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New annulation methods employing bifunctional conjunctive reagents : total syntheses of (-)-homalomenols… Oballa, Renata M. 1995

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NEW ANNULATION METHODS EMPLOYING BIFUNCTIONALCONJUNCTIVE REAGENTS.TOTAL SYNTHESES OF (-)-HOMALOMENOLS A AND B.byRENATA M. OBALLAB. Sc. (Hons.), The University of British Columbia, 1989A THESIS SUBMITTED IN PARTIAL FULFILLMENT OFTHE REQUIREMENTS FOR THE DEGREE OFDOCTOR OF PHILOSOPHYmTHE FACULTY OF GRADUATE STUDIESDEPARTMENT OF CHEMISTRYWe accept this thesis as conformingto the required standardTHE UNiVERSITY OF BRITISH COLUMBIAMay 1995© Renata M. Oballa, 1995In 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.(Signature)Department of (‘ (1 5/’4/ s7PThe University of British ColumbiaVancouver, CanadaDate_____________DE-6 (2/88)UABSTRACTThis thesis is divided into two parts. Part 1 describes the use of the bifunctionalconjunctive reagent 13 in novel annulation sequences. As previously developed in ourlaboratories, compound 13 was converted into the key organocopper(I) reagent 15 which canbe used as the synthetic equivalent of a 1-butenea2,d4-synthon 14 or a 1-butened2,d4-synthon 21.The preparation of structurally complex tricycic ring systems of general structures 32and 32a was accomplished via an annulation sequence involving: (a) the stereoselectiveconjugate addition of the organocopper(I) reagent 15 to bicyclic enones of general structure19 to afford the vinylgermane intermediates 19a, (b) conversion of the vinylgermane adducts19a into the corresponding keto vinyl iodides 19b, and (c) intramolecular Pd(O)-catalyzedcoupling reactions of the vinyl iodides 19b to generate the unique tricydic keto alkenes 32and 32a.The use of the organocopper(I) reagent 15 as the synthetic equivalent of thed2,d4-synthon 21 was employed in an annulation sequence designed to generate tricycliccompounds bearing an allylic, angular hydroxyl group (see general structure 33). The keystep in this sequence involved the cyclization of the keto vinyl iodides 19b via a lithium-iodine exchange reaction and subsequent closure of the resultant vinyllithium species ontothe carbonyl carbon.Part 2 of this thesis describes the first total syntheses of the sesquiterpenes (-)-homalomenol A (168b) and B (169b). The preparation of these products involved theconversion of the enantiomerically homogeneous allylic acetate 181b to the bicyclic enone17Th via a known five-membered ring annulation sequence. The key steps were thestereoselective conjugate additions of the organocopper(I) reagents 178 and 179 to thebicyclic enone 177b. The resultant bicyclo[4.3.O]nonan-2-ones 175b and 176b were thenreadily converted to the products 168b and 169b, respectively, via two synthetic steps.Me3GeX13 X=I15 X=Cu(CN)Liaid14dLd21111HR32aHM QH(I 68b19a X=GeMe319b X=IMeAcO181 bTBDPSO Me1 77bTBDPSO Me175b R=176b R=u(CN)Li178rCu179R’3319HOMe1 69bivTABLE OF CONTENTSPageABSTRACT iiTABLE OF CONTENTS ivLIST OF TABLES xviiLIST OF FIGURES xmLIST OF GENERAL PROCEDURES xxiiiLIST OF ABBREVIATIONS xxivACKNOWLEDGMENTS xxviiPART 1: ANNULATION SEQUENCES EMPLOYING THE BIFUNCTIONALCON.JUNCTIVE REAGENTS 4-IODO-2-TRIMETHYLGERMYL-1-BUTENE (13)AND 5-IODO-2-TRIMETHYLGERMYL-1-PENTENE (31).I. INTRODUCTION 11.1. GENERAL 11.2. BACKGROUND 31.3. PROPOSALS 8II. DISCUSSION 112.1. F1VE-MEMBERED RING ANNULATIONS BASED ONPALLADIUM(O)-CATALYZED INTRAMOLECULARCOUPLING 112.1.1. INTRODUCTORY REMARKS 112.1.2. PREPARATION OF THE BIFUNCTIONAL REAGENT 4-IODO-2-TRIMETHYL-GERMYL-1-BUTENE (13) 162.1.3. PREPARATION OF THE CYCLIZATION SUBSTRATES 192.1.4. CYCLIZATION STUDIES 24V2.1.5. CONCLUSION .332.2. ATTEMPTS TO ACHIEVE SIX-MEMBERED RINGANNULATIONS BASED ON PALLADIUM(O)-CATALYZEDINTRAMOLECULAR COUPLING 352.2.1. INTRODUCTORY REMARKS 352.2.2. PREPARATION OF THE BIFUNCTIONAL REAGENT 5-IODO-2-TRIMETHYL-GERMYL- 1-PENTENE (31) 362.2.3. PREPARATION OF THE CYCLIZATION PRECURSORS 382.2.4. CYCLIZATION STUDIES 412.3. THE FORMATION OF TRICYCLIC RING SYSTEMSEMPLOYING THE ANNULATION METHOD BASED ON THEPALLADIUM(O)-CATALYZED INTRAMOLECULARCOUPLING 442.3.1. INTRODUCTORY REMARKS 442.3.2. PREPARATION OF THE BICYCLIC[4.3.O]NON-9-EN-2-ONES 442.3.3. PREPARATION OF THE BICYCLIC KETOVINYLGERMANES 492.3.3.1. Literature Precedent for Conjugate Addition Reactionsto Bicyclo[4.4.O]dec- 10-en-2-ones 492.3.3.2. Literature Precedent for Conjugate Addition Reactionsto Bicyclo[3.3.0]oct-8-en-2-ones 522.3.3.3. Literature Precedent for Conjugate Addition Reactionsto Bicyclo[4.3.0]non-9-en-2-ones 552.3.3.4. Conjugate Addition Reactions to the Bicyclo[4.3.0]non-9-en-2-ones 74, 75, 95, and 96 562.3.4. PREPARATION OF THE KETO VINYL IODIDES 742.3.5. CYCLIZATION STUDIES 792.3.6. CONCLUSION 1012.4. THE FORMATION OF TRICYCLIC COMPOUNDS BEARING ANALLYLIC, ANGULAR HYDROXYL GROUP VIA A METAL-HALOGEN EXCHANGE REACTION 1032.4.1. INTRODUCTORY REMARKS 103vi2.4.2. CYCLIZATION STUDIES.1032.4.3. CONCLUSION 119III. EXPERIMENTAL 1213.1. GENERAL 1213.1.1. DATA ACQUISITION AND PRESENTATION 1213.1.2. SOLVENTS AND REAGENTS 1243.2. SYNTHESIS OF BICYCLIC COMPOUNDS VIA THE FIVEMEMBERED RING ANNULATION SEQUENCE 1263.2.1. SYNTHESIS OF 2-(CARBOMETHOXY)-2-CYCLOHEXEN-1-ONE(47) 1263.2.2. SYNTHESIS OF 4-IODO-2-TRIMETHYLGERMYL-1-BUTENE (13) VIA THE CORRESPONDINGVINYLSTANNANE REAGENT 1273.2.2.1. Synthesis of 3-Trimethylstannyl-3-buten- 1-ol (48a) 1273.2.2.2. Synthesis of 4-Chloro-2-trimethylstannyl- 1-butene(45) 1283.2.2.3. Synthesis of 4-Iodo-2-trimethylgermyl- 1-butene (13):.. 1283.2.3. SYNTHESIS OF 4-IODO-2-TRIMETHYLGERMYL-1-BUTENE (13) VIA A PLATINUM CATALYZEDHYDROGERMYLATION REACTION 1303.2.3.1. Synthesis of 3-Trimethylgermyl-3-buten-1-ol (52) 1303.2.3.2. Synthesis of 4-Iodo-2-trimethylgermyl-1-butene (13):.. 1313.2.4. PREPARATION OF THE CUPRATh REAGENT 15 1323.2.5. GENERAL PROCEDURE 1: PREPARATION OF THE KETOVINYLGERMANES 1323.2.5.1. Synthesis of 3- [3-(trimethylgermyl)-3-butenyl]cyclo-hexanone (59) 1333.2.5.2. Synthesis of 3-Methyl-3- [3-(trimethylgermyl)-3-butenyl]cyclohexanone (60) 1343.2.5.3. Synthesis of 3,5,5-Trimethyl-3-[3-(trimethylgermyl)-3-butenyl]cyclohexanone (61) 135viia. Via Conjugate Addition of the Cuprate Reagent 15 toIsophorone (55) in the Presence of BF3•Et2& 135b. Via Conjugate Addition of the Cuprate Reagent 15 toIsophorone (55) in the Presence of TMSBr 136c. Via Conjugate Addition of the Cuprate Reagent 15 toIsophorone (55) in the Presence of TMSC1 andBF3•Et20 136d. Via Conjugate Addition of the Cuprate Reagent 15 toIsophorone (55) in the Presence of TMSBr andBF3•Et20 1373.2.5.4. Synthesis of (3 R, 5R )-2-Methyl-5-( 1-methylethenyl)-3-[3-(trimethylgermyl)-3-butenyl]-cyclohexanone (62): .. 1373.2.5.5. Synthesis of 2-Carbomethoxy-3-[3-(trimethylgermyl)-3-butenyl]cyclohexanone (63) 1383.2.5.6. Synthesis of (3 R, 5R)-2,3-Dimethyl-5-(1-methyl-ethenyl)-1-trimethylsioxycyclo-hexene (70) and (2S,3R, 5R )-2-(2-Bromo-2-propenyl)-2,3-dimethyl-5-(1-methylethenyl)cyclo-hexanone (71) 1393.2.6. GENERAL PROCEDURE 2A: PREPARATION OF THEKETO VINYL IODIDES FROM THE CORRESPONDINGKETO VINYLGERMANES 1413.2.6.1. Synthesis of 3-(3-Iodo-3-butenyl)cyclohexanone (64):. 1423.2.6.2. Synthesis of 3-(3-Iodo-3-butenyl)-3,5,5-trimethyl-cyclohexanone (66) 1433.2.6.3. Synthesis of (3 R, 5R)-3-(3-Iodo-3-butenyl)-2-methyl-5-( 1-methylethenyl)cyclo-hexanone (67) 1443.2.6.4. Synthesis of 2-Carbomethoxy-3-(3-iodo-3-butenyl)-cyclohexanone (68) 1453.2.7. GENERAL PROCEDURE 2B: PREPARATION OF THEKETO VINYL IODIDES FROM THE CORRESPONDINGKETO VINYLGERMANES 1413.2.7.1. Synthesis of 3-(3-Iodo-3-butenyl)-3-methylcyclo-hexanone (65)’ 1423.2.8. GENERAL PROCEDURE 3: Pd(O)-CATALYZEDCYCLIZATION REACTION OF THE KETO VINYLIODIDES 1463.2.8.1. Synthesis of 9-Methylbicyclo[4.3.O]non-9-en-2-one(74)’ 146viiia. Via the Pd(0)-Catalyzed Cyclization ReactionDescribed in General Procedure 3: 146b. Via the Pd(0)-Catalyzed Cyclization ReactionEmploying Modified Conditions (high dilution(0.008 M)) 147c. Via the Pd(0)-Catalyzed Cyclization ReactionEmploying Modified Conditions (high dilution(0.008 M) and no t-BuOH present in the basemixture) 1473.2.8.2. Synthesis of 6,9-Dimethylbicyclo[4.3.0]non-9-en-2-one (75) 1483.2.8.3. Synthesis of 4,4,6,9-Tetramethylbicyclo[4.3.0]non-9-en-2-one (76) 1493.2.8.4. Synthesis of (iS, 4R, 6R)- 1-Methyl-9-methylene-4-(1-methylethenyl)bicyclo[4.3.0] -nonan-2-one (77) 150a. Via the Pd(0)-Catalyzed Cycization ReactionEmploying 19 mol% Pd(PPh3)4 150b. Via the Pd(0)-Catalyzed Cyclization ReactionEmploying 15 mol% Pd(PPh3)4 150c. Via the Pd(0)-Catalyzed Cydization ReactionEmploying 10 mol% Pd(PPh3)4 151d. Via the Pd(0)-Catalyzed Cyclization ReactionEmploying 5 mol% Pd(PPh3)4 151e. Via the Pd(0)-Catalyzed Cycization ReactionEmploying CuC1 as an Additive 151f. Via the Pd(0)-Catalyzed Cyclization ReactionEmploying Pd2(dba)3IPPh3 as the Catalyst 152g. Via the Pd(0)-Catalyzed Cyclization ReactionEmploying Pd2(dba)3IPh3As as the Catalyst 152h. Via the Pd(0)-Catalyzed Cyclization ReactionEmploying Pd2(dba)3ITri(2-furyl)-phosphine (67a)as the Catalyst 153i. Via the Pd(0)-Catalyzed Cycization ReactionEmploying Pd2(dba)3/Triisopropyl-phosphite (6Th)as the Catalyst 153j. Via the Pd(0)-Catalyzed Cycization ReactionEmploying PdCl2(dppf) as the Catalyst 154xk. Via the Pd(0)-Catalyzed Cyclization ReactionEmploying Pd(OAc)2/PPh3 as the Catalyst 1541. Via the Cyclization Reaction Employing aStoichiometric Amount of Ni(COD)2 1553.2.8.5. Synthesis of (1 R*, 6S*) 1 -Carbomethoxy-9-methylenebicyclo[4.3.0]nonan-2-one (78) 156a. Via the Pd(0)-Catalyzed Cydization ReactionEmploying Pd(PPh3)4 as the Catalyst and C52CO3as the Base 156b. Via the Pd(0)-Catalyzed Cyclization ReactionEmploying Pd2(dba)3/PPh3 as the Catalyst andCs2CO3 as the Base 1573.2.8.6. Synthesis of(1S, 2R, 4R, 5S)-1,2-Dimethyl-6-methylene-4-(1 -methylethenyl)bicyclo-[3.2. 1]heptan-8-one (81) 1583.3. ATTEMPTS AT SYNTHESIS OF SIX-MEMBERED RINGS VIA APALLADIUM(O)-CATALYZED INTRAMOLECULAR COUPLINGREACTION 1603.3.1. SYNTHESIS OF 5-IODO-2-TRIMETHYLGERMYL-1-PENTENE (31) VIA THE CORRESPONDINGVINYLSTANNANE COMPOUND 1603.3.1.1. Synthesis of 5-Chloro-2-trimethylstannyl- 1-pentene(83a) 1603.3.1.2. Synthesis of 5-Iodo-2-trimethylgermyl- 1 -pentene(31) 1613.3.2. SYNTHESIS OF THE CUPRATE REAGENT 87 AND THEKETO VINYLGERMANES 1623.3.2.1. Synthesis of 3- [4-(Trimethylgermyl)-4-pentenyl]-cyclohexanone (85) 1623.3.2.2. Synthesis of (3 R, 5R)-2-Methyl-5-( 1-methylethenyl)-3-[4-(trimethylgermyl)-4-pentenyl]-cyclohexanone (86): 1643.3.3. SYNTHESIS OF THE KETO VINYL IODIDES 1653.3.3.1. Synthesis of 3-(4-Iodo-4-pentenyl)cyclohexanone(91) 1653.3.3.2. Synthesis of (3 R, 5R)-3-(4-Iodo-4-pentenyl)-2-methyl-5-( 1-methylethenyl)cyclohexanone (92): 166x3.3.4. CYCLIZATION REACTIONS TO FORM SIX-MEMBEREDRINGS 1673.3.4.1. Synthesis of 10-Methylbicyclo[4.4.0]dec- 10-en-2-one(93) 167a. Via the Pd(0)-Catalyzed Cycization ReactionConditions Described in General Procedure 3 167b. Via the Pd(0)-Catalyzed Cyclization ReactionEmploying Modified Conditions (0.02 M dilutionand no t-BuOH present in the base mixture) 167c. Via the Pd(0)-Catalyzed Cycization ReactionEmploying Modified Conditions (0.004 M dilutionand no t-BuOH present in the base mixture) 1683.3.4.2. Synthesis of (4R, 6R )- 1-Methyl- 10-methylene-4-(1-methylethenyl)bicyclo[4.4.0]decan-2-one (94) 1693.4. THE FORMATION OF TRICYCLIC RING SYSTEMSEMPLOYING THE ANNULATION METHOD BASED ON THEPALLADIUM(O)-CATALYZED INTRAMOLECULARCOUPLING 1703.4.1. SYNTHESIS OF THE BICYCLIC ENONES 1703.4.1.1. Synthesis of 3-[2-(1 ,3-Dioxan-2-yl)ethyl]cyclo-hexanone (1O2) 1703.4.1.2. Synthesis of Bicyclo[4.3.0]non-9-en-2-one (95) 1713.4.1.3. Synthesis of 3-[2-(1,3-Dioxan-2-yl)ethyl]-3-methyl-cyclohexanone (103) 1723.4.1.4. Synthesis of 6-Methylbicyclo[4.3.0]non-9-en-2-one(96) 1743.4.2. SYNTHESIS AND EPIMERIZATION OF THE BICYCLICKETO VINYLGERMANES 1753.4.2.1.Synthesis of (1S*, 6S*,germyl)-3-butenyl]bicyclo[4.3.0]nonan-2-one (130a)and (1R, 6S*,3-butenyl]bicyclo[4.3.0]nonan-2-one (130b) 1753.4.2.2. Epimerization of compounds 130a and 130b 1803.2.2.3. Synthesis of (1 S*, 6S*, 9S*>6,9..Djmethyl.9..[3..(trimethylgermyl)-3-butenyljbicyclo[4.3.0]nonan-2-one (131a) and (1R*, 6S*, 9S*>.6,9..Dimethyl...9..[3..(trimethylgermyl)-3-butenyljbicyclo[4.3.0]nonan-2-xone(131b). 1813.4.2.4. Epimerization of compounds 131a and 131b• . 1853.4.2.5. Synthesis of (1 S*, 65*,butenyl]bicyclo[4.3.0]nonan-2-one (132a) and (1R ‘,65*, 95*)9[3.(thmethy1geniy1>..3...buteny1]..bicyclo[4.3.0]-nonan-2-one (132b ) 1863.4.2.6. Epimerization of compounds 132a and 132fr 1893.4.2.7. Synthesis of (1R*, 65*, 95*).6.Methyl..9..[3..(th..methylgermyl)-3-butenyl]bicyclo-[4.3.OJnonan-2-one(133a) and (15*, 65*, 95*).6..Methyl...9... [3-(trimethyl-germyl)-3-butenyl]-bicyclo[4.3.0]nonan-2-one(133b) 1903.4.2.8. Epimerization of compounds 133a and 133fr 1963.4.3. CONVERSION OF THE BICYCLIC KETO VINYLGERMANES INTO THE CORRESPONDING KETO VINYLIODIDES 1973.4.3.1. Synthesis of (15*, 65*, 95*)9.(3.4odo..3..butenyl>9.methylbicyclo[4.3.Ojnonan-2-one (135a) and (1 R*,65*, 95*)9.(34odo.3...butenyl).9...methylbicyclo...[4.3.0]nonan-2-one (135b) 1973.4.3.2. Synthesis of (1 S*, 6S*, 9S*)..6,9..Djmethyl.9..(34odo..3-butenyl)bicyclo[4.3.0]nonan-2-one (136) 1993.4.3.3. Synthesis of (15*, 65*, 95*)..9..(34odo..3.butenyl).bicyclo[4.3.0]nonan-2-one (137a) and (1R*, 65*, 95*)..9-(3-Iodo-3-butenyl)bicyclo[4.3.0]nonan-2-one(137b) 2003.4.3.4. Synthesis of (1R*, 65*, 9S*)9.(3..Iodo.3..butenyl)..6..methylbicyclo[4.3.0]nonan-2-one (138a) and (15*,65*, 9S*)9.(34odo.3..butenyl).6..methylbicyclo..[4.3.0]nonan-2-one (138b) 2023.4.4. Pd(0)-CATALYZED CYCLIZATION REACTIONS OF THEBICYCLIC VINYL IODIDES TO PRODUCE TRICYCLICRING SYSTEMS 2043.4.4.1. Synthesis of (15*, 55*, 8S*)..5Methy12methy1ene..tricyclo[6.4.0.0“]dodecan-12-one (139) and (1S*,45*, 7R*, 1 1S*) 1 -Methyl-8-methylenetricyclo-[5.3.2.011]dodecan 12-one (140) 204a. Via a Pd(0)-Catalyzed Cycization of the Cis-FusedVinyl Iodide 135w 204xb. Via a Pd(0)-Catalyzed Cyclization of the TransFused Vinyl Iodide 135b 210c. Via a Pd(0)-Catalyzed Cyclization of the TransFused Vinyl Iodide 135b employing modifiedreaction conditions 2103.4.4.2. Synthesis of (1 S*, 5S*, 8S*, 12S*)5Methyl2methylenericyclo[6.4.0.&‘5]dodecan- 1 2-ol (142) 2113.4.4.3. Synthesis of (1S*, 45’*, 7R*, 11S, 12S*)1Methyl8methylenetricyclo[5.3.2.0J‘]dodecan- 12-ol (144) 2123.4.4.4. Synthesis of (1S*, 4S*, 7R*, 11S, 12S*)1Methyl8methylene- 12-p-nitrobenzoyloxytricyclo[5.3.2.0 ij..dodecane (145) 2153.4.4.5. Synthesis of (1R*, 4S*, 7R*, 11S*)1,4Dimethyl8methylenetricyclo[5.3.2.0’1‘]-dodecan- 12-one (146): 2173.4.4.6. Synthesis of (1 R*, 5S*, 8S*)2Methylenetricyclo[6.4.0.0’5]dodecan-12-one (147) and (1S*, 4R*, 7R*,1 1S*)8Methylenetricyclo[5.3.2.0J]dodecan- 12-one (148): 220a. Via a Pd(0)-Catalyzed Cydization of the Cis-FusedVinyl Iodide 137w 220b. Via a Pd(0)-Catalyzed Cyclization of the TransFused Vinyl Iodide 137b 2233.4.4.7. Synthesis of (1R*, 4R*, 7R*, 11R*)4Methyl8methylenetricyclo[5.3.2.0’1]-dodecan- 12-one (149)and (1R*, 6S*,[4.3.0]nonan-2-one (15O) 224a. Via a Pd(0)-Catalyzed Cydization of the Cis-FusedVinyl Iodide 138a 224b. Via a Pd(0)-Catalyzed Cyclization of the TransFused Vinyl Iodide 138b 2273.5. SYNTHESIS OF TRICYCLIC COMPOUNDS BEARING ANALLYLIC, ANGULAR HYDROXYL GROUP 2283.5.1. GENERAL PROCEDURE 4: CYCLIZATION REACTIONSOF THE KETO VINYL IODIDES VIA A METAL-HALOGENEXCHANGE REACTION 2283.5.1.1. Synthesis of (1S*, 4S*, 8R*, 12R*)1Methyl9methylenetricyclo[6.3. 1 ‘]dodecan-8-ol (154) 228Xlii3.5.1.2. Synthesis of (1S*, 45*, 8R*, 12S*)1Methy19methylenetricyclo[6.3. i.04,12]dodecan-8-ol (157),(15*, 45*, 85*,[6.3.1.0”]dodecan-8-ol (158), and (15*, 6S*, 9R*)9-(3-Butenyl)-9-methylbicyclo[4.3.0]nonan-2-one(159) 2333.5.1.3. Synthesis of (15*, 45*, 8R*, 12S*)1,4Dimethy19methylenetricyclo[6.3. i.04,1]dodecan-8-ol (160) and(15*, 65*,[4.3.Ojnonan-2-one (161) 2393.5.1.4. Synthesis of (15*, 45*, 8 R*, 12R*)9Methy1enetricyclo[6.3.1.0’2]dodecan-8-ol (155) 2463.5.1.5. Synthesis of (15*, 45*, 8R*, 12S*)9Methy1enetricyclo[6.3. 1 0”2]dodecan-8-ol (162), (1 S*, 45*,85*, 12S*)9Methy1enetricyc1o[6.3. 1 12]dodecan...8-ol (163), and (15*, 6S*, 9R*)9(3Buteny1)bicyc1o[4.3.0]nonan-2-one (164): 2503.5.1.6. Synthesis of (15*, 45*, 8R*, 12S*)4Methy19methylenetricyclo[6.3.1.0’2]dodecan-8-ol (156) 2563.5.1.7. Synthesis of (15*, 4S*, 8R*, 12R*)4Methy19methylenetricyclo[6.3. 1 ‘]dodecan-8-ol (165),(15*, 45*, 85*,[6.3.1.0”2]dodecan-8-ol (166), and (1R*, 65*, 9R*)9-(3-Butenyl)-6-methylbicyclo[4.3.0]nonan-2-one(167) 260PART 2: TOTAL SYNTHESES OF (-)-HOMALOMENOLS A AND B.I. INTRODUCTION 2661.1. GENERAL 2661.2. PROPOSAL 266II. DISCUSSION 2702.1. RETROSYNTHETIC ANALYSIS 2702.2. SYNTHESIS OF (-)-HOMALOMENOL B (169b) 272xiv2.2.1. PREPARATION OF THE ENANTIOMERICALLYHOMOGENEOUS ALLYLIC ACETATE 181b 2722.2.2. PREPARATION OF THE ENANTIOMERICALLYHOMOGENEOUS BICYCLIC ENONE 177b 2792.2.3. SYNTHESIS OF THE BICYCLIC KETONE 176b 2852.2.4. SYNTHESIS OF (-)-HOMALOMENOL B (169b) 2912.3. SYNTHESIS OF (-)-HOMALOMENOL A (168b) 2952.3.1. PREPARATION OF THE BICYCLIC KETONE 175b 2952.3.1.1. Model Studies for the Preparation of Reagent 178 2952.3.1.2. Literature Precedent on the Effects of VariousAdditives on the Stereoselectivity of ConjugateAddition Reactions 2972.3.1.3. Conjugate Addition of the Cuprate Reagents 178 and203 to the Bicydic Enone 17Th 3002.3.2. SYNTHESIS OF (-)-HOMALOMENOL A (168b) 3072.3.3. SYNTHESIS OF THE (-)-MONOACETATE 215 3102.4. CONCLUSION 313III. EXPERIMENTAL 3153.1. SYNTHESIS OF (-)-HOMALOMENOL B (169b) 3153.1.1. PREPARATION OF THE ENANTIOMERICALLYHOMOGENEOUS ALLYLIC ACETATE 181b 3153.1.1.1. Synthesis of 3-Methyl-3-cyclohexen-1-one (182) 3153.1.1.2. Synthesis of 1 -Methyl-7-oxabicyclo[4. 1 .0]heptan-3-one (185) 3173.1.1.3. Synthesis of 4-Acetoxy-3-methyl-2-cyclohexen-1-one(181) 3183.1.1.4. Synthesis of (R)-(+)-4-Hydroxy-3-methyl-2-cyclohexen- 1-one (186a) and (S)-(-)-4-Acetoxy-3-methyl-2-cyclohexen-1-one (181b) 3193.1.1.5. Synthesis of the ester 188b 3213.1.2. PREPARATION OF THE ENANTIOMERICALLYHOMOGENEOUS BICYCLO[4.3.0] ENONE 17Th 323xv3.1.2.1. Synthesis of (S)-(+)-4-(tert-Butyldiphenylsioxy)-3-methyl-2-cyclohexen- 1-one (180b): 3233.1.2.2. Synthesis of (35, 4S)-(+)-4-(tert-Butyldiphenylsiloxy)-3-[2-( 1 ,3-dioxan-2-yl)ethyl]-3-methylcyclohexanone(l89) 3253.1.2.3. Synthesis of (5 S, 6S)-(-)-5-(tert-Butyldiphenylsioxy)-6-methylbicyclo[4.3 .0]non-9-en-2-one (177b ) 3283.1.2.4. Synthesis of 2-methyl-3-(tri-n-butylstannyl)propene(194) 3303.1.3. PREPARATION OF THE BICYCLIC KETONE 176b 3313.1.3.1. Synthesis of (1R, 5S, 6S, 95)-(-)-5-(tert-Butyldiphenylsiloxy)-6-methyl-9-(methaflyl)bicyclo-[4.3.0]nonan-2-one (196) and (iS, 5S, 6S, 9S)-(-)-5-(tert-Butyldiphenylsiloxy)-6-methyl-9-(methallyl)-bicyclo[4.3.0]nonan-2-one (176b) 3313.1.3.2. Epimerization of compound 176fr 3363.1.4. SYNTHESIS OF (-)-HOMALOMENOL B (169b) 3373.1.4.1. Synthesis of (15, 2R, 5S, 6S, 9S)-(-)-5-(tert-Butyldiphenylsiloxy)-2,6-dimethyl-9-(methallyl)-bicyclo[4.3.0]nonan-2-ol (197) 3373.1.4.2. Synthesis of (-)-Homalomenol B (169b) 3403.2. ROUTE TO THE SYNTHESIS OF (-)-HOMALOMENOL A (168b) . 3443.2.1. PREPARATION OF THE BICYCLIC KETONE 175b 3443.2.1.1. Synthesis of 1-Iodo-2-methylpropene (2O2) 3443.2.1.2 Synthesis of (1R, 55, 6S, 9R)-(-)-5-(tert-Butyldiphenyl-sioxy)-6-methyl-9-(2-methyl- 1-propenyl)bicyclo-[4.3.0]nonan-2-one (213), (iS, 55, 6S, 9S)-(-)-5-(tert-Butyldiphenylsiloxy)-6-methyl-9-(2-methyl-1-propenyl)bicyclo[4.3.Ojnonan-2-one (175b), and (i R,5S, 65, 9S)-(-)-5-(tert-Butyldiphenylsiloxy)-6-methyl-9-(2-methyl-i -propenyl)bicyclo[4.3.Ojnonan-2-one(212) 346a. Via Conjugate Addition of the Cuprate Reagent 178to the Enone 177b in the Presence of TMSBr andBF3•Et20; General Procedure 5 346xvib. Via Conjugate Addition of the Cuprate Reagent 178to the Enone 17Th in the Presence of TMSBr at-78°C 353c. Via Conjugate Addition of the Cuprate Reagent 178to the Enone 17Th in the Presence of TMSBr at-78°Cto-1O°C 3533.2.2. SYNTHESIS OF (-)-HOMALOMENOL A (168b) 3553.2.2.1. Synthesis of (iS, 2R, 5S, 6S, 9S)-(-)-5-(tert-Butyl-diphenylsiloxy)-2,6-dimethyl-9-(2-methyl-1-propenyl)bicyclo[4.3.Ojnonan-2-ol (214) 3553.2.2.2. Synthesis of (-)-Homalomenol A (168b) 3573.2.3. SYNTHESIS OF (iS, 2R, 5S, 6S, 9S)-(-)-5-ACETOXY-2,6-DIMETHYL-9-(2-METHYL- 1-PROPENYL)-BICYCLO-[4.3.O]NONAN-2-OL (215) 361IV. REFERENCES AND FOOTNOTES 363V. APPENDIX 3745.1. APPENDIX 1: X-RAY CRYSTALLOGRAPHIC DATA 374xviiLIST OF TABLESTable Page1. Preparation of the Cyclization Substrates 202. Palladium(0)-Catalyzed Cydization Reactions of the Keto Vinyl Jodides 253. The Effects of Different Catalysts on the Cycization Reaction 294. Attempts at the Synthesis of Bridged Bicyclic Ketones using the Pd(0)-Catalyzed Cyclization Reaction 335. Preparation of the Cyclization Precursors for the Six-Membered RingAnnulation Sequence 416. Attempts at Six-Membered Ring Formation by Employing the Pd(0)-Catalyzed Cydization Reaction 437. Preparation of the Bicyclic Enones 95 and % According to a ModifiedVersion of HelquisCs Annulation Sequence 488. Results of the Conjugate Addition Reactions of Reagent 15 to the Bicyclo[4.3.0]non-9-en-2-ones 589. Consistent JR and ‘H nmr Differences Between the Cis-Fused and TransFused Vinylgermane Epimers 6910. The Thermodynamically Controlled Equilibration of the Cis- and Trans-fusedBicyclo[4.3.0]nonan-2-ones 7111. Equilibration Studies of the Vinylgermane Bicyclo[4.3.Ojnonan-2-ones 7312. Conversion of the Keto Vinylgermanes into the Corresponding Keto Vinyllodides 7513. Differences in the Position of the Carbonyl Absorbances in the Cis- andTrans-Fused Vinyl lodides 7814. Cyclization Studies in Forming Fused and Bridged Tricyclic Keto Alkenes 9415. Cyclization Reactions of the Trans-Fused Vinyl lodides to Yield TricyclicCompounds Bearing an Allylic, Angular Hydroxyl Group 10416. A ppm for those Protons in a 1,3-Diaxial Relationship with the AngularHydroxyl Group 10917. Cyclization Reactions of the Cis-Fused Vinyl lodides to Yield TricyclicCompounds Bearing an Ailylic, Angular Hydroxyl Group 11018. A ppm for those Protons in Close Proximity to the Angular Hydroxyl Groupin the Beta-OH Products 112xviii19. Differences in the Chemical Shift of the Vinyl Proton H-x’ Between the Beta-OH and Alpha-OH Products 11420. ‘H nmr Data (400 MHz, CDC13) for the Bridged Keto Alkene 81: COSY andNOE Experiments 15921. 1H nmr Data (400 MHz, C6D6) for the Trans-Fused Compound 130b: COSYExperiment 17722. ‘H nmr Data (400 MHz, acetone-d6) for the Cis-Fused Compound 130a:COSY and NOE Experiments 17923. ‘H nmr Data (400 MHz, acetone-d6) for the Cis-Fused VinylgermaneCompound 131a: COSY and NOE Experiments 18424. ‘H nmr Data (400 MHz, CDC13) for the Cis-Fused Vinylgermane Compound132a: COSY and NOE Experiments 18825. ‘H nmr Data (400 MHz, C6D6) for the Trans-Fused VinylgermaneCompound 133b: COSY and NOE Experiments 19226. ‘H nmr Data (400 MHz, C6D6) for the Cis-Fused Vinylgermane Compound133a: COSY and NOE Experiments 19427. ‘H nmr (500 MHz, C6D6) and ‘3C nmr (125.8 MHz, C6D6) Data for the CisFused Vinylgermane Compound 133a: HMQC and HMBC Experiments 19528. ‘H nmr Data (400 MHz, CDCI3) for the Fused Tricyclic Compound 139:COSY and NOE Experiments 20629. ‘H nmr Data (400 MHz, CDC13) for the Bridged Tricyclic Compound 140:COSY and NOE Experiments 20830. ‘H nmr (500 MHz, CDC13) and 13C nmr (125.8 MHz, CDC13) Data for theBridged Compound 140: HMQC and HMBC Experiments 20931. ‘H nmr Data (400 MHz, CDC13) for the Bridged Alcohol 144: COSYExperiment 21432. ‘H nmr Data (400 MHz, C6D6) for the Bridged Compound 146: COSY andNOE Experiments 21933. ‘H nmr Data (400 MHz, CDC13) for the Fused Tricyclic Compound 147:COSY and NOE Experiments 22234. ‘H nmr Data (400 MHz, C6D6) for the Bridged Compound 149: COSY andNOE Experiments 22635. nmr Data (400 MHz, CDC13) for the Tricyclic Compound 154: COSYExperiment 23136. ‘H nmr Data (400 MHz, pyridine-d5) for the Tricyclic Compound 154:COSY Experiment 23137. Comparison of the ‘H nmr (400 MHz) Chemical Shifts of Compound 154 inCDC13 vs. Pyridine-d5 23238. ‘H nmr Data (400 MHz, CDC13) for the Tricycic Compound 158: COSYand NOE Experiments 23439. ‘H nmr Data (400 MHz, CDC13) for the Tricycic Compound 157: COSYExperiment 23740. ‘H nmr Data (400 MHz, pyridine-d5) for the Tricycle Compound 157:COSY Experiment 23741. Comparison of the 1H nmr (400 MHz) Chemical Shifts of Compound 157 inCDC13 vs. Pyridine-d5 23842. ‘H nmr Data (400 MHz, CDC13) for the Tricyclic Compound 160: COSYExperiment 24243. ‘H nmr Data (400 MHz, pyridine-d5) for the Tricyclic Compound 160:COSY and NOE Experiments 24244. Comparison of the ‘H nmr (400 MHz) Chemical Shifts of Compound 160 inCDC13 vs. Pyridine-d5 24345. ‘H nmr (500 MHz, CDC13) and ‘3C nmr (100.4 MHz, CDC13) Data for theTricycle Compound 160: HMQC and HMBC Experiments 24446. ‘H nmr (500 MHz, pyridine-d5) and ‘3C nmr (125.8 MHz, pyridine-d5) Datafor the Tricyclic Compound 160: HMQC and HMBC Experiments 24547. ‘H nmr Data (400 MHz, CDC13) for the Tricycle Compound 155: COSYExperiment 24848. ‘H nmr Data (400 MHz, pyridine-d5) for the Tricycle Compound 155:COSY Experiment 24849. Comparison of the ‘H nmr (400 MHz) Chemical Shifts of Compound 155 inCDC13 vs. Pyridine-d5 24950. ‘H mnr Data (400 MHz, CDC13) for the Tricycic Compound 163: COSYExperiment 251xx51. ‘H nmr Data (400 MHz, CDC13) for the Tricyclic Compound 162: COSYExperiment 25452. 1H nmr Data (400 MHz, pyridine-d5) for the Tricycic Compound 162:COSY Experiment 25453. Comparison of the ‘H nmr (400 MHz) Chemical Shifts of Compound 162 inCDC13 vs. Pyridine-d5 25554. ‘H nmr Data (400 MHz, CDC13) for the Tricyclic Compound 156: COSYExperiment 25855. ‘H nmr Data (400 MHz, pyridine-d5) for the Tricyclic Compound 156:COSY Experiment 25856. Comparison of the ‘H nmr (400 MHz) Chemical Shifts of Compound 156 inCDC13 vs. Pyridine-d5 25957. ‘H nmr Data (400 MHz, CDC13) for the Tricydic Compound 166: COSYExperiment 26158. ‘H nmr Data (400 MHz, CDC13) for the Tricyclic Compound 165: COSYExperiment 26459. ‘H nmr Data (400 MHz, pyridine-d5) for the Tricyclic Compound 165:COSY Experiment 26460. Comparison of the ‘H nmr (400 MHz) Chemical Shifts of Compound 165 inCDC13 vs. Pyridine-d5 26561. Attempts to Cyclize Keto Acetal 189 to Form the Bicyclic Enone 177b 28362. The Effects of Additives on the Conjugate Addition of Reagents 178 or 203 tothe Enone 177b 30163. ‘H nmr Data (400 MHz, CDC13) for the Keto Acetal 189: COSYExperiment 32764. ‘H nmr Data (400 MHz, CDC13) for the Trans-Fused Compound 176b:COSY and NOE Experiments 33365. ‘H nmr Data (400 MHz, CDC13) for the Cis-Fused Compound 196: COSYand NOE Experiments 33566. ‘H nmr Data (400 MHz, CDC13) for the Tertiary Alcohol 197: COSY andNOE Experiments 33967. 1H nmr Data (400 MHz, CDC13) for (-)-Homalomenol B (169b): COSY andNOE Experiments 342xx68. Comparison of the Reported Spectral Data for (÷)-Homalomenol B (169a)with that of the Synthetic (-)-Homalomenol B (169b) 34369. ‘H nmr Data (400 MHz, CDC13) for Compound 175b: COSY and NOEExperiments 35070. ‘H nmr Data (400 MHz, CDC13) for Compound 212: COSY and NOEExperiments 35271. ‘H nmr Data (400 MHz, CDC13) for (-)-Homalomenol A (168b): COSY andNOE Experiments 35972. Comparison of the Reported Spectral Data for (+)-Homalomenol A (168a)with that of the Synthetic (-)-Homalomenol A (168b) 36073. Comparison of the Reported Spectral Data for the (+)-Monoacetate 215 withthat of the Synthetic Monoacetate 215 362xdiLIST OF FIGURESFigure Page1. The ‘H nmr Spectrum (400 MHz, C6D6) of the Cis-Fused Vinylgermane133a 642. The ‘H nmr Spectrum (400 MHz, C6D6) of the Trans-Fused Vinylgermane133b 663. The ‘H nmr Spectrum (400 MHz, C6D6) of the Cis-Fused Vinyl Iodide 138a .764. The ‘H nmr Spectrum (400 MHz, C6D6) of the Trans-Fused Vinyl Iodide138b 775. The ‘H nmr Spectrum (400 MHz, CDC13) of the Fused Keto Alkene 139 836. The ‘H nmr Spectrum (400 MHz, CDC13) of the Bridged Keto Alkene 140 867. The ‘H nmr Spectrum (400 MHz) of the Tricycic Alcohol 154 in a) CDC13and b) pyridine-d5 1068. The ‘H nmr Spectra (400 MHz, CDC13) of 188a and 188b in a) the absenceand b) presence of Eu(fod)3 2769. The ‘H nmr Spectrum (400 MHz, CDC13) of the Cis-Fused Ketone 196 28710. The ‘H nmr Spectrum (400 MHz, CDC13) of the Trans-Fused Ketone 176b . 28911. The ‘H nmr Spectrum (400 MHz, CDC13) of (-)-Homalomenol B (169b) 29412. The ‘H nmr Spectrum (400 MHz, CDC13) of the Trans-Fused Ketone 17Th ...30413. The ‘H nmr Spectrum (400 MHz, CDC13) of (-)-Homalomenol A (168b) 30914. The ‘H nmr Spectrum (400 MHz, CDC1 3) of the (-)-Monoacetate 215 31115. The ‘H nmr Spectrum (200 MHz, CDC13) of the (+)-Monoacetate 215 fromDr. T. V. Sung 312xxiliLIST OF GENERAL PROCEDURESGeneralProcedure Page1. Preparation of the Keto Vinylgermanes 1322a. Preparation of the Keto Vinyl lodides from the Corresponding KetoVinylgermanes 1412b. Preparation of the Keto Vinyl lodides from the Corresponding KetoVinylgermanes 1413. Pd(O)-Catalyzed Cyclization Reaction of the Keto Vinyl lodides 1464. Cyclization Reactions of the Keto Vinyl lodides Via a Metal-HalogenExchange Reaction 2285. The Conjugate Addition of the Cuprate Reagent 178 to the Enone 17Th 346xxivLIST OF ABBREVIATIONSA- angstrom(s)cx - 1,2 relative position[cx] b - specific rotation at the sodium D line (589.3 nm) and at thetemperature tAc - acetyl or acetateanal. - analysisAPT - attached proton lestaq - aqueous13 - 1,3 relative positionlx - broadBnBr - benzyl bromideBu - butylc - concentration in gIlOO mLcalcd. - calculatedCOSY - (1H- ‘H homonuclear) rrelation pectroscopyC-x- carbon number xd - doublet- chemical shift in parts per million from TMSA - refluxA6- chemical shift differencedba - dibenzilideneacetoneDCC- N,N-dicyclohexylcarbodiimideDEG - diethyleneglycolDIBAL- diisobutylaluminum hydrideDMAP- 4-dimethylaminopyridineDMF - N,N-dimethylformamidexxvDMSO - dimethylsuifoxidedppf - 1,1 ‘-bis(diphenylphosphino)ferroceneEd., Eds. - editor, editorsequiv. - equivalentEt - ethylFT - Fourier transform- 1,4 relative positiongic- gas liquid chromatographyHMBC- heteronuclear multiple bond coherenceHMPA- hexamethyiphosphoramideHMQC- heteronuclear multiple quantum oherenceH.O. - higher orderHRMS - high resolution mass spectroscopyH-x- hydrogen number xi - isoJR - infraredJ - coupling constant in HzLDA - lithium diisopropylamidelit. - literatureL.O. - lower orderLRMS - low resolution mass spectroscopym- multipletm - metam-CPBA- m-chloroperbenzoic acidMe- methylnmr- nuclear magnetic resonanceNOE- nuclear verhauser ffectxxvip - paraP- protecting groupPCC - pyridinium chlorochromatePh- phenylpH- -logio[HjPLE - pig liver esteraseppm - parts per millionPPTS - pyridinium p-toluenesulfonatePr- propylq - quartetRf- retardation factor (ratio of distance traveled by the center of a zoneto the distance simultaneously traveled by the mobile phase)it - room temperatures - singlett - triplett - tertiaryTBAF - tetrabutylammonium fluorideTBDPS- tert-butyldiphenylsilylTh - thienylTHF - tetrahydrofurantic - thin layer chromatographyTMS - trimethylsilylTris - tris(hydroxymethyl)aminomethanep-Ts - para-toluenesulfonyl-ye - negative•- coordination or complexxxviiACKNOWLEDGMENTSFirst of all, I would like to thank my research supervisor, Dr. Edward Piers, for hiscommitment, support, and meticulous guidance during the course of my stay at UBC.I would also like to thank all members, past and present, of the Piers group forproviding a stimulating and enjoyable work environment. Special thanks to René and Toddfor very helpful suggestions regarding my research projects as well as for providing technicaladvice and interesting glassware arrangements.The efficient recording of the spectral data by the technical staff of the nmr, massspectrometry, and elemental analyses laboratories is gratefully acknowledged. Thanks aredue particularly to Mrs. L. Darge and Mrs. M. Austria from the nmr laboratory.I am indebted to Dr. Christine Rogers, Dr. Pat Burns, Dr. Wen-Lung Yeh, Dr. Weiler,René Lemieux, and Todd Schindeler for proof-reading my thesis.Financial support from the Natural Sciences and Engineering Research Council ofCanada and Bio-Méga Inc. was greatly appreciated.Finally, I would like to thank my parents for their support and Derrick for hisunending encouragement and help throughout all these years.1PART 1: ANNULATION SEOUENCES EMPLOYING THE BIFUNCTIONALCONJUNCTIVE REAGENTS 4-IODO-2-TRIMETHYLGERMYL-1-BUTENE (13)AND 5-IODO-2-TRIMETHYLGERMYL-1-PENTENE (31).I. INTRODUCTION1.1. GENERALSynthetic organic chemists have always striven to achieve more effective andselective ways to push forward the boundaries of organic synthesis. The construction ofcomplex molecules, for example, has seen a dramatic and continuing growth which hasparalleled our increase in knowledge of the chemical sciences. In the past decade there hasbeen a tremendous amount of growth in the design of new synthetic methods for thestereoselective construction of carbon-carbon bonds. In addition to discovering newsynthetically useful reactions, the organic chemist faces the challenge of learning to controlreactivity so that selectivity of product formation can be accomplished.The discovery of new and efficient methods for the construction of highlyfunctionalized ring systems is of considerable interest to the synthetic chemist. Thisobjective has, in part, led to the development of bifunctional conjunctive reagents whichpossess two potentially reactive sites. These bifunctional conjunctive reagents have beendefined by Trost1 as “simple building blocks which are incorporated in whole or in part into amore complex system”. The two reactive sites can be either nucleophilic or electrophilic innature and have been termed “donor” (d) and “acceptor” (a) sites, respectively.2 Thebifunctional conjunctive reagents must be constructed to allow the coexistence of the tworeactive sites which can be deployed either simultaneously or sequentially. The number ofsuch reagents that have been developed recently are too numerous to mention here.3 Thefollowing example4(Scheme 1), however, illustrates how such a reagent can be effectivelyemployed in an annulation sequence.20da BrMg a1 HCI, H20,CuBr•Me2S, HMPA, THE, ATMSCI, THE, -78 °CThe bifunctional Grignard reagent 1 serves as the synthetic equivalent of an a’,d3-synthon.The acceptor site in the reagent is masked as an acetal and is revealed in the second step ofthe sequence by conversion of the acetal to an aldehyde moiety. The first step of thesequence deploys the donor site in an intermolecular copper(I)-catalyzed conjugate additionof a Grignard reagent to form the keto acetal 2. This is followed by an intramolecular aldolcondensation to form the bicyclic enone 3. The use of bifunctional conjunctive reagents toperform similar annulation processes will be the focus of much of the work described in Part1 of this thesis.2Scheme i331.2. BACKGROUNDThe application of bifunctional reagents to annulation sequences has been studiedextensively in our laboratories, and three such sequences are outlined in Scheme 2. In eachannulation sequence the substrate is an cx,13-unsaturated ketone and the bifunctionalconjunctive reagent serves as the synthetic equivalent of a 1-butene synthon. Theregioisomeric methylenecyclopentane annulation sequences A6 and B7 employ synthonswhich bear umpolung8 reactivity. The methylenecyclohexane annulation sequence C9employs a 1-butened2,d4-synthon.ad a__ixScheme 2A discussion of the bifunctional conjunctive reagents developed to carry out the annulationsequences A, B, and C (Scheme 2), along with their application to the synthesis of naturalproducts follows.Previous work in our laboratories has led to the development of themethylenecyclopentane annulation sequence shown in Scheme 3 (see also route A, Scheme2).6 The bifunctional conjunctive reagent used in this route, 4-chloro-2-trimethylstannyl-l -butene (4), 10 serves as the synthetic equivalent of the 1-butened2,a4-synthon 5. The latentdonor activity of 4 is first unmasked by transmetallation with MeLi. A copper(I) salt is thenadded, thereby forming the organocopper(I) reagent 6, which adds in a conjugate fashion to4cyclic enone systems. The acceptor site is then deployed in the subsequent intramolecularalkylation step to generate the bicyclic keto alkene 7.Me3SnCI d L..._ a//2) CuSPh orCuCNM CI6THE, -78 °CM = CuSPh(Li) orCuCN(Li)Scheme 36This annulation sequence has been successfully employed in the synthesis of natural productssuch as (±)-A92)-capneUene (8),h1 (±)-pentalene (9),h1 and (±)-methylcantabrenonate(10)12 (the incorporated bifunctional reagent is highlighted in each natural product shownbelow).5KH,7——sIThe annulation sequence illustrated in Scheme 3 has been extended to the formation of sixmembered rings (general structure 11) by employing the bifunctional conjunctive reagent 12(the one-carbon homologue of reagent 4). 139 10R125More recently, work in our laboratories7has led to the development of acomplementary, regioisomeric methylenecyclopentane annulation procedure (route B,Scheme 2) using the bifunctional conjunctive reagent 13 (Scheme 4). 4-Iodo-2-trimethylgermyl- 1-butene (13) serves as the synthetic equivalent of the 1-butene a2,d4-synthon 14 and possesses umpolung reactivity compared with that of the previous synthon 5.By converting reagent 13 to the organocopper(I) species 15, the donor site of the bifunctionalreagent can be utilized in a 1,4-conjugate addition reaction to an enone.Me3G I131) t-BuLi (2 equiv.),THE, -98 °C2) CuCN,-78 °C —* -35 °CScheme 47The vinylgermane function in 13 is stable to the lithium-iodine exchange conditions requiredto generate reagent 15, in contrast to the more labile vinylstannane moiety.14 Unmasking ofaL..-d140Me3Ge(CuCN(LDTMSCI, THE, -78 °C35% - 88%R’ t-BuOK in THF/t-BuOH18 58%-74% 176the acceptor site of the bifunctional reagent 13 is achieved by converting the vinylgermaneadduct 16 to the corresponding vinyl iodide 17. The final step in the annulation sequenceemploys a Pd(0)-catalyzed coupling reaction between an enolate carbon (donor) and the iodosubstituted alkene carbon (acceptor) to generate bicydic keto alkenes of general structure 18.In practice, this was accomplished by the slow addition of a solution of t-BuOK in THFt-BuOH to a solution of Pd(PPh3)4 (—20 mol%) and the vinyl iodide 17 in THF. Under thesebasic reaction conditions, when R = H, isomerization of the alkene function from theexocyclic position to the conjugated endocyclic position occurs, generating bicyclic enonesof general structure 19. The general applicability of this annulation method (Scheme 4) hasresulted in its use for the total synthesis of (±)-crinipellin B (20) (Scheme 5). 15Scheme 5151)12, CH2I2) Pd(PPh34THE, t-BuOK,t-BuOHThe vinylgermane bifunctional reagent 13 can also be employed in an annulationsequence designed to generate ring systems bearing a tertiary allylic alcohol function (routeC, Scheme 2).9,16 In this route, the bifunctional conjunctive reagent 13 serves as thesynthetic equivalent of the 1-butened2,d4-synthon 21.several Li(CN)CuTMSBr, THE,-78 °C to -48 °C00OH207Me3Ge’N d dThis sequence was employed in the total synthesis of (±)-ambliol B (22) (Scheme 6). 9 Theconversion of the exocyclic enone 23 to the bicyclic allylic alcohol 24 (Scheme 6) illustratesthe use of reagent 13 in the annulation sequence described above. The 1,4-conjugate additionreaction to generate compound 25 deploys the d4 center of reagent 15 and is similar to thatdescribed in the previous annulation sequence (Scheme 4). The ring closure step harnessesthe donor capability of the vinyl iodide moiety of compound 26 via a lithium-iodineexchange reaction. The resulting vinyllithium species attacks the carbonyl carbon in anintramolecular fashion, thereby generating the bicyclic compound 24. Further functionalgroup manipulations in this compound led to the synthesis of the target compound 22.severalstepsa Me3G23OHTMSCI, THE,-78 °Cn-BuLi (2 equiv.)THE, -78 °COH241) Ac20,C5HN2) Li, NH3 THE2622Scheme 681.3. PROPOSALSThe bifunctional conjunctive reagent 4-iodo-2-trimethylgermyl- 1 -butene (13) hasproven synthetically useful in promoting two novel annulation sequences (routes B and C,Scheme 2, page 3). One of the aims of the research described in Part 1 of this thesis dealswith the optimization of the annulation sequence illustrated in Scheme 4 (page 5). Could theconditions for the conjugate addition and cyclization reactions be modified to improve theyields of these steps? Could a catalyst other than Pd(PPh3)4 be used to effect the ringclosure step? How general is this sequence? It follows that one might be able to extend thePd(O)-catalyzed cyclization reaction to generate different types of ring systems. For example,could such a cyclization reaction be utilized to convert the enolate 27 to the bridged bicyclicketo ailcene 28 (equation 1)?eMO28(1)The use of a higher homologue reagent such as the vinylstannane compound 12 hasproven successful in promoting a methylenecyclohexane annulation method.13 That is, bygenerating the one-carbon homologue of the vinylstannane reagent 4, themethylenecyclopentane annulation sequence depicted in Scheme 3 (page 4) was extended togenerate functionalized bicyclo[4.4.O]dodecane compounds of general structure 11 (Scheme7). Could the annulation sequence in Scheme 4 be augmented to allow for the formation ofsix-membered rings of general structure 29 (Scheme 7)? To do so would require the use of a1-pentene a2,d5 synthon 30. The bifunctional reagent 5-iodo-2-trimethylgermyl- 1 -pentene(31) could be used as a viable synthetic equivalent of the 1-pentene synthon 30.R9cIMe3Sn12III+ daLIIIMe3G31Scheme 7The ease of synthesis of the bicyclic enones of general structure 19 (generated inScheme 4) prompted us to envisage their use in a further annulation sequence to generatetricyclic ring systems. Could the bifunctional vinylgermane reagent 13, used as the syntheticequivalent of the 1-butenea2,d4-synthon 14, generate more complex ring systems of generalstructure 32? What would be the stereochemical outcome of the conjugate addition reactionof the organocuprate 15 (Scheme 4) to the bicycle enone 19?M G0e3adR’11R’2919 3210Finally, the annulation sequence depicted in Scheme 6 (page 7), in which thevinylgermane reagent 13 serves as the synthetic equivalent of the 1-butened2,d4-synthon 21,has only been utilized in this one example.17 How general is this annulation method? Couldthis method also be applied to generate more complex, tricyclic ring systems of generalstructure 33 (Scheme 8)?Me3G 1319 Scheme 8 33The exploration of these possibilities was an important motivation in the syntheticinvestigations which are to be detailed in Part 1 of this thesis. It was the purpose of this workto improve and extend the use of the bifunctional conjunctive reagent 4-iodo-2-trimethylgermyl-1-butene (13) (as the synthetic equivalent of either the 1-butene a2,d4-synthon 14 or the 1-butened2,d4-synthon 21) in the annulation sequences outlined above.11II. DISCUSSION2.1. FIVE-MEMBERED RING ANNULATIONS BASED ON PALLADIUM(O)CATALYZED INTRAMOLECULAR COUPLING2.1.1. INTRODUCTORY REMARKSRecent work7 in our laboratories has led to the development of a five-membered ringannulation sequence employing the bifunctional reagent 13 as the synthetic equivalent to the1-butenea2,d4-synthon 14 (Scheme 4, page 5). The vinylgermane 13 was converted to thekey organocopper(I) reagent 15 by performing a metal-halogen exchange reaction followedby the addition of a copper(I) source (equation 2). “ Thus, treatment of a cold (-98 °C) THFsolution of reagent 13 with two equivalents of tert-butyllithium followed by the addition of1.1 to 1.2 equivalents of CuCN and brief warming to -35 °C, gave a homogeneous tansolution containing the organocopper(I) reagent 15. The structure of the organocopper(I)reagent 15 is displayed below as a simple monomer, even though there is no evidence tosupport this. For simplistic purposes, all future organocopper(I) reagents will be displayed asmonomers.Me3G I a d1) t-BuLi (2 equiv.),Me3G I 2) to Me3G Cu(CN)Li (2)13-35°C 15Me3Ge’I+ Me3Ge LiMeaGe 1GeMe3 (3)It was found necessary to employ two equivalents of tert-butyllithium to avoidformation of the coupled product 34 (equation 3). The reaction of tert-butyllithium (35) with12tert-butyl iodide (36, formed from the metal-halogen exchange with 13) appears to becompetitive with the lithium-iodine exchange process, probably giving 2-methylpropane(37), 2-methylpropene (38), and lithium iodide (39) (equation 4). This reaction consumesone equivalent of tert-butyllithium. Thus, if less than two equivalents of tert-butyllithium areused, the iodide 13 and the alkyllithium species 40 (produced by the metal-halogen exchangewith reagent 13) are present together in solution and will react to form the coupled product 34(equation 3).MeMe ) Li + CH3..>JH (CH3) + (CH3)2C=CH + Lii (4)37 38 39The annulation sequence commences with the 1,4-addition of the organocopper(I)reagent 15 to a suitable c3-unsaturated ketone (Scheme 9). This reaction proceeded in thepresence of trimethylsilyl chloride18 to afford the intermediate silyl enol ether 41 which,upon hydrolysis gave the keto vinylgermane 16. The reported yields7 for this reaction rangedfrom 35% to 88%, depending on the structure of the starting cL,f3-unsaturated ketone (videinfra).Me3Ge’Cu(CN)UTMSCI, THE, -78 °CGeMe3Scheme 9OTMSR’.GeMe3H20, NH4CICould the conditions for the conjugate addition reaction be optimized to increase the yields13of the keto vinylgermane products? In particular, could the yield for the cuprate addition ofreagent 15 to the hindered enone isophorone (reported yield7for this reaction was 35%) beenhanced?The second step of the annulation sequence (the conversion of the vinylgermanes 16into the vinyl iodides 17) was shown to proceed without incident and in high yield (equation5).7 With the vinyl iodide substrates in hand, the cyclization reactions could be executed.(5)Yields range from70% to 97%As reported,7reaction conditions (route i, Scheme 10) were developed to convert thevinyl iodides 17 into the bicyclic keto alkenes 18 or the enones 19 (Scheme 10). Thecyclization reaction occurred upon the addition of a solution of t-BuOK in THF/t-BuOH to asolution of Pd(PPh3)4 (—20 mol%) and the vinyl iodide 17 in THF. It was essential tomaintain a low concentration of base in the reaction media (route i, Scheme 10 employs aslow addition of base over 3 h via a syringe pump) since higher concentrations of base (routeii, Scheme 10) favored elimination of HI to form the undesired alkyne 42.19RMeEut-BuOK, THF/t-BuOH, 0°C, 5 mm;then Pd(PPh3)4(10 mol%), 0°CScheme 1014The mechanism of the cyclization reaction was not studied; however, a catalytic cyclebased on literature precedent was proposed by Marais.2° Three basic processes arepostulated, labeled A through C in Scheme 11. In step A (oxidative addition and enolateanion formation), the palladium(O) catalyst inserts into the carbon-iodine bond of compound17 and the potassium enolate 43a is formed by reaction with the base t-BuOK. Two possiblepotassium enolates can be formed (43a and 43b) under the equilibration conditions. Onlyspecies 43a participates in the next step, thus the equilibrium between the two enolates iscontinually shifted to the left as 43a is consumed in step B. In step B, the six-membered ringpalladacycle 44 is formed from the enolate 43a. This process is formally a transmetallationsince the potassium enolate is replaced by a “palladium enolate” in which the palladium(ll) isbonded to the a-carbon rather than the oxygen atom. Empirical evidence supports this stepsince as soon as the dropwise addition of the base commences, potassium iodide starts toprecipitate from the reaction mixture. The final step in the catalytic cycle (step C) is thereductive elimination of palladium(O) from the palladacycle 44. In this step, carbon-carbonbond formation takes place to give compound 18 and the palladium(O) catalyst is regenerated.Finally, due to the basic reaction conditions, when the product 18 has R=H, isomerization ofthe double bond into conjugation with the ketone occurs to give enones of general structure19.The reported yields7 for this novel Pd(O)-catalyzed cyclization reaction ranged from58% to 74% (vide infra). Could the reaction conditions be modified to improve the yield ofthis reaction? Is it necessary to employ 20 mol% of Pd(PPh3)4? Could other Pd(0) or Ni(0)catalysts be employed to effect this cyclization reaction? These questions motivated us tofurther investigate the general applicability and use of this annulation sequence. Sections2.1.3. (pages 19-23) and 2.1.4. (pages 24-33) detail the experiments that were carried out toimprove both the conjugate addition reaction and the Pd(0)-eatalyzed cyclization reaction.152 PPh3Pd(L2)IPd(PPh3)4t-BuOHA2 PPh3KI Pd(L2)I43aScheme 1143b162.1.2. PREPARATION OF THE BIFUNCTIONAL REAGENT 4-IODO-2-TRIMETHYL -GERMYL- 1-BUTENE (13)The bifunctional reagent 13 was originally synthesized7via the corresponding 4-chloro-2-trimethylstannyl-1-butene (45) (Scheme 12). The vinyistannane compound 45, inturn, was prepared from the commercially available 3-butyn-1-ol (46) via thestannylcopper(I) reagent 47•21 The synthesis of the vinylstannane reagent 48a could beaccomplished on large scale (vide infra); however, the two regioisomers that are formed (48aand 48b) can only be separated by drip column chromatography. This is a particularly timeconsuming operation, especially when working on large scale. The vinyistannane alcohol48a was converted to the chloride 45 in 95% yield. Transmetallation of the vinyistannanechloride 45 with MeLi at -78 °C, followed by the addition of trimethylgermanium bromide tothe resultant vinyllithium species 49, afforded 4-chloro-2-trimethylgermyl- 1-butene (50)(Scheme 12). The volatile vinylgermane chloride 50 was immediately converted to theiodide 13 via a halide interconversion. The bifunctional reagent was thereby formed in an84% yield (from the vinylstannane chloride 45) and could be stored indefinitely in the freezerunder an atmosphere of argon.MeLi, THE . CuBr•Me2S(Me3Sn)2-20 0Me3SnLi-78 0 Me3SnCu•Me22) MeOHMe3SnMe3SntLCIpphaL Me3Sn’’QH +(95%) (52%) : 1I MeLi, THE,-78°C[L_-IL._--....CI ] Me3GeBr acetone Me3Ge’-N(84%)Scheme 1217This synthesis7involves the use of two expensive reagents, namely hexamethylditin(—$5 per gram) and trimethylgermanium bromide (—$5 per gram). Moreover, the reaction toform the vinylstannane alcohol 48a is low yielding (52%) and involves a very tediousseparation from the corresponding regioisomer 48b.While we were conducting the annulation studies, a discovery was made in ourlaboratories which gave us access to a more expedient and economical route for thepreparation of the vinylgermane reagent 13 (Scheme 13).22 With this route in hand, wecould eliminate the expensive, time-consuming preparation of the vinylstannane chloride 45.Starting with the commercially available 3-butyn-l-ol (46), the dianion was formed withMeLi at -78 °C and silylated with trimethylsilyl chloride to form 4-trimethylsiloxy-1-trimethylsilyl-1-butyne (51) in 95% yield.22 The key step involves a platinum catalyzedhydrogermylation reaction of the alkyne 51 with Me3GeH. This was accomplished using acatalytic amount of H2PtC12•xH2O and 1.5 equivalents of Me3GeH.2 The resultant productmixture contained two major compounds, 51a and Sib, which were immediately subjected toa protodesilylation reaction employing p-TsOH•H20. Both isomers, 51a and Sib, wereconverted to the vinylgermane alcohol 52, which was isolated in 71% overall yield. That thevinylgermane moiety was present in this compound was shown by the LH nmr spectrum (400MHz, CDC13), which exhibited a nine proton singlet at 60.23 (-GeM3) and two one protonmultiplets at 6 5.34 and 5.63 (vinyl protons). The alcohol 52 was converted to the iodide 13by reaction with PPh3•12.24 With a high yielding, convenient synthesis of the bifunctionalreagent 13 in hand, we turned our attention to the annulation sequence.181) MeLI (2.2 equiv.)THF,-78°C,2h TMS———-\2) TMSCI (2.5 equiv.) 