® cap --O.-0.1 M Na0AcH2O pH 4.5WorkelectrodeCounterelectrodeReferenceelectrodeTop viewHgAr inletTeflon®tubing'IL■ Pt wireFigure 2.29 Electrochemical Mercury Cell (Actual Size)1621632.5.3.5. Electrolysis of the Methoxy-Protected Adeninium Derivative 302The electrolysis of the methoxy-adeninium derivative 302 was effected usingreaction conditions similar to those described for the demethoxylation of the geraniolderivative 313 (see equation 2.73). Synthetic (-)-agelasine B (31) was obtained in53% yield (57% yield based on recovered 302) after purification by chromatographywith TLC grade silica gel using a mixture of methanol and dichloromethane as solvent(equation 2.74). Even though a relatively large difference in polarity exists between31 and 302, the separation of these salts by chromatography was very difficult.Repetitive chromatographies and filtration through a microporous membrane(to remove any residual silica particles [Nylon membrane 0.2 gm, # C619000 fromChromatographic Specialties Inc. Brockville, Ont.]) had to be done in order to obtainpure (-)-agelasine B (31). The physical data of the synthetic (-)-agelasine B (31) wasin good agreement with that reported for the natural (-)-agelasine B (31) and with thenatural (-)-agelasine B (31) isolated from the Agelas sponge obtained from theresearch group of Dr. Andersen (see Table 2.28).218 The natural and synthetic(-)-agelasine B (31) had identical behavior by TLC. The 1 H NMR spectra of(-)-agelasine B (31) are presented in Figures 2.30 (synthetic 31, 400 MHz), 2.31(natural 31, 400 MHz), 2.32 (Tokoroyama's synthetic 31, 100 MHz), and 2.33(Tokoroyama's natural 31, 100 MHz).302Br -Me 1) Hg, -1.0 V^N -FN .^(vs. Ag/AgCI)N^NaOAc bufferN— IMeO Ni-j2 equiv of e -H2) NaCI, H2O53%1 64Table 2.28: Comparison of the Reported Spectral Data for (-)-Agelasine B (31) andthe Spectral Data for the Synthetic and Natural (-)-Agelasine B (31)Data^0^Synthetic 31 Natural 31 I^Reported 31M.P. 165-170 °C 170-175 °C 167-170 °Ca , bIR (1% KBr, cm -1 )3329 3350 3370a,c3146 3160 31601646 1646 16401592 1592 15901473 1462 14601301 1302 13001096 1086 10901 H NMR400 MHz8 (mutt., # of H, J in Hz)0.69 (s, 3H) 0.69 (s, 3H) 0.70 (s, 3H)a0.75 (d, 3H, 6) 0.75 (d, 3H, 6) 0.76 (d, 3H, 5.2)0.98 (s, 3H) 0.98 (s, 3H) 0.97 (s, 3H)1.55 (m, 3H) 1.55 (m, 3H) 1.57 (s, 3H)1.84(s, 3H) 1.84(br s, 3H) 1.86 (br s, 3H)0.70-2.1 (m, 14H) 0.70-2.1 (m, 14H) 0.70-2.2 (m, 14H)4.08 (s, 3H) 4.08 (s, 3H) 4.10 (s, 3H)5.16 (br s, 1H) 5.16 (br s, 1H) 5.17 (br s, 1H)5.40 (br t, 1H, 6.5) 5.40 (br t, 1H, 6.5) 5.41 (br t, 1H, 6.5)5.72 (d, 2H, 6.5) 5.72 (d, 2H, 6.5) 5.71 (br d, 2H, 6.5)6.51 (br s, 2H)d , e 6.69 (br s, 2H)d ,e 6.84 (br s, 2H)d ,e8.50 (s, 1H) 8.50 (s, 1H) 8.50 (s, 1H)11.19 (s, 1H)d ,e 11.10 (s, 1H)d ,e 10.89 (s, 11913C NMR125.8 MHz16.10 16.00 16.0 (q)a ,f17.65 17.57 17.5 (q)17.99 17.94 17.9 (q)18.36 18.31 18.3 (t)18.39 18.28 18.3 (q)19.96 19.89 19.9 (q)26.93 26.85 26.9 (t)27.47 27.39 27.5 (t)32.02 31.96 32.0 (q)33.14 33.09 33.1 (t)36.30 36.26 36.3 (d)36.32 36.28 36.3 (t)36.81 36.76 36.8 (t)6 38.20 38.15 38.2 (s)38.72 38.68 38.7 (s)46.43 46.40 46.4 (d)48.78 48.72 48.7 (t)109.95 109.9 109.7 (d)115.86 116.0 115.7 (d)120.38 120.3 120.3 (d)142.00 142.3 141.7 (d)144.50 144.5 144.3 (s)147.66 147.6 147.5 (s)149.63 149.6 149.5 (s)152.31 152.3 152.5 (s)156.22 156.3 156.0 (d)L R MS M+-CI(422) M+-C1(422) M4--HCI(421)aHRMS (421.3202)g 421.3201 421.3204 421.3204a165UV (MeOH) 272.5 nm, E 10429 272.5 nm, E 8420^272 nm, e 8240a[ a ]p (MeOH) -27.2° (1.00, 25 °C) ^h^I-21.5° (1.0)a-34.8° (1.0, 21 °C)ba Reference 192b; b Reference 31; c In CHCI3; d Exchanged with D20; 19e The chemical shifts of the adeninium hydrogens vary with concentration in CDCI3; 181f 22.5 MHz in CDCI3, 5 (multiplicity of the off resonance hydrogen decoupled 13C NMR spectra);g Calculated value for C261-139%; h Not enough material.In summary, the total synthesis of enantiomerically pure (-)-agelasine B (31)was accomplished in 23% yield from the TIPS-ether 282. A new, direct preparation ofthe allyl bromide 300 from the TIPS-ether 282 was used in conjunction with amodification of Tokoroyama's coupling procedure of the bromide 300 withN6-methoxy-9-methyl adenine (301) to give the methoxy-protected adenine derivative302 in acceptable yields. Finally, a new electrolytic process was developed toremove the methoxy protecting group in a mild, controllable fashion to yield thedesired (-)-agelasine B (31). The identity of the synthetic (-)-agelasine B (31) wasconfirmed by comparison of its spectral data with that reported in the literature, andwith a sample of natural (-)-agelasine B (31) isolated from an Age/as species sponge.315. IA^4. 0^3. 0^2.0^1.0H2OCI -+ N—MeH2N-(\10.0^9.0 8. 0^7. 011.06. 0PPM",.Figure 2.30 400 MHz 1 H NMR Spectrum of the Synthetic (-)-Agelasine B (31)CH2Cl24,Nialftwoword11. 0 10.0^9.0 8.0^7.0PPM5 . u .0^3.0 2.0^1. 0Figure 2.31 400 MHz 1 H NMR Spectrum of the Natural (-)-Agelasine B (31)CI' N—Me4.10jr io8.500.99qq 0.711tf'ttrvw4104,"•444-tmes-0~A•mopiviFigure 2.32 100 MHz 1 H NMR Spectrum of Tokoroyama's Synthetic (-)-Agelasine B (31)4.071.86 0.97037 0.690 6110.531.55Figure 2.33 100 MHz 1 H NMR Spectrum of Tokoroyama's Natural (-)-Agelasine B (31)3. CONCLUSIONIn summary, we have prepared the enantiomerically pure trimethylstannylenone 64 and have demonstrated that it serves as an effective substrate formethylenecyclohexane, methylenecyclopentane and (Z)-ethylidenecyclopentaneannulation sequences. The resulting bicyclic ketones 124, 132 and 133 wereconveniently destannylated using lithium in ammonia to give the alcohols 165, 175and 176. The scope and the compatibility of the destannylation procedure with otherfunctional groups was demonstrated by carrying out the destannylation of a series ofcompounds containing hydroxyl, olefinic, and ether functions.The I3-trimethylstannyl cyclohexanones obtained during the course of the workdescribed in this thesis were studied by circular dichroism. The results obtainedconfirmed unambiguously Hudec's conclusion that, in 0-trimethylstannylcyclohexanones, an equatorially oriented Me3Sn group is strongly consignate and anaxially oriented Me3Sn moiety is weakly dissignate.The alcohol 165 was used as an intermediate for the total syntheses of thetrans-clerodane diterpenoids (-)-kolavenol (65) and (-)-agelasine B (31) (Scheme3.1). The alcohol 165 was converted efficiently in five steps to the ether 214. Thiscompound was transformed into the iodide 213, which was converted into theorganozinc species 318. Palladium(0)-catalyzed coupling of 318 with the vinyliodide 265 gave 282, which was easily transformed into (-)-kolavenol (65).(-)-Kolavenol (65) was thus prepared in 14 steps and an overall yield of 19.4% fromthe enantiomerically pure cyclohexenone 64.170165 RR = H, 175R = Me, 176171The TIPS ether 282 was converted directly into the allylic bromide 300, which,upon reaction with the adenine derivative 301, gave 302 (Scheme 3.1). A new,mild electrochemical reduction of 302 was developed to yield (-)-agelasine B (31) in atotal of 16 steps and 5.6% overall yield from the enone 64.''''SnMe3R = H, 132R R = Me, 1331 6 5 -71-.1-- _/—OTIPSI /+2 1 4 265213 R = I318 R = ZnBrR = OTIPS 282R = OH 65R = Br 300\N'Me(N._ NMeO NH 301172Scheme 3.11734. EXPERIMENTAL4.1. GENERAL4.1.1. Data Acquisition and PresentationProton nuclear magnetic resonance ( 1 H NMR) spectra were recorded on eithera Varian XL-300 spectrometer or on Bruker AC-200, WH-400 or AMX-500spectrometers using deuteriochloroform (CDCI3) as the solvent and tetramethylsilaneor chloroform (8 7.25) as the internal standard, unless otherwise noted. Signalpositions are given in parts per million (8) from tetramethylsilane. Coupling constants(J) are given in Hertz (Hz). The multiplicity, number of protons, coupling constant(s),and assignments (when known) are given in parentheses. Abbreviations used are: s,singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. When a hydrogen wasobserved to be coupled with the same coupling constant to two, three, four or fiveprotons which are chemically and magnetically non-equivalent, the designation dd,ddd, dddd and dddt are used instead of using t, q, quintet and sextet, respectively. Forcompounds exhibiting AB and ABX type spin systems, the quoted values for chemicalshifts and coupling constants are measured as if they were first order systems,although these values only approximate the real values. 219 Selective decouplingexperiments refer to 1 H- 1 H spin decoupling experiments. Tin-hydrogen couplingconstants (ii Sn-H) are given as an average of the 117Sn and 119Sn values.The nuclear Overhauser enhancement difference experiments (NOE) 220 wererecorded on a Bruker WH-400 NMR spectrometer.1 H- 1 H Homonuclear correlation experiments (COSY) 73 were recorded onBruker WH-400 or AC-200 spectrometers. The heteronuclear 1 H- 13C shift correlation174experiments (HSC) 221 were recorded on a Varian XL-300 spectrometer. 1 H- 13 CHeteronuclear multiple quantum coherence experiments (HMQC),222 th e 1H-13Cheteronuclear multiple bonds connectivity experiments (HMBC) 222 (2-3 bondscorrelations) and (ROESY)223 were recorded on Bruker AMX-500 spectrometer.Carbon nuclear magnetic resonance ( 13 C NMR) spectra and the attachedproton test experiments (APT) 76 were recorded on a Varian XL-300 spectrometer at75.3 MHz or on Bruker AM-200 (50.3 MHz), AM-400 (100.4 MHz) or AMX-500 (125.8MHz) spectrometers, using deuteriochloroform as the solvent, unless otherwise noted.Signal positions are given in parts per million (8) from tetramethylsilane, measuredrelative to the chloroform signal at 8 77.0. 117 Signals with negative intensity in theattached proton test are so indicated in brackets (-ve) following the chemical shift.Fluorine nuclear magnetic resonance ( 19F NMR) spectra were recorded on aBruker AM-200 (188.3 MHz) spectrometer, using deuteriochloroform as the solvent.Signal positions are given in parts per million (8) from the spectrometer with anexternal trifluoroacetic acid reference.Infrared (IR) spectra were recorded from liquid films between sodium chlorideplates or from potassium bromide pellets using a Perkin-Elmer 1710 Fourier TransformSpectrophotometer with internal calibration.Low and high resolution electron impacts mass spectra (LRMS, HRMS andFABMS respectively) were recorded on a Kratos MS50 mass spectrometer (70 eV).The ion type is presented followed by its relative intensity (ex.: LRMS: M+(110), 9855%) Desorption chemical ionization mass spectra (DCIMS) were recorded with aDelsi Nermag R-10-10 C mass spectrometer. The following atomic mass were used tocalculate the mass of the fragments observed in the HRMS: 1 H 1.007825;12C 12.0000; 14 N 14.00307; 16 0 15.99491; 19 F 18.99840; 28 5i 27.97693;32S 31.97207; 35C1 34.96885; 120Sn 119.9021; 127 1 126.9044.Elemental analyses were performed on a CARLO ERBA CHN elementalanalyzer, Model 1106, by the UBC Microanalytical Laboratory.175Circular dichroism spectra (CD), optical rotatory dispersion spectra (ORD) andspecific rotations at the sodium D line (589.3 nm) or at the wavelength X. and thein (dezgcm2)temperature t ([ a ID or Xt^where deg = degree (°) and dag = decagram.)were measured on a JASCO J710 spectropolarimeter. The specific ellipticity at the(deg•cm 2 \wavelength A and the temperature t ([ IP ]xt in^and the peak width at halfdag ,height (A112) are reported in the following manner: A (specific ellipticity, A112).Ultraviolet spectra (UV) were recorded on a Perkin Elmer Lambda 2 UV/VISspectrophotometer. The Amax and the extinction coefficient are reported.Melting points were measured on a Fisher-Johns melting point apparatus andare uncorrected. Distillation temperatures refer to air-bath temperatures of Kugelrohrdistillations and are uncorrected.Gas-liquid chromatography (GLC) analyses were performed on Hewlett-Packard Model 5880A or 5890 capillary gas chromatographs, each having a flameionization detector and a fused silica column, either -20 m x 0.21 mm coated withcross-linked SE-54 or -25 m x 0.20 mm coated with 5% phenyl-methyl silicone,respectively.Thin layer chromatography (TLC) was carried out on commercial aluminiumbacked silica gel 60 plates (E. Merck, type 5554, 0.2 mm). Reverse phase TLC wasperformed on commercially available, glass backed plates (Whatman, typeKC18/KC18F). Visualization was accomplished with ultraviolet light (254 nm), asolution of phosphomolybdic acid (PMA) in EtOH (20% w/v, Aldrich), a solution ofvanillin in a sulfuric acid-EtOH mixture (vanillin: 6% vanillin w/v, 4%sulfuric acid and10% water, v/v, in EtOH), iodine or Dragendorff reagent. 224 Flash chromatography88was done on 230-400 mesh silica gel (E. Merck, Silica Gel 60). "TLC grade silicachromatography" 225 was done on 10-50 1.1m Type H silica (S-6628, Sigma). Radialch romatography 128 was done on a Chromatotron® Model 7924 using 1 and 2 mmthick radial plates (silica gel 60, PF 254, with calcium sulfate, E. Merck #7749).176All compounds that were subjected to high resolution mass spectrometry andelemental analysis were homogeneous by TLC analyses and >95% pure by GLCanalyses.Unless otherwise stated, all reactions were carried out under an atmosphere ofdry argon using glassware that had been thoroughly flame or oven (-140 °C) dried.The glass syringes for handling anhydrous solvent and reagents were oven driedwhile the plastic syringes, the needles and the Teflon® cannulae were flushed with astream of dry argon prior to use.Concentration, evaporation or removal of the solvent under reduced pressure(water aspirator) refer to solvent removal via a Bachi rotary evaporator at -15 torr.Cold temperatures were maintained by use of the following baths: 0 °C,ice/water; -10 °C, ice/acetone; -20 °C, -30 °C, -40 °C and -48 °C, aqueous calciumchloride/CO2 ( 27, 35, 43 and 47 g CaCO3/100 ml H2O, respectively) 226 ; -60 °C,chloroform/CO2; -78 °C, acetone/CO2; -98 °C, Me0H/liquid nitrogen.This thesis was prepared on a Macintosh computer using the word processorMicrosoft Word 4.0 and 5.0. The drawings were done using the chemical drawingprogram ChemDrawn" version 2.1.3 from Cambridge Scientific Computing.4.1.2. Solvents and ReagentsSolvents and reagents were purified and dried using known procedures.227Petroleum ether refers to a hydrocarbon mixture with by 30-60 °C. Ether refers todiethyl ether. Ether and THE were distilled from sodium benzophenone ketyl. DMEwas distilled from the sodium/potassium benzophenone ketyl. Carbon tetrachloridewas refluxed and then distilled from phosphorus pentoxide. Benzene,dichloromethane, diisopropylamine, N,N-diisopropylethylamine, DMA, DMF, DMPU,DMSO, HMPA (WARNING: carcinogenic), TMP, acetonitrile, 1,2-dibromoethane,177pyridine, toluene and triethylamine were refluxed over and then distilled from calciumhydride. HMPA, DMF, DMPU and pyridine were stored over 4A molecular sieves.Magnesium was added to Me0H and, after refluxing the mixture, the Me0H wasdistilled from the resulting solution of magnesium methoxide. EtOH, diethylene glycol,triethylene glycol and ammonia were treated with sodium and distilled. 2-Methyl-2-propanol was passed through a short column of flame dried 4A molecular sieves.Trimethylsilyl chloride (TMSCI) was dried by refluxing over calcium hydride andwas distilled before use.Solutions of methyllithium (LiBr complex in ether), butyllithium and tert-butyllithium (both in hexane) were obtained from Aldrich Chemical Co., Inc. and werestandardized using either the procedure of Kofron and Baclawski 228 or the one ofSuffert.229Lithium diisopropylamide (i-Pr2NLi) and lithium 2,2,6,6-tetramethylpiperidide(LTMP) solutions were prepared by the addition of a solution of butyllithium (1.0 equiv)in hexane to a solution of diisopropylamine or TMP (1.1 equiv) in THE at -78 °C. Theresulting colorless or faintly yellow solution was stirred at 0 °C for ten minutes beforeuse.Copper(I) cyanide was washed sequentially with anhydrous Me0H andanhydrous ether and then was kept under vacuum (0.1 torr, vacuum pump) overnightat room temperature. Copper(I) bromide-dimethyl sulfide complex was prepared bythe method described by Wuts. 230lodomethane, chloroform and deuteriochloroform were dried by passingthrough a short column of oven dried basic alumina (activity I).Aqueous ammonium chloride solution (pH 9) was prepared by addition of 50mL of aqueous ammonium hydroxide (58%) to 950 mL of saturated aqueousammonium chloride.4.2. EXPERIMENTAL PROCEDURES4.2.1. Methylenecyclohexane, Methylenecyclopentane and (Z)-Ethylidenecyclopentane Annulation Sequences4.2.1.1. Preparation of (-)-(R)-5-Methyl-2-cyclohexen-1-one (55) and 3-Methyl-2-cyclohexen-1-one (73)50,51,58,62,64A) Preparation of the Say' Enol Ethers 71 and 7217871 72A cooled (-78 °C) solution of TMSCI (59 mL, 470 mmol, 5 equiv) in THE(180 mL) was added over a period of 20 min to a stirred solution of LTMP (110 mmol,1.2 equiv) in THE (180 mL) at -78 °C via a wide bore Teflon cannula. A cold (-78 °C)solution of (R)-(+)-3-methylcyclohexanone (10.5 g, 94 mmol) in THE (180 mL) wasadded via a Teflon® cannula over a period of 30 min. The mixture was stirred at-78 °C for 15 min. Triethylamine (79 mL, 564 mmol, 6.0 equiv) was added, themixture was stirred 5 min and then was poured into a stirred mixture of saturatedaqueous sodium bicarbonate (1.5 L) and petroleum ether (600 mL). The two layerswere separated and the aqueous layer was extracted twice with petroleum ether (1.5 Ltotal volume). The combined organic layer was washed with 1 M aqueous citric aciduntil it was neutral. The organic layer was dried over anhydrous sodium sulfate andthen carefully removed under reduced pressure (-25 °C bath). The resultant colorlessoil was fractionally distilled (76-82 °C/18 torr) to give 16.0 g (93%) of a 4:1 mixture ofsay' enol ethers 71 and 72, respectively. The mixture gave the following selectedspectral data: IR (neat): 2956, 2926, 2844, 1671, 1457, 1370, 1252, 1186, 894, 846cm -1 ; 1 H NMR (300 MHz) 5: 0.12 and 0.18 (two s, 9H, Me3Si), 0.92 and 0.95 (two d,1793H, J ---- 6 Hz), 4.72 (m, 0.16 H, H-a, 72), 4.82 (m, 0.84 H, H-a,71); LRMS: M+(184)21.2%; HRMS calcd for Ci 01-1200Si: 184.1283, found: 184.1288; TLC: 9:1hex:ether, PMA.B) Preparation of the a-Seleno Ketones 82, 83, 84, and 85SePh82, 83 84, 85 Bromine (2.45 mL, 48 mmol, 0.55 equiv) was slowly added via an additionfunnel to a cold (0 °C) solution of diphenyldiselenide (15.9 g, 50 mmol, 0.57 equiv) inether (180 mL). The resultant solution of phenylselenenyl bromide was transferred viaTeflon® cannula to a cold (-78 °C) solution of the silyl enol ether mixture (71, 72, 16 g,87 mmol) in ether (90 ml). The dark red mixture was stirred for 10 min at -78 °C and for10 min at 0 °C. The solution was cooled to -78 °C and then was poured into avigorously stirred mixture of saturated aqueous sodium bicarbonate (1 L) and ether(200 mL). The layers were separated and the aqueous layer was extracted twice withether (2 x 200 mL). The combined yellow organic layers were dried with sodiumsulfate. The solvent was removed under reduced pressure and the dark orange oilwas stirred under vacuum (vacuum pump, 0.1 torr) for 1 h to remove the residual3-methylcyclohexanone. The excess diphenyldiselenide was removed by flashchromatography (600 g silica gel, 9:1 petroleum ether:ether) to give a mixture ofisomeric a-phenylseleno ketones 82, 83, 84 and 85 (23 g, -100% yield). TLC: 9:1hex:ether, UV, PMA.C) Preparation of the Cyclohexenones 55 and 73H-6a1800 H-4a Me-7^H-6eH-4eH-3 H-2H-5 5 57^45573Aqueous hydrogen peroxide (30%, 24 g, -200 mmol, 4.6 equiv in 25 mL ofwater) was added slowly to a solution of the a-phenylseleno ketone mixture (11.6 g,43 mmol) in dichloromethane (200 mL). (WARNING: there is an induction period).An exothermic reaction took place and the flask was cooled with a -10 °C bath. Theinternal temperature of the reaction mixture was kept below 42 °C. The mixture wasstirred an additional 10 min at room temperature and was poured into a mixture ofsaturated aqueous sodium bicarbonate (1.5 L) and dichloromethane (400 mL). Thelayers were separated and the top layer was extracted twice with dichloromethane (2 x200 mL). The combined organic layers were washed with water (1 L) and dried oversodium sulfate. The solvent was removed by distillation through a 50 cm Vigreuxcolumn. The residual oil was purified by flash chromatography (160 g of silica gel, 9:1petroleum ether:ether). The most polar fractions were concentrated to give -1 g(-20%) of 3-methylcyclohex-2-enone (73). The less polar fractions were combinedand the solvents were distilled using a 50 cm Vigreux column to give a slightly yellowoil. The oil was distilled (50-90 °C/15 torr) to give 3.3 g (68%) of (-)-(R)-5-methyl-2-cyclohexen-1-one (55), a colorless oil which exhibited IR (neat): 3037, 2959, 1680,1618, 1458, 1429, 1392,880, 735 cm -1 ; 1 H NMR (400 MHz) 8: 1.07 (d, 3H, J=5.6 Hz,Me), 2.01-2.30 (m, 3H, H-4a, H-5, H-6a), 2.38-2.54 (m, 2H, H-4e, H-6e), 6.04 (m, 1H,H-2), 6.96 (m, 1H, H-3); 13C NMR (50.3 MHz) 8: 20.87 (-ve, Me), 30.02 (-ve, C-5),Me-8 H-6eH-30H-5H-4e""'SnMe3^H-I6aSnMe39 2^H-4a^H-28Me-718133.69, 45.95 (C-4, C-6), 129.23 (-ve, C-3), 149.58 (-ve, C-2), 199.57 (C-1); LRMS:M+(110) 51.5%; HRMS calcd for C7H100: 110.0732, found: 110.0741; [ a ] p30-86.9°, c = 2.6 in chloroform (lit., -90.1° c = 2.55 chloroform) 50 ; CD: c = 2.6chloroform: [ VO: 316.0 nm (+377.4, 32.2 nm), 352.6 nm (-428.1, 25.6 nm).4.2.1.2. Preparation of (+)-(2R.3R.5S)-2.5-Dimethy1-3-trimethylstannylcyclohexan-1- one (92)65a,68,70,231A solution of methyllithium (1.63 M, 100 mL, 163 mmol, 2 equiv) was added to acold (-20 °C) solution of hexamethylditin (33.7 mL, 163 mmol, 2 equiv) in THF(500 mL). The mixture was stirred for 20 min at -20 °C, for 5 min at 0 °C, and then wascooled back to -20 °C to give a faint yellow solution of trimethylstannyllithium (86).Solid copper(I) phenyl sulfide 232 (28.2 g, 163 mmol, 2 equiv) was added in one portionto the trimethylstannyllithium (86) solution and the mixture was stirred at -20 °C for20 min to give a dark red solution of the (trimethylstannyl)(phenylthio)cuprate (89).A solution of freshly distilled enone 55 (9 g, 82 mmol) in THF (80 mL) was added, viacannula, over a period of 10-20 min. The mixture was stirred 1 h at -20 °C and wasthen cooled to -78 °C. lodomethane (51 mL, 817 mmol, 10 equiv) and HMPA(WARNING: carcinogenic, 28.5 mL, 163 mmol, 2 equiv) were successively addedand the mixture was stirred 30 min at -78 °C. The solution was warmed to -20 °C andmixed at this temperature for an additional 40 min. Florisil® (500 g) and ether(500 mL) were mixed together and the mixture was packed into a chromatographiccolumn. The cold reaction mixture was poured into the ether layer at the top of the182column. The solvents were eluted and the Florisil® was washed with an additional500 mL of ether. The combined eluants were concentrated and the dark oil waspassed through a column of Florisil® (200 g) and the column was washed with 500 mLof ether. The combined eluants were concentrated and the residue was stirred undervacuum (vacuum pump, 0.1 torr) for 2 h to remove the thioanisole. The mixture waspurified by flash chromatography (1 kg silica gel, 9:1 petroleum ether:ether) and theacquired oil was distilled (80-110 °C/0.07 torr) to give 18.4 g (78%) of 92, a colourlessoil which exhibited IR (neat): 2960, 2909, 1708, 768, 526 cm -1 ; 1 H NMR (400 MHz) 6:0.11 (s, 9H, 2J Sn-H = 52 Hz, Me3Sn), 0.97 (d, 3H, J = 7 Hz, Me-8), 1.02 (d, 3H,J=6.5 Hz, Me-7), 1.62 (ddd, 1H, J = 12, 12, 3.5 Hz, H-3), 1.71 (dddd, 1H, J = 14, 3.5,3.5, 2 Hz, H-4e), 2.01 (ddd, 1H, J. 14, 12, 4 Hz, H-4a), 2.17 (ddd, 1H, J=13,3.5, 2 Hz,H-6e), 2.41-2.51 (m, 2H, H-2, H-5), 2.57 (dd, 1H, J = 13, 6 Hz, H-6a); COSY: seeTable 2.1; 1 H NMR decoupling experiments (400 MHz): irradiation of the signal at8 0.97 (Me-8) led to simplification of the signal at 8 2.41-2.51 (H-5); irradiation at8 1.02 (Me-7) produced a doublet at 6 2.45 (J = 12 Hz, H-2); NOE differenceexperiments: Irradiation at 6 0.97 (Me-8) led to the enhancement of signals at 6 1.62(H-3), 0 1.71 (H-4e), 8 2.17 (H-6e), 0 2.47 (H-5); irradiation at 0 1.62 (H-3) led to theenhancement of signals at 6 0.97 (Me-8), 0 1.02 (Me-7) [Note, H-4e is too close to H-3to see an enhancement]; 13C NMR (75.3 MHz) 0: -10.13 (-ve, 1,-/ Sn-c = 320 Hz,Me3Sn), 15.94 eve, Sn-C = 60 Hz, Me-7), 18.66 eve, Me-8), 29.22 eve,Sn-C = 375 Hz, C-3), 35.07 (-ve, C-5), 35.41 ( 2 J Sn-C = 40 Hz, C-4), 48.28 (C-6),48.32 (-ve, C-2), 214.14 (C-1); LRMS: M+(290) 5.9%; HRMS calcd for C11H220Sn:290.0692, found: 290.0693; Anal. calcd for C11 H220Sn: C 45.72, H 7.67, found:C 45.89, H 7.59; [ a ]D28 +134.1°, c = 1.022 in MeOH; CD: c = 1.022 in MeOH:[ ]A,28 : 299.7 nm (+18030, 34.5 nm), 232.6 nm (-6789, 6.0 nm).H-4a^H-6aMe-8H-207H-6eH-4e H_3#11SnMe3H-5^RA _,9 3^SnMe3 me"1834.2.1.3. Preparation of (-)-(2S.3R.5S)-2.5-Dimethy1-3-trimethylstannylcyclohexan-1- one (93) Sodium hydride (5 mg, 0.13 mmol, 0.3 equiv, 60% in oil) was added toa solution of the cyclohexanone 92 (121 mg, 0.42 mmol) in Me0H (2.5 mL). After themixture had been stirred at room temperature for 26 hours, the ratio between 92 and93 became constant at 1:1.1 (GLC) and some decomposition was observed. Brine(10 mL) was added and the mixture was extracted with ether (3 x 10 mL). The etherextracts were dried with magnesium sulfate and concentrated to give 105 mg ofcolourless oil. The oil was purified by flash chromatography (10 g silica gel,30:67.5:0.5 dichloromethane:hex:ether). The more polar fraction (65 mg, 54%) wasa mixture of 92 and 93. The less polar fraction was distilled (85-95 °C/0.1 torr) to give16.6 mg (14%) of pure cyclohexanone 93, a colourless oil which exhibited IR (neat):2963, 2924, 2824, 1712, 769, 524 cm -1 ; 1 H NMR (400 MHz) 5: 0.11 (s, 9H,2 J Sn-H = 52 Hz, Me3Sn), 1.01 (d, 3H, J = 6 Hz, Me-8), 1.04 (d, 3H, J = 6 Hz,4J sn H = 4 Hz, Me-7), 1.75-1.85 (m, 1H, H-5), 1.85 (ddd, 1H, J = 12.5, 12, 5 Hz,H-4a), 1.97 (ddd, 1H, J . 