51-78 °c - 0 °c (95%)Me3GeH (1.5 equiv.)H2PtCI6•xHO(1.5 mol%)CH2I,0°C —* ii, 15 hL H SiMe3 Me3Si%..GeMeMe3G + II ]OTMS HOTMS51a 51bp-TsOH.H20(1.2 equiv.)CH2I,30 °C, 1 hMe3GeN12 (3.1 equiv.)PPh3 (3.1 equiv.)Me3G13 imidazole (3.1 equiv.) 52(92%) Et20:CH3CN (3:1) (71%)10mm, rtScheme 13192.1.3. PREPARATION OF THE CYCLIZATION SUBSTRATESIn order to prepare the keto vinyl iodide cyclization substrates, the enones 53-57 inTable 1 were chosen as starting materials. All of the enones are commercially available,except for enone 57 which was synthesized from 2-(carbomethoxy)cyclohexanone (58)25 byemploying a selenoxide elimination reaction (equation •26OMe 1)NaH,THF,0°C OMe (6)2) PhSeBr, THE, 0 °C3) H20,CH2I rtTable 1 contains a summary of the preparation of the keto vinyl iodide cyclizationprecursors along with results previously obtained by Piers and Marais.7 The synthesis of theketo vinyl iodide 64 (entry 1) was accomplished, for example, in the following manner. Theorganocopper(I) reagent 15 was prepared as described in the introductory remarks (equation2) and was allowed to react, in the presence of an additive (TMSC1 or TMSBr), with 2-cyclohexen-1-one (53). After hydrolysis of the intermediate silyl enol ether, workup of thereaction mixture and purification of the crude oil, the conjugate addition adduct 59 wasisolated in pure form (89% yield using TMSBr as the additive or 73% yield7 using TMSC1 asthe additive). Confirmation of the assigned structure was obtained from the ‘H nmrspectrum (400 MHz, CDC13) of 59, which exhibited a nine-proton singlet at 6 0.20 for themethyl substituents on germanium, and two one-proton multiplets in the vinylic region at 65.19 and 5.50. Treatment of the vinyl germane compound 59 with iodine indichloromethane27afforded the corresponding vinyl iodide cydization precursor 64 in 94%yield. The ‘H nmr (400 MHz, CDC13) resonances of the vinyl protons of 64 appeared at 65.69 (m, 1H) and 6.02 (m, 1H), significantly downfield from the values for the correspondingprotons in the starting material 59 (vide supra). Also, the singlet at 6 0.20 (9H, -GeM3),evident in ‘H nmr spectrum of compound 59, was no longer present in the spectrum of thevinyl iodide 64. Thus, it was evident that the replacement of the trimethylgermane moiety58 5720Table 1: Preparation of the Cyclization Substrates1) IIRMeaGe(’Cu(CN)Li\ Additive, THE, -78 °C Ia- Reaction conciltions: reagentb- Reaction conditions employed by Piers and Marais7:reagent 15, TMSC1 (—3 equiv.), THF, -78 °C; H20.c- Reaction conditions: 12, CH2C12, rt, overnight.d- The conjugate addition of reagent 15 to this enone was not explored by Piers and Marais.e- HMPA was added and the reaction mixture was allowed to warm slowly to 11 overnight.21with the more electronegative iodine atom had taken place. The remaining keto vinyl iodides65-68 were prepared in an analogous manner. The synthesis of the vinylgermane adducts 61-63 requires a few additional comments.The addition of the organocopper(I) reagent 15 to (R)-(-)-carvone (56) proceeded inthe precedented28stereoselective manner, trans to the substituent at carbon five. The ‘H nmrspectrum (400 MHz, CDC13) indicated that the product 62 was, in fact, a pair ofdiastereomers (epimers at C-2, in a ratio of —4:1, vide infra). Starting with the o3-unsaturated keto ester 57, the conjugate addition product 63 was obtained in good yield(90%). The ‘H nmr spectrum (400 MHz, CDC13) confirmed that 63 was a mixture oftautomers (63a and 63b, vide infra). The presence of the vinyl germane moiety wasconfirmed by signals at 0.20 and 0.21 (s, s, 9H, ratio undetermined). Two singlets at 3.69and 3.73 (3H, ratio —5:1) confirmed the presence of the carbomethoxy group.Conjugate addition reactions of organocopper(I) reagents are known to occur muchmore readily in the presence of additives such as TMSC118and TMSBr.29 In Table 1, entries1, 3 and 4 compare the results of the conjugate addition reaction in the presence of TMSBr tothat obtained by Piers and Marais7 using TMSC1 as the additive. It was found thatreplacement of the additive TMSC1 by TMSBr increased the yields of the reactionssignificantly. Particularly striking is the improvement in yield for ently in which the yieldof the conjugate addition of reagent 15 to isophorone (55) increased from 35% to 59%.Isophorone is a highly hindered enone and the reluctance of this enone to undergo 1,4-additions is well documented.3°However, by replacing TMSC1 with TMSBr, one can effectthe reaction without using HMPA and obtain the adduct 61 in a much better yield. Thisresult led us to investigate the effectiveness of other additives used in conjugate additionreactions. For example, the mixture of the Lewis acid BF3 with cuprates has been proven toenhance carbon-carbon bond forming reactions.31 BF3•Et20 has also been used inconjunction with TMSC1 in a variety of conjugate addition reactions.32 As seen in Scheme14, BF3•Et20 alone did not effectively promote the conjugate addition of the reagent 15 to22isophorone (55) (yield of 61 = 19%). However, when this Lewis acid was used with eitherTMSC1 or TMSBr, the yield of the reaction improved dramatically. The optimum conditions(yield of 61 = 72%) for the conjugate addition reaction to isophorone (55) were found toemploy both TMSBr (3.2 equiv.) and BF3•Et20 (1.1 equiv.) as additives.i)JMe3G15 Cu(CN)LiAdditive, THE, -78 °c .GeMe32) H20AdditiveTMSC1 35%7TMSBr 59%BF3•Et20 19%TMSC1 + BF3•Et20 66%TMSBr + BF3•Et20 72%Scheme 14The synthesis of two additional cyclization precursors will now be described.Starting with the commercially available zM-unsaturated ketones (R)-(-)-carvone (56) and 2-methyl-2-cyclohexen-1-one (69), the cyclization precursors 70 and 71 were formed (Scheme15). This was accomplished by treating the enones 56 and 69 with Me2CuLi and trappingthe resultant enolates with TMSC1. The enolates were regenerated by reacting the silyl enolethers 72 and 73 with MeLi. Alkylation of the resultant enolates with 2,3-dibromopropeneprovided the cyclization precursors 70 and 71. While this synthesis could, in theory, beaccomplished in one pot, the yields were much better when the silyl enol ethers 72 and 73were isolated.57 61Yield23Scheme 15The ‘H nmr spectrum (400 MHz, CDC13) confirmed that the vinyl bromide 70 was,in fact, a single diastereomer. The presence of the added methyl group in compound 70 wasconfirmed by the three proton doublet at 8 0.92 (J = 8 Hz, secondary Me). The signals at 64.72 (s, 1H), 4.79 (s, 1H), 5.52 (m, 1H), and 5.56 (m, 1H) confirmed the presence of fourvinyl protons. The expected stereochemistry of the conjugate addition reaction and thesubsequent alkylation was based on literature precedent.33’4The ‘H nmr spectrum (400 MHz, CDC13) of 71 indicated a 3:1 mixture ofdiastereomers; the expected stereochemistry34of the major product is indicated in Scheme15. The two doublets at 6 0.95 and 1.10 (3H, ratio —3:1, J = 8 Hz for each d) confirmed thepresence of the secondary methyl group in compound 71. The signals at 6 2.62, 2.71, 3.09,and 3.18 (d, d, d, d, 2H, ratio —1:3:1:3, J = 14 Hz for each d) revealed the presence of theallylic protons and the signals at 6 5.50, 5.55, 5.58, and 5.63 (m, m, m, m, 2H, ratio -1:3:l:3)confirmed the presence of the two vinyl protons.560 BrMe2CuLiTHE, TMSCI,-78 °CMe2CuLiTHE, TMSCI,-78 °C72(99%)70(46%)1) MeLi, THF,0°C2) HMPA,Brf-20 °C —* rt1) MeLi, THE,0°C2) HMPA,Br1&-20 °C — rt69Br73(98%)71(51%)242.1.4. CYCLIZATION STUDIESAs previously mentioned, Piers and Marais7 developed a palladium(0)-catalyzedcyclization reaction to convert the keto vinyl iodides 17 into the bicyclic ketones 18 or theenones 19 (Scheme 10, page 13). Table 2 contains a summary of the cycization reactionsthat were performed using this method. Marais7had performed the cyclization reactions onthe substrates listed in entries 1, 3, and 4 of Table 2. These examples were repeated in thehopes of improving the yields. A solution of the keto vinyl iodide 65 and Pd(PPh3)4 (23mol%) in THF was treated with t-BuOK in THF/t-BuOH (dropwise addition over 3-4 h) toprovide, after workup and purification, the enone 75 in 65% yield. The JR spectrum of thiscompound revealed the presence of a conjugated enone (1679, 1627 cm4). The ‘H nmrspectrum (400 MHz, CDC13) of 75 showed signals due to a tertiary methyl group (6 0.83 (s,3H)) and a vinylic methyl group (6 1.99 (br s, 3H)). In a similar fashion, substrates 64 and66-68 were converted into the annulation products 74 and 76-78, respectively. In the case ofthe vinyl iodide 68, the relatively low pKa of the proton at carbon two (proton alpha to theketone and ester functions) allowed us to employ the weaker base C52CO3 for thecycization reaction. The cis-fused stereochemistry of the keto diene 77 was confirmed byNOE difference experiments.35 Compound 78 was thus assumed to also possess a cis-fusedring junction.Decreasing the quantity of Pd(PPh3)4 (10 mol% vs. 20 mol%) used in the cydizationreactions was initially explored by Piers and Marais, as shown in equation 7•19 However, inthis experiment employing 10 mol% of Pd(PPh3)4 (equation 7), the base was added in oneportion, thereby increasing the probability of HI elimination. In fact, the ailcyne 79 wasobtained almost exclusively.0t-BuOK, THF/t-BuOH, 0 °C, 5 mm;áen10 mol% Pd(PPh3)4,0°C —rt (7)7925Table 2: Pafladium(O)-Catalyzed Cydization Reactions of the Keto Vinyl lodides64% ba- Reaction conditions: -20 mol% Pd(PPh3)4, TNF, rt, 10 mm; then dropwise addition of t-BuOKin THF/t-BuOH.b- Piers and Marais7 reported a 59% yield for this reaction.c- Piers and Marais7 reported a 74% yield for this reaction.d- Piers and Marais7 reported a 65% yield for this reaction.e- Reaction conditions: Cs2CO3 (5 equiv.), THF, rt; then Pd(PPh3)4 (28 mol%), 50-60 °C, 6 h.It was important to investigate the effect of the amount of palladium catalyst on theyield, using the standard cyclization reaction conditions (slow addition of base). For this747565%Entry Keto Vinyl Iodide Product Yield a102á<037683% C4M80% d5 43% eH7826study, the keto vinyl iodide 67 was chosen as the substrate for the Pd(0)-catalyzed cyclizationreaction. Scheme 16 summarizes the results from this study. The yield of the reactiondecreased when the amount of palladium catalyst used was decreased. The yield ofcompound 77 dropped off significantly when the amount of palladium catalyst was scaleddown from 10 mol% to 5 mol% (70% yield vs. 52% yield, respectively). This indicates thatthe catalytic cycle is not entirely efficient. For this reason, the amount of palladium catalystused in all subsequent reactions was —20-30 mol%.0Pd(PPh3)4,THE, rt;slow addition of Me.t-BuOK in THF/t-BuOHmol% ofPd(PPh3) Yield of 7720 mol% 80%15 mol% 73%lOmol% 70%5 mol% 52%Scheme 16How do the other reaction conditions affect this reaction? The equilibration of thetwo possible enolate anions of the starting material (see 43a and 43b, Scheme 11, page 15)occurs intermolecularly with the proton source, t-BuOH. The cyclization reaction, however,is an intramolecular process. The effect of the concentration of the catalyst, substrate andbase in the reaction mixture on the yield of the reaction was investigated. By increasing thedilution of the catalyst, substrate and base in the reaction mixture (0.002 M vs. 0.02 M, 0.008M vs. 0.1 M, and 0.009 M vs. 0.08 M, respectively; see entry 2, Scheme 17), the yield of thecyclized product 74 dropped slightly from 64% to 52%. When t-BuOH was removed fromthe base mixture (entry 3, Scheme 17), the yield of 74 dropped further to 42%. By increasing06727the dilution of the reactants in the reaction mixture and decreasing the availability of a protonsource, we can assume that the equilibration of the two possible enolates is slowedsomewhat. In theory, this should not affect the yield of the reaction since the desired enolateis being constantly consumed in the cyclization reaction (Scheme 11, page 15). In practice(Scheme 17), however, these changes to the reaction conditions did lower the yield of theproduct 74 slightly. It is difficult to speculate whether these changes in the yield of thereaction were statistically significant.Entry Reaction Conditions Yield of 74Pd(PPh3)4 (24 mol%),1 THF (0.1 M concentration a); 64%t-BuOK in THF/t-BuOHPd(PPh3)4 (26 mol%),2 THF (0.008 M concentrationb); 52%t-BuOK in THF/t-BuOHPd(PPh3)4 (22 mol%),3 THF (0.008 M concentrationc); 42%t-BuOK in THF (not-BuOH)a-0.1 M refers to the concentration of 64 in the reaction mixture;the concentration of Pd(PPh3)4 in the reaction mixture was 0.02 M;the concentration of the base in the reaction mixture was -0.08 M.b-0.008 M refers to the concentration of 64 in the reaction mixture;the concentration of Pd(PPh3)4 in the reaction mixture was 0.002 M;the concentration of the base in the reaction mixture was —0.009 M.c-0.008 M refers to the concentration of 64 in the reaction mixture;the concentration of Pd(PPh3)4 in the reaction mixture was 0.002 M;the concentration of the base in the reaction mixture was —0.009 MScheme 17As seen in Table 2 (page 25), the cyclized products 74-78 were obtained in moderateto good yields. Could the moderate yields be improved by employing a different Pd(0)7428catalyst or, perhaps, a Ni(0) catalyst? A number of Pd(0) catalysts were initially investigatedusing the vinyl iodide 67 as the cycization precursor. Table 3 summarizes the results of thisstudy. It was obvious that Pd(PPh3)4 (entry 1, 80% yield of 77) is the best catalyst to datefor this particular cyclization reaction. The only other comparable Pd(0) catalyst wasPd2(dba)3IPPh3 (entry 3, Table 3), which provided the target compound 77 in 67% yield.The use of Pd2(dba)3IPPh3 and Pd2(dba)3IPh3As as catalysts in coupling reactions has beenreported by Farina et aL (equation 8)36 and Trost and Lee (equation 9). 370Me3SnSnMePd2dbailPPh• (8)rt, 40 mm., NMP02NQAc— cat. (dba)3Pd2.CHCIE PoIymhhy&oIoxane +(9)52% 27%E = CO2H3When the Pd2(dba)3IPPh3 catalyst was employed with the vinyl iodide substrate 68, aslightly better yield of product 78 was obtained (47% (equation 10) vs. 43% with Pd(PPh3)4(entry 5, Table 2)). On the other hand, the use of Pd2(dba)3/AsPh3 as a catalyst for thecyclization of 67 (entries 4 and 5, Table 3) failed to generate 77 in an acceptable yield.Cs2O3,THE,OMe Pd(dba) (20 moI% (10)PPh3 (38 mol%),52 °C, 5h°‘b.0MeH68 78 (47%)29Table 3: The Effects of Different Catalysts on the Cyclization Reaction1IENTRY CATALYST LIGAND SOLVENT YIELD OF 77(mol%) (mol%)1 Pd(PPh3)4 (20 mol%) — THF 80%2 Pd(PPh3)4 (10 mol%), —- 32%CuC1 (50 mol%)3 Pd2(dba)3 (19 mol%) PPh3 (38 mol%) TEIF 67%4 Pd2(dba)3 (23 mol%) Ph3As (88 mol%) THF 6%5 Pd2(dba)3 (20 mol%) Ph3As (40 mol%) THF 8%(r6 Pd2(dba)3 (19 mol%) \o7P THF 34%38mo1%(i-7 Pd2(dba)3 (20 mol%) NMP negligible40 mol%8 Pd2(dba)3 (20 mol%)(o•iI 16%40 mol%9 PdC12(dppf) (18 mol%) dppf THF 6%10 Pd(OAc)2 (20 mol%) PPh3 (40 mol%) THF negligible11 Pd(OAc)2 (20 mol%)(onegligible40 mol%12mol%),CuI(4Omol%) PPh3 (40 mol%) DMF negligibleno 77,13 Ni(COD)2 (1.1 equiv.) COD80 (70%)CATALYST,SOLVENT, rt;slow addition oft-BuOK inTHF/t-BuOH30The use of copper(I)halides in Pd(0)-catalyzed coupling reactions has been known toimprove the yields of such reactions.38 However, when we attempted the cyclization of 67with Pd(PPh3)4 in the presence of 50 mol% CuC1, the cyclized product 77 was obtained inpoor yield (entry 2, Table 3). Similarily, the use of PdC12(PPh3)2 and Cu139 provided only anegligible amount of the product 77 (entry 12, Table 3).It has been proposed4°that the rate-determining step in Pd(0)-catalyzed couplingreactions is the transmetallation step (step B, Scheme 11, page 15), consisting of anucleophilic attack at Pd(II). Farina et al.36 hypothesized that making the palladium speciesless electron-rich should enhance the transmetallation rate. The use of a more electron-withdrawing ligand, such as tri(2-furyl)phosphine, was shown to dramatically enhance theyield of the coupling reaction illustrated in Scheme 18.36I;’SOCCO2HPh2HCO2HPhConditions % YieldPd(PPh3)4“SnBu321%LiBr, THE, 16 h, 50 °CPd2(dba)3 ((..0“‘SnBu3 91%ZnCI2, NMP, rtScheme 183631However, as seen in Table 3, the use of more electron-withdrawing ligands such as tri(2-furyl)phosphine (entries 6 and 7, Table 3) and triisopropyl phosphite41 (entries 8 and 11,Table 3) did not effectively promote the cyclization reaction to produce the desired product77.The use of PdC12(dppf)4 has proven successful in catalyzing cross-couplingreactions; one such example42is illustrated in equation 11. However, the use of this catalyst(entry 9, Table 3) failed in our attempts to synthesize compound 77.NZnBr IL 1. (11)2 PdCI2(dppf), THF, rt NH2Semmeihack et al.43 have reported the stoichiometric use of Ni(COD)2 in anintramolecular coupling reaction (see equation 12). However, in our case, the use ofNi(COD)2 (entry 13, Table 3) seemed to promote the HI elimination reaction and 70% of theuncyclized acetylene 80 was obtained instead of the desired bicyclic compound 77. The JRspectrum of 80 exhibited the absorbances characteristic of a terminal acetylene at 3296 and2117 cm-’, while a carbonyl stretch was in evidence at 1709 cm1. This disappointing resultled us to abandon the study of other Ni(0) reagents for the cycization reaction.0.1) Ph3CLi, THE0 (12)2) Ni(COD) (1.1 equiv.)OMeIOMe32We wanted to extend the 5-membered ring Pd(0)-catalyzed annulation sequence togenerate bridged bicyclic keto alkenes (equation 1, page 8). The cyclization precursors 70and 71 shown in Table 4 were thus subjected to the Pd(0)-catalyzed cyclization conditionsdescribed above. When the vinyl bromide 70 was treated under Pd(0)-catalyzed cyclizationconditions (entry 1, Table 4), the bridged bicycic compound 81 was obtained in 51% yield(70% based on consumed starting material). A combination of ‘H nmr, COSY and NOEexperiments was used to determine the structure of compound 81 (see Table 20,experimental, page 159). The bridgehead proton (H-5) was evident as a broad singlet at 62.79; this proton showed COSY correlations to H-4 (6 2.70, br d, J = 12 Hz), H-14 (6 4.69,br s), and H-14’ (8 5.13, br s). Irradiation of the signal due to Me-lO (6 0.90, d, J = 8 Hz) ledto the nuclear Overhauser enhancement of the signal due to H-4; this result was consistentwith the relative stereochemistry shown below.Me12This cyclization result was only obtained in one instance and could aQi bereproduced. Since it was no longer necessary to choose a base that would allow enolateequilibration, we repeated the cyclization reaction employing KN(SiMe3)2 (entry 2, Table4). This resulted in no product formation, but rather a mixture of starting material andunidentifiable side products. Moreover, the attempt to cyclize the vinyl bromide 71 (—3:1mixture of diastereomers; the expected stereochemistry of the major compound is indicatedin entry 3, Table 4) employing the Pd(0)-catalyzed conditions failed to produce any of thedesired cyclized product. These results could be due to the fact that the vinyl bromidefunction was present versus the usual vinyl iodide moiety. We eventually abandoned our1413 81 H Me33attempts at forming bridged bicyclic compounds using the Pd(O)-catalyzed cyclizationconditions.Table 4: Attempts at the Synthesis of Bridged Bicyclic Ketones using the Pd(O)-CatalyzedCyclization ReactionEntry Cydization Precursor Conditions ProductBr1) Pd(PPh34,THE,1492) slow addition of 12 ±4 2Jt-BuOK in THF/t-BuOH1113 81(51%)Br1) KN(SiMe32,THE, 0 °C No Cycized Product2) Pd(PPh34,rt, 22 h Obtuned1) Pd(PPh34,THE, rtNo Cyclized Product2) slow addition oft-BuOK in THE/t-BuOH Obtained2.1.5. CONCLUSIONThe five-membered ring annulation sequence developed by Piers and Marais7wasemployed to generate the bicycic enones 74-76 and the bicycic keto alkenes 77 and 78. Theconditions for the conjugate addition of the organocopper(I) reagent 15 to a,3-unsaturatedenones were optimized by replacing TMSC1 with TMSBr. This modification improved theyields of the conjugate addition reactions, particularly in the case of the hindered enoneisophorone (see page 22). The Pd(O)-catalyzed cyclization reaction was also studied. It was70r71found that 20 mol% of Pd(PPh3)4 was necessary to obtain the cyclized products in goodyield. The yields for the cycization of certain keto vinyl iodides (see entries 1, 3, and 4,Table 2, page 25) were improved from that reported by Piers and Marais.7 It was also foundthat the use of other Pd(0) and Ni(0) catalysts did not effectively promote the cycizationreaction. Finally, the Pd(0)-catalyzed cyclization reaction was unsuccessful in formingbridged bicydic keto alkenes (see Table 4).34352.2. ATTEMPTS TO ACHIEVE SIX-MEMBERED RING ANNULATIONS BASEDON PALLADIUM(O)-CATALYZED INTRAMOLECULAR COUPLING2.2.1. INTRODUCTORY REMARKSThe five-membered ring annulation method employing the bifunctional conjunctivereagent 4-chloro-2-trimethylstannyl-1-butene (4) was extended to allow for the formation ofsix-membered rings (Scheme 7a).44 This was accomplished by utilizing the one-carbonhomologue of reagent 4 (i.e. 5-chloro-2-trimethylstannyl- 1-pentene (12)).Me3SnCIIII++ diacIMe3Sn12Scheme 7aIn a similar manner, we hoped to extend the Pd(O)-catalyzed cyclization reaction to theformation of six-membered rings with the specific aim of preparing substances of generalstructure 29 (Scheme 7b). The following sections outline the synthesis of the bifunctionalvinylgermane reagent 31 (the one-carbon homolog of reagent 13) and the attempts ofutilizing this reagent in conjunction with the Pd(O)-catalyzed cyclization reaction tosynthesize six-membered rings.36Me3G31+ ad29Scheme 7b2.2.2. PREPARATION OF THE BIFUNCTIONAL REAGENT 5-IODO-2-TRTMETHYL-GERMYL- 1 -PENThNE (31)In order to attempt the formation of six-membered rings employing the Pd(O)catalyzed cyclization reaction, we required a bifunctional reagent that would serve as thesynthetic equivalent of the 1-pentenea2,d5-synthon 30, namely 5-iodo-2-trimethylgermyl-1-pentene (31).Me3G I = a31 30dSince the stereoselective platinum-catalyzed hydrogermylation method for constructing 2-trimethylgermyl-1-alkenes22(Scheme 13, page 18) had not yet been developed at the timeduring which we carried out this brief study, compound 31 was synthesized from thecorresponding vinyistannane 12 (Scheme 19). The commercially available 5-chloro-1-pentyne (82) was treated with the stannylcopper(I) reagent 47 to generate a 12:1 mixture ofthe vinyistannane regioisomers 83a and 83b. The desired isomer 83a was separated by dripcolumn chromatography and isolated in 66% yield. Transmetallation of 83a with MeLi,followed by the addition of trimethylgermanium bromide, afforded the vinylgermanechloride 84. The chloride 84 was immediately converted into the desired compound 31 (84%yield from the corresponding vinyistannane chloride 83a) by means of a halideR’37interconversion. The 1H nmr spectrum (400 MHz, CDC13) of 31 confirmed the presence ofthe vinylgermane moiety by a 9-proton singlet at 6 0.20 (-Geyk3) and two 1-protonmultiplets at 6 5.26 and 5.57 (vinyl protons).1) Me3SnCu•Me2 Me3Sn47+THE, -78 °C, 8 h82 2) CH3OOH Me3Sn83a 83b12 1(66%)1) MeLi, THE, -78 °C2) Me3GeBrMeaGeINal, acetoneMe3GA 8431(84%)Scheme 19382.2.3. PREPARATION OF THE CYCLIZATION PRECURSORSIn order to prepare the keto vinyl iodide cyclization precursors, the commerciallyavailable enones 53 and 56 in Table 5 (page 41) were chosen as starting materials. Thesynthesis of the keto vinylgermanes 85 and 86 required the formation and use of theorganocopper(I) reagent 87 (Scheme 20). Treatment of a cold (-98 °C) TEIF solution ofcompound 31 with two equivalents of tert-butyllithium followed by the addition of 1.1equivalents of CuCN and brief warming to -35 °C, gave a homogeneous tan solutioncontaining the organocopper(I) reagent 87 (Scheme 20). Trimethylsilyl bromide and 2-cyclohexen-l-one (53) were then added to the organocopper(I) species 87. After hydrolysisof the intermediate silyl enol ether and workup of the reaction mixture, the glc analysis of thecrude oil indicated a complex mixture of products. Three identifiable products were presentin a 75:17:8 ratio and accounted for —70% of the crude mixture. The major product was thedesired keto vinylgermane 85 which, after purification, was obtained in 50% yield. The nextmajor product was determined to be the tert-butyl adduct 88. The 1H nmr spectrum (400MHz, CDC13) of 88 had a characteristic 9-proton singlet at 6 0.90, indicating the presence ofthe tertiary butyl group.1)t-BuLi (2 equiv.)Me3G THE, -98 C Me GeCu(CN)Li31 2) CuCN, 87-78°C---35°C 0L)2) H20Me3GeM3GeMe3Scheme 20Finally, the minor product was found to be the vinylgermane dimer 89. The ‘H nmr39spectrum (400 MHz, CDC13) of 89 indicated an 18-proton singlet at 6 0.20 (-GeM3 groups),an 8-proton multiplet at 6 1.22-1.43, a 4-proton triplet at 62.17 (J = 10Hz, allylic methyleneprotons) and two 2-proton multiplets at 6 5.12 and 5.50 (vinyl protons).The presence of the two byproducts 88 and 89 indicated that the reaction of t-BuLi(35) with compound 31 (equation 13) was competitive with the reaction of the resultantlithium species 90 with unreacted 31 (equation 14). The reaction of t-BuLi (35) with theiodide 31 generates the desired lithium species 90 and t-BuI (36). A second equivalent of tBuLi (35) is necessary to react with t-BuI (36) to generate compounds 37, 38, and 39(equation 13). Thus, two equivalents of t-BuLi (35) are required for each equivalent of thevinylgermane iodide 31. Since the formation of the byproduct 89 consumes some of theiodide 31 (equation 14), it follows that there must be some unreacted t-BuLi (35) present inthe reaction media. The unreacted tert-butyllithium, in the presence of a copper(I) source,will add in a conjugate fashion to the enone 53, hence accounting for the formation of thetert-butyl adduct 88.t-BuLi + Me3GeI Me GeL + tBuI (13)31 9036It-BuLi35(CH3)C + (CH3)2C=CH + Lii:::::In order to avoid these side reactions (i.e. the formation of the dimer 89 and the tertbutyl adduct 88), it was decided to alter the experimental procedure so as to minimize the40reaction shown in equation 14. This was accomplished by slow addition of a solution ofcompound 31 to a cold (-98 °C) solution of tert-butyllithium in dry THF (i.e. inverse order ofaddition of reagents as compared to Scheme 20; see equation 15). To the resultant lithiumspecies 90 was added copper(I) cyanide followed by trimethylsilyl bromide and the enone 53.The vinylgermane adduct 85 was thus obtained in 75% yield, and the byproducts 88 and 89were no longer detected by gic analysis of the crude reaction mixture.M G IIt-BuLi e3 e 31 (15)THE, addition over 15 mm 872) CuCN, -78 °C — -35 °C0 I 53, TMSBrGeMe385 (75%)Table 5 summarizes the preparation of the keto vinyl iodide cycization precursors.By employing the modified conditions for the preparation of the lithium species 90, asdescribed above, we were able to obtain the vinylgermane adducts 85 and 86 in good yields(75% and 70%, respectively). The keto vinyl iodides 91 and 92 were obtained in excellentyields (97% and 95%, respectively) by treating the vinylgermane adducts 85 and 86 withiodine in CH2C12. With the cyclization precursors in hand, we were now able to conduct thePd(0)-catalyzed cyclization studies.41Table 5: Preparation of the Cyclization Precursors for the Six-Membered Ring AnnulationSequencea- Reaction conditions: reagent 87 prepared via the slow addition of 31 to teil-butyllithium, TMSBr (—3 equiv.),THF, -78 °C; H20.b- Reaction conditions: 12, CH2C12, rt, overnight.2.2.4. CYCLIZATION STUDIESPrevious studies (Table 3, page 29) had indicated that Pd(PPh3)4 was the bestcatalyst for effecting the intramolecular cyclization reaction to generate five-membered rings.Table 6 (page 43) summarizes our attempts at forming six-membered rings with thePd(PPh3)4 catalyst. The optimum conditions used for the five-membered ring annulationreaction (entry 1, Table 6) failed to work for this six-membered ring example. The bicydicenone 93 was obtained in only 5% yield. The vinyl methyl group in compound 93 was0 01GeMe353 85 (75%) 91(97%)Entry Enone Keto Vinylgermane Keto Vinyl Iodide(Yield)a (Yield)b2156 86 (70%) 92 (95%)42evident in the ‘H nmr spectrum (400 MHz, CDC13) as a three-proton doublet at 6 1.85 (J =2Hz). When the conditions were modified by increasing the dilution of the catalyst, substrateand base in the reaction mixture (i.e. the concentration of 91 was diluted from 0.1 M to 0.02M) and eliminating the t-BuOH from the base mixture (entry 2, Table 6), the yield of product93 increased from 5% to 27%. As shown in entry 3, the best yield for enone 93 (41%) wasachieved by increasing the dilution of the reactants in the reaction mixture to 0.004 M. Theseresults are difficult to explain since similar modifications in the five-membered ring studiesled to a decrease in product yield (Scheme 17, page 27). The use of different palladiumcatalysts did not improve this result, as was the case in the five-membered ring annulationstudies (Table 3, page 29). When the optimized conditions described in entry 3 (Table 6)were applied to the vinyl iodide 92, the cyclized product 94 was obtained in a dismal 2%yield (entry 4, Table 6). The methyl groups in the keto diene 94 were evident in the ‘H nmrspectrum (400 MHz, CDC13) as two 3-proton singlets at 6 1.27 (tertiary methyl group) and1.75 (vinyl methyl group). The vinyl protons were evident as four 1-proton singlets at 64.70,4.75, 4.81, and 4.94. Unfortunately, we did not have a sufficient amount of compound 94 todetermine the stereochemistry at the ring junction.These poor results led us to abandon any further attempts at forming six-memberedrings using the Pd(0)-catalyzed cycization conditions. The synthesis of six-membered ringsusing this method requires the formation of a seven-membered ring palladacycle (see step B,Scheme 11, page 15). The formation of this palladacycle is probably the rate determiningstep (vide supra). Thus, if the seven-membered ring formation is slow, the cycle might breakdown and other side reactions could compete with the intended cyclization. It should benoted that the mass balance for the reactions reported in Table 6 was poor and no startingmaterial was recovered. Attempts to recover and identify any side products wereunsuccessful.43Table 6: Attempts at Six-Membered Ring Formation by Employing the Pd(O)-CatalyzedCyclization ReactionEntry Keto Vinyl Iodide Conditions Product1) Pd(PPh34(34 mol%),THF(O.1M)2) slow addition oft-BuOK in THF/t-BuOH1) Pd(PPh34(34 mol%),THF (0.02 M)2) slow addition oft-BuOK in THFb1) Pd(PPh34(36 mol%),THE (0.004 M)2) slow addition oft-BuOK in THFb1) Pd(PPh34(36 mol%),THF (0.005 M)2) slow addition oft-BuOK in THFba- Conditions used for this entry were very similar to those reported for the five-membered ring annulationsequence.b- No t-BuOH was used in the base mixture.442.3. THE FORMATION OF TRICYCLIC RING SYSTEMS EMPLOYING THEANNULATION METHOD BASED ON THE PALLADIUM(O)-CATALYZEDINTRAMOLECULAR COUPLING2.3.1. INTRODUCTORY REMARKSAs described in Section 2.1., the methylenecyclopentane annulation sequence wasoptimized and successfully employed in the synthesis of functionalized bicyclo[4.3.O]nonanesystems 18 and 19. The latter products (general structure 19) could undergo yet anotherannulation sequence with the bifunctional vinylgermane reagent 13 to produce more complextricyclic ring systems of general structure 32. The exploration of this possibility is the mainfocus of the work to be described. There were several questions which needed to beaddressed. How reactive are enones 19 to the 1,4-conjugate addition conditions employed inthe methylenecyclopentane annulation sequence? What would be the stereochemicaloutcome of such reactions? And finally, will the Pd(O)-catalyzed cyclization reactionproceed smoothly and effectively to afford the tricyclo[6.4.O.01’5]dodecan-12-ones ofgeneral structure 32?18RMe3Ge’N2.3.2. PREPARATION OF THE BICYCLIC[4.3.O]NON-9-EN-2-ONESIn order to begin our attempts at synthesizing the tricyclic keto alkenes of generalstructure 32, it was first necessary to prepare the bicyclic enones 74, 75, 95, and 96. Theenones 74 and 75 (in which R = Me) were prepared as previously described in Section 2.1.(page 25). However, when R = H (enones 95 and 96), an annulation route employing a threecarbon synthon was necessary for their construction (see below).R’324574 R=Me, R’=H75 R=Me, R’=Me95 R=H, R’=H96 R=H, R’=MeThe Grignard reagents 1 and 97 are suitable synthetic equivalents to the asynthon 98 and can be obtained by reacting concentrated solutions of the correspondingcommercially available bromo acetals 99 and 100 with an excess of freshly groundmagnesium turnings (Scheme 21).Br Br0D99 100Mg, THE, Mg, THE,BrMg0= dQH= BrMgScheme 21Helquist and coworkers4’6developed an annulation sequence which involves the conjugateaddition of the Grignard reagent 1 to an enone substrate, followed by hydrolysis of the acetalfunction and an intramolecular aldol cycization reaction. Four such examples are presentedin Scheme 22. 2-Cyclopenten- 1-one, 2-cyclohexen-1-one, 3-methyl-2-cyclohexen-1-one and2-cyclohepten-1-one underwent a copper(I)-catalyzed conjugate addition with the Grignardreagent 1 to provide the resultant keto acetals 101-104 in isolated yields ranging from 74% to87%. The next step in the sequence involved acidic treatment of the acetals 101-104. Thebicyclic ketol 105 did not undergo spontaneous dehydration following the acid mediatedR’46CuBr•Me2S,THE, Me2S-78 °C, 10 h; warm up to0°Cover6h;0°C,2h2) aqueous NH4CI-NHO0HCI, H20,101 n=1, R’=H (77%)102 n=2, R’=H (85%)103 n=2, R’=Me (74%)104 n=3, R’=H (87%)95 n=2, R=H (89%)96 n=2, R’=Me (77%)106 n=3, R’=H (80%)Stowell47 discovered that the formation of the Grignard reagent 97 from the sixmembered ring bromo acetal 100 was higher yielding than the formation of reagent 1 fromthe corresponding five-membered ring bromo acetal 99 (Scheme 20). For this reason, wechose to employ the Grignard reagent 97 in Heiquist’s annulation method to generate enones95 and 96. This annulation procedure was further modified according to the method ofKuwajima and coworkers.48 Kuwajima and coworkers reported that the use of TMSC1 andHMPA greatly improves the yields of copper(I)-catalyzed conjugate addition reactions,particularly in cases of unreactive enones (see Scheme 23).cyclization reaction. It seems that -hydroxy ketones of this type do not undergo eliminationof water under these reaction conditions. However, in the other three cases, dehydrationoccurred to yield, after workup and purification, enones 95, 96, and 106.R’OHScheme 22 105 (54%)47Additive Yield of KetoneNone 1-2%TMSC1 (2 eguiv.) 30-40%TMSC1IHMPA(1-2 eguiv. each)Scheme 2348Table 7 summarizes the preparation of the bicyclic enones 95 and 96. By employingthe modifications reported by Kuwajima and coworkers,48the preparation of the keto acetals102 and 103 was accomplished cleanly and efficiently (see Table 7). Thus, treatment of 2-cyclohexen-1-one (53) with the Grignard reagent 97 in the presence of TMSC1, HMPA, and acatalytic amount of CuBr•Me2S afforded, after workup and purification, the keto acetal 102in 88% yield (entry 1, Table 7). The JR spectrum of 102 exhibited an absorbance at 1714cm’ for a carbonyl function characteristic of cyclohexanones, and the -H nmr spectrum (400MHz, C6D6) indicated the presence of the cyclic acetal moiety (two broad dd, 2H each, at 63.30-3.36 and 3.79-3.83; and a triplet, 1H, at 6 4.29-4.32).A solution of each of the keto acetals 102 and 103 in THF was refluxed in thepresence of 0.1 M hydrochloric acid to generate the bicyclic enones 95 and 96 in 73% and61% yield, respectively (Table 7). The spectral data of enones 95 and 96 were identical withthose reported by Helquist and coworkers.4 Helquist’s cyclization conditions were carriedout at room temperature (Scheme 22). We found that by refluxing a solution of each ketoacetal in HC1IH2OITHF, the reaction went to completion in a much shorter time (14-19 h(Table 7) vs. 72 h (Scheme 22)). However, the yields of the bicyclic enones 95 and % wereslightly lower than those reported by Helquist and coworkers. With the bicydic enones 74,1) 5% CuBr, DMS+ BuMgBr ÷ AdditiveTHE, -78 °C2) H20Bu4875, 95, and 96 in hand, we were ready to attempt the annulation sequence to generate thetricycic keto alkenes of general structure 32.Table 7: Preparation of the Bicyclic Enones 95 and % According to a Modified Version ofHeiquist’s Annulation SequenceEntry F Enone Keto Acetal Bicyclic Enone(Yield)a (Yield)b12103(95%)Me96(61%)a- Reaction Conditions:1) Grignard reagent 97 (1.3 equiv.), TMSC1 (2.5 equiv.), HMPA (2.5 equiv.), CuBr•Me2S (—15 mol%),TFIF, -78 °C 3-5 h; warmed to -48 °C for lh2)1120; aqueous NH4C1-NH4OHb- Reaction Conditions: THFIO.l M HC1 (2:1), A, 14-19 h492.3.3. PREPARATION OF THE BICYCLIC KETO VINYLGERMANESThe first step in the preparation of the cycization precursors involves the conjugateaddition of the organocopper(I) reagent 15 to a bicyclo[4.3.O]non-9-en-2-one (equation 1).Similar addition reactions have been reported for bicyclo[4.4.O]dec- lO-en-2-ones andbicyclo[3.3.O]oct-8-en-2-ones, and these examples will be described below.1)MeGe’’Cu(CN)Li GeMe3(16)TMSBr, THE, -78 °C2) H20; NH4CI-NHO2.3.3.1. Literature Precedent for Conjugate Addition Reactions to Bicyclo[4.4.O]dec-lO-en-2-onesIt has been suggested that the preferred mode of addition of organometallic reagentsto cç-unsaturated ketones is antiparallel entry during which continuous overlap of thedeveloping sigma bond with the t system of the enone is possible through the transitionstate.49 Conjugate addition reactions are typically under kinetic control and thestereochemical result has often been explained on the basis of attack of the nucleophileperpendicular to the olefinic bond, and from the least hindered side of the molecule.50’1 Incyclohexenones where there are no over-riding steric factors, the stereochemical outcome ofthis process is axial substitution. For example, House and Thompson50found that thereaction of phenyl magnesium bromide and copper(I) chloride with the bicyclo[4.4.O]dec- 10-en-2-one (106) resulted in the stereoselective formation of the phenyl adduct 107 (equation17).PhMgBr(17)CuCIR’H106 10750Scheme 24 illustrates the two possible pathways (A and B) for the conjugate additionreaction that allows the cuprate reagent to approach the enone 106 in a perpendicular fashion.Pathway A proceeds via a chair-chair transition state and generates the observed adduct 107.Pathway B, on the other hand, must adopt a chair-boat conformation to preserve thestereoelectronic stabilization. The chair-boat conformation is clearly less favorable than thechair-chair conformation and this explains the sole formation of adduct 107 (House andThompson report no evidence of adduct 108).Scheme 2450Similar stereochemical results have been observed by Ley et aL52 (equation 18) andWeizel and coworkers53 (equation 19). In both cases, the conjugate addition reactionproceeded stereoselectively to yield the axial adducts 109 and 110 (equations 18 and 19,respectively). The relative stereochemistry of the minor 0-alkylation product 111 (equation19) was not determined.MeSC1ç3MePhMgBrH106RPh1081)(’’)CuLi (2.2equivTHF, -40 °C2) CH2O, -40 °CMe(18)10951In the conjugate addition reactions depicted in equations 17, 18, and 19 there were noserious steric interactions. That is, these reactions were controlled exclusively bystereoelectronic factors. Obviously, steric factors can play an important role in determiningthe nature of the transition state.54 What would be the stereochemical outcome of a case inwhich the reagent approaching the enone system from a perpendicular direction wouldencounter severe non-bonded interactions? One such case, reported by Boeckman andSilver,49 is the copper(I)-catalyzed addition of an isopropenyl Grignard reagent to 6-methylbicyclo[4.4.O]dec-lO-en-2-one (112) (equation 20). The equatorial adducts 113 and114 were, in this case, favored over the axial adduct 115.(20)As illustrated in Scheme 25, two possible pathways A and B result in the formation of theadducts 113-115. Although pathway A leads to a chair-chair transition state, this route isdisfavored due to a severe pseudo 1,3-diaxial steric interaction between the angular methylgroup and the incoming organocopper(I) reagent. Pathway B is the major route since itMOMe 1) Me3SnLi,THE, -78°C2) Mel,-10 °C—20 °COMe(19)1104.4OMe SnMe31111MgBr5 mol% Cul, THE-30°C —* 10°C112 113 114_______2)Me11519 : I52allows for the less hindered approach of the isopropenyl Grignard reagent while retaining theperpendicular approach of the reagent. In the absence of the angular methyl group, thestereochemical outcome of the conjugate addition reaction would be reversed, resulting in thesole formation of the axial adduct (see equation 17 and Scheme 24).112c §Me-jFrom the above examples, one can see that there is a balance between steric andstereoelectronic factors. Both these factors must be taken into account when attempting topredict the stereochemical outcome of a conjugate addition reaction.2.3.3.2. Literature Precedent for Conjugate Addition Reactions to Bicyclo[3.3.Ojoct-8-en-2 -onesThere is ample literature precedent for stereoselective conjugate addition reactions tobicyclo[3.3.O]oct-8-en-2-ones. If stereoelectronic factors play a key role in regulating thestereochemistry of such reactions, the transition states can be assumed to be product-like (i.e.enolate-like) in nature. Thus, the developing bond at the 13-carbon of the enone system iscreated, as nearly as possible, in a direction perpendicular to the plane of the forming enolateanion. Piers and Renaud12’55found that the addition of the organocopper(I) reagent 116 to 5-115Scheme 2553Upon examination of molecular models of the two possible enolate anions (119 and 120) thatcould result from the reaction of 116 with 117, only 119 can comfortably adopt aconformation such that the newly introduced side chain is attached to the ring system in anorientation perpendicular to the plane of the adjacent enolate double bond. 56As a result, the conjugate addition of the organocopper(I) reagent 116 takes place cis to theangular methyl group, even though this is the more hindered face of the enone system. Thisresult is in contrast to that obtained for the conjugate addition reactions to bicyclo-[4.4.O]dec-1O-en-2-ones in which there is an angular methyl group (equation 20). Obviously, in thelatter cases, steric factors play a bigger role than in the conjugate addition reactions tobicyclo[3.3.O] oct-8-en-2-ones.Another example of a stereoselective conjugate addition reaction to abicyclo[3.3.O]oct-8-en-2-one was reported by Paquette and Leone-Bay57in their work on themethylbicyclo[3.3.O]oct-8-en-2-one (117) led to the stereoselective formation of the 1,4-addition adduct 118 (equation 21).o NCr—Cu(CN)Li116 (21)THE, -78 °C, HMPAMe117 118Me119 12054synthesis of (±)-silphinene (121). The copper(I)-catalyzed conjugate addition of the Grignardreagent 97 to the enone 122 afforded exclusively the adduct 123, in which the side chain hadbeen introduced stereoselectively cis to the angular hydrogen (equation 22).B rMCu B r•Me2S(±)-silph inene(121)In a paper describing their synthesis of (±)-coriolin (124), Ikegami and coworkers58reported the stereoselective addition of lithium dimethylcuprate to the functionalized bicyclo[3.3.O}oct-8-en-2-one 125 (equation 23). The adduct 126, in which the methyl group hadbeen introduced cis to the angular hydrogen, was an intermediate in the synthesis of (±)-coriolin (124).122 123(22)HMe2CuLiEt20, -78 °C125H(23)1260(±)-coriolin(124)552.3.3.3. Literature Precedent for Conjugate Addition Reactions to Bicyclo [4.3.Ojnon-9-en-2 -onesAs previously described, there has been extensive literature precedent for conjugateaddition reactions to functionalized bicyclo [4.4.Oldec-1O-en-2-ones and bicyclo[3.3.O]oct-8-en-2-ones. The stereochemistry of such additions has been governed by both steric andstereoelectronic factors. The annulation sequence to be detailed in this section involvesconjugate addition of a cuprate reagent to bicyclo[4.3.O]non-9-en-2-ones. Surprisingly, thereis very little literature precedent for predicting the stereochemical outcome of such a reaction.In the synthesis of 18-oxo-3-virgene, Paquette and Wang59 exposed enone 127 to a mixedhigher order cuprate prepared from tri-n-butyl(vinyl)stannane and Me2Cu(CN)Li2 (equation24). The sole adduct 128 was obtained. Paquette and Wang rationalize that the 1,4-additionand subsequent protonation both occurred from the less hindered direction (i.e. that stericeffects govern this reaction).SnBu3 (24)Me2Cu(CN)LiTHE, -78 °C127The only other known example of an addition to a bicyclo[4.3.Ojnon-9-en-2-one wasreported by Snider and Faith6° in their synthesis of (±)-ptilocaulin (129) (equation 25).However, this reaction is known to be reversible and ptilocaulin is the thennodynamicallymore stable of the two possible isomers.6’12856NHH2N NH2 (5)A, C6H(±)-ptilocau line(129)2.3.3.4. Conjugate Addition Reactions to the Bicyclo[4.3.O]non-9-en-2-ones 74, 75, 95, and96There is no obvious literature precedent for a steric and/or stereoelectronic bias forconjugate addition reactions to bicyclo[4.3.O]non-9-en-2-ones. If, however, thestereochemical outcome of the conjugate addition to these enones behaves in a mannersimilar to that observed with bicyclo[4.4.O]dec-1O-en-2-ones and bicyclo[3.3.O]oct-8-en-2-ones, one would expect the addition to proceed cis to the angular group, providing there areno serious steric interactions. Table 8 summarizes the results of the conjugate addition of theorganocopper(I) reagent 15 to the bicyclo[4.3.O]non-9-en-2-ones. The intermediate silyl enolethers were hydrolyzed to give, in all cases, a mixture of cis- and trans-fused additionproducts, with the cis-fused epimer predominating. We were very pleased to observe that theconjugate addition reaction had proceeded stereoselectively in each case and that the yieldsfor these reactions were excellent. Interestingly enough, in each of the cases studied, thevinylgermane side chain had been introduced trans to the angular group. This result isopposite to that observed with the bicyclo[4.4.O]dec-lO-en-2-ones and the bicyclo[3.3.O]oct-8-en-2-ones.Within the set of substrates examined, the size of the angular group clearly had nosignificant effect on the stereochemical outcome of the addition. When the angular group is aproton (R’ = H, see entries 1 and 3, Table 8), there are no significant steric differencesbetween the approach of cuprate reagent 15 to the alpha or beta face of the enone. Yet, inHH57these cases, the cuprate reagent was still introduced trans to the angular proton. Since stericfactors do not seem to govern the stereochemistry of the conjugate addition reaction, we triedto rationalize the results based on stereoelectronic factors. As previously discussed (seepages 52-53), if the transition state is assumed to be product-like in nature, the developingbond at the 13-carbon of the enone system is created, as nearly as possible, in a directionperpendicular to the plane of the forming enolate anion. Upon examination of molecularmodels of the two possible enolate anions (129a and 129b) that could result from the reactionof reagent 15 with an enone of general structure 19, it appears that 129b can morecomfortably adopt a conformation such that the newly introduced vinylgermane side chain isin an orientation perpendicular to the plane of the adjacent enolate double bond. However,our results indicate that the enolate 129a must be the intermediate in the conjugate additionreaction. Clearly, we cannot rationalize our results based on either steric or conventionalstereoelectronic effects. Each entry in Table 8 will now be discussed in detail, including theverification of the stereochemistry for each product.LiO RR’ R’1 29a 1 29b58Table 8: Results of the Conjugate Addition Reactions of Reagent 15 to the Bicyclo[4.3.0]non-9-en-2-ones0 R1Me3GeCu(CN)Li‘GeM He3 + GeMe- 15 (1.5-2equivTMSBr (4-7 equiv.),R THF,-78°C R’ R’2) H20; NH4CI-NHOEntry Bicyclic R R’ Yielda Cis-Fused Adduct Trans-Fused AdductEnone — — p,pjjb130a 130b1 74 Me H 89% 9 : 1131a 131b2 75 MeMe 86% 20 : 1— —132a 132b3 95 H H 88% 5 1133a 133b4 96 H Me 98% 6 : 1a- This yield refers to the isolated yield of the cis- and trans-fused adducts combined.b- The ratio was determined by 1H nmr spectroscopic analysis of the crude product mixture.14 149l3 GeMe35Th%1.4GeMe3130a 130bEnone 74 (entry 1, Table 8) was treated with two equivalents of the organocopper(I)reagent 15 in the presence of TMSBr to afford, after hydrolysis of the intermediate silyl enolether, a 9:1 mixture of the cis- and trans-fused adducts 130a and 130b in 89% overall yield.59It was evident that these isomers were epimeric when, under epimerizing conditions(NaOMe/MeOH, vide infra), isomer 130a equilibrated to a mixture of 130a and 130b.Similarly, isomer 130b was also equilibrated to a mixture of 130a and 130b when treatedwith NaOMe/MeOH (vide infra). These two isomers were readily separated by flashchromatography. In fact, separation of the cis- and trans-fused epimers was easilyaccomplished for all the entries listed in Table 8.100 Me13 GeMeThe ‘H nmr spectrum (400 MHz, acetone-d6) of 130a revealed a signal for theM3Ge group at 6 0.20 (s), a signal for the tertiary methyl group (Me-lO) at 6 1.13 (s), andtwo signals for the vinylic protons at 64.61 (d, J = 1 Hz) and 4.96 (br s). The angular protonH-i was evident as a doublet at 6 2.31 (J = 9 Hz). The COSY spectrum allowed theassignment of the other angular proton H-6 (6 2.43-2.47, m) through the correlation of itssignal to the H-i resonance (see Table 22, experimental, page 179). NOE differenceexperiments were consistent with the assignment of the relative configuration at each of thecarbons 1, 6 and 9. Irradiation of the signal at 6 1.13 (Me-lO) caused an enhancement of thesignal at 6 2.31 (H-i). Irradiation of the signal at 6 2.43-2.47 (H-6) also caused anenhancement of the signal at 6 2.31 (H-i). These experiments confirmed that the ringjunction was cis-fused and they were consistent with the assigned stereochemical outcome ofthe conjugate addition reaction.c-NMe1 30a6014100 Me ivie3e Me1113 GeMe31 30bThe ‘H nmr spectrum (400 MHz, CDC13) of the trans-fused isomer 130b indicated asignal for the 3Ge group at 6 0.19 (s), a signal for the tertiary methyl group (Me-lO) at 61.09 (s), and two signals for the vinyl protons at 6 5.12-5.13 (m) and 5.48-5.49 (m). Theangular proton H-i was evident as a doublet at 6 1.85 with a larger coupling constant (J =12.5 Hz) than that observed for the corresponding proton in the cis-fused isomer 130a (J =9Hz). Compound 130b was epimerized to a mixture of 130a and 130b. Thus, thestereochemistry at C-9 was shown to be identical to that observed for the epimer 130a.GeMe3 GeMe3Me Me10 10131a 131bWhen enone 75 (entry 2, Table 8) was treated with two equivalents of theorganocopper(I) reagent i in the presence of TMSBr, a 20:1 mixture of the cis- and transfused adducts 131a and 131b was obtained in 86% overall yield. The 1H nmr spectrum (400MHz, acetone-d6) of the cis-fused epimer 131a revealed the following diagnostic signals: 60.20 (s, -Gek3), 1.08 (br s, Me-lO), 1.13 (br s, Me-il), 1.96 (br s, H-i), 4.61-4.62 (m, H15), and 4.95-4.96 (m, H-is’).611511OMe1314 GeMe3 ieMe10131aNOE difference experiments were consistent with the stereochemistry of the cis-fusedadduct 131a. Irradiation of the signal at 6 1.08 (Me-lO) caused an enhancement of the signalat 6 1.96 (H-i), thereby confirming