13, 12.5, 1 Hz, H-6a), 2.00-2.05 (m, 2H, H-3, H-4e), 2.40(ddd, 1H, J = 13, 4, 2 Hz, H-6e), 2.77 (dqd, 1H, J . 6.5, 6, 1 Hz, 3J sn-H = 132 Hz, H-2);COSY: see Table 2.2; Selective decoupling experiments: irradiation of the signal at5 1.04 (Me-7) produced a doublet of doublets at 5 2.77 (J = 6.5, 1 Hz, 3 J Sn-H =132 Hz, H-2); irradiation at 8 2.77 (H-2) simplified the signals at 6 1.04 (s, 4 ../ Sn-H =4 Hz, Me-7), 1.97 (dd, J = 13, 12.5 Hz, H-6a), 2.00-2.05 (H-3); 13C NMR (75.3 MHz)6: -8.80 78 (-ve, 1 J sn-c = 315 Hz, Me3Sn), 15.78 (-ve, 3J sn - c = 20 Hz, Me -7), 22.32(-ye, Me-8), 33.54 (-ye, 1 J sn-c = 367 Hz, C-3), 35.43 (-ye, 3J sn-c = 20 Hz, C-5), 38.44184(2,/ Sn-c = 10 Hz, C-4), 48.37 (-ve, C-2), 49.90 (C-6), 212.08 (C-1); LRMS: M+(290)8.7%; HRMS calcd for C1iH220Sn: 290.0692, found: 290.0684; Anal. calcd forC11H220Sn: C 45.72, H 7.67, found: C 45.78, H 7.49; [ a )D 25 -44.1°, c = 0.935 inMeOH; CD: c = 0.935 in MeOH: [ T Jx25 : 300.0 nm (+973.2, 35.5 nm), 221.2 nm(-2127, 27.0 nm).4.2.1.4. Preparation of (-)-(5R.6R)-3.6-Dimethy1-5-trimethylstanny1-2-cyclohexen-1- one (64)59A) Preparation of the Trimethylstannyl Silyl Enol Ether 9999A solution of the 3-trimethylstannylcyclohexanone 92 (8.83 g, 30.6 mmol) inTHE (18 mL) was added over a period of 15 min, via cannula, to a freshly preparedsolution of i-Pr2NLi (36.6 mmol, 1.2 equiv) in THE (60 mL) at -78 °C. The mixture wasstirred for 1.5 h at -78 °C and TMSCI (7.8 mL, 61 mmol, 2 equiv) was added. Thesolution was warmed to room temperature and the white suspension wasconcentrated. Dry pentane (200 mL) was added and the suspension was trituratedand then was filtered through Celite® and the Celite® was washed with pentane. Thepentane was removed under reduced pressure and the pentane/Celite® treatmentwas repeated. The residual oil was distilled (85-95 °C/0.5 torr) to give -11 g (-100%)of the silyl enol ether 99 as a colourless oil. No further purification was done and thesilyl enol ether was used directly for the next step. The oil gave the following selectedspectral data: IR (neat): 2958, 2869, 2840, 1660, 1455, 898, 847, 760, 524 cm -1 ;1 H NMR (400 MHz) 8: 0.07 (s, 9H, 2 J sn-H = 30 Hz, Me3Sn), 0.19 (s, 9H, Me3Si), 0.97H-5H-4e Me-70H-2OMe-8''''SnMe3^Me3Sn I6 4 H-4a H-6185(d, 3H, J. 7.6 Hz, Me), 1.09 (d, 3H, J. 7.6 Hz, Me), 1.37-1.43 (m, 1H), 1.52-1.58 (m,1H), 1.79-1.87 (m, 1H), 2.14-2.21 (m, 2H), 4.68 (d, 1H, J. 2.8 Hz, H-2).B) Preparation of the Trimethylstannylcyclohexenone 64A solution of DDQ (13.87 g, 61.1 mmol, 2 equiv) in benzene (330 mL) wasadded over a period of 1.5 h, via cannula, to a mixture of collidine (8.5 mL, 64.1 mmol,2.1 equiv) and the silyl enol ether 99 (11 g, 30.5 mmol) in benzene (90 mL) at roomtemperature. The black mixture was stirred for an additional 1.5 h after the end of theaddition. The suspension was filtered through a loose plug of cotton wool directly intoa mixture of saturated aqueous sodium bicarbonate (1.5 L) and ether (1 L) and thephases were separated. The aqueous layer was extracted with ether (3 x 250 mL).The combined organic extracts were washed successively with saturated aqueoussodium bicarbonate (200 mL) and brine (300 mL). The ether extract was dried oversodium sulfate and concentrated. The residual material was purified by flashchromatography (275 g silica gel, 85:15 hex:ether). The resulting oil was distilled (70-110 °C/0.07 torr) to give 5.0 g (57%) of the enone 64 as a low melting solid (mp: 22-24°C). The compound exhibited IR (neat): 2976, 2911, 1669, 1437, 1377, 1227, 768,526 cm -1 ; 1 H NMR (400 MHz) 8: 0.08 (s, 9H, 2,./ Sn-H = 52 Hz, Me3Sn), 1.16 (d, 3H,J.7 Hz, Me-8), 1.69 (ddd, 1H, J. 12, 10, 6 Hz, H-5), 1.94 (s, 3H, Me-7), 2.35-2.50(m, 3H, H-6, H-4a, H-4e), 5.86 (br s, 1 H, H-2); 1 H NMR (400 MHz, C6D6) 8: 0.03 (s,9H, 2J Sn-H = 52 Hz, Me3Sn), 1.21 (d, 3H, J. 7 Hz, Me-8), 1.34 (ddd, 1H, J. 12, 9,6 Hz, H-5), 1.45 (s, 3H, Me-7), 1.90-2.00 (m, 2H, H-4a, H-4e), 2.17-2.26 (m, 1H, H-6),5.96 (br s, 1H, H-2); 13C NMR (75.3 MHz) 8: -10.36 (-ve, 1 J sn-c = 340 Hz, Me3Sn),18616.54 (-ve, 3J sn-c = 23 Hz, Me-8), 23.81 (-ve, 4J S n-C = 6 Hz, Me-7), 28.87 (-ve,i siSn-c = 400 Hz, C-5), 35.10 (2 ,./ sn-c = 11 Hz, C-4), 43.87 (-ve, 24./ sn-C = 16 Hz, C -6),125.95 (-ve, 4Jsn_c = 9 Hz, C-2), 162.62 (C-3), 202.18 (C-1); HSC: see Table 2.3;LRMS: M -4-(288) 7.0%; HRMS calcd for C11 H200Sn: 288.0535, found: 288.0543;Anal. calcd for CiiH200Sn: C 46.04, H 7.02, found: C 46.23, H 7.12; [ a ]D 29 -45.2°,c = 1.072 in MeOH; CD: c = 1.072 in MeOH: [ W ]x 29 : 329.5 nm (+2365, 44 nm),264.3 nm (+2666, -'8.5 nm).4.2.1.5. Preparation of the 5-Chloro-2-trimethylstanny1-1-pentene (12)87a-c,233A solution of methyllithium (1.27 M, 245 mL, 311 mmol, 1 equiv) was added toa cold (-20 °C) solution of hexamethylditin (64 mL, 311 mmol, 1 equiv) in THE (1.3 L).The mixture was stirred for 30 min at -20 °C to give a faint yellow solution oftrimethylstannyllithium (86). The solution was cooled to -78 °C (15 min) and solidcopper(I) bromide-dimethyl sulfide complex (63.9 g, 311 mmol, 1 equiv) was added inone portion. The dark red solution was stirred at -78 °C for 30 min and 5-chloro-1-pentyne (32.9 mL, 311 mmol) was added over a period of 30 min, via a Teflon®cannula. The mixture was stirred for 8 h at -78 °C and then glacial acetic acid(88.9 mL, 1.55 mol, 5 equiv) was added. The solution was stirred for 15 min at -78 °Cand aqueous ammonium chloride (pH 9, 100 mL) was added and the mixture waswarmed to room temperature (30 min). The content of the flask was poured into a 4 LErlenmeyer flask containing a mixture of aqueous ammonium chloride (pH 9, 1 L) andether (1 L) and the mixture was efficiently stirred overnight. The layers were separatedand the dark blue layer was extracted with ether (2 x 1 L). The combined etherextracts were washed successively with ammonium chloride pH 9 solution (1 L) andCI 5 ' H-11DH-1'aH-6eMe-8H-4e100Me-7H-6aSnMe3 H-2H-4a187brine (1 L). The organic layer was dried with magnesium sulfate and concentrated togive a colourless oil (75 g). The oil was purified by a slow (7 h) chromatography onsilica gel (2.25 kg, petroleum ether) to give 66.2 g (68%) of 5-chloro-2-trimethylstannyl-1-pentene (12) as colourless oil after distillation (100-105 °C/30 torr). The spectraldata derived from this compound were identical with those reported previously. 97c4.2.1.6. Preparation of (+)-(2R.3R.5S)-5-(5-Chloro-2-pent-1-eny1)-2.5-dimethy1-3-trimethylstannylcyclohexanone (100) and (2R.3R.5R)-5-(5-Chloro-2-pent-1- n I -2^im th I- -trimeth I tann lc cl•h x non 101 and + 2R R2.5.5-Trimethy1-3-trimethylstannylcyclohexanone (1021A) Preparation of the Chloro Ketone 100A solution of methyllithium (1.5 M, 607 pit, 0.91 mmol, 1.8 equiv) was added toa cold (-78 °C) solution of 5-chloro-2-trimethylstannyl-1-pentene (12, 257 mg,0.96 mmol, 1.9 equiv) in THF (10 mL) and the mixture was stirred at this temperaturefor 20 min. A cold (-78 °C) solution of lithium chloride-copper(I) Cyarlide89,234,235 (LiCI:77 mg, 1.82 mmol, 3.6 equiv; CuCN: 82 mg, 0.9 mmol, 1.8 equiv) in THF (2 mL) wastransferred, via cannula, to the resultant solution. A mixture of the enone 64 (144 mg,0.5 mmol) and TMSCI (320 111_, 2.5 mmol, 5 equiv) in THF (2 mL) was added viacannula and the orange solution was stirred for 2 h at -78 °C. Boron trifluorideetherate 91 (68 pl, 0.55 mmol, 1.1 equiv) was added and the mixture was stirred at-78 °C for 2 h. Aqueous ammonium chloride (pH 9, 15 mL) was added and thereaction mixture was opened to the air and was then warmed to room temperature.188Ether (15 mL) was added and the mixture was stirred until the aqueous layer turn deepblue. The layers were separated and the aqueous blue layer was extracted with ether(3 x 15 mL). The combined organic extracts were washed successively with aqueousammonium chloride (pH 9, 15 mL) and brine (15 mL) and then the ether extracts weredried with magnesium sulfate. The solvents were removed under reduced pressureand the resulting oil was purified by flash chromatography (10 g silica gel, 9:1hex:ether, 80 mL). The less polar fraction was composed mostly of the ketone 102(9 mg, -4% yield). The more polar, major fraction gave, after distillation (120-130 °C/0.1 torr), 170 mg (86 %) of the pure chloro ketone 100, which exhibitedIR (neat): 2965, 1708, 1637, 1456, 1377, 768, 526 cm -1 ; 1 H NMR (400 MHz) 5: 0.10(s, 9H, 2 J sn-H = 52 Hz, Me3Sn), 0.96 (d, 3H, J. 6.5 Hz, Me-7), 1.11 (s, 3H, Me-8),1.26 (ddd, 1H, J. 14, 13, 2.5 Hz, 2,-/ Sn-H = 45 Hz, H-3), 1.63 (dd, 1H, J. 14, 14 Hz,3,/ Sn-H = 21 Hz, H-4a), 1.87-1.98 (m, 2H, H-4'), 2.03-2.13 (m, 3H, H-4e, H-3'),2.17-2.30 (m, 2H, H-2, H-6a), 2.73 (dd, 1H, J. 14, 3 Hz, H-6e), 3.55 (m, 2H, H-5'), 4.88(br s, 1H, H-1'b), 4.96 (s, 1H, H-1'a); COSY: see Table 2.4; NOE differenceexperiments: irradiation of the signal at 6 1.26 (H-3) led to enhancement of the signalsat 6 0.96 (Me-7), 6 2.03-2.13 (H-4e, H-3'), 6 4.96 (H-1'a); irradiation of the signal at5 1.63 (H-4a) led to enhancement of the signals at 5 1.11 (Me-8), 6 2.06 (H-4e),5 2.17-2.30 (H-2, H-6a); irradiation of the signal at 8 4.96 (H-1'a) led to enhancementof the signals at 5 1.26 (H-3), 5 2.73 (H-6e), 5 4.88 (H-1'b); 13 C NMR (50.3 MHz)5: -10.15 (-ve, 1 Jsn-c = 366 Hz, Me3Sn), 15.47 (-ve, 3,-/ Sn-C = 11 Hz, Me-7), 27.39(C-4'), 28.92 (-ve,./1 - sn-c = 376 Hz, C-3), 29.34 (-ve, Me-8), 31.32 (C-3'), 40.04(2,/ Sn-C = 12 Hz, C-4), 44.71 (C-6), 47.87 (-ve, 2J sn-c = 18 Hz, C-2), 48.38 (C-5),52.68 (C-5'), 112.11 (C-1'), 150.66 (C-2'), 204.17 (C-1); DCIMS(NH3): MH+(393);HRMS calcd for C16H29CIOSn: 392.0928, found: 392.0927; Anal. calcd forC16H29CIOSn: C 49.08, H 7.47, found: C 49.28, H 7.64; [ a ]D 29 +86.4°, c = 1.10 inMe0H; CD: c = 1.10 in Me0H; [W]x29 : 299.7 nm (+10820, 35 nm), 230.9 nm (-2666,7.5 nm).0Me-9^H-6e 0H-3Me-8H-4eH-6aSnMe3 H-2H-4a102Me-7B) (+)-(2R,3R)-2,5,5-Trimethyl-3-trimethylstannylcyclohexanone (102)189Distilled (90-100 °C/0.1 torr); IR (neat): 2959, 1708, 1455, 1367, 764, 525 cm -1 ;1 H NMR (400 MHz) 8: 0.11 (s, 9H, 2J Sn-H = 52 Hz, Me3Sn), 0.89 (s, 3H, Me-8),236 0.99(d, 3H, J. 7 Hz, Me-7), 1.05 (s, 3H, Me-9), 1.51 (ddd, 1H, J. 13.5, 13.5, 3.5 Hz,2J Sn-H = 42 Hz, H-3), 1.53-1.60 (m, 1H, H-4e), 1.73 (dd, 1H, J. 14.5, 13.5 Hz,3 .-/ Sn-H = 26 Hz, H-4a), 2.13 (dd, 1H, J. 12.5, 2 Hz, H-6e), 2.28 (d, 1H, J. 12.5 Hz,H-6a), 2.35 (dq, 1H, J. 13.5, 7 Hz, H-2); 13 C NMR (50.3 MHz) 8: -10.14 (-ve,1,./ Sn-C = 315 Hz, Me3Sn), 15.27 (-ve, 3 J sn-c = 11 Hz, Me-7), 24.83 (-ve, Me-8),30.03 (-ve, 1 J Sn-C = 378 Hz, C-3), 31.84(-ve, Me-9), 40.00 (3J sn_c = 69 Hz, C-5),43.43 (2 J sn_c = 14 Hz, C-4), 47.41 (-ve, 2 J sn_c = 19 Hz, C-2), 55.06 (C-6), 213.50(3 J Sn-c = 65 Hz, C-1); LRMS: M+(304) 3.1%; HRMS calcd for C12H240Sn :304.0848, found: 304.0854; Anal. calcd for C12H240Sn: C 47.57, H 7.98, found:C 47.71, H 7.95; [ a ]D26 +134.0°, c = 1.008 in MeOH; CD: c = 1.008 in MeOH:[ IP JA,26 : 298.4 nm (+17950, 39 nm), 232.3 nm (-7454, 7 nm).C) Preparation of the Mixture of Chloro Ketones 100 and 101A solution of methyllithium (1.44 M, 2.4 mL, 3.46 mmol, 1.4 equiv) was added toa cold (-78 °C) solution of the chioro vinylstannane 12 (923 mg, 3.45 mmol,1901.38 equiv) in THF (25 mL) and the mixture was stirred at this temperature for 20 min.Solid magnesium bromide etherate (907 mg, 3.51 mmol, 1.4 equiv) was added in oneportion and the white suspension was stirred at -78 °C for 20 min. Solid copper(I)bromide-dimethyl sulfide (26 mg, 0.13 mmol, 0.05 equiv), a solution of thetrimethylstannylcyclohexenone 64 (719 mg, 2.51 mmol) in THF (4 mL) and borontrifluoride etherate (340 1.11, 2.76 mmol, 1.1 equiv) were successively added. Theyellow suspension was stirred at -78 °C for 4 h. Aqueous ammonium chloride (pH 9,25 mL) was added and the mixture was warmed to room temperature and was pouredinto ether (30 mL) in an Erlenmeyer flask. The mixture was vigorously stirred in thepresence of air until the aqueous layer became deep blue. The layers were separatedand the aqueous blue layer was extracted with ether (3 x 30 mL). The combinedorganic layers were successively washed with aqueous ammonium chloride (pH 9,25 mL) and brine (25 mL) and the ether extracts were dried with sodium sulfate. Thesolvents were removed under reduced pressure to give 1.2 g of a colourless oil. Theoil was purified by flash chromatography (35 g silica gel, 85:15 petroleum ether:ether,400 mL) to give 884 mg (90%) of a colourless oil after distillation (120-150 °C/0.08torr). The oil was a 5.3:1 mixture of chloro ketones 100 and 101 by GLC analysis andwas inseparable by flash chromatography on silica gel. The 1 H NMR (400 MHz)spectrum of the mixture showed, in addition to the signals derived from 100, 6: 0.12(s, 9H, Me3Sn), 1.01 (d, 3H, J. 6.5 Hz, Me-7), 1.02 (s, 3H, Me-8), 2.35 (m, 1H, H-2),4.79 (br s, 1H, H-1'b).4.2.1.7. Preparation of (+)-(2/3.3R.5S)-5-(5-lodo-2-pent-1-eny1)-2.5-dimethyl-3- trimethylstannylcyclohexanone (126) and (2R.3R.5R)-5-(5-lodo-2-pent-1- eny1)-2.5-dimethyl-3-trimethylstannylcyclohexanone (129) A) Preparation of the lodo Ketone 126191The chioro ketone 100 (4.11 g, 10.5 mmol) was added, neat, to a solution ofsodium iodide (flame dried under vacuum, vacuum pump, 0.1 torr, 25.2 g, 168 mmol,16 equiv) in dry acetone (120 mL) and the flask was rinsed with acetone (-2 mL). Thestirred mixture was protected from light with aluminium foil and was refluxed for 10 h.Water (120 mL) was added to the yellow suspension and the mixture was extractedwith ether (4 x 200 mL). The ether extracts were dried with magnesium sulfate, filteredand concentrated to give 8 g of crude oil. The oil was purified by flashchromatography (150 g silica gel, 9:1 hex:ether, 1.2 L). to give 4.84 g (95%) of theiodo ketone 126. An analytical sample, obtained by distillation of the oil (200-210 °C/0.07 torr), exhibited IR (neat): 2965, 1707, 1636, 1456, 1376, 768, 526 cm -1 ;1 H NMR (400 MHz) 8: 0.13 (s, 9H, 2 J sn_H = 52 Hz, Me3Sn), 0.98 (d, 3H, J. 6.5 Hz,Me-7), 1.13 (s, 3H, Me-8), 1.28 (ddd, 1H, J. 14, 14, 2.5 Hz, 2J sn-H = 48 Hz, H-3), 1.65(dd, 1H, J. 14, 14 Hz, 3J sn_H = 21 Hz, H-4a), 1.87-2.01 (m, 2H, H-4'), 2.02-2.07 (m,2H, H-3'), 2.10 (ddd, 1H, J. 14, 3, 2.5 Hz, H-4e), 2.21 (dd, 1H, J. 14, 1 Hz, H-6a), 2.25(m, 1H, H-2), 2.74 (dd, 1H, J. 14, 3 Hz, H-6e), 3.23 (m, 2H, H-5'), 4.89 (br s, 1H,H-1'b), 4.97 (s, 1H, H-1'a); 13C NMR (75.3 MHz) 8: -10.06 (-ye, 1 Jsn-c = 316 Hz,Me3Sn), 6.93 (C-5'), 15.33 (-ye, 3J s n_c 11 Hz, Me-7), 28.87 (-ye, 1 J sn-c = 376 Hz,C-3), 29.41 (-ye, Me-8), 31.09 ( 2J sn_c = 12 Hz, C-4), 32.03 (C-3'), 40.02 (C-6), 47.97io H^ H-9a^H-4^SnMe3iiH-10e—H-1192(-ve, 2 ,/ s n_c = 18 Hz, C-2), 48.35 (C-5), 52.64 (C-4'), 112.20 (C-1'), 150.32 (C-2'),212.26 (C-1); DCIMS(NH3): MH+(485); HRMS calcd for C15H2610Sn (M+-Me):469.0049, found: 469.0044; Anal. calcd for C16H2910Sn: C 39.79, H 6.05, found:C 39.74, H 6.12; [ a ]D 26 +76.6°, c = 1.014 in MeOH; CD: c = 1.014 in MeOH:['F ]a,26 : 300.1 nm (+9034, 35 nm), 227.9 nm (-8814, 9 nm).B) Preparation of the Mixture of lodo Ketones 126 and 129IThe 5.3:1 mixture of chloro ketones 100 and 101 (884 mg, 2.26 mmol) wasconverted into the mixture of iodo ketones 126 and 129 (5.3:1, 1.1 g, 100%) using aprocedure identical with that described above. The 1 H NMR (400 MHz) spectrum ofthe mixture showed in addition to the signals due to 126, 8: 0.14 (s, 9H, Me3Sn), 1.02(d, 3H, J. 6.5 Hz, Me-7), 1.03 (s, 3H, Me-8), 4.79 (br s, 1H, H-1'b).4.2.1.8. Preparation of (+)-(1 R.3R.4R.6R)-3.6-Dimethyl-7-methylene-4-trimethyl-stannylbicyclo[4.4.0]decan-2-one (124) and (+)-(1S,3R.4R.6S)-3,6-Dimethyl-7-methylene-4-trimethylstannylbicyclo[4.4.0]decan-2-one (130) A) Preparation of the Bicyclic Ketone 124Me-110 H3"'SnMe35^ H-8He-9eH-5a12 /H-10^H-13b 1^H-5e13124 ^H-8a^H-13aMe-12193A solution of the iodo ketone 126 (5.73 g, 11.9 mmol) in THF (20 mL) wasadded over a period of 20 min, via a small bore Teflon® cannula, to a cold (-78 °C)solution of i-Pr2NLi (0.5 M, 26.1 mL, 13 mmol, 1.1 equiv) in THF (50 mL). The mixturewas stirred at -78 °C for 1 h and then was warmed for 20 min (water bath, 35 °C).Aqueous citric acid (0.1 M, 50 mL) and ether (100 mL) were added. The layers wereseparated and the aqueous layer was extracted with ether (3 x 100 mL). Thecombined organic extracts were washed with brine (50 mL) and then were dried withmagnesium sulfate. The solvents were removed under reduced pressure and theresidual solid was purified by flash chromatography (180 g silica gel, 97:3 petroleumether:ether) to give 3.84 g (93%) of the bicyclic ketone 124 as a white solid afterdistillation (120-150 °C/0.06 torr). The product was recrystallized from Me0H to affordcolourless needles, mp 55.5-56 °C. The product exhibited IR (2% KBr): 2976, 2937,1702, 1636, 1452, 1380, 899, 772, 527 cm -1 ; 1 H NMR (400 MHz) 8: 0.14 (s, 9H,2JSn-H = 51 Hz, Me3Sn), 0.95 (d, 3H, J= 6.5 Hz, Me-11), 1.28 (s, 3H, Me-12), 1.56-1.66 (m, 2H), 1.69-1.87 (m, 3H), 2.06-2.18 (m, 2H), 2.23-2.47 (m, 4H), 4.51 (br s, 1 H,H-13), 4.77 (br s, 1 H, H-13); 1 H NMR (400 MHz, C6D6) 8: 0.05 (s, 9H, 2 ,./ Sn-H = 51 Hz,Me3Sn), 1.04 (d, 3H, J= 6.5 Hz, Me-11), 1.07 (s, 3H, Me-12), 1.40 (dddd, 1H, J= 14,14, 5, 5 Hz, H-10a), 1.50-1.60 (m, 1H, H-9a partially buried under H-5a), 1.55 (dd, 1H,J= 14, 14 Hz, 34/ sn-H = 24 Hz, H-5a), 1.81 (ddd, 1H, J= 14, 14, 2.5 Hz, 2J sn-H = 43 Hz,H-4), 1.95 (d, 1H, J= 5 Hz, H-1), 2.00-2.10 (m, 3H, H-3, H-5e, H-8a), 2.12-2.30 (m, 3H,H-8e, H-9e, H-10e), 4.58 (br s, 1H, H-13a)4.78 (br s, 1H, H-13b); HSC: seeTable 2.5; COSY: see Table 2.6; Selective decoupling experiments (C6D6):irradiation of the signal at 8 1.04 (Me-11) led to a doublet at 8 2.08 (H-3, J = 14 Hz);irradiation at 8 1.40 (H-10a) simplified the signals at 8 1.50-1.60 (H-9a), 1.95 (s, H-1),2.12-2.30 (H-9e, H-10e); irradiation at 8 1.81 (H-4) simplified the signals at 8 1.55 (dd,J = 14, 2.5 Hz, H-5a), 2.00-2.10 (H-3, H-5e); irradiation at 8 1.95 (H-1) simplified thesignals at 8 1.40 (ddd, J = 14, 14, 5 Hz, H-10a), 2.12-2.30 (H-10e); NOE differenceexperiments (C6D6): irradiation of the signal at 6 1.04 (Me-11, [ NOTE: the signal atMe-11H-Me-12H-13b130H-8eH-9e1948 1.07 (Me-12) was also irradiated]) led to the enhancement of signals at 6 1.81 (H-4),6 1.95 (H-1), 6 2.00-2.10 (H-3, H-5e, H-8a); irradiation of the signal at 6 1.07 (Me-12)led to the enhancement of the signals at 5 1.55 (H-5a), 6 1.95 (H-1), 6 2.05 (H-5e,H-8a); irradiation of the signal at 6 1.81 (H-4) led to the enhancement of signals at8 1.04 (Me-11) and 8 4.58 (H-13a); irradiation of the signal at 8 1.95 (H-1) led to theenhancement of signals at 6 1.07 (Me-12), 8 1.40 (H-10a), 8 1.55 (H-5a), 6 2.22(H-10e); 13C NMR (75.3 MHz, C6D6) 8: -10.34 (-ve, 1 Jsn-c = 315 Hz, Me3Sn), 16.37(-ve, 3J Sn -C = 15 Hz, Me-11), 21.87 (C-10), 23.75 (C-9), 29.24 (-ve, 1 J Sn-C = 382 Hz,C-4), 30.39 (-ve, Me-12), 33.10 (C-8), 41.55 ( 2 J sn-c = 13 Hz, C-5), 48.12 (-ve,2J sn_c = 15 Hz, C-3), 48.46 (C-6), 56.06 (-ve, 4 J sn_c = 3 Hz, C-1), 107.78 (C-13),150.76 (C-7), 209.92 (C-2); LRMS: M+(356) 3.2%; HRMS calcd for C16H280Sn:356.1161, found: 356.1164; Anal. calcd for Ci6H280Sn: C 54.12, H 7.95, found:C 54.22, H 8.03; [ a ]D 28 +109.0°, c = 1.014 in MeOH; CD: c = 1.014 in MeOH:['g ]x28 : 307.5 nm (+13980, 36 nm), 234.5 nm (-9123, 6.5 nm).B) Preparation of the Bicyclic Ketones 124 and 130The ketones 124 and 130 were prepared from the mixture of iodo ketones 126and 129 (5.3:1, 1.11 g, 2.3 mmol) using a procedure identical with that describedabove except for the purification. An initial flash chromatography (75 g silica gel, 9:1195petroleum ether:ether) of the crude product gave the ketone 124 (74 mg, 9%) anda mixture of the ketones 124 and 130 (620 mg, 76%). Three additional, careful flashchromatographies (silica gel [100-150:1 silica gel:mixture w:w], 95:5 petroleumether:ether) were performed and the appropriate fractions were combined to give theketone 124 (559 mg, 68%), a mixture of the ketones 124 and 130 (54 mg, 7%) andthe ketone 130 (62 mg, 8%). The ketone 130 was distilled (110-120 °C/0.1 torr) togive a white solid. The solid was recrystallized from Me0H to afford small prisms,mp 69.5-70.5 °C. The solid exhibited IR (2% KBr): 2960, 2940, 2864, 1698, 1632,1450, 1379, 900, 769, 527 cm -1 ; 1 H NMR (400 MHz) 8: 0.11 (s, 9H, 2J sn-H = 52 Hz,Me3Sn), 0.99 (d, 3H, J. 6.5 Hz, Me-11), 1.10 (s, 3H, Me-12), 1.18 (ddd, 1H, J. 14, 4,1.5 Hz, H-5e), 1.30 (ddddd, 1H, J. 14, 14, 13, 4, 4 Hz, H-9a), 1.57 (ddd, 1H, J= 14, 13,4 Hz, H-4), 1.62-1.69 (m, 1H, H-10e), 1.83 (m, 1H, H-10a), 1.84-1.91 (m, 1H, H-9e),2.14 (ddd, 1H, J. 13, 4, 1.5 Hz, H-1), 2.23 (dm, 1H, J. 14 Hz, H-8e), 2.37-2.45 (m, 1H,H-8a), 2.43 (dd, 1H, J. 14, 14 Hz, H-5a), 2.65 (dq, 1H, J. 13, 6.5 Hz, H-3), 4.71 (br s,1H, H-13b), 4.73 (br s, 1H, H-13a); HSC: see Table 2.7; COSY: see Table 2.8;Selective decoupling experiments: irradiation of the doublet at 6 0.99 (Me-11) led tosimplification of the signal at 6 2.65 (d, J = 13 Hz, H-3); irradiation at 6 1.57 (H-4)simplified the signals at 6 1.18 (dd, J = 14, 1.5 Hz, H-5e), 2.43 (d, J . 14 Hz, H-5a),2.65 (q, J = 6.5 Hz, H-3); irradiation at 6 2.65 (H-3) simplified the signals at 6 1.00 (s,Me-11), 6 1.57 (dd, J = 14, 4 Hz, H-4); NOE difference experiments: irradiation at5 1.10 (Me-12) led to the enhancement of signals at 6 1.57 (4%,H-4), 6 2.14 (3%,H-1), 8 4.73 (3%, H-13a); irradiation at 6 1.57 (H-4) led to the enhancement of signalsat 8 1.00 (Me-11), 8 1.10 (5%, Me-12), 8 1.18 (H-5e); 13C NMR (50.3 MHz) 8: -10.13( 1 .-/Sn-c = 315 Hz, Me3Sn), 15.53 ( 3J sn-c = 15 Hz, Me-11), 24.09 (Me-12), 27.15 (C-9),27.73 (C-10), 29.57 ( 1 J sn-c = 390 Hz, C-4), 32.78 (C-8), 36.19 (2J sn-c = 12 Hz, C-5),42.62 (2J sn-c = 19 Hz, C-3), 45.23 (3J sn_c = 65 Hz, C-6), 60.11 (C-1), 107.69 (C-13),153.63 (C-7), 216.30 (C-2); LRMS: M+(356) 2.8%; HRMS calcd for C16H280Sn:356.1161, found: 356.1161; Anal. calcd for C16H280Sn: C 54.12, H 7.95, found:CI4Me3Sn 2110196C 54.32, H 7.92; [ a ]D25 +209.0°, c = 0.900 in MeOH; CD: c = 0.900 in MeOH:[ T. ]),,25 : 304.5 nm (+14946, 36 nm), 236.2 nm (-8015, 9 nm).4.2.1.9. Preparation of (+)-(2R.3R.5S)-5-(4-Chloro-2-but-1-eny1)-2.5-dimethy1-3-trimethylstannylcyclohexanone (117) A solution of methyllithium (1.47 M, 930 !IL, 1.37 mmol, 1.2 equiv) was added toa solution of freshly distilled 4-chloro-2-trimethylstannyl-1-pentene (110, generouslysupplied by Johanne Renaud, 318 mg, 1.26 mmol, 1.1 equiv) in THF (3 mL) at -78 °C.The colourless mixture was stirred for 30 min at -78 °C and then a cold (-78 °C)solution of lithium chloride-copper(I) cyanide complex (LiCI: 107 mg, 2.52 mmol,2.2 equiv; CuCN: 113 mg, 1.26 mmol, 1.1 equiv) in THF (3.6 mL) was added viacannula. The bright yellow solution was stirred for 15 min at -78 °C and then a mixtureof the enone 64 (331 mg, 1.15 mmol) and TMSCI (365 lit, 2.88 mmol, 2.5 equiv) inTHF (1 mL) was added. Boron trifluoride etherate (1554, 1.26 mmol, 1.1 equiv) wasadded to the orange solution and the mixture was stirred for 3 h at -78 °C. Aqueousammonium chloride (pH 9, 10 mL) and ether (10 mL) were added, the mixture waswarmed to room temperature and was stirred in the presence of air until the bottomlayer turned dark blue. The layers were separated and the aqueous layer wasextracted with ether (3 x 20 mL). The combined organic extracts were washed withbrine (10 mL) and dried with magnesium sulfate. The solvents were removed underreduced pressure to give 409 mg of a colourless oil. The oil was purified by flashchromatography (50 g silica gel, 95:5 petroleum ether:ether). The least polar fraction197gave 36 mg (10%) of the ketone 102 while the most polar fraction gave 33 mg (10%)of the starting enone 64. The major fraction gave 300 mg (69%, 76% based onrecovered starting material) of the chloro ketone 117 as a colourless oil afterdistillation (110-120 °C/0.04 torr). The chloro ketone 117 exhibited IR (neat): 2966,2929, 2872, 1707, 1636, 1456, 1377, 776, 525 cm -1 ; 1 H NMR (400 MHz) 6: 0.11 (s,9H, 2J sn-H = 52 Hz, Me3Sn), 0.97 (d, 3H, J. 6.5 Hz, Me-7), 1.12 (s, 3H, Me-8), 1.29(ddd, 1H, J. 14, 14, 3 Hz, 2 J sn-H = 46 Hz, H-3), 1.66 (dd, 1H, J. 14, 14 Hz,3,./ Sn-H = 21 Hz, H-4a), 2.04 (ddd, 1H,J= 14, 3, 3 Hz, 3 ,./ sn-H = 24 Hz, H-4e), 2.22 (d,1H, J. 15 Hz, H-6a), 2.20-2.30 (m, 1H, H-2), 2.30-2.50 (m, 2H, H-3'), 2.72 (dd, 1H,J. 15, 3 Hz, H-6e), 3.61 (m, 2H, H-4'), 4.94 (br s, 1H, H-1'b), 5.04 (s, 1H, H-1'a);13 C NMR (50.3 MHz) 6: -10.18 (-ve, 1 J sn-c = 317 Hz, Me3Sn), 15.29 (-ve,3J sti_c = 11 Hz, Me-7), 28.79 (-ve, 1 J s n_c = 373 Hz, C-3), 29.10 (-ve, Me-8), 33.96(C-3'), 39.88 (2J sn-c = 12 Hz, C-4), 43.19 (C-6), 47.68 (-ve, 2 J sn_c = 17 Hz, C-2),48.22 (C-5), 52.43 (C-4'), 113.67 (C-1'), 148.60 (C-2'), 212.50 (C-1); LRMS:MA--Me(363); HRMS calcd for C14H24C1OSn: 363.0537, found: 363.0533; Anal.calcd for C15H27C1OSn: C 47.72, H 7.21, found: C 47.89, H 7.26; [ a 1D 25 +87.7°,c = 1.212 in MeOH; CD: c = 1.212 in MeOH: ['F ]x25 : 299.8 nm (+11630, 35 nm),231.7 nm (-6780, 7 nm).4.2.1.10. Preparation of (Z)-5-Chloro-3-trimethylstannyl-2-pentene (115) 13d ,95A) Preparation of Ethyl (Z)-3-Trimethylstannyl-3-pentenoate (113)COOEtMe3SnCiCOOEtMe3Sn - -•1 12A solution of ethyl (E)-3-trimethylstannyl-2-pentenoate (112, generouslysupplied by Timothy Wong, 1.09 g, 3.73 mmol) in THF (4 mL) was slowly added (5-10 min) to a solution of i-Pr2NLi (0.27 M in THF, 48 mL, 13.1 mmol, 3.5 equiv) at198-78 °C. The mixture was stirred for 30 min at -78 °C and for 1 h at 0 °C. The mixturewas recooled to -78 °C and was transferred, via a wide bore Teflon® cannula, to asolution of glacial acetic acid (2.25 mL, 39.3 mmol, 10.5 equiv) in ether (38 mL) at-98 °C. The mixture was warmed to room temperature, saturated aqueous sodiumbicarbonate (40 mL) was added and the layers were separated. The aqueousfraction was extracted with ether (2 x 20 mL). The combined ether extracts werewashed with brine and were dried over magnesium sulfate. The solvents wereremoved under reduced pressure to give 1.25 g of a yellow oil. The oil was purified byflash chromatography (30 g silica gel, 98:2 petroleum ether:ether, 400 mL) to give887 mg (82%) of ethyl (Z)-3-trimethylstannyl-3-pentenoate (113) as a colourless oilafter distillation (50-70 °C/0.08 torr). The spectral data derived from this compoundwere identical with those reported previously. 