the nature of the ring junction (cis). Irradiation of thesignal at 6 1.13 (Me-il) also caused an enhancement of the signal at 6 1.96 (H-i).Irradiation of the signal at 6 i.96 (H-i) caused enhancement of the signals of both methylgroups (Me-lO and Me-i i). These results were consistent with the assigned stereochemistryatC-9.Me10131bThe 1H nmr spectrum (400 MHz, acetone-d6) of the trans-fused adduct 131b revealedsignals at 6 0.19 (s,-GeM3), 0.92 (s, Me), 1.30 (s, Me), 2.28 (s, H-i), 5.i4 (br s, H-i5), and5.50 (br s, H-15’). In NOE difference experiments, irradiation of the signal at 6 0.92 (Me)caused an enhancement of the signal at 6 i.30 (Me) and vice versa. Upon examination ofmolecular models, it becomes clear that a nuclear Overhauser enhancement between the twomethyl groups is possible only when the ring junction is trans-fused. When this epimer wassubjected to equilibrating conditions (NaOMe/MeOH, vide infra), it was completelyconverted into the cis-fused isomer 131a.Mle62910 12 GeMe3 e Me3132a 132bEnone 95 (entry 3, Table 8) was treated with 1.5 equivalents of the organocopper(I)reagent 15 in the presence of TMSBr to give a 5:1 mixture of 132a and 132b in 88% overallyield. The ‘H nmr spectrum (400 MHz, CDC13) of the major cis-fused epimer 132a revealeda signal for the k3Ge group at 6 0.18 (s), a signal for H-i at 6 2.68-2.72 (dd, J = 8, 8 Hz),and two multiplets at 8 5.13-5.14 and 5.46-5.47 for the vinyl protons (H-i3 and H-13’). TheCOSY spectrum allowed the assignment of H-6 (6 2.08-2.15, m) and H-9 (6 2.37-2.43, m)through the correlation of their signals to that of the angular proton H-i (see Table 24,experimental, page 188).eMe3,,,1Ge Me3I 32aNOE difference experiments were consistent with the assignment of the relativeconfiguration at each of the carbons 1, 6, and 9. Irradiation of the signal at 6 2.08-2.15 (H-6)led to the enhancement of the signal at 6 2.68-2.72 (H-i). Irradiation of the signal at 6 2.37-2.43 (H-9) also led to enhancement of the signal at 6 2.68-2.72 (H-i). Irradiation of thesignal at 6 2.68-2.72 (H-i) produced enhancement of the signals at 6 2.08-2.15 (H-6) and2.37-2.43 (H-9).6313Me3G H12 GeMe31 32bThe ‘H nmr spectrum (400 MHz, CDC13) of the trans-fused adduct 132b revealedresonances at 6 0.20 (s, -Ge3), 5.14 (br s, vinyl proton), and 5.50 (br s, vinyl proton). Thesignal due to the angular proton H-i could not be assigned; however, 132b equilibrated to amixture of 132a and 132b when treated with base (vide infra).i913 GeMe3 GeMe3133a 133bEnone 96 (entry 4, Table 8) was treated with two equivalents of the organocopper(1)reagent 15 in the presence of TMSBr to afford a 6:1 mixture of the cis- and trans-fusedadducts 133a and 133b in 98% overall yield. The 1H nmr spectrum (400 MHz, C 6D6) of themajor cis-fused epimer 133a, illustrated in Figure 1, revealed the following characteristicsignals: the 3Ge signal at 6 0.26 (s), the angular methyl group (Me-lO) at 6 0.83 (s), theangular proton H-i at 6 2.33 (d, J = 10.5 Hz), and the vinyl protons (H-14 and H-14’) at 65.27 (br d, J = 2.5 Hz) and 5.61-5.62 (m). The COSY spectrum allowed the assignment ofH-9 (6 —2.10-2.15, m) through the correlation of its signal to that of the angular proton H-i(see Table 26, experimental, page 194). The L3C nmr spectrum (125.8 MHz, C6D 6)indicated the presence of a carbonyl function at 6 211.7 and a disubstituted double bond at 6122.1 and 153.8. An APT experiment allowed the differentiation of the signals due to.iJIIIIII5,O (ppm)4(ppm)Figure1:The1HnmrSpectrum(400MHz,C6D6)oftheCis-FusedVinylgermane133a0\I65quaternary carbons and to methylene (CH2) carbons from those associated with methine(CH) and methyl (CH3) carbons (see Table 27, experimental, page 195). Most of the signalsof the 1H nmr and ‘3C nmr spectra were assigned through the use of ‘H, ‘H-homonuclearcorrelation and1H,-C-heteronuclear correlation 2D nmr spectra (COSY and HMQCexperiments, respectively; see Tables 26 and 27, experimental, pages 194 and 195). AHMBC experiment provided evidence that the signal at 6 45.4 was due to the quaternaryangular carbon (C-6), as indicated by the long range heteronuclear coupling between C-6 andH-i, H-4’, H-5’, H-7, H-7’, and Me-lO. The following NOE difference experiments wereconsistent with the assigned relative configuration at each of the carbons 1, 6 and 9.OHJJ1 l3GeMe=Me10I 33aIrradiation of the signal at 6 0.83 (Me-lO) caused an enhancement of the signal at 62.33 (H-i). Irradiation of the signal at 6 2.33 (H-i) caused an enhancement of the signals at6 0.83 (Me-lO) and 2.10-2.15 (H-9). These results were consistent with the assigned cisfused ring junction stereochemistry as well as the assigned stereochemistry at C-9 (i.e. thecuprate reagent 15 was introduced trans to the angular methyl group).The 1H nmr spectrum (400 MHz, C6D6) of the trans-fused adduct 133b is illustratedin Figure 2 and revealed a signal due to the 43Ge group at 6 0.30 (s), a signal due to thetertiary methyl group (Me-lO) at 6 0.56 (s), a signal due to the angular proton H-i at 6 1.75(d, J 10 Hz), and two signals due to the vinyl protons at 6 5.31 (br d, J = 1 Hz) and 5.70(m). The COSY spectrum allowed the assignment of H-9 (part of the m at 6 2.28-2.39)through the conelation of its signal to that of the angular proton H-i and the homoallylicprotons H-il and H-il’ (see Table 25, experimental, page 192).IIIIII4(ppm)(ppm)14o13GeMe3Me10133b5:65:4IFigure2:The1HnmrSpectrum(400MHz,C6D6)oftheTrans-FusedVinylgermane133b679hu13GeMe3Me101 33bThe stereochemistry at the ring junction was confirmed by an NOE differenceexperiment. Irradiation of the signal at 0.56 (Me- 10) caused an enhancement of the signalat 2.29-2.34 (H-9). Molecular models indicate that a positive NOE result between Me-lOand H-9 could only result when there is a trans-fused ring junction. This NOE result alsoconfirms the stereochemistry of the conjugate addition reaction.The relative stereochemistries of the conjugate addition adducts 130a-133b wereconsistent with the results of the NOE difference experiments, as discussed above. Therewas, however, added empirical evidence to distinguish the cis- and trans-fused epimers for agiven reaction. For instance, in all cases, the cis-fused epimer was more polar than thecorresponding trans-fused adduct and was always the second compound to be eluted from asilica gel chromatographic column. Upon examination of the JR spectra for each compound,it was found that the positions of the carbonyl absorbances for the trans-fused epimers areconsistently at a wavenumber higher than those for the corresponding cis-fused epimers (seeTable 9, page 69). The differences in the position of the carbonyl absorbances in the transand cis-fused epimers ranged from 11 cm4 (entry 3, Table 9) to 22 cm4 (entry 2, Table 9).Moreover, in the 1H nmr spectra (CDC13 or C6D6), the angular proton H-i in the cisfused adducts is more deshielded by the adjacent carbonyl group than the same proton in thecorresponding trans-fused adducts. Thus, the 1H nmr signal for H-i in the cis-fused adductsappeared downfield in comparison to the H-i signal for the trans-fused epimer (Table 9, Appm for H-i (cis-fused vs. trans-fused) ranged from 0.10 ppm (entry 2) to 0.58 ppm (entry4)).H68In the case of the cis- and trans-fused epimers 133a and 133b, further evidence for thestereochemistry of the ring junction was obtained by comparing the 13C nmr signals for theangular methyl groups. The 13C nmr signal for the angular methyl carbon (Me-lO) of thecis-fused adduct 133a appeared at 6 28.4 ppm, considerably downfield from that of the transfused epimer 133b, which appeared at 6 18.7 ppm (A6 = 28.4 - 18.7 9.7 ppm). Literatureprecedent for the determination of ring junction stereochemistry based on the shielding ofangular methyl carbons is well established and one such example is illustrated below.62eM ecis-fused AB ring junction trans-fused AB ring junctionI IzS.öfor C-19 [(cis-fused) - (trans-fused)] = 11.2 ppm69Table 9: Consistent JR and 1H nmr Differences Between the Cis-Fused and Trans-FusedVinylgermane Epimers0H R GeMe3rRLçiYR’HRGeMe3LçlR’Compourni# Compound#Entry R R JR (cm-’) carbonyl JR (cm-1)carbonylabsorbance absorbance‘H nmr shift for H-i ‘H nmr shift for H-i130a 130b1 Me H 1694cm 1713cm’62.34(d, J =9.5Hz)a 6 1.85(d, J = 12.5 Hz)a131a 131b2 Me Me 1695cm-’ 1717cm6 2.05 (br s)b 6 1.95 (br s)b132a 132b3 H H 1703 cm1 1714cm6 2.68-2.72 (dd, J = 8, 8 Hz)a133a 133b4 H Me 1698 cm-’ 1714cm6 2.33 (d, J = 10.5 Hz)b 6 1.75 (d, J = 10 Hz)ba- This signal was obtained from the tH nmr spectrum (400 MHz) using CDC13 as the solvent.b- This signal was obtained from the ‘H nmr spectrum (400 MHz) using C6D as the solvent.c- The H-i proton was not identifiable in the 1H nmr spectrum (400 MHz, CDC13) of compound 132b.70As seen in Table 8 (page 58), the cis-fused adducts 130a-133a were the majorepimers obtained in the conjugate addition reactions of the cuprate reagent 15 to the enones74, 75, 95, and 96, respectively. The hydrolysis of the silyl enol ether intermediates ispresumed to be a kinetically controlled process, since, under the conditions of the workup, noequilibration of the products would be expected to take place. Thus, protonation of theenolate from the side cis to the angular group (to form the cis-fused ring junction) mustinvolve an energy of activation lower than that leading to the trans-fused isomer. We wereinterested in examining the thermodynamically controlled equilibration of the cis- and transfused epimers. Before describing the results of this study, literature precedent for theequilibration of cis- and trans-fused bicyclo[4.3.0]nonan-2-ones will be discussed.The cis- and trans-fused ratio of bicyclo[4.3.0]nonan-2-ones obtained upon athermodynamically controlled equilibration reaction is greatly dependent on the location andconfiguration of the substituents in the ring system. Dana and coworkers63have shown thatwhen the R substituent at C-9 is çj to the angular group R’ (i.e. both R and R’ are on thesame face of the molecule), the cis-fused isomer predominates in the equilibrium mixture(see entries 1-3, Table 10). This is particularly evident when both R and R’ Me, as seen bythe > 99: < 1 ratio in favor of the cis-fused epimer (entry 1, Table 10). This result can beexplained in terms of the disfavored pseudo 1,3-diaxial interaction between R and R’ thatwould be present in the trans-fused epimer (see below).Conversely, when the R substituent at C-9 is trans to the angular group R’, the trans-fusedisomer predominates as seen in the 1:15.7 and 1:2.2 ratios (entries 4 and 5, respectively,Table 10).MMe H71Table 10: The Thermodynamically Controlled Equilibration of the Cis- and Trans-fusedBicyclo[4.3.O]nonan-2-ones6ct:t:j> aq.NaOHorEntry I R I R’ CISFUSEDa TRANSFUSEDaaj>Oj>1 Me Me >99 : <12 H H 3.2 : 13 H Me 11.5 14 Me H 1 : 15.75 Me Me 1 2.2a- The ratios were determined either by ‘H nmr spectroscopic analysis or VPC analysis.Another example of the thermodynamically controlled equilibration of functionalizedbicyclo[4.3.O]nonanes was reported by Paquette et aL64 (equation 26). The trans-fusedepimer 134 is the thermodynamically more stable compound of the two possible isomers.72This result is in accord with Dana’s fmdings, since the ethyl substituent at C is trans to theangular proton at C (compare with entry 4, Table 10).Table 11 summarizes our equilibration studies on the bicyclic keto vinylgermanes130a and 130b, 131a and 131b, 132a and 132b, and 133a and 133b. In all cases, exceptentry 2, the trans-fused isomer is the thermodynamically more stable epimer. The cis- andtrans-fused isomers were separated and each epimer was subjected to identical equilibrationconditions (NaOMe/MeOH, rt). Thus, when compound 130a (entry 1) was equilibrated, a1:3 ratio of 130a and 130b was obtained, as determined by 1H nmr spectroscopic analysis.Similarly, when the trans-fused epimer 130b was equilibrated, the same 1:3 ratio wasobtained, thereby verifying that this ratio is, in fact, the equilibrium ratio. This 1:3 ratio is inthe same direction as Dana’s result in entry 4, Table 10 (1:15.7 ratio in favor of the transfused epimer).In entry 2, Table 11 (both R and R’ = Me) the cis-fused isomer 131a is favored by aratio of> 99 : < 1. This result is comparable with that observed by Dana and coworkers63(see entry 1, Table 10). Upon examination of molecular models, it is obvious why, in thiscase, the cis-fused epimer 131a is the thermodynamically more stable isomer. The twotertiary methyl groups in the trans-fused isomer 131b experience a pseudo 1,3-diaxialinteraction (see page 61) which is alleviated upon epimerization to the cis-fused isomer 131a.The findings summarized in entries 3 and 4 (Table 11), in which R = H, are verysimilar to Dana’s results (entries 4 and 5, Table 10). In these cases, the substituents at C-9are trans to the angular group R’ and the trans-fused epimers are favored. In entry 3, TableMe..,IIIK2C03MeOHHMeiMe••“ (26)1347311 (R = = H), the equilibrium ratio is 1:30 in favor of the trans-fused epimer 132b. It isnot surprising that this result is comparable to the 1:15.7 ratio observed by Dana (entry 4,Table 10) since the subsituents at C-9 are similar in both entries. In entry 4, Table 11 (R =H, R’ = Me), the equilibrium ratio is 1:5 in favor of the trans-fused epimer 133b (compare tothe 1:2.2 ratio observed by Dana in entry 6, Table 10).Table 11: Equilibration Studies of the Vinylgermane Bicyclo[4.3.0]nonan-2-onesGeMe3H RMeOH,GeMe3Entry R R’ CIS-FUSED TRANS-FUSEDa130a 130b1 Me H 1 : 3131a 131b2 Me Me >99 : <1132a 132b3 H H 1 : 30133a 133b4 H Me 1 : 5a- For entries 1, 3 and 4, the ratio was determined by the H nmr spectroscopic analysis of the crude productmixture. For entry 2, the cis-fused isomer 131a was the only isomer evident in the ‘H nmr spectrum of thecrude oil.742.3.4. PREPARATION OF THE KETO VINYL IODIDESThe next step in the preparation of the cyclization precursors was the conversion ofthe vinylgermane adducts 130a-133b into the corresponding vinyl iodides 135a-138b. Thiswas accomplished by treating a mixture of the cis- and trans-fused vinylgermane adductswith iodine in CH2C12 at room temperature. The results, summarized in Table 12, indicatethat the yields for these conversions are excellent (91% - 99%). Partial epimerization at C-i(i.e. equilibration of the ring junction stereochemistry) was found to occur during most of thereactions. For example, in entry 1, a 9:1 mixture of 130a and 130b was converted to a 1.5:1mixture of the cis- and trans-fused vinyl iodides 135a and 135b, respectively. The epimericmixtures of the cis- and trans-fused vinyl iodides could be separated, either partially orcompletely, via column chromatography on silica gel. As was the case with the ketovinylgermane epimers, the cis-fused vinyl iodides were always eluted from the silica gelcolumn after the corresponding trans-fused vinyl iodides.Spectroscopic evidence for the conversion of the keto vinylgermanes into the vinyliodides was obtained from ‘H nmr spectroscopic analysis. For example, the ‘H nmrspectrum (400 MHz, C6D6) of the cis-fused vinyl iodide 138a (entry 4, Table 12) isillustrated in Figure 3 and revealed resonances for the vinyl protons at 5.54 (m) and 5.70-5.71 (br d, J = 1.5 Hz), significantly downfield from the values for the correspondingprotons in the starting material 133a (see Figure 1). This supported the replacement of theMe3Ge moiety with the more electronegative iodine atom. Similarly, the ‘H nmr spectrum(400 MHz, C6D 6) of the trans-fused epimer 138b, illustrated in Figure 4, revealedresonances for the vinyl protons at 5.56 (m) and 5.78-5.79 (m).The epimers could also be differentiated by comparing the positions of the carbonylabsorbances in the IR spectra of the cis- and trans-fused compounds. As reported in Table13 (page 78), the carbonyl absorbances for the trans-fused epimers are consistently at awavenumber higher than those for the corresponding cis-fused epimers.75Table 12: Conversion of the Keto Vinylgermanes into the Corresponding Keto Vinyl lodidescc%.._-ll-GeMe312, CHIrt, overnightR’ R’Substrate(s) Vinyl Iodide Product(s)Entry Cis-Fused Trans-Fused R R’ Yieldb Cis-Fused Trans-FusedRxrIoa RATIOC1 130a 130b Me H 91% 135a 135b9 : 1 1.5 : 12d 131a Me Me 99% 1363 132a 132b H H 98% 137a 13Th19 : 1 5 : 14 133a 133b H Me 92% 138a 138b1 : 4 1 : 5a- The ratio of the cis- and trans-fused keto vinylgermane adducts was determined by 1H nmr spectroscopicanalysis of the mixture.b- Except for entry 2, the yield refers to the combined isolated yield of the cis- and trans-fused vinyl iodides.c- For entry 1, the ratio of the cis- and trans-fused vinyl iodides was determined by 1H nmr spectroscopicanalysis of the crude mixture. For entries 3 and 4, the ratio of the cis- and trans-fused vinyl iodides wasdetermined by gic analysis of the crude mixture.d- In this case, only the cis-fused isomer was available for conversion to the corresponding cis-fused vinyliodide.IIIII4(ppm)(ppm)I14HH13IMe10138a‘1’5dFigure3:The1HnmrSpectrum(400MHz,C6D6)oftheCis-FusedVinylIodide138aliii5.’lO5.5(ppm)4(ppm)IFigure4:The1HnmrSpectrum(400MHz,C6D6)of theTrans-FusedVinylIodide138b78Table 13: Differences in the Position of the Carbonyl Absorbances in the Cis- and TransFused Vinyl lodidesj%J%.Compound # Compound #Entry R JR (cm-1)carbonyl JR (cm-1)carbonylabsorbance absorbance135a 135b1 Me H 1694cm-’ 1710cm-1362 Me Me 1692cm-’137a 13Th3 H H 1707cm 1713cm’138a 138b4 H Me 1698 cm-’ 1708 cm1a- The corresponding trans-fused vinyl iodide was not obtained.792.3.5. CYCLIZATION STUDIESWith the bicyclic keto vinyl iodide precursors in hand, we were now ready to attemptthe Pd(O)-catalyzed cyclization reactions to form the tricyclic keto alkenes of generalstructure 32 (equation 27).0 IIiL. Pd(PPh3)4,THE, rt;F f\ (27)slow addition ofR’t-BuOK in THF/t-BuOHR’32The cis-fused vinyl iodide 135a was treated with Pd(PPh3)4 (24 mol%), followed by a slowaddition of t-BuOK in a 4:1 mixture of dry THF and dry t-BuOH (equation 28). Uponcompletion of the reaction, glc and tic analysis of the crude reaction mixture indicated thatthe reaction had yielded two products. ‘H nmr spectroscopic analysis revealed that bothproducts lacked the vinyl iodide moiety. The two products were readily separated by flashchromatography and were subsequently subjected to ‘H nmr and mass spectroscopicanalysis, which revealed that cycization had occurred to yield two constitutional isomers.H13’ H140 M e 13H/\ 14I:;;:;::‘ H171211jMe(28)H THF/t-BuOH H H135a 139 14041% 33%1.2 . 1The first product eluted was the expected fused tricyclic keto alkene 139 which was obtainedin 41% yield (equation 28). To our surprise, the other product was determined to be (videinfra) the seven-membered ring bridged compound 140, obtained in 33% yield (equation 28).This seven-membered ring bridged moiety is quite exceptional since its synthesis requires the80formation of an eight-membered ring palladacycle (see intermediate 140b, Scheme 26). Theproposed pathway for the formation of 139 and 140 from 135a is detailed in Scheme 26.As shown in Scheme 26, oxidative addition of the Pd(0) catalyst forms theorganopalladium(ll) species 135c. The added base can generate two enolates, 139a and140a, and, under the reaction conditions, these should be in equilibrium with each other. Theorder of the two steps (i.e. oxidative addition and enolate formation) is not known withcertainty but has been arbitrarily portrayed as shown in Scheme 26. The more highlysubstituted of the two possible enolates, 139a, proceeds to form the six-membered ringpalladacycle 139b, which undergoes reductive elimination of Pd(0) to produce the fusedcompound 139. On the other hand, enolate 140a generates the eight-membered ringpalladacycle 140b, which will subsequently form the bridged product 140. Thespectroscopic evidence for the assigned structures of these two cyclized products, 139 and140, will now be discussed in detail.812PPh3Pd(PPh3)4MeHI 40b2PPh3Pd(PPh3)4H M e140e135aPd(PPh3)42PPh3MeH1 35ct-BuOHH139a 140aMe MeHH139Scheme 2682The IR spectrum of the fused tricyclic compound 139 revealed absorbances at 1703and 1636 cm-1, indicative of carbonyl and olefinic moieties. The ‘H nmr spectrum (400MHz, CDC13), illustrated in Figure 5, revealed a signal at 6 1.16 (s) for the tertiary methylgroup (Me-14), and two signals for the vinyl protons at 6 5.08 (br s, H-13) and 5.16 (br s, H-13’). The COSY spectrum allowed the assignment of nearly all the proton signals (see Table28, experimental, page 206). Confirmation that the cydization had occurred to generate 5-methyl-2-methylenetricyclo[6.4.0.0‘5]dodecan- 12-one (139) was obtained by NOEdifference experiments. Irradiation of the signal at 6 1.16 (Me-14) caused an enhancement ofthe signal at 6 2.05-2. 12 (H-8). Irradiation of the signal at 6 2.57-2.64 (H-il’) caused anenhancement of the signal at 6 5.08 (11-13). Irradiation of the signal at 6 5.08 (H-13) causedan enhancement of the signals at 6 1.83-1.95 (H-9’), 2.57-2.64 (H-il’), and 5.16 (H-13’).Irradiation of the signal at 6 5.16 (H- 13’) caused an enhancement of the signals at 6 2.39-2.45(H-3 and H-3’) and 5.08 (H-13).13H13H/\ H QMe=139 LH1Z)It is highly doubtful that the stereochemistry at C-i is epimeric with that shown in139 (see formula 141, page 84). To form 141, approach of the side chain would have tooccur on the top face of the molecule. This is unlikely due to steric hindrance from theadjacent tertiary methyl group (Me-14). However, the NOE results obtained for compound139 could not rule out this possibility (i.e. the NOB results could also apply to structure 141,see below).5:04:5(ppm)1510Figure5:The1HnmrSpectrum(400MHz,CDC13)oftheFusedKetoAlkene13913’139403.02.52.00084H13’ (—Z.:I;--)13141NOB POSSIBILITIESTherefore, in order to distinguish between compounds 139 and 141, the ketone function of139 was reduced with DIBAL. A single alcohol 142 was obtained in 90% yield. Thehydroxyl moiety was evident in the JR spectrum by absorbances at 3467 and 3394 cm-1. The‘H nmr spectrum (400 MHz, CDC13) revealed the proton H-12 at 6 3.58-3.65 (m).Irradiation of the signal at 6 1.14 (Me-14) caused an enhancement of the signal at 6 3.58-3.65(H-12) and vice versa.HO\’ 14 HMe16M eHThese NOE difference experiments indicated the following: the reduction of 139 hadoccurred stereoselectively by attack of the reducing agent from the less hindered beta face ofthe molecule and the stereochemistry at C-i could only be assigned as shown in compounds139 and 142. If the tricyclic alcohol had possessed the stereochemistry depicted in 143, anNOE between Me-l4 and H-12 would not be possible (see the conformational drawing of143 below).2Mi4Me14385The structural assignment of the bridged tricyclic compound 140 was accomplishedby examining the 1H nmr spectrum, as well as by carrying out COSY, NOE, HMQC, andHMBC experiments. The relative stereochemistry was confirmed by X-ray crystallographicanalysis of a derivative (vide infra). The IR spectrum of 140 revealed absorbances at 1700and 1633 cm1, indicative of ketone and olefinic functions. The ‘H nmr spectrum (400MHz, CDC13) of 140, illustrated in Figure 6, indicated the presence of a methyl group (Me-13) at 6 1.10 (s), an angular proton H-il at 6 2.38 (br d, J = 8.5 Hz), and two vinyl protonsat 6 4.81 (br s) and 4.95 (br s). There was a significantly deshielded proton at 6 3.26 (br s)which was not present in the ‘H nmr spectrum of the other isomer 139. The COSY spectrumallowed the assignment of this signal to H-7 through the correlation of its signal to that of H-14, H-14’, H-6, H-6’, and H-li (w-coupling) (see Table 29, experimental, page 208). Thechemical shift of H-7 can be explained by its close proximity to the deshielding cones of boththe carbonyl and olefinic functions. The COSY spectrum also allowed the assignment of allthe protons of compound 140, including H-9 and H-9 (through correlation of their signals tothat of the vinyl proton H-14’) and H-10 and H-10’ (through the correlation of their signals tothose of H-9 and H-9’). The carbon signals in the 13C nmr spectrum (500 MHz, CDC13)were assigned on the basis of their heteronuclear correlation to the proton signals (HMQCand HMBC experiments, see Table 30, experimental, page 209). For example, the signal at S55.3 showed a one-bond correlation to its attached proton H-7 (HMQC experiment) and twothree-bond correlations to the vinylic protons H-14 and H-14’ (HMBC experiment) and wasthus assigned to C-7. The signal at 6 45.4 was assigned to the quatemary carbon C-i on thebasis of its long range correlation to H-9’ andlor H-i 165 and Me-13. The HMQC and HMBCcorrelations also helped to confirm the proton assignments, particularly those that wereimbedded in multiplets (i.e. protons H-2, H-2’, H-3, H-3’, H-S. H-5’, H-6, H-6’, H-b, and H-10’). With these assignments in hand, NOE difference experiments were conducted todetermine the relative configuration at each of the carbons i, 4, 7, and 11.5O(ppm)Figure6:The1HnmrSpectrum(400MHz,CDC13)oftheBridgedKetoAlkene140H14’14013‘Me454O353O252O1.51O0087H14 H1414H09Hlo% 14H%HeIrradiation of the signal at 6 1.10 (Me-13) caused an enhancement of the signals at 61.43-1.52 (H-b), 2.12-2.19 (H-9), and 2.36 (H-il). The NOE between Me-13 and H-liconfirmed that the 5,6 ring junction was cis-fused. In order to unambiguously verify thisunique structure, the ketone 140 was reduced to the alcohol 144 which, in turn, wasderivatized to the p-nitrobenzoate 145 (Scheme 27). X-ray crystallographic analysis of thecrystalline compound 145 was carried out. The stereoview of this substance is shown inScheme 27.The IR spectrum of 144 revealed absorbances at 3468 and 3420 cm-1,characteristicof a hydroxyl moiety. The ‘H nmr spectrum (400 MHz, CDC13) of the alcohol 144 revealeda signal at 6 1.14 (s) for the methyl group (Me-13), a signal at 6 1.51-1.72 for the 011 (whichdisappeared upon the addition of D20), a signal at 6 3.99 (hr s, which collapsed to a dd (J =6, 6 Hz) upon the addition of D20) for the proton H-12, and two signals at 6 4.77 (br d, J =2.5 Hz) and 4.84 (hr s) for the vinyl protons H-14 and H-14. The COSY spectrum allowedthe assignment of H-7 (6 2.68) and H-il (part of the m at 6 2.01-2.14) through the correlationof their signals to that of H-12 (see Table 31, experimental, page 214).The p-nitrobenzoate 145 was recrystallized from MeOH-H20 to afford thincolourless plates. X-ray crystallographic analysis66 of this material confirmed theconstitution and relative configuration of 145 (Scheme 27). This data also provideddefinitive evidence for the stereochemistry of the conjugate addition reaction (i.e. thevinylgermane side chain had been introduced trans to the angular group in the conjugateaddition of reagent 15 to enone 74).88DIBAL, THE,_H.l211lMe-78 °CH144140H (93%)I4Pr2N/ DMAP,THF,A/ (92%)N 02“8 9 H 1O 13Hj712111Me145 H04 0403 03Hi NiC19 ciCiB CiBC20 C2Oczi Ci? Cl?Cis Cl6C15 cisC14 C14OZ 02Cl3 01 cio C13 01 cioCo ‘ CoCO Cl Co ciC? 1 ci C? CiZC4 CZ C4 C2CO C3 CO C3C5 C5Scheme 2789The trans-fused vinyl iodide 135b was subjected to the Pd(O)-catalyzed cyclizationconditions in order to examine the effects of the trans-fused ring junction on the ratio of fusedto bridged cyclized products (equation 29).Pd(PPh3)4,THE, rt; JLF MeH ‘ Meslowadditionof + (29)THF/t-BuOH H H139 14036% 29%1.2 . 1The overall yield of the two cyclized products 139 and 140 was slightly lower than thatobtained using the cis-fused epimer 135a as the starting material (65% (equation 29) vs. 74%(equation 28, page 79)). However, the ratio of the fused to bridged compounds 139 and 140was 1.2:1, which was identical with that observed using the cis-fused epimer 135a. Theproposed pathway for the formation of compounds 139 and 140 from the trans-fused vinyliodide 135b is detailed in Scheme 28.As in Scheme 26 (page 81), the oxidative addition in Scheme 28 (135b —* 135d) isshown to occur prior to enolate formation. The reaction of the ketone 135d with baseproceeds to yield two enolates, 139a and 140c. Enolate 139a can generate the fusedcompound 139 via the palladacycle 139b (see route B, Scheme 28). The cyclization of theother enolate 140c to the intermediate 140d is highly unlikely since the examination ofmolecular models indicated that the palladacycle 140d is very strained. Under thethermodynamically controlled base equilibration conditions, enolate 139a can epimerize tothe enolate 140a via the cis-fused ketone 135c (see route A, Scheme 28). Enolate 140a canthen proceed to form the bridged keto alkene 140. Thus, the formation of compound 140from the trans-fused epimer 135b necessitates epimerization at C-li, followed by thecyclization reaction. In order to obtain similar fused to bridgedOMe1 35b90[139]Pd(L2)II 35dt-BuOH t-BuOKOKMeHI 39bPd(L2)IH14OcN.J KI‘Met-B uH1 40d[140 1KIH HI 40a140bScheme 2891product ratios from 135a and 135b (see Schemes 26 (page 81) and 28, respectively), itfollows that the rate of epimerization must be fast compared with the rate of cydization.There were two questions which needed to be addressed. First of all, could wemodify the reaction conditions to change the product ratio and secondly, what effect do thesubstituents R and R’ (see compound 19b) have on the ratio of fused (general structure 32) tobridged (general structure 32a) product formation (equation 30)?+ H RIn an experiment related to the first question, the trans-fused epimer 135b was subjected to acycization procedure employing the following modifications: the reaction was conducted ata higher dilution (i.e. the concentration of 135b in the reaction mixture was diluted from 0.05M to 0.008 M) and the t-BuOH was omitted from the base mixture (equation 31).As shown in Scheme 28, the enolate 139a can proceed directly to form the fusedcompound 139 via the intermediate palladacycle 139b (route B) or enolate 139a canepimerize to the enolate 140a via the cis-fused ketone 135c (route A). The bridged productR’0vNPd(O)baseR’321 9b(30)32aH1 35bPd(PPh3)4,rt,THE (0.008 M);slow addition oft-BuOK in THE(no t-BuOH)Me13966%17+HMe1404%1(31)92140 can then be generated from the enolate 140a. If the epimerization rate is slowedsomewhat compared to the rate of cyclization, we would expect to obtain less of the bridgedcompound 140, since its synthesis requires epimerization of 135d prior to cyclization. Asdiscussed in Section 2.1. (page 27), the modifications described in equation 31 can beassumed to slow both the rate of epimerization at the ring junction and the equilibration ofthe two possible enolates. As predicted, the modified reaction conditions produced more ofthe fused product 139 than the bridged compound 140; the reaction yielded a 17:1 ratio ofproducts 139 and 140 (equation 31). Thus, we were able to control the reaction conditions toselectively generate more of the fused compound 139.With respect to the second question posed above, the effects of the substituents R andR’ on the outcome of the cyclization reaction are summarized in Table 14 (page 94). Thecis-fused vinyl iodide 136 (entry 2) was cyclized employing the Pd(O)-cataiyzed conditions(equation 32). Only one cyclized product was evident in the ‘H nmr spectrum of the crudereaction mixture. The sole cyclized product was isolated in 63% yield and was determined tobe the bridged compound 146.Pd(O) HH ?Me(32)baseMe136 146The 1H nmr spectrum (400 MHz, C6D6) of 146 revealed resonances at 6 0.86 (s) and1.01 (br s) for the tertiary methyl groups (Me-14 and Me-13, respectively), 6 2.16 (br s) forthe angular proton H-il, 6 3.28 (br s) for the bridgehead proton H-7, and 6 4.68 (br s) and4.71 (br d, J = 1 Hz) for the vinyl protons (H-15 and H-i5’, respectively). The COSYMe93spectrum allowed the assignment of H-6’ (6 1.7 1-1.84) through correlation of its signal to thatof H-7 (see Table 32, experimental, page 219).H’515H 13HjeMe14146The stereochemistry was confirmed by the following NOE difference experiments.Irradiation of the signal at 6 0.86 (Me-14) caused an enhancement of the signal at 6 2.16 (H11). Irradiation of the signal at 6 1.01 (Me-13) also caused an enhancement of the signal at 62.16 (H-li) while irradiation of the signal at 6 2.16 (H-il) caused enhancement of thesignals at 6 0.86 (Me-14) and 1.01 (Me-13). Irradiation of the signal at 6 3.28 (H-7) causedan enhancement of the signal at 6 4.68 (H- 15). These experiments confirm that H-il, Me- 13and Me-14 must be on the same face of the molecule.The cyclization reaction was not performed on the trans-fused counterpart of the vinyliodide 136 since this substrate was not synthesized (i.e. when R = R’ = Me, the cis-fusedcompound 136 was not only the kinetically formed epimer in the hydrolysis of the silyl enolether intermediate but was also the thermodynamically more stable of the two possibleepimers, see pages 60 and 73, respectively).94Table 14: Cyclization Studies in Forming Fused and Bridged Tricycic Keto Alkenesa- Isolated yield of both the fused and bridged cyclized products.b- This ratio refers to the isolated product ratio.c- This cyclization reaction was carried out using modified reaction conditions (0.008 M dilutionBuOH in the base mixture).+ HRR’ THF/t-BuOH R’ R’Entry Vinyl R R’ Total FUSED PRODUCT BRIDGED PRODUCTIodide Yield a PKflOb1 135a Me H 74% 139 1401.2 : 12 136 Me Me 63% 146<1 : >993 137a H H 45% 147 14811 14 138a H Me 41% 149<1 : >99OR IIii.. FJ.%%%%__J4%%.JPd(PPh3)4,( THE. ri: FUSED + BRIDGEDL L 1 slow addition of PRODUCT PRODUCT--i’ t-BuOK inR’ THF/t-BuOH5 135b Me H 65% 139 1401.2 : 16C 1351, Me H 70% 139 14017 : 17 13Th H H 52% 147 1488 : 18 138b H Me 38% 149<1 : >99and no t95H 13’H H13Hd,,+147 148l37acis-fusedepimer 11 1137b trans-fused epimer 8 . 1Entries 3 and 7 (Table 14, page 94) describe the results of the cyclization of the cisand trans-fused vinyl iodides 137a and 137b, respectively. The ratio of fused to bridgedproducts 147 and 148 was similar in both cases (— 11:1 and —8:1, respectively, see equation33). The major product in each case was the fused tricyclic compound 147. The 1H nmrspectrum (400 MHz, CDC13) of 147 revealed two signals at 6 5.15 (br s) and 5.26 (br s) forthe vinyl protons (H-13 and H-13’, respectively). The COSY spectrum allowed theassignment of H-3 and H-3’ (6 2.39-2.48, m) through the correlation of their signal to that ofH-13 and H-13’ (see Table 33, experimental, page 222). The signals H-4 (6 1.52-1.56, m)and H-4’ (6 —1.80-1.85, m) were assigned due to their correlations with H-3 and H-3’. Thesignals H-li (6 2.27-2.33, m) and H-li’ (part of the m at 6 2.74-2.83) were assigned on thebasis of their chemical shift (deshielding due to the adjacent carbonyl group). The signalsdue to H-b (6 —1.61-1.75, m) and H-b’ (6 —2.06-2.11) were assigned due to theircorrelations to H-il and H-il’. In turn, one of the protons at C-9 (6 —1.85-1.88, m, H-9) wasassigned through its correlation to H- 10 and H- 10’. The following NOE differenceexperiments verified the relative configuration of 147 and also allowed the assignment of thevinyl protons H-13 and H-13’.96H 13’5 HHf H147 (H1L)Irradiation of the signal at 6 2.39-2.48 (H-3 and H-3’) caused an enhancement of thesignals at 6 1.52-1.56 (H-4), 1.61-2.11 (11-4’), and 5.26 (H-13’). Irradiation of the signal at 62.74-2.83 (H-li’) caused an enhancement of the signals at 6 2.27-2.33 (H-il) and 5.15 (H-13). Irradiation of the signal at 6 5.15 (H-13) caused an enhancement of the signals at 6 1.61-2.11 (H-9), 2.74-2.83 (H-li’), and 5.26 (H-l3’). Irradiation of the signal at 6 5.26 (H-13’)caused an enhancement of the signals at 6 2.39-2.48 (H-3 and H-3’) and 5.15 (H- 13).The minor cycized product was determined to be the bridged compound 148. The‘H nmr spectrum (400 MHz, CDC13) of 148 revealed a signal at 6 2.74-2.29 (dd, J = 8.5, 8.5Hz) corresponding to the angular proton H-il, a signal at 6 3.29 (br s) indicative of thebridgehead proton H-7, and two signals at 6 4.82-4.83 (dd, J = 1.5, 1.5 Hz) and 4.94-4.95(dd, J = i.5, 1.5 Hz) for the vinyl protons H-13 and H-13’.1HH71i1H H”97Entries 4 and 8 (Table 14, page 94) describe the results of the cyclization of the cisand trans-fused vinyl iodides 138a and 138b, respectively (see equation 34). In both cases,the bridged product 149 was the sole cyclized product. In each case, however, there wasproduced a small amount of uncyclized reduced byproduct 150.H1471211+Me Me Me13 10138a cis-fused1 38b trans-fusedslow addition oft-BuOK in THF/t-BuOHVinyl Iodide 149 150138a 41% 8%5 : 1138b 38% 4%10 : 1The IR spectrum of the minor product 150 revealed absorbances at 1698 and 1641 cm’,indicative of carbonyl and olefinic moieties. The 1H nmr spectrum (400 MHz, CDC13)revealed three vinyl protons (64.90-4.93 (dddd, J 10, 1.5, 1.5, 1.5 Hz, H-14); 6 4.94-5.00(dddd, J = 17, 1.5, 1.5, 1.5 Hz, H-14’); and 6 5.69-5.79 (dddd, J = 17, 10, 7, 7 Hz, H-13))whose multiplicities and coupling constants are indicative of a monosubstituted double bond.Thus, the reduced byproduct was assigned structure 150.The major product was determined to be the bridged compound 149. The ‘H nmrspectrum (400 MHz, C6D 6) of 149 had signals at 6 0.86 (s) for the tertiary methyl group(Me-13), 6 2.49 (br d, J = 10.5 Hz) for the angular proton H-il, 8 3.31 (br s) for thebridgehead proton H-7, and 6 4.69 (br dd, J = 1, 1 Hz) and 4.75 (br d, J 1 Hz) for the vinylprotons H-14 and H-14’, respectively. The COSY spectrum allowed the assignment of H-i(part of the m at 6 2.22-2.34) through the correlation of its signal to that of H-il (see Table9834, experimental, page 226). The assignment of H-6 (6 —1.60-1.68, m) and H-6’ (6 1.78-1.86,m) was made on the basis of their correlations to the signal H-7. The assignment of H-9 (61.97-2.03, br dd, J = 15, 9 Hz) and H-9’ (6 2.22-2.34, m) was made on the basis of theircorrelations to the signal H-14’. Based on these assignments, we were able to confirm thestereochemistry with NOE difference experiments.H14’Irradiation of the signal at 6 0.86 (Me-13) caused an enhancement of the signal at 62.49 (H-i 1). Irradiation of the signal at 6 2.49 (H-il) caused an enhancement of the signalsat 6 0.86 (Me-13) and 2.22-2.34 (H-i). This result confirmed that H-i, H-il, and Me-13must be on the same face of the molecule. Irradiation of the signal at 6 3.31 (H-7) caused anenhancement of the signal at 6 4.69 (H-14), confirming the assignment of the vinyl protonsH-14 and H-14’.It is apparent from the results in Table 14 (page 94) that the ratio of fused to bridgedproducts does not depend on the nature of the ring junction of the starting material but ratheron the nature of the substituents R and R’. When both R and R’ = Me (vinyl iodide 136, entry2, Table 14, page 94), only the bridged product 146 was obtained. Scheme 29 (page 99)illustrates a possible rationalization for the sole formation of compound 146. The formationof the more highly substituted enolate 152a involves removal (by base) of the stericallyhindered angular proton of compound 151 (i.e. the angular proton is adjacent to twoquaternary centers). Moreover, this deprotonation probably occurs from the less stable14’H14999Me136Pd(PPh3)42PPh3Pd(L2)I151 aA CH2R = -(CH2)C-Pd(LI Me151t-BuOH1, t-BuOK151 bOK Me,J2)Me1(L2)I1 52a I 52bMeH% M eMe146SSSSSMe153Scheme 29100of the two conformers iMa and 151b (i.e. the conformer 1Mb), in which the axial angularproton H-i is nearly perpendicular to the plane of the ketone function. The formation of thekinetically favored enolate, 152b, involves removal of H-3 from conformer 151a or H-3’from conformer 151b. It is likely that the deprotonation occurs mainly from conformer151b, in which H-Y is sterically much more accessible than H-3 in conformer 151a (seeScheme 29). The abstraction of H-i from conformer 151b is much more sterically hinderedthan the abstraction of H-3’ from conformer 151b. Thus, the enolate 152b is formedpreferentially over the enolate 152a, thereby accounting for the preferential formation of thebridged compound 146 (none of the fused compound 153 was obtained).e Me140When R’ = H and R = Me (vinyl iodides 135a and 135b, entries 1 and 5, Table 14,page 94), an intermediate result is obtained with the formation of a 1.2:1 ratio of fused tobridged compounds 139 and 140. The proposed pathways for the formation of compounds139 and 140 from the cis- and trans-fused vinyl iodides 135a and 135b are shown inSchemes 26 (page 81) and 28 (page 90), respectively. The product ratio could bemanipulated by modifying the cycization conditions (see entry 6, Table 14, page 94).It is difficult to rationalize the results obtained from the experiments summarized inentries 3, 4, 7, and 8 (Table 14, page 94). First of all, the mass balance and overall yieldsobtained from these reactions were poor (i.e. the yields ranged from 38% to 52%). Since themass balance was poor, it is difficult to speculate on where the remaining material went.Secondly, several reactions are occurring concurrently (i.e. deprotonation, enolateequilibration, and cycization) and without further study, one cannot predict which reaction isH H H135a 135b 139101controlling the product ratio. It was observed that when the angular group (R’) is a methylgroup (entries 2, 4, and 8, Table 14, page 94), only the bridged product is obtained,regardless of the configuration of the ring junction (i.e. compare entries 4 and 8, Table 14).147FI.3H148At the other extreme, when R = R’ = H (vinyl iodides 137a and 137b, entries 3 and 7,Table 14, page 94), the fused product 147 is favored by ratios of 11:1 and 8:1 over thebridged product 148. In this case (R = R = H), it is likely that the rate of epimerization isfast relative to the rate of cyclization. Thus, the cyclization to form the six-membered ringpalladacycle (which leads to the formation of the fused product 147) must be faster than thecyclization to form the eight-membered ring palladacycle (which leads to the formation ofthe bridged product 148).2.3.6. CONCLUSIONThe conjugate addition of the organocopper(I) reagent 15 to the bicyclic enones 74,75, 95, and 96 was shown to proceed stereoselectively to give cis- and trans-fusedvinylgermane adducts. These adducts were converted into the corresponding vinyl iodideprecursors, which were subsequently subjected to the Pd(0)-catalyzed cyclization conditions.These cyclizations provided us with the expected fused tricyclic compounds 139 and 147 aswell as the structurally unique bridged compounds 140, 148, and 149.Although the nature of the two substituents R and R’ did not affect thestereochemistry of the conjugate addition reaction, they did influence the ratio of the cis- andtrans-fused vinylgermane adducts obtained upon thermodynamically controlled equilibrationH H137a 137breactions. Moreover, the substituents R and R’ had a significant effect on the fused tobridged product ratio of the cycization reactions as discussed above.1021032.4. THE FORMATION OF TRICYCLIC COMPOUNDS BEARING AN ALLYLIC,ANGULAR HYDROXYL GROUP VIA A METAL-HALOGEN EXCHANGEREACTION2.4.1. INTRODUCTORY REMARKSIn Sections 2.1. and 2.3., the vinylgermane bifunctional reagent 13 was employed inannulation sequences as the synthetic equivalent of an2,d4-synthon. Reagent 13 can alsoserve as the synthetic equivalent of a 1-butened2,d4-synthon 21, as depicted in equation 35.The first two steps in this sequence are identical with those described in Sections 2.3.3.4. and2.3.4. (i.e. the stereoselective conjugate addition of the organocopper(I) reagent 15 tobicyclo[4.3.0]non-9-en-2-ones, followed by the conversion of the vinylgermane adducts tothe corresponding vinyl iodides). The proposed ring closure step involves conversion of thevinyl iodide moiety into a donor center via a lithium-iodine exchange reaction. In this way,we hoped to gain access to tricycic allylie alcohols of general structure 33. Examination ofthe stereochemical outcome of such a reaction was also a motivating factor for these studies.M G = d de313210R IIA HO* jRJj) . 9!-L.... (35)R’ R’ R’332.4.2. CYCLIZATION STUDIESThe cyclization reactions were performed on the bicyclic trans-fused vinyl iodides135b, 13Th, and 138b (Table 15, page 104) and the cis-fused vinyl iodides 135a, 136, 137a,and 138a (Table 17, page 110). The results of the cyclization reactions of the trans-fusedvinyl iodides are summarized in Table 15 and indicate that the lithium-iodine exchangereaction and subsequent closure of the vinyllithium species onto the carbonyl carbon104proceeded cleanly and in good yield in all cases. Upon examination of molecular models, itwas clear that the approach of the vinyllithium moiety to the carbonyl carbon from the alphadirection is much more favorable than approach from the beta face of the molecule (see154a). Nonetheless, the stereochemistry of each cyclization reaction was confirmed by ‘Hnmr experiments (vide infra).1 54aTable 15: Cyclization Reactions of the Trans-Fused Vinyl lodides toCompounds Bearing an Allylic, Angular Hydroxyl Groupdi’__HO*Jh1R8n-BuLl, THE,-78°CR’ R’lized ProductEntry Vinyl RIodide1 135b Me H 154(95%)2 13Th H H 155(83%)3 138b H Me 156(85%)Yield TricyclicH105H Me154The trans-fused vinyl iodide 135b (entry 1, Table 15) was treated with 2.6equivalents of n-BuLi at -78 °C to provide, after workup and purification, the crystallinetricydic compound 154 in 95% yield. Interestingly, nucleophilic attack of n-BuLi on thecarbonyl function does nç compete with the lithium-iodine exchange and intramolecularcyclization reactions. The IR spectrum of 154 revealed absorbances at 3568, 3449, 3079, and1646 cm-1, typical of hydroxyl and olefinic moieties. The ‘H nmr spectrum (400 MHz,CDC13), illustrated in part a of Figure 7 (page 106), revealed a signal at 6 0.78 (d, J = 12.5Hz) for the angular proton H-12, a signal at 6 1.08 (s) for the tertiary methyl group, and twosignals at 6 4.80 (dd, J = 2, 2 Hz) and 4.86 (dd, J = 2, 2 Hz) for the vinyl protons. TheCOSY spectrum allowed the assignment of the protons H-4, H-7, H-7’, H-b, H-b’, H-il,and H-il’ (see Table 35, experimental, page 231). The relative configuration at each of thecarbons 1, 4, and 12 was known from the starting keto vinyl iodide. Therefore, the onlyunknown stereochemistry was at C-8 (i.e. the carbon bearing the angular hydroxyl group).Attempts at observing a nuclear Overhauser enhancement of the hydroxyl proton failed. Forthis reason, we needed to utilize a technique other than NOE difference experiments to verifythe C-8 stereochemistry of the tricyclic alcohols.Pyridine-d5 has been used as a non-invasive shift reagent to establish both the locationand stereochemical orientation of protons situated in the vicinity of hydroxyl functions.67Demarco et al.67 report that protons occupying positions i,3-diaxial, vicinal, or geminal to ahydroxyl function are deshielded on the order of 0.15 - 0.40 ppm in pyridine relative tochloroform. Pyridine is believed to complex to the alcohol moiety via a hydrogen bondingassociation (Scheme 30, page 107).14—Me-13(ppm)b)TheHnmrspectrumof154inpyridine-d5—Me-1311-450454035302520151.0(ppm)a)The‘Hnmrspectrumof154inCDC13Figure7:The1HnmrSpectrum(400MHz)oftheAllylicAlcohol154ina)CDCI3andb)pyridine-d513 MeH10’H1°154107In the case of hydrogen bonding of a hydroxyl proton to pyridine, it is assumed that theN•• •H-0 bond is co-linear (i.e. the 0-H bond lies along the axis of symmetry of the nitrogenlone-pair electrons). For steric reasons, this association must take place from the side of thering away from the axial methyl group. Thus, in light of the known mechanism by whichdeshielding can occur, the geometrical relationship, illustrated in Scheme 30, explains the Avalues (A =6 (pyridine-d5) - 6 (CDC13)) reported for the axial methyl group (A = 0.30) andthe geminal proton (A = 0.25). 67In order to verify the stereochemical result of the cycization reaction, we investigatedthe effects of pyridine-d5 on the chemical shifts of the protons of the tricyclic compound 154.The 1H mnr spectrum (400 MHz) of 154 in pyridine-d5 (see part b of Figure 7, page 106)revealed the following characteristic signals: 6 0.73 (d, J = 13 Hz) for H-12, 6 1.32 (s) forthe tertiary methyl group, and 6 4.85-4.86 (dd, J = 2, 2 Hz) and 4.92-4.93 (dd, J = 2, 2 Hz)for the vinyl protons. The COSY spectrum allowed the identification of many of the otherprotons (see Table 36, experimental, page 231).0HScheme 306710814H‘H1°Figure 7 (page 106) compares the 1H nmr spectra of 154 in CDC13 versus that inpyridine-d5. Three signals, H-4 (A = 0.36), H-10’ (A = 0.26), and Me-13 (A = 0.24), weresignificantly shifted downfield in pyridine-ds relative to CDC13 (see Table 37, experimental,page 232). Since the relative configuration at carbons 1 and 4 is known, it follows that thehydroxyl group must be on the same face of the molecule as H-4 and Me-13, therebyverifying the stereochemistry at C-8. The protons H-4, H-b’, and Me-13 exist in a 1,3-diaxial relationship to the hydroxyl group, thus explaining the downfield shifts observed forthese protons in pyridine-d5 relative to CDC13. As indicated in Table 37 (experimental,page 232), the chemical shifts of all the other assigned protons did change significantly inpyridine-ds relative to CDC13.The remaining two trans-fused vinyl iodides 137b and 138b were cyclized to yieldthe tricyclic alcohols 155 and 156 in 83% and 85% yield, respectively (entries 2 and 3, Table15, page 104). The stereochemistry of the cyclization reaction was verified by comparing the‘H nmr spectra of 155 and 156 in pyridine-d5 versus those in CDC13 (see Tables 49 and 56,experimental, pages 249 and 259, respectively). As with compound 154, those protons in a1,3-diaxial relationship to the angular hydroxyl group were shifted downfield in pyridine-d5relative to CDC13 (see Table 16). The downfield shifts ranged from 0.22 ppm (entry 3,Table 16) to 0.88 ppm (entry 2, Table 16). Thus, the n-BuLi mediated cyclization of thetrans-fused vinyl iodides provided a stereoselective route to the synthesis of the tricydicalcohols 154-156.154j12109Table 16: A ppm for those Protons in a 1,3-Diaxial Relationship with the Angular HydroxylGroupHOhi R—R’ H12Entry Tricyclic R R’ A for R’ 1afor R A forAlcohol (ppm) (ppm) H-b’(ppm)1b 154 Me H 0.36 0.24 0.262C 155 H H 0.88 0.40 0.343d 156 H Me 0.22 0.28 0.34a - A = 6 (pyridine-d5) - 6 (CDC13).b- Data from Table 37, experimental, page 232.c- Data from Table 49, experimental, page 249.d- Data from Table 56, experimental, page 259.110The results of the cyclization of the cis-fused vinyl iodides 135a, 136, 137a, and138a, summarized in Table 17, were not as straightforward as those obtained with the transfused vinyl iodides. Upon examination of molecular models, it was evident that thevinyllithium species, obtained from the reaction of the cis-fused vinyl iodides with n-BuLi,could approach the carbonyl carbon from two different directions (i.e. attack from either thealpha or beta face of the molecule).Table 17: Cyclization Reactions of the Cis-Fused Vinyl lodides to Yield TricyclicCompounds Bearing an Allylic, Angular Hydroxyl GroupHOR + HOR +Beta-OH Alpha-OH UncycizedEntry Vinyl R R’ Products Products Byproduct TotalIodide (Yield) a (Yield) a (Yield) a YieldpjiOb157 158 1591 135a Me H 24% 51% 8% 83%1 : 2.1160 1612 136 Me Me 65% c 35% 100%>99 : <1162 163 1643 137a H H 26% 37% 11% 74%1 1.4165 166 1674 138a H Me 40% 35% 20% 95%1.1 : 1— —a- Yielct refers to the isolated yield.b- This is the ratio between the two cyclized products.c- None of this product was obtained.111The cyclization of the cis-fused vinyl iodide 135a provided, after workup andpurification, products 157, 158, and 159 in yields of 24%, 51%, and 8%, respectively (entry1, Table 17). The two major products, 157 and 158, were determined to be epimeric tricyclicalcohols, whereas the minor compound 159 was found to be an uncycized byproduct inwhich the iodine moiety had been replaced by a proton. The spectroscopic evidence for thesethree products will now be discussed.14HO1157 Me13The JR spectrum of the cyclized product 157 revealed absorbances at 3472, 3387,3087, and 1642 cm-’, characteristic of hydroxyl and olefinic moieties. The ‘H nmr spectrum(400 MHz, CDC13) revealed signals at 6 1.01 (s) for the tertiary methyl group (Me-13), 61.41 (d, J = 7 Hz) for the angular proton H-12, and 64.81-4.82 (m) and 5.10 (br d, J = 1 Hz)for the vinyl protons H-14 and H-14’. The COSY spectrum allowed the assignment ofseveral other protons (see Table 39, experimental, page 237). The ‘H nmr spectrum (400MHz) of 157 in pyridine-d5 was also examined, and a comparison of the chemical shifts ofthe assigned protons in pyridine-d relative to CDC13 was made (see Table 41, experimental,page 238). Upon examination of molecular models, it was clear that one of the sixmembered rings must exist in either a boat or twist-boat conformation. The conformationdepicted above explains why the protons H-4, H-12, and H-14’ were all significantly shifteddownfield in pyridine-d5 relative to CDC13 (entry 1, Table 18). The angular proton H-4 (L= 0.16) is in a 1,3-diaxial relationship with the OH group, while proton H-12 (A = 0.37) is ina cis vicinal position, and the vinyl proton H-14’ (A = 0.48) is in very close proximity to thehydroxyl group. As was previously observed, the chemical shift of the other assignedprotons did not change signficantly in pyridine-d5 relative to CDC13.112Table 18: A ppm for those Protons in Close Proximity to the Angular Hydroxyl Group inthe Beta-OH ProductsHO11R HXEntry Tricyclic R a for R’ La for A forAlcohol (ppm) H-12 H-x’(ppm) (ppm)1b 157 Me H 0.16 0.37 0.482C 160 Me Me 0.19 0.39 0.493d 162 H H 0.16 0.38 0.494e,f 165 H Me 0.18 0.52 0.50a - A = 6 (pyridine-d5) - 6 (CDC13).b- Data from Table 41, experimental, page 238.c-Data from Table 44, experimental, page 243.d- Data from Table 53, experimental, page 255.e- Data from Table 60, experimental, page 265.f- In this compound, H-x was also deshielded by 0.16 ppm in pyridine-d5 relative to CDC13.H14 H1414IIiiFX?= 1H:e13158The JR spectrum of the other cycized product 158 revealed absorbances at 3600,3494, 3079, and 1639 cm’, indicative of hydroxyl and olefinic functions. The ‘H nmr113spectrum (400 MHz, CDC13) possessed signals at 6 0.71 (s) due to the hydroxyl proton(which disappeared upon the addition of D20), 6 0.99 (s) for the tertiary methyl group (Me13), 6 1.14 (d, J = 7 Hz) for the angular proton H-12, and 6 4.7 1-4.72 (m) and 4.89 (br d, J= 1 Hz) for the vinyl protons H-14 and H-14’, respectively. The COSY spectrum allowed theassignment of H-4 (6 —2.31-2.38, m) through the correlation of its signal to that of H-12 (seeTable 38, experimental, page 234). The allylic protons H-10 (6 — 2.26-2.31, m) and H-b’ (6—2.38-2.43, m) were identified via their correlations to the vinyl protons H-14 and H-14’.Similarly, the protons H-li (6 —1.42-1.50, m) and H-ll’ (6 2.00-2.07, ddd, J = 12.5, 12.5,4.5 Hz) were assigned through their correlations to H-b and H-b’.The following NOE difference experiments were consistent with the assigned relativeconfiguration at carbons 1, 4, and 12. Irradiation of the signal at 6 0.99 (Me-13) caused anenhancement of the signals at 6 1.14 (H-12) and —2.3 1-2.38 (H-4). Irradiation of the signal at6 1.14 (H-12) caused an enhancement of the signal at 6 —2.3 1-2.38 (H-4). These experimentsestablished that H-4, H-12, and Me-13 are on the same face of the molecule. Irradiation ofthe signal at 6 4.7 1-4.72 (H-14) caused an enhancement of the signals at 6 —2.38-2.43 (H-b’)and 4.89 (H-14’), thus allowing the assignment of the vinyl protons H-14 and H-14’.Comparison of the ‘H nmr spectra of 158 in pyridine-d5 versus CDC13 did notprovide conclusive evidence for the stereochemical assignment at C-8. Nonetheless,compound 158 is epimeric to the corresponding alcohol 157, and must thus possess therelative configuration shown above. Moreover, it was found that the alpha-OH products 158,163, and 166 were readily differentiated from the corresponding beta-OH products 157, 160,162, and 165 on the basis of their polarity in column chromatography. The alcohols 158,163, and 166 were much less polar than their corresponding epimers 157, 162, and 165 (thedifference in Rf (using 9:1 petroleum ether - diethyl ether) was —0.5). The difference inpolarity can be explained by the fact that the hydroxyl groups of compounds 158, 163, and166 are buried in the concave face of the molecules and are thus much less accessible thanthe hydroxyl groups of compounds 157, 162, and 165.114Other evidence that distinguished the epimeric tricyclic alcohols was obtained fromthe chemical shifts of the vinylic protons H-x’. Table 19 lists the chemical shifts of H-x’ forthe tricyclic alcohols obtained in the cycization reactions of the cis-fused vinyl iodides. Thechemical shifts of H-x’ in the beta-OH products 157, 160, 162, and 165 were more downfieldin comparison to those shifts for the corresponding alpha-OH products. The hydroxyl groupin the beta-OH products is situated very close to H-x’ and thus deshields this proton, as wasfurther confirmed in the pyridine-d5 studies.Table 19: Differences in the Chemical Shift of the Vinyl Proton H-x’ Between the Beta-OHand Alpha-OH ProductsR’ R’Beta-OH Products Alpha-OH Productsp# Compound#Entry R R’ nmr shift for H-x’ a 1H nmr shift for H-x’ a157 1581 Me H 65.10 64.891602 Me Me 65.09162 1633 H H 65.10-5.11 64.86165 1664 H Me 65.08 64.90XH.H 1Ra- CDC1 3 was the solvent used in these 1H nmr spectra.b- This compound was not obtained.115g1113H159The JR spectrum of the byproduct 159 revealed absorbances at 3076, 1694, and 1641cm4, typical of ketone and olefinic moieties. The ‘H nmr spectrum (400 MHz, CDC13)possessed three signals at 4.90-4.92 (br d, J = 10 Hz, H-14), 4.95-5.00 (dddd, J = 17,2, 2,2 Hz, H-14’), and 5.72-5.82 (dddd, J = 17, 10, 6.5, 6.5 Hz, H-13), indicative of amonosubstituted double bond.°Me‘M HOMe‘ HMe Me Me136 160 161Of the remaining three cis-fused vinyl iodides 136, 137a, and 138a, the latter twosubstrates were cyclized to yield a product composition similar to that obtained from 135a(see entries 3 and 4, Table 17, page 110). On the other hand, iodide 136 (entry 2) yieldedonly two products upon treatment with n-BuLi, 160 and 161. The only cyclized product,160, was determined to be that obtained from alpha attack of the vinyllithium species ontothe carbonyl carbon (i.e. the beta-OH product). The other compound was the uncycizedbyproduct 161. The assignments of the tricyclic structures in Table 17 were based onanalyses of the 1H nmr spectra of each compound. The relative configuration at C-8 for thebeta-OH products (157, 160, 162, and 165) was confirmed by analyzing the ‘H nmr spectraof these compounds in pyridine-d relative to that in CDC13 (Table 18, page 112).116In the cydization of the cis-fused vinyl iodides, the nature of the substituents R and R’influences the ratio of the products obtained. For example, the formation of the alpha-OHproduct was slightly favored when R’ = H (entries 1 and 3, Table 17, page 110). Anapproximately equal amount of epimeric alcohols was obtained when R = H and R’ = Me(entry 4, Table 17). When both R and R’ = Me, the approach of the vinyllithium speciesoccurred exclusively from the alpha face of the molecule, resulting in the sole formation ofthe beta-OH product 160 (entry 2, Table 17). This latter result can be rationalized byexamining the two possible conformations, 136b and 136c, of the vinylithium species 136a(see Scheme 31). Upon examination of molecular models, it was concluded that thevinyllithium side chain in conformer 136b can approach the carbonyl carbon only from thealpha face of the molecule, resulting in the formation of the beta-OH product 160. In theother conformer, 136c, the vinyllithium side chain can approach the carbonyl carbon fromeither direction (leading to the formation of the alcohols 160a and 160). However, conformer136c is significantly less stable than 136b due to a pseudo 1,3-diaxial interaction between thetwo tertiary methyl groups. Thus, one can conclude that the cyclization reaction proceeds viaconformer 136b, resulting in the sole formation of product 160.117136capproach ,“from the ,‘beta ,“direction,’pthe vinyllithiumspecies canonly approachfrom the alphadirectionB U LiMe136MeI 36aIIILi-MeLiMeMeI 36bS approachfrom the alphadirection[T.s.] [T.s.]SSSSSSSST.S. rMe HSSMe “1 60aMeMe160Scheme 31118HOMe HThe beta-OH products (157, 160, 162, and 165) were obtained in yields varying from24% to 65% (see Table 17, page 110). The chemical shifts of those protons in closeproximity to the hydroxyl group (R’, H-12, and H-x’) were all shifted downfield in pyridined5 relative to CDC13 (see Table 18, page 112). The shifts, which ranged from 0.16 ppm to0.52 ppm, verified the stereochemistry at C-8.The alpha-OH products were obtained in yields varying from 35% to 51% (see Table17, page 110), depending on the nature of the R and R’ substituents. The configuration at C-8for compounds 158, 163, and 166 was confirmed by examining the chemical shifts of thevinyl protons H-x’ in comparison to the shifts of H-x’ for the corresponding epimeric alcohols(see Table 19, page 114). Also, the relative poiarity of the alpha-OH and beta-OH productsin column chromatography was indicative of the relative configuration at C-8 (vide supra).157 160Me H Me165162H H Me158 163 166119HIn the reactions of the cis-fused vinyl iodides with n-BuLi, bicyclic byproducts (159,161, 164, and 167) were also obtained (Table 17, page 110). Increasing the reaction time diddecrease the amount of byproduct formed. This indicated that the byproduct is probablyformed by protonation of the vinyllithium species by the acidic protons adjacent to thecarbonyl carbon, rather than by quenching of the reaction during workup. Since theconfiguration at the ring junction (C-i) does not epimerize (i.e. only cis-fused byproductswere obtained), it follows that the protonation of the vinyllithium species probably occurs bytransfer of one of the acidic protons at C-3.2.4.3. CONCLUSIONThe cycization of the cis- and trans-fused vinyl iodides via a lithium-iodine exchangereaction provided an excellent route to the synthesis of tricyclic compounds bearing anallylic, angular hydroxyl group. In this way, the annulation sequence utilized thevinylgermane reagent 13 as the synthetic equivalent of a 1-butened2,d4-synthon. Thecyclization of the trans-fused vinyl iodides proceeded stereoselectively; the nature of the159 161 164Me167substituents R and R’ did not affect the stereochemistry of the addition (i.e. thestereochemistry at C-8). On the other hand, the cyclization of the cis-fused vinyl iodidesprovided an epimeric mixture of alcohols, the composition of which depended on thesubstituents R and R.120121III. EXPERIMENTAL3.1. GENERAL3.1.1. DATA ACQUISiTION AND PRESENTATIONInfrared (IR) spectra were recorded as films between sodium chloride plates (liquidsamples) or as potassium bromide pellets (solid compounds), employing either a PerkinElmer 1710 FT-IR or a Bomem Michelson 100 FT-IR Spectrophotometer, both with internalcalibration.Proton nuclear magnetic resonance (‘H nmr) spectra were recorded on a Brukermodel AC-200, WH-400, or AMX-500 spectrometer using deuteriochioroform (CDC13) asthe solvent, unless otherwise noted. Signal positions (6) are given in parts per million fromtetramethylsilane and were measured relative to the signals of chloroform (6 7.26), benzene(8 7.15), acetone (6 2.04), or pyridine (6 8.71, C-2 proton). Coupling constants (J values)are given in Hertz (Hz). The spectral data are reported in the following format: chemicalshift (ppm), (multiplicity, number of protons, coupling constant(s), and assignments (whenknown)). Abbreviations used are: s, singlet; d, doublet; q, quartet; m, multiplet; br, broad. Inthe ‘H nmr spectra, H-x and H-x’ have been used to designate protons on the same carbon,with H-x’ being the proton resonating at lower field. In some cases, the proton assigmnentswere supported by COSY (‘H- ‘H homonuclear correlation spectroscopy) and/or NOE(nuclear Overhauser enhancement) difference experiments. These experiments were carriedout using a Bruker model WH-400 spectrometer.Carbon nuclear magnetic resonance (13C mnr) spectra and the attached proton testexperiments (APT) were recorded on a Varian XL-300 spectrometer at 75.3 MHz or on aBruker model AM-400 (100.4 MHz) or AMX-500 (125.8 MHz) spectrometer, usingdeuteriochioroform as the solvent, unless otherwise noted. Signal positions (6 values) aregiven in parts per million from tetramethylsilane and were measured relative to the signals ofchloroform-d (6 77.0), benzene-d6 (6 128.0), or pyridine-d5 (6 149.9, C-2). Signals withnegative phase in the attached proton test are so indicated in brackets (-ye) following the122chemical shift. The 1l3 heteronuclear multiple quantum coherence experiments(HIVIQC)68 and the ‘H - 13C heteronuclear multiple bonds connectivity experiments(HMBC)68were recorded on a Bruker model AMX-500 spectrometer.Low and high resolution electron impact mass spectra were recorded on a KratosMS5O mass spectrometer (70 eV). Desorption chemical ionization mass spectra wererecorded with a Delsi Nermag R-10-10 C mass spectrometer. Gas-liquid chromatography-low resolution mass spectrometry (GLCLRMS) was accomplished using a combination of aCarlo Erba model 4160 capillary gas chromatograph (15 m x 0.25 m fused silica columncoated with DB-5) and a KratosIRFA MS 80 mass spectrometer, interfaced with a hollowcapillary tube. The following atomic masses were used to calculate the mass of fragmentsobserved in the HRMS: ‘H 1.007825; ‘2C 12.00000; ‘4N 14.00307; 160 15.99491; 28Si27.97693; 74Ge 73.921177; 1271 126.9044. All compounds subjected to high resolutionmass measurements were homogeneous by gic and/or tlc analysis. For some of thecompounds containing trimethylgermyl groups, the high resolution mass spectrometrymolecular mass determinations were based on the (M+ - Me) peak.Elemental analyses were performed on a CARLO ERBA CHN elemental analyzer,model 1106, by the UBC Microanalytical Laboratory.Specific rotations at the sodium D line (589.3 nm) and the temperature t ([ce] b) weremeasured on a JASCO J7 10 spectropolarimeter using spectroscopic grade chloroform as thesolvent.Gas-liquid chromatography (glc) analyses were performed on a Hewlett-Packardmodel 5880A or 5890 gas chromatograph, both equipped with flame ionization detectors andfused silica capillary columns, either —20 m x 0.21 mm coated with cross-linked SE-54 or—25 m x 0.20 mm coated with 5% phenylmethyl silicone. Chiral gas-liquid chromatography(glc) analyses were performed on a Hewlett-Packard model 5880A gas chromatograph usingan Altech Chirasil-Val ifi capillary column, 25 m x 0.25 mm x 0.16 aim.123Thin layer chromatography (tic) was carried out on commercial aluminum-backedsilica gel 60 plates (E. Merck, type 5554, 0.2 mm). Reverse phase tic was performed oncommercially available, glass-backed plates (Whatman, type KCj/KCF). Visualizationwas accomplished with either ultraviolet light (254 nm) and/or iodine followed by heating theplates after staining with an appropriate reagent. The stains used were (a) phosphomolybdicacid (PMA) in EtOH (20% w/v, Aldrich), (b) ammonium molybdate and cerium sulfate in10% aqueous sulfuric acid (5% ammonium molybdate w/v and 0.1% Ce(S04)2 w/v), (c)vanillin in a sulfuric acid-EtOH mixture (6% vanillin w/v, 4% sulfuric acid vfv, and 10%water v/v in EtOH), or (d) anisaldehyde in a sulfuric acid-EtOH mixture (5% anisaldehydev/v and 5% sulfuric acid v/v). Conventional (drip) and flash chromatography69wereperformed using 230-400 mesh silica gel (B. Merck, Silica Gel 60). Tic grade silicachromatography70was performed on 10-50 p.m Type H silica (S-6628, Sigma). Radialchromatography71was performed on a Chromatotron® Model 7924 using 1 or 2 mm thickradial plates (silica gel 60, PF254, with calcium sulfate, E. Merck #7749).Melting points were measured on a Fisher-Johns melting point apparatus and areuncorrected. Distillation temperatures refer to air-bath temperatures of Kugelrohr (bulb-tobulb) distillations and are uncorrected. Viscous and/or high molecular weight compoundswere often heated under reduced pressure (vacuum pump) to remove residual solvent; thiswas accomplished using a Kugelrohr distillation apparatus.Unless stated otherwise, all reactions were carried out under an atmosphere of dryargon using glassware that had been thoroughly flame and/or oven (—140 °C) dried. Theglass syringes, Teflon® cannulae and needles used for handling anhydrous solvent andreagents were oven dried, while plastic syringes were flushed with dry argon prior to use.Gas-tight syringes (Hamilton series 1700) were placed under reduced pressure (vacuumpump) for 10 mm and flushed with dry argon prior to use. The small and large Teflon®cannulae were purchased from Canlab (Mississauga, ON.) and have the followingdimensions: the small cannula (catalogue # R5360-11 1) has an inner diameter of 0.38 mm124and a wall thickness of 0.23 mm; the large cannula (catalogue # R5360-1 17) has an innerdiameter of 0.97 mm and a wall thickness of 0.30 mm.Concentration, evaporation, or removal of solvent under reduced pressure (wateraspirator) refer to solvent removal via a Büchi rotary evaporator at —15 Torr.Cold temperatures were maintained by the use of the following baths: 0 °C, ice/water;-20 °C, -35 °C, and -48 °C, aqueous calcium chloride/CO 2 (27, 39, and 47 g CaC12/100 mLH20, respectively);72-78 °C, acetone/C02; -98 °C, MeOHlliquid nitrogen.3.1.2. SOLVENTS AND REAGENTSAll solvents and reagents were purified and dried using established procedures.73Benzene and dichioromethane were distilled from calcium hydride. Diethyl ether andtetrahydrofuran were distilled from sodium benzophenone ketyl. The four aforementionedsolvents were distilled under an atmosphere of dry argon and used immediately. Acetonitrile,N,N-diisopropylethylamine, N,N-dimethylformamide, dimethylsulfoxide, HMPA(WARNING: carcinogenic), 2-methyl-2-propanol (t-BuOH), pyridine, triethylamine, andtrimethylsilyl chloride were refluxed over and then distilled from calcium hydride. N, NDimethylformamide, HMPA, and 2-methyl-2-propanol (t-BuOH) were stored over 4Amolecular sieves. Trimethylsilyl bromide was distilled from calcium hydride using aKugelrohr distillation apparatus and was used immediately. Magnesium was added to MeOHand, after refluxing the mixture, the MeOH was distilled from the resulting solution ofmagnesium methoxide and was stored over 4A molecular sieves. Acetic anhydride andcarbon tetrachloride were refluxed over and then distilled from phosphorous pentoxide.Petroleum ether refers to a hydrocarbon mixture with a boiling range of 30-60 °C. All othersolvents were obtained commercially and were used without purification.Boron trifluoride-etherate was purified by distillation from calcium hydride underreduced pressure (60 °C/20 Torr).125Solutions of methyllithium (as a complex with LiBr) in diethyl ether, n-butyllithiumin hexanes, and tert-butyffithium in pentane were obtained from Aldrich Chemical Co., Inc.and standardized using the procedure of Kofron and Baclawski.74Hexamethylditin was obtained from Organometallics Inc. (East Hampstead, N.H.)and was distilled at aspirator pressure prior to use.A solution of NaOMe in dry MeOH was prepared in the following manner: to a cold(-78 °C) flask containing dry NaH was added the appropriate amount of dry MeOH. Themixture was stirred at -78 °C for 10 mlii, warmed to rt, and used immediately.Copper(I) bromide-dimethyl sulfide complex was prepared by the method describedby Wuts75 and was stored in a dessicator under an atmosphere of dry argon. Copper(I)chloride (99%) and copper(I) cyanide were purchased from Aldrich Chemical Co., Inc. andwere used without purification.Tetrakis(triphenylphosphine)palladium(0) was either purchased from AldrichChemical Co., Inc. and used without purification or was prepared by the method described byCoulson.76Chloroform and deuteriochioroform were dried by filtration through a short columnof basic alumina (activity I), which had been dried in an oven (—140 °C) overnight and thenallowed to cool in a dessicator prior to use.All other reagents are commercially available and were used without purification.Aqueous ammonium chioride-ammonium hydroxide (NH4C1-NH4OH, pH 8-9)solution was prepared by the addition of —50 mL of aqueous ammonium hydroxide (58%) to950 mL of a saturated aqueous ammonium chloride solution.1263.2. SYNTHESIS OF BICYCLIC COMPOUNDS VIA THE FIVE-MEMBERED RINGANNULATION SEQUENCE3.2.1. SYNTHESIS OF 2-(CARBOMETHOXY)-2-CYCLOHEXEN-1-ONE (57):OOMeA solution of PhSeBr in THF was prepared as follows: to a stirred solution ofPh2Se2 (1.70 g, 5.50 mmol, 1.2 equiv.) in dry THF (5.5 mL) at rt was added Br2 (0.80 g, 5.0mmol, 1.1 equiv.). The resultant solution (containing -10 mmol of PhSeBr) was stirred at rtfor 10 mm and used immediately in the following reaction.To a cold (0 °C), stirred solution of 2-(carbomethoxy)cyclohexanone77(737 mg, 4.72mmol, 1 equiv.) in dry THF (18 mL) was added, in one portion, sodium hydride (226 mg,9.42 mmol, 2 equiv.). The suspension was stirred at 0 °C for 40 mm. A solution of PhSeBrin dry THF (1.8 M, 3.9 mL, 7.0 mmol, 1.5 equiv.) was added, dropwise, to the enolatesolution. The mixture was stirred at 0°C for 40 mm and was poured into a stirred suspensionof diethyl ether (20 mL), petroleum ether (20 mL), and saturated aqueous NaHCO3 (15 mL).The layers were separated and the aqueous layer was extracted with diethyl ether - petroleumether (1:1, 3 x 50 mL). The combined organic extracts were washed with saturated aqueousNaHCO3 (1 x 50 mL) and brine (1 x 50 mL), and concentrated under reduced pressure.The crude selenide was dissolved in CH2C12 (15 mL) at rt and a solution of H202(1.2 mL of 30% aqueous H 202, —2.5 equiv.) in water (2.5 mL) was added to the mixture inthree equal portions at intervals of 10 mm. Occasional cooling in an ice-water bath ensuredthat the mixture remained at ii. Saturated aqueous NaHCO3 (50 mL) and CH2C12 (50 mL)were added and the layers were separated. The aqueous layer was extracted with CH2C12 (3x 50 mE) and the combined organic extracts were washed with brine (1 x 50 mL), dried over127anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude productthus obtained was distilled (air-bath temperature 90-100 °CI0.15 Torr) to afford 670 mg(92%) of 2-(carbomethoxy)-2-cyclohexen-l-one (57),78 as a colourless oil.3.2.2. SYNTHESIS OF 4-IODO-2-TRIMETHYLGERMYL-1-BUTENE (13) VIA THECORRESPONDING VINYLSTANNANE REAGENT3.2.2.1. Synthesis of 3-Trimethylstannyl-3-buten- 1-ol (48a):Me3SnOH48aTo a cold (-20 °C), stirred solution of hexamethylditin (77.2 g, 236 mmol, 1.5 equiv.)in dry THF (600 mL) was added a solution of methyllithium in diethyl ether (1.52 M, 155mL, 236 mmol, 1.5 equiv.). The yellow solution was stirred at -20 °C for 25 mm. Thereaction mixture was cooled to -78 °C and solid CuBr•Me2S (48.7 g, 236 mmol, 1.5 equiv.)was added in one portion. The red/brown mixture was stirred at -78 °C for 30 mm. Asolution of 3-butyn-1-ol (11.0 g, 156 mmol, 1 equiv.) in dry THF (10 mL) was added,dropwise, to the mixture. Methanol (318 mL, 7.80 x mmol, 50 equiv., unpurified HPLCgrade) was added and the mixture was stirred at -78 °C for 3.5 h and was warmed to 0 °C for3h. Aqueous NH4C1 - NH4OH (pH 8-9, 400 mL) and diethyl ether (400 mL) were addedand the mixture was opened to the atmosphere and stirred vigorously until the aqueous phasebecame bright blue in colour. The layers were separated and the aqueous layer was extractedwith diethyl ether (3 x 300 mL). The combined organic extracts were washed with brine (1 x300 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.The crude oil thus obtained was divided into two equal portions and subjected to drip columnchromatography on two separate columns (—500 g silica gel for each column, 200 mLpetroleum ether followed by 750 mL of 9:1 petroleum ether - diethyl ether, and finally 4:1128petroleum ether - diethyl ether). The vinyistannane alcohol fractions obtained from bothcolumns were combined, concentrated under reduced pressure, and distilled (air-bathtemperature 60 °C120 Torr) to yield 19.1 g (52%) of 3-trimethylstannyl-3-buten-1-ol (48a),79as a colourless oil.3.2.2.2. Synthesis of 4-Chloro-2-trimethylstannyl-1-butene (45):Me3Sn’CITo a stirred solution of 3-trimethylstannyl-3-buten-1-ol (48a) (19.1 g, 81.3 mmol, 1equiv.) in dry CC14 (400 mL) at rt was added dry triethylamine (17.0 mL, 122 mmol, 1.5equiv.) and triphenylphosphine (32.0 g, 122 mmol, 1.5 equiv.). The mixture was heated toreflux for 17 h, cooled to rt, and diluted with hexanes (2 L) to precipitate triphenyiphosphineoxide. The slurry was filtered through Florisil (500 g) using water aspirator pressure. Thefiltrate was concentrated under reduced pressure and flash chromatographed (400 g silica gel,petroleum ether). The oil thus obtained was distilled (air-bath temperature 50-60 °C120 Torr)to yield 19.4 g (95%) of 4-chloro-2-trimethylstannyl-1-butene (45),80 as a colourless oil.3.2.2.3. Synthesis of 4-Iodo-2-trimethylgermyl- 1-butene (13):Me3Ge’CI Me3Ge’NTo a cold (-78 °C), stirred solution of 4-chloro-2-trimethylstannyl-1-butene (45) (3.80g, 15.0 mmol, 1 equiv.) in dry THF (75 mL) was added a solution of methyllithium in diethylether (1.46 M, 13.3 mL, 19.4 mmol, 1.3 equiv.). The solution was stirred at -78 °C for 0.5 h.129Bromotriniethylgermane (4.14 g, 21.0 mmol, 1.4 equiv.) was cannulated into the solution andthe resulting mixture was stirred at -78 °C for 2 h. Aqueous NH4C1 - NH4OH (pH 8-9, 50mL) and diethyl ether (60 mL) were added, the mixture was warmed to rt, and the layerswere separated. The aqueous phase was extracted with diethyl ether (3 x 50 mL) and thecombined organic extracts were washed with brine (1 x 50 mL), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The crude 4-chloro-2-trimethylgermyl-1-butene (50) was used immediately in the following step without furtherpurification.To a solution of the crude 4-chloro-2-trimethylgermyl-1-butene (50) (—15.0 mmolbased on the theoretical amount) in acetone (75 mL, unpurified HPLC grade) at P was addedsodium iodide (34.0 g, 225 mmol, 15 equiv. based on the vinyistannane chloride 45). Thesuspension was heated to reflux for 65 h and then cooled to ii. The acetone was removed byrotary evaporation and the residual material was dissolved in diethyl ether (75 mL) and water(75 mL). The layers were separated and the aqueous phase was extracted with diethyl ether(4 x 50 mL). The combined organic extracts were washed with brine (2 x 50 mL), dried overanhydrous magnesium sulfate, and concentrated under reduced pressure. The crude productwas subjected to flash chromatography (125 g silica gel, petroleum ether) and the oil thusobtained was distilled (air-bath temperature 80-90 °C115 Torr) to afford 3.75 g (84% from thevinylstannane chloride) of 4-iodo-2-trimethylgermyl-1-butene (13),81 as a colourless oil.‘H nmr (400 MHz) & 0.23 (s, 9H, -GeMe3), 2.73-2.78 (tt, 2H, J = 8, 1 Hz, allylic methyleneprotons), 3.18-3.22 (t, 2H, J = 8 Hz, ICU2CH2-), 5.32 (m, 1H, vinyl proton), 5.59 (m, 1H,vinyl proton).nmr (75.3 MHz) & -2.0 (-ye, -Ge(H3)3), 4.3, 41.4, 123.6 (H2=C-), 152.6 (CH2=-).Anal. calcd. for C7H l5GeO: C 28.14, H 5.06, 142.48; found: C 28.16, H 5.07,142.31.1303.2.3. SYNTHESIS OF 4-IODO-2-TRIMETHYLGERMYL-1-BUTENE (13) VIA APLATINUM CATALYZED HYDROGERMYLATION REACTION3.2.3.1. Synthesis of 3-Trimethylgermyl-3-buten- 1-ol (52):TMS——OTMS Me3GeOHTo a stirred solution of 4-trimethylsilyloxy-1-trimethylsilyl-1-butyne (51)82 (2.89 g,13.5 mmol, 1 equiv.) in dry CH2C12 (14 mL) at rt was added hydrogenhexachloroplatinate(IV) hydrate (H2PtC16•xH2O, 108 mg, 0.207 mmol, 1.5 mol%). Theresulting heterogeneous orange solution became a cloudy orange suspension within minutes.The suspension was cooled to 0 °C and trimethylgermane83(2.4 mL, 20 mmol, 1.5 equiv.)was added via a gas-tight syringe. The orange precipitate dissipated soon after the additionof Me3GeH. The solution was warmed to rt and stirred for 15 h. The reaction mixture wasfiltered (100 g silica gel, 300 mL diethyl ether as eluant) and the filtrate was concentratedunder reduced pressure. The residual material was dissolved in CH2C12 (135 mL). To thestirred solution was added p-TsOH•H2O (3.08 g, 16.2 mmol, 1.2 equiv.). The mixture waswarmed to 30 °C for 1 h. Saturated aqueous NaHCO3 (100 mL) was added and the layerswere separated. The aqueous layer was extracted with diethyl ether (3 x 300 mL) and ethylacetate (2 x 100 mL). The combined organic extracts were dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residual crude product waschromatographed84(150 g tic grade silica gel, 4:1 petroleum ether - ethyl acetate) and the oilthus obtained was distilled (air-bath temperature 80 °(Y20 Torr) to afford 1.8 g (7 1%) of 3-trimethylgermyl-3-buten-1-ol (52), as a colourless oil.IR (film): 3365, 1606, 1047, 825 cm4.131‘H nmr (400 MHz) : 0.23 (s, 9H, -Ge3), 1.40 (br s, 1H, -OH; this signal exchanges upontreatment with D20), 2.47-2.50 (br t, 2H, J = 6.5 Hz, aflylic methylene protons), 3.65-3.69(q, 2H, J = 6.5 Hz, HOCH2CH2-; this signal collapses to a triplet upon treatment with D20),5.34 (m, 1H, vinyl proton), 5.63 (m, 1H, vinyl proton).nmr (75.3 MHz) & 1.9 (-ye, -Ge(CH3)3), 40.4, 61.1, 124.6 (CH2=C-), 150.3 (CH2=C-).ExactMass calcd. for C6H l3GeO (M- Me): 175.0178; found: 175.0179.Anal. calcd. for C7H l6GeO: C 44.53, H 8.54; found: C 44.64, H 8.70.3.2.3.2. Synthesis of 4-Iodo-2-trimethylgermyl- 1-butene (13):Me3Ge’NTo a cold (0 °C), stirred solution of triphenyiphosphine (7.65 g, 29.2 mmol, 3.1equiv.) in dry diethyl ether (70 mL) and dry acetonitrile (23 mL) was added iodine (7.41 g,29.2 mmol, 3.1 equiv.) in two portions. A solution of the vinylgermane alcohol 52 (1.78 g,9.37 mmol, 1 equiv.) in dry diethyl ether (5 mL) was cannulated into the yellow suspension.The suspension was warmed to it and stirred for 15 mm. Saturated aqueous Na2S 203 (50mL) and diethyl ether (100 mL) were added and the layers were separated. The organicphase was washed with saturated aqueous Na25203 (2 x 75 mL), 10% aqueous CuSO4 (2 x75 mL), and water (1 x 75 mL). The combined aqueous layers were extracted with diethylether (3 x 75 mL) and the combined organic extracts were dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue was flash chromatographed(150 g silica gel, petroleum ether) and the oil thus obtained was distilled (air-bath132temperature 85-92 °C115 Torr) to provide 2.58 g (92%) of 4-iodo-2-trimethylgermyl-1-butene (13), as a colourless oil (spectral data are identical with those reported above).3.2.4. PREPARATION OF THE CUPRATE REAGENT 15:Me3G Cu (CN ) LiTo a cold (-98 °C), stirred solution of freshly distilled 4-iodo-2-trimethylgermyl- 1-butene (13) (886 mg, 2.97 mmol, 1 equiv.) in dry THF (40 mL) was rapidly added a solutionof tert-butyilithium in pentane (1.7 M, 3.4 mL, 5.8 mmol, 1.95 equiv.). The resultant clearyellow solution was stirred at -98 °C for 10 mm and was warmed to -78 °C. Copper(I)cyanide (279 mg, 3.12 mmol, 1.05 equiv.) was added in one portion and the suspensionbecame colourless. Brief warming (2-4 mm) of the reaction mixture at -35 °C provided alight tan homogeneous solution containing the cuprate reagent 15, which was cooled to -78°C and used immediately. CAUTION: While it is necessary for the solution to becomehomogeneous, prolonged warming will result in the decomposition of the cuprate reagent.3.2.5. GENERAL PROCEDURE 1: PREPARATION OF THE KETOVINYLGERMANES85To a cold (-78 °C), stirred solution of the cuprate reagent 15 (1.3 - 2 equiv., preparedas described above) in dry THF was added, dropwise, dry trimethylsilyl bromide (3 - 8equiv.). This was followed by the dropwise addition (via a large cannula) of a solution ofenone (1 equiv.) in dry THF (—1 mL per mmol of enone). The yellow-orange solution wasstirred at -78 °C until the reaction was complete, as determined by gic and/or tic analysis of133an aliquot. In some cases, warming of the solution was required for the reaction to reachcompletion. Water (—2 mL per mmol of enone) was added and the reaction mixture waswarmed to rt and stirred vigorously, open to the atmosphere, for 1 h until the hydrolysis ofthe silyl enol ether was complete (as indicated by tic analysis). Aqueous NH4CJ - NH4OH(pH 8-9, 15 mL per mmol of enone) and diethyl ether (20 mL per mmol of enone) wereadded and the mixture was stirred vigorously until the aqueous layer became bright blue incolour. The layers were separated and the aqueous layer was extracted with diethyl ether (3 x(—30 mL per mmol of enone)). The combined organic extracts were washed with brine (1 x(—30 mL per mmol of enone)), dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure. The crude product was flash chromatographed and the acquiredliquid was distilled to provide the desired keto vinylgermane.3.2.5.1. Synthesis of 3-[3-(trimethylgermyl)-3-butenyl]cyclohexanone (59):á_yGeMe3Following general procedure 1, a solution of the cuprate reagent 15 (2.97 mmol, 1.4equiv.) in dry THF (40 mL) was treated sequentially with trimethylsilyl bromide (1.00 g,6.53 mmol, 3 equiv.) and a solution of 2-cyclohexen-1-one (209 mg, 2.17 mmol, 1 equiv.) indry THF (2 mL). The reaction mixture was stirred at -78 °C for 4 h. The crude product wasflash chromatographed (70 g silica gel, 5.7:1 petroleum ether - diethyl ether) and the oil thusobtained was distilled (air-bath temperature 120-130 °CI0.2 Torr) to provide 519 mg (89%)of the keto vinylgermane 59,86 as a colourless oil.134‘H nmr (400 MHz) & 0.20 (s, 9H, -Ge3), 1.21-2.09 (m, 8H), 2.18-2.48 (m, 5H), 5.19 (m,1H, vinyl proton), 5.50 (m, 1H, vinyl proton).3.2.5.2. Synthesis of 3-Methyl-3-[3-(trimethylgermyl)-3-butenyl]cyclohexanone (60):0Me60GeMe3Following general procedure 1, a solution of the cuprate reagent 15 (3.38 mmol, 1.5equiv.) in dry THF (45 mL) was treated sequentially with trimethylsilyl bromide (1.00 g,6.53 mmol, 3 equiv.) and a solution of 3-methyl-2-cyclohexen-l-one (243 mg, 2.21 mmol, 1equiv.) in dry THF (2 mL). The reaction mixture was stirred at -78 °C for 4 h and subjectedto the workup conditions described in general procedure 1. ‘H nmr spectroscopic analysis ofthe crude product revealed the presence of a silyl enol ether function. The crude oil was thusdissolved in a mixture of THF (20 mL) and 5% hydrochloric acid (2 mL) and the solutionwas stirred at rt for 10 mm (at which point tic analysis confirmed the hydrolysis of the silylenol ether). Water (20 mL) and diethyl ether (40 mL) were added to the mixture and thelayers were separated. The aqueous layer was extracted with diethyl ether (4 x 75 mL) andthe combined organic extracts were dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The crude product was flash chromatographed (35 gsilica gel, 9:1 petroleum ether - diethyl ether) and the oil thus obtained was distilled (air-bathtemperature 117-120 °C/0.2 Torr) to afford 543 mg (95%) of the keto vinylgermane 60, as acolourless oil.JR (film): 1714, 1600, 1234, 825 cm1.135‘H nmr (400 MHz, C6D6) 6: 0.22 (s, 9H, -GeM3), 0.69 (s, 3H, Me), 1.07-1.28 (m, 4H),1.41-1.48 (m, 2H), 1.87-2. 10 (m, 6H), 5.23 (m, 1H, vinyl proton), 5.54 (m, 1H, vinyl proton).nmr (50.3 MHz, C6D6) 6: -1.7 (-ye, -Ge(H3)3), 21.1, 24.7 (-ye, Me), 31.5, 35.9, 38.2,40.8,41.8, 53.4, 122.1 (CH2C-), 154.0 (CH2=-), 208.7 (-C=O).Exact Mass calcd. for C13H23GeO (M- Me): 269.0961; found: 269.0965.Anal. calcd. for C14H26GeO: C 59.43, H 9.26; found: C 59.62, H 9.32.3.2.5.3. Synthesis of 3,5,5-Trimethyl-3- [3-(trimethylgermyl)-3-butenyl]cyclohexanone (61):Me%MeMe3a. Via Conjugate Addition of the Cuprate Reagent 15 to Isophorone (55) in thePresence of BF3•Et20:Following general procedure 1, a solution of the cuprate reagent 15 (1.28 mmol, 1.6equiv.) in dry THF (12 mL) was treated sequentially with BF3Et2O (110 p,L, 0.894 mmol,1.1 equiv.) and a solution of isophorone (55) (111 mg, 0.803 mmol, 1 equiv.) in dry THF (1mL). The yellow reaction mixture was stirred at -78 °C for 8 h and was warmed to -30 °Cover a period of 1.5 h. The crude product was subjected to flash chromatography (15 g silicagel, 9:1 petroleum ether - diethyl ether) and the oil thus obtained was distilled (air-bath136temperature 80-85 °CI0.2 Torr) to yield 47 mg (19%) of the keto vinylgermane 61,87 as acolourless oil.‘H nmr (400 MHz) 6: 0.20 (s, 9H, -Gey3), 1.04, 1.05, 1.07 (s, s, s, 3H each, tertiarymethyl groups), 1.30-1.48 (m, 2H), 1.55 (d, IH, J = 14.5 Hz, H-4), 1.62 (d, 1H, J = 14.5 Hz,H-4’), 2. 10-2.24 (m, 6H), 5.18 (m, 1H, vinyl proton), 5.50 (m, 1H, vinyl proton).l3 nmr (75.3 MHz) 6: -1.8 (-ye, -Ge(.H3)3), 27.1 (-ye, Me), 30.5 (-ye, Me), 31.3, 32.5(-ye, Me), 36.1, 38.7, 44.6, 49.2, 53.0, 54.2, 122.0 (.H2=C-), 154.0 (CH2=.-), 212.3(-c=O).Anal. calcd. for C16H300eO: C 61.78, H 9.72; found: C 61.96, H 9.68.b. Via Conjugate Addition of the Cuprate Reagent 15 to Isophorone (55) in thePresence of TMSBr:Following general procedure 1, a solution of the cuprate reagent 15 (2.25 mmol, 1.7equiv.) in dry THF (19 mL) was treated sequentially with trimethylsilyl bromide (614 mg,4.01 mmol, 3 equiv.) and a solution of isophorone (55) (185 mg, 1.34 mmol, 1 equiv.) in dryTHF (2 mL). The yellow reaction mixture was stirred at -78 °C for 8 h and was warmed to-20 °C over the course of 2 h, at which point the solution became colourless. The crudeproduct was flash chromatographed (35 g silica gel, 9:1 petroleum ether - diethyl ether) andthe oil thus obtained was distilled to afford 245 mg (59%) of the keto vinylgermane 61(spectral data are identical with those reported above).c. Via Conjugate Addition of the Cuprate Reagent 15 to Isophorone (55) in thePresence of TMSC1 and BF3’Et20:Following general procedure 1, a solution of the cuprate reagent 15 (1.81 mmol, 1.6equiv.) in dry THF (16 mL) was treated sequentially with BF3•Et20 (150 giL, 1.22 mmol, 1.1137equiv.), trimethylsilyl chloride (420 iL, 3.31 mmol, 3 equiv.), and a solution of isophorone(55) (152 mg, 1.10 mmol, 1 equiv.) in dry THF (1 mL). The yellow solution was stirred at-78 °C for 8 h and was warmed to -30 °C over 1.5 h. The crude product was flashchromatographed (35 g silica gel, 9:1 petroleum ether - diethyl ether) and the oil thusobtained was distilled to yield 224 mg (66%) of the keto vinylgermane 61 (spectral data areidentical with those reported above).d. Via Conjugate Addition of the Cuprate Reagent 15 to Isophorone (55) in thePresence of TMSBr and BF3•Et20:Following general procedure 1, a solution of the cuprate reagent 15 (2.18 mmol, 1.7equiv.) in dry THF (18 mL) was treated sequentially with BF3•Et20 (170 jiL, 1.38 mmol, 1.1equiv.), trimethylsilyl bromide (630 mg, 4.11 mmol, 3.2 equiv.), and a solution of isophorone(55) (175 mg, 1.27 mmol, 1 equiv.) in dry THF (1.5 mL). The yellow reaction mixture wasstirred at -78 °C for 8 h and was warmed to -30 °C over a period of 1.5 h. The crude productwas subjected to flash chromatography (35 g silica gel, 9:1 petroleum ether - diethyl ether)and the oil thus obtained was distilled to afford 283 mg (72%) of the keto vinylgermane 61(spectral data are identical with those reported above).3.2.5.4. Synthesis of (3R, 5R )-2-Methyl-5-(1-methylethenyl)-3-[3-(trimethylgermyl)-3-butenyl]-cyclohexanone (62):0 0Me4Following general procedure 1, a solution of the cuprate reagent 15 (2.45 mmol, 1.6equiv.) in dry THF (33 mL) was treated sequentially with trimethylsilyl bromide (615 mg,1384.02 mmol, 2.6 equiv.) and a solution of (R)-(-)-carvone (56) (230 mg, 1.53 mmol, 1 equiv.)in dry THF (1.5 mL). The reaction mixture was stirred at -78 °C for 3 h. The crude productwas subjected to flash chromatography (35 g silica gel, 9:1 petroleum ether - diethyl ether)and the oil thus obtained was distilled (air-bath temperature 96-100 °C/0.2 Torr) to afford471 mg (95%) of the keto vinylgermane 62,88 as a colourless oil. 1H nmr spectroscopicanalysis of the compound 62 revealed that it consisted of a —4:1 mixture of epimers at carbontwo.‘H nmr (400 MHz) 6: 0.19, 0.20 (s, s, ratio undetermined, 9H, -Gey3), 1.00, 1.11 (d, d,ratio —4:1, 3H, J = 7 Hz, secondary Me), 1.20-1.48 (m, 2H), 1.73 (br s, 3H, vinyl Me), 1.93-2.67 (m, 9H), 4.68, 4.72, 4.76, 4.80 (br s, br s, br s, br s, ratio —1:4:4:1, 2H, Ha and Hb), 5.15(m, 1H, Hc or Hd), 5.48 (m, 1H, Hc or Hcj).3.2.5.5. Synthesis of 2-Carbomethoxy-3-[3-(trimethylgermyl)-3-butenyl]cyclohexanone (63):o 0 0 OHbOGeMe357 63a 63bFollowing general procedure 1, a solution of the cuprate reagent 15 (1.28 mmol, 1.7equiv.) in dry THF (15 mL) was treated sequentially with trimethylsilyl bromide (352 mg,2.30 mmol, 3 equiv.) and a solution of 2-(carbomethoxy)-2-cyclohexen-1-one (57) (118 mg,0.765 mmol, 1 equiv.) in dry THF (1 mL). The reaction mixture was stirred at -78 °C for 2 h.Flash chromatography of the crude oil (25 g silica gel, 5.7:1 petroleum ether - diethyl ether)and removal of trace amounts of residual solvent (vacuum pump) from the resultant oilafforded 224 mg (90%) of the keto vinylgennane 63, as a colourless oil. The vinylgermane139compound 63 is unstable to heat and thus distillation was avoided. Analysis of the 1H nmrspectrum of compound 63 indicated a —5:1 mixture of tautomers 63a and 63b, respectively.IR(film): 1746, 1714, 1652, 1612, 1220, 1150, 827 cm-1.‘H nmr (400 MHz) & 0.20, 0.21 (s, s, ratio undetermined, 9H, -GeM3), 1.20-2.85 (m, 11H),3.12, 8.18 (d, s, ratio —5:1, 1H, J = 11.5 Hz, Ha and Hb, respectively), 3.69, 3.73 (s, s, ratio—5:1, 3H, -C(O)O), 5.13, 5.17 (m, m, ratio undetermined, vinyl protons), 5.48, 5.51 (m,m, ratio undetermined, vinyl protons).Exact Mass calcd. for C14H23GeO3 (M - Me): 313.0859; found: 313.0864.3.2.5.6. Synthesis of (3R, 5R )-2,3-Dimethyl-5-(1-methylethenyl)- 1 -trimethylsioxycyclohexene (72) and (2S, 3R, 5R)-2-(2-Bromo-2-propenyl)-2,3-dimethyl-5-(1-methylethenyl) -cyclohexanone (70):0 OTMS 0To a cold (-78 °C), stirred solution of methyllithium (1.53 M in diethyl ether, 4.4 mL,6.7 mmol, 4 equiv.) in dry THF (17 mL) was added solid CuBr•Me2S (686 mg, 3.34 mmol, 2equiv.). The resultant pale yellow solution was stirred at -78 °C for 50 mm. Trimethylsilylchloride (0.64 mL, 5.1 mmol, 3 equiv.) was added, followed by the dropwise addition of asolution of (R)-(-)-carvone (56) (254 mg, 1.69 mmol, 1 equiv.) in dry THF (1 mL). Thesolution was stirred at -78 °C for 3.5 h and Et3N (0.71 mL, 5.1 mmol, 3 equiv.) was added.140The solution was warmed to rt and pentane (20 mL) and aqueous NH4C1 - NH4OH (pH 8-9,15 mL) were added. The layers were separated and the aqueous phase was extracted withpentane (3 x 50 mL). The combined organic layers were washed with 0.1 M aqueous citricacid (3 x 25 mL), dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The product was distilled under reduced pressure (high vacuum) to yield 401 mg(99%) of the silyl enol ether 72, as a colourless oil. The silyl enol ether 72 was usedimmediately in the next step.‘H nmr (400 MHz) 6: 0.19 (s, 9H, -Si3), 1.04 (d, 3H, J = 8 Hz, secondary Me), 1.48-1.57(m, 2H), 1.58 (br s, 3H, vinyl Me), 1.73 (s, 3H, vinyl Me), 1.97-2.07 (m, 2H), 2.15-2.21 (m,1H), 2.36-2.43 (m, 1H), 4.69-4.72 (m, 2H, vinyl protons).To a cold (0 °C), stirred solution of the silyl enol ether 72 (189 mg, 0.793 mmol, 1equiv.) in dry THF (8 mL) was added a solution of methyllithium in diethyl ether (1.53 M,0.58 mL, 0.89 mmol, 1.1 equiv.). The resultant solution was stirred at 0 °C for 1.5 h andcooled to -20 °C. Dry HMPA (0.41 mL, 2.4 mmol, 3 equiv.) was added followed by theaddition of 2,3-dibromopropene (0.33 mL, 3.2 mmol, 4 equiv.). The solution was stirred at-20 °C for 2 h, 0 °C for 3.5 h, and was warmed to rt and left stirring overnight. Diethyl ether(50 mL) and saturated aqueous NH4C1 (50 mL) were added and the layers were separated.The aqueous phase was extracted with diethyl ether (2 x 50 mL) and the combined organiclayers were washed with brine (2 x 30 mL), dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The crude product was flash chromatographed (25 gsilica gel, 1.2:1 petroleum ether- CH2CI2) and the oil thus obtained was distilled (air-bathtemperature 100-105 °CI0.15 Torr) to provide 105 mg (46%) of the alkylated product 70, asingle diastereomer by ‘H nmr spectroscopy.141‘H nmr (400 MHz) 6: 0.92 (d, 3H, J = 8 Hz, secondary Me), 1.05 (s, 3H, tertiary Me), 1.57-1.65 (m, 1H), 1.75 (s, 3H, vinyl Me), 2.01-2. 10 (m, 1H), 2.15-2.23 (m, 1H), 2.35-2.42 (m,1H), 2.52-2.61 (m, 1H), 2.68-2.75 (dd, 1H, J = 12, 12 Hz), 2.80 (d, 1H, J = 14 Hz, allylicproton), 3.05 (d, 1H, J = 14 Hz, allylic proton), 4.72 (s, 1H, vinyl proton), 4.79 (s, 1H, vinylproton), 5.52 (m, 1H, vinyl proton), 5.56 (m, 1H, vinyl proton).3.2.6. GENERAL PROCEDURE 2A: PREPARATION OF THE KETO VINYL IODIDESFROM THE CORRESPONDING KETO VINYLGERMANESTo a stirred solution of the appropriate keto vinylgermane (1 equiv.) in dry CH2C12(21 mL per mmol of vinylgermane) at rt was added a solution of iodine in dry CH2C12 (0.04M, 1.5 equiv.). The dark purple reaction mixture was stirred at rt until the reaction wasdetermined to have reached completion (by gic and/or tlc analysis), usually overnight.Saturated aqueous Na2S 203 (-.40 mL per mmol of product) was added and the layers wereseparated. The aqueous phase was extracted with CH2C12 (3 x (40 mL per mmol ofproduct)) and the combined organic extracts were dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The crude product was subjected to flashchromatography and the oil thus obtained was distilled, or the residual traces of solvent wereremoved (vacuum pump), to yield the required keto vinyl iodide.3.2.7. GENERAL PROCEDURE 2B: PREPARATION OF THE KETO VINYL IODIDESFROM THE CORRESPONDING KETO VINYLGERMANES89To a stirred solution of the appropriate keto vinylgermane (1 equiv.) in dry CH2C12(25 mL per mmol of vinylgermane) at rt was added solid iodine (1.5 equiv.) in one portion.The remaining procedure is identical with that of general procedure 2a.1423.2.6.1. Synthesis of 3-(3-Iodo-3-butenyl)cyclohexanone (64):Following general procedure 2a, the keto vinylgermane 59 (507 mg, 1.88 mmol) wasconverted into the keto vinyl iodide 64. The crude product was flash chromatographed (73 gsilica gel, 5.7:1 petroleum ether - diethyl ether) and the residual solvent was removed(vacuum pump) from the acquired oil to yield 494 mg (94%) of the vinyl iodide 64,90 as acolourless oil.‘H nmr (400 MHz) & 1.30-1.40 (m, 1H), 1.45-1.70 (m, 3H), 1.73-1.95 (m, 2H), 1.98-2.06(m, 2H), 2.20-2.45 (m, 5H), 5.69 (m, 1H, vinyl proton), 6.02 (m, 1H, vinyl proton).3.2.7.1. Synthesis of 3-(3-Iodo-3-butenyl)-3-methylcyclohexanone (65):Following general procedure 2b, the keto vinylgermane 60 (1.12 g, 3.96 mmol) wastransformed into the corresponding keto vinyl iodide 65. The crude product was flashchromatographed (90 g silica gel, 5.7:1 petroleum ether - diethyl ether) and the oil thusobtained was distilled (air-bath temperature 94-98 °CI0.09 Torr) to afford 1.13 g (98%) of theketo vinyl iodide 65, as a colourless oil.143JR (film): 1713, 1618, 1229, 1102, 1050, 892 cm-1.‘H miir (400 MHz) & 0.94 (s, 3H, Me), 1.48-1.64 (m, 4H), 1.86-1.91 (m, 2H), 2.13 (d, 1H, J= 14 Hz, H-2), 2.20 (d, 1H, J = 14 Hz, H-2’), 2.29 (t, 2H, J =7 Hz), 2.34-2.40 (m, 2H), 5.67(br d, 1H, J = 1.5 Hz, vinyl proton), 6.02 (q, 1H, J = 1.5 Hz, vinyl proton).nmr (100.4 MHz) 6: 22.0, 24.8 (-ye, Me), 35.8, 38.1, 39.9, 40.9, 41.2, 53.6, 111.8(CH2=-), 125.4 (H2=C-), 211.6 (-=0).Exact Mass calcd. for Ci iH 1710: 292.0323; found: 292.0323.Anal. calcd. for Ci iH 1710: C 45.22, H 5.87, 143.44; found: C 45.18, H 5.93, I 43.22.3.2.6.2. Synthesis of 3-(3-Iodo-3-butenyl)-3,5,5-trimethylcyclohexanone (66):Following general procedure 2a, the keto vinylgermane 61 (399 mg, 1.28 mmol) wasconverted into the corresponding keto vinyl iodide 66. The product was subjected to flashchromatography (35 g silica gel, 5.7:1 petroleum ether - diethyl ether) and removal of traceamounts of solvent (vacuum pump) from the acquired oil yielded 390 mg (95%) of the desiredvinyl iodide 66,91 as a pale yellow oil.144‘H nmr (400 MHz) 5: 1.03, 1.05, 1.06 (s, s, s, 3H each, tertiary Me groups), 1.45-1.69 (m,4H), 2.11-2.25 (m, 4H), 2.35-2.47 (m, 2H), 5.67-5.68 (m, 1H, vinyl proton), 6.01-6.02 (m,1H, vinyl proton).3.2.6.3. Synthesis of (3R, 5R)-3-(3-Iodo-3-butenyl)-2-methyl-5-( 1 -methylethenyl)cyclo -hexanone (67):0Me:: Hb 67(Following general procedure 2a, the keto vinylgermane 62 (471 mg, 1.46 mmol) wasconverted into the corresponding keto vinyl iodide 67. The crude product was flashchromatographed (35 g silica gel, 5.7:1 petroleum ether - diethyl ether) and removal of traceamounts of solvent (vacuum pump) from the resultant liquid afforded 464 mg (97%) of theketo vinyl iodide 67.92 Analysis of the ‘H nmr spectrum revealed that the slightly yellow oilconsisted of a —1.5:1 mixture of epimers at carbon two.‘H nmr (400 MHz) & 1.05, 1.13 (d, d, ratio —1.5:1, 3H, J = 8 Hz, secondary Me), 1.02-1.25(m, 1H), 1.42-1.51 (m, 1H), 1.55-1.75 (m, 2H), 1.74, 1.76 (br s, br s, ratio undetermined, 3H,vinyl methyl protons), 1.87-2.02 (m, 1H), 2.07-2.65 (m, 6H), 4.66, 4.73, 4.75, 4.78 (br s, br s,br s, br s, ratio —1:1.5:1.5:1, 2H, Ha and Hb), 5.68 (m, 1H, He orHd), 6.01 (m, 1H, Hc orHj).13C nmr (75.3 MHz) & 11.7 (-ye), 14.1 (-ye), 20.6 (-ye), 21.5 (-ye), 26.3, 31.2, 32.9, 33.1,38.6 (-ye), 39.3 (-ye), 40.4 (-ye), 40.8 (-ye), 42.4, 42.8, 43.6, 46.1, 48.4 (-ye), 49.4 (-ye),145110.0, 110.1, 111.4, 111.5, 125.8, 125.9, 146.8, 147.2, 212.5, 213.3.Anal. calcd. for C14H2110: C 50.61, H 6.37, I 38.20; found: C 50.69, H 6.35, I 38.38.3.2.6.4. Synthesis of 2-Carbomethoxy-3-(3-iodo-3-butenyl)cyclohexanone (68):0 0 OHOllHaIl b10Me-.. ThMe68a 68bFollowing general procedure 2a, a mixture of the keto vinylgermanes 63a and 63b(292 mg, 0.893 mmol) was converted into the corresponding mixture of keto vinyl iodides68a and 68b. The crude product was flash chromatographed (25 g silica gel, 5.7:1 petroleumether - diethyl ether) to yield, after removal of residual solvent (vacuum pump) from theresultant liquid, 283 mg (94%) of the keto vinyl iodides 68a and 68b. Analysis of the ‘H nmrspectrum of the product indicated a —2.5:1 mixture of the tautomers 68a and 68b,respectively.IR(film): 1746, 1713, 1653, 1615, 1440,1260,1221,1149cm-’.