13d ,95B) Preparation of (Z)-3-Trimethylstanny1-3-penten-1-ol (114)A solution of ethyl (Z)-3-trimethylstannyl-3-pentenoate (113, 997 mg,3.42 mmol) in ether (4 mL) was slowly added to a cold (-20 °C) solution-suspension oflithium aluminium hydride (85 mg, 2.24 mmol, 0.65 equiv) in ether (20 mL). Themixture was stirred for 3 h at -20 °C and then powdered sodium sulfate decahydrate(0.5 g) was added and the mixture was warmed to room temperature. The suspensionwas filtered through a column of Florisil® (10 g) and the Florisil® was washed withether (120 mL). The solvent was removed to give 879 mg of a colourless oil. The oilwas purified by flash chromatography (25 g silica gel, 3:2 petroleum ether:ether,200 mL) to give 620 mg (73%) of (Z)-3-trimethylstannyl-3-penten-1-ol (114) asa colourless oil after distillation (60-70 °C/0.1 torr). The spectral data derived from thiscompound were identical with those reported previously.13c1,95199C) Preparation of (Z)-5-Chloro-3-trimethylstannyl-2-pentene (115)12 CIMe3Sn 3 v 51 15Solid triphenylphosphine (1.31 g, 4.98 mmol, 2 equiv) was added to a mixtureof triethylamine (382 pt, 2.74 mmol, 1.1 equiv) and (Z)-3-trimethylstannyl-3-penten-1-01 (114, 620 mg, 2.49 mmol) in dry carbon tetrachloride (15 mL). The mixture wasrefluxed for 24 h and then was cooled to room temperature. Petroleum ether (25 mL)was added and the suspension was filtered through a column of Florisil® (15 g) andthe Florisil® was washed with petroleum ether (75 mL). The solvents were carefullyremoved under reduced pressure to give 731 mg of oil. The oil was distilled (40-60 °C/0.1 torr) to yield 612 mg (92%) of (Z)-5-chloro-3-trimethylstannyl-2-pentene(110) as a colourless oil. The spectral data derived from this compound wereidentical with those reported previously. 13d ,954.2.1.11. Preparation of (+)-(2R.3R.5S)-5-[(Z)-5-Chloro-3-pent-2-enyl]-2.5-dimethy1-3-trimethylstannylcyclohexanone (121) 990 1211 'A solution of methyllithium (1.47 M, 300 4L, 0.44 mmol, 1.26 equiv) was addedto a cold (-78 °C) solution of freshly distilled (Z)-5-chloro-3-trimethylstannyl-2-pentene(115, 107 mg, 0.4 mmol,1.14 equiv) in THE (2 mL). The mixture was stirred for 20 minat -78 °C and solid magnesium bromide etherate (140 mg, 0.54 mmol, 1.5 equiv) was200added in one portion. The milky suspension was stirred for 25 min at -78 °C and thenether (4 mL) was slowly added (4 min). The mixture was stirred for 10 min at -78 °Cand then solid copper(I) bromide-dimethyl sulfide (27 mg, 0.13 mmol, 0.38 equiv),a solution of the trimethylstannylcyclohexenone 64 (100 mg, 0.35 mmol) in ether(1 mL) and boron trifluoride etherate (45 111_, 2.76 mmol, 1.1 equiv) were successivelyadded. The yellow suspension was stirred at -78 °C for 3 h [NOTE: the yellow colourpersisted only for 1 h]. Aqueous ammonium chloride (pH 9, 3 mL) and ether (10 mL)were added and the mixture was warmed to room temperature. The mixture wasvigorously stirred in the presence of air until the aqueous layer became deep blue.The layers were separated and the aqueous blue layer was extracted with ether (2 x10 mL). The combined organic layers were successively washed with water (3 mL)and brine (3 mL) and the extracts were dried with magnesium sulfate. The solventswere removed under reduced pressure to give 136 mg of a colourless oil. The oil waspurified by flash chromatography (10 g silica gel, from 9:1 to 7:3 petroleum ether:ether)to give 23 mg (23%) of recovered starting material 64 and 88 mg (65%, 84% based onrecovered starting material) of the chloro ketone 121 as a colourless oil afterdistillation (120-150 °C/0.08 torr). The chloro ketone 121 exhibited IR (neat): 2968,1707, 1640, 1455, 1378, 773, 525 cm -1 ; 1 H NMR (400 MHz) 8: 0.15 (s, 9H,Sn-H = 52 Hz, Me3Sn), 1.02 (d, 3H, J ---- 6.5 Hz, Me-7), 1.22 (s, 3H, Me-8), 1.39(ddd, 1H, J. 14, 13, 2.5 Hz, 2 ,./ sn-H = 44 Hz, H-3), 1.64 (dd, 1H, J. 14, 14 Hz,3J sn H = 19 Hz, H-4a), 1.75 (d, 3H, J. 7.5 Hz, Me-1'), 2.11 (d, 1H, J. 14 Hz H-6a),2.30-2.42(m, 2H, H-4'), 2.50-2.60 (m, 2H, H-2, H-4e), 2.85 (dd, 1H, J. 14, 3 Hz, H-6e),3.54 (m, 2H, H-5'), 5.38 (q, 1H, J. 7.5 Hz, H-2'); 130 NMR (50.3 MHz) 8: -10.22 (-ve,1,./Sn-c = 316 Hz, Me3Sn), 15.30 (-ve, 3 ../ sn-c = 11 Hz, Me-7), 15.73 (-ve, Me-1'), 29.68(-ve, Me-8), 29.89 (-ve, 1 J sn-c = 374 Hz, C-3), 39.27 (C-4'), 42.19 (2J sn-c = 12 Hz,C-4), 44.59 (C-6), 48.07 (-ve, 2J sn-c = 18 Hz, C-2), 48.65 (C-5), 53.81 (0-5'), 124.63(-ve, C-2'), 139.05 (C-3'), 212.30 (0-1); LRMS: M+-Me(377); HRMS calcd forC15H26CIOSn: 377.0693, found: 377.0696; Anal. calcd for C16H29CIOSn: C 49.08,H112^1Me-10H-3SnMe3—H-1H-5a0H-4H-9eH-8eH-12b13 21H-9a H-5eH-12a Me-11H-8a10''SnMe3201H 7.47, found: C 49.26, H 7.57; [ a]D 25 +116.2°, c = 1.036 in MeOH, CD: c = 1.036 inMeOH: ['F ]A,25 : 302.5 nm (+11310, 37 nm), 233.5 nm (-7568, 7 nm).4.2.1.12. Preparation of (+)-(1R.3R.4R.6R)-3.6-Dimethy1-7-methylene-4-trimethyl-stannylbicyclo[4.3.0jnonan-2-one (132) 025A solution of the chloro ketone 117 (327 mg, 0.87 mmol) in THF (3 mL) wasadded over a period of 20 min, via a small bore Teflon cannula, to a cold (-78 °C)solution of i-Pr2NLi (0.5 M in THF, 2.1 mL, 1.05 mmol, 1.2 equiv). The mixture wasstirred at -78 °C for 1 h and then was warmed for 45 min (water bath, 45 °C). Aqueouscitric acid (0.1 M, 3 mL) and ether (5 mL) were added. The layers were separated andthe aqueous layer was extracted with ether (3 x 5 mL). The combined organic extractswere washed with brine (5 mL) and then were dried with magnesium sulfate. Thesolvents were removed under reduced pressure to give 308 mg of a faint yellow oilthat crystallized at room temperature. The solid was purified by flash chromatography(8 g silica gel, 7:3 hex:dichloromethane, 100 mL) to give 260 mg (88%) of the bicyclicketone 132 as a white solid after distillation (80-100 °C/0.15 torr). The product wassublimed (70 °C/0.1 torr) to afford colourless needles, mp 59.9-60.2 °C. The productexhibited IR (2% KBr): 2979, 2918, 1687, 1652, 1460, 1378, 883, 765, 522 cm -1 ;1 H NMR (400 MHz) 5: 0.11 (s, 9H, 2 ,./ sn-H = 52 Hz, Me3Sn), 0.95 (d, 3H, J . 6.5 Hz,Me-10), 1.13 (s, 3H, Me-11), 1.42 (ddd, 1H, J. 14, 13.5, 3 Hz, 2 ,./ sn_H = 42 Hz, H-4),1.53-1.65 (m, 2H, H-8e, H-9a), 1.90 (dd, 1H, J . 14, 14 Hz, 3J sn-H = 24 Hz, H-5a),H-8aH-8eH-12Me-10H-3SnMe3—H-1H-5a1H-9a H-5e^133Me-13 Me-11H-9e0H-40132022.06 (dd, 1H, J=14, 3 Hz, 3J sn-H = 20 Hz, H-5e), 2.23 (m, 1H, H-3), 2.38-2.44 (m, 3H,H-1, H-8a, H-9e), 4.60 (dd, 1H, J= 2.5, 2 Hz, H-12a), 4.82 (dd, 1H, J= 2, 2 Hz, H-12b);NOE difference experiments: Irradiation at 6 1.13 (Me-11) led to the enhancement ofsignals at 8 1.53-1.65 (2%, H-9a), 6 1.90 (3%, H-5a), 8 2.06 (1.5%, H-5e), 8 2.42 (4%,dd, J = 6, 5 Hz, H-1), 6 4.60 (1%, H-12a); irradiation at 6 1.42 (H-4) led to theenhancement of signals at 6 0.95 (2%, Me-10), 6 2.06 (3%, H-5e), 6 2.38-2.44 (9%,H-8a); irradiation at 6 1.90 (H-5a) led to the enhancement of signals at 6 1.13 (4%,Me-11); 13C NMR (50.3 MHz) 6: -10.11 (-ye, 1 J sn-c = 315 Hz, Me3Sn), 16.06 (-ye,3 J Sn-C = 16 Hz, Me-10), 20.98 (C-9), 29.96 (-ye, 1 J sn-c = 378 Hz, C-4), 30.15 (C-8),31.20 (-ye, Me-11), 38.63 (2J sn_c = 13 Hz, C-5), 47.89 (-ye, 2J sn-c = 19 Hz, C-3),54.84 (3J sn_c = 72 Hz, C-6), 59.97 (-ye, C-1), 103.74 (C-12), 155.60 (C-7), 222.30(3,./Sn-c = 65 Hz, C-2); LRMS: MA- (342) 4%; HRMS calcd for C15H260Sn: 342.1005,found: 342.1013; Anal. calcd for C15H260Sn: C 52.83, H 7.68, found: C 52.90,H 7.74; [ a iD26 +76.7°, c = 1.14 in MeOH; CD: c = 1.14 in MeOH: ['P ]x26 : 301.8 nm(+14980, 37 nm), 233.2 nm (-6307, 6 nm).4.2.1.13. Preparation of (+)-(1R.3R.4R.6R)-3.6-Dimethy1-7-(Z)-ethylidene-4-trimethyl-stannylbicyclo[4.3.0)nonan-2-one (133) 203The chloro ketone 121 (145 mg, 0.37 mmol) was converted into the bicyclicketone 133 using a procedure identical with that described for the preparation of thebicyclic ketone 132. The ketone 133 was obtained in 83% yield (109 mg) afterchromatography (4 g silica gel, 95:5 hex:ether) and distillation (120-130 °C/0.15 torr).The ketone 133 was recrystallized from Me0H to afford colourless plates, mp 56.4-57.3 °C. The product exhibited IR (2% KBr): 2967, 1687, 1458, 1376, 767, 527 cm -1 ;1 H NMR (400 MHz) 6: 0.12 (s, 9H, 2 J sn_H = 52 Hz, Me3Sn), 1.01 (d, 3H, J. 6.5 Hz,Me-10), 1.25 (s, 3H, Me-11), 1.38 (ddd, 1H, J. 14, 13.5, 2 Hz, 2 ../ Sn-H = 45 Hz, H -4),1.55(m, 1H, H-9a), 1.62 (ddd, 3H, J. 7.5, 2, 2 Hz, Me-13), 1.85 (dd, 1H, J. 14, 14 Hz,3Li Sn-H = 21 Hz, H-5a), 2.19-2.45 (m, 5H, H-1, H-3, H-8a, H-8e, H-9e), 2.59 (dd, 1H,J. 14, 2 Hz, 3 J sn-H = 24 Hz, H-5e), 5.27 (ddq, 1H, J. 2, 2, 7.5 Hz, H-12); NOEdifference experiments: Irradiation at 6 1.25 (Me-11) led to the enhancement ofsignals at 6 1.62 (1%, Me-13), 6 1.85 (1.5%, H-5a), 6 2.30 (3%, d, J. 5 Hz, H-1), 6 2.59(2%, H-5e); irradiation at 6 2.59 (H-5e) led to the enhancement of signals at 6 1.25(1.5%, Me-11), 6 1.62 (3.6%, Me-13), 6 1.85 (27%, H-5a); 13C NMR (50.3 MHz)6: -10.23 (-ve, 1 J sn_c = 315 Hz, Me3Sn), 13.26 (-ve, Me-13), 16.23 (-ve, 3J sn-C =15 Hz, Me-10), 22.76 (C-9), 28.67 (-ve, Me-11), 29.55 (-ve, 1 ,./sn_c = 380 Hz, C-4),33.79 (C-8), 39.16 (2 ,./ sn_c = 14 Hz, C-5), 48.44 (-ve, 2J sn-c = 18 Hz, C-3), 53.92(3J Sn-c = 80 Hz, C-6), 62.42 (-ve, C-1), 115.24 (-ve, C-12), 145.35 (C-7), 213.20(C-2); LRMS: M+(356) 18%; HRMS calcd for C16H280Sn: 356.1161, found:356.1154; Anal. calcd for C16H280Sn: C 54.12, H 7.95, found: C 54.26, H 8.06;ll[ a ]D 26 +77.1°, c = 0.978 in Me0H; CD: c = 0.978 in MeOH: [ I b„26 : 303.4 nm(+13329, 37 nm), 234.6 nm (-4821, 6 nm).1113H-2OH Me-11H-34.2.2. Dissolved Metal Reductions of TrimethylstannylcyclohexaneDerivatives4.2.2.1. Preparation of (+)-(1R2R.3S,6R)-3.6-Dimethy1-7-methylenebicyclo[4.4.01-decan-2-ol (165) 204H-9a^H-4a^H-4eH-10e—H-1H-9eH-8e^ H 5a1165^H-13b1^iH -10 H-5e^H-8a^H-13aMe -12A mixture of the bicyclic ketone 124 (144 mg, 0.4 mmol) and 2-methy1-2-propanol (770 1.11, 8.1 mmol, 20 equiv) in THE (5 mL) was transferred, via cannula, toa cold (-78 °C), deep blue solution of lithium (28 mg, 4.1 mmol, 10 equiv) in ammonia(30 mL). The mixture was stirred for 1 h at -78 °C and was refluxed for 1 h. Solidammonium chloride (400 mg) was added and the color of the suspension turned fromdeep blue to yellow and then became colorless. Ether (10 mL) was added and theammonia was evaporated. Water (10 mL) and ether (20 mL) were added to theresidual material and the layers were separated. The aqueous layer was extractedwith ether (2 x 20 mL) and the combined ether extracts were washed with brine(10 mL) and then dried with magnesium sulfate. The solvents were removed underreduced pressure to give 91 mg of a colorless oil. The oil was purified by flashchromatography (4 g silica gel, 47:48:5 hex:dichloromethane:ether, 100 mL) to give71 mg (89%) of the bicyclic alcohol 165 as a white solid after distillation (80-110 °C/0.1 torr). The product was recrystallized from acetonitrile to afford colourlessneedles, mp 87.5-88 °C. The product exhibited IR (2% KBr): 3280, 3084, 2982, 2930,1637, 1460, 1374, 1078, 1021, 892 cm -1 ; 1 H NMR (400 MHz) 5: 1.01 (d, 3H, J= 7 Hz,Me-11), 1.15 (s, 3H, Me-12), 1.25 (d, 1H, J = 6 Hz, OH [exchanged with D20]),H-2 H-3H-9a^H-4^SnMe3H-10e—H-12051.20-1.60 (m, 7H, H-1, H-3, H-4a, H-4e, H-5a, H-9a, H-9e), 1.70-1.82 (m, 1H, H-10a),1.98-2.07 (m, 2H, H-5e, H-10e), 2.18 (br d, 1H, J . 13.5 Hz, H-8e), 2.35-2.45 (m, 1H,H-8a), 3.15 (ddd, 1H, J = 10, 10, 6 Hz, H-2 [becomes dd, J = 10, 10 Hz, with D20]),4.60 (dd, 1H, J= 1.5, 1.5 Hz, H-13a), 4.79 (dd, 1H, J= 1.5, 1.5 Hz, H-13b); COSY: seeTable 2.9; Selective decoupling experiments: irradiation of the signal at 8 1.00(Me-11) led to simplification of the signal at 6 1.40 (H-3); irradiation at 6 1.70-1.82(H-10a) simplified the signals at 5 1.37 (br s, H-1), 6 1.59 (H-9a, H-9e), 8 2.05 (H-10e);irradiation at 6 2.18(H-8e) simplified the signals at 6 1.59 (H-9a, H-9e), 8 2.05 (H-10e),6 2.40 (H-8a); irradiation at 6 2.40 (H-8a) simplified the signals at 6 1.59 (H-9a, H-9e),6 2.18 (H-8e), 6 4.60 (d, J =1.5 Hz, H-13a), 6 4.79 (d, J. 1.5 Hz, H-13b); irradiation at6 3.15 (H-2) simplified the signals at 6 1.25 (s, OH), 6 1.37 (br s, H-1), 6 1.40 (H-3);13C NMR (50.3 MHz) 6: 18.95 (-ye, Me-11), 21.55 (C-10), 21.58 (C-4), 29.20 (C-9),30.27 (-ve, Me-12), 32.99 (C-5), 36.76 (C-8), 40.75 (-ve, C-3), 41.10 (C-6), 50.68 (-ve,C-1), 73.56 (-ve, C-2), 107.80 (C-13), 151.07 (C-7); LRMS: M+(194) 5%; HRMS calcdfor C13H220: 194.1671, found: 194.1662; Anal. calcd for C13H220: C 80.36,H 11.41, found: C 80.20, H 11.37; [ a ]D24 +37.0°, c = 0.892 in chloroform.4.2.2.2. Preparation of (-)-(1R.2S.3R.4R.6R)-3.6-Dimethy1-7-methylene-4-trimethyl-stannylbicyclo[4.4.0]decan-2-ol (166) Me-11OHH-9eH-8e^ H-5a1H-13b H-10a H-5eH-8a^H-13aMe-12^16 6Calcium metal (15 mg, 0.37 mmol, 1.1 equiv) was added to a cold (-78 °C)solution of the bicyclic ketone 124 (121 mg, 0.34 mmol) and 2-methyl-2-propanol206(161 iaL, 1.7 mmol, 5 equiv) in THF:ammonia (13 mL:25 mL). The mixture was stirredfor 15 min at -78 °C and was refluxed for 1.5 h. During that period, the suspensionbecame colorless. Solid ammonium chloride (400 mg) and ether (15 mL) were addedand the ammonia was evaporated. Water (10 mL) and ether (15 mL) were added andthe layers were separated. The aqueous layer was extracted with ether (2 x 15 mL)and the combined ether extracts were washed with brine (10 mL) and then dried withmagnesium sulfate. The solvents were removed under reduced pressure to give123 mg of a colorless oil. The oil was purified by flash chromatography (14 g silicagel, 35:60:5 hex:dichloromethane:ether, 200 mL) to give 38 mg (31%) of the startingmaterial 124, 8 mg (12%) of the bicyclic alcohol 165 and 52 mg (42%) of the bicyclictrimethylstannyl alcohol 166 as a white solid after distillation (110-120 °C/0.1 torr).The product was recrystallized from acetonitrile to afford colourless cubes, mp 59-60 °C. The product exhibited IR (2% KBr): 3290, 3078, 2981, 2928, 1637, 1450,1374, 1084, 1044, 1018, 893, 764, 523 cm -1 ; 1 H NMR (400 MHz) 5: 0.08 (s, 9H,2 ,./ sn_Fi = 51 Hz, Me3Sn), 1.01 (d, 3H, J= 6 Hz, Me-11), 1.12 (s, 3H, Me-12), 1.25 (d,1 H, J = 6 Hz, OH [exchanged with D20}), 1.26-1.50 (m, 4H, H-1, H-3, H-4, H-5a), 1.50-1.60 (m, 2H, H-9a, H-9e), 1.70- 1.82 (m, 1H, H-10a), 2.02 (br d, 1H, J= 14 Hz, H-10e),2.07 (br dd, 1H, J= 14, 1 Hz, H-5e), 2.17 (br d, 1H, J = 15 Hz, H-8e), 2.32-2.40 (m, 1H,H-8a), 3.16 (ddd, 1H, J = 10, 10, 6 Hz, H-2 [become dd, J = 10, 10 Hz, with D20]), 4.51(dd, 1H, J = 1.5, 1.5 Hz, H-13a), 4.80 (dd, 1H, J = 1.5, 1.5 Hz, H-13b), COSY: seeTable 2.10; Selective decoupling experiments: irradiation of the signal at 5 1.01(Me-11) led to simplification of the signal at 5 1.42 (H-3); irradiation at 5 1.70-1.82(H-10a) simplified the signals at 5 1.32 (br d, J = 10 Hz, H-1), 5 1.50-1.60 (H-9a, 9e),5 2.02 (br s, H-10e); irradiation at 5 2.17 (H-8e) simplified the signals at 5 1.50-1.60(H-9a, H-9e), 5 2.02 (H-10e), 5 2.32-2.40 (H-8a); irradiation at 5 2.32-2.40 (H-8a)simplified the signals at 5 1.50-1.60 (H-9a, H-9e), 5 2.17 (br s, H-8e); irradiation at5 3.16 (H-2) simplified the signals at 5 1.25 (s, OH), 5 1.35 (br s, H-1), 5 1.42 (H-3);13 C NMR (50.3 MHz) 5: -10.32 (-ve, 1 ,./ s n _c = 306 Hz, Me3Sn), 19.94 (-ve,10H3H-4e—H-1H-5aiH-12b^I H-9a H-5e17 5^H-12a Me -11H-8aH-2H-4aH-9eH-8e2073,-/Sn-C = 16 Hz, Me-11), 21.49 (C-10), 21.70 (C-9), 27.43 (-ye, 1 Jsn-c = 399 Hz,C-4), 30.09 (-ve, Me-12), 32.97 (C-8), 41.47 ( 2J sn_c = 14 Hz, C-5), 42.50 (C-6), 44.32(-ve, 2Jsn_c = 19 Hz, C-3), 50.66 (-ve, C-1), 74.35 (-ve, C-2), 107.89 (C-13), 150.99(C-7); LRMS: M+(358) 6.1%; HRMS calcd for C16H300Sn: 358.1318, found:358.1317; Anal. calcd for C16H300Sn: C 53.81, H 8.46, found: C 53.66, H 8.47;[ a ]o25 -9.52°, c = 1.505 in chloroform.4.2.2.3. Transformation of the Bicyclic Trimethylstannyl Alcohol 166 Into the BicyclicAlcohol 165The bicyclic trimethylstannyl alcohol 166 (142 mg, 0.4 mmol) was convertedinto the bicyclic alcohol 165 (73 mg, 94%) using a procedure identical with thatdescribed for the transformation of the bicyclic ketone 124 into the bicyclic alcohol165 (4.2.2.1).4.2.2.4. Preparation of (-)-(1R.2R,3a6R)-3,6-Dimethy1-7-methylenebicyclo[4.3.0]-nonan-2-ol (175) Me-10OHThe bicyclic trimethylstannyl ketone 132 (90 mg, 0.26 mmol) was converted intothe bicyclic alcohol 175 (36 mg, 75%) using a procedure identical with that describedfor the transformation of the bicyclic ketone 124 into the bicyclic alcohol 165 (4.2.2.1).The product of the reduction was purified by repetitive flash chromatography (5 g silicagel, 20:3:2 hex:dichloromethane:ethyl acetate) and by distillation (70-75 °C/0.09 torr).The product was recrystallized from acetonitrile to afford colourless needles, mp 68.5–OH Me-10H-2^H 3H-4a^H-4eH-9e-H-1H-5aiH-12^H-9a H-5eMe-13 Me-11H-8aH-8e20869 °C. The product exhibited IR (2% KBr): 3264, 3069, 2953, 2917, 1654, 1457, 1372,1058, 1033, 1019, 877 cm -1 ; 1 H NMR (400 MHz) 8: 0.95 (d, 3H, J= 6.5 Hz, Me-10),0.98 (s, 3H, Me-11), 1.08 (dddd, 1H, J . 14.5, 14, 14, 3 Hz, H-4a), 1.22-1.33 (m, 1H,H-3), 1.31 (d, 1 H, J = 6 Hz, OH [exchanged with D20]), 1.37-1.49 (m, 3H, H-1, H-4e,H-5a), 1.78-1.90 (m, 3H, H-5e, H-9a, H-9e), 2.35-2.45 (m, 1H, H-8a), 2.48-2.57 (m, 1H,H-8e), 2.65 (ddd, 1H, J = 10, 10, 6 Hz, H-2 [become dd, J. 10, 10 Hz, with D20]), 4.67(br s, 1H, H-12a), 4.80 (br s, 1H, H-12b), 13C NMR (50.3 MHz) 8: 18.57 (-ve, Me-10),23.34 (C-4), 28.84 (C-9), 29.28 (C-5), 30.67 (-ve, Me-11), 33.34 (C-8), 39.22 (-ve, C-3),47.42 (C-6), 54.98 (-ve, C-1), 76.96 (-ve, C-2), 102.91 (C-12), 156.50 (C-7);^LRMS:M+(180) 18.6%; HRMS calcd for C12H200: 180.1514, found: 180.1520; Anal. calcdfor C12H200: C 79.94, H 11.18, found: C 80.07, H 11.04; [ a 11) 23 -72.4°, c = 0.716in chloroform.4.2.2.5. Preparation of (-)-(1R.2R.3S.6R)-3.6-Dimethy1-7-[(Z)-ethylidenejbicyclo[4.3.0]- nonan-2-ol (176) 17610 13The bicyclic trimethylstannyl ketone 133 (111 mg, 0.31 mmol) was convertedinto the bicyclic alcohol 176 (40 mg, 66%) using a procedure identical with thatdescribed for the transformation of the bicyclic ketone 124 into the bicyclic alcohol165 (4.2.2.1). The product of the dissolved metal reduction was purified by flashchromatography (8 g silica gel, 20:3:2 hex:dichloromethane:ethyl acetate, 100 mL)and by distillation (90-105 °C/0.08 torr). The product was recrystallized fromOH Me-9 -6eH-1H-3aMe-8H-4eH-6aH-4aH-3e^H-2OHMe-7177209acetonitrile to afford colourless needles, mp 52.5-53.5 °C. The product exhibitedIR (2% KBr): 3326, 2965, 2918, 2851, 1655, 1441, 1375, 1352, 1061, 1015, 862 cm -1 ;1 H NMR (400 MHz) 8: 0.98 (d, 3H, J.6.5 Hz, Me-10), 1.00-1.10 (m, 1H, H-4a), 1.07 (s,3H, Me-11), 1.25-1.40 (m, 3H, H-3, H-4e, H-5a), 1.31 (d, 1H, J. 6 Hz, OH [exchangedwith D20]), 1.50 (ddd, 1H, J. 13, 7, 3.5 Hz, H-1), 1.62 (ddd, 3H, J. 7, 2, 2 Hz, Me-13),1.70-1.85 (m, 2H, H-9a, H-9e), 2.30 (ddd, 1H, J. 14, 3, 3 Hz, H-5e), 2.37-2.45 (m, 2H,H-8a, H-8e), 2.77 (ddd, 1H, J = 10, 10, 6 Hz, H-2 [becomes dd, J = 10, 10 Hz, withD20]), 5.25 (br q, 1H, J. 7 Hz, H-12); COSY: see Table 2.14; 13C NMR (50.3 MHz)8: 12.93 (-ve, Me-13), 18.80 (-ve, Me-10), 23.97 (C-4), 28.10 (-ve, Me-11), 29.75 (C-9),31.65 (C-5), 34.36 (C-8), 39.28 (-ve, C-3), 47.62 (C-6), 57.38 (-ve, C-1), 76.93 (-ve,C-2), 114.77 (-ve, C-12), 145.52 (C-7); LRMS: M+(194) 33.2%; HRMS calcd forC13H220: 194.1671, found: 194.1670; Anal. calcd for C13H220: C 80.36, H 11.41,found: C 80.10, H 11.47; [ a ])23 -35.2°, c = 0.995 in chloroform.1S2^-Trim h I^1•h x n 1 177The trimethylstannyl ketone 102 (124 mg, 0.41 mmol) was converted into thealcohol 177 (39 mg, 66%) using a procedure identical with that described for thetransformation of the bicyclic ketone 124 into the bicyclic alcohol 165 (4.2.2.1). Theproduct of the reduction was purified by flash chromatography (5 g silica gel, 8:1:1hex:dichloromethane:ethyl acetate) and by distillation (90-110 °C/15 torr). The productexhibited IR (neat): 3351, 2916, 1456, 1387, 1365, 1080, 1048, 1029, 921 cm -1 ;1 H NMR (400 MHz) 8: 0.90 (s, 3H, Me-9), 0.94 (s, 3H, Me-8), 1.02 (d, 3H, J. 6 Hz,Me-7), 1.00-1.05 (m, 1H, H-3a), 1.10 (dd, 1H, J. 10, 12.5 Hz, H-6a), 1.15-1.25 (m, 2H,HOH-2 H-3H-9a^H-4^SnMe3H-10e—H-1H-9eH-8e^ H-5aH-10^H-5eH-13a Me-12H-13bH-8a 178210H-2, H-4a), 1.27 (d, 1H, J = 5 Hz, OH [exchanged with D20]), 1.28-1.33 (m, 1H,H-3e),.1.52-1.57 (m, 1H, H-4e), 1.67 (ddd, 1H, J. 12.5, 4, 2.5 Hz, H-6e), 3.30 (m, 1H,w1/2 = 26 Hz, H - 1 [w112 becomes 22 Hz with D20]); COSY: see Table 2.15;Selective decoupling experiments (CDCI3 and D20): irradiation of the signal at 6 1.03(Me-7, H-3a and maybe H-6a at 1.10 6) led to simplification of the signal at 6 1.15-1.25(H-2, H-4a), 8 1.28-1.33 (H-3e), 8 1.52-1.57 (H-4e), 1.67 (H-6e), 3.30 (H-1); irradiationof the signal at 6 1.10 (H-6a and H-2) led to simplification of the signal at 6 1.02 (s,Me-7), 6 1.28-1.33 (H-3e), 6 1.52-1.57 (H-4e), 6 1.67 (br s, H-6e), 6 3.30 (H-1);irradiation of the signal at 6 1.67 (H-6e) led to simplification of the signal at 6 1.10 (d,J. 12 Hz, H-6a), 6 3.30 (br dd, J. 10, 10 Hz, H-1); irradiation of the signal at 6 3.30(H-1) led to simplification of the signal at 6 1.10 (d, J = 12.5 Hz, H-6a), 6 1.67 (dd, J.12.5, 2.5 Hz, H-6e), 6 1.15-1.25 (H-2); 130 NMR (50.3 MHz) 6: 18.26 (-ve, Me-7),25.09 (-ve, Me-8), 29.97 (C-3), 32.53 (C-5), 32.99 (-ve, Me-9), 38.70 (C-4), 40.54 (-ye,C-2), 48.44 (C-6), 73.47 (-ve, C-1); LRMS: M 4.(142) 3.4%; HRMS calcd for C91-1180:142.1358, found: 142.1348; Anal. calcd for C9H180: C 76.00, H 12.75, found:C 75.77, H 12.85; [ a ])24 +27.6°, c = 1.125 in chloroform.4.2.2.7. Preparation of (-)-(1R2R.3R.4R.6R)-3.6-Dimethy1-7-methylene-4-trimethyl-stannylbicyclo[4.4.0)decan-2-ol (178) Me-11211A solution of diisobutylaluminum hydride (1 M hex, 2.24 ml, 2.24 mmol, 3 equiv)was added to a cold (-78 °C) solution of the ketone 124 (265 mg, 0.75 mmol) in THE(5 mL). The solution was stirred at -78 °C for 50 min and then at room temperature for10 min. The reaction mixture was recooled to -78 °C and then Mc0H (250 ILL),saturated aqueous ammonium chloride (4 drops) and ether (10 mL) were added. Themixture was stirred at room temperature for 1 h and magnesium sulfate (0.5 g) wasadded. The milky white suspension was filtered through a column containing Florisil®(2 g) and a layer of Celite® (0.5 g) on top. The solids were triturated and washed withether (25 mL) and the solvents were removed under reduced pressure to give acolourless oil. The oil was purified by flash chromatography (10 g silica gel, 95:5hex:ether, 65 mL) to give 254 mg (96%) of the bicyclic trimethylstannyl axial alcohol178 as a colourless oil after distillation (120-130 °C/0.05 torr). The product exhibitedIR (neat): 3558, 3080, 2918, 1632, 1441, 1396, 1376, 1188, 1081, 980, 895, 764, 523cm -1 ; 1 H NMR (400 MHz) 6: 0.10 (s, 9H, 2 Jsn-H = 52 Hz, Me3Sn), 0.91 (d, 3H,J. 6.5 Hz, Me-11), 1.10 (s, 3H, Me-12), 1.32 (dd, 1H, J. 15, 14 Hz, 3J sn-H = 14 Hz,H-5a), 1.45 (br d, 1H, J 5.5 Hz, H-1), 1.55 (ddd, 1H, J 14, 14, 2.5 Hz, 2J sn_H =53 Hz, H-4), 1.60-1.75 (m, 3H, H-3, H-9a, H-10e), 1.71 (d, 1H, J 12 Hz, OH[exchanged with D2O]), 2.03-2.16 (m, 1H, H-10a), 2.17-2.33 (m, 3H, H-5e, H-8e, H-9e),2.40-2.53 (m, 1H, H-8a), 3.55 (ddd, 1H, J = 12, 2.5, 2.5 Hz, H-2 [becomes br s withD20]), 4.76 (br s, 1H, H-13a), 4.83 (br s, 1H, H-13b); COSY: see Table 2.16;13C NMR (50.3 MHz) 6: -10.41 (-ve, 1 Jsn_c = 307 Hz, Me3Sn), 20.06 (-ve, 3Jsn-C =16 Hz, Me-11), 21.71 (-ve, 1 Jsn_c = 400 Hz, C-4), 24.58 (C-10), 27.05 (C-9), 30.09(-ve, Me-12), 32.13 (C-8), 38.86 (C-5), 41.66 (-ve, C-3), 41.85 (C-5), 47.99 (-ve, C-1),79.76 (-ve, 3Jsn _c = 56 Hz, C-2), 106.28 (C-13), 155.49 (C-7); LRMS: M+(358) 5.1%;HRMS calcd for C16H300Sn: 358.1318, found: 358.1322; Anal. calcd forC16H300Sn: C 53.81, H 8.46, found: C 53.96, H 8.52; [ a ]D 24 -68.6°, c = 1.138 inchloroform.OH Me-9^OHH-3 H-6eH-1Me-7H-6aH-4aSnMe3 H-2179Me-8H-4e2124.2.2.8. Preparation of (-)-(1R.2R.3R)-2.5.5-Trimethy1-3-trimethylstannylcyclohexanol(179) The trimethylstannyl ketone 102 (283 mg, 0.934 mmol) was converted into thetrimethyistannyl alcohol 179 (257 mg, 90%) using a procedure identical with thatdescribed for the transformation of the bicyclic ketone 124 into the bicyclic alcohol178 (4.2.2.7). The product of the reduction was purified by flash chromatography (7 gsilica gel, 4:1 hex:ether) and by distillation (70-80 °C/0.09 torr). The product exhibitedIR (neat): 3482, 2950, 2900, 1458, 1386, 1363, 1188, 1071, 1020, 1007, 932, 763,523 cm -1 ; 1 H NMR (400 MHz, C6D6) 8: 0.09 (s, 9H, 2J sn -H = 50 Hz, Me3Sn), 0.74 (m,1H, OH), 0.84 (s, 3H, Me-8),0.87 (d, 3H, J. 7 Hz, Me-7), 1.18 (dd, 1H, J . 14, 3 Hz,H-6a), 1.19 (s, 3H, Me-9), 1.27 (dd, 1H, J. 14, 13.5 Hz, H-4a), 1.36 (ddq, 1H, J.14, 3,7 Hz, H-2), 1.48-1.58 (m, 2H, H-4e, H-6e), 1.69 (ddd, 1H, J. 14, 13.5, 3 Hz, 2J Sn -H =48 Hz, H-3), 3.51 (m, 1H, wv2 = 7.8 Hz, H-1); 13C NMR (75.3 MHz, C6D6) 8: -10.33(-ve, 1 Jsn-c = 310 Hz, Me3Sn), 20.13 (-ye, 3J sn_c = 8 Hz, Me-7), 22.95 (-ve, Me-8),27.68 (-ve, 1 J sn-c = 338 Hz, C-3), 30.16 ( 3J sn-c = 56 Hz, C-5), 34.23 (-ve, Me-9),40.20 (2J sn -c = 14 Hz, C-2), 44.88 ( 2J sn -c = 8 Hz, C-4), 46.11 (4J sn -c = 3 Hz, C-6),72.20 (-ve, 3 J sn_c = 59 Hz, C-1); LRMS: M+(306) 0.3%; HRMS calcd forCi2H260Sn: 306.1005, found: 306.1006; Anal. calcd for C12H260Sn: C 47.25,H 8.59, found: C 47.40, H 8.53; [ a ]D28 -55.0°, c = 1.008 in Me0H.OMe132134.2.2.9. Preparation of (+)-(1a2R.3/3,4R.6R)-3.6-Dimethyl-2-methoxy-7-methylene-4- trimethylstannylbicyclo[4.4.0]decane (184) MeOH-2 Me-11H-3H-9a^H-4^SnMe3H-10e-H-1H-9e/ H-10^H-5e/ iH-8e^H 5aH-13bH-81^H-13a Me-12^184DMSO (5 gL, 0.07 mmol, 1 equiv) was added to a suspension of potassiumhydride (23 mg, 35% in oil, washed with ether [3 x 1 mL] using a syringe to add andremoved the ether and dried under vacuum [vacuum pump], 0.2 mmol, 3 equiv) inDMF (300 4). The mixture was stirred for 10 min at room temperature and a solutionof the bicyclic trimethylstannyl axial alcohol 178 (24 mg, 0.07 mmol) in DMF (1 mL)was added via cannula. Some bubbling was observed. The grayish suspension wasstirred for 10 min at room temperature and then was cooled to 0 °C. lodomethane(42 4, 0.7 mmol, 10 equiv) was added and the mixture was stirred at roomtemperature for 1 h. Water (4 mL) and hex (4 mL) was added and the layers wereseparated. The aqueous layer was extracted with hex (3 x 5 mL). The combinedorganic layers were washed with brine (5 mL) and then dried with magnesium sulfate.The solvents were removed under reduced pressure to give 25 mg of oil. The oil waspurified by flash chromatography (2.5 g silica gel, 9:1 hex: dichloromethane) to give23 mg (91%) of the bicyclic trimethylstannyl ether 184 after distillation (95-110 °C/0.1 torr). The product exhibited IR (neat): 3079, 2908, 1640, 1461, 1375,1192, 1093, 884, 764, 523 cm -1 ; 1 H NMR (400 MHz) 5: 0.05 (s, 9H, 2J sn-H = 51 Hz,Me3Sn), 0.96 (d, 3H, J. 6.5 Hz, Me-11), 1.06 (s, 3H, Me-12), 1.21 (dd, 1H, J . 15,14 Hz, 3,-1 Sn-H = 14 Hz, H-5a), 1.45 (br dd, 1 H, J. 3.5, 3.5 Hz, H-1), 1.52-1.80 (m, 4H,H-3, H-4, H-9a, H-10e), 1.90-2.12 (m, 2H, H-9e, H-10a), 2.15-2.25 (m, 2H, H-5e, H-8e),--".^SiMe30 1 .2 'Me-9 H _3 H-6eMe-8H-4e185Me-7H-1OSEMH-6aH-4aSnMe3 H-22142.42 (ddddd, 1H, J = 15, 12.5, 6, 2.5, 2.5 Hz, H-8a), 3.12 (dd, 1H, J = 3.5, 2.5 Hz,4 .-/ Sn-H = 18 Hz, H-2), 3.38 (s, 3H, OMe), 4.55 (br s, 1H, H-13a), 4.68 (br s, 1H, H-13b);COSY: see Table 2.17; Selective decoupling experiments: irradiation of the signalat 8 0.96 (Me-11) led to simplification of the signal at 8 1.61 (dd, J = 12.5, 2.5 Hz, H-3);irradiation of the signal at 5 1.21 (H-5a) led to simplification of the signal at 5 1.73 (dd,J = 14, 5 Hz, H-4), 8 2.20 (d, J = 5 Hz, H-5e); irradiation of the signal at 5 2.42 (H-8a)led to simplification of the signal at 8 1.60 (H-9a), 8 2.00 (H-9e), 8 1.98 (H-8e);irradiation of the signal at 8 3.12 (H-2) led to simplification of the signal at 8 1.45 (br d,J . 3.5 Hz, H-1), 8 1.61 (H-3); 13C NMR (50.3 MHz) 8: -10.51 (-ve, 1 Jsn_c = 303 Hz,Me3Sn), 20.30 (-ve, 3Jsn-c = 19 Hz, Me-11), 23.19 (-ve, 1 J sn_c = 405 Hz, C-4), 23.54(C-10), 26.75 (C-9), 30.95 (-ve, Me-12), 32.46 (C-8), 38.92 (C-6), 42.25 ( 3Jsn-C =15 Hz, C-5), 42.76 (-ve, 2 J sn_c = 19 Hz, C-3), 48.01 (-ve, C-1), 61.56 (-ve, OMe),89.55 (-ve, 3Jsn_c = 54 Hz, C-2), 104.49 (C-13), 153.22 (C-7); LRMS: M+(372) 3.6%;HRMS calcd for C17H320Sn: 372.1474, found: 372.1481; Anal. calcd forC17H320Sn: C 55.02, H 8.69, found: C 55.20, H 8.75; [ a ] D24 +3.90, c = 0.98 inchloroform.4.2.2.10. Preparation of (-)-(1R.2a3R)-2_.5.5-Trimethy1-1-(2'-trimethylsilylethoxy)-methoxy-3-trimethylstannylcyclohexane (185) 119SEM-CI (201 1.1L, 1.13 mmol, 3 equiv) was added to a solution of thetrimethylstannyl alcohol 179 (115 mg, 0.38 mmol) and N,N-diisopropylethylamine215(329 gL, 1.89 mmol, 5 equiv) in dry dichloromethane (200 ML). The mixture was stirredfor 1.5 h and then saturated aqueous ammonium chloride (1 mL) was added. Themixture was extracted with dichloromethane (2 x 10 mL) the combined organic extractswere washed with brine (2 mL) and then dried with magnesium sulfate. The solventswere removed under reduced pressure to give 326 mg of oil. The oil was purified byflash chromatography (3 g silica gel, 95:5 hex: ether) to give 145 mg (88%) of thetrimethyistannyl SEM ether 185 after distillation (130-140 °C/0.03 torr). The productexhibited IR (neat): 2952, 1459, 1364, 1250, 1101, 1033, 861, 836, 764, 523 cm -1 ;1 H NMR (400 MHz, C6D6) 5: 0.03 (s, 9H, Me3Si), 0.12 (s, 9H, 2 ,./ sn-H = 50 Hz,Me3Sn), 0.89 (s, 3H, Me-8), 0.99 (two dd's, 2H, J. 1.5, 7 Hz, H-2'), 1.08 (d, 3H,J. 7 Hz, Me-7), 1.09-1.13 (m, 1H, H-6a), 1.22 (s, 3H, Me-9), 1.33 (dd, 1H, J. 14,13.5 Hz, 3J sn-H = 16 Hz, H-4a), 1.49 (ddq, 1H, J. 14, 7, 3 Hz, H-2), 1.62 (ddd, 1H,J.13.5, 3, 3 Hz, 3J sn_H = 14 Hz, H-4e), 1.75-1.90 (m, 2H, H-3, H-6e), 3.62-3.70 (m,2H, H-1, H-1'), 3.72-3.81 (m, 1H, H-1'), 4.59 (d, 1H, J. 7 Hz, OCH2O), 4.76 (d, 1H,J. 7 Hz, OCH2O); 13C NMR (75.3 MHz, C6D6) 5: -10.32 (-ve, 1 Js n_c = 298 Hz,Me3Sn), -1.18 (-ve, 1 Jsi_c = 51 Hz, Me3Si), 18.37 (C-2'), 20.44 (-ve, 3J sn_c = 23 Hz,Me-7), 23.88 (-ve, 1 J sn_c = 411 Hz, C-3), 27.07 (-ve, Me-8), 30.39 ( 3J sn_c = 62 Hz,C-5), 34.17 (-ve, Me-9), 40.26 (-ve, 2J sn_c = 18 Hz, C-2), 41.94 (C-6), 44.93 ( 2J sn-C =14 Hz, C-4), 65.14 (C-1'), 76.96 (-ve, 3J sn-c = 58 Hz, C-1), 93.65 (OCH2O); LRMS:M+-Me(421) 6%; HRMS calcd for C18H4002SiSn: 421.1584, found: 421.1588; Anal.calcd for C18H4002SiSn: C 49.67, H 9.26, found: C 49.88, H 9.21; [ a ] D28 -68.9°,c = 1.008 in Me0H.HOH-9a^H-4aH-7 H-10eH-2 H-3^OHio HH-4e—H-1H 5a^12 513H-9eH-8eH-10H-8a Me-133^11H-5e^18 6Me-122164.2.2.11. Preparation of (-)-(1 R.2S.3S.6S.7R)-3.6.7-Trimethylbicyclo[4.4.0]decan-2-ol (186) Me-11The bicyclic trimethylstannyl alcohol 178 (137 mg, 0.38 mmol) was convertedinto the alcohol 186 (68 mg, 91%) using a procedure identical with that described forthe transformation of the bicyclic ketone 124 into the bicyclic alcohol 165 (4.2.2.1).The product of the reduction was purified by flash chromatography (5 g silica gel, 95:5hex:ether) and by distillation (75-90 °C/0.15 torr). The product was a low melting (25-30 °C) colourless solid. The product exhibited IR (neat): 3515, 2920, 1446, 1382,1371, 1170 1044, 1013, 975, 951 cm -1 ; 1 H NMR (400 MHz) 8: 0.74 (d, 3H, J. 7 Hz,Me-13), 0.83 (s, 3H, Me-12), 0.94 (d, 3H, J. 6 Hz, Me-11), 0.98 (ddd, 1H, J= 13.5, 13,3 Hz, H-5a), 1.13-1.26 (m, 2H, H-1, H-3), 1.30 (d, 1H, J . 4.5 Hz, OH [exchanged withD20]), 1.35 (dddd, 1H, J . 13, 13, 13, 4.5 Hz, H-8a), 1.40-1.55 (m, 5H, H-4a, H-4e,H-8e, H-9a, H-10a), 1.83-2.13 (m, 4H, H-5e, H-7, H-9e, H-10e), 3.73 (br s, 1H, H-2[almost no change with D20]); COSY: see Table 2.18; Selective decouplingexperiments: irradiation of the signal at 8 0.74 (Me-13) led to simplification of thesignal at 8 2.08 (dd, J = 11, 3.5 Hz, H-7); irradiation at 6 0.94 (Me-11 and H-5a)simplified the signals at 8 1.15-1.20 (H-3), 6 1.50-1.55 (H-4a, H-4e), 6 1.91 (H-5e);NOE difference experiments: Irradiation at 8 0.74 (Me-13) led to the enhancement ofsignals at 6 1.35 (H-8a), 6 1.40-1.55 (H-8e), 6 1.92 (H-5e), 8 2.09 (H-7); irradiation at6 0.83 (Me-12) led to the enhancement of signals at 6 1.22 (H-1), 6 1.35 (H-8a), 6 1.92(H-5e); irradiation at 8 0.94 (Me-11 and H-5a) led to the enhancement of signals at2176 1.30 (OH), 8 1.50-1.55 (H-4a, H-4e), 6 1.92 (H-5e), 6 3.73 (H-2); irradiation at 6 0.98(H-5a) led to the enhancement of signals at 6 1.15 (-NOE, H-3) , 6 1.24 (-NOE, H-1),6 1.30 (-NOE, OH), 6 1.92 (H-5e); irradiation at 6 1.35 (H-8a and OH) led to theenhancement of signals at 6 0.74 (Me-11), 6 0.83 (Me-12), 6 0.94 (Me-13), 6 2.08(H-9e), 3.75 (H-2); irradiation at 8 3.73 (H-2) led to the enhancement of signals at6 1.24 (H-1), 6 1.30 (OH), 6 1.45-1.55 (H-10e); 13C NMR (50.3 MHz) 6: 16.09 (-ve,Me-12), 17.98, (-ve, Me-11), 22.44 (-ve, Me-13), 23.54, 23.72, 26.89, 30.31 (C-4, 8, 9,10), 31.51 (-ye, C-7), 35.51 (C-6), 37.18 (C-5), 38.30 (-ye, C-3), 46.74 (-ve, C-1), 78.52(-ve, C-2); LRMS: M+(196) 0.2%; HRMS calcd for C13H240: 196.1827, found:196.1820; Anal. calcd for C13H240: C 79.53, H 12.32, found: C 79.50, H 12.42;[ a ]D25 -13.9°, c = 0.985 in chloroform.4.2.2.12. Preparation of (+)-(1 R.2S.3S.6R)-3.6-Dimethyl-2-methoxy-7-methylene-bicyclo[4.4.0]decane (191) MeOH-9a^H-4aH-10eH-9eH-8eH-13b 1H-8aMe-11H-2H-4e—H-1H 5a191H-3The bicyclic trimethylstannyl methyl ether 184 (56 mg, 0.15 mmol) wasconverted into the alcohol 191 (16 mg, 52%) using a procedure identical with thatdescribed for the transformation of the trimethylstannyl bicyclic ketone 124 into thebicyclic alcohol 165 (4.2.2.1). The product of the reduction was purified by flashchromatography (4 g silica gel, 4:1 hex:dichloromethane) and by distillation (70-80 °C/0.2 torr). The product exhibited IR (neat): 3084, 2931, 1640, 1461, 1381, 1195,1123, 1101, 1056, 1039, 914, 886 cm -1 ; 1 H NMR (400 MHz) 6: 0.97 (d, 3H, J. 7 Hz,OH Me-9^OHH-3a H-6eMe-8H-4eH-6a1 9 2^H-4aH-3e^H-2H-1Me-7OH218Me-11), 0.90-1.08 (m, 1H, H-5a), 1.13 (s, 3H, Me-12), 1.35-1.45 (m, 1H, H-9a), 1.45-1.62 (m, 4H, H-1, H-4a, H-4e, H-10a),.1.75-1.85 (m, 1H, H-3), 1.85-2.02 (m, 2H, H-9e,H-10e), 2.06 (ddd, 1H, J. 14.5, 7.5, 4 Hz, H-5e), 2.18-2.26 (m, 1H, H-8e), 2.29-2.38(m, 1H, H-8a), 3.29-3.38 (m, 1H, H-2), 3.33 (s, 3H, OMe), 4.67 (s, 2H, H-13a, H-13b);COSY: see Table 2.19; Selective decoupling experiments: irradiation of the signalat 6 0.97 (Me-11 and H-5a) led to simplification of the signal at 6 1.45-1.62 (H-4a,H-4e), 6 1.75-1.85 (H-3), 6 2.06 (H-5e); irradiation at 6 1.05 (H-5a) simplified thesignals at 6 1.45-1.62 (H-4a, H-4e), 8 2.06 (dd, J . 7.5, 4, H-5e); irradiation at 6 1.80(H-3) simplified the signals at 6 0.97 (s, Me-11), 6 1.45-1.62 (H-1, H-4a, H-4e), 6 3.29-3.38 (H-2); irradiation at 8 2.06 (H-5e) simplified the signals at 6 0.90-1.08 (H-5a),8 1.45-1.62 (H-4a, H4e); irradiation at 8 3.33 (H-2) simplified the signals at 8 1.45-1.62 (H-1), 8 1.85-2.02 (H-3); 13C NMR (75.3 MHz) 8: 16.90 (-ve, Me-11), 25.24(C-10), 25.59 (C-4), 26.03 (C-9), 27.89 (-ve, Me-12), 30.75 (C-5), 32.90 (C-8), 35.10(-ve, C-3), 39.15 (C-6), 46.83 (-ve, C-1), 59.03 (OMe), 84.74 (-ve, C-2), 105.35 (C-13),155.20 (C-7); LRMS: M+(208) 6.2%; HRMS calcd for C14H240: 208.1827, found:208.1827; Anal. calcd for C14H240: C 80.71, H 11.61, found: C 80.20, H 11.78;[ a ID24 +4.40, c = 0.69 in chloroform.4.2.2.13. Preparation of (+)-(1R.2S)-2.5.5-Trimethylcyclohexan-l-ol j192) The trimethylstannylcyclohexanol 179 (123 mg, 0.40 mmol) was converted intothe alcohol 192 (40 mg, 70%) using a procedure identical with that described for thetransformation of the trimethylstannyl bicyclic ketone 124 into the bicyclic alcohol 165(4.2.2.1). The volatile product of the reduction was purified by flash chromatographyOSEM219(6 g silica gel, 9:1 pentane:ether) and by distillation (85-95 °C/17 torr). The productexhibited IR (neat): 3367, 2927, 1465, 1387, 1366, 1176, 1068, 1037, 1011 cm -1 ;1 H NMR (400 MHz) 8: 0.90 (s, 3H, Me-8), 0.93 (d, 3H, J. 7. Hz, Me-7), 0.99 (s, 3H,Me-9), 1.07-1.15 (m, 1 H, H-4a), 1.21 (d, 1 H, J = 4.5 Hz, OH [exchanged with D20]),1.33-1.60 (m, 5H, H-3a, H-3e, H-4e, H-6a, H-6e), 1.82 (m, 1H, H-2), 3.88 (dddd, 1H,J. 7, 4.5, 4, 4 Hz, H-1 [becomes ddd, J . 7, 4, 4 Hz with D20]); COSY: seeTable 2.20; 13C NMR (50.3 MHz) 8: 13.20 (-ve, Me-7), 26.42 (C-3), 28.72 (-ve,Me-8), 30.86 (-ve, Me-9), 31.10 (C-5), 34.74 (-ve, C-2), 35.14 (C-4), 43.44 (C-6), 70.37(-ve, C-1); LRMS: M+(142) 1.5%; HRMS calcd for C9H180: 142.1358, found:142.1366; [ a ]87825 +11°, c = 0.040 in chloroform (for the enantiomer (195):[ a ]578 25 -11 ° , c = 0.027 in chloroform) 123 ; [ a ]578 25 +16.3°, c = 1.080 inchloroform; [ a ]D25 +2.6 ° , c = 1.080 in chloroform.4.2.2.14. Preparation of (-)-(1R2S)-2.5.5-Trimethy1-1-(2-trimethylsilylethoxy)methoxy-cyclohexane (196) „SiMe3^Me-9H-3a H-6e0^0 - v2'Me-8^H-1H-4e Me-7H-6a1 96^H-4aH-3e^H-2The trimethylstannyl SEM-ether 185 (137 mg, 0.31 mmol) was converted intothe alcohol 196 (73 mg, 85%) using a procedure identical with that described for thetransformation of the trimethylstannyl bicyclic ketone 124 into the bicyclic alcohol 165(4.2.2.1). The product of the reduction was purified by flash chromatography (6 g silicagel, 9:1 hex:dichloromethane) and by distillation (70-80 °C/0.15 torr). The productexhibited IR (neat): 2954, 1462, 1366, 1250, 1195, 1175, 1145, 1103, 1056, 937, 920,836 cm -1 ; 1 H NMR (400 MHz) 8: 0.01 (s, 9H, Me3Si), 0.89 (s, 3H, Me-8), 0.90 (d, 3H,J= 7 Hz, Me-7), 0.90-0.95 (m, 2H, H-2'), 0.95 (s, 3H, Me-9), 1.03-1.12 (m, 1H, H-4a),3'MeO PFrs3 , ,\sijo..,6 1-1 52 '1'0010 H E 1151213115C6.,.,OMe2' 0F3C3, Me-11H-2^H-3H-9a^H-4a H-4eH-10e171 H-13b,^/H-10^H-5e^H-8a^H-13a Me-12H-9eH 5aI-I-8e2201.25 (dd, 1H, J. 13.5, 4 Hz, H-6e), 1.35 (ddd, 1H, J. 13.5, 10, 4 Hz, H-3a), 1.40-1.56(m, 3H, H-3e, H-4e, H-6a), 1.83-1.93 (m, 1H, H-2), 3.58-3.67 (m, 2H, H-1'), 3.74 (ddd,1H, J. 8, 4, 4 Hz, H-1), 4.62-4.70 (two d, 2H, J. 8 Hz, OCH2O); COSY see Table2.21; 13C NMR (50.3 MHz) 6: -1 18 (-ye, 1 Jsi_c = 50 Hz, Me3Si), 13.58 (-ve, Me-7),18.08 (C-2'), 26.72 (-ve, C-3), 28.58 (-ve, Me-8), 30.74 (-ve, Me-9), 31.12 (C-5), 33.14(-ve, C-2), 35.16 (C-4), 40.31 (C-6), 64.75 (C-1'), 74.95 (-ve, C-1), 92.81 (OCH2O);LRMS: M+-Me3Si(199) 6.4%; DCIMS(NH3): MNH4+(290); HRMS calcd forC12H2502Si: 229.1624, found: 229.1621; Anal. calcd for C15H3202Si: C 66.11,H 11.84, found: C 66.35, H 11.89; [ a ]D 25 -4.8°, c = 1.005 in chloroform.4.2.3. Mosher's Esters4.2.3.1. Preparation of (-)-(1R.2R,3S.6R)-3.6-Dimethyl-7-methylenebicyclo[4.4.0]- decan-2-y1 (2S)-2-Methoxy-2-phenyl-3.3,3-trifluoropropanoate (171)112,114,140—H-1(R)-(-)-2-Methoxy-2-phenyl-3,3,3-trifluoropropanoyl chloride (168) 237 (26 pl,0.14 mmol, 1.4 equiv) was added to a solution of the bicyclic alcohol 165 (19.5 mg,0.1 mmol) in pyridine (300 pt) and carbon tetrachloride (300 gL). The mixture wasstirred at room temperature for 4 days. During that period the solution turned slightlyyellow and a small amount of white precipitate was observed. 3-Dimethylamino-221propylamine (24 p,L, 0.19 mmol, 1.9 equiv), ether (5 mL) and cold (0 °C) aqueoushydrochloric acid (1 M, 3 mL) were added and the layers were separated. The organiclayer was washed successively with cold (0 °C) saturated aqueous sodiumbicarbonate (3 mL) and brine (3 mL). The ether extract was dried with magnesiumsulfate and the solvent was removed under reduced pressure to give 29 mg of solid.A 1 H NMR (400 MHz) of the crude product was recorded. The mixture was purified byflash chromatography (2 g silica gel, in gradient from 95:5 to 2:3 hex:ether) to give8 mg (40%) of the starting alcohol 165 and 17 mg (41%,69% based on recoveredstarting alcohol) of the Mosher's ester 171 as a white solid. The ester wasrecrystalized from hex to afford colourless prisms, mp 99.5-100 °C. The productexhibited IR (2% KBr): 3084, 2985, 2936, 2873, 1734, 1638, 1493, 1451, 1376, 1301,1264, 1190, 1159, 1104, 1082, 1026, 971, 906, 723 cm -1 ; 1 H NMR (400 MHz) 5: 0.86(d, 3H, J= 7 Hz, Me-11), 1.11 (s, 3H, Me-12), 1.16 (br dd, J= 10, 3 Hz, H-10e), 1.20-1.31 (m, 1H, H-5a), 1.37- 1.45 (m, 1H, H-9e), 1.50-1.60 (m, 5H, H-1, H-4a, H-4e, H-9a,H-10a), 1.60-1.72 (m, 1H, H-3), 2.03 (ddd, 1H, J = 13, 4, 4 Hz, H-5e), 2.18 (br dd, 1H,J . 13, 3 Hz, H-8e), 2.30-2.40 (m, 1H, H-8a), 3.56 (unresolved q, 3H, 5J F_H = 1 Hz,OMe), 4.62 (br s, 1H, H-13a), 4.83 (br s, 1H, H-13b), 4.96 (dd, 1H, J=10, 10 Hz, H-2),7.35-7.40 (m, 3H, aromatic H's), 7.60-7.64 (m, 2H, aromatic H's); COSY: seeTable 2.11; 19 F NMR (188.3 MHz); 5: 4.85 (intensity: 469.8, 1 J F-C = 288.3 Hz,2J F-C = 43.7 Hz, 3J F-C = 27.4 Hz, (1 R,2R,2'S,3S,6R)-isomer), 5.05 (intensity: 2.9,other isomer); 13C NMR (75.3 MHz) 5: 18.98 (Me-11), 21.31 (C-10), 21.57 (C-4),29.14 (C-9), 30.00 (Me-12), 32.68 (C-5), 36.34 (C-8), 38.65 (C-3), 41.23 (C-6), 48.01(C-1), 55.41 (OMe), 79.30 (C-2), 108.74 (C-13), 127.47, 128.18, 128.23 (2C's), 128.31,129.52, 149.82 (C-7), 166.20 (C-1'); LRMS: M -1- (410) (saturated); HRMS calcd forC23H29F303: 410.2063, found: 410.2069 (peak matched); Anal. calcd forC23H29F303: C 67.30, H 7.12, found: C 67.50, H 7.20; [ a ]D28 -23.9°, c = 0.463 inchloroform; [ tif ]2,28 268.9 nm (+306.8, 4 nm), 262.5 nm (+400.0, 4 nm), 256.4 nm(+235.1, 3.5 nm), 233.3 nm (-1867, 15 nm), 226.9 nm (+1486, 2 nm).3' OMeF3C ,,,, 2. 0H5C6 1 ' Me-11HH-2^3C HMe0 6 5- CF33 '4.2.3.2. Preparation of (+)-(1R.2R.3S.6R)-3.6-Dimethy1-7-methylenebicyclo[4.4.0]-decan-2-y1 (2R)-2-Methoxy-2-phenyl-3.3.3-trifluoropropanoate (172) 2220 0^ H-4a^H-4e10 H E^ H-9aii H-10e—H-1H-9e H 5aH-8e 1 72 13 12 5 H-13b ^/H-1 Oa H-5eH-8a^H-13aMe-12The bicyclic alcohol 165 (19.5 mg, 0.1 mmol) was converted into the Mosher'sester 172 (17 mg, 41% {60 % based on recovered starting alcohol 165, 6 mg}) usinga procedure identical with that described for the transformation of the bicyclic alcohol165 into the Mosher's ester 171 (4.2.3.1) using (S)-(+)-2-methoxy-2-phenyl-3,3,3-trifluoropropanoyl chloride (170) (26 piL, 0.14 mmol, 1.4 equiv). The ester wasrecrystalized from hex at -20 °C to afford colourless prisms, mp 105-105.5 °C. Theproduct exhibited IR (2% KBr): 3079, 2982, 2957, 2926, 1737, 1637, 1455, 1301,1265, 1181, 1159, 1027, 972, 725 cm -1 ; 1 H NMR (400 MHz) 8: 0.77 (d, 3H, J. 6.5 Hz,Me-11), 1.14 (s, 3H, Me-12), 1.20-1.30 (m, 1H, H-5a),.1.35 (br d, J. 13 Hz, H-10e),1.45-1.75 (m, 7H, H-1, H-3, H-4a, H-4e, H-9a, H-9e, H-10a), 2.02 (ddd, 1H, J. 14, 3,3 Hz, H-5e), 2.17 (br d, 1H, J = 14 Hz, H-8e), 2.30-2.40 (m, 1H, H-8a), 3.56 (m, 3H,OMe), 4.63 (br s, 1H, H-13a), 4.83 (br s, 1H, H-13b), 4.92 (dd, 1H, J. 10.5, 10.5 Hz,H-2), 7.36-7.42 (m, 3H, aromatic H's), 7.55-7.62 (m, 2H, aromatic H's); 19F NMR(188.3 MHz); 8: 4.85 (intensity: 20, other isomer); 5.02 (intensity: 1274, 1 ../ F-C =289.3 Hz, 2J F-C = 43.9 Hz, 3J F_C = 27.0 Hz, (1 R,2R,2'R,3S,6R)-isomer); 13C NMR(C-9), 30.09 (Me-12),55.21 (OMe), 79.68(125.8 MHz) 8:^18.56 (Me-11), 21.53 (C-10), 21.79 (C-4), 29.0832.68 (C-5), 36.40 (C-8), 38.58 (C-3), 41.30 (C-6), 48.15 (C-1),(C-2),(C-1');223108.70 (C-13), 127.80, 128.30 (3 C's), 129.5, 131.80, 149.90 (C-7), 166.20LRMS:^M -F-C14H2102(1 89) 14.4%, Mi- -000C(Ph)(0Me)CF3(177) 100%;DCIMS(NH3): MNH4+(428); HRMS calcd for C9H8F30: 189.0527, found: 189.0523;calcd for C13H21: 177.1643, found: 177.1645; Anal. calcd for C23H29F303: C 67.30,H 7.12, found: C 67.39, H 7.26; [ a ]D 30 +31°, c = 0.503 in chloroform; [ IP ]X25 :268.9 nm (-155.4 3 nm), 262.4 nm (-240.7, 4 nm), 256.2 nm (-138.5, 3 nm), 240.4 nm(+584.9, 11 nm).Me-170H-2aH-7aH-leH8H-7e—H-102244.2.4. Total Synthesis of (-)-Kolavenol (65)4.2.4.1. Preparation of (-)-(1/3.3S.6R)-3.6-Dimethy1-7-methylenebicyclo[4.4.0]decan-2- one (47)238O17H-2eH-3e/ H-1a^H-6a19= 6H-18b 1^ -6e18^ 47"a H-18aMe-19Solid TPAP (73 mg, 0.21 mmol, 0.05 equiv) was added to a solution-suspension of molecular sieves (powdered then flame dried under vacuum (vacuumpump), 2.1 g), 4-methylmorpholine-N-oxide (732 mg, 6.25 mmol, 1.5 equiv) and thebicyclic alcohol 165 (810 mg, 4.17 mmol) in dry dichloromethane (8.5 mL). 125 [NOTE:Efficient stirring was done with a large magnetic stirrer plate and a 2 cm hexagonalbar]. The mixture was initially dark green and after 1 min became black. Thesuspension was stirred for 50 min at room temperature and was then filtered through acolumn of silica gel (10 g). The silica was washed with ethyl acetate (100 mL), thesolvents were removed under reduced pressure. The resulting oil was purified byflash chromatography (20 g silica gel, 9:1 petroleum ether:ether, 200 mL) and bydistillation (80-90 °C/0.3 torr) to give 765 mg (96%). The product exhibited IR (neat):3085, 2934, 2869, 1708, 1639, 1456, 1376, 1080, 1043, 897, 874 cm -1 (3084, 1708,1639, 894 and 874 CM -1 ) 239 ; 1 H NMR (400 MHz) 5: 0.98 (d, 3H, J= 6 Hz, Me-17[NOTE: Clerodane numbering system]), 1.28 (s, 3H, Me-19), 1.52-1.80 (m, 6H), 2.06-2.14 (m, 2H), 2.18-2.35 (m, 4H), 4.60 (br s, 1H, H-18a), 4.73 (br s, 1H, H-18b); [5: 0.98(d, 3H, J= 6 Hz), 1.31 (s, 3H), 1.55-1.92 (m, 6H), 2.08-2.17 (m, 2H), 2.25-2.39 (m, 4H),4.63 (br s, 1H), 4.74 (br s, 1 F)F47 ; 13C NMR (75.3 MHz) 8: 14.81 (-ve, Me-17), 21.41225(C-1), 23.36 (C-2), 30.71 (-ve, Me-19), 30.85, 32.75, 36.38 (C-3, C-6, C-7), 44.70 (-ve,C-8), 45.50 (C-5), 56.22 (-ve, C-10), 107.66 (C-18), 150.38 (C-4), 212.51 (C-9); LRMS:M+(192) 77.6%; HRMS calcd for C13H200: 192.1514, found: 192.1521; Anal. calcdfor C13H200: C 81.20, H 10.48, found: C 81.20, H 10.59; [ a ]D 25 -32.6°, c = 1.175in chloroform; CD: c = 1.175 in chloroform: ['P 4 25 : 302.8 nm (-477.1, 45 nm, withshoulders at 310.9, 298.0, 293.9 and 287.5 nm).4.2.4.2. Preparation of (+)-(1S.3a6R)-3.6-Dimethy1-7-methylenebicyclo[4.4.0jdecan-2-one (17)240H-2a^H-10^H-817^ H-le H-6aH- e Me-17H-3e^ H-7aH-la1 7^ H-6eH-18b^Me-19H-3a^H-18aH-4aThe bicyclic ketone 47 (70 mg, 0.36 mmol) was stirred with potassium tert-butoxide (82 mg, 0.73 mmol, 2 equiv) in 2-methyl-2-propanol for 48 h at roomtemperature. Cold (0 °C) aqueous hydrochloric acid (1 N, 2.5 mL) was added and themixture was extracted with hex (3 x 2.5 mL). The combined organic extracts werewashed with brine (2.5 mL) and then, were dried with magnesium sulfate. Thesolvents were removed under reduced pressure to give 77 mg of oil. The oil waspurified by flash chromatography (7 g silica gel, 95:5 hex:ether) to give 51 mg (73%) ofa mixture (94:6 by 1 H NMR) of the ketones 17 and 47 respectively. The mixture waspurified by two radial chromatographies (A: 1 mm silica gel, 95:5 hex:ether; B: 1 mmsilica gel, 3:1:1 chloroform:carbon tetrachloride:hex) to give an analytical sample of theketone 17 after distillation (70-80 °C/0.25 torr). The product exhibited IR (neat): 3087,17215^H-18bIH-1a H-6e H-9 ' NMe-19^H-4aH-18aH-2eH-3eH-3aH-2a H-10^H-8H-1e H-6a CN H-9Me-17H-7aCN2262935, 2868, 1713, 1639, 1447, 1377, 1079, 1034, 895, 882 cm -1 [3086, 1713, 1638,1895 and 876 cm -1 j24i; 1 H NMR (400 MHz) 5: 0.88 (s, 3H, Me-19 [NOTE: Clerodanenumbering system]), 0.99 (d, 3H, J. 6.5 Hz, Me-17), 1.20-1.32 (m, 1H), 1.52-1.68 (m,3H), 1.80-1.90 (m, 2H),.1.97 (ddd, J. 13.5,13, 4 Hz, 1H), 2.05-2.40 (m, 5H), 4.69 (br s,2H, H-18); [0.87 (s, 3H), 0.99 (d, 3H, J. 6 Hz), 1.15-1.32 (m, 1H), 1.50-1.69 (m, 3H),1.78-1.90 (m, 2H), 1.96 (dt, 1H, J. 4, 13 Hz), 2.04-2.40 (m, 5H), 4.70 (br s 2H)] 249 ;13C NMR (100.6 MHz) 5: 14.42 (Me-17), 18.94 (C-1), 21.05 (C-2), 26.60 (Me-19),31.75, 32.19, 35.90 (C-3, C-6, C-7), 44.55 (C-8), 45.22 (C-5), 57.99 (C-10), 105.62(C-18), 155.88 (C-4), 213.26 (C-9); LRMS: M+(192) 62.8%; HRMS calcd forC13H200: 192.1514, found: 192.1519; Anal. calcd for C13H200: C 81.20, H 10.48,found: C 81.04, H 10.34; [ a ]p 25 +144.4°, c = 1.38 in chloroform; CD: c = 1.38 inchloroform: ['P ]a,25 : 299.5 nm (+5194, 37 nm, with shoulders at 309.8, 292.6 and283.7 nm).4.2.4.3. Preparation of (1 R.2S.3R.6R)- and (1 R.2R.3R.6R)-2-Cyano-3.6-dimethyl-7-methylenebicyclo[4.4.0]decane (215) 242,243Solid potassium tert-butoxide (3.61 g, 32.2 mmol, 7.2 equiv) was added to acold (0 °C) solution of TosMIC 244 (2.62 g, 13.4 mmol, 3 equiv) in DMPU (15 mL). Thethick dark yellow paste was stirred for 30 min at 0 °C and then a solution of the bicyclicketone 47 (848 mg, 4.4 mmol) and 2-methyl-2-propanol (422 p.L, 4.47 mmol,2271.01 equiv) in DMPU (2 mL) was added. The mixture was stirred 1 h at roomtemperature and then 95 h at 45 °C (oil bath temperature). The solution was pouredinto a cold (0 °C), stirred mixture of aqueous hydrochloric acid (1N, 30 mL) and hex(30 mL). The layers were separated and the aqueous layer was extracted with hex(2 x 30 mL). The combined organic extracts were successively washed with water(30 mL), saturated aqueous copper(II) sulfate (2 x 30 mL) and brine (2 x 30 mL). Theextracts were dried with magnesium sulfate and the solvents were removed underreduced pressure to give 900 mg of yellow oil. The oil was purified by flashchromatography (50 g silica gel, 15:1 petroleum ether:ether) to give 733 mg of amixture of the bicyclic nitrites 215 after distillation (60-70 °C/0.1 torr) (85:15, 82%, 88%based on 56 mg of recovered starting material). The identity of the mixture wasconfirmed by comparison of its data (IR, 1 H NMR, TLC and GLC) with that of anauthentic sample of the racemic mixture (prepared by John Wai). The productexhibited IR (neat): 3086, 2932, 2863, 2235, 1640, 1447, 1379, 893 cm -1 ; 1 H NMR(400 MHz) 5: 0.96 (s, 3H, Me-19, 215 (3-cN, [NOTE: Clerodane numbering system]),1.12 (d, 3H, J= 6 Hz, Me-17, 215 a-CN), 1.15 (d, 3H, J= 6 Hz, Me-17, 215 (3-CN),1.24 (s, 3H, Me-19, 215 a-CN), 1.25-1.78 (m, 8H, 215 (3-CN, 215 a-CN), 1.85-2.00(m, 2H, 215 R-CN, 215 a-ON), 2.03-2.10 (dd, 1H, J = 10, 10 Hz, H-9, 215 (3-CN), 2.10-2.20 (m, 1H, H-3e, 215 I3-CN, 215 a-CN), 2.30-2.45 (m, 1H, H-3a, 215 P-CN, 215a-CN), 2.60 (dd, 1H, J = 4.5 Hz, H-9, 215 a-CN), 4.56 (br s, 1H, H-18a, 215 a-ON),4.61 (br s, 1H, H-18b, 215 a-ON), 4.62 (br s, 1H, H-18a, 215 R-CN), 4.68 (br s, 1H,H-18b, 215 R-CN); LRMS: M+(203) 84.1%; HRMS calcd for O14H21N: 203.1674,found: 203.1672; Anal. calcd for C14H21N: C 82.70, H 10.41, found: C 82.64,H 10.36.318 H-2a H-10 12H-1e H-6a0^0■N./ ••■H-8H-2e^ Me-17H-3e H-7aH-1a H-6e CNMe-19^H-4aH-18aH-18bH-3a2284.2.4.4. Preparation of (+)-(1S.2/3.3a6R)-2-Cyano-3.6-dimethy1-2-(3.5-dioxahexyl)-7-methylenebicyclo[4.4.0]decane (2 1 6)245A solution of the bicyclic mixture of nitrites (215: 707 mg, 3.5 mmol) and HMPA(WARNING: carcinogenic, 1.2 mL, 7 mmol, 2 equiv) in THF (5 mL) was slowlyadded, via cannula, to a cold (0 °C) solution of i-Pr2NLi (0.13 M in THF, 40 mL,5.2 mmol, 1.5 equiv). The mixture was stirred for 30 min at 0 °C. 2-lodo-1-methoxy-methoxyethane (319: 620 41_, 4.9 mmol, 1.4 equiv) 246 was added neat to the yellowsolution. The resulting colourless solution was stirred at 0 °C for 30 min and at roomtemperature for 3.5 h. The solution was diluted with petroleum ether (100 mL) andwas washed successively with cold (0 °C) aqueous hydrochloric acid (1N, 40 mL),saturated aqueous copper(II) sulfate (2 x 40 mL), aqueous sodium thiosulfate (10%,30 mL) and brine (40 mL). The extracts were dried with magnesium sulfate and thesolvents were removed under reduced pressure to give 1.2 g of oil. The oil waspurified by TLC grade silica chromatography (31 g H type silica, 8:2 hex:ether, 100 mLand 3:1 hex:ether, 200 mL) to give 950 mg (94%) of the bicyclic alkylated nitrite 216.The product exhibited IR (neat): 3087, 2930, 2228, 1639, 1448, 1381, 1213, 