‘H nmr (400 MHz) 6: 1.40-2.83 (m, 11H), 3.12, 8.16 (d, s, ratio —2.5:1, 1H, J = 11.5 Hz, Haand Hb respectively), 3.69, 3.61 (s, s, ratio —2.5:1, 3H, -C(O)OM), 5.68, 5.70 (m, m, ratioundetermined, 1H, vinyl proton), 5.90, 6.10 (m, m, ratio undetermined, 1H, vinyl proton).ExactMass calcd. for C12H 17103: 336.0222; found: 336.0220.1463.2.8. GENERAL PROCEDURE 3: Pd(0)-CATALYZED CYCLIZATION REACTION OFTHE KETO VINYL IODIDES93To a stirred solution of the appropriate keto vinyl iodide (1 equiv.) in dry THF (10 mLper mmol of vinyl iodide) at rt was added solid tetrakis(triphenylphosphine)palladium(0)94(20-30 mol% with respect to the starting vinyl iodide). The reaction mixture was stirred for10 mm until a light brown homogeneous solution resulted. A solution of t-BuOK(commercial, Aldrich) in a 4:1 mixture of dry THF and dry t-BuOH (—0.24 M, 1.15 equiv.)was added, via syringe pump, over the course of —4 h. Potassium iodide precipitated from themixture as the reaction proceeded. After the mixture had been stirred for an additional 1-2 hat rt, diethyl ether (25 mL per mmol of the vinyl iodide) and brine (20 mL per mmol of thevinyl iodide) were added. The layers were separated and the aqueous layer was extracted withdiethyl ether (3 x (30 mL per mmol of the vinyl iodide)). The combined organic extracts werewashed with brine (1 x (30 mL per mmol of the vinyl iodide)), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The crude material was flashchromatographed and distilled to give the desired bicycic product.3.2.8.1. Synthesis of 9-Methylbicyclo[4.3.0]non-9-en-2-one (74):a. Via the Pd(0)-Catalyzed Cyclization Reaction Described in General Procedure 3:Following general procedure 3, the keto vinyl iodide 64 (479 mg, 1.72 mmol) wasconverted to the bicyclic enone 74 by employing 475 mg of Pd(PPh3)4 (0.411 mmol, 24mol%). The crude product was flash chromatographed (35 g silica gel, 9:1 petroleum ether -diethyl ether) and the oil thus obtained was distilled (air-bath temperature 125-135 °C/20Torr) to afford 166 mg (64%) of the bicyclic enone 74•95147‘H nmr (400 MHz) 6: 1.20-1.31 (dq, 1H, J = 3, 13 Hz), 1.41-1.52 (m, 1H), 1.68-1.81 (m,1H), 1.93-2.32 (m, 5H), 2.08 (br s, 3H, vinyl Me), 2.39-2.50 (m, 2H), 2.8 1-2.92 (m, 1H).b. Via the Pd(0)-Catalyzed Cyclization Reaction Employing Modified Conditions(high dilution (0.008 M)):To a stirred solution of the keto vinyl iodide 64 (130 mg, 0.47 mmol, 1 equiv.) in dryTHF (58 mL, 0.008 M dilution) at rt was added Pd(PPh3)4 (141 mg, 0.122 mmol, 26 mol%).A solution of t-BuOK in a 4:1 mixture of dry THF and dry t-BuOH (0.20 M, 2.7 mL, 0.54mmol, 1.15 equiv.) was added, via syringe pump, over the course of 3.5 h. The mixture wasstirred for an additional 15 mm at rt and then subjected to the workup conditions as describedin general procedure 3. The crude product was flash chromatographed (15 g silica gel, 9:1petroleum ether - diethyl ether) and the oil thus obtained was distilled (air-bath temperature125-135 °C120 Torr) to yield 37 mg (52%) of the bicyclic enone 74 (spectral data are identicalwith those reported above).c. Via the Pd(0)-Catalyzed Cyclization Reaction Employing Modified Conditions(high dilution (0.008 M) and no t-BuOH present in the base mixture):To a stirred solution of the keto vinyl iodide 64 (146 mg, 0.525 mmol, 1 equiv.) in dryTHF (65 mL, 0.008 M dilution) at rt was added Pd(PPh3)4 (135 mg, 0.117 mmol, 22 mol%).A solution of t-BuOK in dry THF (0.20 M, 3.0 mL, 0.60 mmol, 1.15 equiv.) was added, viasyringe pump, over the course of 3.5 h. The mixture was stirred for an additional 4 h at rt andwas then subjected to the workup conditions as described in general procedure 3. The crudeproduct was flash chromatographed (25 g silica gel, 9:1 petroleum ether - diethyl ether) andthe oil thus obtained was distilled (air-bath temperature 125-135 °C/20 Torr) to yield 33 mg(42%) of the bicyclic enone 74 (spectral data are identical with those reported above).1483.2.8.2. Synthesis of 6,9-Dimethylbicyclo[4.3.Ojnon-9-en-2-one (75):Me75Following general procedure 3, the keto vinyl iodide 65 (153 mg, 0.524 mmol) wasconverted into the bicyclic enone 75 by employing 138 mg of Pd(PPh3)4 (0.119 mmol, 23mol%). The crude product was flash chromatographed (25 g silica gel, 9:1 petroleum ether -diethyl ether) and the oil thus obtained was distilled (air-bath temperature 64-68 °CI0. 1 Tort)to yield 56 mg (65%) of the bicycic enone 75, as a colourless oil.JR (film): 1679, 1627, 1454,1216,1124cm-.nmr (400 MHz, C6D6) 6: 0.83 (s, 3H, angular Me), 1.21-1.28 (dt, IH, J = 2.5, 13 Hz),1.40-1.63 (m, 5H), 1.81-1.88 (dd, 1H, J =18, 9 Hz), 1.93-2.02 (m, 1H), 1.99 (br s, 3H, vinylMe), 2.21-2.30 (m, 1H), 2.3 1-2.37 (m, 1H).nmr (75.3 MHz, C6D6) 6: 16.0 (-ye), 21.5, 24.3 (-ye), 36.4, 38.8, 40.7, 41.6, 48.7, 140.6,148.2, 198.9 (C-2).ExactMass calcd. for C11H 160: 164.1201; found: 164.1198.Anal. calcd. for Ci 1160: C 80.44, H 9.82; found: C 80.57, H 9.88.1493.2.8.3. Synthesis of 4,4,6,9-Tetramethylbicyclo[4.3.O]non-9-en-2-one (76):Me Me76Following general procedure 3, the keto vinyl iodide 66 (328 mg, 1.02 mmol) wasconverted into the corresponding bicyclic enone 76 by employing 236 mg of Pd(PPh3)4(0.204 mmol, 20 mol%). The crude product was flash chromatographed (35 g silica gel, 9:1petroleum ether - diethyl ether) and the oil thus obtained was distilled (air-bath temperature135-140 °C120 Torr) to afford 164 mg (83%) of the bicycic enone 76,96 as a colourless oil.‘H mnr (400 MHz) & 0.93, 1.03, 1.10 (s, s, s, 3H each, tertiary Me groups), 1.58-1.90 (m,4H), 2.08 (br s, 3H, vinyl Me), 2.13-2.28 (m, 3H), 2.49-2.59 (m, 1H).l3 nmr (75.3 MHz) 6: 16.4 (-ye, Me), 28.8 (-ye, Me), 29.4 (-ye, Me), 31.6 (-ye, Me), 32.9,37.1, 43.2, 46.7, 51.6, 53.6, 139.1, 152.0, 200.5 (C-2).Anal. calcd. for C13H200: C 81.20, H 10.48; found: C 80.96, H 10.47.1503.2.8.4. Synthesis of (iS, 4R, 6R)- 1 -Methyl-9-methylene-4-(1-methylethenyl)bicyclo[4.3.0] -nonan-2-one (77):OHCJHd2r9\HaXja. Via the Pd(0)-Catalyzed Cyclization Reaction Employing 19 mol% Pd(PPh3)4:Following general procedure 3, the keto vinyl iodide 67 (88 mg, 0.265 mmol) wasconverted into the bicycic ketone 77 by employing 58 mg of Pd(PPh3)4 (0.050 mmol, 19mol%). Flash chromatography (15 g silica gel, 9:1 petroleum ether - diethyl ether) of thecrude product and distillation (air-bath temperature 130-135 °C120 Torr) of the oil thusobtained provided 43 mg (80%) of the bicyclic ketone 77,97 as a colourless oil.‘H nmr (400 MHz) 8 1.22 (s, 3H, angular Me), 1.45-1.57 (m, 1H), 1.70-1.90 (m, 3H), 1.73(br s, 3H, vinyl Me), 2.09-2. 17 (dt, 1H, J 12, 6 Hz), 2.35-2.53 (m, 4H), 2.58-2.63 (m, 1H),4.68 (br 5, 1H, Ha or Hb), 4.82 (m, 2H, Ha or Hb and Hc or Hd), 5.00 (t, 1H, J 2 Hz, Hc orHd).b. Via the Pd(0)-Catalyzed Cyclization Reaction Employing 15 mol% Pd(PPh3)4:Following general procedure 3, the keto vinyl iodide 67 (98 mg, 0.29 mmol, 1 equiv.)was converted into the bicycic enone 77 by employing 53 mg of Pd(PPh3)4 (0.046 mmol, 15mol%). The crude product was flash chromatographed (15 g silica gel, 9:1 petroleum ether -diethyl ether) and the oil thus obtained was distilled (air-bath temperature 130-135 °C/20Torr) to afford 44 mg (73%) of the bicyclic enone 77 (spectral data are identical with thosereported above).151c. Via the Pd(0)-Catalyzed Cyclization Reaction Employing 10 mol% Pd(PPh3)4:Following general procedure 3, the keto vinyl iodide 67 (94 mg, 0.28 mmol, 1 equiv.)was converted into the bicyclic enone 77 by employing 35 mg of Pd(PPh3)4 (0.030 mmol, 10mol%). The crude product was flash chromatographed (15 g silica gel, 9:1 petroleum ether -diethyl ether) and the oil thus obtained was distilled (air-bath temperature 130-135 °C120Torr) to afford 40 mg (70%) of the bicyclic enone 77 (spectral data are identical with thosereported above).d. Via the Pd(0)-Catalyzed Cyclization Reaction Employing 5 mol% Pd(PPh3)4:Following general procedure 3, the keto vinyl iodide 67 (93 mg, 0.28 mmol, 1 equiv.)was converted into the bicycic enone 77 by employing 15 mg of Pd(PPh3)4 (0.013 mmol, 5mol%). The crude product was flash chromatographed (15 g silica gel, 9:1 petroleum ether -diethyl ether) and the oil thus obtained was distilled (air-bath temperature 130-135 °C/20Torr) to afford 30 mg (52%) of the bicydic enone 77 (spectral data are identical with thosereported above).e. Via the Pd(0)-Catalyzed Cyclization Reaction Employing CuCl as an Additive:To a stirred solution of the keto vinyl iodide 67 (83 mg, 0.25 mmol, 1 equiv.) in dryTHF (2.5 mL) at rt was added sequentially Pd(PPh3)4 (14 mg, 0.012 mmol, 5 mol%) andCuCl (1.3 mg, 0.013 mmol, 5 mol%). A solution of t-BuOK in a 4:1 mixture of dry THF anddry t-BuOH (0.24 M, 1.2 mL, 0.29 mmol, 1.15 equiv.) was added, via syringe pump, over thecourse of 3 h. After the mixture was stirred for an additional 6 h at rt, tlc analysis indicatedthat the keto vinyl iodide 67 had not been consumed. An additional 14 mg of Pd(PPh3)4 (5mol%), 1.4 mg of CuC1 (5 mol%), and 0.3 mL of the t-BuOK solution (0.3 equiv., added over1 h via syringe pump) were added and the mixture was stirred at ii overnight. Analysis (tlc)confinned that the vinyl iodide 67 had been consumed and the mixture was subjected to theworkup conditions as described in general procedure 3. The crude product was flash152chromatographed (15 g silica gel, 9:1 petroleum ether - diethyl ether) and the oil thus obtainedwas distilled (air-bath temperature 130-135 °C120 Torr) to afford 16 mg (32%) of the bicyclicenone 77 (spectral data are identical with those reported above).f. Via the Pd(0)-Catalyzed Cyclization Reaction Employing Pd2(dba)3JPPh3 as theCatalyst:To a stirred solution of Pd2(dba)398(21 mg, 0.048 mmol of Pd, 20 mol%) in dry THF(1.2 mL) at rt was added solid PPh3 (24 mg, 0.092 mmol, 38 mol%, —2:1 ratio of PPh3:Pd).The red solution was stirred for 10 mm and a solution of the keto vinyl iodide 67 (80 mg, 0.24mmol, 1 equiv.) in dry THF (1.2 mL) was added via a large cannula. A solution of t-BuOK ina 4:1 mixture of dry THF and dry t-BuOH (0.24 M, 1.2 mL, 0.28 mmol, 1.15 equiv.) wasadded, via syringe pump, over the course of 3 h. The reaction mixture was stirred for anadditional 1 h at rt and was subjected to the workup conditions as described in generalprocedure 3. The crude product was flash chromatographed (15 g silica gel, 9:1 petroleumether - diethyl ether) and the oil thus obtained was distilled (air-bath temperature 130-135°C/20 Torr) to provide 32 mg (65%) of the bicyclic ketone 77 (spectral data are identical withthose reported above).g. Via the Pd(0)-Catalyzed Cyclization Reaction Employing Pd2(dba)3IPh3As as theCatalyst:To a stirred solution of Pd2(dba)398 (24 mg, 0.052 mmol of Pd, 20 mol%) in dry THF(1.2 mL) at rt was added solid Ph3As (32 mg, 0.10 mmol, 40 mol%, —2:1 ratio of Ph3As:Pd).The yellowish brown solution was stirred for 10 mm and a solution of the keto vinyl iodide 67(85 mg, 0.26 mmol, 1 equiv.) in dry THF (1 mL) was added via a large cannula. A solution oft-BuOK in a 4:1 mixture of dry THF and dry t-BuOH (0.09 M, 3.0 mL, 0.27 mmol, 1.05equiv.) was added, via syringe pump, over the course of 3 h. The reaction mixture was stirredat P for an additional 43 h and was subjected to the workup conditions as described in generalprocedure 3. The crude product was flash chromatographed (25 g silica gel, 9:1 petroleum153ether - diethyl ether) to provide 4 mg (8%) of the bicyclic ketone 77 (spectral data areidentical with those reported above).Vo767ah. Via the Pd(0)-Catalyzed Cyclization Reaction Employing Pd2(dba)3)Tri(2-furyl)-phosphine (67a) as the Catalyst:To a stirred solution of Pd2(dba)398(17 mg, 0.037 mmol of Pd, 20 mol%) in dry THF(1 mL) at rt was added solid tri(2-furyl)phosphine99(67a) (17 mg, 0.074 mmol, 38 mol%,—2:1 ratio of tri(2-furyl)phosphine:Pd). The yellowish brown solution was stirred for 10 mmand a solution of the keto vinyl iodide 67 (63 mg, 0.19 mmol, 1 equiv.) in dry THF (1.2 mL)was added via a large cannula. A solution of t-BuOK in a 4:1 mixture of dry THF and dry tBuOH (0.24 M, 0.9 mL, 0.22 mmol, 1.15 equiv.) was added, via syringe pump, over thecourse of 2.5 h. The reaction mixture was stirred at rt for an additional 8 h and was subjectedto the workup conditions as described in general procedure 3. The crude product was flashchromatographed (15 g silica gel, 9:1 petroleum ether - diethyl ether) to provide 13 mg (34%)of the bicydic ketone 77 (spectral data are identical with those reported above).(>-O%P67bi. Via the Pd(0)-Catalyzed Cyclization Reaction Employing Pd2(dba)3lTriisopropyl-phosphite (6Th) as the Catalyst:To a stirred solution of Pd2(dba)398(24 mg, 0.052 mmol of Pd, 20 mol%) in dry THF(0.8 mL) at rt was added triiisopropylphosphite100(6Th) (26 .iL, 0.10 mmol, 40 mol%, —2:1ratio of triisopropylphosphite:Pd). The yellowish green solution was stirred for 10 mm and a154solution of the keto vinyl iodide 67 (88 mg, 0.26 mmol, 1 equiv.) in dry THF (1.8 mL) wasadded via a large cannula. A solution of t-BuOK in a 4:1 mixture of dry THF and dry t-BuOH(0.24 M, 1.3 mL, 0.31 mmol, 1.2 equiv.) was added, via syringe pump, over the course of 3.5h. The reaction mixture was stirred at rt for an additional 10 h and was subjected to theworkup conditions as described in general procedure 3. The crude product was flashchromatographed (15 g silica gel, 9:1 petroleum ether - diethyl ether) to provide 9 mg (16%)of the bicycle ketone 77 (spectral data are identical with those reported above).j. Via the Pd(0)-Catalyzed Cyclization Reaction Employing PdC12(dppf) as theCatalyst:To a stirred solution of PdC12(dppf)’° (39 mg, 0.053 mmol, 18 mol%) in dry THF(1.0 mL) at rt was added a solution of the keto vinyl iodide 67 (97 mg, 0.29 mmol, 1 equiv.) indry THF (2.0 mL). A solution of t-BuOK in a 4:1 mixture of dry THF and dry t-BuOH (0.24M, 1.4 mL, 0.34 mmol, 1.15 equiv.) was added, via syringe pump, over the course of 4 h. Thereaction mixture was stirred at rt for an additional 50 h and was subjected to the workupconditions as described in general procedure 3. The crude product was flash chromatographed(15 g silica gel, 9:1 petroleum ether - diethyl ether) to provide 4 mg (6%) of the bicyclicketone 77 (spectral data are identical with those reported above).k. Via the Pd(0)-Catalyzed Cyclization Reaction Employing Pd(OAc)2IPPh3 as theCatalyst:To a stirred solution of the keto vinyl iodide 67 (77 mg, 0.23 mmol, 1 equiv.) in dryTHF (2.3 mL) was added solid Pd(OAc)2 (11 mg, 0.05 mmol, 20 mol%) and PPh3 (26 mg,0.10 mmol, 40 mol%). A solution of t-BuOK in a 4:1 mixture of dry THF and dry t-BuOH(0.24 M, 1.1 mL, 0.27 mmol, 1.15 equiv.) was added, via syringe pump, over the course of 4h. The reaction mixture was stirred at rt for an additional 48 h and was subjected to theworkup conditions as described in general procedure 3. ‘H nmr spectroscopic analysis of the155crude product indicated that there was only a trace amount of the desired bicyclic ketone 77present.0Me1. Via the Cydization Reaction Employing a Stoichiometric Amount of Ni(COD)2:To a flask containing Ni(COD)2’°2(75 mg, 0.27 mmol, 1.1 equiv.) was added asolution of the vinyl iodide 67 (84 mg, 0.25 mmol, 1 equiv.) in dry THF (3.5 mL). To theresultant black solution was added, via syringe pump (3 h), a solution of t-BuOK in a 4:1mixture of dry THF and dry t-BuOH (0.24 M, 1.1 mL, 0.27 mmol, 1.15 equiv.). The reactionmixture was stirred at rt overnight and was subjected to the workup conditions as describedin general procedure 3. The crude product was flash chromatographed (15 g silica gel, 9:1petroleum ether - diethyl ether) to provide, after removal of trace amounts of solvent from theresultant oil, 36 mg (70%) of the keto acetylene 80, as a colourless oil. None of the desiredbicyclic ketone 77 was obtained. ‘H nmr spectroscopic analysis of the acetylene 80 revealedthat it consisted of a — 1:1 mixture of epimers at carbon two.IR (film): 3296, 2117, 1709, 1646, 1455, 1217, 896 cm.‘H nmr (400 MHz) & 1.04, 1.15 (d, d, ratio —1:1, 3H, J = 7.5 Hz, secondary Me), 1.16-1.30(m, 2H), 1.42-1.70 (m, 2H), 1.77 (br s, 3H, vinyl Me), 1.77-1.83 (m, 1H), 1.97 (br s, 1H,acetylenic proton), 2.00-2.71 (m, 6H), 4.71, 4.75, 4.79, 4.83 (s, s, s, s, ratio —1:1:1:1, 2H,vinyl protons).1563.2.8.5. Synthesis of (1 R *, 6S*) 1 -Carbomethoxy-9-methylenebicyclo[4.3.0}nonan-2-one(78):0 11\OMeO12a. Via the Pd(0)-Catalyzed Cyclization Reaction Employing Pd(PPh3)4 as theCatalyst and C52CO3 as the Base:To a stirred suspension of flame dried Cs2CO3103 (330 mg, 1.01 mmol, 5.1 equiv.) indry THF (1 mL) at rt was added a solution of the vinyl iodide 68 (67 mg, 0.20 mmol, 1 equiv.)in dry THF (1 mL). Pd(PPh3)4 (66 mg, 0.057 mmol, 28 mol%) was added to the mixture inone portion and the suspension was heated to 50-60 °C for 6 h. The mixture was cooled to rt,and diethyl ether (15 mL) and water (15 mL) were added to the suspension. The layers wereseparated and the aqueous phase was extracted with diethyl ether (3 x 25 mL). The combinedorganic extracts were washed with brine (1 x 25 mL), dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The crude product was subjected to flashchromatography (14 g silica gel, 5.7:1 petroleum ether - diethyl ether) and the oil thusobtained was distilled (air-bath temperature 110-120 °C/20 Torr) to yield 18 mg (43 %) of thebicyclic keto ester 78, as a colourless oil.JR (film): 1719, 1653, 1435, 1250, 899 cm1.‘H nmr (400 MHz) & 1.49-1.59 (m, ill), 1.64-1.73 (m, 1H), 1.80-1.99 (m, 3H), 2.32-2.53 (m,5H), 3.00-3.08 (br dt, 1H, J = 12, 6 Hz), 3.76 (s, 3H, Me-li), 4.96 (m, 1H, H-12), 5.24 (m,1H, H-12’).157nmr (75.3 MHz) & 23.9, 26.0, 28.2, 29.7, 39.4, 477 (-ye), 52.7 (-ye), 71.9, 112.0 (C-12),147.9 (C-9), 171.2 (C-b), 206.1 (C-2).ExactMass calcd. for C12H 1603: 208.1099; found: 208.1092.Anal. calcd. for C12H 1603: C 69.21, H 7.74; found C 68.82, H 7.75.b. Via the Pd(0)-Catalyzed Cyclization Reaction Employing Pd2(dba)3/PPh3 as theCatalyst and C52CO3 as the Base:To a flask containing flame dried Cs2CO3 (270 mg, 0.829 mmol, 5.3 equiv.) wasadded sequentially Pd2(dba)398(14 mg, 0.032 mmol, 20 mol%), dry THF (0.4 mL), andPPh3 (16 mg, 0.061 mmol, 38 mol%, —2:1 ratio of PPh3:Pd). The yellow/orange suspensionwas stirred at rt for 5 mm and a solution of the vinyl iodide 68 (53 mg, 0.16 mmol, 1 equiv.)in dry THF (1.2 mL) was added. The mixture was heated to 52 °C for 5 h. As described inthe above procedure, the reaction mixture was worked up and the crude product was purifiedto yield 15 mg (47%) of the bicyclic keto ester 78 (spectral data are identical with thosereported above).1583.2.8.6. Synthesis of (1 S, 2R, 4R, 5 S)- 1 ,2-Dimethyl-6-methylene-4-( 1 -methylethenyl)bicyclo -[3.2.1]heptan-8-one (81):Br12%32e70 13 81To a stirred solution of the vinyl bromide 70 (52 mg, 0.18 mmol, 1 equiv.) in dry ThF(4 mL) at ii was added solid Pd(PPh3)4 (61 mg, 0.053 mmol, 29 mol%). The reactionmixture was stirred for 10 mm until a light brown homogeneous solution resulted. A solutionof t-BuOK in a 4:1 mixture of dry THF and dry t-BuOH (0.1 M, 1.8 mL, 0.18 mmol, 1equiv.) was added, via syringe pump, over the course of 3 h. The reaction mixture was stirredat rt for an additonal 1 h and was subjected to the workup conditions as described in generalprocedure 3. The crude product was flash chromatographed (15 g silica gel, 9:1 petroleumether- diethyl ether) to provide 2 fractions. The first compound eluted was the bicyclicproduct 81. The appropriate fractions were concentrated and the oil thus obtained wasdistilled (air-bath temperature 115-120 °C/20 Torr) to yield 19 mg (51%) (70% based onconsumed starting material) of the bridged bicyclic keto alkene 81, as a colourless oil.IR (film): 3089, 1752, 1654, 1454, 1096, 885 cmi.‘H nmr (400 MHz) 8: 0.90 (d, 3H, J = 8 Hz, Me-lO), 1.04 (s, 3H, Me-9), 1.22-1.29 (dd, 1H,J = 14, 6 Hz, H-3), 1.74 (br s, 3H, Me-l2), 1.91-1.97 (m, 1H, H-3’), 2.00-2.05 (m, 1H, H-2),2.49 (br d, 1H, J = 16 Hz, H-7), 2.52 (br d, 1H, J = 16 Hz, H-7’), 2.70 (br d, 1H, J = 12 Hz,H-4), 2.79 (br s, 1H, H-5), 4.65 (br s, 1H, H-13), 4.69 (br s, 1H, H-i4), 4.78 (br s, 1H, H-13’),5.13 (br s, 1H, H-14’).159Detailed 1H nmr data, derived from COSY and NOE experiments, are given in Table 20.Table 20: 1H nmr Data (400 MHz, CDC13) for the Bridged Keto Alkene 81: COSY andNOE Experiments146071294 32‘1081= eH MeAssignment nmr (400 MHz) COSY Correlationsa NOEH-x 6 ppm (mult., J (Hz)) CorrelationsaMe-lO 0.90 (d, J =8) H-2 H-4Me-9 1.04 (s) H-2, H-7H-3 1.22-1.29 (dd, J = 14, 6) HYb, H-4Me-12 1.74(brs) H-13,H-13’H-3’ 1.9 1-1.97 (m) H-2, H-3, H-4H-2 2.00-2.05 (m) Me-lOH-7 2.49 (hr d, J = 16) H-7’, H-14, H-14’H-T 2.52 (br d, J = 16) H-7, H-14, H-14’H-4 2.70 (br d, J = 12) H-3, H-Y, H-5H-5 2.79(m) H-4,H-14,H-14’H-13 4.65 (hr s) Me-12, H-13’H-14 4.69 (hr s) H-5, H-7, H-7’, H-14’H-13’ 4.78 (hr s) Me-12, H-13H-14’ 5.13 (hr s) H-5, H-7, H-T, H-14a- Only those COSY correlations and NOE data that could be assigned are recorded.b- H indicates the hydrogen of a pair which is more downfield (H-3’ is more downfield than H-3).The second compound to be eluted from the column chromatography was the startingbromide 70. The appropriate fractions were concentrated to afford 14 mg of compound 70.1603.3. ATTEMPTS AT SYNTHESIS OF SIX-MEMBERED RINGS VIA APALLADIUM(O)-CATALYZED INTRAMOLECULAR COUPLING REACTION3.3.1. SYNTHESIS OF 5-IODO-2-TRIMETHYLGERMYL-1-PENTENE (31) VIA THECORRESPONDING VINYLSTANNANE COMPOUND3.3.1.1. Synthesis of 5-Chloro-2-trimethylstannyl- 1 -pentene (83a):M S82e383aTo a cold (-20 °C), stirred solution of hexamethylditin (102 g, 0.3 11 mol, 1 equiv.) indry THF (1.3 L) was added a solution of methyllithium in diethyl ether (1.27 M, 245 mL,0.311 mol, 1 equiv.). The resultant yellow solution was stirred at -20 °C for 30 mm andcooled to -78 °C. Solid CuBr•Me2S (64.0 g, 0.311 mol, 1 equiv.) was added in one portionand the reddish brown mixture was stirred at -78 °C for 30 mm. A solution of 5-chloro- 1-pentyne (82) (33.0 g, 0.3 11 mol, 1 equiv.) in dry THF (10 mL) was added, via a droppingfunnel, over the course of 40 mm. The reaction mixture was stirred at -78 °C for 8 h andglacial acetic acid (89.0 mL, 1.55 mmol, 5 equiv.) was added. The resultant mixture wasstirred at -78 °C for 20 mm, was warmed to rt, and was poured into a stirred suspension ofaqueous NH4C1 - NH4OH (pH 8-9, 1 L) and diethyl ether (1 L). The mixture was stirred,open to the atmosphere, overnight. The layers were separated and the bright blue aqueousphase was extracted with diethyl ether (2 x 1 L). The combined organic extracts werewashed with aqueous NH4C1 - NH4OH (pH 8-9, 1 x 1 L) and brine (1 x 1 L), dried overanhydrous magnesium sulfate, and concentrated under reduced pressure. The crude materialwas subjected to drip chromatography (1.75 Kg silica gel, petroleum ether) and the oil thusobtained was distilled (air-bath temperature 50-55 °C/20 Torr) to afford 55 g (66%) of 5-chloro-2-trimethylstannyl-1-pentene (83a).1041613.3.1.2. Synthesis of 5-Iodo-2-trimethylgermyl- 1 -pentene (31):Me3Ge- Me3GTo a cold (-78 °C), stirred solution of 5-chloro-2-trimethylstannyl-1-pentene (83a)(2.27 g, 8.49 mmol, 1 equiv.) in dry THF (42 mL) was added a solution of methyllithium indiethyl ether (1.31 M, 8.10 mL, 10.6 mmol, 1.25 equiv.). The colourless solution was stirredat -78 °C for 0.5 h. Bromotrimethylgermane (2.48 g, 12.5 mmol, 1.47 equiv.) was cannulatedinto the solution and the resultant mixture was stirred at -78 °C for 2.5 h. Aqueous NH4C1 -NH4OH (pH 8-9, 30 mL) and diethyl ether (40 mL) were added to the solution and the layerswere separated. The aqueous phase was extracted with diethyl ether (3 x 30 mL) and thecombined organic extracts were washed with brine (1 x 30 mL), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The crude 5-chloro-2-trimethylgermyl-1-pentene (84) was used immediately in the following step without furtherpurification.To a solution of the crude 5-chloro-2-trimethylgermyl-1-pentene (84) (—8.5 mmolbased on the theoretical amount) in acetone (42 mL, unpurified HPLC grade) at rt was addedsolid sodium iodide (19.0 g, 127 mmol, 15 equiv. based on the stannyl chloride). Thesuspension was heated to reflux for 13 h and then cooled to ft. The acetone was removed byrotary evaporation and the residual material was dissolved in diethyl ether (50 mL) and water(50 mL). The layers were separated and the aqueous phase was extracted with diethyl ether(4 x 30 mL). The combined organic extracts were washed with brine (2 x 30 mL), dried overanhydrous magnesium sulfate, and concentrated under reduced pressure. The crude productwas flash chromatographed (100 g silica gel, petroleum ether) and the oil thus obtained wasdistilled (air-bath temperature 50-55 °CI0.2 Torr) to afford 2.25 g (85% from the stannylchloride 83a) of 5-iodo-2-trimethylgermyl-1-pentene (31), as a colourless oil.162IR (film): 3046, 1604, 1426, 1235, 824, 601 cm.‘H nmr (400 MHz) 6: 0.20 (s, 9H, -Gej3), 1.89-1.96 (quintet, 2H, J = 8.5 Hz,ICH2CH2CH2-), 2.30 (t, 2H, J = 8.5 Hz, allylic methylene protons), 3.28 (t, 2H, J = 8.5Hz, ICH2CH2-), 5.26 (m, 1H, vinyl proton), 5.57 (m, 1H, vinyl proton).13C nmr (75.3 MHz) 6: -1.9 (-ye, -Ge(.H3)3), 6.5, 32.4, 37.7, 122.7 (CH2=C-), 152.0(CH2-).Exact Mass calcd. for C7H l4GeI (M - Me): 298.9352; found: 298.9355.Anal. calcd. for C8H l7GeI: C 30.72, H 5.48, I 40.58; found: C 30.77, H 5.59, I 40.46.3.3.2. SYNTHESIS OF THE CUPRATE REAGENT 87 AND THE KETOVINYLGERMANES3.3.2.1. Synthesis of 3- [4-(Trimethylgermyl)-4-pentenyl]cyclohexanone (85):Me3GGeMe3To a cold (-98 °C), stirred solution of tert-butyllithium (1.69 M in pentane, 3.4 mL,5.7 mmol, 2.8 equiv.) in dry THF (51 mL) was added (over a period of 15 mm) a solution of5-iodo-2-trimethylgermyl-1-pentene (31) (915 mg, 2.93 mmol, 1.43 equiv.) in dry THF (2mL). The resultant pale yellow solution was stirred at -98 °C for 10 mm and was wanned to-78 °C. Copper(I) cyanide (275 mg, 3.07 mmol, 1.5 equiv.) was added in one portion and thesuspension became colourless. Brief warming (2-4 mm) of the reaction mixture at -35 °C163provided a light tan homogeneous solution containing the cuprate reagent 87 which wascooled to -78 °C. To the solution of the cuprate reagent 87 was added trimethylsilyl bromide(1.10 g, 7.16 mmol, 3.5 equiv.) and a solution of 2-cyclohexen-l-one (197 mg, 2.05 mmol, 1equiv.) in dry THF (1 mL). The reaction mixture was stirred at -78 °C for 3 h and wassubjected to the workup conditions as described in general procedure 1. The crude productwas flash chromatographed (35 g silica gel, 9:1 petroleum ether - diethyl ether) and the oilthus obtained was distilled (air-bath temperature 88-90 °C/0.2 Torr) to afford 433 mg (75%)of the keto vinylgermane 85, as a colourless oil.IR (film): 3044, 1714, 1604, 1421, 1235, 915, 825 cm4.‘H nmr (400 MHz) 6: 0.19 (s, 9H, -Ge3), 1.23-1.44 (m, 5H), 1.55-1.78 (m, 2H), 1.84-1.88(m, 1H), 1.93-2.04 (m, 2H), 2.14 (br t, 2H, J = 7.5 Hz), 2.17-2.26 (m, 1H), 2.29-2.35 (m,1H), 2.36-2.41 (ddt, 1H, J = 14, 4, 2 Hz), 5.16-5.17 (m, 1H, vinyl proton), 5.47-5.48 (dt, 1H,J = 2.5, 1.5 Hz).l3 nmr (75.3 MHz) 6: -1.9 (-ye, -Ge(H3)3), 25.3, 25.8, 31.3, 36.3, 37.3, 39.0 (-ye, C-3),41.5, 48.2, 121.5 (H2=C-), 153.8 (CH2=-), 211.9 (C-i).Exact Mass calcd. for C 4H 26GeO: 284.1195; found: 284.1193.Anal. calcd. for C14H26GeO: C 59.42, H 9.26; found: C 59.49, H 9.15.1643.3.2.2. Synthesis of (3R, 5R)-2-Methyl-5-(1-methylethenyl)-3-[4-(trimethylgermyl)-4-pentenylj-cyclohexanone (86):4To a cold (-98 °C), stirred solution of tert-butyllithium (1.71 M in pentane, 0.82 mL,1.4 mmol, 2.5 equiv.) in dry THF (12 mL) was added (over a period of 15 mm) a solution of5-iodo-2-trimethylgermyl-l-pentene (31) (226 mg, 0.723 mmol, 1.3 equiv.) in dry THF (2mL). The resultant pale yellow solution was stirred at -98 °C for 10 mm and was warmed to-78 °C. Copper(I) cyanide (68 mg, 0.76 mmol, 1.4 equiv.) was added in one portion and thesuspension became colourless. Brief warming (2-4 mm) of the reaction mixture at -35 °Cprovided a light tan homogeneous solution containing the cuprate reagent 87 which wascooled to -78 °C. To the solution of the cuprate reagent 87 was added trimethylsilyl bromide(335 mg, 2.19 mmol, 4 equiv.) and a solution of (R)-carvone (56) (84 mg, 0.56 mmol, 1equiv.) in dry THF (1 mL). The reaction mixture was stirred at -78 °C for 6 h and wassubjected to the workup conditions as described in general procedure 1. The crude productwas flash chromatographed (15 g silica gel, 9:1 petroleum ether - diethyl ether) and the oilthus obtained was distilled (air-bath temperature 110-120 °CI0.15 Torr) to afford 132 mg(70%) of the keto vinylgermane 86, as a colourless oil. 1H nmr spectroscopic analysisindicated that the product consisted of an —2:1 ratio of epimers at carbon two.IR(film): 1713, 1646, 1453, 1220, 914, 825, 772cm-1.‘H nmr (400 MHz) & 0.18, 0.21 (s, s, ratio undetermined, 9H, -Ge3), 1.00, 1.11 (d, d,ratio —2:1, 3H, J = 8 Hz for each d, secondary Me group), 1.72, 2.00 (s, s, ratio —2:1, 3H,165vinyl Me group), 1.12-2.65 (m, 13H), 4.71, 4.73, 4.79, 4.80 (br s, br s, br s, br s, ratioundetermined, 2H, Ha and Hb), 5.19, 5.50 (m, m, 2H, Hc and Hd).Exact Mass calcd. for C18H32GeO: 338.1665; found: 338.1661.3.3.3. SYNTHESIS OF THE KETO VINYL IODIDES3.3.3.1. Synthesis of 3-(4-Iodo-4-pentenyl)cyclohexanone (91):Following general procedure 2b, the keto vinylgermane 85 (419 mg, 1.48 mmol, 1equiv.) was converted into the keto vinyl iodide 91. The crude product was flashchromatographed (35 g silica gel, 9:1 petroleum ether - diethyl ether) and removal of traceamounts of solvent (vacuum pump) from the resultant oil yielded 418 mg (97%) of the vinyliodide 91, as a pale yellow oil.IR (film): 1712, 1617, 1427, 1225, 894, 773 cm4.nmr (400 MHz) ö: 1.21-1.37 (m, 2H), 1.48-2.06 (m, 8H), 2.20-2.43 (m, 5H), 5.65 (m, 1H,vinyl proton), 5.98 (m, 1H, vinyl proton).Exact Mass calcd. for Ci 1H 1710: 292.0323; found: 292.0326.1663.3.3.2. Synthesis of (3R, 5R )-3-(4-Iodo-4-pentenyl)-2-methyl-5-(1-methylethenyl)cyclo-hexanone (92)::92Following general procedure 2b, the keto vinylgermane 86 (217 mg, 0.644 mmol, 1equiv.) was converted into the keto vinyl iodide 92. The crude product was flashchromatographed (25 g silica gel, 9:1 petroleum ether - diethyl ether) and removal of traceamounts of solvent (vacuum pump) from the resultant oil afforded 211 mg (95%) of the vinyliodide 92, as a pale yellow oil. ‘H nmr spectroscopic analysis revealed that the productconsisted of a —2:1 mixture of epimers at carbon two.IR(film): 3074,1709,1646,1618,1429,1164,896cm-.‘H nmr (400 MHz) 6: 1.00, 1.13 (d, d, ratio —2:1, 3H, J = 8 Hz for each d, secondary Megroup), 1.25-1.70 (m, 5H), 1.63, 1.65 (s, s, ratio undetermined, 3H, vinyl Me group), 1.98-2.68 (m, 8H), 4.70, 4.75, 4.78, 4.82 (br s, br s, br s, br s, ratio —1:2:2:1, 2H, Ha and Hb), 5.70,6.00 (m, m, 2H, Hc and Hd).Exact Mass calcd. for C15H2310: 346.0793; found: 346.0786.1673.3.4. CYCLIZATION REACTIONS TO FORM SIX-MEMBERED RINGS3.3.4.1. Synthesis of 10-Methylbicyclo[4.4.0]dec- 10-en-2-one (93):0 Meca. Via the Pd(0)-Catalyzed Cyclization Reaction Conditions Described in GeneralProcedure 3:To a stirred solution of the keto vinyl iodide 91 (105 mg, 0.359 mmol, 1 equiv.) in dryTHF (3.6 mL, 0.1 M dilution) at rt was added Pd(PPh3)4 (143 mg, 0.123 mmol, 34 mol%).A solution of t-BuOK in a 4:1 mixture of dry THF and dry t-BuOH (0.24 M, 1.7 mL, 0.41mmol, 1.1 equiv.) was added, via a syringe pump, over the course of 3 h. The reactionmixture was stirred for an additional 1 h at rt and was subjected to the workup conditions asdescribed in general procedure 3. The crude product was flash chromatographed (25 g silicagel, 9:1 petroleum ether - diethyl ether) and removal of trace amounts of solvent (vacuumpump) from the resultant oil provided 3 mg (5%) of the bicyclic enone 93.‘H nmr (400 MHz) & 1.17-1.49 (m, 3H), 1.62-1.77 (m, 2H), 1.85 (d, 3H, J = 2 Hz, vinyl Megroup), 1.86-1.99 (m, 3H), 2.08-2.11 (m, 2H), 2.24-2.32 (m, 2H), 2.48 (br d, 1H, J = 15 Hz).Exact Mass calcd. for Ci 1H 160: 164.1201; found: 164.1203.b. Via the Pd(0)-Catalyzed Cyclization Reaction Employing Modified Conditions(0.02 M dilution and no t-BuOH present in the base mixture):To a stirred solution of the keto vinyl iodide 91 (130 mg, 0.45 mmol, 1 equiv.) in dryTHF (30 mL, 0.02 M dilution) at it was added Pd(PPh3)4 (177 mg, 0.153 mmol, 34 mol%).A solution of t-BuOK in dry THF (0.24 M, 2.1 mL, 0.50 mmol, 1.1 equiv.) was added, via a168syringe pump, over the course of 3 h. The reaction mixture was stirred at rt overnight andwas subjected to the workup conditions as described in general procedure 3. The crudeproduct was subjected to flash chromatography (25 g silica gel, 9:1 petroleum ether - diethylether) and removal of trace amounts of solvent (vacuum pump) from the resultant oil yielded20 mg (27%) of the bicyclic enone 93 (spectral data are identical with those reported above).c. Via the Pd(0)-Catalyzed Cyclization Reaction Employing Modified Conditions(0.004 M dilution and no t-BuOH present in the base mixture):To a stirred solution of the keto vinyl iodide 91 (71 mg, 0.24 mmol, 1 equiv.) in dryTHF (60 mL, 0.004 M dilution) at rt was added Pd(PPh3)4 (101 mg, 0.087 mmol, 36 mol%).A solution of t-BuOK in dry THF (0.20 M, 1.4 mL, 0.28 mmol, 1.1 equiv.) was added, via asyringe pump, over the course of 5.5 h. The reaction mixture was stirred at rt overnight andwas subjected to the workup conditions as described in general procedure 3. Flashchromatography (15 g silica gel, 9:1 petroleum ether - diethyl ether) of the crude product andremoval of trace amounts of solvent (vacuum pump) from the resultant oil afforded 16 mg(41%) of the bicyclic enone 93 (spectral data are identical with those reported above).1693.3.4.2. Synthesis of (4R, 6 R)- 1-Methyl- 10-methylene-4-(1-methylethenyl)bicyclo[4.4.0] -decan-2-one (94):MellMeT)k48To a stirred solution of the keto vinyl iodide 92 (75 mg, 0.22 mmol, 1 equiv.) in dryTHF (43 mL, 0.005 M dilution) at rt was added Pd(PPh3)4 (91 mg, 0.079 mmol, 36 mol%).A solution of t-BuOK in dry THF (0.20 M, 1.3 mL, 0.25 mmol, 1.1 equiv.) was added, via asyringe pump, over the course of 5.5 h. The reaction mixture was stirred at ii overnight andwas subjected to the workup conditions as described in general procedure 3. Flashchromatography (15 g silica gel, 9:1 petroleum ether - diethyl ether) of the crude product andremoval of trace amounts of solvent (vacuum pump) from the resultant oil afforded 1 mg(2%) of the bicyclic enone 94.nmr (400 MHz) 6: 1.27 (s, 3H, tertiary Me group), 1.75 (br s, 3H, vinyl Me group), 1.30-2.70 (m, 12H), 4.70, 4.75, 4.81, 4.94 (br s, br s, br s, br s, 1H each, vinyl protons).1703.4. THE FORMATION OF TRICYCLIC RING SYSTEMS EMPLOYING THEANNULATION METHOD BASED ON THE PALLADIUM(0)-CATALYZEDINTRAMOLECULAR COUPLING3.4.1. SYNTHESIS OF THE BICYCLIC ENONES:3.4.1.1. Synthesis of 3- [2-(1 ,3-Dioxan-2-yl)ethyl]cyclohexanone (102):To a stirred suspension of freshly ground magnesium turnings (686 mg, 28.2 mmol,2.7 equiv.) and iodine (a few crystals) in dry THF (1 mL) at rt was added dropwise (via alarge cannula) a solution of 2-(2-bromoethyl)-1,3-dioxane (2.75 g, 14.1 mmol, 1.3 equiv.) indry THF (5 mL). The bromide solution was added at such a rate that reflux of the mixturewas maintained. After the addition was complete, the mixture was heated to reflux for 30mm. The mixture was cooled to rt, diluted with dry THF (19 mL), and cooled to -78 °C.Solid CuBr•Me2S (443 mg, 2.15 mmol, 15 mol% with respect to the Grignard reagent) wasadded in one portion and the cloudy, colourless mixture was stirred at -78 °C for 1 h. DryHMPA (4.6 mL, 26 mmol, 2.5 equiv.) was added and the mixture was stirred for 10 mm. Asolution of 2-cyclohexen-1-one (1.01 g, 10.5 mmol, 1 equiv.) and trimethylsilyl chloride (3.3mL, 26 mmol, 2.5 equiv.) in dry THF (4 mL) was added dropwise, via a large cannula. Theresultant pale yellow mixture was stirred at -78 °C for 3 h and warmed to -48 °C for 1 h.Water (15 mL) was added and the mixture was warmed to rt and stirred for 30 mm. AqueousNH4C1 - NH4OH (pH 8-9, 50 mL) and diethyl ether (75 mL) were added and the mixturewas opened to the atmosphere and stirred vigorously until the aqueous phase became brightblue in colour. The layers were separated and the aqueous phase was extracted with diethylether (3 x 75 mL). The combined organic extracts were washed with water (4 x 75 mL),171dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Thecrude product was flash chromatographed (150 g silica gel, 2.3:1 petroleum ether - ethylacetate) and the oil thus obtained was distilled (air-bath temperature 126-128 °CI0. 15 Torr) toafford 2.0 g (88%) of the acetal compound 102.JR (film): 1714, 1406,1240,1139, 1006, 893 cm-1.‘H nmr (400 MHz, C6D6) 6: 0.64-0.67 (dt, 1H, J = 12.5, 1 Hz), 0.75-0.84 (br q, 1H, J =11.5 Hz), 1.10-1.86 (m, 11H), 2.10-2.14 (br d, 1H, J = 14 Hz), 2.28-2.32 (dt, 1H, J = 14, 2Hz), 3.30-3.36 (br dd, 2H, J = 11.5, 11.5 Hz, axial protons of -0C112-), 3.79-3.83 (br dd, 2H,J = 11.5, 5 Hz, equatorial protons of -OCfl-), 4.29-4.32 (t, 1H, J =5 Hz, -OCHO-).nmr (75.3 MHz, C6D6) 6: 25.1, 26.1, 30.9, 31.1, 32.8, 38.7 (-ye), 41.3, 48.0, 66.7, 102.3(-ye, -OHO-), 208.6 (-=O).ExactMass calcd. for C12H200: 212.1412; found: 212.1409.Anal. calcd. for C12H200: C 67.89, H 9.50; found: C 67.79, H 9.55.3.4.1.2. Synthesis of Bicyclo[4.3.0]non-9-en-2-one (95):CA solution of the acetal compound 102 (912 mg, 4.30 mmol, 1 equiv.) in a mixture ofTHF (29 mL) and 0.1 M hydrochloric acid (15 mL) was refluxed for 14 h. The resultant172brown solution was cooled to rt and cautiously neutralized with saturated aqueous NaHCO3.Diethyl ether (100 mL) and water (50 mL) were added and the layers were separated. Theaqueous phase was extracted with diethyl ether (3 x 75 mL) and the combined organicextracts were washed with water (2 x 50 mL) and brine (1 x 50 mL), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The crude product thusobtained was subjected to radial chromatography (4 mm plate, 9:1 petroleum ether - diethylether) to yield 427 mg (73%) of the bicyclic enone 95,105,106 as a colourless oil.3.4.1.3. Synthesis of 3-[2-( 1 ,3-Dioxan-2-yl)ethyl]-3-methylcyclohexanone (103):eQ)To a stirred suspension of freshly ground magnesium turnings (570 mg, 23.4 mmol,2.6 equiv.) and iodine (a few crystals) in dry THF (1 mL) at ft was added dropwise (via alarge cannula) a solution of 2-(2-bromoethyl)-1,3-dioxane (2.29 g, 11.7 mmol, 1.3 equiv.) indry THF (4 mL). The bromide solution was added at such a rate that reflux of the mixturewas maintained. After the addition was complete, the mixture was heated to reflux for 30mm. The mixture was cooled to rt, diluted with dry THF (15 mL), and cooled to -78 °C.Solid CuBr•Me2S (389 mg, 1.89 mmol, 16 mol% with respect to the Grignard reagent) wasadded in one portion and the cloudy, colourless mixture was stirred at -78 °C for 1 h. DryHMPA (3.9 mL, 22 mmol, 2.5 equiv.) was added and the mixture was stirred for 10 mm. Asolution of 3-methyl-2-cyclohexen-1-one (978 mg, 8.88 mmol, 1 equiv.) and trimethylsilylchloride (2.8 mL, 22 mmol, 2.5 equiv.) in dry THF (4 mL) was added dropwise, via a largecannula. The resultant pale yellow mixture was stirred at -78 °C for 5 h and warmed to -48173°C for 1 h. Water (7 mL) was added and the mixture was warmed to rt and was stirred for 45mm. Aqueous NH4C1 - NH4OH (pH 8-9, 40 mL) and diethyl ether (50 mL) were added andthe mixture was opened to the atmosphere and stirred vigorously overnight. The layers wereseparated and the aqueous phase was extracted with diethyl ether (3 x 50 mL). Thecombined organic extracts were washed with water (4 x 50 mL), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The crude product was flashchromatographed (160 g silica gel, 2.3:1 petroleum ether - ethyl acetate) and the oil thusobtained was distilled (air-bath temperature 132-136 °CI0.15 Torr) to afford 1.9 g (95%) ofthe acetal compound 103.IR(film): 1708, 1461, 1148, 1081, 1007, 894 cm’.1H nmr (400 MHz, C6D6) 6: 0.76 (s, 3H, Me), 0.99-1.06 (m, 1H), 1.13-1.20 (ddd, 1H, J =13.0, 8.5, 4.5 Hz), 1.29-1.98 (m, 12H), 3.30-3.36 (br dd, 2H, J = 11.5, 11.5 Hz, axial protonsof -OCjj2-), 3.79-3.83 (br dd, 2H, J = 11.5, 5 Hz, equatorial protons of -OCij2-), 4.28-4.30(t, 1H, J =5 Hz, -OCjjO-).nmr (75.3 MHz, C6D6) 6: 22.0, 24.9 (-ye, Me), 26.1, 29.8, 35.3, 35.4, 37.7, 40.8, 53.7,66.7, 102.7 (-ye, -OHO-), 209.0 (-=O).Exact Mass calcd. for C13H2203: 226.1569; found: 226.1562.Anal. calcd. for C13H2203: C 68.99, H 9.80; found: C 69.07, H 9.88.1743.4.1.4. Synthesis of 6-Methylbicyclo[4.3.0]non-9-en-2-one (96):CA solution of the acetal compound 103 (800 mg, 3.54 mmol, 1 equiv.) in a mixture ofTHF (28 mL) and 0.1 M hydrochloric acid (14 mL) was refluxed for 19 h. The resultantbrown solution was cooled to rt and cautiously neutralized with saturated aqueous NaHCO3.Diethyl ether (100 mL) and water (50 mL) were added and the layers were separated. Theaqueous phase was extracted with diethyl ether (3 x 75 mL) and the combined organicextracts were washed with water (2 x 50 mL) and brine (1 x 50 mL), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The crude product thusobtained was subjected to flash chromatography (35 g silica gel, 49:1 CH2CI2 - acetone) toafford 324 mg (6 1%) of the bicyclic enone 96,107 as a colourless oil.-zuc‘(HL‘iii)8rl66T‘(i-H‘zilci=f‘HT‘1’)8i‘(HI‘w)06T-181‘(HE‘w)8L1-1c1‘(HV‘ui)zvi-czi‘(OT°N‘HE‘)601‘(EWo-‘116‘s)6T0:(zHNoov)WU1...W‘cioi‘9Ei‘c091‘EIL1:(wjg)‘>jTosspnoooist‘qjinpoidpsnj-su1niouuuqijo(%6)uipiojpo(noigoIiZEI-OETainpuodwqwq-ip)P1IB!PS1MpuunqosnqiuoqipuipoiuouoooJosuogoiijiidoiddioq•qojionpoidpøsnj-suuiqisiiipinoqopunodwoISJ!jøuJspunodwooOMipiojjioi(iqp(qip-ioqiownjoiid1:6‘Ic)pqdtioitwoiqqusiiionpoidpn.iooqs1u!suooidp(qiwAi13OdSø1i’qiJououiøiuqiAqpurnuiopsi‘qjPuOE1SIWOSTqiJOOJPU1:6P!PU!ionpoidptuoqijos!1iuordoosoiiodsUU1116JOJJ,8L-p1JT3sS1Mainxiuiuogoaiqj(‘jwj)Aipu(A!nb1‘ioww99L0‘ucii)tLuouoipAoqqijououniospu(ATnbc‘°“ov‘i.uç9)opuuoiqJAflspCq1w.Bq1MApniunbspO21I1S1M(‘jwi)dHI(pUi(ATnb‘JOWW6VI)siiuiaiidnooqijouo!lnIos‘jainpooidiuUTAXO1TOBO1.HS6HII N.01.:(qØfl)-[p(u3nq--(p(uu‘*S9‘ir)pu(O[)uo--uEuou[oE]-opoiq[p(u3nq--(Juu6‘*S9‘çj)josisqiui(.izS1NVW1I9’IANIAOJDI3I’IDADIqIHLL1ONOIIVZfl1ENId1UNVSISEHINASVEqoi.tiLcU1765.13 (m, 1H, H-14), 5.48-5.49 (m, 1H, H-14’).1H nmr (400 MHz, C6D6) 6: 0.30 (s, 9H, -Ge3), 0.85-0.93 (dq, 1H, J = 4, 12.5 Hz),0.99-1.07 (m, 1H, H-5), 1.24 (s, 3H, Me-lO), 1.18-1.29 (m, 2H, one of which is H-4), 1.41-1.62 (m, 6H, five of which are H-i, H-4’, H-5’, H-6, and H-il), 1.66-1.79 (m, 2H, one ofwhich is H-3), 1.98-2.06 (dt, 1H, J = 4.5, 13 Hz, H-li’), 2.11-2. 13 (m, iH, H-3’), 2.25-2.33(br dt, 1H, J = 4.5, 13 Hz, H-12), 2.37-2.45 (br dt, 1H, J = 4.5, 13 Hz, H-12’), 5.30-5.3 1 (brd, iH, J = 2.5 Hz, H-i4), 5.68-5.69 (m, 1H, H-i4’).Detailed 1H nmr data (C6D6), derived from a COSY experiment, are given in Table 21.nmr (100.4 MHz, C6D6) 6: -1.6 (-ye, -Ge(CH3)3), 22.2 (-ye, Me-lO), 26.9, 29.1, 31.7,33.7, 37.8, 42.3, 42.5, 42.7, 44.7 (-ye), 64.9 (-ye, C-i), 121.6 (C-14), 154.7 (C-13), 208.2 (C2).Exact Mass calcd. for C i7H 3OGeO: 324.1508; found: 324.1511.Anal. calcd. for C17H30GeO: C 63.21, H 9.36; found: C 63.11, H 9.19.177Table 21: ‘H nmr Data (400 MHz, C6D 6) for the Trans-Fused Compound 130b: COSY1410OMe113 GeMeI 30bAssignment 1H nmr (400 MHz) COSY CorrelationsaH-x 6 ppm (mult., J (Hz))-GeM3 0.30 (s)H-5 0.99-1.07 (m) H-4, H4’b, H-5’Me-lO 1.24(s)H-4 Part of them at 1.18-1.29 H-3, H-3’, H-4’, H-5, H-5’H-i Part of them at 1.41-1.62H-4’ Part of them at 1.41-1.62 H-3, H-3’, H-4, H-5, H-5’H-5’ Part of the m at 1.41-1.62 H-4, H-4’, H-5H-6 Part of the m at 1.41-1.62H-li Part of them at 1.41-1.62 H-li’, H-12, H-12’H-3 Part of them at 1.66-i.79 H-3’, H-4, H-4’H-il’ i.98-2.06(dt,J =4.5, 13) H-i1,H-12,H-i2’H-3’ 2.11-2. 13 (m) H-3, H-4, H-4’H-i2 2.25-2.33 (br dt, J = 4.5, 13) H-li, H-li’, H-12’, H-i4, H-14’H-i2’ 2.37-2.45 (br dt, J = 4.5, 13) H-il, H-li’, H-12, H-14, H-14’H-14 5.30-5.31 (brd, J = 2.5) H-12, H-12’, H-14’H-l4’ 5.68-5.69 (m) H-12, H-i2’, H-14a- Only those COSY correlations that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-4’ is more downfield than H-4)Experiment178The fractions containing the second compound to be eluted from the above columnchromatography were concentrated and the oil thus obtained was distilled (air-bathtemperature 120-130 °C/0.28 Torr) to afford 198 mg (80%) of the major cis-fused compound130a, as a colourless oil.IR(film): 1694, 1601, 1176, 1031, 824cm-.‘H nmr (400 MHz) 6: 0.20 (s, 9H, -Ge3), 1.16 (s, 3H, Me-lO), 1.20-1.40 (m, 4H), 1.48-1.63 (m, 2H), 1.76-2.16 (m, 7H), 2.34 (d, ill, J 9.5 Hz, H-i), 2.40-2.46 (m, 2H), 5.13-5. 14(m, 1H, H-14), 5.47-5.48 (m, 1H, H-14’).‘H nmr (400 MHz, acetone-d6) 6: 0.20 (s, 9H, -Ge3), 1.13 (s, 311, Me-lO), 1.25-1.41 (m,411, three of which are H-7, H-il, and H-li’), 1.43-1.53 (m, 1H, H-7’), 1.55-1.66 (m, 1H, H-4), 1.78-2.01 (m, 5H, three of which are H-4’, 11-8, and H-8’), 2.14-2.18 (br t, 2H, J = 8.5 Hz,H-12 and H-12’), 2.31 (d, 1H, J =9 Hz, H-i), 2.3 1-2.34 (m, 1H, H-3’), 2.43-2.47 (m, lH, H-6), 4.61 (d, 1H, J = 1 Hz, 11-14), 4.96 (br s, 1H, H-14’).Detailed ‘H nmr data (acetone-d6), derived from COSY and NOE experiments, are given inTable 22.nmr (400 MHz, CDC13) 6: -1.7 (-ye, -Ge(H3)3), 23.6, 27.0 (-ye), 30.6, 31.1, 32.7,37.2, 37.4, 40.5 (-ye), 42.6, 47.3, 62.7 (-ye, C-i), 121.6 (C-14), 154.3 (C-13), 214.7 (C-2).ExactMass calcd. for C17H3OGeO: 324.1508; found: 324.1512.Anal. calcd. for C17H3OGeO: C 63.21, H 9.36; found: C 63.39, H 9.37.179Table 22: 1H nmr Data (400 MHz, acetone-d6) for the Cis-Fused Compound 130a: COSYand NOE Experiments1410OMe113 GeMe1 30aAssignment ‘H nmr (400 MHz) COSY Correlationsa NOEH-x 6 ppm (mult., J (Hz)) Correlationsa-Ge3 0.20 (s)Me-lO 1.13(s) H-i, H-8, H8’b,H-12, H-12’H-7 Part of them at 1.25-1.41 H-6, H-T, H-8, H-8’H-il Part of them at 1.25-1.41 H-12, H-12’H-li’ Part of them at 1.25-1.41 H-12, H-12’H-7’ 1.43-1.53 (m) H-7, H-8, H-8’H-4 1.55-1.66 (m) H-3’H-4’ Part of the m at 1.78-2.01 H-3’, H-4H-8 Part of the m at 1.78-2.01 H-7, H-7’H-8’ Part of them at 1.78-2.01 H-7, H-7’H-12 and H-12’ 2. 14-2.18 (br t, J 8.5) H-il, H-i 1’, H-14’H-i 2.31 (d, J =9) H-6H-3’ 2.3 1-2.34 (m) H-4, H-4’H-6 2.43-2.47 (m) H-i, H-7 H-iH-14 4.61 (d, J = 1) H-14’H-14’ 4.96 (br s) H-12, H-i2’, H-i4a- Only those COSY correlations and NOB data that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-8’ is more downfield than H-8)1803.4.2.2. Epimerization of compounds 130a and 130b:0 Me Jj 0 MeGe Me3 Ge Me3130a 130b1 3To a cold (-78 °C), stirred solution of the cis-fused compound 130a (11 mg, 0.034mmol, 1 equiv.) in dry MeOH (3.4 mL) was added a solution of NaOMe in dry MeOH (0.30M, 100 tL, 0.030 mmol, 0.9 equiv.). The yellow solution was warmed to rt and was stirredfor 64 h. The MeOH was removed by rotary evaporation and water (5 mL) and diethyl ether(5 mL) were added to the residue. The layers were separated and the aqueous phase wasextracted with diethyl ether (3 x 10 mL). The combined organic extracts were dried overanhydrous magnesium sulfate and concentrated under reduced pressure. The 1H nmrspectroscopic analysis of the oil thus obtained indicated a 3:1 ratio108 of the trans- to cisfused compounds, 130b and 130a.To a cold (-78 °C), stirred solution of the trans-fused compound 130b (13.7 mg,0.0423 mmol, 1 equiv.) in dry MeOH (4.2 mL) was added a solution of NaOMe in dryMeOH (0.30 M, 130 p.L, 0.038 mmol, 0.9 equiv.). The yellow solution was warmed to rt andwas stirred for 64 h. The MeOH was removed by rotary evaporation and water (5 mL) anddiethyl ether (5 mL) were added to the residue. The layers were separated and the aqueousphase was extracted with diethyl ether (3 x 10 mL). The combined organic extracts weredried over anhydrous magnesium sulfate and concentrated under reduced pressure. The ‘Hnmr spectroscopic analysis of the oil thus obtained indicated a 3:1 ratio108 of the trans- to cis -fused compounds, 130b and 130a.1813.2.2.3. Synthesis of (iS *, 65*,bicyclo[4.3.0]nonan-2-one (131a) and (1 R, 6S*, -3-butenyl]bicyclo[4.3.0]nonan-2-one (131b):15eGe Me3 GeMe3Me Me Me•7510I 131a 131bFollowing general procedure 1, a solution of the cuprate reagent 15 (0.877 mmol, 2equiv.) in dry THF (9 mL) was treated sequentially with trimethylsilyl bromide (505 mg,3.30 mmol, 7.5 equiv.) and a solution of the bicyclic enone 75 (72 mg, 0.44 mmol, 1 equiv.)in dry THF (0.5 mL). The reaction mixture was stirred at -78 °C for 9h. nmrspectroscopic analysis of the crude product indicated a 20:1 ratio109 of the two epimericcompounds 131a and 131b. The crude product was flash chromatographed (25 g silica gel,9:1 petroleum ether - diethyl ether) to provide two fractions. The first compound to be elutedwas the trans-fused compound 131b. The appropriate fractions were concentrated and the oilthus obtained was distilled (air-bath temperature 120-125 °CI0.2 Torr) to afford 6 mg (4%) ofthe minor trans-fused compound 131b.IR (ifim): 1717, 1608, 1460, 1235, 914, 825 cm4.nmr (400 MHz, C6D6) 3: 0.25 (s, 9H, -GeM3), 0.74 (s, 3H, Me), 1.08-1.22 (m, 1H),1.32-1.59 (m, 9H), 1.55 (s, 311, Me), 1.60-1.86 (m, 1H), 1.95 (s, 1H, H-i), 2.11-2.25 (m, 2H),2.38-2.44 (m, 1H), 5.28-5.29 (m, 1H, H-15), 5.63-5.64 (m, 1H, H-15’).182‘H nmr (400 MHz, acetone-d6) 6: 0.19 (s, 9H, -Gej3), 0.92 (s, 3H, Me), 1.30 (s, 3H, Me),1.35-1.53 (m, 3H), 1.55-1.70 (m, 4H), 1.74-1.80 (m, 1H), 1.87-1.97 (m, 2H), 2.05-2.12 (m,2H), 2. 17-2.33 (m, 2H), 2.28 (br s, 1H, H-i), 5.14 (br s, 1H, H-15), 5.50 (br s, ill, H-15’).NOE difference experiments (in acetone-d6): irradiation of the signal at 6 0.92 (Me) causedan enhancement of the signal at 6 1.30 (Me); irradiation of the signal at 6 1.30 (Me) causedan enhancement of the signal at 6 0.92 (Me).nmr (75.3 MHz, C6D6) 6: -1.7 (-ye, -Ge(H3)3), 20.0 (-ye, Me), 23.5, 25.1 (-ye, Me),30.2, 33.7, 39.2, 39.7, 40.5, 42.3, 46.5, 49.0, 67.1 (-ye, C-i), 121.5 (C-15), 154.6 (C-14),208.6 (C-2).Exact Mass calcd. for C18H32GeO: 338.1665; found: 338.1674.Anal. calcd. for C18H32GeO: C 64.15, H 9.57; found: C 64.35, H 9.81.The second product to be eluted was the cis-fused compound 131a. The appropriatefractions were concentrated and the oil thus obtained was distilled (air-bath temperature 125-130 °C/0.i Torr) to afford 120 mg (82%) of the major cis-fused compound 131a.IR(film): 1695, 1460,1176, 824cm’.nmr (400 MHz, C6D6) 6: 0.24 (s, 9H, -Ge3), 0.83 (s, 3H, Me), 1.20 (s, 3H, Me), 1.17-1.51 (m, 9H), 1.62-1.69 (q, 1H, J = 7 Hz), 1.90-1.97 (m, iH), 2.05 (br s, iH, H-i), 2.10-2.15(m, iH), 2. 19-2.24 (m, 1H), 2.27-2.33 (m, iH), 5.24 (br t, 1H, J = 1 Hz, H-15), 5.58-5.59(m, 1H, H-15’).183‘H nmr (400 MHz, acetone-d6) & 0.20 (s, 9H, -Ge3), 1.08 (br s, 3H, Me-lO), 1.13 (br s,3H, Me-li), 1.17-1.23 (m, 1H, H-12), 1.25-1.86 (m, 9H, three of which are H-4, H-4’, and H-12’), 1.96 (br s, 1H, H-i), 2.06-2.10 (m, 1H, H-3), 2.11-2.18 (m, 2H, H-13 and H-13’), 2.24-2.31 (m, 1H, H-3’), 4.61-4.62 (m, 1H, H-15), 4.95-4.96 (m, 1H, H-15’).Detailed ‘H nmr data (acetone-d6), derived from COSY and NOE experiments, are given inTable 23.13C nmr (100.4 MHz, C6D6) 6: -1.6 (-ye, -Ge(H3)3), 21.0, 28.0 (-ye, Me), 29.4 (-ye, Me),33.3, 36.1, 37.1, 38.0, 40.4, 42.2, 43.9, 48.1, 70.8 (-ye, C-i), 122.1 (C-iS), 154.3 (C-14),211.6 (C-2).Exact Mass calcd. for C18H32GeO: 338.1665; found: 338.1660.Anal. caicd. for C18H32GeO: C 64.15, H 9.57; found: C 64.45, H 9.69.184Table 23: ‘H nmr Data (400 MHz, acetone-d6) for the Cis-Fused Vinylgermane Compound131a: COSY and NOE Experiments67:GeMe3Me10131 aAssignment ‘H nmr (400 MHz) COSY Correlationsa NOEH-x 6 ppm (mult., J (Hz)) Correlationsa-GeM3 0.20 (s)Me-lO 1.08 (br s) H-i H-iMe-il i.i3(brs) H-i H-i, H-i2,H-i3, H-i3’H-i2 1.17-1.23 (m) H-i2’, H-i3, H-i3’H-12t ‘-4.25-1.51 (m), part of the H-12, H-i3, H-iYm at 1.25-1.86H-4 —1.65-1.73 (m), part of the H-3, H-3’, H-4’m at 1.25-1.86H-4’ —1.80-i.86 (m), part of the H-3, H-3’, H-4m at 1.25-1.86H-i 1.96 (br s) H3’C, Me-lO, Me-li Me-lO, Me-liH-3 2.06-2.10 (m) H-3’, H-4, H-4’H-13 and H-13’ 2.11-2.18 (m) H-i2, H-i2’, H-iS’H-3’ 2.24-2.3 1 (m) H1C, H-3, H-4, H-4’H-iS 4.61-4.62 (m) H-i5’H-i5’ 4.95-4.96 (m) H-13, H-13’, H-15a- Only those COSY correlations and NOE data that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-12’ is more downfield than H-12).c- W coupling1853.4.2.4. Epimerization of compounds 131a and 131b:0 Me 0 MeGeMe3 GeMe3Me Me131a 131b>99 <1To a cold (-78 °C), stirred solution of the cis-fused compound 131a (42 mg, 0.12mmol, 1 equiv.) in dry MeOH (2.5 mL) was added a solution of NaOMe in dry MeOH (0.30M, 0.37 mL, 0.11 mmol, 0.9 equiv.). The yellow solution was warmed to rt and was stirredfor 48 h. The MeOH was removed by rotary evaporation and water (10 mL) and diethylether (10 mL) were added to the residue. The layers were separated and the aqueous phasewas extracted with diethyl ether (3 x 15 mL). The combined organic extracts were dried overanhydrous magnesium sulfate and concentrated under reduced pressure. The cis-fusedcompound 131a was the only isomer evident in the ‘H nmr spectrum of the crude oil.To a cold (-78 °C), stirred solution of the trans-fused compound 131b (10 mg, 0.030mmol, 1 equiv.) in dry MeOH (1.0 mL) was added a solution of NaOMe in dry MeOH (0.30M, 90 IlL, 0.027 mmol, 0.9 equiv.). The yellow solution was warmed to rt and was stirredfor 48 h. The MeOH was removed by rotary evaporation and water (5 mL) and diethyl ether(5 mL) were added to the residue. The layers were separated and the aqueous phase wasextracted with diethyl ether (3 x 10 mL). The combined organic extracts were dried overanhydrous magnesium sulfate and concentrated under reduced pressure. 