1153,1110, 1042, 894 cm -1 ; 1 H NMR (400 MHz) 5: 1.12 (d, 3H, J. 6 Hz, Me-17, [NOTE:Clerodane numbering system]), 1.24 (s, 3H, Me-19), 1.25-1.35 (m, 2H), 1.45-1.75 (m,6H), 1.82 (dm, 1H, J. 14.5 Hz), 1.94 (dm, 1H, J. 12 Hz), 2.04-2.16 (m, 3H, two of themH-11), 2.38 (ddddd, 1H, J. 14, 14, 5.5, 1.5, 1.5 Hz, H-3a), 3.32 (s, 3H, OMe), 3.48 (m,2H, H-12), 4.53 (br s, 1H, H-18a), 4.54 (s, 2H, OCH2O), 4.57 (dd, 1H, J. 1.5, 1.5 Hz,H-6a180^0H-8H-2a H-1eH-10 12H-2e^ Me-17H-3e H-7aH-1a H-6eOHCMe-19 H-4aH-18aH-18bH-3a229H-18b); 13C NMR (50.3 MHz) 5: 17.65 (-ve, Me-17), 19.00 (-ve, Me-19), 23.08, 27.65,28.42, 32.20, 33.81, 36.24 (C-1, C-2, C-3, C-6, C-7, C-11), 37.57 (-ve, C-8), 40.10(C-5), 43.58 (C-9), 48.50 (-ve, C-10), 55.37 (-ve, OMe), 62.56 (C-12), 95.50 (OCH2O),104.18 (C-18), 122.32 (CN, C-20), 157.85 (C-4); LRMS: Mi -(291) 1.2%; HRMS calcdfor C18H29NO2: 291.2198, found: 291.2202; Anal. calcd for Ci8H29NO2: C 74.18,H 10.03, N 4.81, found: C 74.13, H 10.14, N 4.88; [ a ]) 25 +56.9°, c = 1.06 inchloroform.4.2.4.5. Preparation of (+)-(1S.2R.3R6R)-3.6-Dimethyl-2-(3.5-dioxahexyl)-2-methanoy1-7-methylenebicyclo[4.4.0]decane (218) 253A solution of i-Bu2AIH (1 M in hex, 13 mL, 13 mmol, 4 equiv) was added to asolution of the nitrile 216 (943 mg, 3.4 mmol) in freshly distilled DME (32 mL) and themixture was stirred at 50-60 °C for 6 h. The reaction mixture was cooled and wascarefully poured into degassed water (32 mL) under a blanket of argon. Ether(100 mL) and aqueous hydrochloric acid (1 N, 10 mL) were added to the thick paste.The layers were separated and aqueous hydrochloric acid (1 N, 4 mL) and ether(50 mL) were added to the aqueous layer and the layers were separated. The lastprocedure was repeated until the aqueous layer become acidic (10 times, 600 mL totalvolume of ether). The combined organic layers were dried with magnesium sulfateand concentrated to give 894 mg of a greenish oil. The oil was dissolved in a mixtureof THE (39 mL), glacial acetic acid (39 mL) and water (6 mL) and the solution was120^0*■./H-2a H-1eH-10 i -1H-6aH-8H-2e Me-17H-3e H-7aIH-1a^Me-20H-6eMe-19^H-4aH-18aH-18bH-3a18230stirred at room temperature for 12 h. The solvents were removed under vacuum(0.2 torr, vacuum pump) and the residue was dissolved in ether (150 mL) andsuccessively washed with saturated aqueous sodium bicarbonate (30 mL) and brine(2 x 20 mL) and the ether layer was dried with magnesium sulfate. The solvent wasremoved under reduced pressure and the colorless residual oil was kept undervacuum (vacuum pump) overnight to give 851 mg (89%) of the aldehyde 218 (thealdehyde decompose rapidly in chloroform if the chloroform is not passed throughflame dried basic alumina). The product exhibited IR (neat): 3085, 2928, 2768, 1713,1637, 1448, 1377, 1212, 1153, 1109, 1044, 894 cm -1 ; 1 H NMR (400 MHz) 8: 0.97 (s,3H, Me-19, [NOTE: Clerodane numbering system]), 1.03 (d, 3H, J. 7 Hz, Me-17),1.20-1.95 (m, 11H), 2.10-2.30 (m, 3H), 3.33 (s, 3H, OMe), 3.47 (m, 2H, H's-12), 4.55(m, 2H, H's-18), 4.56 (s, 2H, OCH2O), 9.96 (s, 1H,CH0); 130 NMR (50.3 MHz)8: 16.89 (-ve, Me-17), 21.26 (-ve, Me-19), 22.20, 27.42, 28.35, 28.55, 32.63, 36.77(C-1, C-2, C-3, C-6, C-7, C-11), 36.04 (-ve, C-8), 39.92 (C-5), 50.50 (-ve, C-10), 53.64(0-9), 55.16 (-ve, OMe), 62.75 (C-12), 96.35 (OCH2O), 103.84 (C-18), 158.32 (C-4),206.52 (-ve, CHO, C-20); LRMS: M+(294) 0.5%; HRMS calcd for C18H3003:294.2195, found: 294.2202 (matched peak); Anal. calcd for C18H3003: C 73.43, H10.27, found: C 73.62, H 10.40; [ a )1) 25 +69.2°, c = 1.035 in chloroform; CD: c =1.035 in chloroform; ['F ]x 25 : 310.7 nm (+853.5, 44 nm).4.2.4.6. Preparation of (+)-(1 R.2S.3R.6R)-2-(3.5-Dioxahexyl)-7-methylene-2.3.6-trimethylbicyclo[4.4.0]decane (214) 148,247231Anhydrous hydrazine [DANGER, ARGON ATMOSPHERE]248,249,250 (3.15 mL,98 mmol, 100 equiv) was added via syringe to a solution of the aldehyde 218(284 mg, 0.96 mmol) in anhydrous diethylene glycol (4 mL) and the mixture washeated between 120-140 °C (sand bath temperature) for 7 h. The mixture was cooledto room temperature and the excess hydrazine was distilled under vacuum (vacuumpump, 0.2 torr, 70-80 °C sand bath temperature). Powdered potassium hydroxide(552 mg, 9.8 mmol, 10 equiv) was added and the mixture was heated at 230 °C (sandbath temperature) for 1.5 h. The mixture was cooled to room temperature and thenwater (15 mL) and ether (50 mL) were added. The layers were separated and theaqueous layer was extracted with ether (4 x 30 mL). The combined organic layerswere washed with brine (15 mL) and dried with magnesium sulfate. The solvents wereremoved under reduced pressure to give 292 mg of oil. The oil was purified by flashchromatography (4 g silica gel, 95:5 hex:ether) to give 221 mg (82%) of the ether 214as a colourless oil after distillation (110-140 °C/0.2 torr). The product exhibited IR(neat): 3086, 2928, 1636, 1448, 1385, 1213, 1149, 1109, 1078, 1041, 892 cm -1 ;1 H NMR (400 MHz) 8: 0.75 (s, 3H, Me-19, [NOTE: Clerodane numbering system]),0.85 (d, 3H, J. 6 Hz, Me-17), 1.04(s, 3H, Me-20),1.20-1.70 (m, 11H), 1.88 (br d, 1H,J.12 Hz, H-2e), 2.10 (br dd, 1H, J . 4, 13.5 Hz, H-3e), 2.29 (br tdt, 1H, J. 1.3, 5,13.5 Hz, H-3a), 3.34 (s, 3H, OMe), 3.38 (ddd, 1 H, J.5, 10, 11 Hz, H-12b), 3.47 (ddd,1H, J. 6, 10, 11 Hz, H-12a), 4.49 (br s, 2H, H's-18), 4.57 (s, 2H, OCH2O); 13C NMR(50.3 MHz) 8: 16.19 (-ve, Me-17), 17.86 (-ve, Me-20), 20.84 (-ve, Me-19), 22.00, 27.47,28.55, 33.04, 37.25 (2 x CH2) (C-1, C-2, C-3, C-6, C-7, C-11), 37.57 (-ve, C-8), 39.09(C-5), 40.11 (C-9), 49.50 (-ve, C-10), 55.05 (-ve, OMe), 63.50 (C-12), 96.38 (OCH2O),102.75 (C-18), 160.35 (C-4); LRMS: M+-Me0H(248) 12.2%; HRMS calcd forC18H3202: 280.2402, found: 280.2396; Anal. calcd for Ci8H3202: C 77.09, H 11.50,found: C 77.20, H 11.46; [ a ]) 25 +75.7°, c . 1.165 in chloroform.12H-8IH-la H-6eM e-20H-4aMe-19H-2eH-3231 Me-18Me-17H-7aH-10H-le^iiH-6aH-2aH-8H-18bH-3a2324.2.4.7. Preparation of (1 R.2S.3R.6R)-2-(2-Hydroxyethyl)-7-methylene-2.3.6-trimethylbicyclo[4.4.0]decane (232). (-)-(1R.6R.7S.8R)-7-(2-Hydroxyethy0- 1.2.7.8-tetramethylbicyclo[4.4.01dec-2-ene (231). the Acetals 253-255 and (-)-(1 R.5 S.6R.9S)-5.6.10.10-Tetramethy1-2-oxatricyclo[7.4.0.0 1,51tridecane(233) A) Preparation of the Mixture of Alcohols 231 and 232OHOH12H-10H-le^iiH-6aH-2e^ Me-17H-3e H-7a1Me-20H-la H-6e^H-4aMe-19H-18aH-2aA solution of dimethylboron bromide (2 M in dichloromethane, 460 4.,0.92 mmol, 3 equiv) was added to a cold (-78 °C) solution of the ether 214 (86 mg,0.3 mmol) in dry dichloromethane (4 mL). The mixture was stirred for 4.5 h at -78 °Cand was carefully transferred via cannula into a rapidly stirred mixture of DME (9 mL),saturated aqueous sodium bicarbonate (4 mL) and saturated aqueous sodiumcarbonate (5 mL). The reaction flask was rinsed with a small amount of DME (-3 mL)and the DME was added, via cannula, to the work-up mixture and the mixture wasefficiently stirred for 6 h at room temperature. Ether (20 mL) was added and the layerswere separated. The aqueous layer was extracted with ether (3 x 20 mL). Thecombined organic layers were washed successively with 10%(w/v) aqueous sodium233thiosulfate (6 mL) and brine (2 x 10 mL) and the ether extracts were dried withmagnesium sulfate. The solvents were removed under reduced pressure to give101 mg of oil. The oil was purified by flash chromatography (6 g silica gel, 7:3 to 3:1hex:ether, 100 mL) to give 62 mg (86%) of the isomeric alcohols 232 and 231 (1:4 by1 H NMR) after distillation (100-120 °C/0.15 torr). The mixture exhibited 1 H NMR(400 MHz) 8: 0.73 (s, 3H, Me-19, 231, [NOTE: Clerodane numbering system]), 0.75(s, Me-19, 232), 0.86 (d, 3H, J. 6 Hz, Me-17, 232 and 231), 1.00 (s, 3H, Me-20,231), 1.04(s, Me-20, 232), 1.10-2.35 (m, 16H, 232 and 231 including 8 1.57 [m, 3H,Me-18, 231]), 3.45-3.70 (m, 2H, H-12, 232 and 231), 4.49 (d, in a ratio 1:2 with thesignal at 8 5.18, J. 1.6 Hz, H-18, 232) 251 , 5.18 (m, 1H, H-3, 231).B) Preparation of the Acetals 253-255( 103 ,1819253-25520 „,Os'CH211 12 017If the work-up time in (A) is shorter or if only sodium bicarbonate is employed, assuggested by Guindon and coworkers, 152b we observed the formation of varyingamounts (0%-30%) of the acetals 253-255 (mixture of exo-exo, endo-endo and exo-endo double bonds; the ratio of the double bonds exo:endo was 2.5:1 by 1 H NMR). 252A pure sample of this material was obtained by TLC grade silica chromatography (2 gH type silica, 98:2 hex:ether). The product exhibited IR (neat): 2963, 2921, 1636,1448, 1384, 1109, 1080, 1038, 891 cm -1 ; 1 H NMR (400 MHz) 8: 0.72 and 0.74 (two s,3H, Me-19, [NOTE: Clerodane numbering system]), 0.83 (d, 3H, J. 6 Hz, Me-17), 0.95and 1.02 (two s, 3H, Me-20), 1.10-2.35 (m, 15H, including 8 1.57 [m, 3H, endo Me-18]),2343.30-3.50 (m, 2H, H-12), 4.49 (d, 2H, J. 1.6 Hz, H-18), 4.55-4.60 (three s, 2H,OCH2O), 5.18 [m, H-3 (endo double bond) in a ratio 1:5 with the signal of the exo-methylene at 6 4.49]; LRMS: M+-C16H260(248) 4.4%; DCIMS(NH3): MNH4+(502);DCIMS(i-Bu): M+(484); HRMS calcd for C33H5602: 484.4280, found: 484.4276;Anal. calcd for C33H5602: C 81.76, H 11.64, found: C 81.92, H 11.72C) Preparation of the Alcohol 231Anhydrous p-TsOH (12 mg, 0.07 mmol, 0.16 equiv) was added to a solution ofthe alcohols 232 and 231 (1:2.2, 103 mg, 0.44 mmol) in dry chloroform (10 mL, driedby passing through 5 g of flame dried basic alumina) at room temperature. Themixture was stirred for 24 h and the solvent was removed under reduced pressure.The resulting oil was immediately purified by flash chromatography (6 g silica gel, 7:3hex:ether) to give 96 mg (93%) of a mixture of alcohols 232 and 231 (1:52 by1 H NMR) after distillation (100-120 °C/0.2 torr). The product exhibited IR (neat):3354, 2962, 1461, 1383, 1028, 980 cm -1 ; 1 H NMR (400 MHz) 6: 0.73 (s, 3H, Me-19,[NOTE: Clerodane numbering system]), 0.86 (d, 3H, J. 6 Hz, Me-17), 1.00 (s, 3H,Me-20), 1.10-1.80 (m, 14H,including 6 1.54 [m, 1H, OH exchanges with D20] and6 1.58 [m, 3H, Me-18]), 1.95-2.10 (m, 2H, H's-2), 3.55-3.67 (m, 2H, H's-12), 4.49 (d,very small, 232), 5.18 (m, 1H, H-3); 13C NMR (50.3 MHz) 6: 16.19 (-ve, Me-17), 17.93(-ve, Me-20), 18.02 (-ve, Me-19), 19.96 (-ve, Me-18), 18.54, 26.80, 27.47, 36.67, 38.24,38.75 (C-1, C-2, C-5, C-6, C-7, C-11), 37.30 (-ve, C-8), 40.92 (C-9), 47.96 (-ve, C-10),56.63 (C-12), 120.41 (-ve, C-3), 144.23 (C-4); LRMS: M+-(236) 0.9%; DCIMS(NH3):M+(236) 3 %; HRMS calcd for C16H280: 236.2140, found: 236.2147; Anal. calcd forC16H280: C 81.29, H 11.94, found: C 81.49, H 12.13; [ a ]D25 -48.7°, c = 1.035 inchloroform.D) Preparation of the Ether 233323515 251A solution of the ether 214 (15 mg, 0.05 mmol) in THE (1 mL) and aqueoushydrochloric acid (6 N, 1 mL) was heated at 50 °C for 20 h. Water (1 mL) was addedand the mixture was extracted with ether (2 x 10 mL). The combined organic extractswere washed successively with saturated aqueous sodium bicarbonate (2 x 1.5 mL)and brine (2 x 1.5 mL) and the ether extracts were dried with magnesium sulfate. Thesolvents were removed under reduced pressure to give 8.6 mg (69%) of the tricyclicether 233 after flash chromatography (0.3 g silica gel, 95:5 hex:dichloromethane) anddistillation (75-85 °C/0.07 torr). The product exhibited IR (neat): 2947, 1464, 1386,1365, 1064, 1039, 1023, 1001, 950, 912 cm -1 [lit. 1 62 (CCI4): 1383, 1368, 1044, 1030cm -1 ]; 1 H NMR (400 MHz, CCI4, TMS) 8: 0.80 (s, 3H), 0.81 (d, 3H, J. 6 Hz, Me-15),0.86 (s, 3H), 0.91 (s, 3H), 0.95-1.20 (m, 4H), 1.20-1.60 (m, 8H), 1.60-1.80 (m, 2H), 3.66(ddd, 1H, J = 3, 8.5, 10 Hz, H-3), 3.76 (ddd, 1H, J = 8.5, 8.5, 8.5 Hz, H-3); [lit. 162 ,1H NMR (CCI4, TMS) 8: 0.80 (s, 3H), 0.82 (d, 3H, J= 6 Hz, Me-15), 0.87 (s, 3H), 0.92(s, 3H), 3.72 (center m, CH20)];.. 1 H NMR (400 MHz) 6: 0.81 (s, 3H, Me-14), 0.81 (d,3H, J= 6 Hz, Me-15), 0.87 (s, 3H, Me-16), 0.94 (s, 3H, Me-17), 1.00-1.20 (m, 4H, H-8a,H-9, H-11 a, H-13a), 1.30-1.40 (m, 3H, H-7e, H-11e, H-12e), 1.41-1.51 (m, 3H, H-6,H-7a, H-8e), 1.52-1.65 (m, 2H, H-4a, H-13e), 1.70 (ddddd, 1H, J. 3, 3.5, 13, 13, 13 Hz,12a), 1.77 (ddd, 1H, J. 3, 8.5, 12.5 Hz, H-4b), 3.71 (ddd, 1H, J. 3, 8.5, 10 Hz, H-3a),3.82 (ddd, 1H, J. 8.5, 8.5, 8.5 Hz, H-3b); COSY: see Table 4.1.Table 4.1: The 400 MHz 1 H NMR and COSY Data for the Tricyclic Ether 233Assignment(H-X)1H NMR5 ppm (mutt., # of H, J (Hz))COSY Correlation(H-X)Me-14 0.81 (s, 3H) ^aMe-15 0.81 (d, 3H, 6) 6Me-16 0.87 (s, 3H) ^aMe-17 0.94 (s, 3H) 9(LR), 11a(LR)7a911a13a1.00-1.20 (m, 4H)6, 7e, 8a, 8eMe-17(LR)11e, 12a, 12e13e8a11e12e1.30-1.40 (m, 3H)6, 7a, 7e, 8e, 911a, 12a13a, 13e67e8e1.41-1.51 (m, 3H)Me-15, 7a8a94b13e1.52-1.65 (m, 2H) 3a, 4a, 4b12a, 12e, 13a12a 1.70 (ddddd, 1H, 3, 3.5, 13, 13, 13) 11a, 11e, 12e, 13a, 13e4a 1.77 (ddd, 1H, 3, 8.5, 12.5) 3a, 3b, 4b3b 3.71 (ddd, 1H, 3, 8.5, 10) 3a, 4a,4b3a 3.82 (ddd, 1H, 8.5, 8.5, 8.5) 3b, 4a, 4ba No correlation.b (LR) = Long range correlation.HMBC: see Table 2.24, HMQC: see Table 2.24; Selective decouplingexperiments: irradiation of the signal at 5 0.81 (Me-15) led to simplification of thesignal at 5 1.41-1.51 (H-6); irradiation of the signal at 5 1.41-1.51 (H-6, H-7e, H-8a) ledto simplification of the signal at 5 0.81 (s, Me-15), 5 1.00-1.20 (H-7a, H-9) and 1.30-1.40 (H-8e); irradiation of the signal at 5 1.70 (H-12a) led to simplification of the signalat 5 1.00-1.20 (H-11a, H-13a), 5 1.30-1.40 (H-11e, H-12e) and 5 1.52-1.65 (H-13e);236237irradiation at 6 3.71 (H-3a or b) simplified the signal at 6 1.53-1.65 (H-4a or b),produced a doublet of doublets at 8 1.77 (J = 8.5, 12.5 Hz, H-4a or b) and a doublet ofdoublets at 6 3.82 (J = 8.5, 8.5 Hz, H-3b or a); irradiation at 6 3.82 (H-3b or a)simplified the signal at 6 1.53-1.65 (H-4a or b), produced a doublet of doublets at8 1.77 (J = 3.5, 12.5 Hz, H-4b or a) a doublet of multiplets at 6 3.71 (J = 10 Hz, H-3a orb); NOE difference experiments: Irradiation of the signals at 8 0.81 (Me-14 andMe-15) enhanced the signals at 8 1.00-1.20 (H-7a, H-13a), 8 1.41-1.51 (H-6, H-7e),8 1.52-1.65 (H-13e, H-4b), 8 1.77 (H-4a, ddd, J . 3, 8.5, 12.5 Hz): Irradiation of thesignals at 8 0.83 (mostly Me-15) enhanced the signals at 8 1.00-1.20 (H-7a), 8 1.41-1.51 (H-6, H-7e), 8 1.77 (H-4a, ddd, J = 3, 8.5, 12.5 Hz): Irradiation of the signal at5 0.87 (Me-16) enhanced the signals at 8 1.30-1.40 (dm, J . 11 Hz, H-11e), 8 1.41-1.51 (dm, J = 13.5 Hz, H-8e): Irradiation of the signal at 8 0.94 (Me-17) enhanced thesignals at 8 1.30-1.40 (dm, J = 11 Hz, H-11e and m, H-8a), 8 1.41-1.51 (dm, J =13.5 Hz, H-8e): Irradiation of the signal at 8 1.15 (mostly H-11 a) enhanced the signalsat 8 0.87 (Me-16), 8 1.30-1.40 (H-11e, H-12e), 8 1.52-1.65 (H-13e negative NOE),5 1.70 (ddddd, negative NOE, H-12a): Irradiation of the signal at 8 1.70 (H-12a)enhanced the signals at 8 0.94 (Me-17), 8 1.30-1.40 (H-11e, H-12e), 8 3.71 (ddd, J = 3,8.5, 10 Hz, H-3b): Irradiation of the signal at 8 1.77 (H-4a) enhanced the signals at5 1.41-1.51 (H-6), 8 1.52-1.65 (H-4b), 8 3.82 (H-3a): Irradiation of the signal at 8 3.71(H-3b) enhanced the signals at 8 1.52-1.65 (H-4b), 5 3.82 (H-3a): Irradiation of thesignal at 8 3.82 (H-3a) enhanced the signals at 8 1.77 (H-4a), 8 3.71 (H-3b); 13C NMR(50.3 MHz) 8: 13.47 (-ve, Me-14), 17.44 (-ve, Me-15), 18.44 (C-12), 22.10 (C-7), 22.37(-ve, Me-17), 31.28 (C-8), 31.42 (C-13), 32.27 (-ve, Me-16), 34.09 (C-10), 35.37 (C-4),35.46 (-ve, C-6), 42.70 (C-11), 47.03 (C-5), 47.91 (-ve, C-9), 62.44 (C-3), 85.10 (C-1);LRMS: MA--(236) 6.4%; HRMS calcd for Ci6H280: 236.2140, found: 236.2147; Anal.calcd for C16H280: C 81.29, H 11.94, found: C 81.00, H 12.10; [ a ]D 25 -36.3°, c =1.77 in chloroform [Iit. 162 [ a ]p25 for the enantiomer +39.1°, c = 6.3 in chloroform].20^11 12 I178 .......19^21318H-2aIH-la H-6eM e-20H-4aMe-192384.2.4.8. Preparation of (-)-(1R.6R.7S.8R)-7-(2-lodoethyl)-1.2.7.8-tetramethylbicyclo-j4.4.01dec-2-ene (213) 168Solid iodine (217 mg, 0.84 mmol, 2.4 equiv) was added to a cold (0 °C) mixtureof triphenylphosphine (230 mg, 0.88 mmol, 2.5 equiv) and imidazole (60 mg,0.88 mmol, 2.5 equiv) in dry dichloromethane (5 mL). The mixture was stirred for20 min at 0 °C and for 10 min at room temperature to give a yellow precipitate in abright yellow solution. The mixture was cooled back to 0 °C and a solution of thebicyclic alcohol 231 (83 mg, 0.35 mmol) in dry dichloromethane (3 mL) was slowlyadded. The mixture was stirred at room temperature for 24 h and then saturatedaqueous sodium bicarbonate (10 mL) and ether (20 mL) were added. The layers wereseparated and the aqueous layer was extracted with ether (3 x 10 mL). The combinedorganic layers were dried with magnesium sulfate and were passed through a columnof Florisil® (10 g) and the Florisil® was washed with ether (50 mL). The combinedeluants were concentrated and the resulting oil was purified by TLC grade silicachromatography (10 g H type silica, hex) to give 109 mg (90%) of the bicyclic iodide213 as a low melting solid (mp 29-30 °C) after distillation (90-130 °C/0.1 torr). Theproduct exhibited IR (neat): 2963, 1664, 1437, 1383, 1158, 797, 621, 530 cm -1 ;1 H NMR (400 MHz) 5: 0.70 (s, 3H, Me-19, [NOTE: Clerodane numbering system]),0.82 (d, 3H, J. 6 Hz, Me-17), 0.97 (s, 3H, Me-20), 1.15 (dd, 1H, J. 8, 12.5 Hz), 1.29(dd, 1H, J. 2, 12 Hz), 1.35-1.60 (m, 8H, including 5 1.56 [d, 3H, J. 1.5 Hz, Me-18]),1.69 (ddd, 1H, J. 2.5, 3, 13 Hz), 1.94-2.13 (m, 4H), 3.02 (ddd, 1H, J. 5.5, 9, 12.5 Hz,H-12a), 3.11 (ddd, 1H, J. 5.0, 9, 12.5 Hz, H-12b), 5.18 (m, 1H, H-3); 13C NMRM )—/C°0Ete3Sn Me3Sn)— \COOEt260^COOEt258 259239(75.3 MHz) 8: 1.09 (C-12), 16.21 (-ve, Me-17), 17.81 (-ve, Me-20), 18.00 (-ve, Me-19),19.97 (-ve, Me-18), 18.45, 26.80, 27.28, 36.63, 43.86 (C-1, C-2, C-6, C-7, C-11), 36.40(-ve, C-8), 38.06, 42.33 (C-5, C-9), 46.45 (-ve, C-10), 120.42 (-ve, C-3), 144.14 (C-4);LRMS: M+(346) 17.8%; HRMS calcd for C16H271: 346.1157, found: 346.1155; Anal.calcd for C16H271: C 55.49, H 7.86, found: C 55.84, H 7.83; [ a )D 25 -45.7°,c = 1.75 in chloroform.4.2.4.9. Preparation of (E)-3-Trimethylstanny1-2-buten-1-ol (261) A) Preparation of Ethyl (E)- and (Z)-3-Trimethylstannyl-2-butenoate (259 and 260) 169A solution of methyllithium (1.4 M, 32 mL, 44.7 mmol, 1.3 equiv) was slowlyadded to a cold (-20 °C) solution of hexamethylditin (9.3 mL, 44.7 mmol, 1.3 equiv) inTHE (250 mL). After 20 min, the solution was faintly yellow and the stir bar was blue.The solution was cooled to -78 °C and stirred at this temperature for 10 min. Solidcopper(I) cyanide (4.0 g, 44.7 mmol, 1.3 equiv) was added, in one portion, to thealmost colorless solution. The yellow-red solution/suspension was stirred 6 min at-78 °C and 15 min at -48 °C. The clear orange solution of the cuprate 87 was cooledto -78 °C and was stirred at this temperature for 10 min. Anhydrous EtOH (2.6 mL,44.7 mmol, 1.3 equiv) was added dropwise and a solution of ethyl 2-butynoate (258,4.0 mL, 34.3 mmol) in THE (30 mL) was added via a small bore Teflon® cannula overa period of 40 min at -78 °C. The pale yellow solution was stirred at -78 °C for 3 h.A stopper was removed and aqueous ammonium chloride (pH 9, 50 mL) was rapidlyadded via a 50 mL disposable plastic syringe to the efficiently stirred reaction mixture.The red-brown mixture was warmed to room temperature and aqueous ammoniumchloride (pH 9, 15 mL) was added and the mixture was poured into a large Erlenmeyer240flask. Ether (800 mL) was added and the mixture was efficiently stirred overnight. Thelayers were separated and the deep blue aqueous layer was reextracted with ether(100 mL). The combine organic layers were dried with magnesium sulfate and thesolvents were removed under reduced pressure. The resulting oil was purified by TLCgrade silica chromatography (160 g H type silica, 200:3 petroleum ether:ether, 2 L) togive 17.48 g (79%) of ethyl (E)-3-trimethylstannyl-2-butenoate (259) after distillation(50-70 °C/0.1 torr) and 1.33 g (14%) of a 1:1 mixture of the ester 259 and ethyl (Z)-3-trimethylstanny1-2-butenoate (260). A pure sample of the ester 260 was obtained byfurther chromatography. The (E)-ester 259 exhibited IR (neat): 2981, 2912, 1715,1604, 1447, 1367, 1340, 1179, 1039, 865, 772, 530 cm -1 ; 1 H NMR (400 MHz) 8: 0.17(s, 9H, 2J sn-H = 54 Hz, Me3Sn), 1.28 (t, 3H, J. 7 Hz, OCH2Me), 2.38 (d, 3H, J. 2 Hz,3 .-1 Sn-H = 50 Hz, Me-4), 4.15 (q, 2H, J. 7 Hz, OCH2Me), 5.97 (q, 1H, J. 2 Hz, 3../ sn-H =74 Hz, H-2); 13C NMR (75.3 MHz) 6: -10.07 (-ve, 1 J s n_c = 340 Hz, Me3Sn), 13.31(-ve, OCH2Me), 21.39 (-ve, 2 J sn-c = 34 Hz, Me-4), 59.51 (OH2Me), 127.84 (-ve,2 .-I Sn-C = 40 Hz, C-2), 164.43 (C-3), 168.05 (C-1); LRMS: M+-Me(263) 46.6%;DCIMS(NH3): MH+(279); HRMS calcd for C8H15O2Sn (M+-Me): 263.0093, found:263.0094; Anal. calcd for C9H18O2Sn: C 39.03, H 6.55, found: C 38.37, H 6.47.The (Z)-ester 260 exhibited IR (neat): 2981, 1703, 1604, 1445, 1369, 1318,1202, 1103, 1044, 864, 773, 535 cm -1 ; 1 H NMR (400 MHz) 6: 0.19 (s, 9H, 2J Sn-H =56 Hz, Me3Sn), 1.29 (t, 3H, J. 7 Hz, OCH2L/19.), 2.15 (d, 3H, J. 2 Hz, 3L/ sn-H = 44 Hz,Me-4), 4.17 (q, 2H, J. 7 Hz, OCH2Me), 6.40 (q, 1H, J. 2 Hz, 3J sn_H = 117 Hz, H-2);LRMS: M+-Me(263) 58.5%; DCIMS(NH3): M+(278); HRMS calcd for C8H15O2Sn(M+-Me): 263.0093, found: 263.0092; Anal. calcd for C9H18O2Sn: C 39.03, H 6.55,found: C 38.88, H 6.59.B) Preparation of (E)-3-Trimethylstanny1-2-buten-1-01 (261)_____/---OHMe3Sn 2 61241A solution of i-Bu2AIH (1 M hex, 43.3 mL, 43.3 mmol, 3 equiv) was added to acold (-78 °C) solution of the (E)-ester 259 (4.0 g, 14.4 mmol) in ether (350 mL). Themixture was stirred for 50 min at -78 °C and for 2 h at 0 °C. Saturated aqueousammonium chloride (10 mL) was added and the mixture was stirred for 1 h at roomtemperature. Magnesium sulfate (10 g) was added and the white suspension wasstirred for 2 h. The gel was filtered through Florisil® (190 g) and the Florisil® waswashed with ether (1.75 L). The ether was removed under reduced pressure and theoil was purified by distillation (60-90 °C/0.25 torr) to give 3.27 g (97%) of the(E)-alcohol 261. The (E)-alcohol 261 exhibited IR (neat): 3303, 2981, 2907, 1435,1189, 1117, 1061, 1006, 768, 526 cm -1 ; 1 H NMR (400 MHz) 6: 0.13 (s, 9H, 2J Sn-H =55 Hz, Me3Sn), 1.32 (t, 1H, J. 6 Hz, OH [exchanged with D20]), 1.90 (d, 3H, J. 2 Hz,3 .-ISn-H = 52 Hz, Me-4), 4.28 (dd, 2H, J. 6, 6.5 Hz, H's-1 [became a d, J. 6.5 Hz, withD20]), 5.78 (qt, 1H, J. 2, 6.5 Hz, 3J sn-H = 76 Hz, H-2); 13C NMR (50.3 MHz) 6: -10.26(-ve, Me3Sn), 18.56 (-ve, Me-4), 58.84 (C-1), 138.67 (-ve, C-2), 142.70 (C-3); LRMS:M+-Me(221) 100%; HRMS calcd for C6H130Sn (M+-Me): 220.9987, found:220.9994; Anal. calcd for C7H16OSn: C 35.79, H 6.87, found: C 35.52, H 6.89.4.2.4.10. Preparation of (E)-1-(tent-Butyldimethylsilyloxy)-3-trimethylstanny1-2-butene(262) and (E)-1-(Triiiso-propylisilyloxy)-3-trimethylstanny1-2-butene (263) /-0TBDMS ) /0TIPSMe3Sn 262 ^Me3Sn 263A) Preparation of the TBDMS-Ether 262Solid TBDMSCI (2.37 g, 15.7 mmol, 2 equiv) was added to a solution of the(E)-alcohol 261 (1.85 g, 7.86 mmol) and imidazole (1.61 g, 23.6 mmol, 3 equiv) in drydichloromethane (125 mL). The white solution/suspension was stirred at roomtemperature for 3.5 h. Saturated ammonium chloride (100 mL) was added and the242layers were separated. The aqueous layers was extracted with dichloromethane (3 x50 mL) and the combined organic layers were washed with brine (100 mL). Theorganic extracts were dried with magnesium sulfate and the solvent was removedunder reduced pressure. The resulting oil was filtered through silica gel (11 g) and thesilica was washed with a mixture of hex and dichloromethane (95:5, 125 mL). Thesolvents were removed under reduced pressure to give 2.72 g (99%) of the(E)-TBDMS ether 262 after distillation (80-90 °C/0.06 torr). The (E)-TBDMS ether 262exhibited IR (neat): 2980, 2956, 1473, 1373, 1256, 1190, 1093, 1042, 1007, 838, 775,528 cm -1 ; 1 H NMR (400 MHz) 8: 0.09 (s, 6H, Me2Si), 0.11 (s, 9H, 2J sn-H = 55 Hz,Me3Sn), 0.91 (s, 9H, t-Bu), 1.84 (d, 3H, J . 2 Hz, 3 J sn-H = 51 Hz, Me-4), 4.29 (d, 2H,J . 6.5 Hz, 4J sn-H = 16 Hz, H's-1), 5.68 (qt, 1H, J= 2, 6.5 Hz, 3J sn-H = 76 Hz, H -2);13C NMR (50.3 MHz) 8: -10.29 (-ve, 1 J sn-c = 347 Hz, Me3Sn), -5.06 (-ve, 1 Jsi-c =50 Hz, Me2Si), 18.42 (SiCMe2), 18.56 (-ve, Me-4), 26.01 (-ve, SiCMg3), 59.95(3Jsn-c = 60 Hz, C-1), 139.52 (C-3), 140.12 (-ve, C-2); LRMS: M+-Me(335) 45.8%;HRMS calcd for C12H270SiSn (M+-Me): 335.0852, found: 335.0857 (peak matched);Anal. calcd for Ci3H300SiSn: C 44.72, H 8.66, found: C 44.90, H 8.76.B) Preparation of the TIPS-Ether 263TIPSCI 173 (2.7 mL, 12.6 mmol, 1.1 equiv) was added to a solution of the(E)-alcohol 261 (2.7 g, 11.5 mmol) and imidazole (1.6 g, 23 mmol, 2 equiv) in drydichloromethane (100 mL). The white solution/suspension was stirred at roomtemperature for 22 h. Saturated ammonium chloride (85 mL) was added and thelayers were separated. The aqueous layers was extracted with dichloromethane (3 x50 mL) and the combined organic layers were washed with brine (85 mL). Theorganic extracts were dried with magnesium sulfate and the solvent was removedunder reduced pressure. The resulting oil was filtered through silica gel (20 g) and thesilica was washed with a mixture of hex and dichloromethane (95:5, 200 mL). Thesolvents were removed under reduced pressure to give 4.3 g (96%) of the (E)-TIPS243ether 263 after distillation (110-130 °C/0.15 torr). The product exhibited IR (neat):2962, 2944, 2867, 1464, 1366, 1256, 1190, 1042, 1014, 996, 883, 766, 683, 528 cm -1 ;1 H NMR (400 MHz) 6: 0.10 (s, 9H, 2 J sn-H = 53 Hz, Me3Sn), 1.02-1.15 (m, 21H,U-Prj3Si), 1.82 (td, 3H, J. 0.8, 2 Hz, 3J sn-H = 51 Hz, Me-4), 4.35 (qd, 2H, J. 0.8,5.5 Hz, 4 ../ sn-H = 19 Hz, H's-1), 5.69 (qt, 1H, J. 2, 5.5 Hz, 3 J sn-H = 77 Hz, H -2);13C NMR (50.3 MHz) 8: -10.27 (-ye, 1 Jsn-c = 327 Hz, Me3Sn), 12.05 (-ye, 2,./Sn-C =60 Hz, C-4), 18.00 (-ye, Si[CHIa2]3), 18.63 (-ye, Si[aHMe2]3), 60.20 ( 3Jsn-c = 80 Hz,C-1), 138.84 (C-3), 140.59 (-ye, 3Jsn-c = 25 Hz, C-2); LRMS: M+-Me(377) 23.5%;DCIMS(NH3): M+(391) 5.96%; HRMS calcd for C15H330SiSn (Mt-Me): 377.1322,found: 377.1329; Anal. calcd for C16H360SiSn: C 49.12, H 9.27, found: C 49.22,H 9.29.4.2.4.11. Preparation of (E)-1-(tert-Butyldimethylsilyloxy)-3-iodo-2-butene (264) and(E)-3-lodo-1-(tri-Uso-propyllsilyloxy)-2-butene (265) 174I.^264) /-0TIPS265IA) Preparation of the TBDMS-lodide 264A solution of iodine (1.19 g, 4.68 mmol, 1.1 equiv) in dry dichloromethane(30 mL) was added, dropwise via a Teflon® cannula, to a solution of the (E)-TBDMSether 262 (1.48 g, 4.25 mmol) in dry dichloromethane (30 mL), at room temperature,until a yellow coloration persisted. The mixture was stirred for 30 min and was washedwith aqueous sodium thiosulfate (10% w/v, 5 mL) and brine (5 mL). Thedichloromethane solution was dried with magnesium sulfate and the solvent wasremoved under reduced pressure to give 2.27 g of a colorless oil. The oil was purifiedby flash chromatography (60 g silica gel, 95:5 hex:ether [note: the trimethylstannyliodide decomposes on the top of the column to give a yellow band]) to give 1.27 g(95 %) of the (E)-TBDMS iodoether 264 after distillation over copper(0) (60-80 °C,2440.1 torr). The product was kept over copper(0) and was protected from the light. The(E)-TBDMS iodoether 264 exhibited IR (neat): 2956, 2711, 1639, 1472, 1381, 1257,1092, 1042, 1007, 939, 838, 777, 669 cm -1 ; 1 H NMR (400 MHz) 8: 0.06 (s, 6H,Me2Si), 0.89 (s, 9H, t-Bu), 2.40 (dt, 3H, J. 2, 1 Hz, Me-4), 4.11 (dd, 2H, J. 1, 6.5 Hz,H's-1), 6.28 (qt, 1H, J. 2, 6.5 Hz, H-2); 13C NMR (50.3 MHz) 8: -5.22 (Me2Si), 18.32(SiaMe3), 25.87 (-ve, SiCMe.3), 28.08 (Me-4), 60.67 (C-1), 95.97 (C-3), 140.64 (C-2).B) Preparation of the TIPS-Iodide 265A solution of iodine (3.45 g, 13.6 mmol, 1.05 equiv) in dry dichloromethane(100 mL) was added, dropwise via a Teflon® cannula, to a solution of the (E)-TIPSether 263 (5.06 g, 12.9 mmol) in dry dichloromethane (100 mL), at room temperature,until a yellow coloration persisted. The mixture was stirred for 1.6 h and was washedwith aqueous sodium thiosulfate (10% w/v, 20 mL) and brine (20 mL). Thedichloromethane solution was dried with magnesium sulfate and the solvent wasremoved under reduced pressure to give a colorless oil. The oil was purified by flashchromatography (200 g silica gel, 95:5 hex:ether, 1.75 L, [note: the trimethylstannyliodide decomposes on the the top of the column to give a yellow band]) to give 4.2 g(92%) of the (E)-TIPS iodoether 265  after distillation over copper(0)(85-110 °C/0.1 torr). The product was kept over copper(0) and was protected fromthe light. The (E)-TIPS iodoether 265 exhibited IR (neat): 2943, 2867, 1640, 1463,1382, 1255, 1110, 1043, 1014, 996, 883, 772, 684 cm -1 ; 1 H NMR (400 MHz) 5: 0.95-1.25 (m, 21H, [i-Pr]3Si), 2.40 (td, 3H, J. 1, 2 Hz, Me-4), 4.20 (qd, 2H, J. 1, 6.5 Hz,H's-1), 6.31 (qt, 1H, J. 2, 6.5 Hz, H-2); 13 C NMR (50.3 MHz) 8: 11.97 (-ve,Si[aHMe03), 17.90 (-ve, Si[CHMeA3), 28.15 (-ve, C-4), 60.96 (C-1), 95.42 (C-3),140.96 (-ve, C-2); LRMS: M+(354) 0.2%; HRMS calcd for C13H2710Si: 354.0875,found: 354.0877; Anal. calcd for C13H2710Si: C 44.06, H 7.68, found: C 44.28,H 7.53.16136^282191820,,,,11 12 14I20H-la H-6eM e-Me-19^H-4a15OTIPSH-2aMe-182454.2.4.12. Preparation of (1 R.6R.7S.8R)-7-Ethyl-1 2.7.8-tetramethylbicyclo[4.4.0]dec-2- ene (283). the Dimer 284 and (-)-(1 R.6R.7S.8R)-7-{3-Methyl-5-(tri-jisopropyl]-silyloxy)-3-(E-penteny1)}-1.2.7.8-tetramethylbicyclo[4.4.0]clec-2-ene (282) A) Copper(I) Catalyzed Vinylmagnesium-alkyl Iodide CouplingA solution of tert-butyllithium (1.7 M in hex, 450 4, 0.76 mmol, 7.1 equiv) wasslowly added to a cold (-78 °C) solution of the (E)-TIPS iodoether 265 (135 mg,0.38 mmol, 3.5 equiv) in THE (1.5 mL). The yellow solution was stirred at -78 °C for20 min and solid magnesium bromide etherate (98 mg, 0.38 mmol, 3.5 equiv) wasadded. The white suspension/solution was stirred for 15 min at -78 °C and 10 min atroom temperature. The clear, colourless solution was added via cannula, in 15 min, toa cold (7 °C) solution of tributylphosphine (freshly distilled, 19 ilL, 0.07 mmol,0.7 equiv), tributylphosphine-copper(I) iodide complex (21 mg, 0.053 mmol,0.5 equiv), HMPA (WARNING: carcinogenic, 107 kiL, 0.54 mmol, 5 equiv) and thebicyclic iodide 213 (37 mg, 0.11 mmol) in THE (0.5 mL). During the addition, theinitially bright yellow solution became pale yellow after 7 min, colorless after 12 min,246pale yellow after 15 min and again bright yellow after 25 min. After 1 h thetemperature had risen to 12 °C and the solution was bright yellow. At 15 °C (after 2 h),the solution turned dark green. Then as the temperature increased to roomtemperature, the solution became pale green (20 °C, 4.3 h) and then colorless (26 °C,7.3 h). After 20 h, the flask was opened and aqueous ammonium chloride (pH 9,5 mL) and ether (3 mL) were added to the reaction mixture. The mixture wasvigorously stirred until the aqueous layer became bright blue and then was extractedwith ether (3 x 10 mL). The combined organic layers were washed successively withsaturated aqueous copper(II) sulfate (2 x 5 mL), brine (5 mL), aqueous sodiumthiosulfate (10%, 5 mL) and brine (5 mL). The organic extracts were dried withmagnesium sulfate and the solvents were removed under reduced pressure to give131 mg of oil. The oil was purified by TLC grade silica chromatography (3.2 g H typesilica, hex, 50 mL; 95:5, 30 mL and 9:1, 20 mL, hex:dichloromethane) to give: -lesspolar fraction: 5.5 mg of a mixture consisting of the bicyclic iodide 213 (-70%) andsmaller amounts of the reduced bicyclic compound 283 and the dimer 284253 ; -morepolar fraction: 21.5 mg (45%, 53% based on recovered starting material) of thedesired TIPS ether of (-)-kolavenol 282.The (1R,6R,7S,8R)-7-ethyl-1,2,7,8-tetramethylbicyclo[4.4.0]dec-2-ene (283)(distilled: 65-75 °C/0.08 torr) exhibited IR (neat): 2964, 1663, 1460, 1382, 1242, 1176,1003, 980, 797 cm -1 ; 1 H NMR (400 MHz) 8: 0.68 (s, 3H, Me-20 [NOTE: Clerodanenumbering system]), 0.69 (t, 3H, J= 8.5 Hz, Me-12), 0.75 (d, 3H, J. 6.5 Hz, Me-17),0.98 (s, 3H, Me-19), 1.10-1.50 (m, 12H, including 8 1.55 [dd, 3H, J= 2, 2.5 Hz, Me-18]),1.68 (ddd, 1H, J = 2.5, 4, 12.5 Hz), 1.95-2.05 (br m, 2H, H's-2), 5.19 (br m, 1H, H-3);130 NMR (50.3 MHz) 8: 7.21 (-ve, Me-12), 15.93 (-ve, Me-17), 18.00 (-ve, Me-20),18.36 (-ve, Me-19), 19.90 (-ve, Me-18), 18.17, 26.88, 27.52, 30.42 (C-1, C-6, C-7,C-11), 35.47 (-ve, C-8), 36.86, 38.09, 38.27 (C-2, C-5, C-9), 46.69 (-ve, C-10), 120.49(-ve, C-3), 144.62 (C-4); LRMS: M+(220) 22.6%; HRMS calcd for C16H28: 220.2191,found: 220.2183.247The dimer 284 (mp: 129-130 °C, pumped overnight [vacuum pump]) exhibitedIR (2% KBr): 2933, 1636, 1457, 1382, 1174, 1000, 980, 798 cm -1 ; 1 H NMR (400 MHz)8: 0.69 (s, 6H, 2 x Me-20 [NOTE: Clerodane numbering system]), 0.79 (d, 6H,J. 6.5 Hz, 2 x Me-17), 0.98 (s, 6H, 2 x Me-19), 1.00-1.30 (m, 8H, 2 x H's-12,?), 1.30-1.60 (m, 20 H, including [8 1.57, dd, 6H, J. 2, 2.5 Hz, 2 x Me-18]), 1.69 (ddd, 2H,J = 2.5, 4, 12.5 Hz), 1.95-2.05 (br m, 4H, 2 x H's-2), 5.15 (br m, 2H, 2 x H-3);130 NMR (100.6 MHz) 8: 16.11 (-ve, Me-17), 18.01 (-ve, Me-20), 18.39 (-ve, Me-19),19.90 (-ve, Me-18), 18.30, 23.47, 26.90, 27.56 (C-1, C-6, C-7, C-11), 36.21 (-ve, C-8),36.85, 38.13, 38.54, 38.56 (C-2, C-5, C-9, C-12), 46.41 (-ve, C-10), 120.44 (-ve, C-3),144.62 (C-4); LRMS: M -1- (438) 2.8%; HRMS calcd for C32H54: 438.4226, found:432.4225.The (-)-(1R,6R,7S,8R)-743-methyl-5-(tri-[iso-propyl]silyloxy)-3-(E-penteny1)]-1,2,7,8-tetramethylbicyclo[4.4.0]dec-2-ene (282) exhibited IR (neat): 2942, 2866,1669, 1463, 1382, 1257, 1107, 1062, 1014, 883, 777, 682 cm -1 ; 1 H NMR (400 MHz)8: 0.71 (s, 3H, Me-20 [NOTE: Clerodane numbering system]), 0.80 (d, 3H, J. 6.5 Hz,Me-17), 0.99 (s, 3H, Me-19), 1.00-1.20 (m, 22H, [i-Pr]3Si (21H)), 1.25-1.50 (m, 8H),1.59 (dd, 3H, J. 1.5, 2 Hz, Me-18]), 1.61 (s, 3H, Me-16), 1.70 (ddd, 1H, J. 2.5, 3,13 Hz), 1.79 (ddd, 1H, J. 5, 13, 13 Hz, H-12a), 1.86 (ddd, 1H, J. 5, 13, 13 Hz,H-12b), 2.00-2.05 (m, 2H, H's-11), 4.25 (d, 2H, J. 6 Hz, H-15), 5.20 (br s, 1H, H-3),5.31 (qt, 1H, J. 1.5, 6 Hz, H-14); NOE difference experiments: Irradiation at 8 1.59(Me-18) led to the enhancement of signals at 8 5.20 (H-3, 2.3%); irradiation at 8 1.61(Me-16) led to the enhancement of signals at 8 4.25 (H-15, 2%); irradiation at 8 4.25(H-15) led to the enhancement of signals at 8 1.61 (Me-16), 8 5.31 (dd, H-14, 2%);irradiation at 8 5.20 (H-3) led to the enhancement of signals at 8 2.00-2.10 (H-2?);irradiation at 8 5.31 (H-14) led to the enhancement of signals at 8 4.25 (H-15, 2.5%);13C NMR (50.3 MHz) 8: 12.09 (-ve, Si[CHMe2]3), 15.97 (-ye, Me-17), 16.62 (-ve, Me-20), 18.03 (-ve, Si[CHMe2]3), 18.26 (-ve, Me-19), 18.38 (-ve, Me-16), 19.95 (-ve, Me-18), 18.03, 26.89, 27.54, 32.83, (C-1, C-6, C-7, C-11), 36.23 (-ve, C-8), 36.68, 36.86,24838.18, 38.58 (C-2, C-5, C-9, C-12), 46.39 (-ve, C-10), 60.58 (C-15), 120.48 (-ve, C-3),124.35 (-ve, C-14), 137.32 (C-13), 144.53 (C-4); LRMS: MH+(447) 0.3%; HRMScalcd for C29H54SiO: 446.3944, found: 446.3942; Anal. calcd for C29H54SiO:C 77.95, H 12.18, found: C 78.20, H 12.23; [ a ]D 25 -39 7°, c = 1.60 in chloroform.B) Palladium-catalyzed Alkylzinc-vinyl Iodide CouplingA solution of the bicyclic iodide 213 (freshly distilled,91.3 mg, 0.26 mmol) in dryether in a Kugelrohr bulb (0.2 mL) was added, via a small bore Teflon® cannula, to acold (-78 °C) solution of t-BuLi (1.67 M in hex, 363 pl, 0.61 mmol, 2.3 equiv) and thebulb was rinsed with dry ether (3 x 100 gL) into the t-BuLi solution. The colourlesssuspension/solution was stirred for 20 min at -78 °C and for 10 min at roomtemperature. The clear, slightly yellow solution was cooled to -78 °C and a solution offreshly prepared zinc dibromide 254,255 (0.4 mmol, 2 equiv) in THF (0.7 mL) was addedusing the same cannula. The resulting solid mass became, upon warming to roomtemperature for 10 min, a colourless, slightly cloudy solution. A beigesolution/suspension of palladium(0)bis(dibenzylidene)acetone (Pd(dba)2, 4.5 mg,0.008 mmol, 0.03 equiv) and triphenylarsine (9.7 mg, 0.032 mmol, 0.12 equiv) in THF(0.5 mL, prepared 10 min before) was added via a wide bore Teflon® cannula to thesolution of the zinc reagent. The (E)-TIPS iodoether 265 (freshly distilled over Cu(0),140 mg, 0.4 mmol, 1.5 equiv) was added immediately, via syringe, to the red-brownsolution/suspension. The solution/suspension became a clear yellow solution withinone min, then the color gradually changed to a brown-yellow. The mixture was stirredat room temperature for 21 h and ether (3 mL) and saturated aqueous ammoniumchloride (3 mL) were added. The mixture was extracted with ether (3 x 15 mL) and theether layers were washed with aqueous sodium thiosulfate (10% w/v, 2 x 3 mL) andbrine (5 mL). Magnesium sulfate (H g) and Florisil® (-1 g) were added to the organiclayer and the mixture was stirred for a few minutes. The solids were filtered and thesolvents were removed under reduced pressure to give 222 mg of oil. The residueOH^16^1513^OH^11 12^14^H-2a17H-2eH-8Me-17H-7a20 H-10H-1e H-6aH-365Me-18H-la H-6eM e-20Me-19^H-4a1918249was purified by TLC grade silica chromatography (8.5 g H type silica, hex, 60 mL; 98:2hex:dichloromethane, 60 mL; 95:5 hex:dichloromethane, 30 mL; 9:1hex:dichloromethane, 60 mL) to give 6.2 mg (11%) of (1R,6R,7S,8R)-7-ethyl-1,2,7,8-tetramethylbicyclo[4.4.0]dec-2-ene (283), 5.1 mg (9%) of the dimer 284 and 90 mg(77% after removal of traces of solvent by pumping overnight under vacuum [vacuumpump]) of the TIPS ether of (-)-kolavenol 282..4 .1^n •f^R•R 7^R -7-^-^h lor•x^E- • - n n1.2.7.8-tetramethylbicyclo[4.4.0]dec-2-ene (65) [(-)-Kolavenol]A) Synthetic (-)-Kolavenol (65)A solution of Bu4NF (1 M in THF, 0.5 mL, 0.5 mmol, 2.5 equiv) was added to asolution of the TIPS ether of (-)-kolavenol 282 (82 mg, 0.184 mmol) in THF (3 mL).The mixture was stirred at room temperature for 2 h. Water (6 mL) and brine (3 mL)were added to the slightly yellow solution and the mixture was extracted with ethylacetate (4 x 20 mL). The combine organic layers were dried with magnesium sulfateand the solvents were removed under reduced pressure to give a pale yellow oil. Theoil was purified by flash chromatography (4.5 g silica gel, 5:3:2hex:ether:dichloromethane, 60 mL) to give 51 mg (96%) of synthetic (-)-kolavenol (65)after distillation (140-150 °C/0.1 torr). The product exhibited IR (neat): 3319, 2938,1668, 1451, 1382, 1305, 1241, 1172, 1131, 1100, 1075, 1001, 851, 797 cm -1 [lit. 142 b(neat): 3333, 1665, 1240, 1175, 1133, 1100, 1080, 1006, 865, 800 cm -1 1; 1 H NMR15COOMeH-2a18IH-la H-6eM e-20Me-19^H-4a250(400 MHz) 8: 0.70 (s, 3H, Me-20 [NOTE: Clerodane numbering system]), 0.79 (d, 3H,J= 6 Hz, Me-17), 0.99 (s, 3H, Me-19), 1.09 (t, 1H, J. 5.5 Hz, OH [exchanged withD20]), 1.17 (ddd, 1H, J. 4, 13, 13 Hz), 1.30-1.60 (m, 11H, including 8 1.58 [m, 3H,Me-18]), 1.66 (s, 3H, Me-16), 1.70 (ddd, 1H, J= 2.5, 3, 13 Hz), 1.81 (ddd, 1H, J= 5, 13,13 Hz, H-12a), 1.88 (ddd, 1H, J= 5, 13, 13 Hz, H-12b), 1.95-2.05 (m, 2H), 4.13 (dd, 2H,J= 5.5, 6.5 Hz, H-15 [becomes d, J= 6.5 Hz with D20]), 5.18 (br s, 1H, H-3), 5.38 (br t,1H, J= 6.5 Hz, H-14) [lit. 142b (CCI4) for H-15: 8 3.98 (d, 2H, J= 6.5 Hz)]; 13C NMR(125.8 MHz) 8: 15.93 (Me-17), 16.48 (Me-20), 17.94 (Me-19), 18.33 (Me-16), 19.90(Me-18), 18.22, 26.85, 27.47, 32.79, (C-1, C-6, C-7, C-11), 36.22 (C-8), 36.70, 36.81(C-2, C-12), 38.14, 38.58 (C-5, C-9), 46.39 (C-10), 59.40 (C-15), 120.44 (C-3), 122.80(C-14), 140.80 (C-13), 144.53 (C-4); LRMS: M+(290) 7.8%; HRMS calcd forC201-1340: 290.2610, found: 290.2619; Anal. calcd for C201 -1340: C 82.70, H 11.80,found: C 82.47, H 11.70; [ a ]D 25 -56.3°, c = 3.55 in chloroform [lit.142b [ a ]p25 -45.7°,c = 4.2 in chloroform].B) Semi Synthetic (-)-Kolavenol (65)An authentic sample of (-)-methyl kolavenate (33) (-24 mg) was obtained fromDr. Tokoroyama. The sample showed the presence of impurities by GLC and TLC andwas purified by flash chromatography (1.5 g silica gel, 4:1 to 3:2 hex:ether) to givethree major fractions: the least polar fraction (A) (4.7 mg), the middle fraction (B)251(5.8 mg) and the most polar fraction (C) (4.8 mg). The three fractions were treatedwith i-Bu2AIH but only the fraction (A) gave (-)-kolavenol (65). The followingprocedure was used. A solution of i-Bu2AIH (1 M in hex, 70 1.1.L, 0.07 mmol, 4 equiv)was added to a cold (-78 °C) solution of methyl kolavenate (4.7 mg, 0.015 mmol) in dryether (1 mL). The mixture was stirred for 15 min at -78 °C and for 2 h at roomtemperature. Three drops of saturated aqueous ammonium chloride were added andthe mixture was stirred for 15 min. Magnesium sulfate (-0.2 g) was added and themixture was filtered through a column of Florisil® (0.5 g) and the Florisil® was washedwith ether (15 mL). The solvents were removed under reduced pressure to give5.3 mg of an oil. The oil was purified by flash chromatography (0.2 g silica gel, 5:3:2hex:ether:dichloromethane, 10 mL) to give 2 mg (47%) of natural kolavenol afterdistillation (140-150 °C/0.1 torr). This product was identical by GLC and TLC with thesynthetic (-)-kolavenol. The product exhibited IR (neat): 3319, 2927, 1668, 1455,1382, 1305, 1242, 1172, 1131, 1100, 1075, 1000, 851, 797 cm -1 ; 1 H NMR (400 MHz)8: 0.70 (s, 3H, Me-20 [NOTE: Clerodane numbering system]), 0.79 (d, 3H, J. 7 Hz,Me-17), 0.99 (s, 3H, Me-19), 1.09 (m, 1H, [exchanged with D20]), 1.17 (ddd, 1H, J. 4,13, 13 Hz), 1.30-1.60 (m, 11H, including 6 1.58 [m, 3H, Me-18]), 1.66 (s, 3H, Me-16),1.70 (ddd, 1H, J. 2.5, 3, 13 Hz), 1.81 (ddd, 1H, J. 5, 13, 13 Hz, H-12a), 1.88 (ddd, 1H,J. 5, 13, 13 Hz, H-12b), 1.95-2.05 (m, 2H), 4.13 (br d, 2H, J. 6.5 Hz, H-15 [becomesd, J. 6.5 Hz with D20]), 5.18 (br s, 1H, H-3), 5.38 (br t, 1H, J. 6.5 Hz, H-14); LRMS:M+(290) 0.1%; HRMS calcd for C20H340: 290.2610, found: 290.26024.2.5. Total Synthesis of (-)-Agelasine B (31)4.2.5.1. Preparation of 6-Methoxyamino-9-methylpurine (N6-Methoxy-9-methyl-adenine 301) N N -Me4—(k ,,N..._^limMe0^N--gH301A) Preparation of 6-Aminopurine N 1 -Oxide (Adenine N1 -Oxide 307) 198a2528HN 7 N 9H2N 6 \5 N 3N-1/1^230646-Aminopurine (adenine, 306, 10 g, 74 mmol) was dissolved in hot glacialacetic acid (60 mL). The mixture was cooled to room temperature and aqueoushydrogen peroxide (30 %, 37 mL, -326 mmol, -4.4 equiv) was slowly added. Thesolution was stirred for 5 days at room temperature. The crystals were filtered andwere washed with a small amount of cold acetic acid. The product was recrystallizedfrom hot water to give 7.1 g (63%) of 6-aminopurine N1 -oxide (adenine N1 -oxide 307),mp 295-300 °C, dec.(lit. 198a 297-307, dec.). The product exhibited IR (2% KBr):3397, 3105, 3020, 2515, 1877, 1661, 1594, 1448, 1411, 1376, 1328, 1241, 1158,1092, 1027, 904, 648, 554, 531 cm -1 ; 1 H NMR (400 MHz, D20) 5: 8.25 (s, 1H); 8.55(s, 1H); LRMS: M+(151) 7.2%; HRMS calcd for C5H5N50: 151.0494, found:151.0491; Anal. calcd for C5H5N50: C 39.74, H 3.33, N 46.34, found: C 39.81,253H 3.41, N 46.46.B) Preparation of N1 -Methoxy-6-aminopurinium Iodide (N 1 -MethoxyadeniniumIodide 308) 198 CH N \ 1 NN-1/Me01+308lodomethane (passed through a small plug of flame dried basic alumina,7.3 mL, 117 mmol, 2.5 equiv) was added to a suspension of powdered 6-aminopurineN1 -oxide (adenine N 1 -oxide 307, 7.1 g, 47 mmol) in DMA (63 mL). The suspensionwas stirred for 22 h at room temperature and the precipitate was filtered and waswashed with cold EtOH (2 x 5 mL). The solvents were removed from the combinedfiltrate under reduced pressure and the solid residue was washed with EtOH (2 x5 mL). The solids were combined and recrystallized from EtOH:water (7:3) to give8.41 g (61%) of N 1 -methoxy-6-aminopurinium iodide (N 1 -methoxyadeninium iodide308) mp 223-227 °C, lit. 198c 222 °C. The unstable product exhibited IR (1% KBr):3200, 3000, 2564, 1669, 1599, 1537, 1417, 1384, 1343, 1268, 1237, 1148, 1113, 961,923, 808, 721, 654, 582, 544 cm -1 ; LRMS: M+-HI(165) 0.8%; HRMS calcd forC6H7N50 (M+-HI): 165.0650, found: 165.0656.C) Preparation of N 1 -Methoxy Adenine Derivative 309 198cNNl"(H2N—.1 NN--/MeO309254A solution of the Ni-methoxy-6-aminopurinium iodide (Ni-methoxyadeniniumiodide 308, 2.88 g, 9.8 mmol) in warm water (125 mL) was passed through a columnof ion exchange resin (Amberlite® IRA-402-HCO3-, 30 mL). 256 The Amberlite® waswashed with deionized water (300 mL) and the water was removed from the combinedeluant under reduced pressure. The remaining solid was recrystallized from water(50 mL) and the derived material was kept under vacuum (vacuum pump) overnight togive 1.51 g (93%) of M-methoxy adenine derivative 309 as white crystals (mp: 250-260 °C, dec, lit. 198c 255-257 °C, dec). The air-unstable product exhibited IR (1% KBr):3220, 3105, 3020, 2563, 1669, 1599, 1417, 1384, 1268, 1237, 1148, 1113, 923, 808,654, 582, 544 cm-1; LRMS: M+(165) 44.3%; HRMS calcd for C6H7N50: 165.0650,found: 165.0650.D) Preparation of N 1 -Methoxy-9-methyl Adeninium Iodide Derivative 310 198CN'/( 9H2N-4 NN—//MeO310lodomethane (passed through a small plug of flame dried basic alumina,2.4 mL, 37 mmol, 2.5 equiv) was added to a suspension of powdered N 1 -methoxyadenine derivative 309 (2.5 g, 15 mmol) in DMA (48 mL). The suspension was stirredfor 108 h at room temperature. The reaction mixture was cooled to 0 °C and theprecipitate was filtered and was washed with cold EtOH (2 x 15 mL). The colourlesssolid was kept under reduced pressure (vacuum pump) overnight to give 1.61 g (35%)of the AP -methoxy-9-methyl adeninium iodide derivative 310: (mp: 205-215 °C, dec,255lit. 198c 214-215 °C, dec). The product exhibited IR (1% KBr): 3220, 3025, 1678, 1581,1524, 1395, 1239, 959, 688, 529 cm -1 ; Anal. calcd for C71-1101N50: C 27.38, H 3.28,N 22.81, found: C 27.17, H 3.28, N 22.68.E) Preparation of 6-Methoxyamino-9-methyl Adenine Derivative 301 198a9N ^.MeN -____(NN-8H301MeO'A solution of the N 1 -methoxy-9-methyl adeninium iodide derivative 310 (1.0 g,3.25 mmol) in warm water (55 mL) was passed through a column of ion exchangeresin (Amberlite® IRA-402-HCO3 - , 10 mL) 198 a. The Amberlite® was washed withdeionized water (360 mL) and the combined eluants were concentrated to -60 mLunder reduced pressure. The concentrate was refluxed for 3 h, cooled to roomtemperature and then the water was removed under reduced pressure. The yellowsolid was washed with cold EtOH (10 mL). The remaining solid was pumped underreduced pressure (vacuum pump) overnight to give 333 mg (57%) of 6-methoxyamino-9-methyl adenine derivative 301 as pinkish crystals (becomes red upon standing inair) (mp: 230-235 °C dec., lit.198a 239 °C dec.). The product exhibited IR (2% Nujol®mull): 1654, 1594, 1208, 1182, 1136, 1057, 870 cm -1 , 1 H NMR (400 MHz, D20)5: 1.50-3.00 (very br s, 1H, MeONH, exchange with D20), 3.82 (s, 3H, Me), 4.02 (s,3H, OMe), 7.80 (s, 1H, H-2), 8.20 (br s, 1H, H-8); LRMS: M+-HI(179) 15%; HRMScalcd for C7H9N50 : 179.0807, found: 179.0807.OMeN NIIN1099^1^7,z.Br -me/---N"-I- N g.102564.2.5.2. Preparation of Geranyl Bromide (312). 7-Geranyl-6-methoxyamino-9-methylAdeninium Bromide Derivative 313 and 6-(Geranylmethoxyamino)-9-methy(Adenine Derivative 314 ,N^N^ N6^Me0 6 N ---// 6^\__t'313 ^H^8^314 ^9'\ MeA) Preparation of Geranyl Bromide (312)A solution of geraniol (311, 465 111_, 2.68 mmol) in dichloromethane (4 mL) wasadded to a cold (0 °C) suspension of triphenylphosphine dibromide (1.36 g, 3.2 mmol,1.2 equiv) 197 in dichloromethane (7.3 mL). The mixture was stirred at roomtemperature for 1 h and was then filtered rapidly through a column of silica (latrobead®GRS-8060, 10 g) 257 and the silica was washed with hex:dichloromethane (9:1 100mL). The fractions were combined and the solvents were removed under reducedpressure to give 580 mg (-100%) of the unstable (on silica) geranyl bromide (312).The product was used directly for the next step. The product exhibited 1 H NMR (400MHz) 8: 1.65 (s, 3H, Me), 1.73 (s, 3H, Me), 1.78 (s, 3H, Me), 2.00-2.15 (m, 4H, H's-4and H's-5), 4.02 (d, 2H, J = 8 Hz, H's-1), 5.06 (br m, 1 H, H-6), 5.51 (t, 1 H, J = 8 Hz,H-2).B) Reaction of 6-Methoxyamino-9-methyl Adenine Derivative 301 with GeranylBromide (312)A mixture of geranyl bromide (312, 361 mg, 1.66 mmol) and 6-methoxyamino-9-methyl adenine derivative 301 (375 mg, 2.1 mmol, 1.3 equiv) in DMA (10 mL) wasstirred at 55 °C for 2.5 h. The mixture was cooled to room temperature and ether257(45 mL) was added. The mixture was centrifuged, the supernatant was decanted andthe solid was triturated with ether (32 mL). The mixture was centrifuged and thesupernatants, containing mostly 6-(geranylmethoxyamino)-9-methyl adeninederivative 314, were combined. The solvents were removed under reduced pressureand the residue was put aside. The residual solid from the centrifugation wastriturated with dichloromethane (40 mL), the mixture was centrifuged and thesupernatant was removed. The last procedure was repeated once more withdichloromethane (24 mL). The residual solid (211 mg, 56%) was composed mainly of6-methoxyamino-9-methyl adenine derivative 301. The dichloromethane of thesupernatants was removed under reduced pressure to give a white solid. The solidwas dissolved in dichloromethane (12 mL) and ether (24 mL) was added and themixture was centrifuged. The liquid was removed and the last procedure wasrepeated. The solid was kept under reduced pressure (vacuum pump) overnight togive 248 mg (38% based on the geranyl bromide 312) of 7-geranyl-6-methoxyamino-9-methyl adeninium bromide derivative 313, mp 185-186 °C. The product exhibitedIR (1% KBr): 3493, 3123, 2980, 1673, 1597, 1557, 1455, 1398, 1351, 1146, 1056,881, 744 cm -1 ; 1 H NMR (400 MHz) 6: 1.60 (s, 3H, Me), 1.68 (s, 3H, Me), 1.89 (s, 3H,Me), 2.12 (s, 2H, H's-4 or H's-5), 2.13 (s, 2H, H's-4 or H's-5), 3.91 (s, 3H, N-Me), 4.11(s, 3H, 0-Me), 5.05 (br m, 1H, H-6), 5.09 (d, 2H, J . 8 Hz, H-1), 5.50 (t, 1H, J = 8 Hz,H-2), 7.87 (br s, 1H, H-2' [becomes sharp s with D20]), 9.67-9.78 (br m, 1H, H-8'[becomes sharp s with D20]), 10.60-10.90 (br m, 1H, NH [exchanges with D2 0 ]);13C NMR (50.3 MHz) 6: 17.12 (-ye, C-10), 17.70 (-ve, C-9), 25.62 (-ve, C-8), 26.04(C-5), 32.19 (-ve, NMe), 39.45 (C-4), 48.25 (C-1), 62.36 (-ve, OMe), 110.48, 115.42(-ve, C-6), 123.30 (-ve, C-2), 132.12, 135.98, 137.03 (-ve), 141.36, 146.27, 149.02(-ve); FABMS (3-nitrobenzyl alcohol matrix): M -F-Br(316); HRMS calcd forC171-126N50 (M+-Br): 316.2137, found: 316.2130; UV (5.3 x10 -5 M in Me0H):291.0 nm, e 7630.OMeN NIINN\\_....-N9' \ Me258The fraction containing 6-(geranylmethoxyamino)-9-methyl adenine derivative314 was purified by flash chromatography (basic alumina activity (I), 40 g, from 100%dichloromethane to 95:5 dichloromethane:MeOH) to give 59 mg (11%) of the product314.258 The product exhibited IR (neat): 3493, 2980, 2927, 1665, 1577, 1456, 1377,1328, 1297, 1235, 1052, 839, 736 cm -1 ; 1 H NMR (400 MHz) 8: 1.55 (s, 3H, Me), 1.62(s, 3H, Me), 1.79 (s, 3H, Me), 2.00-2.15 (m, 4H, H's-4 and H's-5), 3.83 (s, 3H, N-Me),3.95 (s, 3H, 0-Me), 4.72 (d, 2H, J. 8 Hz, H-1), 5.05 (t, 1H, J. 6.5 Hz, H-6), 5.44 (t, 1H,J . 8 Hz, H-2), 7.89 (s, 1H, H-2'), 8.48 (s, 1H, H-8'); LRMS: M+(315) 0.3%; HRMScalcd for C17H25N50: 315.2059, found: 315.2059.4.2.5.3. Preparation of Kolavenyl Bromide 300. (-)-7-Kolavenyl-N6-methoxy-9-methylAdeninium Bromide Derivative 302 and (-)-N6-Kolavenyl-N6-methoxy-9- methyl Adenine Derivative 303A) Preparation of Kolavenyl Bromide (300)Triphenylphosphine dibromide 197 (55.4 mg, 0.13 mmol, 1.5 equiv) was added toa suspension of the TIPS ether of (-)-kolavenol 282 (39.3 mg, 0.088 mmol) indichloromethane (2 mL). The colourless mixture was stirred for 1 h at roomtemperature and was filtered rapidly through a column of silica (latrobead® GRS-8060,0.8 g) and the silica was washed with hex:dichloromethane (9:1, 30 mL). Two259fractions were collected: the more polar fraction was concentrated and repurified byTLC grade silica chromatography (0.2 g, 7:2:1 hex:ether:dichloromethane) to give2.6 mg (10%) of (-)-kolavenol; the less polar fraction contained 26.1 mg (85%, 94%based on recovered (-)-kolavenol) of kolavenyl bromide 300. The product exhibited1 H NMR (400 MHz) 8: 0.72 (s, 3H, Me-20 [NOTE: Clerodane numbering system]),0.81 (d, 3H, J. 6 Hz, Me-17), 0.98 (s, 3H, Me-19), 1.18 (ddd, 1H, J. 4, 12.5, 12.5 Hz),1.20-1.60 (m, 11H, including 8 1.58 [m, 3H, Me-18]), 1.69 (m, 1H), 1.71 (s, 3H, Me-16),1.83 (ddd, 1H, J. 5, 13, 13 Hz, H-12a), 1.90 (ddd, 1H, J. 5, 13, 13 Hz, H-12b), 1.95-2.10 (m, 2H), 4.00 (d, 2H, J . 