1ii nmrspectroscopic analysis of the crude oil indicated that the trans-fused compound 131b hadcompletely epimerized to the cis-fused compound 131a, thereby verifying that the cis-fusedcompound 131a is the thermodynamically more stable epimer.1863.4.2.5. Synthesis of (1 S*, 6S*,2-one (132a) and (1 R*, 6S*, 9S*)9 [3-(trimethylgermyl)-3-butenyl]bicyclo[4.3.0]nonan-2 -one (132b):C GeMe3 Ge Me3132a 132bFollowing general procedure 1, a solution of the cuprate reagent 15 (2.18 mmol, 1.5equiv.) in dry THF (29 mL) was treated sequentially with trimethylsilyl bromide (1.10 g,7.18 mmol, 5 equiv.) and a solution of the bicyclic enone 95 (199 mg, 1.46 mmol, 1 equiv.)in dry THF (2 mL). The reaction mixture was stirred at -78 °C for 3 h. The crude productwas flash chromatographed (35 g silica gel, 12.3:1 petroleum ether - diethyl ether) to afford398 mg (88%) of a mixture of the cis- and trans-fused compounds, 132a and 132b. ‘H nmrspectroscopic analysis of this oil indicated a 5:1 ratio 10 of compounds 132a and 132b.Further purification by column chromatography (25 g silica gel, 19:1 petroleum ether -diethyl ether) afforded a partial separation of compounds 132a and 132b. The first fewfractions from the column chromatography were concentrated and the oil thus obtained wasdistilled (air-bath temperature 90-92 °CI0. 1 Torr) to provide the pure trans-fused compound132b, as a colourless oil.IR (film): 1714, 1664, 1602, 1235, 914, 825 cm4.nmr (400 MHz) 6: 0.20 (s, 9H, -GeMe3), 1.16-1.42 (m, 5H), 1.59-1.72 (m, 3H), 1.82-2.01(m, 411), 2.08-2.31 (m, 5H), 5.14 (br s, 1H, H-13), 5.50 (br s, 1H, H-13’).18713C nmr (75.3 MHz) & -1.8 (-ye, -GeçH3)3), 28.0, 28.7, 31.0, 31.2, 35.2, 35.9, 36.5 (-ye),41.9, 50.0 (-ye), 63.6 (-ye, C-i), 121.0 (C-13), 154.3 (C-12), 211.3 (C-2).Exact Mass calcd. for C16H28GeO: 310.1352; found: 310.1351.Anal. calcd. for C16H28GeO: C 62.20, H 9.13; found: C 61.89, H 9.18.A few late fractions eluted from the above column chromatography were concentratedand the oil thus obtained was distilled (air-bath temperature 120-124 °C/0.25 Torr) to affordthe pure cis-fused compound 132a, as a colourless oil.JR (film): 1703, 1605, 1452, 1235, 915, 825 cm4.nmr (400 MHz) & 0.18 (s, 9H, -GeM3), 1.34-1.85 (m, 9H, two of which are H-b andH-b’), 1.88-1.95 (m, iH), 2.01-2.08 (br ddd, 1H, H-il, J 15.5, 10, 5.5 Hz, H-il), 2.08-2.15 (m, 2H, one of which is H-6), 2.18-2.24 (m, 1H, H-li’), 2.37-2.43 (m, 2H, one of whichis H-9), 2.68-2.72 (dd, 1H, J = 8, 8 Hz, H-i), 5.13-5. 14 (m, iH, H-13), 5.46-5.47 (m, iH, H13’).Detailed ‘H nmr data, derived from COSY and NOE experiments, are given in Table 24.13C nmr (75.3 MHz) & -1.8 (-ye, -Ge(H3)3), 23.8, 28.7, 29.8, 30.5, 32.0, 36.8, 42.1 (-ye),42.6 (-ye), 42.7, 55.4 (-ye, C-i), 121.5 (C-13), 153.9 (C-12), 214.8 (C-2).Exact Mass calcd. for C16H28GeO: 310.1352; found: 310.1345.Anal. calcd. for CjH2GeO: C 62.20, H 9.13; found: C 62.40, H 8.99.188Table 24: 1H nmr Data (400 MHz, CDC13) for the Cis-Fused Vinylgermane Compound132a: COSY and NOE Experiments13GeMe31 32aAssignment nmr (400 MHz) COSY Correlationsa NOEH-x ppm (mult., J (Hz)) Correlationsa-GeM3 0.18 (s)H-10 —1.34-1.43 (m), part of the H-9, H-li, Hii’bm at 1.34-1.85H-i0’ —1.61-1.69 (m), part of the H-9, H-il, H-li’m at 1.34-1.85H-il 2.01-2.08 (brddd,J = 15.5, H-i0, H-iO’, H-il’, H-i3,10, 5.5) H-i3’H-6 Part of them at 2.08-2.15 H-i H-iH-li’ 2.18-2.24(m) H-lO, H-b’, H-li, H-i3,H-l3’H-9 Part of them at 2.37-2.43 H-i, H-b, H-l0’ H-i, H-ilH-i 2.68-2.72 (dd, J = 8, 8) H-6, H-9 H-6, H-9H-13 5.13-5. 14 (m) H-il, H-li’, H-l3’H-l3’ 5.46-5.47 (m) H-li, H-il’, H-13a- Only those COSY correlations and NOE data that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-il’ is more downfield than H-il).1893.4.2.6. Epimerization of compounds 132a and 132b:GeMe3 GeMe3132a 132b-.1 -30To a cold (-78 °C), stirred solution of the cis-fused compound 132a (13 mg, 0.042mmol, 1 equiv.) in dry MeOH (1.4 mL) was added a solution of NaOMe in dry MeOH (0.30M, 130 pL, 0.038 mmol, 0.9 equiv.). The yellow solution was warmed to rt and was stirredfor 20 h. The MeOH was removed by rotary evaporation and water (5 mL) and diethyl ether(5 mL) were added to the residue. The layers were separated and the aqueous phase wasextracted with diethyl ether (3 x 10 mL). The combined organic extracts were dried overanhydrous magnesium sulfate and concentrated under reduced pressure. nmrspectroscopic analysis of the oil thus obtained indicated that the thermodynamic ratio of thecompounds 132b to 132a was _30:1.110To a cold (-78 °C), stirred solution of the trans-fused compound 132b (21 mg, 0.068mmol, 1 equiv.) in dry MeOH (2.3 mL) was added a solution of NaOMe in dry MeOH (0.30M, 200 iL, 0.06 1 mmol, 0.9 equiv.). The yellow solution was warmed to rt and was stirredfor 20 h. The MeOH was removed by rotary evaporation and water (10 mL) and diethylether (10 mL) were added to the residue. The layers were separated and the aqueous phasewas extracted with diethyl ether (3 x 10 mL). The combined organic extracts were dried overanhydrous magnesium sulfate and concentrated under reduced pressure. The ratio of thetrans- to cis-fused compounds 132b and 132a, as judged by ‘H nmr spectroscopic analysis ofthe crude oil, was determined to be 30:1.1101903.4.2.7. Synthesis of (1R*, 6S*, 9 -[4.3.0]nonan-2-one (133a) and (1 S*, 6S*, 9 -bicyclo[4.3.0]nonan-2-one (133b):14GeMe3 eMe3Me Me Me1096 133a 133bFollowing general procedure 1, a solution of the cuprate reagent 15 (2.35 mmol, 2equiv.) in dry THF (25 mL) was treated sequentially with trimethylsilyl bromide (750 mg,4.90 mmol, 4 equiv.) and a solution of the bicyclic enone 96 (181 mg, 1.20 mmol, 1 equiv.)in dry THF (1.5 mL). The reaction mixture was stirred at -78 °C for 5 h and warmed to -10over the course of 3 h. ‘H nmr spectroscopic analysis of the crude oil indicated that thecis- and trans-fused addition products, 133a and 1 33b, were present in a ratio of 6:1.111Flash chromatography of the crude product (35 g silica gel, 9:1 petroleum ether - diethylether) provided, after removal of trace amounts of solvent (vacuum pump) from the resultantoil, 379 mg (98%) of a mixture of the compounds 133a and 133b. Further purification bycolumn chromatography provided a partial separation of compounds 133a and 133b. Thefirst few fractions eluted from the column chromatography were concentrated and the oil thusobtained was distilled (air-bath temperature 145-150 °CI0. 1 Torr) to afford the pure trans -fused compound 133b, as a colourless oil.IR (film): 1714, 1604, 1457, 1383, 1236, 1179, 914, 826 cm4.‘H nmr (400 MHz, C6D6) 6: 0.30 (s, 9H, -Gek3), 0.56 (s, 3H, Me-lO), 1.10-1.43 (m, 6H,one of which is H-i 1), 1.48-1.58 (m, 2H), 1.75 (d, 1H, J = 10 Hz, H-i), 1.72-1.82 (m, 2H,191one of which is H-3), 1.90-1.93 (m, 1H, H-li’), 2.09-2.14 (dd, 1H, J = 13.5,5Hz, H-3’),2.28-2.39 (m, 3H, H-9, H-12, and H-12’), 5.31 (br d, 1H, J = 1 Hz, H-14), 5.70 (m, 1H, H-14’).Detailed ‘H nmr data, derived from COSY and NOE experiments, are given in Table 25.13C nmr (75.3 MHz, C6D6) 6: -1.7 (-ye, -Ge(H3)3), 18.7 (-ye, Me-lO), 24.1, 27.7, 35.0(-ye), 36.0, 36.7, 38.3, 39.6, 41.3, 48.6, 65.8 (-ye, C-i), 121.7 (C-i4), 154.2 (C-i3), 208.6(C-2).Exact Mass calcd. for C17H30GeO: 324.1508; found: 324.1506.Anal. calcd. for C17H3OGeO: C 63.21, H 9.36; found: C 63.11, H 9.22.192Table 25: ‘H nmr Data (400 MHz, C6D 6) for the Trans-Fused Vinylgermane Compound133b: COSY and NOE Experimentse Me3Me101 33bAssignment 1H nmr (400 MHz) COSY Correlationsa NOE Correlations aH-x 6 ppm (mult., J (Hz))-GeM3 0.30 (s)Me-lO 0.56 (s) H-9H-li Part of them at 1.10-1.43 H-9, H-1i”, H-i2, H-i2’H-i 1.75 (d, J = 10) H-9H-3 Part of the m at 1.72-1.82 H-3’ H-3’H-il’ 1.90-1.93 (m) H-9, H-li, H-i2, H-i2’ H-il, H-12,H-12’H-3’ 2.09-2. 14 (dd, J = 13.5, 5) H-3 H-3H-9 Part of them at 2.28-2.39 H-i, H-u, H-li’H-12 Part of the m at 2.28-2.39 H-u, H-li’, H-14’H-12’ Part of them at 2.28-2.39 H-li, H-il’, H-i4’H-14 5.3i (brd, J = 1) H-14’H-l4’ 5.70(m) H-i2,H-i2’,H-i4a- Oniy those COSY correlations and NOE data that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-il is more downfield than H-li).193The more polar cis-fused compound 133a was also obtained in a pure fonn byconcentrating the late fractions obtained from the above column chromatography. The oilthus obtained was distilled (air-bath temperature 92-94 °CI0.25 Torr) to provide compound133a, as a colourless oil.IR (film): 1698, 1605, 1457, 1235, 915, 825 cm-1.‘H nmr (400 MHz, C6D6) & 0.26 (s, 9H, -Ge3), 0.83 (s, 3H, Me-lO), 1.08-1.47 (m, 8H,H-7’, H-7, H-3’, H-il, H-4, H-5’, H-5, H-3), 1.66-1.91 (m, 3H, H-8, H-il’, H-4’), 2.09-2.30(m, 4H, H-i2’, H-8’, H-9, H-i2), 2.33 (d, iH, J = 10.5 Hz, H-i), 5.27 (br d, iH, J = 2.5 Hz,H-i4), 5.6 1-5.62 (m, 1H, H-i4’).Detailed 1H nmr data, derived from COSY and NOE experiments, are given in Table 26.Detailed 13C nmr data, derived from HMQC and HMBC experiments, are given in Table 27.Exact Mass calcd. for C17H3OGeO: 324.1508; found: 324.1502.Anal. calcd. for Cj7H3GeO: C 63.22, H 9.36; found: C 62.98, H 9.43.194Table 26: 1H nmr Data (400 MHz, C6D6) for the Cis-Fused Vinylgermane Compound 133a:COSY and NOE Experiments141 13 GeMe32184 7Me 133a10Assignment 1H nmr (400 MHz) COSY Correlationsa NOEH-x ppm (mult., J (Hz)) Correlationsa-GeM3 0.26 (s)Me-lO 0.83 (s) H5’b H-i, H-5, H5’,H-7,H-7’11-3 —1.08-1.11 (m), part of the H-3’, H-4, H-4’mat 1.08-1.47H-5 —1.11-1.20 (m), part of the 11-4’mat 1.08-1.4711-5’ —1.20-1.28 (m), part of the Me-lOm at 1.08-1.47H-4 —1.30-1.40 (m), part of the H-3, H-3’, H-4’mat 1.08-1.47H-li —1.32-1.40 (m), part of the H-9, H-ll’, H-12, H-12’mat 1.08-1.47H-3’ —1.35-1.42 (m), part of the H-3m at 1.08-1.4711-7 —1.40-1.47 (m), part of the H-8, H-8’mat 1.08-1.4711-7’ —1.40-1.47 (m), part of the H-8, 11-8’m at 1.08-1.4711-4’ —1.66-1.70 (m), part of the H-3, H-3’, H-4, H-5, H-5’m at 1.66-1.91H-li’ —1.70-1.80 (m), part of the H-9, H-li, 11-12, H-12’ H-limat 1.66-1.91H-8 —1.80-1.91 (m), part of the H-7, H-7’, H-8’, H-9m at 1.66-1.91H-i2 —2.09-2.10 (m), part of the H-il, H-il’, H-12’, H-l4,m at 2.09-2.30 11-14’H-9 —2. 10-2.15 (m), part of the 11-1, H-8, H-li, H-li’m at 2.09-2.3011-8’ —2.15-2.21 (m), part of the H-7, H-7’, H-8m at 2.09-2.30H-12’ —2.21-2.27 (m), part of the H-il, H-li’, H-i2, H-14,m at 2.09-2.30 H-14’H-i 2.33 (d, J = 10.5) 11-9 11-9, Me-iOH-14 5.27 (br d, J 2.5) 11-12, H-i2’, H-l4’11-14’ 5.61-5.62 (m) 11-12, 11-12’, 11-14a- Oniy those COSY correlations and NOE data that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-5’ is more downfield than H-5).195Table 27: ‘H nmr (500 MHz, C6D6) and ‘3C nmr (125.8 MHz, C6D6) Data for the CisFused Vinylgermane Compound 133a: HMQC and HMBC Experimentsr’133214 7M° 133aC-x nmr HMQcb,c ‘H - ‘3C HMBCb,C(125.8 MHz) 1H nmr Correlations Long-range Correlations6 ppm, APTa 6 ppm (assignment) H-x-Ge(H3)3 -1.7 (-ye) . 0.26 (-GeM3)C-7 21.6 Part of the m (8H) at 1.08-1.47 H-5’ (3 bond), H-8 (2 bond)(H-7 and H7’d)Me-lO 28.4 (-ye) 0.83 (Me-lO) H-i (3 bond), H-5 (3 bond), H-5’ (3 bond)C-4 31.0 Part of them (8H) at 1.08-1.47 H-i (4 bond)(H-4); part of the m (3H) at1.66-1.91 (H-4’)C-li 32.6 Part of the m (8H) at 1.08-1.47 H-i (3 bond), H-12 (2 bond)(H-i 1); part of the m (3H) ati.66-i.9i (H-li’)C-5 34.9 Part of the m (8H) at 1.08-1.47 H-i (3 bond), H-3 (3 bond), H(H-5 and H-5’) 7 and H-7’ (3 bond), H-8 (4bond), Me-lO (3 bond)C-i2 37.2 Part of the m (5H) at 2.09-2.30(H-i2 and H-i2’)C-3 40.i Part of them (8H) at i.08-i.47 H-4 (2 bond), H-5’ (3 bond)(H-3andH-3’)C-8 42.i Part of them (3H) at 1.66-1.91 H-5’ (4 bond)(H-8); part of the m (5H) at2.09-2.30 (H-8’)C-9 42.3 (-ye) Part of them (5H) at 2.09-2.30 H-i (2 bond), H-3’ (4 bond),(H-9) H-il’ (2 bond)C-6 45.4 H-i (2 bond), H-4’ (3 bond),H-5’ (2 bond), H-7 and H-7’ (2bond), Me-iO (2 bond)C-i 62.2 (-ye) 2.33 (H-i) Me-iO (3 bond)C-i4 122.1 5.27 (H-14); 5.6 1-5.62 (H-i4’) H-i2 (3 bond)C-i3 153.8 H-i2 (2 bond), H-i4’ (2 bond)C-2 211.7a- The results of the APT experiment are given in parentheses (-ye for CH and CH3 carbon signals).b-The assignment and the chemical shifts of the 13C nmr spectrum are listed in the first and second columns,respectively. The third column shows the 1H nmr signal(s) which correlate(s) with the carbon of the first twocolumns, as obtained from the 1-IMQC experiment (1 bond correlation). The last column lists the hydrogen(s)which correlate(s) with the 13C nmr signal of the first two columns as obtained from HMBC experiments (2, 3,and 4 bond correlations).c- Only those NMQC and 1-IMBC data that could be assigned are recorded.d- H’ indicates the hydrogen of a pair which is more downfield (H-7’ is more downfield than H-7).1963.4.2.8. Epimerization of compounds 133a and 133b:e Me3 e Me3Me Me133a 133b1 5To a cold (-78 °C), stirred solution of the cis-fused compound 133a (8.0 mg,0.O25mmol, 1 equiv.) in dry MeOH (2.5 mL) was added a solution of NaOMe in dry MeOH(0.30 M, 150 ji.L, 0.044 mmol, 1.8 equiv.). The yellow solution was warmed to rt and wasstirred for 72 h. The MeOH was removed by rotary evaporation and water (5 mL) anddiethyl ether (5 mL) were added to the residue. The layers were separated and the aqueousphase was extracted with diethyl ether (3 x 10 mL). The combined organic extracts weredried over anhydrous magnesium sulfate and concentrated under reduced pressure. Analysisof the crude oil by ‘H nmr spectroscopy indicated that the ratio of the trans- to cis-fusedcompounds (133b:133a) was 5:1.111To a cold (-78 °C), stirred solution of the trans-fused compound 133b (5.0 mg, 0.015mmol, 1 equiv.) in dry MeOH (1.5 mL) was added a solution of NaOMe in dry MeOH (0.30M, 92 p,L, 0.028 mmol, 1.8 equiv.). The yellow solution was warmed to rt and was stirredfor 72 h. The MeOH was removed by rotary evaporation and water (5 mL) and diethyl ether(5 mL) were added to the residue. The layers were separated and the aqueous phase wasextracted with diethyl ether (3 x 10 mL). The combined organic extracts were dried overanhydrous magnesium sulfate and concentrated under reduced pressure. The ratio of thetrans- to cis-fused compounds (133b :133a), as judged by ‘H nmr spectroscopic analysis ofthe crude oil, was determined to be 5:1.1111973.4.3. CONVERSION OF THE BICYCLIC KETO VINYLGERMANES INTO THECORRESPONDING KETO VINYL IODJDES3.4.3.1. Synthesis of (1S*, 6S*, [4.3.Ojnonan-2 -one (1 35a) and (1R , 6S,(135b):OMeJ OMeJ%%1213 I I135a 135bFollowing general procedure 2b, a mixture of the epimeric keto vinylgermanes 130aand 130b (160 mg, 0.50 mmol, 1 equiv., ratio of 130a: 130b was 9:1108) was converted intothe corresponding mixture of the keto vinyl iodides 135a and 135b. Flash chromatography(15 g silica gel, 9:1 petroleum ether - diethyl ether) of the crude product resulted in 150 mg(91%) of an epimeric mixture of the vinyl iodides 135a and 135b, in a ratio of _1.5:1.h12Further column chromatography (25 g silica gel, 9:1 petroleum ether - diethyl ether) resultedin the separation of the cis- and trans-fused vinyl iodides, 135a and 135b. The firstcompound to be eluted from the column chromatography was the trans-fused compound135b. Concentration of the appropriate fractions and distillation (air-bath temperature 119-121 °CI0. 1 Torr) of the oil thus obtained, provided 60 mg of the pure trans-fused vinyl iodide135b, as a pale yellow oil.IR(film): 1710,1618,1452,1106,1048cm-’.nmr (400 MHz) & 1.08 (s, 3H, Me-lO), 1.27-1.42 (m, 3H), 1.46-1.69 (m, 3H), 1.82-1.91(m, 3H), 1.99-2.09 (m, 3H), 2.14-2.48 (m, 4H), 5.63 (br s, 1H, H-14), 5.98 (br d, 1H, J = 1198Hz, H-14’).nmr (75.3 MHz) 6: 21.9 (-ye, Me-lO), 26.9, 28.9, 31.6, 37.7, 41.7, 41.8,42.1, 42.4, 44.8(-ye), 64.9 (-ye, C-i), 113.0 (C-i3), 124.8 (C-14), 210.5 (C-2).Exact Mass calcd. for C14H2 110: 332.0636; found: 322.0633.Anal. calcd. for Cj4HI0: C 50.61, H 6.37, I 38.20; found: C 50.66, H 6.39, I 38.00.The second compound to be eluted from the above column chromatography was thecis-fused compound 135a. The appropriate fractions were concentrated and the oil thusobtained was distilled (air-bath temperature 80-90 °C/0.3 Torr) to provide 90 mg of the purecis-fused vinyl iodide 135a, as a pale yellow oil.IR(film): 1694,1618,1457, 1101 cm’.‘H nmr (400 MHz, C6D6) 6: 0.94-1.13 (m, 2H), 1.04 (s, 3H, Me-lO), 1.14-1.32 (m, 2H),1.43-1.63 (m, 6H), 1.80-1.88 (m, 1H), 1.98-2.20 (m, 4H), 2.24 (br d, 1H, J = 13.5 Hz, H-i),5.48 (br s, 1H, H-14), 5.63 (br d, 1H, J = 1 Hz, H-14’).13C nmr (75.3 MHz, C6D6) 6: 23.6, 27.2 (-ye, Me-lO), 30.7, 30.9, 37.3, 37.4, 40.4 (-ye),41.6, 42.5, 46.4, 62.0 (-ye, C-i), 113.4 (C-13), 125.3 (C-i4), 211.5 (C-2).Exact Mass calcd. for CJ4H2 110: 332.0636; found: 332.0634.Anal. calcd. for C14H2110: C 50.61, H 6.37, I 38.20; found: C 50.77, H 6.38, I 38.00.1993.4.3.2. Synthesis of (1S*, 6S*, -2-one (136):1511OMe1314Me10136Following general procedure 2b, the cis-fused keto vinylgermane 131a (112 mg,0.332 mmol, 1 equiv.) was converted into the cis-fused keto vinyl iodide 136. Flashchromatography (15 g silica gel, 9:1 petroleum ether - diethyl ether) of the crude product anddistillation (air-bath temperature 140-144 °CI0. 12 Torr) of the oil thus obtained, afforded 114mg (99%) of the cis-fused vinyl iodide 136, as a pale yellow oil.JR (film): 1692, 1620, 1460, 1238, 893, 739 cm’.‘H nmr (400 MHz, C6D6) ö: 0.79 (s, 3H, Me), 1.04 (s, 3H, Me), 1.09-1.18 (m, 1H), 1.28-1.51 (m, 8H), 1.55-1.63 (dt, 1H, J = 4.5, 13 Hz), 1.87-1.96 (m, 1H), 1.98 (br s, 1H, H-i),2.02-2. 10 (dt, 1H, J =4, 13.5 Hz), 2.12-2.17 (m, 1H), 2.25-2.30 (m, 1H), 5.47 (br d, 1H, J =1 Hz, H-15), 5.61 (br d, 1H, J = 1 Hz, H-15’).nmr (100.4 MHz, C6D6) & 21.0, 28.1 (-ye, Me), 29.4 (-ye, Me), 36.1, 37.1, 37.3, 40.3,40.5,42.8, 46.4, 48.1, 70.6 (-ye, C-i), 114.4 (C-14), 125.3 (C-15), 211.5 (C-2).Exact Mass calcd. for Cj5H3IO: 346.0793; found: 346.0792.Anal. calcd. for C15H2310: C 52.03, H 6.70, I 36.65; found: C 52.35, H 6.75, I 36.42.2003.4.3.3. Synthesis of (1 S*, 6S*, 3.0]nonan-2-one (137a)and (1R, 6S*, 9S*)..9..(3..Iodo..3..butenyl)bjcyclo[4.3.O]nonan..2...one (13Th):9101I137a 137bFollowing general procedure 2b, a mixture of the cis- and trans-fused ketovinylgermanes 132a and 132b (205 mg, 0.663 mmol, 1 equiv., ratio of 132a: 132b was—19:1 110) was converted into the corresponding epimeric mixture of the keto vinyl iodides137a and 13Th. The crude product was subjected to radial chromatography (2 mm plate, 9:1petroleum ether - diethyl ether) to provide, after removal of trace amounts of residual solvent(vacuum pump) from the resultant oil, 208 mg (98%) of a mixture of the cis- and trans-fusedvinyl iodides 137a and 137b, in a ratio of 5:1.h13 Further column chromatography (25silica gel, 9:1 petroleum ether - diethyl ether) resulted in a partial separation of the twoepimeric iodides, 137a and 137b. The first few fractions eluted from the columnchromatography were concentrated and the oil thus obtained was distilled (air-bathtemperature 126-130 °CI0.1 Torr) to afford 20 mg of the pure trans-fused vinyl iodide 13Th,as a pale yellow oil.JR (film): 1713, 1617, 1448, 1227, 1155, 893 cm4.‘H nmr (400 MHz) & 1.29-1.42 (m, 4H), 1.61-2.44 (m, 13H), 5.65 (br s, 1H, H-13), 6.02-6.03 (br d, 1H, J = 1.5 Hz, H-13’).20113c nmr (75.3 MHz) & 28.0, 28.8, 31.0, 31.1, 35.6 (-ye), 35•7, 41.8, 44.3, 50.0 (-ye), 63.5(-ye, C-i), 112.3 (C-12), 125.0 (C-13), 211.1 (C-2).ExactMass calcd. for C13H 1910: 318.0480; found: 318.0485.Anal. calcd. for Cj3H 1910: C 49.07, H 6.02, I 39.88; found: C 48.76, H 5.95,139.90.The late fractions eluted from the above column chromatography were concentratedand the oil thus obtained was distilled (air-bath temperature 98-102 °C/0.13 Torr) to provide88 mg of the pure cis-fused vinyl iodide 137b, as a pale yellow oil.IR(film): 1707, 1616, 1429, 1153, 892 cm-1.‘H nmr (400 MHz) 6: 1.41-1.94 (m, 1OH), 2.05-2.15 (m, 2H), 2.30-2.47 (m, 4H), 2.68-2.72(dd, 1H, J = 8, 8 Hz, H-i), 5.66 (br s, 1H, H-13), 5.99-6.00 (m, 1H, H-13’).‘3C nmr (75.3 MHz) 6: 23.7, 28.2, 29.5, 29.8, 31.8, 41.7 (-ye), 42.4 (-ye), 42.8, 44.7, 55.0(-ye, C-i), 112.2 (C-i2), 125.4 (C-13), 214.6 (C-2).ExactMass calcd. for Cj3H 1910: 318.0480; found: 318.0482.Anal. calcd. for Cj3H 1910: C 49.07, H 6.02, I 39.88; found: C 49.25, H 6.04,139.70.The middle fractions eluted from the above column chromatography wereconcentrated to provide 100 mg of a mixture of the cis- and trans-fused vinyl iodides 137aand 137b.2023.4.3.4. Synthesis of (1R ‘, 6S*, -one (1 38a) and (1 S*, 6S*, .0]nonan-2-one(138b):1913IMe Me10138a 138bFollowing general procedure 2b, an epimeric mixture of the keto vinylgermanes 133aand 133b (193 mg, 0.598 mmol, 1 equiv., the ratio of 133a:133b was 1:4111) was convertedinto the corresponding mixture of the keto vinyl iodides 138a and 138b. The crude productwas subjected to radial chromatography (2 mm plate, 9:1 petroleum ether - diethyl ether) toprovide, after removal of trace amounts of solvent (vacuum pump) from the resultant oil, 182mg (92%) of an epimeric mixture of the cis- and trans-fused vinyl iodides 138a and 138b, ina ratio of P.1:5.114 Further purification by column chromatography (25 silica gel, 19:1petroleum ether - diethyl ether) resulted in a partial separation of the two iodides 138a and138b. The first few fractions eluted from the column chromatography were concentrated andthe oil thus obtained was distilled (air-bath temperature 140-145 °C/0.25 Torr) to afford 83mg of the pure trans-fused vinyl iodide 138b, as a pale yellow oil.JR (film): 1708, 1617, 1456, 1383, 1182, 892 cm’.nmr (400 MHz, C6D6) & 0.50 (s, 3H, Me-lO), 0.94-1.80 (m, 12H), 2.07-2.39 (m, 4H),5.56 (m, 1H, H-14), 5.78-5.79 (m, 1H, H-14’).13C nmr (75.3 MHz) 6: 18.6 (-ye, Me-lO), 24.2, 27.5, 33.6 (-ye), 36.0, 38.3, 39.5, 41.4, 44.5,20349.2, 66.0 (-ye, C-i), 112.3 (C-i3), 125.0 (C-i4), 211.2 (C-2).Exact Mass calcd. for C14H2110: 332.0636; found: 332.0641.Anal. calcd. for C14H21IO: C 50.61, H 6.37, I 38.20; found: C 50.53, H 6.37, I 38.00.The late fractions eluted from the above column chromatography were concentratedand the oil thus obtained was distilled (air-bath temperature 125-130 °/C.0.2 Torr) to afford15 mg of the pure cis-fused vinyl iodide 138a, as a pale yellow oil.IR(film): 1698, 1616, 1456, 1187, 893 cm-1.‘H nmr (400 MHz, C6D6) 6: 0.80 (s, 3H, Me-lO), 1.03-1.26 (m, 4H), 1.32-1.55 (m, 5H),1.72-1.87 (m, 2H), 2.19 (d, 1H, J = 9.5 Hz, H-i), 1.96-2.21 (m, 4H), 5.54 (m, 1H, H-i4),5.70-5.7 1 (br d, iH, J = 1.5 Hz, H-i4’).nmr (75.3 MHz, C6D6) 6: 21.6, 28.7 (-ye, Me-lO), 30.7, 32.5, 35.0, 39.4, 41.2 (-ye),42.1,44.8, 45.5, 61.8 (-ye, C-i), 112.4 (C-13), 125.5 (C-i4), 211.7 (C-2).Exact Mass calcd. for CJ4H2110: 332.0636; found: 332.0637.Anal. calcd. for C14H2 110: C 50.61, H 6.37, I 38.20; found: C 50.58, H 6.38, I 38.08.The middle fractions eluted from the above column chromatography wereconcentrated to provide 84 mg of a mixture of the cis- and trans-fused vinyl iodides 138a and138b.2043.4.4. Pd(0)-CATALYZED CYCLIZATION REACTIONS OF THE BICYCLIC VINYLIODIDES TO PRODUCE TRICYCLIC RING SYSTEMS3.4.4.1. Synthesis of (1 S*, 5S*, 8 S*)5Methyl2methy1enetricyclo[6.4.0.0l‘5]dodecan- 12-one (139) and (1S*, 4S*, 7R *, 1 1S*) 1-Methyl-8-methylenetricyclo[5.3.2.04”1]dodecan-12-one (140):MeI :51Me j7121;Me135a 139 140a. Via a Pd(0)-Catalyzed Cycization of the Cis-Fused Vinyl Iodide 135a:To a stirred solution of the cis-fused vinyl iodide 135a (65 mg, 0.20 mmol, 1 equiv.)in dry THF (3.9 mL) at rt was added Pd(PPh3)4115 (55 mg, 0.048 mmol, 24 mol%). Asolution of t-BuOK in dry THF and dry t-BuOH (0.1 M, 4:1 THF: t-BuOH, 2.3 mL, 0.22mmol, 1.15 equiv.) was added, via a syringe pump, over 6.5 h. The reaction mixture wasstirred at rt for an additional 3 h and worked up as described in general procedure 3. Thecrude product was flash chromatographed (15 g silica gel, 19:1 petroleum ether - diethylether) to yield two cyclized compounds, 139 and 140. The first compound to be eluted wasconcentrated and the oil thus obtained was distilled (air-bath temperature 76-80 °C/0.05 Torr)to afford 17 mg (41%) of the fused tricyclic keto alkene 139, as a colourless oil.IR (film): 1703, 1636, 1462, 1222, 1010, 892 cm4.nmr (400 MHz) 6: 1.16 (s, 3H, Me-14), 1.26-1.36 (m, 1H), 1.40-1.63 (m, 4H, two ofwhich are H-4 and H-7), 1.67-1.78 (m, 2H, H-9 and H-b), 1.83-2. 12 (m, 4H, H-4’, H-8, H-9’,and H-b’), 2.25-2.32 (m, 1H, H-il), 2.39-2.45 (m, 2H, H-3 and H-3’), 2.57-2.64 (m, 1H, Hii’), 5.08 (br s, 1H, H-13), 5.16 (br s, 1H, H-13’).Detailed ‘H nmr data, derived from COSY and NOE experiments, are given in Table 28.nmr (75.3 MHz) & 22.9, 23.8, 24.7 (-ye, Me-14), 27.8, 34.4, 38.4, 38.5, 38.6, 46.8 (-ye,C-8), 52.5, 69.0 (C-i), 110.0 (C-13), 153.9 (C-2), 210.5 (C-12).ExactMass calcd. for C14H200: 204.1514; found: 204.1514.205206Table 28: 1H nmr Data (400 MHz, CDC13) for the Fused Tricyclic Compound 139: COSYand NOE ExperimentsH13’LI13..ri139Assignment ‘H nmr (400 MHz) COSY Correlationsa NOEH-x ö ppm (mult., J (Hz)) CorrelationsaMe-14 1.16 (s) H-8H-7 Partofthematl.40-1.63 H-8H-4 Part of the m at 1.40-1.63 H-3, H3’b, H-4’H-9 Part of the m at 1.67-1.78 H-8, H-9’, H-i0’H-i0 Part of them at 1.67-1.78 H-l0’, H-li, H-il’H-4’ -l.83-1.95 (m), part of the H-3, H-3’, H-4m at 1.83-2.21H-9’ —1.83-1.95 (m), part of the H-8, H-9, H-10, H-10’, H-li’m at 1.83-2.21H-l0’ —1.95-2.05 (m), part of the H-9, H-9’, H-i0, H-li, H-li’m at 1.83-2.2 1H-8 —2.05-2.12 (m), part of the H-7, H-9, H-9’m at 1.83-2.21H-li 2.25-2.32 (m) H-10, H-b’, H-il’ H-li’H-3 and H-3’ Part of the m at 2.39-2.45 H-4, H-4’, H-13, H-13’H-li’ 2.57-2.64 (m) H-9’, H-iO, H-b’, H-il H-10’, H-li,H-13H-13 5.08 (br s) H-3, H-3’, H-13’ H-9’, H-i 1’,H- 13’H-13’ 5.16 (br s) H-3, H-3’, H-i3 H-3 and H-3’,H-i3a- Only those COSY correlations and NOE data that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-3’ is more downfield than H-3)207The second compound to be eluted from the above column chromatography was thebridged keto alkene 140. Concentration of the appropriate fractions and distillation (air-bathtemperature 86-88 °C/0.25 Torr) of the oil thus obtained, provided 13 mg (33%) of thebridged tricycle compound 140, as a colourless oil.JR (film): 1700, 1633, 1457, 1255, 894 cm-1.nmr (400 MHz) & 1.10 (s, 3H, Me-13), 1.43-1.52 (m, 2H, H-3 and H-b), 1.56-1.68 (m,3H, H-2, H-5, and H-5’), 1.71-1.79 (m, 2H, H-3’ and H-b’), 1.84-2.04 (m, 3H, H-2’, H-6, andH-6’), 2.12-2. 19 (br dd, 1H, J = 15, 11 Hz, H-9), 2.38 (br d, 1H, J = 8.5 Hz, H-li), 2.34-2.40 (m, 1H, H-9’), 2.49-2.52 (ddddd, 1H, J = 8.5, 8.5, 8.5, 8.5, 3 Hz, H-4), 3.26 (br s, 1H,H-7), 4.81 (br s, 1H, H-14), 4.95 (br s, 1H, H-14’).Detailed ‘H nmr data, derived from COSY and NOE experiments, are given in Table 29.Detailed 13C nmr data, derived from HMQC and HMBC experiments, are given in Table 30.ExactMass calcd. for CJ4H200: 204.1514; found: 204.1519.Anal. calcd. for C14H200: C 82.30, H 9.87; found: C 82.12, H 10.10.208Table 29: ‘H nmr Data (400 MHz, CDC13) for the Bridged Tricyclic Compound 140:COSY and NOE Experiments14HHj71211Me140Assignment ‘H nmr (400 MHz) COSY Correlationsa NOE Correlations aH-x ppm (mult., J (Hz))Me-13 1.10(s) H-9,H-10,H-11H-3 Part of them at 1.43-1.52 H-2, H-2”, H-3’H-10 Part of the m at 1.43-1.52 H-9, H-9’, H-10’H-2 Part of the m at 1.56-1.68 H-2’, H-3, H-3’, H-4H-5 Part of the m at 1.56-1.68 H-4, H-6, H-6’H-5’ Part of the m at 1.56-1.68 H-4, H-6, H-6’H-3’ Part of the m at 1.71-1.79 H-2, H-2’, H-3H-10’ Part of them at 1.71-1.79 H-9, H-9’, H-10H-2’ Part of the m at 1.84-2.04 H-2, H-3, H-3’H-6 Part of the m at 1.84-2.04 H-5, H-5’, H-6’, H-7H-6’ Part of the m at 1.84-2.04 H-5, H-5’, H-6, H-7H-9 2.12-2.19 (brdd, J = 15, 11) H-9’, H-10, H-b’, H-14’ H-9’, H-b’H11d 2.38 (brd, J = 8.5) H-4, H7C H-9, Me-13, H-14’H9’d 2.34-2.40 (m) H-9, H-b, H-10’, H-14’ H-9, Me-13, H-14’H-4 2.49-2.52 (ddddd, J = 8.5, H-2, H-5, H-5’, H-li8.5, 8.5, 8.5, 3)H-7 3.26(brs) H-6, H-6’, H-il”, H-14,H-14’H-14 4.81 (br s) H-7, H-14’H-14’ 4.95 (br s) H-7, H-9, H-9’, H-14’a- Oniy those COSY correlations and NOB data that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (11-2’ is more downfield than H-2).C- W-couplingd- The multiplet containing both H-9’ and H-li was irradiated in a NOE experiment.209Table 30: ‘H nmr (500 MHz, CDC13) and 13C nmr (125.8 MHz, CDC13) Data for theBridged Compound 140: HMQC and HMBC ExperimentsH14’14HH712Me13140Assignment ‘3C nmr HMQCa,b ‘H - 13C HMBCa,bC-x (125.8 ‘H nmr Correlations (500 MHz) Long-range CorrelationsMHz)6 ppm (assignment) H-x6 ppmC-S 26.8 Part of the m (3H) at 1.52-1.63(H-5 and H5’b)Me-13 28.6 1.10 (Me-13)C-2 30.9 Part of the m (3H) at 1.56-1.68(H-2); part of the m (3H) at 1.84-2.04 (H-2’)C-9 33.2 2. 12-2. 19 (11-9); 2.34-2.40 (H-9’) H-14 (3 bond), H-14’ (3 bond)C-6 33.5 Part of the m (3H) at 1.84-2.04 H-14 (4 bond), H-14’ (4 bond)(H-6 and H-6’)C-b 38.8 Part of the m (211) at 1.43-1.52 H-9’ (2 bond) and/or H-11(3(H-10); part of the m (2H) at bond)C, Me-13 (3 bond)1.71-1.79 (H-b’)C-3 40.4 Part of the m (2H) at 1.43-1.52 Me-13 (4 bond)(H-3); part of the m (2H) at 1.71-1.79 (H-3’)C-4 42.7 2.49-2.52 (H-4)C-i 45.4 11-9’ (3 bond) and/or H-il (2bond)C, Me-13 (2 bond)C-7 55.3 3.26 (11-7) H-14 (3 bond), H-14’ (3 bond)C-il 63.4 2.38 (H-li) Me-13(3bond)C-14 112.7 4.81 (H-14); 4.95 (H-14’)C-8 147.6C-12 214.2 H-il (2bond)a-The assignment and the chemical shifts of the 13C nmr spectrum are listed in the first and second columns,respectively. The third column shows the nnw signal(s) which correlate(s) with the carbon of the first twocolumns, as obtained from the 1-IIvIQC experiment (1 bond correlation). The last column lists the hydrogen(s)which correlate(s) with the 13C nmr signal of the first two columns as obtained from IIMBC experiments (2, 3,and 4 bond correlations).b- Only those HMQC and NMBC data that could be assigned are recorded.c- Since H-9 and H-il have very similar chemical shifts, the correlations to the multiplet containing these twoprotons may be due to H-9 or H-il or both signals.d- H’ indicates the hydrogen of a pair which is more downfield (H-5’ is more downfield than H-5).210o MeI:51Me j712llMe135b 139 140b. Via a Pd(0)-Catalyzed Cyclization of the Trans-Fused Vinyl Iodide 135b:To a stirred solution of the trans-fused vinyl iodide 135b (40 mg, 0.12 mmol, 1equiv.) in dry THF (1.4 mL) at it was added Pd(PPh3)4115 (38 mg, 0.033 mmol, 25 mol%).A solution of t-BuOK in dry THF and dry t-BuOH (0.1 M, 4:1 THF: t-BuOH, 1.4 mL, 0.14mmol, 1.15 equiv.) was added, via a syringe pump, over 4 h. The mixture was stirred at rt foran additional 3.5 h and worked up as described in general procedure 3. The crude productwas subjected to flash chromatography (8 g silica gel, 19:1 petroleum ether - diethyl ether) toprovide 8.8 mg (36%) of the fused thcyclic compound 139 followed by 7.1 mg (29%) of thebridged compound 140 (the spectral data of compounds 139 and 140 are identical with thosereported above).c. Via a Pd(0)-Catalyzed Cyclization of the Trans-Fused Vinyl Iodide 135bemploying modified reaction conditions:116To a stirred solution of the trans-fused vinyl iodide 135b (34 mg, 0.10 mmol, 1equiv.) in dry THF (13.0 mL) at rt was added Pd(PPh3)4115 (32 mg, 0.028 mmol, 28 mol%).A solution of t-BuOK in dry THF (0.1 M, 1.2 mL, 0.12 mmol, 1.15 equiv.) was added, via asyringe pump, over 5.5 h. The mixture was stirred at it for an additional 1 h and subjected tothe workup conditions as described in general procedure 3. Flash chromatography (8 g silicagel, 19:1 petroleum ether - diethyl ether) of the crude product afforded 14 mg (66%) of thefused tricycic compound 139 followed by 1 mg (4%) of the bridged compound 140 (thespectral data of compounds 139 and 140 are identical with those reported above). The ratioof the fused to bridged compounds (139:140) in this modified cycization experiment is21117:1,117 which is in sharp contrast to the 1.2:1 ratio118 observed in the two previousexamples.3.4.4.2. Synthesis of (iS *, 5 S*, 8S, 1 2S*)5Methyl2methylenetricyclo[6.4.0.0 1,5j -dodecan- 1 2-ol (142):HO\2 14142To a cold (-78 °C), stirred solution of the fused tricyclic compound 139 (10 mg, 0.049mmol, 1 equiv.) in dry THF (0.5 mL) was added a solution of DIBAL in hexanes (1 M, 89iiL, 0.089 mmol, 1.8 equiv.). The solution was stirred at -78 °C for 1 h. Water (2 mL) wasadded and the solution was warmed to ii and was stirred for 30 mm. Aqueous NH4C1 -NH4OH (pH 8-9, 2 mL) was added and the layers were separated. The aqueous phase wasextracted with diethyl ether (3 x 15 mL). The combined organic extracts were dried overanhydrous magnesium sulfate and concentrated under reduced pressure. The crude productwas flash chromatographed (2 g silica gel, 9:1 petroleum ether - diethyl ether) to afford 10mg (90%) of the solid alcohol 142, a single diastereomer (as indicated by ‘H nmrspectroscopic analysis). The alcohol 142 was recrystallized from petroleum ether - diethylether to provide a colourless crystalline solid, mp 53-55 °C.JR (KBr): 3467, 3394, 1636, 1467, 1072, 896 cm-’.lHnmr(400 MHz) & i.14(s, 3H, Me-14), 1.20-1.82 (m, 14H), 2.31-2.42 (m, 2H), 3.58-3.65212(m, 1H, H-12), 5.11 (br s, 1H, H-13), 5.28 (br s, 1H, H-1Y).NOE difference experiments: irradiation of the signal at 6 1.14 (Me-14) caused anenhancement of the signal at 6 3.58-3.65 (H-12); irradiation of the signal at 6 3.58-3.65 (H12) caused an enhancement of the signal at 6 1.14 (Me-14).l3 nmr (75.3 MHz) 6: 23.9, 24.4, 24.8 (-ye, Me-14), 29.8, 30.9, 35.2, 39.2, 39.5, 47.2 (-ye,C-8), 53.0, 60.9, 73.2 (-ye, C-12), 111.7 (C-13), 154.6 (C-2).Exact Mass calcd. for C14H220: 206.1671; found: 206.1666.Anal. calcd. for C14H220: C 81.50, H 10.75; found: C 81.32, H 10.78.3.4.4.3. Synthesis of (1S*, 4S*, 7R*, 11S’,[5.3.2.04,1 ‘]dodecan-12-ol (144):13H12ii 1FMe144To a cold (-78 °C), stirred solution of the bridged tricyclic compound 140 (20 mg,0.098 mmol, 1 equiv.) in dry THF (1 mL) was added a solution of DIBAL in hexanes (1 M,171 p.L, 0.17 1 mmol, 1.7 equiv.). The solution was stirred at -78 °C for 1.5 h. Water (4 mL)was added and the solution was warmed to 11 and was stirred for 30 mm. Aqueous NH4C1 -NH4OH (pH 8-9, 4 mL) was added and the layers were separated. The aqueous phase wasextracted with diethyl ether (3 x 20 mL). The combined organic extracts were dried over213anhydrous magnesium sulfate and concentrated under reduced pressure. The crude productwas subjected to radial chromatography (1 mm plate, 9:1 petroleum ether - diethyl ether) andthe oil thus obtained was distilled (air-bath temperature 65-70 °CI0.4 Torr) to provide 19 mg(93%) of the bridged alcohol 144, a single diastereomer (as indicated by ‘H nmrspectroscopic analysis). The alcohol 144 subsequently solidified and was recrystallized frompetroleum ether - diethyl ether to afford a translucent solid, mp 3 1-32 °C.JR (KBr): 3468, 3420, 1630, 1457, 1259, 1067, 889 cm’.‘H nmr (400 MHz) 6: 1.14 (s, 3H, Me-13), 1.29-1.43 (m, 4H, H-2, H-4, H-5, and H-5’), 1.51-1.72 (m, 5H, four of which are -Ofl, H-6, H-lO, and H-10’; this multiplet collapses to 4protons upon the addition of D20), 1.79-1.87 (m, 2H, H-2’ and H-6’), 2.01-2. 14 (m, 2H, oneof which is H-il), 2.35-2.40 (br dd, 1H, J = 12.5, 6 Hz, H-9), 2.45-2.51 (br dd, 1H, J =12.5, 12.5 Hz, H-9’), 2.68 (br s, 1H, H-7), 3.99 (br s, 1H, H-12; this signal collapses to add (J= 6, 6 Hz) upon the addition of D20), 4.77 (br d, 1H, J = 2.5 Hz, H-14), 4.84 (br s, 1H, H14’).Detailed 1H nmr data, derived from a COSY experiment, are given in Table 31.nmr (75.3 MHz) 6: 24.1, 29.7, 30.7, 33.9, 35.7 (-ye), 38.2, 39.9, 41.3 (-ye), 42.6, 47.7(-ye), 53.1 (-ye), 73.4 (-ye, C-12), 115.2 (C-14), 152.5 (C-8).ExactMass calcd. for C14H22O: 206.1671; found: 206.1670.Anal. calcd. for C14H22O: C 81.50, H 10.75; found: C 81.25, H 10.58.214Table 31: ‘H nmr Data (400 MHz, CDC13) for the Bridged Alcohol 144: COSY ExperimentH 10. 13Hj712iMe144Assignment ‘H nmr (400 MHz) COSY CorrelationsaH-x ppm (mult., J (Hz))Me-13 1.14(s)H-2 Part of the m at 1.29-1.43 H-2H-4 Part of the m at 1.29-1.43 H-ilH-5 Part of them at 1.29-1.43 H-6, H-6’H-5’ Part of the m at 1.29-1.43 H-6, H-6’H-6 Part of them at 1.51-1.72 H-5, H-5’, H-6’, H-7H-10 Part of them at 1.51-1.72 H-9, H-9’H-b’ Part of the m at 1.51-1.72 H-9, H-9’-OH Part of themat 1.51-1.72;disappears upon the addition ofD20H-2’ Part of them at 1.79-1.87 H-2H-6’ Part of the m at 1.79-1.87 H-5, H-5’, H-6, H-7H-li Part of them at 2.01-2.14 H-4, H-12H-9 2.35-2.40 (brdd, J = 12.5,6) H-9’, H-b, H-i0’, H-14’H-9’ 2.45-2.51 (brdd, J = 12.5, 12.5) H-9, H-i0, H-i0’, H-14, H-14’H-7 2.68 (br s) H-6, H-6’, H-12H-12 3.99 (br s); 3.99 (dd, J = 6, 6) H-7, H-ilupon the addition of D 20H-14 4.77 (br d, J = 2.5) H-9’, H-14’H-14’ 4.84 (br s) H-9, H-9’, H-14a- Only those COSY correlations and NOB data that could be assigned are recorded.b- If indicates the hydrogen of a pair which is more downfield (H-2’ is more downfield than H-2).2153.4.4.4. Synthesis of (iS , 4S*, 7R*, 115*, 12S*) 1 -Methyl-8-methylene- l2-p-nitrobenzoyloxy-thcyclo[5.3.2.0J1]dodecane (145):NO213Hl2111Me145To a stirred solution of the bridged alcohol 144 (14 mg, 0.068 mmol, 1 equiv.), dry iPr2NEt (24 jiL, 0.13 mmol, 2 equiv.), and DMAP (8 mg, 0.07 mmol, 1 equiv.) in dry THF(3.4 mL) at rt was added p-nitrobenzoyl chloride (62 mg, 0.33 mmol, 5 equiv.). The cloudymixture was refluxed for 3 h; water (10 mL) and brine (10 mL) were added to the mixtureand the layers were separated. The aqueous layer was extracted with CH2C12 (3 x 15 mL)and the combined organic extracts were dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The crude product was flash chromatographed (15 gsilica gel, 9:1 petroleum ether - diethyl ether) and the solid thus obtained was recrystallizedfrom MeOH- H20 to afford 22 mg (92%) of the ester 145, as thin colourless plates, mp 86-87 °C. X-ray crystallographic analysis66 of this material confirmed the constitution andrelative configuration shown above.IR(KBr): 3116, 1722, 1632, 1608, 1530, 1275, 1103, 720 cm-1.‘H nmr (400 MHz) & 1.06 (s, 3H, Me-13), 1.25 (br s, 1H), 1.35-1.50 (m, 3H), 1.60-1.66 (m,1H), 1.72-1.92 (m, 5H), 2.24-2.30 (m, 2H), 2.47-2.52 (dd, 1H, J = 13, 7 Hz, H-9), 2.56-2.63(dd, 1H, J = 13, 13 Hz, H-9’), 2.95-2.97 (m, 1H, H-7), 4.65 (br d, 1H, J = 2.5 Hz, H-14),4.77 (br d, 1H, J = 2.5, H-14’), 5.42 (dd, ill, J = 5.5, 5.5 Hz, H-12), 8.19-8.22 (br d, 2H, J= 9 Hz, aromatic protons), 8.29-2.3 1 (br d, 2H, J = 9 Hz, aromatic protons).13C nmr (75.3 MHz) 6: 24.3, 29.7, 29.8, 31.2, 34.0, 34.7 (-ye), 38.2, 39.3, 41.5 (-ye), 42.9,44.0 (-ye), 50.5 (-ye), 78.1 (-ye, C-12), 114.2 (C-14), 123.6 (-ye), 130.6 (-ye), 151.6 (C-8).Exact Mass calcd. for C21H25N04: 355.1783; found: 355.1777.216•CcI-H‘Hr=r‘HI‘pq)8L17‘(cl-H‘HI‘siq)8917‘(L-H‘HI‘SN)8Z‘(6-H‘Zil01‘c=F‘HT‘ppq).i-ji‘(11-H‘HI‘siq)‘(6-H‘Hc6‘SI=F‘HI‘ppq)lI-9Ol‘(19-H‘HI‘uI)VWI-ILI‘(9-H‘HI‘in)691-E91‘Cm-HSiqnqJOUO‘HE‘in)551-WI‘(01-H!q!qJOuo‘HV‘w8EI-I1‘(EI-I’‘HE‘5N)lOT‘(c-H‘HI‘in)001-L60‘(vI-N‘HE‘s)980:g(9uD‘ziiwoov)nuu1U101768‘LcI‘65171‘EE9I‘L691:(uijg)ai.p0SSIJn010o‘as’a‘9,jpunodulo3op.npopuqoqijo(o9)WLIpp1A0Jd‘pupflqoSnipI!0q1jo(noicI•or. 0176-Z6aini’aidwiqi’aq-iw)uou’ajnsippu’aionpoidpn.oqijo(iqioAqip-ioqwnoxod1:6‘p‘aoqisg)Cqd’a.ioi’auioiqqs’aj(1!opn.ooqijowtudsiwuHjqiU’piusqoSliMpunodwoo)Tf(oulpsnjouoi)9V1punodwooppuqqis’aionpoidpzqoAoojos1’a1pol’aoipuip0pn.ioqijosisi(plu’aidoosoJ1odsmUHjEainpoomc1j’aJuuipqusops’asuoppuoodnjJoMqi01p1o[qnspuiiqzI’auOP!pp’au’amoj‘apupsSliMäIfl1!UIuoo’aazqjqJAO‘dwnduu&s‘a‘alA‘ppp’aSliM(iunbcn‘10mw17I0“1W1L0‘HOa-:tIHl1:17‘No)HOH-‘ppU’aJilli(pUT)IO-1jouounjosv(%Jowç‘JOWUIIEOO‘U19)ç117(EqJJ)pdppp’a‘aAimIli(‘jwc’z)JHI‘‘Pui(ArnbI‘jowwzt•o£17)9ELpipoipCuTApsnj-sioqijouognjospaups‘aoj9171.N.A4LALH:(917J)UO-Z1-u’apop-lI-(ksTI‘*IL‘*S’V‘*II)JOSSq1U(•c•vy9I.LIZDetailed 1H nmr data, derived from COSY and NOE experiments, are given in Table 32.nmr (75.3 MHz, C6D6) 8: 28.5 (-ye, Me), 30.9 (-ye, Me), 31.1, 32.0, 33.3, 38.9, 39.0,40.1, 45.6, 47.2, 56.2 (-ye, C-il), 70.9 (-ye, C-7), 112.9 (C-15), 148.6 (C-8), 210.6 (C-i2).ExactMass calcd. for C15H220: 218.1671; found: 218.1669.Anal. caled. for C15H22O: C 82.52, H 10.16; found: C 82.30, H 10.19.218219Table 32: ‘H nmr Data (400 MHz, C6D6) for the Bridged Compound 146: COSY and NOEH15j7 1211MeMe14146Assignment ‘H nmr (400 MHz) COSY Correlationsa NOEH-x ppm (mult., J (Hz)) CorrelationsaMe-14 0.86 (s) H-&-’, H-liH-5 0.97-1.00 (m) H-6, H-6’Me-13 1.01 (brs) H-b’ H-ilH-10 Part of the m at 1.12-1.38 H-9, H-9’, H-b’H-10’ Part of them at 1.40-1.55 H-9, H-9’, H-iO, Me-13H-6 1.63-1.69 (m) H-5, H-6’H-6’ 1.71-1.84 (m) H-5, H-6 H-6, H-7, Me-14H-9 2.06-2.12 (brdd, J = 15, H-9’, H-b, H-b’, H-15’9.5)H-li 2.16 (br s) H-7 Me-13, Me-14H-9’ 2.21-2.28 (br dd, J = 15, H-9, H-b, H-10’, H-i5’10)H-7 3.28 (br s) H-6, H-6’, H-il, H-15 H-6’, H-15H-15 4.68 (br s) H-7, H-15’H-15’ 4.78 (br d, J = 1) H-9, H-9’, H-i5a- Only those COSY correlations and NOE data that could be assigned are recorded.b- H indicates the hydrogen of a pair which is more downfield (H-6’ is more downfield than H-6).Experiments2203.4.4.6. Synthesis of (1R*, 5S*, 8 S*)2Methylenetricyclo[6.4.0.0l‘5]dodecan- 12-one (147)and (1S*, 4R *, 7R*, 1 1S*)8Methylenetricyclo[5.3.2.041]dodecan- 12-one (148):HI::251H Hj712115137a 147 148a. Via a Pd(0)-Catalyzed Cyclization of the Cis-Fused Vinyl Iodide 137a:To a stirred solution of the cis-fused vinyl iodide 137a (66 mg, 0.21 mmol, 1 equiv.)in dry THF (4.1 mL) at rt was added Pd(PPh3)4115 (53 mg, 0.046 mmol, 22 mol%). Asolution of t-BuOK in dry THF and dry t-BuOH (0.1 M, 4:1 THF : t-BuOH, 2.4 mL, 0.24mmol, 1.15 equiv.) was added, via a syringe pump, over 6 h. The mixture was stirred at rt foran additional 3 h and worked up as described in general procedure 3. Analysis (gic) of thecrude oil indicated an 11:1 ratio of the fused to bridged cycized products, 147 and 148.Flash chromatography (8 g silica gel, 9:1 petroleum ether - diethyl ether) of the crude oilprovided two compounds. The first compound to be eluted was the fused tricyclic compound147. The appropriate fractions were concentrated and the oil thus obtained was distilled (airbath temperature 84-88 °C/0.2 Torr) to afford 16 mg (41%) of the fused compound 147, as acolourless oil.IR(film): 3094, 1707, 1635, 1464, 1222, 894 cm-’.‘H nmr (400 MHz) & 1.20-1.43 (m, 2H), 1.52-1.56 (m, 1H, H-4), 1.61-2.11 (m, 8H, four ofwhich are H-4, H-9, H-b, and H-b’), 2.27-2.33 (m, 1H, H-li), 2.39-2.48 (m, 2H, H-3 andH-3’), 2.74-2.83 (m, 2H, one of which is H-li’), 5.15 (br s, 1H, H-13), 5.26 (br s, 1H, H-13’).Detailed ‘H nmr data, derived from COSY and NOE experiments, are given in Table 33.nmr (75.3 MHz) 6: 23.2, 25.5, 29.7, 29.8, 31.2, 36.4, 37.1, 44•5 (-ye), 52.1 (-ye), 69.4(C-i), 110.8 (C-13), 151.6 (C-2), 210.4 (C-12).ExactMass calcd. for Cj3H 180: 190.1358; found: 190.1361.Anal. calcd. for C13H 180: C 82.06, H 9.53; found: C 82.17, H 9.55.221222Table 33: ‘H nmr Data (400 MHz, CDC13) for the Fused Tricyclic Compound 147: COSYand NOE ExperimentsH13’13H44147Assignment 1H nmr (400 MHz) COSY Correlationsa [NOE Correlations aH-x ppm (mult., J (Hz))H-4 1.52-1.56 (m) H-3, H3’b, H-4’H-4’ —1.80-1.85 (m), part of the H-3, H-3’, H-4m at 1.61-2.11H-9 —1.85-1.88 (m), part of the H-b, H-b’m at 1.61-2.11H-i0 —1.61-1.75 (m), part of the H-9, H-10’, H-il, H-li’m at 1.61-2.11H-i0’ —2.06-2.11 (m), part of the H-9, H-10, H-li, H-il’m at 1.61-2.11H-li 2.27-2.33 (m) H-iO, H-b’, H-li’ H-li’H-3 and H-3’ 2.39-2.48 (m) H-4, H-4’, H-i3, H-bY H-4, H-4’, H-i3’H-li’ Part of the m at 2.74-2.83 H-iO, H-b’, H-il H-il, H-i3H-13 5.15 (brs) H-3, H-3’, H-l3’ H-9, H-li’, H-i3’H-i3’ 5.26 (br s) H-3, H-3’, H-13 H-3 and H-3’, H-i3a- Only those COSY correlations and NOE data that could be assigned are recorded.b- H indicates the hydrogen of a pair which is more downfield (H-3’ is more downfield than H-3).The late fractions eluted from the above column chromatography were concentratedto provide, after removal of trace amounts of solvent (vacuum pump) from the resultant oil,1.5 mg (4%) of the bridged compound 148, as a colourless oil.JR (film): 1710,1632, 1447,1276,750cm-.223‘H nmr (400 MHz) & 1.25-2.52 (m, 14H), 2.74-2.79 (dd, 1H, J = 8.5, 8.5 Hz, H-li), 3.29(br s, 1H, H-7), 4.82-4.83 (dd, 1H, J = 1.5, 1.5 Hz, H-13), 4.94-4.95 (dd, 1H, J = 1.5, 1.5Hz, H-13’).Exact Mass calcd. for C13H 180: 190.1358; found: 190.1353.° HI::25?H j71211iH137b 147 148b. Via a Pd(0)-Catalyzed Cydization of the Trans-Fused Vinyl Iodide 13Th:To a stirred solution of the trans-fused vinyl iodide 137b (32 mg, 0.10 mmol, 1equiv.) in dry THF (2 mL) at rt was added Pd(PPh3)4115 (34 mg, 0.029 mmol, 29 mol%). Asolution of t-BuOK in dry THF and dry t-BuOH (0.1 M, 4:1 THF: t-BuOH, 1.2 mL, 0.12mmol, 1.15 equiv.) was added, via a syringe pump, over 5 h. The mixture was stirred at rtovernight and was worked up as described in general procedure 3. Analysis (gic) of thecrude oil indicated an 8:1 ratio of the fused to bridged cyclized products, 147 and 148. Flashchromatography (8 g silica gel, 9:1 petroleum ether - diethyl ether) of the crude oil yielded 9mg (47%) of the fused tricyclic compound 147 followed by 1 mg (5%) of the bridgedtricyclic compound 148 (the spectral data of compounds 147 and 148 are identical with thosereported above).•(EI-H‘ZHL‘L‘01‘LI=r‘HI‘PPPP)6Lc-69c‘(.vT-H‘ZRci‘ci‘ci‘LI=(‘HI‘PPPP)00ç-V6V‘(VT-H‘ZHci‘ci‘ci‘01=I’‘HI‘PPPP)£6V-06V‘(HE‘w)£v-vE‘(Hz‘w)£rl-V01‘(Ht’‘w)961-18i‘(119‘w)69iIVT‘(HI‘m)i€i-tzi‘(o1-N‘HE‘s)L01:(ZHNoov)WUHj1..WO806‘1E1I‘9cvI‘1V91‘8691:(wlu)lljiossjinojootst‘gjpunodwooiiJo(%8)wz‘uoiurnjnsaiqiwoj(dwndwnnotA)IUAJOSjosunowtt.njojtAOWOJiIjt‘ppTAoJdsuoioiujoitudoiddtqIJouo!It.nuuoDosjpunodwoopzqo(ounoqSflMpInqoipunodwoi.’uu.osjput61‘spunodwooowJoUOtWIOSTqiUTPI1flSJjiopniojo(iqp(qip-iqiwnjondi°u8)Aqdtioitwoiqoqsq•Eainpooidpiuuipq.irspstsuompuodnpoMqioipiqnsstputIqu1Ao11ItpaullsStMOJUIX!Wqjq91AO‘dwndauu(sttIA‘ppptStM(Arnbcri‘rowwEl0“iu£i‘HoH4:H1j:t‘NIo)nq-puJH1i(Jpuiio-jouoirnjosV(%j0W81‘JOUIUEEOO‘w8E)c11P(EtIdJ)Pdj3j3jtSti’iX11It(‘-jm£1)JH1&Tpul(AInbI110‘U6E)ucjpipoTJAUTApSflj-SpqIJOU0IflJOSPaLTISt01:xJpIpOJJ1(uTAPSflJ-SDqiJOU0IItZIpI(DpzktItD-(O)pJtt!AOS6t01.El.eyJefrJeyjHtRLs6HcHLHo:(OSj)uo-z-utuOu[0Ev1‘*S9I)put(6vj)uo-j-utopop-I1ozEc]opAI‘*IL‘*IV‘J[)JoSJSqIuALVVEViZ2251-3c nmr (75.3 MHz) 6: 21.3, 28.2 (-ye, Me-lO), 31.0, 32.4, 33.0, 34.5, 40.5, 42.1, 42.3 (-ye),45.4, 62.6 (-ye, C-i), 114.6 (C-i4), 138.4 (-ye, C-i3), 215.3 (C-2).ExactMass calcd. for C14H220: 206.1671; found: 206.1672.Anal. calcd. for C14H22O: C 81.50, H 10.75; found: C 81.43, H 10.83.The second product to be eluted from the above column chromatography was thebridged tricydic compound 149. The appropriate fractions were concentrated and the oilthus obtained was distilled (air-bath temperature 98-102 °CI0.i5 Torr) to afford 10 mg (41%)of the bridged compound 149, as a colourless oil.JR (film): 1699, 1632, 1459, 1257, 825 cm4.‘H nmr (400 MHz, C6D6) 6: 0.86 (s, 3H, Me-i3), 0.93-0.98 (br dt, 1H, J = 14.5, 4 Hz, H-5),1.12-1.19 (m, 1H), 1.24-1.68 (m, 7H, four of which are H-6, H-5’, H-i0’, and H-b), 1.78-1.86 (m, 1H, H-6’), 1.97-2.03 (br dd, 1H, J = 15, 9 Hz, H-9), 2.22-2.34 (m, 2H, H-i and H9’), 2.49 (br d, iH, J = 10.5 Hz, H-li), 3.31 (br s, 1H, H-7), 4.69 (br dd, 1H, J = 1, 1 Hz, H14), 4.75 (br d, 1H, J = 1 Hz, H-i4’).Detailed ‘H nmr data, derived from COSY and NOE experiments, are given in Table 34.13C nmr (75.3 MHz, C6D6) 6: 27.3 (-ye, Me-13), 30.1, 31.1, 31.7, 31.8, 33.6, 40.6 (-ye),41.1,46.9,56.9 (-ye), 63.9 (-ye), 113.4 (C-i4), 148.1 (C-8), 211.1 (C-12).Exact Mass calcd. for C14H200: 204.1514; found: 204.1517.226Table 34: ‘H nmr Data (400 MHz, C6D6) for the Bridged Compound 149: COSY and NOEH1414HH7 1211Me13149Assignment 1H nmr (400 MHz) COSY Correlationsa NOEH-x 6 ppm (mult., J (Hz)) CorrelationsaMe-13 0.86 (s) H6’b, H-liH-5 0.93-0.98 (br dt, J = 14.5, H-5’, H-6, H-6’, HllC4)H-10 —1.24-1.32 (m), part of the H-i, H-9, H-9’mat 1.24-1.68H-b9 —1.38-1.47 (m), part of the H-i, H-9, H-9’mat 1.24-1.68H-5’ —1.50-1.58 (m), part of the H-5, H-6’m at 1.24-1.68H-6 —1.60-1.68 (m), part of the H-5, H-6’, H-7m at 1.24-1.68H-6’ 1.78-1.86 (m) H-5, H-5’, H-6, H-7H-9 1.97-2.03 (brdd, J = 15, H-9’, H-b, H-b’, H-14’ H-9’, H-14’9)H-i Part of them at 2.22-2.34 H-10, H-10’, H-ilH-9’ Part of the m at 2.22-2.34 H-9, H-b, H-b’, H-i4, H-14’H-il 2.49 (brd, J = 10.5) H1,H5C,H7C H-i,Me-i3H-7 3.31 (br s) H-6, H-6’, H1lC, H-14 H-6, H-6’, H-14H-14 4.69 (br dd, J = 1, 1) H-7, H-9’, H-14’H-14’ 4.75 (br d, J = 1) H-9, H-9’, H-14a- Oniy those COSY correlations and NOE data that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-6’ is more downfield than H-6).c- W couplingExperiments22714 140 H Jj 15N HHj711i1H 91 1 1 13 HMe Me Me13 10138b 149 150b. Via a Pd(0)-Catalyzed Cydization of the Trans-Fused Vinyl Iodide 138b:To a stirred solution of the trans-fused vinyl iodide 138b (40 mg, 0.12 mmol, 1equiv.) in dry THF (2.5 mL) at rt was added Pd(PPh3) 4115 (39 mg, 0.034 mmol, 28 mol%).A solution of t-BuOK in dry THF and dry t-BuOH (0.1 M, 4:1 THF: t-BuOH, 1.4 mL, 0.14mmol, 1.15 equiv.) was added, via a syringe pump, over 7 h. The mixture was stirred at rtovernight and was worked up as described in general procedure 3. Flash chromatography (8g silica gel, 12.3:1 petroleum ether - diethyl ether) of the crude oil yielded 1 mg (4%) of thereduced bicyclic compound 150 followed by 9 mg (38%) of the bridged tricyclic compound149 (the spectral data of compounds 149 and 150 are identical with those reported above).2283.5. SYNTHESIS OF TRICYCLIC COMPOUNDS BEARING AN ALLYLIC,ANGULAR HYDROXYL GROUP3.5.1. GENERAL PROCEDURE 4: CYCLIZATION REACTIONS OF THE KETO VINYLIODTDES VIA A METAL-HALOGEN EXCHANGE REACTION119To a cold (-78 °C), stirred solution of the appropriate vinyl iodide (1 equiv.) in dryTHF (20 mL per mmol of vinyl iodide) was added a solution of n-butyffithium in hexanes(1.32 - 1.60 M, 2.5 equiv.). The resultant solution was stirred at -78 °C until the reactionreached completion, as determined by tlc analysis of an aliquot. Water (15 mL per mmol ofthe vinyl iodide) was added and the reaction mixture was warmed to rt. Diethyl ether (15 mLper mmol of the vinyl iodide) was added and the layers were separated. The aqueous layerwas extracted with diethyl ether (2 x (100 mL per mmol of the vinyl iodide)) and ethylacetate (2 x (100 mL per mmol of the vinyl iodide)). The combined organic extracts weredried over anhydrous magnesium sulfate and concentrated under reduced pressure. Thecrude mixture was flash chromatographed and the product(s) thus obtained was (were)distilled or recrystallized to provide the corresponding cyclized product(s) bearing an allylic,angular hydroxyl group.3.5.1.1. Synthesis of (1S*, 4S*, 8R , 12R *) 1-Methyl-9-methylenetricyclo[6.3. 1.04,121 -dodecan-8-ol (154):14O Me JL 910 13I HOh1 Me135b 154Following general procedure 4, a solution of the trans-fused vinyl iodide 135b (48mg, 0.14 mmol, 1 equiv.) in dry THF (2.9 mL) was treated with a solution of n-butyllithiumin hexanes (1.60 M, 0.23 mL, 0.36 mmol, 2.6 equiv.). The resultant solution was stirred at229-78 °C for 15 mm. The crude product was flash chromatographed (8 g silica gel, 9:1petroleum ether - diethyl ether) and the solid thus obtained was recrystallized from petroleumether - diethyl ether to yield 28 mg (95%) of the tricyclic allylic alcohol 154, a colourlesscrystalline solid, mp 65-68 °C.IR (KBr): 3568, 3449, 3079, 1646, 1155, 1067, 904 cm-1.‘H nmr (400 MHz) & 0.78 (d, 1H, J = 12.5 Hz, H-12), 0.90-0.99 (m, 1H), 1.06 (s, 1H, -OU;this signal exchanges in the presence of D20), 1.08 (s, 3H, Me-13), 1.15-1.41 (m, 3H, one ofwhich is H-li), 1.45-1.56 (m, 2H), 1.62-170 (m, 2H, one of which is H-7), 1.77-1.99 (m, 5H,three of which are H-7’, H-4, and H-il’), 2.12-2. 