8.5 Hz, H's-15), 5.19 (br s, 1H, H-3), 5.50 (br t, 1H,J. 8.5 Hz, H-14). The kolavenyl bromide was used without further purification.B) Reaction of 6-Methoxyamino-9-methyl Adenine Derivative 301 with KolavenylBromide (300)Solid 6-methoxyamino-9-methyl adenine derivative (301, 27 mg, 0.15 mmol,2 equiv) was added to a solution of kolavenyl bromide (300, 26.1 mg, 0.074 mmol) inDMA (1 mL). One small crystal of dry Bu4NI was added and the mixture was stirred at60 °C for 3 h. The solution was cooled to room temperature and the solvent wasremoved under reduced pressure (vacuum pump). 1 H NMR analysis of the crudematerial showed that the products 302 and 303 were obtained in a ratio of 1.25:1.The residual solid was purified by TLC grade silica chromatography (2.5 g H typesilica, 95:5, 35 mL, 9:1, 35 mL, 8:2, 20 mL, dichloromethane:MeOH) to give twofractions. The less polar fraction (16.5 mg) was repurified by TLC grade silicachromatography (1 g H type silica, 95:5, dichloromethane:MeOH, 15 mL) to give12.6 mg (38%) of (-)-N6-kolavenyl-N6-methoxy-9-methyl adenine derivative 303 as avery sticky oil. The product exhibited IR (neat): 2960, 2928, 1660, 1577, 1455, 1382,1328, 1235, 1074, 957, 644 cm -1 [lit. 31 IR (chloroform): 2690(sic?), 1630, 1580, 1380,1330, 950 cm -1 ]; 1 H NMR (400 MHz) 8: 0.68 (s, 3H, Me-20 [NOTE: Clerodanenumbering system]), 0.75 (d, 3H, J. 6 Hz, Me-17), 0.97 (s, 3H, Me-19), 1.12 (ddd, 1H,J. 4, 12.5, 12.5 Hz), 1.20-1.60 (m, 11H, including 8 1.54 [m, 3H, Me-18]), 1.68 (dm, 1H,260J= 13.5 Hz), 1.78 (s, 3H, Me-16), 1.75-1.90 (m, 2H, H's-12), 1.95-2.05 (m, 2H), 3.81 (s,3H, N-Me), 3.92 (s, 3H, 0-Me), 4.72 (d, 2H, J= 8 Hz, H's-15), 5.15 (br s, 1H, H-3), 5.40(br t, 1H, J= 8 Hz, H-14), 7.89 (s, 1H, H-2'), 8.48 (s, 1H, H-8') [lit. 31 1 H NMR (CDCI3)6: 7.73 (s, 1H), 8.39 (s, 1E))259 ; 13C NMR (125.8 MHz) 5: 15.94 (-ye, Me-17), 16.72(-ye, Me-16), 17.92 (-ve, Me-20), 18.31 (-ye, Me-18), 19.88 (Me-19), 18.20, 26.82,27.46, 32.94 (C-1, C-2, C-7, C-11), 29.71 (-ye, NMe), 39.16 (-ve, C-8), 36.57, 36.79,38.11, 38.54 (C-5, C-6, C-9, C-12), 46.33 (-ye, C-10), 48.27 (C-15), 62.50 (-ve, OMe),117.95 (-ve, C-14), 119.22, 120.43 (-ve, C-3), 140.90 (C-13), 141.49, 144.46 (C-4),151.70, 152.34, 155.96; LRMS: MA - (451) 0.9%; HRMS calcd for C27H41 N50:451.3311, found: 451.3313; [ a ]D 25 -38.7°, c . 2.96 in Me0H; UV (1.8 x10 -5 M inMe0H): 277.5 nm, e 14498.The most polar fraction (27 mg) was repurified by TLC grade silicachromatography (2.5 g H type silica, 95:5, 35 mL, 9:1, 35 mL, 8:2, 20 mL,dichloromethane:MeOH) to give 20.5 mg (52%) of the (-)-7-kolavenyl-N 6-methoxy-9-methyl adeninium bromide derivative 302 after the product has been kept overnightunder reduced pressure (vacuum pump) mp 198-199 °C [lit. 31 192-196 °C]. Theproduct exhibited IR (1% KBr): 3414, 2960, 2938, 1672, 1595, 1556, 1438, 1384,1058, 881 cm -1 [lit. 31 IR (chloroform): 3360, 2960, 1670, 1590, 1550, 1050, 880 cm -1 ];1 H NMR (400 MHz) 5: 0.70 (s, 3H, Me-20 [NOTE: Clerodane numbering system]),0.78 (d, 3H, J= 6 Hz, Me-17), 0.98 (s, 3H, Me-19), 1.14 (ddd, 1H, J= 4, 12.5, 12.5 Hz),1.20-1.60 (m, 11H, including 5 1.55 [m, 3H, Me-18]), 1.69 (dm, 1H, J= 12 Hz), 1.89 (s,3H, Me-16), 1.85-2.05 (m, 4H, H's-12,?), 3.92 (s, 3H, N-Me), 4.04 (s, 3H, 0-Me), 5.10(d, 2H, J=8 Hz, H's-15), 5.15 (br s, 1H, H-3), 5.43 (br t, 1H, J= 8 Hz, H-14), 7.82 (d, 1H,J = 4 Hz, H-2' [becomes s with D20]), 9.90 (s, 1H, H-8'), 181 10.49 (br s, 1H, NH[exchanged with D20] [lit. 31 1 H NMR (CDCI3) 5: 7.97 (s, 1H), 9.83 (s, 1H)]; 130 NMR(125.8 MHz) 5:^16.01 (Me-17), 17.50 (Me-16), 17.94 (Me-20), 18.31^(C-1), 19.89(Me-19), 18.28 (Me-18), 26.86, 27.43, 33.02 (C-2, C-7, C-11), 32.20 (NMe), 36.23,36.35, 36.76, 38.14, 38.65 (C-5, C-6, C-8, C-9, C-12), 46.39 (C-10), 48.36 (C-15),16^151411 1217 H2N31CI -7't.^MeN"-1- N -9 ,---•(NN-2/2026162.40 (OMe), 110.40 (C-5'), 115.10 (C-14), 120.30 (C-3), 136.00 (C-8'), 137.10 (C-4'),141.30 (C-6'), 144.40 (C-4), 147.30 (C-13), 148.90 (C-2'); LRMS: M+-HBr(451) 1.3%;HRMS calcd for C27H41 NI80 (M+-HBr): 451.3311, found: 451.3310 (peak matched);Anal. calcd for C271-142N50• 1 /2H20: C 59.88, H 8.00, N 12.93, found: C 60.07, H 8.00,N 12.66.; [ a jD 25 -24.4°, c = 1.02 in Me0H [lit. 31 [ a )D 21 -26.2°, c = 1.00 inMe01-1]; UV (9.0 x 10 -5 M in Me0H): 293.5 nm, c 4452.4.2.5.4. Isolation of Natural (-)-Agelasine B (31) from an Extract of a Papua-NewGuinea Sponge Agelas species (Likely Agelas nakamura,) 1918A mixtures of agelasines (1.3 g) was obtained from Ms. Jana Pika, a Ph Dstudent in Dr. R. Andersen's research group. 260 A portion of the dark yellow extracts(100 mg, dissolved in a minimum amount of Me0H) was applied on top of 3 SepPak®columns (Waters) in series (3 x 0.8 g reverse phase C18 columns, prewashed with20 mL Me0H and then with 20 mL of water) and the agelasines were eluted withportions (10 mL) of a mixture of water and Me0H in the following proportions 1:0, 4:1,3:2, 2:3, 1:4 and 0:1. The fractions were monitored by reverse phase TLC (4:1acetonitrile:0.2 M aqueous sodium chloride, visualized with UV and Dragendorff'sreagent261 ). The two middle fractions (3:2 and 2:3 water-methanol elution) werecombined and the solvents were removed under reduced pressure to give 80 mg of aslightly yellow mixture of agelasines. The three SepPaks® columns were washed withdichloromethane (10 mL), hex (10 mL), Me0H (10 mL) and water (10 mL). The above262chromatographic procedure was repeated on three additional fractions (100 mg each)of the dark yellow extracts yielding a total of 300 mg of slightly yellow mixture ofagelasines.The agelasines mixture was dissolved in a minimum amount of MeOH:water(4 mL, 1:1), the solution was filtered through a 0.22 gm membrane filter (Millex-GV®)and was purified by reverse phase preparative HPLC 192b (Waters Radial-PakTMcartridge, 10 x 250 mm, C18 on 10gm gPorasil® silica). The HPLC system used wascomposed of a System Controller model 600E and Tunable Absorbance Detectormodel 486 [tuned at 272 nm], both from Waters. The Controller and the Detector weresupervised by an IBM clone computer running a Chromatography Workstation Maxima825 version 3.30 program from Dynamic Solution (Millipore). The agelasines werepurified (11 x -350 IA injections) with a MeOH:0.2 M aqueous sodium chloride eluant(flow: 10 mL/min, gradient curve #4, 30 min from 7:3 to 85:15 and 15 min at 85:15 thenreequilibrated at 7:3 for 20 min). The fractions were monitored by reverse phaseanalytical HPLC (Waters Radial-PakTM cartridge, 8 x 100 mm, C18, type 8MBC18 onlOgrn gPorasil® silica). The analytical HPLC hardware was almost the same systemas the preparative HPLC except that the detector was a Waters ProgrammablePhotodiode Array Detector model 994 [tuned at 272 and 254 nm]. The eluant usedwas MeOH:0.2 M aqueous sodium chloride at a flow of 2.5 mUmin (gradient curve #4,15 min from 7:3 to 85:15 and 5 min at 85:15 then reequilibrated 10 min at 7:3). Thefractions derived from the preparative HPLC system were pooled into four groupsaccording to their composition, purity and retention time. Each pool was separatelyconcentrated under reduced pressure (30 °C bath) until a white precipitate appeared.Each concentrate was extracted with ethyl acetate (3 x 100 mL) and each aqueousfraction was passed through three C18 reverse phase SepPaks® (in series) in order torecover any traces of agelasine left in the water after the extractions. In each case air(3 x 20 mL) was pushed through the SepPaks® to removed the excess water and thenMe0H (30 mL) was passed through the SepPaks®. The Me0H was removed under263reduced pressure from each of the eluants and each residue was combined with theappropriate ethyl acetate extract. The extracts were dried with magnesium sulfate andthe solvent was removed under reduced pressure. Pool (A) with an average retentiontime of 22-24 min contained 21.5 mg of mainly agelasine A contaminated withagelasine B,C and D by 1 H NMR; pool (B) with an average retention time of 24-27 mincontained 79.2 mg of mainly agelasine B contaminated with agelasine C and D by1 H NMR; pool (C) with an average retention time of 27-30 min contained 48.5 mg of amixture of agelasine B,C,D and E by 1 H NMR; and pool (D) with an average retentiontime longer than 30 min gave 18.5 mg of almost pure agelasine E by 1 H NMR.The pool (B) (-50 mg dissolved in the minimum amount of MeOH:water 1:1)was purified using the same preparative HPLC column and system, eluting with anisochratic mixture of acetonitrile:0.2 M aqueous sodium chloride (1:1, 5 mUmin). Fourseparate runs were done. Three pools were obtained using the same extractionprotocol as in the preceding preparative HPLC purification: pool (1) with an averageretention time of 52-57 min contained 4.9 mg of agelasine B by 1 H NMR; pool (2) withan average retention time of 57-61 min contained 10.7 mg of a mixture of agelasine Band C by 1H NMR; pool (3) with an average retention time of more than 61 mincontained 4.4 mg of agelasine C by 1 H NMR.The pool (1) was purified further by TLC grade silica chromatography (0.8 g Htype silica, 85:15, 10 mL, 8:2, 10 mL, dichloromethane:MeOH) to give 3.9 mg of purenatural (-)-agelasine B (31) mp 170-175 °C (lit. 31 ,192b 167-170 °C). The productexhibited IR (1% KBr): 3350, 3160, 2962, 1646, 1612, 1592, 1462, 1390, 1302, 1223,1195, 1086, 735 cm-1 [lit . 192b IR (chloroform): 3370, 3160, 2960, 1640, 1610, 1590,1460, 1385, 1300, 1240, 1195, 1090 cm -1 ]; 1 H NMR (400 MHz) 6: 0.69 (s, 3H, Me-20[NOTE: Clerodane numbering system]), 0.75 (d, 3H, J= 6 Hz, Me-17), 0.98 (s, 3H, Me-19), 1.12 (m, 1H), 1.20-1.62 (m, 11H, including 6 1.55 [m, 3H, Me-18]), 1.69 (dm, 1H,J. 12 Hz), 1.84 (s, 3H, Me-16), 1.77-2.10 (m, 4H, H's-12,?), 4.08 (s, 3H, N-Me), 5.16(br s, 1H, H-3), 5.40 (br t, 1H, J. 6.5 Hz, H-14), 5.72 (d, 2H, J. 6.5 Hz, H's-15), 6.69 (br264s, 2H, NH2 [exchanged with D20]), 8.50 (s, 1H), 11.10 (s, 1H [slowly exchanged withD20]), [lit. 192b 1 H NMR (CDCI3) 6: 0.70 (s, 3H), 0.76 (d, 3H, J. 5.2 Hz), 0.97 (s, 3H),1.57 (s, 3H), 1.86 (br s, 3H), 0.7-2.2 (m, 14H), 4.10 (s, 3H), 5.17 (br s, 1H), 5.41 (br t,1 H, J. 6.5 Hz), 5.71 (br d, 2H, J. 6.5 Hz), 6.84 (br s, 2H, [exchanged with D20]), 8.50(s, 1H), 10.89 (s, 1H)]; 13C NMR (125.8 MHz) 6: 16.00 (Me-17), 17.57 (Me-16), 17.94(Me-20), 18.31 (Me-18), 19.89 (Me-19), 18.28, 26.85, 27.39 (C-1, C-2, C-7), 31.96(NMe), 33.09, 36.26, 36.28, 36.76, 38.15, 38.68 (C-5, C-6, C-8, C-9, C-11, C-12), 46.40(C-10), 48.72 (C-15), 109.9 (C-5'), 116.0 (C-14), 120.3 (C-3), 142.3 (C-8'), 144.5 (C-4),147.6 (C-13), 149.6 (C-4'), 152.3 (C-6'), 156.3 (C-2') [lit. 192b 130 NMR (22.5 MHz)8: 16.0 (q, Me-17), 17.5 (q, Me-16), 17.9 (q, Me-20), 18.3 (t, C-1), 18.3 (q, Me-18),19.9 (q, Me-19), 26.9 (t, C-5), 27.5 (t, C-2), 32.0 (q, N-Me), 33.1 (t, C-11), 36.3 (d, C-8),36.3 (t, C-6), 36.8 (t, C-12), 38.2 (s, C-9), 38.7 (s, C-5), 46.4 (d, C-10), 48.7 (t, C-15),109.7 (d, C-5'), 115.7 (d, C-14), 120.3 (d, C-3), 141.7 (d, C-8'), 144.3 (s, C-4), 147.5 (s,C-13), 149.5 (s, C-4'), 152.5 (s, C-6'), 156.0 (d, C-2'); LRMS: M+-C1(422) 0.5%;HRMS calcd for C26H39N5 (M+-HCI): 421.3205, found: 421.3204; UV (1.66 x 10 -4 Min Me0H): 272.5 nm, e 8420 [lit. 192b 272 nm, E 8240].4.2.5.5. Cyclo-voltammetric Studies of 7-Geranyl-N 6-methoxy-9-methyl Adeninium Bromide Derivative 313, (-)-7-Kolavenyl-N6-methoxy-9-methyl Adeninium Bromide Derivative 302 and (-)-Agelasine B (31) The cyclic voltammetry measurements were done using a EG&G PARC(Princeton Applied Research Co.) model 303 Hanging Drop Mercury Electrode(HMDE) as the work electrode, a platinum wire as the counter electrode and asilver/silver chloride reference electrode (Ag wire in saturated AgCI in 4 M aqueousKCI with a Vicor® glass porous bridge). The electrodes were controlled by a EG&GPARC model 264A Polarographic Analyser/Stripping Voltammeter. The voltam-mograms were recorded on a EG&G model RE 0089 X-Y Recorder. The solvent usedfor all samples was a 0.1 M sodium acetate buffer, pH 4.5. 262 The samples weredissolved in the buffer (10 mL) and were put into the cell compartment. The solution265was purged of oxygen for 4 min with nitrogen, a fresh drop of mercury was delivered atthe tip of the capillary work electrode and the system was equilibrated, without stirring,for 15 s before the measurements were done. The voltages were scanned at a rate of100 mV/s.A) Cyclic Voltammogram of 7-Geranyl-N6-methoxy-9-methyl Adeninium BromideDerivative 3137-Geranyl-N6-methoxy-9-methyl adeninium bromide derivative 313 (1.0 mg,2.5 x 10 -3 M) in the sodium acetate buffer was scanned between 0 and -1.2 V. Anirreversible wave was observed at a potential of -1.06 V and at a current of 2.4 plA(E112= -0.99 V). The current reached a minima at a potential of -1.12 V (i = 2.0 gA) andthen the current became very high at -1.15 V (catalytic hydrogen reduction of thesolvent). 217B) Cyclic Voltammogram of (-)-7-Kolavenyl-N6-methoxy-9-methyl Adeninium BromideDerivative 302(-)-7-Kolavenyl-N6 -methoxy-9-methyl adeninium bromide derivative 302(0.7 mg, 1.3 x 10 -3 M) in the sodium acetate buffer was scanned between 0 and-1.3 V. An irreversible wave was observed at a potential of -1.01 V and at a current of1.5 ilA (E112 = -0.95 V). A second irreversible wave was observed at a potential of-1.18 V (i = 0.7 pA) and then become very high at -1.29 V (catalytic hydrogen reductionof the solvent). No maxima, except the solvent reduction limit is observed during thesecond and third cycle. If the wave is "clipped" at -1.23 V still no maxima are observedin the second cycle. If the wave is clipped at -1.08 V, a maxima at -1.01 V (the currentis 80% of the first maxima) is observed.C) Cyclic Voltammogram of Natural (-)-Agelasine B (31)Natural (-)-agelasine B (31, 1.1 mg, 2.4 x 10 -3 M) in the sodium acetate bufferwas scanned between 0.15 and -1.2 V. A small maxima was observed at -1.02 V(i = 0.08 iiA) and the solvent limit was reached at -1.2 V.CI,Me+ N -(H2 N315^N—//C1 -9^1^7./,'N _Me/^N+ N( 9'N^N6^MeO'^N-2/320^H102664.2.5.6. Electrochemical Reduction of 7-Geranyl-N6-methoxy-9-methyl Adeninium Bromide Derivative 313 and (-)-7-Kolavenyl-N6-methoxy-9-methyl Adeninium Bromide Derivative 302The electrochemical reductions were done using a EG&G PARC model 173Potentiostat/Galvanostat equipped with a model 176 Current Follower, a model 176Electrometer and an "in house" (UBC Electronic Shop) Voltage-Time IntegratorEDC-371. The mercury cell used (see Figure 2.29) was made by the UBC glassshop and the UBC mechanical shop. The work electrode was composed of a pool ofmercury (BDH, triply distilled, 6 mL) connected to the potentiostat by a platinum wire.A) Preparation of 7-Geranyl-9-methyl Adeninium Chloride Derivative 315The acetate buffer (0.1 M, pH 4.5, 10 mL each) was put into the counter andwork electrode compartments. The voltage between the work electrode and thereference electrode (ER vs . w) was measured at +0.25 V. The potentiostat was set at-1.8 V and 10 Coulomb (C) were passed between the counter and the workelectrodes. ER vs . w was now -0.8 V. The buffers were removed from bothcompartments and were replaced by fresh ones (ER vs. w = +0.05 V). The potentiostatwas set at +0.6 V and 3.5 C were passed between the electrodes (a white precipitatewas formed, ER vs. w = +0.36 V). The buffers were removed again and were replacedby fresh ones (ER vs. w = +0.35 V) and the potentiostat was set at -1.6 V and 4 C werepassed between the electrodes (ER vs . w = +0.3 V). The buffers were removed againand were replaced by fresh ones (ER vs . w = +0.3 V) and 7-geranyl-N6-methoxy-9-methyl adeninium bromide derivative 313 (powdered, 13.9 mg, 0.035 mmol) was267added (ER vs. w = +0.1 V). The potentiostat was set at -1.0 V producing an initialcurrent of -0.9 mA through the cloudy solution. After 15 min, the current was -0.6 mA,0.6 C had passed between the electrodes and ER vs. w was 0.0 V. After 2.1 h, thesolution was getting clear and the current was -0.4 mA, 3.6 C had passed through thesolution, and ER vs. w was -0.07 V. After 4.1 h, the current passing through the clearsolution was -0.15 mA, 5.5 C had passed between the electrodes and ER vs. w was-0.2 V. After 5.1 h, the current passing through the clear solution was -0.08 mA, 6.1 C(1.9 equiv of electrons) had passed through the solution and ER vs. w was -0.25 V.At this stage the power was shut off and the electrolytes (from the counter and thework electrodes compartment) were transferred into a 100 mL round bottom flask. Theelectrodes and the cell were washed with methanol and the washings were added tothe 100 mL round bottom flask. Powdered sodium chloride (5 g) was added and themixture was concentrated to 20 mL under reduced pressure (bath -25 °C). Theresidue was extracted with chloroform (4 x 30 mL), the aqueous fraction was put asideand the combined organic extracts were washed with brine (5 mL). The two aqueousfractions were put together and were extracted with chloroform (30 mL) and ethylacetate (2 x 30 mL). All the organic extracts were combined and were dried withmagnesium sulfate. The solvents were removed under reduced pressure to give15.4 mg of a white solid. The solid was purified by TLC grade silica chromatography(1.5 g H type silica, 9:1, 20 mL, 8:2, 20 mL, 7:3, 10 mL dichloromethane:MeOH) to give3.4 mg (28%) of 7-geranyl-N6-methoxy-9-methyl adeninium chloride derivative 321and 4.6 mg (41%, 57% based on the recovered 321) of the 7-geranyl-9-methyladeninium chloride derivative 315 mp 154-157 °C [lit. 31 145-150 °C]. The productexhibited IR (1% KBr): 3322, 3131, 2950, 1651, 1613, 1590, 1477, 1373, 1296, 1231,1180 cm -1 ; 1 H NMR (400 MHz) 5: 1.52 (s, 3H, Me-10), 1.61 (s, 3H, Me-8), 1.81 (s, 3H,Me-9), 2.08 (m, 4H, H's-4 and H's-5), 4.07 (s, 3H, N-Me), 4.98 (br s, 1 H, H-6), 5.42 (br t,1H, J. 6.5 Hz, H-2), 5.70 (d, 2H, J. 6.5 Hz, H's-1), 6.78 (br s, 2H, NH2 [exchangedwith D20]), 8.49 (s, 1H, H-2'), 10.95 (s, 1H, H-8' [exchanged with D20]); HMQC and268HMBC: see Table 4.2; 13 C NMR (125.8 MHz)263 5: 17.26 (q, -ve, Me-9), 17.72 (q,-ve, Me-10), 25.61 (q, -ve, Me-8), 25.98 (t, C-5), 32.07 (q, -ve, N-Me), 39.43 (t, C-4),48.68 (t, C-1), 109.86 (s, C-5'), 116.1 (d, -ve, C-2), 123.2 (d, -ve, C-6), 132.3 (s, C-7),141.7 (d, -ve, C-8'), 146.4 (s, C-3), 149.6 (s, C-4'), 152.4 (s, C-6'), 156.0 (d, -ye, C-2');LRMS: M+-HCI(285) 0.2%; HRMS calcd for C16H23N5 (M+-HCI): 285.1953, found:285.1950; UV (2.78 x 10 -4 M in Me0H): 272.5 nm, c 6777.Table 4.2: Assignment of the NMR Data for the Geranyl Methyl Adeninium Derivative313Assignment(C-X)13C SpectrumS (APT)HMQC1 H NMR Correlations5 (mult., # of H, J (Hz),Assignment)Long Range1H-13C HMBCCorrelationsH-XMe-9 17.26, -ve, qa 1.52 (s, 3H, Me-10) H's-4, H-2Me-10 17.72, -ve, q 1.61 (s, 3H, Me-8) Me-8Me-8 25.61, -ve, q 1.81 (s, 3H, Me-9) Me-10, H-6C-5 25.98, t 2.08 (m, 4H, H's-4 and H's-5) H's-4, H-6N-Me 32.07, -ve, q 4.07 (s, 3H, N-Me) ^bC-4 39.43, t 2.08 (m, 4H, H's-4 and H's-5) Me-9, H-2, H's-5C-1 48.68, t 5.70 (d, 2H, J = 6.5 Hz, H's-1) H-2C-5' 109.86, s ^b H's-1, H-8'C-2 116.1, -ve, d 5.42 (br t, 1H, J = 6.5 Hz, H-2) Me-9, H's-1, H's-4C-6 123.2, -ve, d 4.98 (br s, 1H, H-6) Me-8, Me-10C-7 132.3, s ^b Me-8, Me-10C-8' 141.7, -ve, d 10.95 (s, 1H, H-8')c N-Me, H's-1C-3 146.4, s ^b Me-9, H's-1, H's-4C-4' 149.6, s ^b N-Me, H-2', H-8'C-6' 152.4, s ^b H-2'C-2' 156.0, -ve, d 8.49 (s, 1H, H-2')* See Table 2.24 for instruction on how to read this table.a Off resonnance hydrogen decoupled 13C multiplicity, -ve is reported when a negative peak isobserved in the APT experiment.b No correlation.c Exchanged with D20.CI -16^15 7'/,^,Me14^N.+ N 9 .20 11 12 1317 H2N8 so3161819B) Preparation of Synthetic (-)-Agelasine B (31)269The acetate buffer (0.1 M, pH 4.5, 10 mL each) was put into the counter andwork electrode compartments. The voltage between the work electrode and thereference electrode (ER vs . w) was +0.22 V. The potentiostat was set at -1.8 V and10 Coulomb (C) were passed between the counter and work electrodes. ER vs. w wasnow -0.28 V. The buffers were removed from both compartments and were replacedby fresh ones (ER vs. w = +0.05 V). The potentiostat was set at +0.6 V and 3.5 C werepassed between the electrodes (a white precipitate was formed, ER vs. w = +0.37 V).The buffers were removed again and were replaced by fresh ones (ER vs. w = +0.35 V).The potentiostat was set at -1.6 V and 4 C were passed through the solution (ER vs. w =+0.3 V). The buffers were removed again and fresh buffer (10 mL) was added into thecounter electrode cell. A mixture of the (-)-7-kolavenyl-N 6 -methoxy-9-methyladeninium bromide derivative 302 (8.7 mg, 0.016 mmol) and the buffer (8 mL) weresonicated (Branson sonic bath) until the mixture was an almost homogeneous milkysuspension. The suspension was added into the work electrode compartment and theremainings of the suspension were washed with some buffer (2 mL) and the washingswere put into the cell (ER vs . w = +0.05 V). The potentiostat was set at -1.0 V producingan initial current of -0.8 mA through the milky solution. After 40 min, the current was-0.25 mA, 0.6 C had passed between the electrodes and ER vs. w was -0.18 V. After1.3 h, the solution was getting clearer and the current was -0.2 mA, 1.1 C had passedthrough the solution and ER vs. w was -0.18 V. After 2 h, the current passing through270the almost clear solution was -0.18 mA, 1.6 C had passed between the electrodes andER vs. w was -0.18 V. After 2.5 h, the current passing through the clear solution was-0.15 mA, 2.1 C had passed through the solution and ER vs. w was -0.18 V. Additionalbuffer (2 mL) was added into the counter cell. After 4.4 h, the current passing throughthe clear solution was -0.1 mA, 3 C had passed though and ER vs. w was -0.19 V. After5.7 h, the current passing through the clear solution was -0.04 mA, 3.2 C (2.0 equiv ofelectrons) had passed between the electrodes and ER vs. w was -0.26 V. At this stagethe power was turned off and the electrolytes (from the counter and the work electrodecompartments) were transferred to a 100 mL round bottom flask. The electrodes andthe cell were washed with methanol and the washings were added into the 100 mLround bottom flask. Powdered sodium chloride (5 g) was added and the solvents wereconcentrated to 15 mL under reduced pressure (bath -25 °C). The residue wasextracted with chloroform (4 x 30 mL), the aqueous fraction was put aside and thecombined organic extracts were washed with brine (5 mL). The two aqueous fractionswere put together and were extracted with chloroform (30 mL) and ethyl acetate (2 x30 mL). All the organic extracts were combined and were dried with magnesiumsulfate. The solvents were removed under reduced pressure to give 6.4 mg of a whitesolid. The solid was purified by TLC grade silica chromatography (1.5 g H type silica,85:15, 20 mL, 8:2, 10 mL, 7:3, 5 mL, 6:4, 5 mL dichloromethane:MeOH) to give 0.6 mg(8%) of (-)-7-kolavenyl-N6-methoxy-9-methyl adeninium chloride derivative 320 mp179-181 °C and 4.0 mg (53%, 57% based on the recovered starting material) of thesynthetic (-)-agelasine B (31) as an amorphous white solid mp 165-170 °C. Theproduct exhibited IR (1% KBr): 3329, 3146, 2959, 1646, 1605, 1592, 1473, 1383,1301, 1231, 1189, 1096, 789 cm -1 ; 1 H NMR (400 MHz) 8: 0.69 (s, 3H, Me-20 [NOTE:Clerodane numbering system]), 0.75 (d, 3H, J. 6 Hz, Me-17), 0.98 (s, 3H, Me-19),1.12 (m, 1H), 1.20-1.62 (m, 11H, including 8 1.55 [m, 3H, Me-18]), 1.69 (dm, 1H,J. 12 Hz), 1.84 (s, 3H, Me-16), 1.77-2.10 (m, 4H, H's-12,?), 4.08 (s, 3H, N-Me), 5.16(br s, 1H, H-3), 5.40 (br t, 1H, J. 6.5 Hz, H-14), 5.72 (d, 2H, J. 6.5 Hz, H's-15),2716.51 (br s, 2H, NH2 [exchanged with D20]), 8.50 (s, 1H), 11.19 (s, 1H [exchangedwith D20]), 13c NMR (125.8 MHz) 5: 16.10, 17.65 (Me), 17.99 (Me), 18.36 (Me), 19.96(Me), 18.39, 26.93, 27.47, 33.14, 32.02 (NMe), 36.30, 36.32, 36.81, 38.20, 38.72,46.43 (C-10), 48.78 (C-15), 109.95, 115.86, 120.38, 142.00, 144.50, 147.66, 149.63,152.31, 156.22; LRMS: M+-CI(422) 0.1%; HRMS calcd for C26H39N5 (M+-HCI):421.3205, found: 421.3201 (peak matched); Anal. calcd for C26H40N5•1-120: C 65.59,H 8.89, N 14.71, found: C 65.28, H 9.00, N 13.01.; [ a ]D25 -27.2°, c = 1.00 in Me0Hpit . 31,192b [ a ] p -21.5°, c = 1.00 in Me0H and [ a ] D 21 _ 38.4°, c = 1.00 in Me0H];UV (1.96 x 10 -4 M in Me0H): 272.5 nm, c 10429.272REFERENCES1. 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Bhattacharya, A.; DiMichele, L. M.; Dolling, U.-H.; Grabowski, E. J. J.; Grenda,V. J. J. Org. Chem. 1989, 54, 6118.61. a) Clive, D. L. Tetrahedron 1978, 34, 1049; b) Reich, H. J. Acc. Chem. Res.1979, 12, 22; Liotta, D. Acc. Chem. Res. 1984, 17, 28.62. Ryu, I.; Murai, S.; Niwa, I.; Sonoda, S. Synthesis, 1977, 874.63. Ozone oxidation also gives an equivalent yield of enone 55 after elimination ofthe selenoxide, but is less convenient to use than hydrogen peroxide.64. Reich, H.J.; Reich, I.L.; Renga, J.M. J. Am. Chem. Soc. 1973, 95, 5813.65. a) Stork, G. Pure Appl. Chem. 1968, 17, 383; b) Johnson, C. R.; Penning, T.D. J. Am. Chem. Soc. 1988, 110, 4726.66. See reference 42, pp 221-242.67. See reference 42, pp 274-284.68.