17 (ddd, 1H, J = 14,4, 2.5 Hz, H-b), 2.69-2.78 (dddt, lH, J = 14, 14, 4.5, 2 Hz, H-b’), 4.80 (dd, 1H, J =2, 2 Hz, H-i4), 4.86 (dd, 1H,J =2, 2 Hz, H-14’).Detailed ‘H nmr data (CDC13), derived from a COSY experiment, are given in Table 35.nmr (400 MHz, pyridine-d5) ö: 0.73 (d, lH, J = 13 Hz, H-12), 0.89-0.98 (m, 1H), 1.13-1.28 (m, 1H), 1.32 (s, 3H, Me-13), 1.33-1.50 (m, 3H, one of which is H-il), 1.51-1.54 (m,iH, H-7), 1.63-1.68 (m, 1H, H-7’), 1.8 1-2.04 (m, 5H, one of which is H-li’), 2. 15-2.20 (ddd,iH, J = 14, 3, 3 Hz, H-b), 2.20-2.30 (m, 1H, H-4), 2.96-3.03 (dddt, 1H, J = 14, 14, 2, 2 Hz,H-b’), 4.85-4.86 (dd, 1H, J = 2, 2 Hz, H-l4), 4.92-4.93 (dd, 1H, J =2, 2 Hz, H-l4’).Detailed 1H nmr data (pyridine-d5), derived from a COSY experiment, are given in Table36.‘H mnr data comparing the chemical shifts in CDC13 versus those in pyridine-d5 are given inTable 37.nmr (75.3 MHz) 6: 20.1 (-ye, Me-13), 22.6, 27.8, 30.0, 33.3, 33.8 (-ye), 36.2, 39.4, 40.0,41.0, 59.7 (-ye, C-12), 72.7 (C-8), 107.4 (C-14), 153.8 (C-9).Exact Mass caled. for C14H220: 206.1671; found: 206.1670.Anal. calcd. for C14H220: C 81.50, H 10.75; found: C 81.40, H 10.85.230231Table 35: ‘H nmr Data (400 MHz, CDC13) for the Tricyclic Compound 154: COSYExperiment14HO 9ii13H15413 H10’Me= f7L.H1°Assignment ‘H nmr (400 MHz) COSY CorrelationsaH-x 6 ppm (mult., J (Hz))H-12 0.78 (d, J = 12.5) H-4-Okj 1.06(s)Me-13 1.08 (s)H-li Partofthematl.15-1.41 Hl0,H10’b,Hi1’H-7 Part of the m at 1.62-1.70 H-7’H-li’ --1.77-1.84 (m), part of them at 1.77-1.99 H-iO, H-l0’, H-liH-4 —1.86-1.92 (m), part of them at 1.77-1.99 H-12H-7’ —1.93-1.99 (m), part of the m at 1.77-1.99 H-711-10 2.12-2. 17 (ddd, J = 14,4, 2.5) H-b’, H-li, H-li’H-l0’ 2.69-2.78 (dddt, J = 14, 14, 4.5, 2) 11-10, H-il, H-il’, H-14, H-i4’H-14 4.80 (dd, J =2, 2) H-10’, H-14’H-14’ 4.86 (dd, J =2, 2) H-iO’, H-14a- Only those COSY correlations that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-b’ is more downfield than H-b).Table 36: ‘H nmr Data (400 MHz, pyridine-d5) for the Tricyclic Compound 154: COSYExperimentAssignment 1H nmr (400 MHz) COSY CorrelationsaH-x 6 ppm (mult., J (Hz))11-12 0.73 (d, J = 13) 11-4Me-13 1.32 (s)H-il Part of them at 1.33-1.50 H-iO, Hl0’b, H-li’H-7 1.51-1.54(m) H-7’H-7’ 1.63-1.68(m) H-7H-il’ —1.81-1.85 (m), part of them at 1.81-2.04 H-i0, H-l0’, H-il11-10 2.15-2.20 (ddd, J = 14,3,3) H-10’, H-li, H-il’11-4 2.20-2.30 (m) H-1211-10’ 2.96-3.03 (dddt, J =14, 14, 2, 2) 11-10, H-il, H-li’, H-i4, H-14’H-14 4.85-4.86 (dd, J =2, 2) 11-10’, 11-14’H-14’ 4.92-4.93 (dd, J =2, 2) H-b’, H-l4a- Only those COSY correlations that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-b’ is more downfield than H-b).232Table 37: Comparison of the ‘H nmr (400 MHz) Chemical Shifts of Compound 154 inCDC13 vs. Pyridine-d514HO 9ii13H154HO 13 H10’= H1°H-x ppm in CDC13 ö ppm in Pyridine-d Aa, bH-4 —1.86-1.92 2.20-2.30 0.36H-7 —1.62-1.70 1.51-1.54 -0.14H7’C— 1.93-1.99 1.63-1.68 -0.31H-i0 2.12-2. 17 2. 15-2.20 0.03H-10’ 2.69-2.78 2.96-3.03 0.26H-li —1.20-1.41 —1.33-1.50 0.11H-il’ —1.76-1.84 —1.81-1.85 0.03H-12 0.78 0.73 -0.03Me-13 1.08 1.32 0.24H-14 4.80 4.85-486 0.05H-14’ 4.86 4.92-4.93 0.06a - A = 6 (pyridine-d5) - 6 (CDC13);i.e. [(2.20-2.30)/2 - (1 .86+1 .92)/21 = 0.36.b - Only those A’s > 0.15 are recorded in bold font.c - H’ indicates the hydrogen of a pair which is more downfield (H-7’ is more downfield than H-7).2333.5.1.2. Synthesis of (1 S*, 4S*, 8R , 12S*) 1-Methyl-9-methylenetricyclo[6.3. 1 12..dodecan-8-ol (157), (1 S*, 4S*, 8S*, 12S*) 1-Methyl-9-methylenetricyclo[6.3.1.0442]-dodecan-8-ol (158), and (1 S*, 6S*,(159):14 14OMe 010$1N H0MeHO.%%JH135a 157 158 159Following general procedure 4, a solution of the cis-fused vinyl iodide 135a (107 mg,0.322 mmol, 1 equiv.) in dry THF (6.5 mL) was treated with a solution of n-butyllithum inhexanes (1.58 M, 0.51 mL, 0.81 mmol, 2.5 equiv.). The resultant solution was stirred at -78°C for 3 h. The crude product mixture was subjected to radial chromatography (1 mm plate,9:1 petroleum ether - diethyl ether) to give three fractions. The first compound to be elutedwas the tricyclic compound 158. The appropriate fractions were concentrated and the oilthus obtained was distilled (air-bath temperature 75-80 °CI0.08 Torr) to afford 34 mg (5 1%)of the tricydic compound 158, as a colourless oil.IR (film): 3600, 3494, 3079, 1639, 1153, 1066, 896 cm1.nmr (400 MHz) ö: 0.71 (s, 1H, -OH; this signal exchanges in the presence of D20), 0.99(s, 3H, Me-13), 1.14 (d, 1H, J = 7 Hz, H-12), 1.34-1.94 (m, 11H, one of which is H-li),2.00-2.07 (ddd, 1H, J = 12.5, 12.5, 4.5 Hz, H-il’), 2.26-2.43 (m, 3H, H-b’, H-4, and H-b),4.7 1-4.72 (m, 1H, H-14), 4.89 (br d, 1H, J = 1 Hz, H-14’).Detailed ‘H mnr data (CDC13), derived from COSY and NOE experiments, are given inTable 38.234mnr (75.3 MHz) ö: 17.2, 26.1, 28.4, 30.2, 30.4 (-ye), 34•4, 35.8, 36.4 (-ye), 41.0, 41.6,52.7 (-ye, C-12), 71.9 (C-8), 105.2 (C-14), 154.2 (C-9).Exact Mass calcd. for C14H220: 206.1671; found: 206.1669.Anal. calcd. for C14H220: C 81.50, H 10.75; found: C 81.50, H 10.78.Table 38: 1H nmr Data (400 MHz, CDC13) for the Tricyclic Compound 158: COSY andNOE ExperimentsH1413MeH158H414’“ H’2=_E;;?::;J:::?:_.Me’3Assignment ‘H nmr (400 MHz) COSY Correlationsa NOEH-x ppm (mult., J (Hz)) Correlationsa-OH 0.71 (s)Me-13 0.99 (s) H-4, H-il, H-1211-12 1.14 (d, J = 7) H-4 H-4H-li —1.42-1.50 (m), part of the H-iO, Hi0’b, H-li’m at 1.34-1.94H-li’ 2.00-2.07 (ddd, J 12.5, H-b, H-iO’, H-li H-li12.5, 4.5)H-i0 —2.26-2.31 (m),partofthe H-lO’, H-li, H-li’, H-14,m at 2.26-2.43 H-14’H-4 —2.31-2.38 (m), part of the H-12m at 2.26-2.43H-b’ —2.38-2.43 (m), part of the H-iO, H-li, H-il’, H-14,m at 2.26-2.43 H-i4’H-l4 4.7 1-4.72 (m) H-b, H-i0’, H-l4’ H-b’, H-14’H-l4’ 4.89 (br d, J = 1) H-b, H-i0’, H-i4 H-14a- Only those COSY correlations and NOE data that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-b’ is more downfield than H-b).235The second compound to be eluted was the bicycic compound 159. Concentration ofthe appropriate fractions and removal of trace amounts of solvent (vacuum pump) from theresultant oil, yielded 5.5 mg (8%) of the compound 159, as a colourless oil.IR (film): 3076, 1694, 1641, 1459, 1177, 908 cm-1.‘H nmr (400 MHz) 8: 1.14 (s, 3H, Me-lO), 1.22-1.50 (m, 4H), 1.51-1.67 (m, 2H), 1.74-2.13(m, 7H), 2.34 (d, 1H, J = 9.5 Hz, H-i), 2.40-2.47 (m, 2H), 4.90-4.92 (br d, 1H, J = 10 Hz,H-14), 4.95-5.00 (dddd, iH, J = 17, 2, 2, 2 Hz, H-14’), 5.72-5.82 (dddd, iH, J = 17, 10, 6.5,6.5 Hz, H-13).nmr (100.4 MHz) 6: 23.5, 27.0 (-ye, Me-lO), 29.2, 30.3, 30.9, 36.9, 37.4, 40.6 (-ye),42.5, 47.1, 62.1 (-ye, C-i), 114.1 (C-14), 139.1 (-ye, C-13), 214.7 (C-2).Exact Mass calcd. for C14H220: 206.1671; found: 206.1662.The last compound to be eluted was the tricyclic compound 157. The appropriatefractions were concentrated and the oil thus obtained was distilled (air-bath temperature 90-95 °C/0.3 Torr) to provide 16 mg (24%) of the compound 157, as a colourless oil.IR (film): 3472, 3387, 3087, 1642, 1470, 1103, 982 cm-1.‘H nmr (400 MHz) 6: 1.01 (s, 3H, Me-13), 1.12-1.25 (m, 2H), 1.40-1.78 (m, 12H, three ofwhich are H-li’, H-li, and H-12), 2.24-2.26 (m, ill, H-4), 2.43-2.48 (m, 1H, H-b), 2.50-2.54 (m, 1H, H-b’), 4.8 1-4.82 (m, 1H, H-14), 5.10 (br d, 1H, J = 1 Hz, H-14’).Detailed 1H nmr data (CDC13), derived from a COSY experiment, are given in Table 39.236‘H nmr (400 MHz, pyridine-d5) 6: 1.04 (s, 3H, Me-13), 1.09-1.20 (dq, 1H, J = 4, 13 Hz),1.31-1.81 (m, 11H, three of which are H-12 (d, J = 7Hz), H-il’, and H-il), 1.90-1.94 (m,1H), 2.38-2.43 (m, 1H, H-4), 2.43-2.51 (m, 1H, H-b), 2.56-2.62 (m, 1H, H-b’), 4.95 (br d,1H, J = 1.5 Hz, H-i4), 5.58 (br s, 1H, H-14’).Detailed 1H nmr data (pyridine-d5), derived from a COSY experiment, are given in Table40.‘H nmr data comparing the chemical shifts in CDC13 versus those in pyridine-d5 are given inTable 41.nmr (75.3 MHz) 6: 20.3, 27.2, 27.6, 30.4 (-ye, Me-13), 35.1, 35.4, 38.8 (-ye), 40.4, 40.8,57.6 (-ye, C-12), 74.0 (C-8), 106.4 (C-i4), 152.6 (C-9).Exact Mass calcd. for C14H220: 206.1671; found: 206.1666.237Table 39: ‘H nmr Data (400 MHz, CDC13) for the Tricyclic Compound 157: COSYExperimentH14131MeH157H14Me’3Assignment ‘H nmr (400 MHz) COSY CorrelationsaH-x ppm (mult., J (Hz))Me-13 1.01 (s)H-12 1.41 (d, J =7), part of them at 1.37-1.78 H-4H-li —1.54-1.58 (m), part of them at 1.37-1.78 H-10, Hl0’b, H-il’H-li’ —1.61-1.64 (m), part of them at 1.37-1.78 H-l0, H-i0’, H-ilH-4 2.24-2.26 (m) H-12H-b 2.43-2.48 (m) H-10’, H-li, H-li’, H-14, H-14’H-b’ 2.50-2.54 (m) H-b, H-il, H-il’, H-l4, H-l4’H-14 4.81-4.82 (m) H-10, H-b’, H-14’H-14’ 5.10 (brd, J = 1) H-iO, H-1O’, H-14a- Only those COSY correlations that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-b’ is more downfield than H-b).Table 40: ‘H nmr Data (400 MHz, pyridine-d5) for the Tricyclic Compound 157: COSYExperimentAssignment ‘H nmr (400 MHz) COSY CorrelationsaH-x ppm (muit., J (Hz))Me-13 1.04(s)H-il —1.55-1.60 (m), part of them at 1.31-1.81 H-b, Hl0’b, H-li’H-li’ —1.65-1.71 (m), part of them at 1.31-1.81 H-i0, H-iO’, H-liH-12 1.78 (d, J = 7) H-4H-4 2.38-2.43 (m) H-i2H-b 2.43-2.51 (m) H-iO’, H-il, H-li’, H-14, H-14’H-b’ 2.56-2.62 (m) H-b, H-li, H-ll’, H-i4, H-14’H-i4 4.95 (br d, J = 1.5) H-iO, H-b’, H-i4’H-14’ 5.58 (br s) H-b, H-b0’, H-14a- Only those COSY correlations that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-b’ is more downfield than H-b).238Table 41: Comparison of the ‘H nmr (400 MHz) Chemical Shifts of Compound 157 inCDC13 vs. Pyridine-d5H14131MeH157H’’Me13H-x j 6 ppm in CDC13 6 ppm in Pyridine-d5 bH-4 2.24-2.26 2.38-2.43 0.16H-10 2.43-2.48 2.43-2.51 0.02H10’C 2.50-2.54 2.56-2.62 0.07H-li —1.54-1.58 —1.55-1.60 0.02H-il’ —1.61-1.64 —1.65-1.71 0.06H-12 1.41 1.78 0.37Me-13 1.01 1.04 0.03H-14 4.8 1-4.82 4.95 0.14H-14’ 5.10 5.58 0.48a - A = 6 (pyridine-d) - 6 (CDCI3); i.e. [(2.38+2.42)/2 - (2.24+2.26)/2] = 0.15.b - Only those A’s> 0.15 are recorded in bold font.c - H’ indicates the hydrogen of a pair which is more downfield (H-b’ is more downfield than H-b).2393.5.1.3. Synthesis of (1S, 4S ‘, 8R ‘,[6.3.1 ‘2]dodecan-8-ol (160) and (1 S, 6S, 9R *)9...(3..Bunyl>..6,9..djmethylbicyclo -[4.3.OJnonan-2-one (161):15 150 Me 1011 13 0 AeHOH Me 13 14 HMe Me Me14 10136 160 161Following general procedure 4, a solution of the cis-fused vinyl iodide 136 (79 mg,0.23 mmol, 1 equiv.) in dry THF (4.6 mL) was treated with a solution of n-butyllithium inhexanes (1.55 M, 0.37 mL, 0.57 mmol, 2.5 equiv.). The resultant solution was stirred at -78°C for 1 h. The crude product mixture was subjected to radial chromatography (1 mm plate,9:1 petroleum ether - diethyl ether) to provide two fractions. The first compound to be elutedwas the bicyclic compound 161. The appropriate fractions were concentrated and the oil thusobtained was distilled (air-bath temperature 92-94 °CI0. 15 Tort) to afford 18 mg (35%) of thebicycic compound 161, as a colourless oil.JR (film): 3077, 1693, 1641, 1460, 908 cm-’.nmr (400 MHz) : 1.07 (s, 3H, Me), 1.14 (s, 3H, Me), 1.24-1.32 (m, 1H), 1.38-1.72 (m,8H), 1.75-2.01 (m, 3H), 2.03 (br s, 1H, H-i), 2.09-2.16 (m, 1H), 2.36-2.41 (br d, 1H, J =16.5 Hz), 4.90-4.92 (br d, 1H, J = 10 Hz, H-15), 4.95-5.00 (br dd, 1H, J = 17, 2 Hz, H-is’),5.72-5.82 (dddd, iH, J = 17, 10, 6.5, 6.5 Hz, H-14).13c nmr (75.3 MHz) 6: 21.0, 28.0 (-ye, Me), 29.2 (-ye, Me), 29.4, 35.6, 37.3, 37.4, 40.2,42.1, 44.5,48.1, 7i.0 (-ye, C-i), 114.2 (C-15), 139.1 (-ye, C-14), 214.8 (C-2).240Exact Mass calcd. for C15H240: 220.1827; found: 220.1822.Anal. calcd. for C15H24O: C 81.76, H 10.98; found: C 81.51, H 11.01.The second compound to be eluted was the tricycic compound 160. Concentration ofthe appropriate fractions and distillation (air-bath temperature 90-94 °CI0.4 Torr) of the oilthus obtained, provided 33 mg (65%) of the compound 160, as a colourless oil.IR(KBr): 3446,1644,1451,1129,899cm-.1H (400 MHz) 6: 1.01 (s, 3H, Me), 1.05 (s, 1H, H-12), 1.10 (br s, 1H, -011; this signalexchanges in the presence of D20), 1.20 (s, 3H, Me), 1.21-1.26 (m, 1H), 1.38-1.60 (m, 8H,one of which is H-i 1), 1.69-1.89 (m, 3H, one of which is H-i 1’), 2.37-2.45 (m, iH, H-b),2.47-2.56 (m, 1H, H-b’), 4.79-4.8 1 (m, 1H, H-i5), 5.09 (br s, 1H, H-15’).Detailed ‘H nmr data (CDC13), derived from a COSY experiment, are given in Table 42.‘H nmr (400 MHz, pyridine-d) 6: 1.03 (s, 3H, Me-i3), 1.21-1.25 (m, 1H, H-7), 1.31-1.57(m, 8H, four of which are H-6, H-7’, H-li, and H-i2), 1.39 (s, 3H, Me-14), 1.65-1.79 (m, 3H,two of which are H-5 and H-li’), 2.07-2.14 (m, iH, H-6’), 2.43-2.48 (m, 1H, H-b), 2.52-2.61 (m, 1H, H-b’), 4.95 (br d, 1H, J = 1.5 Hz, H-b5), 5.58 (br s, 1H, H-15’).Detailed 1H nmr data (pyridine-d5), derived from COSY and NOE experiments, are given inTable 43.‘H nmr data comparing the chemical shifts in CDC13 versus those in pyridine-d5 are given inTable 44.241Detailed 13C nmr data (CDC13), derived from HMQC and HMBC experiments, are given inTable 45.Detailed 13C nmr data (pyridine-d5), derived from HMQC and HMBC experiments, aregiven in Table 46.Exact Mass calcd. for C15H240: 220.1827; found: 220.1822.Anal. calcd. for C15H240: C 81.76, H 10.98; found: C 81.46, H 11.05.242Table 42: ‘H nmr Data (400 MHz, CDC13) for the Tricyclic Compound 160: COSYExperimentAssignment ‘H nmr (400 MHz) COSY CorrelationsaH-x 6 ppm (mult., J (Hz))Me-13 1.01 (s)H-12 1.05 (s)-011 1.i0(brs)Me-14 1.20(s)H-li —1.48-1.52 (m), part of them at 1.38-1.60 H-iO, H10’b, H-li’H-li’ —1.69-1.75 (m), part of them at 1.69-1.89 H-iO, H-b’, H-ilH-b 2.37-2.45 (m) H-b’, H-il, H-li’, H-i5, H-15’H-10’ 2.47-2.56 (m) 11-10, H-il, H-li’, H-15, H-15’H-15 4.79-4.81 (m) H-10, H-10’, H-iS’11-15’ 5.09 (brs) H-b, H-lO’, H-b5Assignment 1H nmr (400 MHz) COSY Correlationsa NOEH-x 6 ppm (mult., J (Hz)) CorrelationsaMe-13 1.03 (s) H-12H-7 1.21-1.25 (m) H-6, H6’b, H-7’ H-6’11-6 Part of the m at 1.3 1-1.57 H-5, H-6’, H-7H-7’ Part of the m at 1.3 1-1.57 11-6’, H-7H-il Part of them at 1.31-1.57 11-10, H-b’, H-il’H-12 Part of the m at 1.3 1-1.57Me-14 1.39 (s)H-S Part of the m at 1.65-1.79 H-6, H-6’H-il’ Part of the m at 1.65-1.79 11-10, 11-10’, H-lbH-6’ 2.07-2. 14 (m) 11-5, H-6, H-7, H-7’ H-5, 11-6H-10 2.43-2.48 (m) 11-10’, H-li, H-li’, H-b5,11-15’H-10’ 2.52-2.61 (m) H-l0, H-il, H-il’, 11-15, H-10, H-li, HH-b5’ 11’, Me-13, H-iS11-15 4.95 (brd, J 1.5) H-b, H-bO’, H-15’H-i5’ 5.58 (br s) H-lO, H-lO’, 11-15H15L1J160 Me14151H=H15Me’3a- Only those COSY correlations that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-b’ is more downfield than H-b).Table 43: 1H nmr Data (400 MHz, pyridine-d5) for the Tricycic Compound 160: COSYand NOE Experimentsa- Only those COSY correlations and NOE data that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-6’ is more downfield than H-6).243Table 44: Comparison of the 1H nmr (400 MHz) Chemical Shifts of Compound 160 inCDC13 vs. Pyridine-d5H1513H M eMe”160— H15Me’3H-x 6 ppm in CDC13 6 ppm in Pyridine-d5 a, bH-b 2.37-2.45 2.43-2.48 0.04H10’C 2.47-2.56 2.52-.261 0.05H-li —1.48-1.52 Partofmatl.31-1.57 —-0.06H-il’ —1.69-1.75 Part of m at 1.65-1.79 —0.00H-12 1.05 Partofmatl.31-1.57 —0.39Me-13 1.01 1.03 0.02Me-14 1.20 1.39 0.19H-15 4.79-4.81 4.95 0.15H-15’ 5.09 5.58 0.49a - A = 6 (pyridine-d5) - 6 (CDC13); i.e. [(2.43+2.48)/2 - (2.37+2,45)/21 = 0.04.b - Only those A’s> 0.15 are recorded in bold font.c - H’ indicates the hydrogen of a pair which is more downfield (H-lOis more downfield than H-b).244Table 45: 111 nmr (500 MHz, CDC13) and 13C nmr (100.4 MHz, CDC13) Data for theTricycle Compound 160: HMQC and HMBC ExperimentsH151011 13M eMe’4160Assignment ‘3C nmr f{f4Q(c,d 111 - 13C HMBCC,dCxa (100.4 MHz) ‘H nmr Correlations Long-range Correlationsppm,APTb H-xppm (assignment)17.6C-i0 27.5 11-10 (2.37-2.45); H10’e H-15 (3 bond), H-15’ (3 bond)(2.47-2.56)Me-14 28.7 (-ye) Me-14 (1.20)Me-13 31.1 (-ye) Me-13 (1.01)32.434.9C-li 35.0 H-li (1.48-1.52); H-li’ (1.69-1.75)39.840.1C-i andC-4 42.3 and H-l0 (3 bond)t, H-li (242.4 bond)f, H-il’ (2 bond)f, Me-13 (2 bond)f, Me-14 (2 bond)gC-i2 63.3 (-ye) 11-12 (1.05)C-8 74.7 11-15 (3 bond), H-15’ (3 bond)C-15 106.4 H-15 (4.79-4.8 1); H-15’ (5.09)C-9 153.2a- Oniy those assignments which could be assigned are recorded.b- The results of the AFT experiment are given in parentheses (-ye for CH and CH3 carbon signals).c-The assignment and the chemical shifts of the 13C nmr spectrum are listed in the first and second columns,respectively. The third column shows the nmr signal(s) which correlate(s) with the carbon of the first twocolumns, as obtained from the 1-IMQC experiment (1 bond correlation). The last column lists the hydrogen(s)which correlate(s) with the 13C nmr signal of the first two columns as obtained from HMBC experiments (2, 3,and 4 bond correlations).d- Only those HMQC and HlvIBC data that could be assigned are recorded.e- H’ indicates the hydrogen of a pair which is more downfield (H-7’ is more downfield than H-7).f- This long range correlation corresponds to C-i.g- This long range correlation corresponds to C-4.245Table 46: ‘H nmr (500 MHz, pyridine-d5) and 13C nmr (125.8 MHz, pyridine-d5) Data forthe Tricycle Compound 160: HMQC and HMBC ExperimentsH1513H M eMe14160Assignment ‘3C nmr HMQC’b ‘H - 13C HMBCa,bC-x (125.8 1H nmr Correlations (500 MHz) Long-range CorrelationsMHz) 6 ppm (assignment) H-x6 ppmC-6 18.2C-b 28.0 Me-13(4bond)Me-14 29.2 Me-14 (1.39) H-6 (4 bond)Me-13 30.0 Me- 13 (1.03) H-il (3 bond), H-i 1’C (3 bond)C-7 31.4 H-7 (1.21-1.25); H-7’ (1.31-1.57)C-S 33.1 H-S (1.65-1.79)C-li 35.4 H-il (1.31-1.57); H-li’ (1.65-1.79) Me-13 (3 bond)C-2 or C-3 40.2 Me-13 (3 or 4 bond)d; Me-14 (3or 4 bond)dC-2 or C-3 40.6 “ “C-i or C-4 42.4C-i or C-4 42.7C-i2 62.7 H-12 (1.3 1-1.57) Me-13 (3 bond); Me-14 (3 bond)C-8 74.1C-15 107.0 H-iS (4.95); H-iS’ (5.58) H-10(3 bond); H-10’ (3 bond)C-9 154.8 H-10 (2 bond); H-10’ (2 bond)a-The assignment and the chemical shifts of the 13C nnw spectrum are listed in the first and second columns,respectively. The third column shows the nmr signal(s) which correlate(s) with the carbon of the first twocolumns, as obtained from the FIMQC experiment (1 bond correlation). The last column lists the hydrogen(s)which correlate(s) with the 13C nmr signal of the first two columns as obtained from HMBC experiments (2, 3,and 4 bond correlations).b- Only those HMQC and HMBC data that could be assigned are recorded.c- H’ indicates the hydrogen of a pair which is more downfield (H-il’ is more downfield than H-i 1).d- These correlations correspond to either C-2 or C-3.2463.5.1.4. Synthesis of (1S*, 4S*, 8 R*, 12R*)9Methylenetricyclo[6.3.1.0442]dodecan8ol(155):á..;%JN H1H137b 155Following general procedure 4, a solution of the trans-fused vinyl iodide 137b (35mg, 0.11 mmol, 1 equiv.) in dry THF (2.2 mL) was treated with a solution of n-butyffithiumin hexanes (1.32 M, 0.21 mL, 0.28 mmol, 2.5 equiv.). The resultant solution was stirred at-78 °C for 1 h. The crude product mixture was subjected to radial chromatography (1 mmplate, 1:1 CH2C12 - petroleum ether) and the solid thus obtained was recrystallized frompetroleum ether - diethyl ether to afford 18 mg (83%) of the tricyclic compound 155, acolourless crystalline solid, mp 35-37 °C.IR(KBr): 3436, 3078, 1646, 1454, 1161, 1063, 902 cm-1.‘H nmr (400 MHz) & 0.58-0.64 (dd, 1H, J = 12, 12 Hz, H-12), 0.85-1.25 (m, 5H, two ofwhich are H-4 and H-li), 1.46-2.00 (m, 1OH, two of which are H-i and H-li’), 2.18-2.23 (brddd, 1H, J = 14, 4, 2.5 Hz, H-b), 2.47-2.55 (br ddd, J = 14, 14, 5 Hz, H-b’), 4.77 (br dd,lH, J 1.5, 1.5 Hz, H-13), 4.82-4.83 (dd, iH, J = 1.5, 1.5 Hz, H-13’).Detailed ‘H nmr data (CDC13), derived from a COSY experiment, are given in Table 47.nmr (400 MHz, pyridine-d5) & 0.54-0.60 (dd, 1H, J = 12, 12 Hz, H-12), 0.88-0.98 (dq,1H, J = 3.5, 12Hz), 1.04-1.20 (m, 2H, one of which is H-li), 1.47-1.56 (dt, 1H, J = 3.5, 13247Hz), 1.65-2.11 (m, 1OH, three of which are H-i, H-4, and H-il’), 2.20-2.25 (ddd, ill, J13.5, 4, 2.5 Hz, H-b), 2.8 1-2.89 (br ddd, iH, J = 13.5, 13.5, 5 Hz, H-b’), 4.81-4.82 (m, 1H,H-13), 4.89 (br d, 1H, J 1.5 Hz, H-13’).Detailed 1H nmr data (pyridine-d5), derived from a COSY experiment, are given in Table48.‘H nmr data comparing the chemical shifts in CDC13 versus those in pyridine-d5 are given inTable 49.nmr (75.3 MHz) 6: 22.6, 28.3, 29.6, 32.2, 32.7, 33.5, 34.3, 37.1 (-ye, C-i or C-4), 37.2(-ye, C-i or C-4), 59.5 (-ye, C-12), 71.7 (C-8), 107.0 (C-13), 153.3 (C-9).ExactMass calcd. for C13H200: 192.1514; found: 192.1510.248Table 47: 1H nmr Data (400 MHz, CDC13) for the Tricyclic Compound 155: COSYExperimentHch1 H155H10=H1°12Assignment ‘H nmr (400 MHz) COSY CorrelationsaH-x 6 ppm (mult., J (Hz))H-12 0.58-0.64 (dd, J = 12, 12) H-i, H-4H-il —1.05-1.10 (m), part of the m at 0.85-1.25 H-iO, Hi0’b, H-liH-4 —1.10-1.14 (m), part of the m at 0.85-1.25 H-i2H-i —1.65-1.72 (m), part of them at 1.46-2.00 H-il, H-il’, H-12H-li’ —1.93-2.00 (m), part of the m at 1.46-2.00 H-lO, H-b’, H-liH-l0 2.18-2.23(brddd, J = 14, 4, 2.5) H-b’, H-li, H-li’, H-13H-10’ 2.47-2.55 (brddd, J = 14,14,5) H-b, H-il, H-li’, H-13, H-13’H-13 4.77 (br dd, J = 1.5, 1.5) H-10, H-10’, H-13’H-13’ 4.82-4.82 (dd, J = 1.5, 1.5) H-10’, H-13a- Only those COSY correlations that could be assigned are recorded.b- H indicates the hydrogen of a pair which is more downfield (H-1O is more downfield than H-b).Table 48: 1H nmr Data (400 MHz, pyridine-d5) for the Tricyclic Compound 155: COSYExperimentAssignment ‘H nmr (400 MHz) COSY CorrelationsaH-x 6 ppm (mult., J (Hz))H-i2 0.54-0.60 (dd, J = 12, 12) H-i, H-4H-li Part of them at 1.04-1.20 H-i, H-b, H10’b, H-li’H-il’ —1.93-1.99 (m), part of them at 1.65-2.11 H-iO, H-b’, H-liH-4 —1.98-2.02 (m), part of the m at 1.65-2.11 H-i2H-i —2.05-2.11 (m), part of the m at 1.65-2.11 H-il, H-12H-b 2.20-2.25 (ddd, J = 13.5,4, 2.5) H-b’, H-ll, H-li’H-i0’ 2.81-2.89 (br ddd, J = 13.5, 13.5, 5) H-b, H-il, H-b 1’, H-13, H-b3’H-i3 4.8 1-4.82 (m) H-b’, H-b3’H-13’ 4.89 (br d, J = 1.5) H-l0’, H-b3a- Only those COSY correlations that could be assigned are recorded.b- H indicates the hydrogen of a pair which is more downfield (H-b’ is more downfield than H-b).249Table 49: Comparison of the 1H nmr (400 MHz) Chemical Shifts of Compound 155 inCDC13 vs. Pyridine-d513HO91Hj2215510’=10H-x 6 ppm in CDC13 6 ppm in Pyridine-d5 a, bH-i —1.65-1.72 —2.05-2.11 0.40H-4 —1.10-i.14 —1.98-2.02 0.88H-iO 2.18-2.23 2.20-2.25 0.02H1O’c 2.47-2.55 2.81-2.89 0.34H-li —1.05-1.10 —1.04-1.20 0.04H-li’ —1.93-2.00 —i.93-l.99 -0.01H-l2 0.58-0.64 0.54-0.60 -0.04H-13 4.77 4.81-4.82 0.04H-i3’ 4.82-4.83 4.89 0.06a- A = ö (pyridine-d) - ö (CDC13);i.e. [(2.05÷2.11)/2 - (1.65+1.72)/2] = 0.40.b - Oniy those As> 0.15 are recorded in bold font.c - H’ indicates the hydrogen of a pair which is more downfield (H-b’ is more downfield than H-b).2503.5.1.5. Synthesis of (1 S*, 4S*, 8R , 12S*)9Methy1enetricyclo[6.3. 1 12]dodecan-8-ol(162), (1 S*, 4S*, 8 S*, 1 2S*)9Methylenetricyc1o[6.3. 1 ‘2]dodecan..8o1 (163), and (1S*,6S*, (164):HOH137a 162 163 164Following general procedure 4, a solution of the cis-fused vinyl iodide 137a (98 mg,0.31 mmol, 1 equiv.) in dry THF (5 mL) was treated with a solution of n-butyllithium inhexanes (1.32 M, 0.58 mL, 0.77 mmol, 2.5 equiv.). The resultant solution was stirred at -78°C for 30 mm. The crude product mixture was flash chromatographed (15 g silica gel, 9:1petroleum ether - diethyl ether) to afford three fractions. The first compound to be elutedwas the tricydic compound 163. Concentration of the appropriate fractions and distillation(air-bath temperature 74-78 °C/0.22 Torr) of the oil thus obtained, provided 22 mg (37%) ofthe compound 163, as a colourless oil.IR (film): 3600, 3078, 1640, 1461, 1068, 900 cm’.‘H nmr (400 MHz) 6: 0.71 (br s, 1H, -OH; this signal exchanges in the presence of D20),1.32-1.97 (m, 13H, two of which are H-il and H-li’), 2.06-2.11 (m, 1H), 2.18-2.28 (m, 2H,one of which is H-b), 2.45-2.51 (br ddd, 1H, J = 15.5, 5, 5 Hz, H-b’), 4.71-4.72 (m, 1H, H-13), 4.87 (br s, 1H, H-13’).Detailed 1H nmr data (CDC13), derived from a COSY experiment, are given in Table 50.25113C nmr (75.3 MHz) 6: 17.4, 25.9, 27.8, 29.5, 30.0, 32.5, 34.4, 38.2 (-ye, C-i or C-4), 38.8(-ye, C-i or C-4), 46.3 (-ye, C-12), 72.3 (C-8), 105.3 (C-13), 154.2 (C-9).Exact Mass calcd. for C13H200: 192.1514; found: 192.1519.Anal. calcd. for C13H200: C 81.20, H 10.48; found: C 81.31, H 10.38.Table 50: ‘H nmr Data (400 MHz, CDC13) for the Tricycic Compound 163: COSYExperimentH9hiH163=H1Assignment ‘H nmr (400 MHz) COSY CorrelationsaH-x 6 ppm (mult., J (Hz))-OH 0.71 (br s)H-li —1.68-1.75 (m), part of the m at 1.32-1.97 H-i0, H10’b, H-li’H-il’ —1.86-1.97 (m), part of them at 1.32-1.97 H-10, H-10’, H-ilH-i0 —2.22-2.28 (m), part of them at 2.18-2.28 H-10’, H-il, H-il’, H-13, H-13’H-b’ 2.45-2.51 (br ddd, J = 15.5, 5, 5) H-10, H-il, H-i 1’, H-13, H-13’H-13 4.71-4.72 (m) H-10, H-b’, H-13’H-l3’ 4.87 (br s) H-b, H-i0’, H-13a- Only those COSY correlations that could be assigned are recorded.b- H indicates the hydrogen of a pair which is more downfield (H-b’ is more downfield than H-b).252The second compound to be eluted was the bicyclic compound 164. The appropriatefractions were concentrated to provide, after removal of trace amounts of solvent (vacuumpump) from the resultant oil, 6.4 mg (11%) of the compound 164, as a colourless oil.JR (fiim): 3074, 1702, 1639, 1452, 994, 909 cm1.‘H nmr (400 MHz) 6: 1.33-2.18 (m, 14H), 2.37-2.44 (m, 2H), 2.69-2.74 (dd, 1H, J = 8.5, 8Hz, H-i), 4.90-4.93 (br ddd, 1H, J = 10, 1.5, 1.5 Hz, H-13), 4.95-5.01 (dddd, 1H, J = 17,1.5, 1.5, 1.5 Hz, H-1Y), 5.72-5.82 (dddd, 1H, J 17, 10, 6.5, 6.5 Hz, H-12).ExactMass calcd. for Cj3H2O: 192.1514; found: 192.1517.The last compound to be eluted was the tricyclic compound 162. Concentration ofthe appropriate fractions and distillation (air-bath temperature 88-92 °CI0. 1 Torr) of the oilthus obtained, afforded 15 mg (26%) of the compound 162, as a colourless oil.IR (film): 3478, 3085, 1640, 991, 894 cm-1.‘H nmr (400 MHz) 6: 1.03-1.11 (m, 1H), 1.23 (s, 1H, -OU; this signal exchanges in thepresence of D 20), 1.31-1.76 (m, 1OH, two of which are H-li and H-li’), 1.80-1.89 (m, 2H,one of which is H-i2), 2.09-2.18 (m, 2H, H-i and H-4), 2.43-2.50 (m, 2H, H-l0 and H-b’),4.79-4.80 (m, 1H, H-13), 5. 10-5.11 (m, 1H, H-13’).Detailed ‘H nmr data (CDC13), derived from a COSY experiment, are given in Table 51.1H nmr (400 MHz, pyridine-d5) 6: 0.99-1.10 (dq, 1H, J =4, 13 Hz), 1.22-1.81 (m, 1OH, twoof which are H-il and H-il’), 1.92-1.96 (m, 1H), 2.08-2.11 (m, 1H, H-i), 2.22-2.27 (dd, 1H,253J = 11, 11 Hz, H-12), 2.30-2.34 (m, 1H, H-4), 2.49-2.53 (m, 2H, H-b and H-b’), 4.93-4.95(m, 1H, H-13), 5.59-5.60 (m, 1H, H-13’).Detailed bH nmr data (pyridine-d5), derived from a COSY experiment, are given in Table52.‘H nmr data comparing the chemical shifts in CDC13 versus those in pyridine-d5 are given inTable 53.nmr (75.3 MHz) & 20.6, 27.9, 29.2, 29.6, 31.0, 32.0, 36.4, 37.1 (-ye, C-i or C-4), 37.4(-ye, C-i or C-4), 50.2 (-ye, C-12), 73.7 (C-8), 106.2 (C-13), 153.7 (C-9).ExactMass calcd. for C13H200: 192.1524; found: 192.1506.Anal. calcd. for C13H200: C 81.20, H 10.48; found: C 81.42, H 10.60.254Table 51: 1H nmr Data (400 MHz, CDC13) for the Tricyclic Compound 162: COSYExperimentH13HO811HH162131H= H13Assignment ‘H nmr (400 MHz) COSY CorrelationsaH-x 6 ppm (mult., J (Hz))-011 1.23(s)H-li —1.41-1.46(m), part of them at 1.31-1.76 H-4, H10andHl0’b,H1i’H-il’ —1.71-1.75 (m), part of them at 1.31-1.76 H-4, H-b and H-b’, H-liH-12 —1.85-1.89 (m), part of them at 1.80-1.89 H-i, H-4H-i —2.09-2.12 (m), part of the m at 2.09-2.18 H-li, H-il’, H-12H-4 —2.13-2.18(m), part of them at 2.09-2.18 H-12H-b and H-b0’ 2.43-2.50 (m) H-il, H-li’, H-13, H-13’H-b3 4.79-4.80 (m) H-10 and H-iO’, H-i3’H-13’ 5.10-5.11 (m) H-b and H-10’, H-l3a- Oniy those COSY correlations that could be assigned are recorded.b- H indicates the hydrogen of a pair which is more downfield (H-b is more downfield than H-b).Table 52: 1H nmr Data (400 MHz, pyridine-d5) for the Tricycic Compound 162: COSYExperimentAssignment ‘H nmr (400 MHz) COSY Correlationsa-xo ppm_(mult., J (Hz))H-li —1.42-1.50 (m), part of them at 1.22-1.81 H-i, H-b and H10’b, H-il’H-li’ —1.63-1.71 (m), part of them at 1.22-1.81 H-i, H-10 and H-b’, H-ilH-i 2.08-2.11(m) H-bi,H-i1’,H-12H-12 2.22-2.27 (dd, J = ii, 11) H-b, H-4H-4 2.30-2.34 (m) H-12H-iO and H-b’ 2.49-2.53 (m) H- 1, H-li’, H-13, H-13’H-13 4.93-4.95 (m) H- 0 and H-b0’, H-13’H-i3’ 5.59-5.60 (m) H-b and H-10’, H-i3a- Only those COSY correlations that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-b’ is more downfield than H-b).255Table 53: Comparison of the ‘H nmr (400 MHz) Chemical Shifts of Compound 162 inCDC13 vs. Pyridine-d5H1313HHO HH162=H13H-x 6 ppm in CDC13 6 ppm in Pyridine-d5 Aa, bH-i —2.09-2.12 2.08-2.11 -0.01H-4 —2.13-2.18 2.30-2.34 0.16H-b and Hi0c 2.43-2.50 2.49-2.53 0.04H-li —1.41-1.46 —1.42-1.50 0.02H-il’ —1.71-1.75 —1.63-1.71 -0.06H-12 —1.85-1.89 2.22-2.27 0.3811-13 4.79-4.80 4.93-4.95 0.14H-13’ 5.10-5.11 5.59-5.60 0.49a - A = 6 (pyridine-d5) - 6 (CDC13); i.e. [(2.08+2.11)/2 - (2.09+2.12)/2] = -0.01.b - Only those As> 0.15 are recorded in bold font.c - H’ indicates the hydrogen of a pair which is more downfield (H-lOis more downfield than H-b).2563.5.1.6. Synthesis of (1 S*, 4S*, 8R , 12S*)4Methyl9methylenetricyclo[6.3. 1.04,121 -dodecan-8-ol (156):143L, HO11HMe Me13138b 156Following general procedure 4, a solution of the trans-fused vinyl iodide 138b (42mg, 0.13 mmol, 1 equiv.) in dry THF (2.5 mL) was treated with a solution of n-butyllithiumin hexanes (1.51 M, 0.21 mL, 0.32 mmol, 2.5 equiv.). The resultant solution was stirred at-78 °C for 30 mm. The crude product was subjected to radial chromatography (1 mm plate,1:1 CH2C12 - petroleum ether), and the solid thus obtained was recrystallized from petroleumether - diethyl ether to afford 22 mg (85%) of the tricyclic compound 156, as a colourlesscrystalline solid, mp 60°C.JR (KBr): 3563, 3463, 3076, 1641, 1456, 1079, 900 cm1.nmr (400 MHz) & 0.72-0.76 (d, 1H, J = 13 Hz, H-12), 1.04 (s, 3H, Me-13), 1.06-1.17(m, 4H, one of which is H-li), 1.20-1.28 (m, 1H), 1.40-1.46 (m, 1H), 1.51-1.64 (m, 2H),1.73-2.07 (m, 6H, two of which are H-i and H-li’), 2.16-2.21 (ddd, 1H, J = i4, 3.5, 2.5 Hz,H-b), 2.44-2.52 (br dd, 1H, J = 14, 14 Hz, H-b’), 4.71-4.72 (m, 1H, H-i4), 4.80-4.81 (m,1H, H-14’).Detailed 1H nmr data (CDC13), derived from a COSY experiment, are given in Table 54.257‘H nmr (400 MHz, pyridine-dS) 6: 0.68-0.71 (d, 1H, J = 13 Hz, H-12), 1.06-1.20 (m, 3H,one of which is H-il), 1.21-1.26 (m, 1H), 1.29 (s, 3H, Me-13), 1.40-1.42 (m, 1H), 1.54-1.61(m, 2H), 1.76-1.85 (m, 2H), 1.98-2.04 (m, 2H, one of which is H-li’), 2.15-2.22 (m, 2H, oneof which is H-b), 2.22-2.35 (m, 1H, H-i), 2.78-2.86 (br ddd, 1H, J 13.5, 13.5, 4.5 Hz, H10’), 4.75-4.76 (m, 1H, H-14), 4.86-4.87 (m, 1H, H-14).Detailed ‘H nmr data (pyridine-d5), derived from a COSY experiment, are given in Table55.‘H nmr data comparing the chemical shifts in CDC13 versus those in pyridine-d5 are given inTable 56.nmr (75.3 MHz) 6: 19.6, 20.7 (-ye, Me-13), 26.6, 32.8, 33.7 (-ye, C-i), 34.5, 35.4, 39.8,39.9, 41.2, 59.6 (-ye, C-12), 73.0 (C-8), 106.4 (C-l4), 154.1 (C-9).Exact Mass calcd. for C14H22O: 206.1671; found: 206.1671.Anal. calcd. for C14H22O: C 81.50, H 10.75; found: C 81.31, H 10.58.258Table 54: 1H nmr Data (400 MHz, CDC13) for the Tricycic Compound 156: COSYExperiment14HO91HMe1315610’=Assignment ‘H nmr (400 MHz) COSY CorrelationsaH-x 6 ppm (mult., J (Hz))H-12 0.72-0.76 (d, J = 13) H-iMe-i3 1.04(s)H-il —1.06-1.09 (m), part of them at 1.06-1.17 H-i, H-b, Hi0’b, H-il’H-i —2.00-2.02 (m), part of the m at 1.73-2.07 H-il, H-i2H-il’ —2.02-2.07 (m), part of the m at 1.73-2.07 H-l0, H-b’, H-liH-l0 2.16-2.21 (ddd, J = 14, 3.5, 2.5) H-iO’, H-li, H-li’H-l0’ 2.44-2.52 (brdd, J = 14, 14) H-10, H-il, H-il’, H-i4, H-14’H-14 4.7 1-4.72 (m) H-l0’, H-14’H-l4’ 4.80-4.8 1 (m) H-10’, H-14a- Only those COSY correlations that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-b’ is more downfield than H-lO).Table 55: ‘H nmr Data (400 MHz, pyridine-d5) for the Tricyclic Compound 156: COSYExperimentAssignment 1H nmr (400 MHz) COSY CorrelationsaH-x 6 ppm (mult., J (Hz))H-12 0.68-0.7 1 (d, J = 13) H-iH-ll —1.06-1.13 (m), part of the m at 1.06-1.20 H-i, H-10, Hl0’b, H-li’Me-13 1.26 (s)H-li’ —2.01-2.04 (m), part of them at 1.98-2.04 H-l, H-b, H-b’, H-llH-b —2.18-2.22 (m), part of the m at 2.15-2.22 H- 10’, H-l 1, H-il’H-l 2.22-2.35(m) H-ll,H-ll’,H-12H-b’ 2.78-2.86 (brddd, J = 13.5, 13.5, 4.5) H-b, H-il, H-il’, H-14, H-14’H-14 4.75-4.76 (m) H-l0’, H-14’H-14’ 4.86-4.87 (m) H-l0’, H-14a- Only those COSY correlations that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-b’ is more downfield than H-b).259Table 56: Comparison of the ‘H nmr (400 MHz) Chemical Shifts of Compound 156 inCDC13 vs. Pyridine-d51243Me13156H10’=10H-x 6 ppm in CDC13 6 ppm in Pyridine-d5 a, bH-i -2.00-2.02 2.22-2.35 0.28H-10 2.16-2.21 —2.18-2.22 0.02Hi0’c 2.44-2.52 2.78-2.86 0.34H-il —1.06-1.09 —1.06-1.13 0.02H-il’ —2.02-2.07 —2.01-2.04 -0.02H-12 0.72-0.76 0.68-0.71 -0.04Me-13 1.04 1.26 0.22H-i4 4.7 1-4.72 4.75-4.76 0.04H-i4’ 4.80-4.8 1 4.86-4.87 0.06a - A = 6 (pyridme-c15) - 6 (CDC13); i.e. [(2.22+2.35)/2 - (2.00+2.02)/2] = 0.28.b - Only those A’s > 0.15 are recorded in bold font.c - H’ indicates the hydrogen of a pair which is more downfield (H-lOis more downfield than H-b).2603.5.1.7. Synthesis of (1S*, 4S*, 8R ‘, 12R *)4.Methyl.9...methylenethcyclo[6.3.1.Oi] .dodecan-8-ol (165), (1 S*, 4S*, 8S*, 12R*)4Methyl9methylenetricyclo[6.3.1.04,12] -dodecan-8-ol (166), and (1 R*, 6S*,(167):áHHOH H9hi H 911Me Me Me13 Me1°138a 165 166 167Following general procedure 4, a solution of the cis-fused vinyl iodide 138a (112 mg,0.337 mmol, 1 equiv.) in dry THF (6.7 mL) was treated with a solution of n-butyllithium inhexanes (1.58 M, 0.53 mL, 0.84 mmol, 2.5 equiv.). The resultant solution was stirred at -78°C for 1 h. The crude product mixture was subjected to radial chromatography (1 mm plate,9:1 petroleum ether - diethyl ether) to provide three fractions. The first compound to beeluted was the tricyclic compound 166. Concentration of the appropriate fractions anddistillation (air-bath temperature 76-80 °C/0. 1 Torr) of the oil thus obtained, afforded 24 mg(35%) of the compound 166, as a colourless oil.JR (film): 3549, 3079, 1640, 1457, 1140, 897 cm-1.‘H nmr (400 MHz) & 0.66 (s, 1H, -011; this signal exchanges in the presence of D20), 0.91(s, 3H, Me-13), 1.10-1.39 (m, 4H, one of which is H-12), 1.45-1.53 (m, 2H), 1.67-2.11 (m,7H, two of which are H-li and H-li’), 2. 19-2.28 (ddddd, ill, J = 16, 16, 5, 2.5, 2.5 Hz, H-10), 2.36-2.42 (br ddd, ill, J = 16, 4, 4 Hz, H-b’), 2.47-2.54 (sextet, 1H, J = 8 Hz, H-i),4.69-4.71 (m, 1H, H-14), 4.90 (m, 1H, H-14’).Detailed ‘H nmr data (CDCI3), derived from a COSY experiment, are given in Table 57.261l3 nmr (75.3 MHz) & 17.8, 27.5, 29.5, 31.3 (-ye), 32.0, 34.5, 35.0, 35.8, 35.9 (-ye), 42.0,51.7 (-ye, C-12), 72.1 (C-8), 105.6 (C-14), 154.0 (C-9).Exact Mass calcd. for C14.H220: 206.1671; found: 206.1665.Anal. calcd. for C14H220: C 81.50, H 10.75; found: C 81.66, H 10.79.Table 57: ‘H nmr Data (400 MHz, CDC13) for the Tricyclic Compound 166: COSYExperimentH14-H9hiHMe13166H14=Assignment ‘H nmr (400 MHz) COSY CorrelationsaH-x ppm (mult., J (Hz))-O 0.66 (s)Me-13 0.91 (s)H-12 i.19(d,J=8) H-iH-il —1.76-1.81 (m), part of the m at 1.67-2.11 H-i, H-b, Hi0’b, H-li’H-il’ —1.85-1.92 (m), part of them at 1.67-2.11 H-i, H-b, H-10’, H-ilH-b 2.19-2.28 (ddddd, J = 16, 16, 5, 2.5, 2.5) H-iO’, H-il, H-li’, H-14, H-14’H-b’ 2.36-2.42 (brddd, J = 16,4,4) H-b, H-li, H-li’, H-14, H-14’H-i 2.47-2.54 (sextet, J = 8 Hz) H-il, H-li’, H-12H-i4 4.69-4.7i (m) H-iO, H-b’, H-i4’H-i4’ 4.90 (m) H-iO, H-b’, H-14a- Only those COSY correlations that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-b’ is more downfield than H-b).262The second compound to be eluted was the bicycic compound 167. The appropriatefractions were concentrated and the oil thus obtained was distilled (air-bath temperature 84-88 °C/0.15 Torr) to provide 14 mg (20%) of the compound 167, as a colourless oil.JR (film): 1698, 1641, 1456, 1232, 908 cm1.‘H nmr (400 MHz) & 1.07 (s, 3H, Me-lO), 1.27-1.31 (m, 1H), 1.41-1.69 (m, 6H), 1.81-1.96(m, 4H), 2.04-2.13 (m, 2H), 2.34-2.43 (m, 3H), 4.90-4.93 (dddd, 1H, J = 10, 1.5, 1.5, 1.5 Hz,H-14), 4.94-5.00 (dddd, 1H, J = 17, 1.5, 1.5, 1.5 Hz, H-14’), 5.69-5.79 (dddd, 1H, J = 17,10, 7, 7 Hz, H-13).13C nmr (75.3 MHz) 6: 21.3, 28.2 (-ye, Me-lO), 31.0, 32.4, 33.0, 34.5, 40.5, 42.1, 42.3 (-ye),45.4, 62.6 (-ye, C-i), 114.6 (C-14), 138.4 (-ye, C-13), 215.3 (C-2).Exact Mass calcd. for C14H220: 206.1671; found: 206.1672.Anal. calcd. for C14H220: C 81.50, H 10.75; found: C 81.43, H 10.83.The last compound to be eluted was the tricyclic compound 165. The appropriatefractions were concentrated and the oil thus obtained was distilled (air-bath temperature 84-87 °CI0. 15 Torr) to provide 28 mg (40%) of the compound 165, as a colourless oil.JR (film): 3611, 3411, 1641, 1466, 1059, 898 cm1.‘H nmr (400 MHz) 6: 1.15 (s, 1H, -OH; this signal exchanges in the presence of D20), 1.17(s, 3H, Me-13), 1.19-1.46 (m, 9H, two of which are H-il and H-12), 1.62-1.72 (m, 2H, one263of which is H-li’), 1.75-1.87 (m, 2H), 2.18-2.24 (m, 1H, H-i), 2.38-2.48 (m, 2H, H-l0 andH-b’), 4.76-4.77 (m, 1H, H-14), 5.08 (m, 1H, H-14’).Detailed ‘H nmr data (CDC13), derived from a COSY experiment, are given in Table 58.‘H nmr (400 MHz, pyridine-d5) & 1.19-1.33 (m, 4H), 1.35 (s, 3H, Me-13), 1.37-1.54 (m,3H, one of which is H-li), 1.58-1.69 (m, 1H, H-il’), 1.70-1.76 (m, 3H), 1.86 (d, 1H, J =11.5 Hz, H-12), 2.10-2.19 (m, 2H, one of which is H-i), 2.45-2.52 (m, 2H, H-b and H-b’),4.92-4.94 (m, bH, H-14), 5.57-5.59 (m, 1H, H-14’).Detailed 1H nmr data (pyridine-ds), derived from a COSY experiment, are given in Table59.‘H nmr data comparing the chemical shifts in CDC13 versus those in pyridine-d5 are given inTable 60.nmr (75.3 MHz) 6: 17.8, 28.4 (-ye, Me-13), 28.8, 29.5, 30.4, 33.2, 36.1, 38.5 (-ye, C-i),41.0, 41.6, 55.4 (-ye, C-12), 74.3 (C-8), 106.2 (C-14), 154.2 (C-9).Exact Mass calcd. for C14H220: 206.1671; found: 206.1665.Anal. calcd. for C14H22O: C 81.50, H 10.75; found: C 81.54, H 10.65.264Table 58: 1H nmr Data (400 MHz, CDC13) for the Tricyclic Compound 165: COSYExperimentH1414’H-j’NHOJçHMe13165HO H14H’Assignment H- ‘H nmr (400 MHz) COSY Correlationsaxo ppm_(mult., J (Hz))-011 1.15(s)Me-13 1.17(s)H-12 —1.32-1.37 (m), part of them at 1.19-1.46 H-iH-il —1.45-1.51 (m), part of them at 1.19-1.46 H-i, H-10 and H10’b, H-il’H-li’ Part of them at 1.62-1.72 H-i, H-l0 and H-b’, H-ilH-i 2.i8-2.24(m) H-il, H-il’, H-l2H-iO and H-iO’ 2.38-2.48 (m) H-li, H-il’, H-i4, H-i4’H-14 4.76-4.77 (m) H-10 and H-10’, H-14’H-i4’ 5.08 (m) H-10 and H-iO’, H-i4a- Only those COSY correlations that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-b’ is more downfield than H-b).Table 59: 1H nmr Data (400 MHz, pyridine-d5) for the Tricycic Compound 165: COSYExperimentAssignment H- ‘H nmr (400 MHz) COSY Correlationsaxo ppm_(mult., J (Hz))Me-i3 1.35(s)H-il —1.48-1.53 (m), part of them at 1.37-1.54 H-i, H-10 and H10’b, H-li’H-il’ 1.58-1.69(m) H-i,H-i0andH-iO’,H-iiH-12 i.86(d,J=11.5) H-iH-i —2.12-2.19 (m), part of them at 2. 10-2. i9 H-il, H-li’, H-12H-b and H-10’ 2.45-2.52 (m) H-li, H-il’, H-i4, H-i4’H-14 4.92-4.94 (m) H-b and H-iO’, H-l4’H-14’ 5.57-5.59 (m) H-b and H-10’, H-i4a- Only those COSY correlations that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-b’ is more downfield than H-bO).265Table 60: Comparison of the ‘H nmr (400 MHz) Chemical Shifts of Compound 165 inCDC13 vs. Pyridine-d5H14H11HMe13165HO H14H1H-x ppm in CDC13 ppm in Pyridine-d5 a, bH-i 2.18-2.24 —2.12-2.19 -0.06H-b and Hb0’C 2.38-2.48 2.45-2.52 0.06H-li —1.45-1.51 —1.48-1.53 0.02H-li’ Partofmatl.62-l.72 1.58-1.69 —-0.04H-12 —1.32-1.37 1.86 0.52Me-13 1.17 1.35 0.18H-14 4.76-4.77 4.92-4.94 0.16H-i4’ 5.08 5.57-5.59 0.50a - A = ö (pyridine-d5) - 6 (CDC13); i.e. [(2.12+2.19)/2 - (2.18÷2.24)/2] = -0.06.b - Only those A’s> 0.15 are recorded in bold font.c - H’ indicates the hydrogen of a pair which is more downfield (H-lOis more downfield than H-b).266PART 2: TOTAL SYNTHESES OF (--HOMALOMENOLS A AND B.I. INTRODUCTION1.1. GENERALIn the first century of organic chemistry, the focus was on chemical change in thedirection of chemical reactions (i.e. reactant —> products). By the mid-1960’s, a different andmore systematic approach known as retrosynthetic analysis was developed. Corey12Odefmesretrosynthetic analysis as a problem solving technique for transforming the structure of asynthetic target molecule to a sequence of progressively simpler structures along a pathwaywhich ultimately leads to simple or commercially available starting materials for a chemicalsynthesis. The synthesis of complex organic molecules involves a number of steps:1) choice of the molecule to be synthesized;2) development of a synthetic strategy via retrosynthetic analysis;3) the selection of specific individual steps and their ordering; and4) the experimental execution of the synthesis.In the last decade, it has been increasingly crucial to design synthetic strategies that allow forthe asymmetric synthesis of natural products.1.2. PROPOSALIn Part 1 of this thesis, highly stereoselective conjugate addition reactions of theorganocopper(I) reagent 15 to bicyclo[4.3.O]non-9-en-2-ones were studied in detail (equation36). How general is this reaction? Could other cuprate reagents be added stereoselectively tothese enones?1)Me3Ge’Cu(CN)Li GeMe3TMSBr, THE, -78 °c (36)R’ 2) H20; NH4CI - NH4O267In order to provide at least a partial answer to these questions, it was decided to use thischemistry to develop a total synthesis of the recently isolated sesquiterpene alcohols, (+)-homalomenol A (168a) and (+)-homalomenol B (169a).MHHOMe1 68aSesquiterpenes 168a and 169a were isolated from the roots of Homalomenaaromatica (Roxb.) Schott (Araceae) by Sung et al.121 and have not been previouslysynthesized. The roots of Homalomena aromatica are used in Vietnamese folk medicine asan anti-inflammatory agent, a tonic drug, and for the treatment of stomach diseases. Theroots are also used in the aroma industry as a source of homalomenol oil which contains up to80% linalool.121 The chloroform extract of the dried roots afforded six compounds, three ofwhich were already known (oplopanone (170), oplodiol (171), and bullantantriol (172)). Thethree unknown sesquiterpenes were named homalomenol A (168a) and B (169a), and 1f, 41,7cc-trihydroxyeudesmane (173). The absolute stereochemistry assigned to the homalomenols(shown above) was based on a positive Cotton effect observed for the ketone derived fromthe oxidation of the trihydroxyeudesmane sesquiterpene 173. This assignment was laterconfirmed by our asymmetric synthesis.HOMeOHHOMeI 69aOH172170 171 173268There are several other natural products that are very similar in structure tohomalomenals A (168a) and B (169a), one of which is the sesquiterpene oppositol (174).This compound was isolated from the marine epiphytic red alga Laurencia suboppositaSetchell, and the absolute stereochemistry (shown below) was obtained from single-crystalX-ray diffraction analysis.122 The absolute stereochemistry of oppositol (174) is opposite tothat of (+)-homalomenols A (168a) and B (169a). An extremely arduous 28 step racemicsynthesis of oppositol (174) was carried out by Masamune and coworkers123 (see Scheme32).MeMeBrMe174269o AcO A0OH HOHj,jjiii,IV,V ,“H HviiI I HCHOO AcO AcO0 viii’ix,x, xi, xiiHO°MeOBn BOBn BnOH.41exiii, xiv,,COBn‘xviii,/xixMeBr Br Br MBr,Me MeBnH LOB OBn 0 OBnHO Me OBnxxv’BrBr BrMe Me Mexxvii,xxviii___HeK HecHQ OH174i) LiAIH4, THF, rt; ii) Ac20, Pyridine, DMAP; iii) 03, CH2C12, -78 °C; Zn, AcOH-H20;iv) p-TsOH, C6H6, reflux; v) H2, 1-% Pd-C, EtOH, it; vi) Jones reagent, acetone, 0 °C; vii)LiA1H4, THF, -20 °C; viii) EtOCH=CH2, PPTS, CH2C12, rt; ix) LiA1H4, THF, 0 °C; x)BnBr, KH, DMF, rt; xi) 0.5 M HC1, rt; xii) PCC, CH2C12, rt; xiii) HCOOEt, NaOEt, C6H6,rt; xiv) BuSH, p-TsOH, MgSO4, C6H6, it; xv) Mel, t-BuOK, DME, -78 °C; xvi) KOH,DEG, reflux; xvii) NaBH4, MeOH, 0 °C to rt; xviii) MsC1, Et3N, CH2C12, 0 °C; xix)Bu4NBr, toluene, 95-97 °C; xx) H2, 10% Pd-C, 1 M HC1, EtOH, rt; xxi) BnBr, NaH, DMF,-70 °C; xxii) PCC, CH2C12, rt; xxiii) p-TsOH, CH2C12, rt; xxiv) MeLi, ether, -20 °C; xxv)Bu4NBr, toluene, 115 °C; xxvi) H2, Pd-C, 1 M HC1, EtOH, rt; xxvii) PDC, CH2C12, rt;xxviii) Ph3P=C(CH3)2, THF, 0°C.Scheme 32123270II. DISCUSSION2.1. RETROSYNTHETIC ANALYSISHaving chosen the target to be synthesized, the next step was to develop a syntheticstrategy via retrosynthetic analysis. Our retrosynthetic plan towards the syntheses of (+)-homalomenols A (168a) and B (169a) is pictured in Scheme 33. Homalomenols A (168b)and B (169b) could, in principle, be obtained from the stereoselective methylation of thecarbonyl moieties and deprotection of the secondary alcohols of the intermediates 175a and176a, respectively. The functionalized bicyclo[4.3.Ojnonan-2-ones 175a and 176a could, inturn, result from the stereoselective conjugate addition of the organocopper(I) reagents 178and 179 to the bicyclic enone 177a. In these key steps, the stereochemical results arepredicted to resemble those obtained in the conjugate addition reactions of theorganocopper(I) reagent 15 to the bicyclo[4.3.Ojnon-9-en-2-ones 74, 75, 95, and 96 (seeSection 2.3.3.4., page 56).The bicydic x,-unsaturated ketone 177a could be derived from the enone 180a via afive-membered ring annulation process. The modified version of HelquisCs annulationmethod utilized in Section 2.3.2. (pages 44-48) could be employed in the synthesis of 177a.That is, the Grignard reagent 97 could be added in a conjugate fashion to the enone 180a, andthe resultant product could be converted, via an intramolecular aldol reaction, into the keybicycic enone 177a. The conditions for the aldol reaction would have to leave the protectinggroup intact.The enone 180a could be obtained from functional group manipulations of the allylicacetate 181a. Acetate 181a has been previously synthesized in an asymmetric fashion byPolla and Frejdl24 via a kinetically controlled enzymatic ester hydrolysis reaction. Polla andFrejd124 report that the racemic acetate 181 could be obtained from epoxidation of the 13,y-unsaturated enone 182, followed by base-promoted isomerization of the intermediate epoxideand acetylation of the resultant allylic alcohol. The [3,y-unsaturated enone 182 could, in turn,be derived from the Birch reduction of the commercially available 3-methylanisole (183). 1252710 0 OMeMe Me MeAcO 182 183181 aScheme 33MMeHIHOMe1 68aHOMeI 69a00 Ii/175a R =176a R=+or Cu178 179MeI 80aI 77aUCY_MBr +2722.2. SYNTHESIS OF (-)-HOMALOMENOL B (169b)2.2.1. PREPARATION OF THE ENANTIOMERICALLY HOMOGENEOUS ALLYLICACETATh 181bThe method of Rubottom and Gruber125 was used to prepare the f,’y-unsaturatedenone 182. Thus, treatment of 3-methylanisole (183) with LiJNH3 and tert-butyl alcoholprovided the enol ether 184 (equation 37). The crude enol ether 184 was then hydrolyzedwith oxalic acid to yield, after workup and distillation, 3-methyl-3-cyclohexen-1-one (182) in84% overall yield (equation 37).OMe OMe 0Li/NH3,Et20 oxalic acid(37)Me tBuOH, 33 °C Me MeOH:H20, Me(3:1)183 184 182(84%)The ‘H nmr spectrum (400 MHz, C6D6) of 182 revealed a vinyl methyl signal at1.35 (br s) and a vinyl proton signal at 8 5.17 (br s), identical with data reported for enone182.125 Solutions of both the enol ether 184 and the f3,y-unsamrated enone 182 wereconcentrated by distillation of the solvent at atmospheric pressure through a jacketed Vigreuxcolumn to avoid loss of product. The enone 182 was found to be stable when stored in thefreezer under an atmosphere of argon.According to Polla and Frejd,124 the enone 182 could be transformed to the epoxide185 with peracetie acid (equation 38). In the literature preparation, the crude epoxide 185was immediately converted to the allylic alcohol 186 with Et3N (equation 38).O%Me12C12Jt [r.Me1Et3NMe182 185° OH186273We found that the allylic alcohol 186 was not very stable to purification and could notbe stored for any length of time. We modified this procedure by using m-CPBA as theoxidizing agent instead of peracetic acid (equation 39). The epoxide 185 was isolated andwas converted to the allylic acetate 181 directly (equation 39) to avoid having to isolate theintermediate alcohol 186.0 0 0mCPBA (1.3 equiv.) Et(eqiv.) rNCH2I,0°C LM equiv.) L_il%Me()182 185 AcO(94%) 181(84%)Upon workup and distillation, the epoxide 185 was obtained in 94% yield. The ‘Hnmr spectrum (400 MHz, CDC13) of 185 indicated a signal at 6 1.36 (s) for the tertiarymethyl group, signals at 62.56 (d, J = 19 Hz) and 2.78 (d, J = 19 Hz) for protons H-2 andH-2’, and a signal at 6 3.20 (br d, J = 2.5 Hz) for H-6, thereby confirming that theepoxidation had taken place.Epoxide 185 was treated with acetic anhydride, in the presence of i-Pr2NEt andDMAP, to provide, after flash column chromatography and distillation, the racemic allylicacetate 181 in 84% yield (equation 39). The 1H nmr spectrum (400 MHz, CDC13) of 181indicated the following characteristic signals: 6 1.94 (br dd, J = 1, 1 Hz) corresponding tothe vinyl methyl group; 6 2.13 (s) for the acetate methyl group; 6 5.54-5.58 (br dd, J = 7.5, 5Hz) for the proton H-4; and 6 5.94 (br s) for the vinyl proton. The allylic acetate 181 couldbe stored indefinitely in the freezer under an atmosphere of argon with no signs ofdecomposition. It is interesting to note that Polla and Frejd124 claim that the acetate 181 isunstable and must be used immediately in the next step.Kinetic resolution of the racemic acetate 181 was accomplished with the enzyme, pigliver esterase (PLE), which was purchased as a suspension in 3.2 M (NH4)2S04, pH 8, from274Sigma. Polla and Frejd1 report that the hydrolysis of 181 with PLE in the presence of a 0.3M Tris-HC1 buffer (pH 7) and 25% DMSO resulted in the isolation of the (R)-allylic alcohol186a with 90% ee (Scheme 34). The reaction was monitored by gic and was stopped at 45%conversion. Since we wished to obtain the alcohol 186a in an enantiomeric excess of 95%,we ran this reaction allowing for only a 36% conversion (Scheme 34). The enantiomericexcess obtained for the (R)-allylic alcohol 186a did not improve; in fact, the value obtained(88% ee) was slightly lower than that reported.MeAcO1810.3M Tris-HCI (pH 7)25% DMSO, PLE20°C Me1 86a0+Ac0181 bConversion 182a 17Th%ee %ee45% 9i3%36% 88% 84%a- This reaction was reported by Polla and Frejd124b- This ee was not reported.Scheme 34The enantiomeric excess was determined by treating the allylic alcohol 186a with (-)-menthoxyacetic acid (187) to afford a mixture of diastereomeric esters 188a and 188b(equation 40). 