^Still, W. C. J. Am. Chem. Soc. 1977, 99, 4836.27669. The CD spectra of the compounds obtained in this thesis that display a Cottoneffect will be discussed in a separate section.70. Piers, E.; Morton, H. E.; Chong, J. M. Can. J. Chem. 1987, 65, 78.71. Piers, E.; Tillyer, R. D. J. Org. Chem. 1988, 53, 5366.72. Gordon, A. J.; Ford, R. A. The Chemist's Companion: A Handbook of Practical,Data,Techniques, and References; John Wiley & Sons: New York, 1972;p 187.73. Aue, W. P.; Bartholdi, E.; Ernst, R. R. J. Chem. Phys. 1976, 64, 2229.74. Derome, A. E.; Modern NMR Techniques for Chemistry Research; Pergamon:Oxford, 1987; p 97.75. Breitmaier, E.; Voelter, W. Carbon-13 NMR Spectroscopy: High-ResolutionMethods and Applications in Organic Chemistry and Biochemistry, 3rd ed.;VCH: Weinheim, 1987; pp 297-299.76. Patt, S. L.; Shoolery, J. N. J. Magn. Res. 1982, 46, 535.77. The conformational free-energy difference (-AG°) is the difference in energybetween the axial and equatorial orientation of a substituent on a cyclohexanering. See March, J. Advanced Organic Chemistry: Reactions, Mechanisms andStructure; 2nd ed.; McGraw-Hill: New York, 1977; p 130.78. Kitching, W.; Doddrell, D.; Grutzner, J. B. J. Organomet. Chem. 1976, 107, C5.79. Chem 3D+ version 3.0 Cambridge Scientific Computing, 1991.80. Wickham, G.; Olszowy, H. A.; Kitching, W. J. Org. Chem. 1982, 47, 3788.81. Kitching, W.; Olszowy, H.; Waugh, J.; Doddrell, D. J. Org. Chem. 1978, 43,898.82. See reference 75, p 299.83. Fevig, T. L.; Elliott, R. L.; Curran, D. P. J. Am. Chem. Soc. 1988, 110, 5064.84. Demuth, M.; Hinsken, W. Helv. Chim. Acta 1988, 71, 569.85. See reference 74, p 245.86. Dodrell, D.; Burfitt, I.; Kitching, W.; Bullpitt, M.; Lee, C.-H.; Mynott, R. J.;Considine, J.L.; Kuivila, H. G.; Sarma, R. H. J. Am. Chem. Soc. 1974, 96,1640.87.^a) Piers, E.; Chong, J. M. J. Chem. Soc., Chem. Commun. 1983, 934;b) Chong, J. M. Ph. D. Thesis, University of British Columbia, Oct. 1983, p 244;c) Piers, E.; Chong, J. M. Can. J. Chem. 1988, 66, 1425; d) See reference 27,p 122.27788. Still, W.C.; Kahn, M.; Mitra, A.J. J. Org. Chem. 1978, 43, 2923.89. Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem. 1988, 53,2390.90. a) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6019; b) Lipshutz, B.H.; Ellsworth, E. L.; Siahaan, T. J.; Shirazi, A. Tetrahedron Lett. 1988, 29,6677.91. Rieke and coworkers independently used a combination of TMSCI andBF3.0Et2 to conjugately add an high-order cuprate to a hindered enone.cf. Wu, T.-C.; Xiong, H.; Rieke, R. D. J. Org. Chem. 1990, 55, 5045.92. The structure of trimethylstannylcyclohexanone 102 was unambiguouslyestablished using the spectral data and analyses. The 1 H NMR and the 130NMR spectra can be fully assigned by analogy with the chloro ketone 100.93. Zdero, C.; Bohlmann, F.; Mungai, G. M. Phytochemistry 1990, 29, 3233.94. See reference 13f. The chloro butene 110 was generously supplied by Ms.Johanne Renaud from Dr. Piers' research group at UBC.95. Piers, E.; Gavai, A. V. J. Org. Chem. 1990, 55, 2374.96. The (E)-trimethylstannyl ester 112 was generously provided by Mr. TimothyWong from Dr. Piers' research group at UBC.97. The epimeric chloro ketone 118 was never isolated and its structure isproposed from the 1 H NMR spectra of the mixture of 117 and 118 and from thesimilarity with the results from the methylenecyclohexane annulation.98. M+ is used instead of M+. all through this thesis for convenience.99. Piers, E.; Gavai, A.V. Tetrahedron Lett. 1986, 27, 313.100. A( 1 ,3) strain stands for the allylic strain between the substituents in a 1,3-relationon a double bond. This was first developed for 6-membered rings and wasextrapolated to other systems. See: Johnson, F., Chem. Rev. 1968, 68, 9 375.101. No enhancement for H-5e could be observed when Me-12 was irradiated dueto the proximity of its 1 H NMR signal with the irradiated signal (A6 0.08) (see130a).102. Kadow, J. F.; Johnson, C. R. Tetrahedron Lett. 1984, 25, 5255. See Davis, D.D.; Chambers, R. L.; Johnson, H. T. J. Organomet. Chem. 1970, 25, C13 for aleading reference.103. a) Macdonald, T. L.; Mahalingam, S. J. Am. Chem. Soc. 1980, 102, 2113; b)Macdonald, T. L.; Mahalingam, S.; O'Dell, D. E. J. Am. Chem. Soc. 1981, 103,6767; c) Macdonald, T. L.; Mahalingam, S. Tetrahedron Lett. 1981, 22, 2077;d) Macdonald, T. L.; Delahunty, C. M.; Mead, K.; O'Dell, D. E. Tetrahedron278Lett. 1989, 30, 1473.104. Posner, G. H.; Asirvatham, E.; Webb, K. S.; Jew, S.-s. Tetrahedron Lett. 1987,28, 5071.105. Baldwin, J. E.; Adlington, R. M.; Robertson, J. J. Chem. Soc., Chem. Commun.1988, 1404.106. Olszowy, H. A.; Kitching, W. J. Org. Chem. 1982, 47, 5230.107. Newman-Evans, R. H.; Carpenter, B. K. Tetrahedron Lett. 1985, 26, 1141.108. Caine, D Org. React. 1976, 23, 1.109. Wai, J. S. M. Ph. D. Thesis, University of British Columbia, Feb. 1988, p 35.110. Piers, E; Roberge, J. Y. Tetrahedron Lett. 1991, 39, 5219.111. See reference 109, p 160.112. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543.113. The acids and their respective acid chlorides are available from AldrichChemical Company, Milwaukee, USA.114. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.115. Raban, M.; Mislow, K Modern Methods for the Determination of Optical Purity;In Topics in Stereochemistry; Allinger, N. L.; Eliel, E. L., Eds.; John Wiley &Sons: New York, 1967; Vol. 2; p 222.116. Dale and Mosher have made it clear that the models 173 and 174 werededuced a posteriori and do not represent the preferred ground stateconformations of the MTPA esters. They speculate about the reason for theobserved differences in chemical shifts but give no evidence. See reference114.117. Silverstein, R.M.; Bassler, G.C.;Morrill, T.C.; Spectrometric Identification ofOrganic Compounds; Fourth ed.; John Wiley & Sons: New York, 1981, p 107.118. Johnstone, R. A. W.; Rose, M. E. Tetrahedron, 1979, 35, 2169.119. Lipshutz, B. H.; Pegram, J. J. Tetrahedron Lett. 1980, 21, 3343.120. Pretsch,E.; Clerc, T.; Seibl, J.; Simon, W. (Translated from German byBiemann, K.) Tables of Spectral Data for Structure Determination of OrganicCompounds 13C NMR 1H NMR IR MS UV/VIS; Boschke, F. L.; Fresenius,W.; Huber, J. F. K.; Pungor, E.; Rechnitz, G. A.; Simon, W.; West, Th. S., Eds.;Chemical Laboratory Practice; Springer-Verlag: Berlin, 1983; p. 1250.121. See reference 109, p 73.122. Menger gives a good discussion for an explanation of the increase of the rates279of intramolecular reactions. Menger, F. M. Acc. Chem. Res. 1985, 18, 128.123. Kergomard, A.; Renard, M.-F.; Veschambre, H. J. Org. Chem. 1982, 47, 792124. The combination of a low concentration and a small [ a ]578 of 192 and 195makes this measurement unreliable proof of both the identity and theenantiomeric purity of the compound 192.125. a) Griffith, W. P.; Ley, S. V. Aidrichimica Acta, 1990, 23, 13; b) Griffith, W. P.;Ley, S. V.; Whitcombe, G. P., White, A. D. J. Chem. Soc., Chem. Commun.1987, 1625.126. See reference 109, p 35.127. See reference 109, p 160.128. See the experimental section and Harrison, I. T. Instruction Manual; HarrisonResearch: 1985.129. a) Barrett, G. C. In Elucidation of Organic Structures by Physical and ChemicalMethods; Bentley, K. W.; Kirby, G. W., Eds.; Techniques of Chemistry IV;Weissberger, A.; Wiley: New York, 1972; Vol. 4, Chapter VIII, p.515;b) Purdie, N.; Swallows, K. A. Anal. Chem., 1989, 61, 77A.130. The usual wavelength range of the general-use commercial spectropolarimeteris 175-800 nm, which is the normal ultraviolet-visible (UV-VIS) range.131. Kirk, D. N. Tetrahedron, 1986, 42, 777.132. See reference 129a, p.557.133. See reference 129a, p.559.134. The Cotton effects in this thesis are reported as the specific ellipticity and thetilCD. The specific ellipticity is defined as ['F ]xt = iT -. , where 'F is the(measured angle of ellipticity in millidegrees (m°), I is the distance of the lightpath in centimeters (cm), c is the concentration in grams per 100 milliliters(g/100 cm -3 ), t is the temperature in °C and X is the wavelength of theabsorption in nanometers (nm). The units are in (cleg.cril2) where deg = (°) anddagdag = decagram.135. The circular dichroism Ac in L•mol -1 •cm -1 is the difference between the left andthe right molar extinction coefficient, and is more adequate for comparison ofthe CD spectra of compounds of different molecular weight than is the specificellipticity. The circular dichroism is related to the specific ellipticity by280[^] x t = (3.3 xM05•Ae), where M is the molecular weight of the compoundunder comparison.136. Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry; Part A: Structureand Mechanisms; 2nd ed.; Plenum: New York, 1984; p 123.137. The polarizability of a moiety on a chiral molecule has been linked to thestrength of the measured optical rotation. See Brewster, J. H. J. Am. Chem.Soc. 1959, 81, 5475.138. See reference 129a, p 560.139. A bisignate CD curve is observed when two non-coincidental Cotton effects ofopposite sign overlap. See reference 131.140. Barth, G.; Voelter, W.; Mosher, H. S.; Bunnenberg, E.; Djerassi, C. J. Am.Chem. Soc. 1970, 92, 875.141. Misra, R.; Pandey, R. C.; Dev, S. Tetrahedron Lett. 1964, 5, 3751.142. a) Misra, R.; Dev, S. Tetrahedron Lett. 1968, 9, 2685; b) Misra, R.; Pandey,R. C.; Dev, S. Tetrahedron, 1979, 35, 985.143. Hubert, T. D.; Wiemer, D. F. Phytochemistry, 1985, 24, 1197.144. Kusumoto, S.; Okazaki, T.; Ohsuka, A.; Kotake, M. Bull. Chem. Soc. Jpn.1969, 42, 812.145. See reference 109, p 165.146. For a review on i-Bu2AIH reductions see Winterfeldt, E. Synthesis, 1975, 617.147. See reference 109, p 227.148. See Smith, A. B., Ill; Leenay, T. L. J. Am. Chem. Soc. 1989, 111, 5761; andreference 36.149. a) Huang-Minlon J. Am. Chem. Soc. 1946, 68, 2487; b) Huang-Minlon J. Am.Chem. Soc. 1949, 71, 3301.150. Barton, D. H. R.; Ives, D. A. J.; Thomas, B. R. J. Chem. Soc. 1955, 2056.151. See reference 109, p 231.152. a) Guindon, Y.; Morton, H. E.; Yoakim, C. Tetrahedron Lett. 1983, 24, 3969;b) Guindon, Y.; Yoakim, C.; Morton, H. E. J. Org. Chem. 1984, 49, 3912.153. See reference 109, p 238.154. For other examples of boron halide-acid catalyzed double bond isomerizationssee: Hawkins, J. M.; Loren, S. D.; Kim, Y.-K. Tetrahedron Lett. 1991, 32, 1635.281155. Greene, T. W. Protective Group in Organic Synthesis; Wiley-Interscience: NewYork, 1981.156. See reference 120, p. I 90.157. The HMQC (Heteronuclear Multiple Quantum Coherence) experiment is areverse detection (detect the insensitive nuclei through the more sensitive 1 H)NMR experiment that gives a correlation between a carbon and the hydrogen(s)directly attached to it (1 bond). See the Experimental section for reference.158. The HMBC experiment (Heteronuclear Multiple Bond Connectivity) is a reversedetection NMR experiment that gives a correlation between a carbon and thehydrogen(s) attached two and three bonds away from it. See the Experimentalsection for reference.159. Winter, B. He/v. Chim. Acta, 1989, 72, 1278.160. Escher, S.; Giersch, W.; Niclass, Y.; Bernardinelli, G.; Ohloff, G. He/v. Chim.Acta, 1990, 73, 1935.161. For other examples of synthesis of tetrahydrofuran derivatives with hydroxylgroups acting as the internal nucleophilic terminator see: Snowden, R. L.;Eichenberger, J.-C.; Linder, S. M.; Sonnay, P.; Vial, C.; Schulte-Elte, K. H.J. Org. Chem. 1992, 57, 955.162. Sibirtseva, V. E.; Vlad, P. F.; Dragalin I. P.; Guzun, M.V.; Prokopyshina, L. V.;Koltsa, M. N.; Sitnova, L. M.; Skvortsova, A. B.; Tokareva, V. Ya. USSR PatentSU 1,312,091, 1984; Otkrytiya, Izobret. 1987, 19, 103; Chem. Abstr. 1988,108, 156280a; We are grateful to Mr. Veljko Dragojiovic for the translation ofthe Russian patent.163. Vlad, P. F.; Koltsa, M. N.; Dragalin I. P.; Zadorozhnaya, L. A.; Sibirtseva, V. E.;Sitnova, L. M. Zhurna/ Obshchei Khimii, 1988, 58, 2289; Chem. Abstr. 1989,111, 134534w; Translation from Plenum Publishing Co.164. See reference 109, p 238.165. The ratio of alcohols 231:232 varied unpredictably between 1:10 to 5:1.166. Guindon and coworkers have also observed the formation of a formaldehydedimenthol acetal in the hydrolysis of a menthol-methoxyethoxymethyl ether(menthol-MEM). They have suggested the use of THE and aqueous sodiumbicarbonate in the work-up to avoid the formation of the acetal. See reference152a.167. See reference 109, pp 232 and 238.168. Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Chem. Commun. 1979, 978.169. Piers, E.; Wong, T.; Ellis, K. A. Can. J. Chem. 1992, 70, 2058.282170. A 1:1 mixture of the esters 259 and 260 was also obtained after the initialchromatography (-14% yield). An analytical sample of 260 was obtained aftera second tic grade silica chromatography.171. Leusink, A. J.; Budding, H. A.; Marsman, J. W. J. Organomet. Chem., 1967, 9,285.172. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.173. a) Ogilvie, K. K.; Sadana, K. L.; Thompson, E. A.; Quilliam, M. A.; Westmore,J. B. Tetrahedron Lett. 1974, 15, 2861; b) Ogilvie, K. K.; Thompson, E. A.;Quilliam, M. A.; Westmore, J. B. Tetrahedron Lett. 1974, 15, 2865; c) Cunico,R. F.; Bedell, L. J. Org. Chem. 1980, 45, 4797.174. Skerlj, R. T. Ph. D. Thesis, University of British Columbia, Jan. 1988, p 248.175. a) Linstrumelle, G. Tetrahedron Lett. 1974, 15, 3809; b) Millon, J.; Lorne, R.;Linstrumelle, G. Synthesis, 1975, 434.176. Crich, D.; Ritchie, T. J. Tetrahedron, 1988, 44, 2319.177. Corey, E. J.; Bock, M. G.; Kozikowski, A. P.; Rao, A. V. R.; Floyd, D.; Lipshutz,B. Tetrahedron Lett. 1978, 19, 1051.178. For a review of copper(I)-catalyzed reactions with Grignard reagents see Erdik,E. Tetrahedron, 1988, 40, 641.179. Millar, J. G.; Underhill, E. W. J. Org. Chem. 1986, 51, 4726.180. Kauffman, G. B.; Teter, L. A. lnorg. Synthesis, 1963, 7, 9.181. Asao, K.; lio, H.; Tokoroyama, T. Tetrahedron Lett. 1989, 30, 6401.182. Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.; Hirotsu, K. J.Am. Chem. Soc. 1984, 106, 158.183. a) See reference 89; b) Knochel, P.; AchyuthaRao, S. J. Org. Chem. 1991,56, 4591; c) Knochel, P.; AchyuthaRao, S. J. Am. Chem. Soc. 1991, 113,5735.184. For mechanistic studies of the lithium-halogen exchange see Bailey, W. F.;Patricia, J. J.; Nurmi, T. T.; Wang, W. Tetrahedron Lett. 1986, 27, 1861 andBailey, W. F.; Patricia, J. J. J. Organomet. Chem. 1988, 352, 1.185. Negishi, E.-i.; Swanson, D. R.; Rousset, C. J. J. Org. Chem. 1990, 55, 5406.See also Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404 for asimilar study.186. a) Rettig, M. F.; Maitlis, P. M. lnorg. Synthesis, 1977, 17, 134; b) Takahashi,Y.; Ito, T.; Sakai, S.; Ishii, Y. J. Chem. Soc., Chem. Commun. 1970, 1065.187. Knochel, P.; Rao, C. J. J. Org. Chem. 1991, 56, 4593.283188. Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.189. Corey, E. J.; Snider, B. B. J. Am. Chem. Soc. 1972, 94, 2549.190. We thank Dr. T. Tokoroyama for a sample of (-)-methyl kolavenate and forproviding a copy of the spectra (IR, 1 H and 13C NMR) of (-)-kolavenol.191. Tokoroyama, T., Osaka City University, personal communication, 1991.192. a) Nakamura, H.; Wu, H.; Ohizumi, Y.; Hirata, Y. Tetrahedron Lett. 1984, 25,2989; b) Wu, H.; Nakamura, H.; Kobayashi, J.; Kobayashi, M.; Ohizumi, Y.;Hirata, Y. Bull. Chem. Soc. Jpn. 1986, 59, 2495.193. See reference 192 and Kobayashi, M.; Nakamura, H.; Wu, H.; Kobayashi, J.;Ohizumi, Y. Archives of Biochemistry and Biophysics, 1987, 259, 179.194. Bergquist, P. R. Sponges; University of California: Berkeley, 1978; pp 14, 166-168.195. Braekman, J.-C.; Daloze, D.; Stoller, C.; Van Soest, R. W. M. BiochemicalSystematics and Ecology, 1992, 20, 417.196. Cullen, E.; Devlin, J. P. Can. J. Chem. 1975, 53, 1690.197. a) Aizpurua, J. M.; Cossio, F. P.; Palomo, C. J. Org. Chem. 1986, 51, 4941;b) Aizpurua, J. M.; Palomo, C. Synthesis, 1982, 684.198. a) Stevens, M. A.; Magrath, D. I.; Smith, H. W.; Brown, G. B. J. Am. Chem. Soc.1958, 80, 2755; b) Fujii, T.; Itaya, T. Tetrahedron 1971, 27, 351; c) Fujii, T.;Itaya, T.; Wu, C. C.; Tanaka, F. Tetrahedron 1971, 27, 2415.199. Fujii, T.; Saito, T.; Date, T.; Nishibata, Y. Chem. Pharm. Bull. 1990, 38, 912.200. Fujii, T.; Tanaka, F.; Mohri, K.; Itaya, T.; Saito, T. Tetrahedron Lett. 1973, 14,4873.201. AS = (Chemical shift of 301)-(chemical shift of 302)202. This compound has been prepared previously by Tokoroyama and coworkers(see reference 31) but the physical properties of this compound have not, so far,been reported.203. Geranyl bromide is available from Aldrich Chemical Co.204. The partial decomposition of compound 313 on basic alumina resulted in lowisolation yield.205. The UV and 13C spectra were recorded only for compound 312.284206. Tokoroyama, T., Osaka City University, personal communication, 1991. Seealso Confalone, P. N.; Pizzolato, G.; Confalone, D. L.; Uskokovi4, M. R. J. Am.Chem. Soc. 1980, 102, 1954.207. Saito, T.; Inoue, I.; Fujii, T. Chem. Pharm. Bull. 1990, 38, 1536.208. A sample of impure agelasine B was also obtained from Dr. D. J. Faulkner. The1 H NMR and IR spectra of synthetic and natural agelasine B were obtained fromDr. T. Tokoroyama. We thank Drs. Andersen, Faulkner and Tokoroyama fortheir assistance.209. The sponge was collected off Motupore Island off Port Moresby southern NewGuinea at a depth of 30 to 50 feet by Mr. Mike Leblanc, UBC Oceanographydepartment technician, in November-December 1988. The sponge wasidentified by Dr. D. J. Faulkner and Ms. Jana Pika.210. See reference 77, p 1126.211. Lund, H.; Kwee, S. Acta Chem. Scand. 1968, 22, 2879.212. Kyriacou, D. K. Basics of Electroorganic Synthesis; John Wiley and Sons: NewYork, 1981; p 26.213. The discussion of cyclic voltammetry is based on Fry, A. J. Synthetic OrganicElectrochemistry; New York, 1989; pp 48-65.214. The voltammograms shown are for reduction processes but the samearguments apply for oxidation processes.215. The residual current is the current observed between the work and counterelectrodes when the scanning is done with only the solvent and the supportelectrolyte in the cell.216. The voltammograms were converted into digital data using an optical scanner(SCANMAN), and the data were processed using the CHEM-DRAW program.217. Janik, B.; Elving, P. Chem. Rev. 1968, 68, 295.218. Piers, E.; Roberge, J. Y. Tetrahedron Left. 1992, 33, 6923.219. Cooper, J.W . Spectroscopic Techniques for Organic Chemist; John Wiley &Sons: New York, 1980; pp 94-96.220. See reference 74, p 97.221. See reference 74, p 245.222. Summers, M. F.; Marzilli, L. G.; Bax, A. J. Am. Chem. Soc. 1986, 108, 4285.223. Bothner-By, A. A.; Stephens, R. L.; Lee, J.-m. J. Am. Chem. Soc. 1984, 106,811.285224. See reference 72, p 379.225. Plante, R.; Poupart, M.-A. Bio-Mega Inc. Montr6al, personal communication.The technique is a major improvement on Rigby and Hunt's method (Chem. andInd. 1967, 1868). The main difference between tic grade silica and flashchromatography is that the tic silica is finer and that in the first case the height ofsilica gel in the column is set to be 2-3 times the diameter of the column.Because the silica is finer higher pressure are necessary (5-15 psi). Cautionshould be taken to avoid overpressure and a shielded apparatus should beused. This technique is the fastest way to achieved difficult separation. SeeTaber, D. F. J. Org. Chem. 1982, 47, 1351.226. Bryan, W. P.; Byrne, R. H. J. Chem. Ed. 1970, 47, 361.227. Perrin, D.D.; Armarego, W.L.F.; Perrin, D.R. Purification of LaboratoryChemicals; Pergamon: Oxford, 1980.228. Kofron, W.G.; Baclawski, L.M. J. Org. Chem. 1976, 41, 1879.229. Suffert, J. J. Org. Chem. 1989, 54, 509.230. Wuts, P.G.M. Synth. Commun. 1981, 11, 139.231. Sato, T.; Watanabe, M.; Watanabe, T.; Onoda, Y.; Murayama, E. J. Org. Chem.1988, 53, 1894.232. Posner, G. H.; Brunelle, D. J.; Sinoway, L. Synthesis, 1974, 662.233. See reference 27, p 122.234. The solution of lithium chloride-copper(I) cyanide complex in THF was preparedusing the following procedure [note: the amount of LiCI, CuCN, and THF usedare given in the appropriate experimental section]: lithium chloride (2 equiv foreach equiv of CuCN) was flame dried under reduced pressure (0.1 torr, vacuumpump), cooled to approximately 80°C, the flask was filled with argon andcopper(I) cyanide was added. The mixture was kept under reduced pressure(vacuum pump) for an hour while the flask is cooling and then the flask wasfilled with argon and the described amount of THF was added before use.235. Lipshutz, B. H.; Elworthy, T. J. Org. Chem. 1990, 55, 1695.236. See reference 117, pp 189-190.237. Mosher's acid chloride ((-)-MTPA-CI) was prepared from (+)-MTPA according toMosher's procedure: see reference 112.238. See reference 109, p 161.239. See reference 109, p 162.240. See reference 109, p 34.286241. See reference 109, p 160.242. See reference 109, p 165.243. Oldenziel, 0. H.; van Leusen, D.; van Leusen, A. M. J. Org. Chem. 1977, 42,3114.244. Impure TosMIC (11 g dissolved in a minimum amount of dichloromethane) wasfiltered through a column of basic alumina (100 g). The alumina was washedwith dichloromethane (200 mL) and the solvent was removed under reducedpressure. The white solid was dissolved in a minimum amount of ether and hexwas added until the crystalization started. The mixture was cooled in arefrigerator (4°C) for a few hours. The solid was filtered, washed with cold (0°C)hex and the residual solvents were removed under vacuum (vacuum pump) togive 6-7 g of pure TosMIC. The crystals were kept at -20°C under an argonatmosphere.245. See reference 109, p 226.246. 2-lodo-1-methoxymethoxy ethane (318) was prepared from 2-chloro-1-methoxymethoxy ethane (prepared by J. S. M. Wai) using a procedure identicalwith that described by Wai: see reference 109, p 225.247. See reference 109, p 52 and p 231.248. Anhydrous hydrazine was prepared by refluxing hydrazine hydrate over anequivalent weight of sodium hydroxide for 2 h and then distilling. An explosionshield was used and care was taken that the anhydrous hydrazine is notexposed to oxygen as an explosive reaction could occur. A lot of cold waterwas added via syringe to the distillation residue before the apparatus wasdisassembled.249. Fieser, L. F.; Fieser, M.; Reagents For Organic Synthesis; John Wiley & Sons:New York, 1967; Vol. 1, p 434.250. Worster, P. M. Ph. D. Thesis, University of British Columbia, Dec. 1975, p 241.251. The ratio of 232:231 varies from 10:1 to 1:5 (by 1 H NMR) depending on thereaction conditions, the work-up and the source or the purity of thedimethylboron bromide.252. Guindon and coworkers have also observed the formation of a formaldehydedimenthol ketal in the hydrolysis of a menthol-methoxyethoxymethyl ether(menthol-MEM). They have suggested the use of THE and aqueous sodiumbicarbonate in the work-up to avoid the formation of the ketal. See reference152a.253. Pure sample of compounds 213, 283 and 284 were isolated after combiningmaterial from a number of reactions and by using repetitive radialchromatography (1 mm, hex).287254. The zinc dibromide solution was prepared by refluxing freshly distilled 1,2-dibromoethane (35 mL, 0.4 mmol) and a suspension of freshly activated zinc(35 mg, 0.53 mmol, 1.3 equiv) in THE (0.7 mL) for 1 h (the disappearance of the1,2-dibromoethane was followed by glc analyses). The solution was thencannulated from the residual excess zinc, via Teflon® cannula, to the alkyllithium.255. See reference 227, p 547256. Prepared by washing a column of Amberlite® IRA-402-C1 - (30 mL) first withsaturated aqueous sodium bicarbonate (300 mL) and then, with deionizedwater (300 mL).257. The latrobead® silica is a neutral (-pH 7) spherical silica that is useful forpurifying unstable compounds. It is available from latron Laboratories Inc.,Tokyo, Japan.258. It was found later that the products 313 and 314 are unstable to basicconditions. See reference 198a.259. Tokoroyama and coworkers, have demonstrated the concentration dependencyof the position of the adenine signals (NH2, H-2' and H-8') in the 1 H NMRspectrum of (±)-ageline A (285). This discrepancy was probably due " to thepropensity of the molecule to associate through the polar moiety..." This mightbe the reason why our observed chemical shifts for the adenine signals in ourspectrum are different from those reported. See reference 181.260. [NOTE: this section is taken from Ms. Jana Pika research notes.] The spongeAge/as (probably nakamurai) was collected by M. Michel Leblanc in Papua-New Guinea. The orange-red sponge (-4 kg) was soaked in methanol whichwas decanted, filtered and concentrated under reduced pressure. The spongewas then soaked in a mixture of dichloromethane:methanol (1:1) which wasalso decanted, filtered and concentrated under reduced pressure. The organicextracts were combined to give -60 g of crude material.The crude was dissolved in water and extracted successively with hex (3 x 250mL), dichloromethane (3 x 250 mL) and ethyl acetate (3 x 250 mL). The organicfractions were dried with sodium sulfate and the solvents were removed underreduced pressure to yield 0.16 g, 11.47 g and 0.67 g, respectively. The residualwater fraction was freeze dried to yield 8.7 g.A portion of the dichloromethane extract (5.0 g) was applied to a gel partitioncolumn (Sigma® lipophilic Sephadex® LH-20-100, bead size 25-100 mm, 2.5 x100 cm, 20:5:2 ethyl acetate:MeOH:water). The agelasines were visualized bytic (3:1:1 butanol:acetic acid:water, uv), the fractions were pooled and thesolvents were removed under reduced pressure to yield 1.3 g of the crudeagelasines.We thank Dr. R. J. Andersen and Ms. Jana Pika for their collaboration.261. See reference 72, p 379.288262. The buffer was prepared by dissolving sodium acetate trihydrate (6.804 g) indoubly deionized water (470 mL) and by adjusting the pH to 4.5 with glacialacetic acid. The pH was measured with glass electrode pH meter calibrated atpH 4.00 and 7.00 using commercial standards. The volume of the buffersolution was made up to 500 mL with doubly deionized water.263. The multiplicity of the signals of the off-resonance hydrogen decoupledspectrum are indicated first.

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