126 The ‘H nmr spectrum (400 MHz, CDC13) of this mixture revealed signals60.79 (d, J =7 Hz) for the secondary methyl group, 6 0.91 (d, J = 6.5 Hz) and 0.92 (d, J =6.5 Hz) for the isopropyl methyl groups, 6 1.94 (dd, J = 1, 1 Hz) for the vinyl methyl group,6 5.64-6.62 (dd, J = 7.5, 5 Hz) for the proton H-4, and 6 5.95 (hr s) for the vinyl proton. Intheory there should be two sets of signals for the diastereomers 188a and 188b; however, inthe absence of a shift reagent, only one set of signals was observed.275o H +(40)DCC (1.1 equiv.) Me MeMe 4-pyrrolidinopyridine O----.,.HO (0.2 equiv.), rt Ii ‘186a 0188a 188b688% ee(79% yield)The enantiomeric excess was determined by the 1H nmr spectroscopic analysis of themixture of the diastereomers in the presence of 0.1 - 0.2 equivalents of Eu(fod)3.127 The94:6 ratio shown in equation 40 was based on integration of the vinyl methyl signals. Figure8 shows the ‘H nmr spectra of a mixture of 188a and 188b in the absence and presence ofEu(fod)3. The vinyl methyl signals (part b, Figure 8), are very well resolved in the presenceof the shift reagent Eu(fod)3 and were thus reliably integrated. The enantiomeric excess ofthe unreacted acetate 181b was determined by converting the acetate to the alcohol (videinfra), forming the ester with (-)-menthoxyacetic acid (187), and analyzing the ‘H nmrspectrum of the diastereomeric mixture of esters in the presence of Eu(fod)3. In this way, theee of the unreacted acetate was determined to be 84%.Since the enantiomeric excess of the (R)-allylic alcohol 186a was syntheticallyacceptable (i.e. <95% ee), we undertook to synthesize the (S-enantiomer 186b by allowing agreater enzymatic conversion (i.e. > 50% hydrolysis). The racemic acetate 181 washydrolyzed with the PLE to an extent of 59% and the unreacted acetate 181b was isolated in40% yield (Scheme 35). A small portion of the acetate 181b was hydrolyzed with Na2CO3in MeOH, and the corresponding aflylic alcohol 186b was esterified with (-)-menthoxyaceticacid (187) (Scheme 35).94JLI I188a188b2.16‘2.122.b8•IIIIIIIIIIIIIIIIIIIIIIII4IIIIIIIIIIIIIIIIIIIIII(ppm)b)The1Hnmrspectrumof188aand188binthepresenceof0.10equivalentsofEu(fod)3I(ppm)4a)The1Hnmrspectrumof188aand188bintheabsenceof Eu(fod)3Figure8:The1HnmrSpectra(400 MHz,CDC13)of188aand188bina)theabsenceandb)presenceofEu(fod)3277Me1 86a(55%)0+ IAcO181 b(40%)>99%eeScheme 35The ‘H nmr spectrum (400 MHz, CDC13) of the ester 188b, in the presence of 0.1 - 0.2equivalents of Eu(fod)3, revealed only one diastereomer (i.e. only one vinyl methyl group).Hence, the unreacted acetate 181b in Scheme 35 was isolated in > 99% ee. Thisenantiomeric excess is in accord with that reported.124MeAcO1810.3M Tris-HCI (pH 7)25% DMSO, PLE20°C, 26 h(59% conversion by gb)Me1 88bOnly one diastereomerwas present in the 1H nmrspectrum with Eu(fod)3H°187DCC (1.1 equiv.)4-pyrrolidinopyridine(0.2 equiv.), rtNa2CO3(5 equiv.)MeOH, rtMeI 86b278MeI 86a88% eeMeAcO181 b>99% eeThe (R)-allylic alcohol 186a could be used to synthesize the naturally occurring (+)-homalomenols A (168a) and B (169a). However, since we could obtain the otherenantiomeric series (i.e. (S)-allylic acetate 181b) in a higher enantiomeric purity (>99% eeversus 88% ee), we chose to synthesize the (-)-homalomenols A (168b) and B (169b).OH1 68b 1 69b2792.2.2. PREPARATION OF THE ENANTIOMERICALLY HOMOGENEOUS BICYCLICENONE 177bTo continue with the synthesis of (-)-homalomenol B, the acetate function of 181bneeded to be replaced with a more chemoresistant group. Hence, the (-)-allylic acetate 181bwas converted to the TBDPS ether 180b (equation 41). Conversion of 181b to thecorresponding alcohol 186b was quickly accomplished with Na2CO3 and since the allylicalcohol 186b was not very stable, it was used immediately in the next step. The alcoholfunction of 186b was protected using TBDPSC1 in the presence of imidazole to provide, afterpurification, the tert-butyldiphenylsilyl ether 180b in 80% overall yield, as a highly viscousoil which could not be distilled (equation 41). Residual solvent was removed by heatingcompound 180b to 75-80 °C/0.2 Torr using a Kugelrohr distillation apparatus.0 0jj 1) Na2CO3(5 equiv.) 2) TBDPSCI (2 equiv.)MeOH, rt, 1.5 h Imidazole (4 equiv.) (41)Me MeDMF,rt,15h MeAcO HO181b 186bPh’ç-1 80b(80%)The presence of the TBDPS group was evident in the ‘H nmr spectrum (400 MHz,CDC13) of 180b via the signals at 6 1.08 (s, 9H, -C3), 7.38-7.48 (m, 6H, aromaticprotons), and 7.68-7.72 (m, 4H, aromatic protons). The signal at 6 1.94 (dd, J = 1, 1 Hz)was assigned to the vinyl methyl group; the signal at 6 4.34 (br dd, J = 7.5, 4.5 Hz) wasassigned to the proton H-4; and the signal at 6 5.79 (br s) was assigned to the vinyl proton.The next step in the synthetic pian was conversion of the enone 180b to the bicyclicenone 17Th by employing a modified version of the five-membered ring annulation sequencereported by Helquist and coworkers4A6(Scheme 36). The strongly acidic conditions280previously used for the intramolecular aldol cyclization (HCIIH2OITHF/A) would need to bemodified to accommodate the TBDPS protecting group.IIIA search of the literature revealed that conjugate addition to a six-membered ringenone will proceed anti to an oxygen substituent at C-4. One such example was reported byPolla and Frejd124 and is illustrated in equation 42.MeQTBDPSMgBrCuBr•SMe2,-75 °CTMSCI, TMEDA, THEThe conjugate addition of the Grignard reagent 97 to the enone 180b proceeded, inthe presence of CuBr•Me2S, TMSC1, and HMPA, to provide the keto acetal 189 in 88% yieldMeOTBDPS177b0MeOTBDPS180b 0BrMg0)/1\ )%%%%MeOTBDPS 0189Scheme 36I(42)OTBDPS2810MgBrTMSCI (2.5 equiv.)HMPA (2.5 equiv.)CuBr•Me2S(15 mol%)THE, -78 °C, 3 h, warmedto -50 °C over 2.5 h2) H20; NH4CI, NH4OThe 1H nmr spectrum (400 MHz, CDC13) of 189 revealed signals at 6 0.96 (s) for thetertiary methyl group, 6 1.09 (s) for the tert-butyl group, 6 3.65-3.72 and 3.66-3.73 (ddd, 1Heach, J = 12, 12, 2 Hz for each ddd) for the axial protons on C-li and C-13, 6 3.81-3.84 (dd,J = 5, 5 Hz) for the proton H-4, 8 4.03-4.07 (ddd, 2H, J = 12, 5, 1 Hz) for the equatorialprotons on C-li and C-13, 6 4.34-4.36 (dd, J = 5, 4.5 Hz) for the proton H-i0, and 6 7.35-7.72 (m) and 7.66-7.72 (m) for the aromatic protons. The signal at 6 2.47-2.5 1 (br d, J = 14Hz) was assigned to H-2’ since only the protons at C-2 could exist as doublets. The COSYspectrum allowed the assignment of H-2 (part of the m at 6 1.96-2.07) through the correlationof its signal to that of H-2’ (see Table 63, experimental, page 327). Various other protons,such as H-5, H-5’, H-6, and H-6’, were also assigned on the basis of COSY correlations.It should be noted that the hydrolysis of the silyl enol ether intermediate 191 (formedafter the conjugate addition reaction) proved to be somewhat troublesome. Typically, H20(equation 43). Only one stereoisomer was evident in the 1H nmr spectrum of the crudeproduct derived from the copper(I)-catalyzed Grignard addition. As expected, anti-additionrelative to the oxygen substituent at C-4 was achieved; however, the stereochemistry wasconfirmed in a subsequent product (vide infra). A small amount of the coupled byproduct190 was formed in this reaction and it was partially separated from the product 189 by flashcolumn chromatography. The keto acetal 189 was subsequently crystallized from petroleumether to completely separate it from the byproduct 190.MeOTBDPSI 80b+OTBDPS189(88%)(43)282was added to the reaction mixture and the resultant mixture was left stirring open to theatmosphere (—2 h to overnight). In most cases, the silyl enol ether 191 was completelyhydrolyzed to the keto acetal 189 under these conditions. Occasionally, however, thehydrolysis of 191 did not proceed to completion; in these cases, the reaction mixture wasworked up and the crude product was treated with one equivalent of TBAF in THF, whichprovided the keto acetal 189 (equation 44). The TBDPS protecting group was found to bestable to TBAF at room temperature.OTMS 0MeTBAF (44)THE, rtOTBDPS 0191In attempts to effect the conversion of the keto acetal 189 to the enone 177b, theconditions reported by Helquist and coworkers4’6 (HCL’H2O1THF) could not be employedbecause the TBDPS ether would, in all likelihood, be hydrolyzed.128 The results of attemptsto promote the aldol cyclization are summarized in Table 61. The conditions utilized inentries 1, 2, and 4 resulted in the nearly quantitative recovery of starting material 189.Integration of the ‘H nmr spectrum of the crude product isolated in entry 3 indicated a —1:1mixture of starting material and product 177b; however, there was also a significant amountof an unidentifiable byproduct.Lavallée and Hanessian128 have shown that TBDPS ethers are stable to 50% aqueousCF3COOH in dioxane at room temperature (equation 45). Use of these conditions in oursystem (entry 4, Table 61) resulted in the recovery of only starting material. However,modification of these conditions (see entry 5, Table 61; 80% aqueous CF3COOH vs. 50%CF3COOH, and 70 °C vs. room temperature) resulted in a satisfactory formation of thedesired enone 17Th.189283dioxane, rt, 15 mmConditions=TBDPSOe189 177bEntry Conditions Resultsia PPTS, aqueous acetone, Mostly starting material, a traceovernight amount of 17Th2b 80% aqueous acetic acid, THF, Mostly starting materialroom temperature, 4 h3C p-TsOH, CH2C12, A, 5 h Starting material : Product 17Th(—1:1 ratio)+ unidentifiable byproduct4d 50% aqueous CF3COOHIdioxane, Mostly starting materialroom temperature, 4 h5 80% aqueous CF3COOHIdioxane 82% Yield of 177b(1:2), 70 °C, 16 ha- The conditions utilized were reported by Hagiwara and Uda129 for the hydrolysis of1,3-dioxolanes (i.e. 5-membered ring acetals).b- The conditions utilized were reported by Babler eta!. 130 for the hydrolysis of 1,3-dioxolanes.c- The conditions utilized were reported by Baudin et aiJ31 for the hydrolysis of 1,3-dioxolanes.d- The conditions utilized were reported by Lavallde and Hanessian128 for the hydrolysis of 1,3-dioxolanes.NH2 NH2TBDPSO TBDPSO0 50% aqueous CF3OOH (45)HO OHTable 61: Attempts to Cyclize Keto Acetal 189 to Form the Bicyclic Enone 177b284A few additional comments on the cyclization procedure (entry 5, Table 61) arenecessary. The reaction mixture was heated at 70°C for 16 h; after workup and flash columnchromatography, the enone 177b was isolated in 77% yield. The column was then flushedwith diethyl ether and, after concentration, the residual material was resubjected to acidicconditions (100% CF3COOHIdioxane (1:2), 70°C) for 15 h. Upon workup and purification,an additional 5% of the enone 17Th was obtained, resulting in an overall yield of 82%.Presumably, the more poiar compounds eluted with diethyl ether are intermediates in thecyclization sequence. Simply utilizing a longer reaction time (i.e. > 20 h) in the originalreaction did not, however, improve the yield (i.e. — 77% yield of 177b was obtained,regardless of the reaction time).0TBDPSO Me1 77bThe JR spectrum of 177b revealed absorbances at 1687 and 1618 cm-’, characteristicof an x,f-unsaturated enone. The ‘H nmr spectrum (400 MHz, CDC13) revealed a signal at6 1.20 (s) for the tertiary methyl group, a signal at 6 3.76-3.80 (dd, J = 11, 4 Hz) for protonH-5, and a signal at 66.42-6.63 (dd, J = 2.5, 2.5 Hz) for the vinyl proton H-9.2852.2.3. SYNTHESIS OF THE BICYCLIC KETONE 176bThe next step in the synthesis of (-)-homalomenol B was the stereoselective conjugateaddition of the organocopper(I) reagent 179 to the bicyclic enone 17Th (equation 46).)Cu17TBDPSO TBDPSO Me1 77bOur initial attempts to prepare 179 involved the reaction of methallyl bromide (192) witheither magnesium (equation 47) or t-BuLi (equation 48). Both attempts failed, due to the soleformation of the coupled byproduct 193. Allyl halides are known to be quite reactive, andthus, it was not surprising that 193 was formed.1321) Mg (2 equiv.)THF.A2) CuBr•MeS, -78 C1931) t-BuLi (2 equiv.)THEA2) CuCN, -78 °CLipshutz and coworkers133 have reported that the copper(I) reagent 179 can beprepared from 2-methyl-3-(tri-n-butylstannyl)propene (194) by sequential treatment of thelatter substance with n-BuLi and LiC1/Cul (equation 49). In our work, it was foundnecessary to use freshly recrystallized Cu1134 for this preparation. The allylstannane 194 wasprepared from 3-chloro-2-methylpropene (195) and tri-n-butylstannyl chloride, according tothe procedure of Keck and Enholm135 (equation 49).1) n-BuLi, THF,78° (49)2) LiCI/Cul 179Me(46)1 76bLBr192‘LBr192(47)(48)193Mg,THF,O°C195 Bu3SnCISnBu3194286The conjugate addition of reagent 179 to the bicyclic enone 17Th, in the presence ofTMSBr, resulted in the formation of a 7:1 mixture of epimers 196 and 176b (equation 50).We were pleased to discover that the conjugate addition reaction had proceededstereoselectively, as expected (see Section 2.3.3.4., page 56). The cis- and trans-fusedepimers 196 and 176b were easily separated by flash column chromatography and wereisolated in 81% and 12% yield, respectively. When this reaction was performed in thepresence of TMSC1 (as reported in related chemistry by Lipshutz and coworkers 133) insteadof TMSBr, the overall yield was decreased by 16%.The ‘H nmr spectrum (400 MHz, CDC13) of the major cis-fused epimer 196 isillustrated in Figure 9 and indicates signals at 6 1.18 (s) for the tertiary methyl group, 6 1.59(s) for the vinyl methyl group, 62.49-2.52 (dd, J = 10.5, 2 Hz) for the angular proton H-i, 63.74-3.77 (dd, J = 8.5, 3.5 Hz) for the proton H-5, and 6 4.48 (br s) and 4.56 (br s) for thevinyl protons H-13 and H-13’. The COSY spectrum allowed the assignment of several otherprotons (see Table 65, experimental, page 335). For example, the signal at 6 1.41-1.47 (brdd, J = 13, 10.5 Hz) was assigned to H-9 through the correlation of its signal to that of H-i.141) )..Cu.TMSBr179THE, -78 °C, 5.5 h2) H20; NH4OH-NHCIOTBDPS1 77b(50)Me MeOTBDPS OTBDPS196 176b(81%) (12%)7 1H13’TBDPSO Me196 Me‘I’ll 3.O(ppm)ji I(ppm)4I.I.II,‘iô’I•I•Iii(ppm)IIIII{IIIIFigure9:The1HnmrSpectrum(400MHz,CDCI3)oftheCis-FusedKetone19614 H13’TBDPSOMe1° 196oc288The relative stereochemistry of 196 was consistent with the following NOE differenceexperiments. Irradiation of the signal at 6 1.18 (Me-lO) caused an enhancement of the signalat 6 2.49-2.52 (H-i) and vice versa. This confirmed the cis-fused nature of the ring junction.Irradiation of the signal at 6 3.74-3.77 (H-5) caused an enhancement of the signal at 6 1.56-1.70 (H-li), thereby verifying that reagent 179 had introduced the methallyl group trans tothe angular methyl group, as predicted.The ‘H nmr spectrum (400 MHz, CDC13) of the minor trans-fused epimer 176b isillustrated in Figure 10. The tertiary methyl group (Me- 10) was revealed as a singlet at 60.89; the vinyl methyl group was observed at 6 1.71 (s); the angular proton H-i was evidentas a doublet at 6 1.87-1.90 (J = ii Hz); the proton H-S was observed as a doublet of doubletsat 6 3.33-3.44 (J = 10.5, 5 Hz); and the vinyl protons H-13 and H-i3’ were evident as broadsinglets at 6 4.59 and 4.64, respectively. The COSY spectrum allowed the assignment of H-9(6 2.49-2.51, m) through the correlation of its signal to that of H-i (see Table 64,experimental, page 333)..OTBDPSTBDThe following NOE difference experiments verified the stereochemistry of 176b.Irradiation of the signal at 60.89 (Me-iO) caused an enhancement of the signal at 62.44-2.51(H-9) and vice versa. This not only confirmed the stereochemistry of the conjugate additionreaction, but also verified the trans-fused ring junction. Examination of molecular modelsindicated that an NOE between H-9 and Me- 10 is only possible when the ring junction istrans-fused. Irradiation of the signal at 6 3.33-3.44 (H-5) caused an enhancement at 6 1.87-1.90 (H-i), further verifying the nature of the ring junction.H13’1 76bI11111111111111113.90(ppm)Figure10:TheHnmrSpectrum(400 MHz,CDCI3)of theTrans-FusedKetone176bhA10TBDPSOivieI76b13i.W(ppm)jJLL_I(ppm)00290The epimer required for the synthesis of (-)-homalomenol B is, in fact, the minortrans-fused isomer 176b. According to our previous equilibration studies (see Table 11,page 73) and results reported by Dana and coworkers63 (Table 10, page 71), the trans-fusedepimer 176b should be thermodynamically more stable than the corresponding cis-fusedepimer 196. In fact, treatment of 196 with NaOMe in MeOH resulted in a 7:1 mixture of176b and 196, respectively (equation 51). The two epimers were separated by flash columnchromatography, and the recovered cis-fused epimer 196 was resubjected to theepimerization conditions. The total yield of the trans-fused epimer 176b after two suchepimerizations was 94% (or 87% based on the enone 17Th).The 7:1 ratio of 176b:196, obtained upon base equilibration, is similar to thatobserved in entry 4, Table 11 (5:1 ratio of the trans- to cis-fused epimers 133b:133a; page73). The thermodynamically controlled base equilibrium ratio of trans- to cis-fusedbicyclo[4.3.OJnonan-2-ones is very dependent on the nature and stereochemistry of thesubstituents at C-6 and C-9 (vide supra). Since 176b and 133b possess similar substituentsin the same stereochemical orientation at carbons 6 and 9, it follows that they should havesimilar trans- to cis-fused ratios upon epimerization.-•GeMe3MeNaOMe/MeOHrt, 17hMe196Me(51)MeTBDPSO176b 1967 : 1TBDPSO Me1 76bMeI 33b2912.2.4. SYNTHESIS OF (-)-HOMALOMENOL B (169b)The remaining two steps in the synthesis of (-)-homalomenol B involve the additionof a methyl carbanion to the bicyclic ketone 176b and cleavage of the TBDPS ether function.The addition of MeLi to the carbonyl moiety of 176b provided the tertiary alcohol 197 in87% yield (equation 52).Me MeJTh MeLi(1.5equiv.) fThEt20, -20 °C; (52)warming to -5 °CTBDPSO Me over 1.5 h1 76b(87%)The stereochemical outcome of this conversion was based on the preferential equatorialapproach of MeLi to the carbonyl carbon. Axial approach of MeLi would involve a 1,3-diaxial interaction between the angular methyl group and the incoming reagent (see below).OTBDPSThe JR spectrum of 197 indicated absorbances at 3583, 3481, 3071, and 1650 cm4,indicative of hydroxyl and olefinic moieties. The ‘H nmr spectrum (400 MHz, CDC13)revealed signals at 6 0.79 (br d, J = 11 Hz) for the angular proton H-i, 6 1.17 (s) for thenewly-introduced tertiary methyl group (Me-lO), 6 1.20 (d, J = 0.6 Hz) for the angularmethyl group (Me-il), 6 3.37-3.41 (dd, J = 11.5, 4.5 Hz) for the proton 11-5, and 64.66 (brs) and 4.71 (br s) for the vinyl protons 11-14 and 11-14’, respectively. The COSY spectrumallowed the assignment of 11-9 (6 2.24-2.32, m) through the correlation of its signal to that ofH-i (see Table 66, experimental, page 339).M ‘H197292The following NOE difference experiments were consistent with the assignedstructure 197. Irradiation of the signal at 60.79 (H-i) caused an enhancement of the signal at8 3.37-3.41 (H-5) and vice versa. Irradiation of the signal at 6 1.17 (Me-lO) caused anenhancement of the signal at 6 0.79 (H-i); this result is consistent with the assignedstereochemistry of the MeLi addition. Irradiation of the signal at 6 1.20 (Me-il) caused anenhancement of the signal at 6 2.24-2.32 (H-9) and vice versa.10H14’ =OTBDPSThe final step, deprotection of the secondary alcohol, was accomplished with TBAF.The usual conditions for the cleavage of a TBDPS group involve treatment with TBAF inTHF at room temperature.136 However, the deprotection of 197 required reflux conditionsfor 17 hours to afford (-)-homalomenol B (169b) in 95% yield (equation 53). These morevigorous conditions are probably required because the secondary alcohol function is quitehindered.M OH MeTBDPSO eMMeMe197TBAF (5 equiv.)THF,A, 17h197(53)10M 15H14’M’11HO1 69b(95%)(-)-HOMALOMENOL B42% Yield from theenantiomerically pureallylic acetate 181b293(-)-Homalomenol B (169b) was recrystallized from ethyl acetate - petroleum ether toafford a colourless, crystalline solid, mp 94-95 °C (lit.121 mp 78-8 1 °C). The IR spectrum of169b revealed absorbances at 3632, 3371, 3070, and 1649 cm-1,characteristic of hydroxyland olefinic moieties. The ‘H nmr spectrum (400 MHz, CDC13) is shown in Figure 11 andindicates signals at 60.92 (d, J = ii Hz) for the angular proton H-i, 1.02 (br d, J 0.9 Hz)for the angular methyl group (Me-i 1), 1.09 (br s, which disappears upon the addition ofD20) for the tertiary alcohol proton, 1.25 (s) for the tertiary methyl group (Me-iO), 1.70 (s)for the vinyl methyl group (Me-15), 3.34-3.38 (ddd, J = 11.5, 4.5, 4.5 Hz, which collapses toa dd (J = 11.5, 4.5 Hz) upon the addition of D20) for the proton H-5, and 4.66 (br s) and4.71 (br s) for the vinyl protons H-i4 and H-14’, respectively. The results of the COSY andNOE experiments are listed in Table 67 (experimental, page 342). The NOE differenceexperiments were very similar to those obtained with the precursor 197. The IR, ‘-H nmr,l3 nmr, and HRMS data for (-)-homalomenol B (169b) are consistent with those of theisolated compound (+)-homalomenol B.121 A comparison of the reported spectral data for(+)-homalomenol B (169a) with that of the synthetic (-)-homalomenol B (169b) is listed inTable 68 (experimental, page 343). That the absolute stereochemistry of the synthetic (-) -homalomenol B is opposite to that of the natural product was confirmed by the sign of thespecific optical rotation (observed [cJ -43.0 (c 1.7 10, CHC13) for the synthetic material;reported121 [c] +20.4 (c 1.745, CHC13) for the natural product).(ppm)I..,,(ppm)151O10 MI 69b(-)-Homalomenol BI1iII.I•(ppm)4O353O252OFigure11:The1HnmrSpectrum(400 MHz,CDC13)of (-)-HomalomenolB(169b)2952.3. SYNTHESIS OF (-)-HOMALOMENOL A (168b)2.3.1. PREPARATION OF THE BICYCLIC KETONE 175b2.3.1.1. Model Studies for the Preparation of Reagent 178For the synthesis of (-)-homalomenol A (168b), we proposed the conjugate additionof the organocopper(I) reagent 178 to the enone 177b to produce the desired ketone 175b(equation 54).(54)In order to prepare reagent 178, we needed to first synthesize the vinyllithium species 198.The studies into the formation of 198, using cyclohexanone as the acceptor reagent, aresummarized in Scheme 36. The vinyllithium species 198 is normally prepared from thereaction of t-butyllithium with 1-bromo-2-methylpropene (199). 137 However, our attempts atforming 198 from the reaction of t-butyllithium with 1-bromo-2-methylpropene (199) yieldeda 5:1 mixture of the desired product 200 and the diene byproduct 201, respectively. It isinteresting to note there were no diene byproducts reported in any of the literaturepreparations and uses of 198.137 This problem was partially overcome by employing 1-iodo-2-methyipropene (202). The iodide 202 is not commercially available and was preparedaccording to the method of Inokawa et al.138 The formation of the vinyllithium species 198from treatment of the iodide 202 with tert-butyllithium resulted in the formation of a 14.5:1mixture of 200 and 201, respectively. We were able to avoid the formation of dienebyproduct 201 altogether by performing a slow addition of a solution of the vinyl iodide 202in dry THF to a solution of t-BuLi in dry THF at -78 °C (see Scheme 36). It is at presentunclear why these modifications avoid the formation of 201; however, it should be noted that178177b 175b296the order of addition of the iodide 202 to t-BuLi is uniquely different from that reported forthe formation of 198 from the bromide 199.137The next step in the formation of the organocopper(I) reagent 178 involved theaddition of a copper(I) source to the vinyllithium species 198. The addition of solid CuCN to198, followed by warming the mixture to -35 °C, was not very effective since the copper(I)reagent decomposed at -30 to -40 °C. Thus, we opted to use a solubilized solution of CuCN(1 equiv.) and LiCl (2 equiv.) in THF139 to avoid having to warm the organocopper(I)solution to allow for the dissolution of CuCN (equation 55).slow addition oft-BuLIX202 [THE, -78 °C200Sole ProductFormedt-BuLi (2 equiv.) [%(1_________Br THE, -78 °C L Li j199 198 200 2015 : 1xl202t-BuLi (2 equiv.)THE, -78 °CIc198 200 20114.5 : 1]á198Scheme 36297slow addition of .. - CuCN/LiCIt-BuLi______________1: 2 [!%. (55)(2equiv.)TI2O2 THE Cu(CN)Li198 178THE, -78 °CWe also prepared the higher order copper(I) reagent 203 by adding one equivalent ofCuCN to two equivalents of the vinyllithium species 198 (equation 56). In this case, thesolution could be warmed to -30 °C to dissolve the CuCN without decomposition of thehigher order organocopper(I) reagent.slow addition of CuCN (1 equiv.)t-BuLi j I I(4 equiv.) %%%%__. -78 °C —* -30 °C \ 2Cu(CN)LiIi202 (2 equiv.) Li198 203THE, -78 °C2.3.1.2. Literature Precedent on the Effects of Various Additives on the Stereoselectivity ofConjugate Addition ReactionsAs will be discussed in Section 2.3.1.3. (page 300), the stereochemical outcome of theconjugate addition reaction of reagent 178 was dependent on the nature of the additives used.Thus, before examining the results of these studies, the literature precedent on the effects ofvarious additives on the stereoselectivity of conjugate addition reactions will be outlinedbelow.In order to improve the chances for effecting a desired conjugate addition reaction, itis now common practice to mix either lower order (L.O.) or higher order (H.O.) cuprates withan additive such as BF3•Et20 or TMSC1, which often leads to spectacular increases in ratesand yields of reactions.14° It is well known that TMSX and/or BF3•Et20 affect thecomposition of H.O. organocuprates. 140,141 For example, Lipshutz and coworkers havefound that BF3 sequesters RLi from the cuprate cluster.141 On the other hand, TMSX was298found to infiltrate the cuprate cluster by undergoing an irreversible reaction with the H.O.cuprate.141 The effects of these additives on the cuprate reagents must somehow beresponsible for the stereochemical outcome of the addition reaction.The effect of TMSC1 on the stereochemical outcome of a conjugate addition reactionhas been explored by Corey and Boaz.142 The addition of the L.O. organocopper(I) reagent204 to the x,f-unsaturated enone 205 in the absence of TMSC1 provided a 56:44 mixture ofthe adducts 206a and 206b, respectively (equation 57). In the presence of TMSC1, however,the trans isomer 206a was the exclusive product.14302 CULI204 + (57)THE, -78 °C0 0205 206a 206bADDITIVE RATIOnone 56 : 44TMSC1 >99 : <1Helquist and Zhao1 report that the stereoselectivity of the conjugate addition of anisobutyl group to the enone 207 was very sensitive to the reaction parameters. The desiredisomer 208a was obtained with a selectivity as high as 5:1 when the organocopper(I) reagentwas employed in the presence of TMSC1 (equation 58). On the other hand, 208b wasfavored, by a factor as large as 3:1, when HMPA was also present. These results cannot, asyet, be explained but they do serve to indicate that care must be taken in choosing conditionsfor effecting stereoseleetive conjugate additions.299H°THE, -78 0(58)I- B u C uMe Me208a 208bADDITIVE RATIOnone 1 : 2.5TMSC1 5 : 1TMSC1+HMPA 1 : 3BF3•Et20 1.3 : 1Another example was reported by Kuwajima and coworkers.145 The use ofBF3•Et20 as an additive changed the stereochemical outcome of the copper(I)-catalyzedaddition of the Grignard reagent 209 to the enone 210. In the absence of BF3•Et20, therewas no stereoselectivity observed, whereas in the presence of BF3•Et20, a > 95:< 5 mixtureof adducts 211a and 211b was obtained (see equation 59). 145ADDITIVE RATIOnone 1BF3•Et20 >95 : <5With these results in mind, we proceeded to study the conjugate addition of reagents 178 and203 to the enantiomerically homogeneous bicyclic enone 17Th.Me207Br, CuBr•Me2STHE, -78 °CAdditiveCO2But210(59)211a 211b3002.3.1.3. Conjugate Addition of the Organocopper(I) Reagents 178 and 203 to the BicycleEnone 17ThTable 62 summarizes the results of the conjugate addition of reagents 178 and 203 tothe enone 177b in the presence of various additives. In entries 1-4, the L.O. organocopper(I)reagent 178 was used and a mixture of three isomers resulted. The cis- and trans-fusedepimers 212 and 175b possessed the desired stereochemistry at C-9. However, the undesiredcis-fused isomer 213 was also formed, in which the configuration at C-9 was opposite to thatpresent in compounds 212 and 175b. The ratios of the desired adducts (212 and 175b) to theundesired adduct (213) were influenced both by the nature of the additive and theorganocopper(I) reagent used. In entry 1, a 4:1 ratio was obtained; however, the reaction didnot go to completion at -78 °C. When this reaction was allowed to warm to -10 °C (entry 2,Table 62), the reaction proceeded to completion but the ratio of the desired to undesiredstereoisomers was changed from 4:1 to 1:1.4. Hence, subsequent L.O. cuprate additions weremaintained at -78 °C. The use of BF3•Et20 and TMSBr (entry 3) forced the reaction tocompletion and provided a 1.9:1 mixture of desired to undesired adducts. This reaction willbe discussed in more detail following the discussion of the results in Table 62. The use ofBF3•Et20 alone (entry 4) provided a similar 1.8:1 ratio. The starting material was consumedbut other unidentifiable byproducts were also formed.The use of the H.O. organocopper(I) reagent 203 is detailed in entries 5-7 in Table62. Inclusion of the additive TMSBr (entry 5) provided a 1:2 mixture of the desired toundesired adducts. This ratio is quite different from that obtained using the L.O. cuprate(entry 1), although it should be noted that the reaction conditions were slightly different.However, as was the case in entry 1, this reaction also did not proceed to completion. Theuse of BF3’Et20 (entries 6 and 7) allowed the reaction to proceed to completion to provideratios ranging from 2.5:1 (entry 6) to 4.2:1 (entry 7). However, these reactions were notclean, and unidentifiable byproducts were observed in the crude ‘H nmr spectra.301Table 62: The Effects of Additives on the Conjugate Addition of Reagents 178 or 203 to theEnone 17Th178 or 203ThFOTBDPS212 + 175bOTBDPS213Entry Organocopper(I) Additive Temp. and RATIOSReagents Time1b SBr -78 °C, 9.5 h 4 : 1Cu(CN)Li1782 178 TMSBr -78°C,6.5h; 1 : 1.4-10°C,2h3 178 TMSBr + -78 °C, 6.5 h 1.9 : 1BF3’Et204C 178 BF3•Et20 -78 °C, 5.5 h 1.8 : 15d TMSBr -78 °C, 2.5 h; 1 : 2\ 2Cu(CN)Li -48°C,lh2036C 203 TMSBr + -78 °C, 5 h; 2.5 : 1BF3•Et20 -60°C,4h7C 203 BF3•Et20 -78 °C, 5.5 h 4.2 : 1a- The ratios were determined by 1H nmr spectroscopic analysis.b- This reaction did not go to completion, approximately 33% starting material was recovered.c- This reaction was not clean; other unidentifiable byproducts were observed in the crude 1H nmr spectrum.d- This reaction did not proceed to completion.1 77b302It is difficult to rationalize the stereochemical results summarized in Table 62. Theconditions listed in entry 3 were found to be optimum; the reaction was clean and proceededto completion to provide a mixture of products 212, 175b and 213 (62:4:34, respectively) in81% overall yield (equation 60).OTBDPS THF,-78°C,6.5h OTBDPS OTBDPS OTBDPS177b 2) H20; NH4CI-NHO 212 175b 21362 : 4 : 3481% overall yieldFlash column chromatography of this mixture provided compound 175b in 3.4% yield and amixture of the cis-fused compounds 212 and 213 in 78% yield. Fortunately, compound 212could be epimerized to a mixture of 212 and 175b, whereas compound 213 did notequilibrate under basic conditions. Not unexpectedly, compound 213 is thermodynamicallymore stable than its corresponding trans-fused epimer. Upon examination of molecularmodels, it is evident that the trans-fused epimer of compound 213 would be destabilized by apseudo 1,3-diaxial interaction between the 2-methyl-1-propenyl group and the angularmethyl group. Thus, when the mixture of adducts 212 and 213 was treated with NaOMe inMeOH, a 28:36:36 mixture of compounds 212, 175b, and 213 was produced (equation 61).OTBDPS OTBDPS OTBDPS OTBDPS OTBDPS212 213 212 175b 2131.8 : 1 8 : : 361 : 1.3303The trans-fused adduct 175b was only slightly more stable than the cis-fused adduct 212, asindicated by the 1.3:1 ratio obtained upon equilibration. This is in contrast to the 7:1 ratioobserved for the trans- and cis-fused adducts 176b and 196 used in the synthesis of (-)-homalomenol B (see page 290). Obviously, the nature of the substituent at C-9 has asignificant effect on the thermodynamically controlled base equilibrium ratio ofbicyclo[4.3.0]nonan-2-ones. The trans-fused adduct 175b obtained upon equilibration wasreadily separated from the mixture by column chromatography. The remaining mixture ofcis-fused adducts 212 and 213 was resubjected to the equilibration conditions and the desiredisomer 175b was obtained by chromatography. After three such epimerizations, the overallyield of the desired trans-fused epimer 175b was 43%, based on the enone 177b.The ‘H nmr spectrum (400 MHz, CDC13) of desired epimer 175b is illustrated inFigure 12 and reveals signals at 0.91 (s) for the angular methyl group (Me-lO), 1.60 (br s)and 1.70 (br s) for the vinyl methyl groups (Me-13 and Me-14, respectively), 3.03-3.10(dddd, J = 10.5, 10.5, 10.5, 6.5 Hz) for the allylic proton H-9, 3.87-3.91 (dd, J = 10.5, 5 Hz)for the proton H-5, and 4.78 (br d, J 10.5 Hz) for the vinyl proton H-il. The COSYspectrum allowed the assignment of the angular proton H-l ( —2.01, d, J = 10.5 Hz) throughthe correlation of its signal with that of H-9 (see Table 69, experimental, page 350).OTBDPSTBDPSO Me1 75bThe following NOE difference experiments were consistent with the abovestereochemical assignments. Irradiation of the signal at 0.91 (Me-lO) caused anenhancement of the signal at 6 3.03-3.10 (H-9) and vice versa, thus confirming thestereochemistry of the conjugate addition at C-9.13(ppm)3.O6‘•(ppm)I13TB175b•1’11’(ppm)IIIIIIIIl,IIIIIIIIIIIIII4Figure12:The1HumrSpectrum(400MHz,CDCJ3)oftheTrans-FusedKetone175b305Irradiation of the signal at 6 3.87-3.91 (H-5) caused an enhancement of the signal at 6 2.01(H-i). Irradiation of the signal at 6 4.78 (H-il) also caused an enhancement of the signal at 62.01 (H-i). These results are consistent with the trans-fused nature of the ring junction aswell the stereochemical assignment at C-9. Irradiation of the signal at 6 1.60 (Me-13) causedan enhancement of the signal at 6 4.78 (H-il) and vice versa, thereby confirming theassignment of the vinyl methyl signals.Column chromatography of the initial mixture of compounds 212, 175b, and 213provided small amounts of pure cis-fused adducts 212 and 213. The 1H nmr spectrum (400MHz, CDC13) of 212 possessed signals at 6 1.17 (s) for the angular methyl group (Me-lO),1.43 (d, J = 0.8 Hz) and 1.50 (br s) for the vinyl methyl groups (Me-i4 and Me-i3,respectively), 2.48-2.51 (hr dd, J = 10, 2 Hz) for the angular proton H-i, 3.12-3.21 (m) forthe allylic proton H-9, 3.77-3.8 1 (br dd, J = 10.5, 5 Hz) for the proton H-5, and 4.51 (br d, J= 10 Hz) for the vinyl proton H-li.The stereochemical assignments were consistent with the following NOE differenceexperiments. Irradiation of the signal at 6 1.17 (Me-lO) caused an enhancement of the signalat 6 2.48-2.51 (H-i), verifying the cis-fused nature of this compound. Irradiation of thesignal at 6 2.48-2.51 (H-i) caused an enhancement of the signals at 6 1.17 (Me-iO) and 3.12-3.21 (H-9) and vice versa. This result was consistent with the assigned stereochemistries atC-6, C-i, and C-9. Irradiation of the signal at 6 3.77-3.8 1 (H-5) caused an enhancement ofthe signal at 6 4.51 (H-li) and vice versa.14 1 13HTBDPSO%...I)TBDPSOMe306The 1H nmr spectrum (400 MHz, CDC13) of the remaining isomer 213 revealedsignals at 6 1.16 (s) for the angular methyl group (Me-lO), 1.42 (d, J = 1 Hz) and 1.61 (d, J= 1 Hz) for the vinyl methyl groups (Me-14 and Me-13, respectively), 2.00 (d, J = 11.5 Hz)for the angular proton H-i, 2.79-2.88 (m) for the allylic proton H-9, 3.86-3.91 (dd, J 10.5,4 Hz) for the proton H-5, and 4.92 (br d, J 9 Hz) for the vinyl proton H-il.14.. i...l3M’áTh°TB DPSOlZ1HOThe following NOE difference experiments were consistent with the stereochemistrydepicted above. Irradiation of the signal at 6 2.00 (H-i) caused an enhancement of thesignals at 6 1.16 (Me- 10) and 4.92 (H-li). Irradiation of the signal at 6 4.92 (H-il) causedan enhancement of the signals at 6 i.6i (Me-13) and 2.00 (H-i). Irradiation of the signal at 63.86-3.91 (H-5) caused an enhancement of the signal at 6 2.79-2.88 (H-9). Theseexperiments were consistent with the assignment of the cis-fused ring junction as well as theassignment of the stereochemistry of the conjugate addition at C-9 (i.e. the 2-methyl-i-propenyl group had been introduced cis to the angular methyl group).112133072.3.2. SYNTHESIS OF (-)-HOMALOMENOL A (168b)The next step in the synthesis of (-)-homalomenol A (168b) involved thestereoselective addition of MeLi to the carbonyl moiety of 175b to provide the tertiaryalcohol 214 in 80% yield (equation 62).The stereochemical outcome of this transformation was based on the preferential equatorialapproach of MeLi to the carbonyl carbon (see page 291). The 1H nmr spectrum (400 MHz,CDC13) of 214 revealed signals at 6 0.86 (d, J = 11.5 Hz) for the angular proton H-i, 0.97 (s,which exchanges upon treatment with D20) for the tertiary hydroxyl proton, 1.01 (s) for theangular methyl group (Me-li), 1.21 (s) for the newly introduced tertiary methyl group (Me-10), 1.62 (d, J = 1 Hz) and 1.63 (d, J = 1 Hz) for the vinyl methyl groups Me-13 and Me-14,2.86-2.95 (m) for the allylic proton H-9, 3.35-3.39 (dd, J = 11.5,4 Hz) for the proton H-5,and 5.00 (br d, J = 9.5 Hz) for the vinyl proton H-i2.F MeLi (2 equiv.)Et20, -20 °C;10M14. 12(62)TBDPSO Me1 75bwarming to -5 °Coverlh MeTBDPSO214(80%)OH( MTBAF (8 equiv)THF,L, 18h214(63)HOMeI 68b(87%)(-)-HOMALOMENOL A17% Yield from theenantiomerically pureallylic acetate 181b308In the final step, the deprotection of the secondary alcohol was accomplished byrefluxing a solution of 214, TBAF (8 equivalents), and THF for 17 h (equation 63). (-)-Homalomenol A (168b) was obtained in 87% yield and was recrystallized from diethyl ether- petroleum ether to provide thin, needle-like plates, mp 99-100 °C (lit. 121 reports (+)-homalomenol A as an oil). The IR spectrum of 168b revealed absorbances at 3617, 3434,and 1581 cm-’, characteristic of hydroxyl and olefinic moieties. The ‘H nmr spectrum (400MHz, CDC13) is illustrated in Figure 13 and indicates signals at 6 0.99 (br d, J = 11.5 Hz)for the angular proton H-i, 1.04 (d, J 0.7 Hz) for the angular methyl group (Me-i 1), 1.10(s) for the tertiary methyl group Me-iO, 1.63 (d, J = 1.5 Hz) and 1.64 (d, J = 1.5 Hz) for thevinyl methyl groups Me-i4 and Me-15, 2.88-2.98 (m) for the allylic proton H-9, 3.35-3.38(dd, J = 11.4, 4.1 Hz) for the proton H-5, and 5.05 (br d, J = 9.5 Hz) for the vinyl proton H-12.15 13 14e0H i’fl—168b(-)-Homalomenol AThe following NOE difference experiments were consistent with the assignedstereochemistry of (-)-homalomenol A (168b). Irradiation of the signal at 6 0.99 (H-i)caused an enhancement of the signals at 3.35-3.38 (H-5) and 5.05 (H-12). Irradiation of thesignal at 6 1.04 (Me-il) caused an enhancement of the signal at 6 2.88-2.98 (H-9) and viceversa. Irradiation of the signal at 6 1.10 (Me-lO) caused an enhancement of the signal at 65.05 (H-i2). Irradiation of the signal at 6 2.88-2.98 (H-9) caused an enhancement of thesignals at 6 1.04 (Me-li) and 1.64 (Me-15). Irradiation of the signal at 6 3.35-3.38 (H-5)caused an enhancement of the signal at 6 0.99 (H-i).(ppm)IIII5.04.515i-1410HIIMe..f“12HOMe11168b(-)-HomalomenolA•4•••323:140353’tJ25(ppm)Figure13:The1HnmrSpectrum(400MHz,CDC13)of(-)-HomalomenolA(168b)C310The IR, ‘H nmr, nmr, and HRMS data for (-)-homalomenol A (168b) areconsistent with those of the isolated (+)-homalomenol A (168a).121 A comparison of thereported spectral data for (+)-homalomenol A with that of the synthetic (-)-homalomenol A islisted in Table 72 (experimental, page 360). The absolute stereochemistry of the synthetic(-)-homalomenol A is opposite to that of the natural product. This was confirmed by the signof the specific optical rotation (observed [cx] -51.5 (c 1.30, CHC13) for the syntheticmaterial; reported121 [cx] +33.2 (c 1.205, CHC13) for the natural product).2.3.3. SYNTHESIS OF THE (-)-MONOACETATE 215The conversion of (-)-homalomenol A (168b) to the monoacetate 215 wasaccomplished in 98% yield by reaction with acetic anhydride and pyridine (equation 64).The ‘H nmr spectrum (400 MHz, CDC13) of the synthetic 215 is illustrated in Figure 14 andreveals a signal at 2.01 (s) for the newly introduced acetoxy methyl group. The 1H nmrspectrum (200 MHz, CDC13) of the (+)-monoacetate 215 derived from the natural product isshown in Figure 15146 and is similar to the spectrum of the synthetic monoacetate 215.Macetic anhydridepyridine, ii, 24 hA comparison of the reported spectral data for the (+)-monoacetate 215 with that of thesynthetic (-)-monoacetate 215 is listed in Table 73 (experimental, page 362) and indicatesthat these two products are enantiomers.MHOMeI 68b(-)-Homalomenol A(64)AcO Me215IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII5.04.54.03.02.0(ppm)Figure14:The1HnmrSpectrum(400MHz,CDC13)ofthe(-)-Monoacetate2153 525IIIIIIIIIII/flIIIII5.45.04.53.02.52.01.51.0(ppm)MI215Figure15:The1HmnrSpectrum(200MHz,CDC13)ofthe(+)-Monoacetate215fromDr.T.V.Sung3132.4. CONCLUSIONThe work described in Part 2 of this thesis culminated in the first total syntheses oftwo sesquiterpene alcohols, (-)-homalomenol A (168b) and (-)-homalomenol B (169b). Thekey steps of the overall synthetic sequences involved the conjugate addition of theorganocopper(I) reagents 178 and 179 to the enantiomerically homogeneous bicyclic enone17Th. In the synthesis of (-)-homalomenol B (169b), this conjugate addition reactionproceeded stereoselectively to provide the desired adduct 176b in excellent yield. However,in the synthesis of (-)-homalomenol A (168b), the stereochemical outcome of the conjugateaddition of 178 to the enone 177b proved to be dependent on the nature of the additive.Nonetheless, the desired adduct 175b was obtained, albeit in moderate yield, and thesynthesis of 168b was successfully completed. A summary of the syntheses of 168b and169b is displayed in Scheme 37.314OMebM:MedMe M e183 182 185 AcO AcO181 181bf, gOk, mMeh,177b 189180b‘,‘q, rIMeOTBDPS0 I OH176b fi H Me, H II 0 ( ‘\ S,y I I)Me OH MeJH --- iMe Meç OTBDPS HO175b (-)-168bHOMe(-)-1 69b(a) LiINH3, Et20, t-BuOH, -33 °C; (b) oxalic acid, MeOH:H20 (3:1), rt, 84%; (c) m-CPBA(1.3 equiv.), CH2C12, 0 °C, 94%; (d) (AcO)20 (2 equiv.), i-Pr2EtN (2 equiv.), DMAP (0.2equiv.), CH2C12, 6 h, rt, 84%; (e) 0.3 M Tris-HC1 (pH 7), 25% DMSO, PLE, 20 °C, 26 h(59% conversion), 40%, > 99% ee; (f) Na2CO3 (5 equiv.), MeOH, rt, 1.5 h; (g) TBDPSC1 (2equiv.), imidazole (4 equiv.), DMF, rt, 15 h, 80%; (h) reagent 97, TMSC1 (2.5 equiv.),HMPA (2.5 equiv.), CuBr•Me2S (15 mol%), THF, -78 °C, 3 h, warming to -50 °C over 2.5h; (i) H20; NH4C1-NH4OH, 88%; (j) 80% aqueous CF3COOHJdioxane (1:2), 70 °C, 16 h,82%; (k) reagent 179, TMSBr (7 equiv.), -78 °C, 5.5 h; (1) H20; NH4C1-NH4OH; (m)NaOMeIMeOH, rt, 17 h, 87%; (n) MeLi (1.5 equiv.), Et20, -20 °C, warming to -5 °C over1.5 h, 87%; (o) TBAF (5 equiv.), THF, A, 17 h, 95%; (p) reagent 178, TMSBr (6 equiv.),BF3•Et20 (6 equiv.), THF, -78 °C, 6.5 h; (q) H20; NH4C1-NH4OH; (r) NaOMeIMeOH, ii,17.5 h, 43%; (s) MeLi (1.5 equiv.), Et20, -20 °C, warming to -5 °C over 1 h, 80%; (t) TBAF(8 equiv.), THF, A, 18 h, 87%.Scheme 37315III. EXPERIMENTAL3.1. SYNTHESIS OF (-)-HOMALOMENOL B (169b)3.1.1. PREPARATION OF THE ENANTIOMERICALLY HOMOGENEOUS ALLYLICACETATE 181b3.1.1.1. Synthesis of 3-Methyl-3-cyclohexen- 1-one (182): 147OMe OMe 0LÀ —Me Me e183 184 182To cold (-78 °C), stirred liquid ammonia (200 mL, distilled from sodium) was addeda solution of 3-methylanisole (183) (8.3 mL, 66 mmol, 1 equiv.) in dry diethyl ether (50 mL).This was followed by the addition of tert-butyl alcohol (62 mL, 660 mmol, 10 equiv.).Lithium metal (2.3 g, 330 mmol, 5 equiv.) was added in small portions over a period of 15mm. The blue solution was refluxed at -33 °C for 3.5 h. The reaction mixture was cooled to-78 °C and the excess lithium metal was destroyed by the portion-wise addition of solidammonium chloride (52 g, 970 mmol, 15 equiv.). The cloudy white suspension was openedto the atmosphere via an air cooled condenser and the ammonia was allowed to evaporate.Pentane (150 mL) was added and the flask was warmed in a water bath to drive off anyresidual ammonia. Water (150 mL) was added and the layers were separated. The aqueouslayer was extracted with pentane (2 x 90 mL) and the combined organic extracts werewashed with water (4 x 100 mL) until no change in the volume of the water extract wasnoted. The organic extracts were dried over anhydrous magnesium sulfate and concentratedby distillation of the solvent at atmospheric pressure through a jacketed Vigreux column (20cm) to avoid loss of product.316The crude enol ether 184 was dissolved in 130 mL of methanol-water (3:1); to themixture was added oxalic acid dihydrate (412 mg, 3.30 mmol, 5 mol% with respect to 3-methylanisole) and the resultant mixture was stirred at rt for 1.5 h. Water (200 mL) wasadded and the suspension was extracted with CH2C12 (6 x 100 mL) until the extracts nolonger contained any product, as indicated by gic analysis. The combined organic extractswere washed with water (1 x 100 mL), dried over anhydrous magnesium sulfate, andconcentrated by distillation of the solvent at atmospheric pressure through a jacketed Vigreuxcolumn (20 cm). The oil thus obtained was distilled (88 °C150 Torr) to give 6.0 g (84%) of3-methyl-3-cyclohexen-1-one (182) 148 (lit.149 bp 6 1-62 °C114 Torr). This compound isstable when stored in the freezer under an atmosphere of argon.‘H nmr (400 MHz, C6D6) & 1.35 (br s, 3H, Me), 1.90 (br s, 2H), 2.07 (t, 2H, J = 8 Hz),2.42 (br s, 2H), 5.17 (br s, 1H, vinyl proton).13C nmr (75.3 MHz, C6D6) 6: 22.6 (-ye, Me), 25.1, 38.1, 44.3, 121.0 (-ye, C-4), 132.3 (C-3),207.6 (C-i).3173.1.1.2. Synthesis of 1 -Methyl-7-oxabicyclo[4. 1 .0]heptan-3-one (185): 150,124O’%Me1182 185To a cold (0 °C), stirred solution of m-CPBA (purity 50-60%, 4.30 g, 12.5 mmol, 1.3equiv.) in dry CH2C12 (90 mL) was added, via a large cannula, a solution of 3-methyl-3-cyclohexen-1-one (182) (1.05 g, 9.53 mmol) in dry CH2C12 (5 mL). After the mixture hadbeen stirred at 0 °C for 2.5 h, excess m-CPBA was destroyed by the addition of saturatedaqueous Na2S 203 (50 mL). The layers were separated and the aqueous layer was extractedwith CH2C12 (2 x 100 mL). The combined organic extracts were washed with saturatedaqueous NaHCO3 (5 x 100 mL, to extract the 3-chlorobenzoic acid byproduct), dried overanhydrous magnesium sulfate, and concentrated by distillation of the solvent at atmosphericpressure through a jacketed Vigreux column (20 cm). The oil thus obtained was distilled (80°C132 Torr) to afford 1.12 g (94%) of the epoxide 185.IR(film): 1713, 1198,1044cm-.‘H nmr (400 MHz) & 1.36 (s, 3H, Me), 2. 14-2.19 (m, 2H), 2.34-2.40 (m, 2 H), 2.56 (d, 1 H,J = 19 Hz, H-2), 2.78 (d, 1H, J = 19 Hz, H-2’), 3.20 (br d, 1 H, J = 2.5 Hz, H-6).nmr (75.3 MHz) 3: 22.1, 22.3 (-ye, Me), 33.8, 43.8, 56.7, 58.1 (-ye, C-6), 207.7 (C-3).Exact Mass calcd. for C7H 100: 126.0681; found: 126.0677.Anal. calcd. for C7H 100: C 66.64, H 7.99; found: C 66.51, H 8.03.3183.1.1.3. Synthesis of 4-Acetoxy-3-methyl-2-cyclohexen-1-one (181): 151Me MeAcO185 181To a stirred solution of the epoxide 185 (4.19 g, 33.2 mmol, 1 equiv.) in dry CH2C12(110 mL) at rt was added dry acetic anhydride (6.3 mL, 66 mmol, 2 equiv.), DMAP (812 mg,6.6 mmol, 0.2 equiv.), and dry i-Pr2NEt (11.6 mL, 66.5 mmol, 2 equiv.). The mixture wasstirred at rt for 6 h. Ethyl acetate (100 mL) and saturated aqueous NaHCO3 (100 mL) wereadded and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x75 mL) and the combined organic extracts were washed with saturated aqueous NaHCO3 (2x 100 mL) and water (1 x 100 mL). The organic extracts were dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The crude product was flashchromatographed (300 g silica gel, 1:1 petroleum ether - CH2C12) and the oil thus obtainedwas distilled (air-bath temperature 90-94 °CI0.2 Torr) to provide 4.7 g (84%) of the allylicacetate 181.152‘H nmr (400 MHz) & 1.94 (br dd, 3H, J = 1, 1 Hz, vinyl Me), 1.95-2.12 (m, 1H), 2.13 (s,3H,-OC(O)CU3), 2.21-2.3 1 (m, 1H), 2.36-2.44 (ddd, 1H, J = 17, 10, 5 Hz, H-6), 2.52-2.59(ddd, 1H, J = 17, 7, 5 Hz, H-6’), 5.54-5.5 8 (br dd, 1H, J = 7.5, 5 Hz, -CjjO-), 5.94 (br s, 1H, vinyl proton).13C nmr (75.3 MHz) 6: 20.4 (-ye, Me), 20.9 (-ye, Me), 28.4, 34.3, 69.8 (-ye, C-4), 128.7 (-ye, C-2), 158.1 (C-3), 170.3, 197.8.3193.1.1.4. Synthesis of (R)-(+)-4-Hydroxy-3-methyl-2-cyclohexen- 1-one (186a) and (S)-(-)-4-Acetoxy-3-methyl-2-cyclohexen- 1-one (181b ): 153+e(R)-186a (S)-181bTo a stirred solution of the racemic allylic acetate 181 (4.57 g, 27.2 mmol) inTris•HC1 buffer,154 pH 7 (0.3 M, 600 mL) and DMSO (200 mL) at rt was added PLE155 (6mL of enzyme suspension, 100 mg of protein, —1.7 x i0 units of activity). The abovematerials were dispensed with glass pipettes or with eppindorf plastic tips. In order to avoidinactivation of the enzyme, metal needles were not used. The pH of the solution wasmonitored using a pH meter (Fischer Accumet pH meter, model 140) and was kept at pH 7by the appropriate addition of 0.1 M aqueous NaOH. A total of 155 mL of 0.1 M aqueousNaOH was used, indicating that the reaction had proceeded to the extent of 57% (i.e. 57% ofthe racemic acetate had been hydrolyzed to the corresponding alcohol). Analysis (gic) at thistime (26 h) confirmed that — 59% of the acetate had been hydrolyzed. The solution wasextracted with ethyl acetate (4 x 600 mL) and the combined organic extracts were washedwith brine (1 x 200 mL), dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. Flash chromatography (275 g silica gel, 3:2 petroleum ether - diethyl etherto elute the unreacted allylic acetate, followed by 100% ethyl acetate to elute the allylicalcohol) provided fractions containing the allylic acetate followed by fractions containing themore polar alcohol. Concentration of the first set of fractions provided 1.81 g (40%) of (-)-4-acetoxy-3-methyl-2-cyclohexen-1-one (181b) as a colourless oil ([cx] -46.7 (c 1.69,CHC13); lit.,124 -35.1 (c 0.61, CDC13)). The spectral data are identical with those derivedMeAcOHO320from the racemic acetate. Concentration of the late fractions afforded 2.0 g (58%) of 4-hydroxy-3-methyl-2-cyclohexen-1-one (186a).156 The alcohol 186a could be distilled (airbath temperature 120-130 °C/0.38 Torr) to afford a colourless oil which exhibited thefollowing spectral data:‘H nmr (400 MHz) 6: 1.96-2.04 (m, 1H), 2.05 (dd, 3H, J = 1, 1 Hz, vinyl Me), 2.17 (d, 1H, J= 6 Hz), 2.25-2.39 (m, 2H), 2.53-2.60 (m, 1H), 4.36 (br dd, 1H, J = 4.5, 4.5 Hz, -CUOH),5.85 (br s, 1H, vinyl proton).13C nmr (75.3 MHz) 6: 20.6 (-ye, Me), 31.8, 34.8, 68.5 (-ye, C-4), 126.8 (-ye, C-2), 163.8(C-3), 199.2 (C-i).The enantiomeric excess of the desired (S)-(-)-4-acetoxy-3-methyl-2-cyclohexen- 1-one (181b) was ascertained by converting the acetate to the corresponding alcohol,124forming the ester with (-)-menthoxyacetic acid (187), 157 and recording the ‘H nmr spectrumof this ester in the presence of 0.1-0.2 equivalents of Eu(fod)3. Only one diastereomer wasobserved, hence an ee > 99% was obtained. The absolute configuration of the (S)-(-)-4-hydroxy-3-methyl-2-cyclohexen-1-one (186b) has been determined by Polla and Frejd124using the exciton chirality method.To obtain (R)-(+)-4-hydroxy-3-methyl-2-cyclohexen- 1-one (186a), the reaction wasstopped at 36% conversion (-9 h reaction time). The enantiomeric excess of the alcohol thusobtained was determined (via the manner described above) to be 88%, and as a result wechose to synthesize (-)-homalomenol A and B using the higher purity (S)-(-)-4-acetoxy-3-methyl-2-cyclohexen- 1-one (181b) (see discussion).3213.1.1.5. Synthesis of the ester 188b:0e M eH Q•181b 186b 187I 88bTo a solution of the (-)-allylic acetate 181b (24 mg, 0.14 mmol, 1 equiv.) in dryMeOH (2.8 mL) at it was added solid sodium carbonate (76 mg, 0.71 mmol, 5 equiv.). Theheterogeneous reaction mixture was stirred at It for 1 h, filtered, and concentrated underreduced pressure. The residue was flash chromatographed (3 g silica gel, 3:1 ethyl acetate -petroleum ether) to afford 16 mg (89%) of (S)-(-)-4-hydroxy-3-methyl-2-cyclohexen-1-one(186b) ([ocj -38.2 (c 1.88, CHC13); lit.,124 -48.8 (c 0.98, CDC13)). The spectral data areidentical with those of 4-hydroxy-3-methyl-2-cyclohexen-1-one reported above.To a stirred solution of the (-)-allylic alcohol 186b (9 mg, 0.07 mmol, 1 equiv.) in drydiethyl ether (2.3 mL) at it was added (-)-menthoxyacetic acid (187) (16 mg, 0.075 mmol, 1.1equiv.), 4-pyrrolidinopyridine (2 mg, 0.01 mmol, 0.2 equiv.), and finally DCC (15 mg, 0.073mmol, 1.1 equiv.). The mixture was stirred at it for 2 h, at which time water (5 mL) anddiethyl ether (10 mL) were added. The organic phase was washed with water (2 x 5 mL), 5%aqueous acetic acid (2 x 5 mL), water (2 x 5 mL), and saturated aqueous NaHCO3 (1 x 5mL). The organic layer was dried, concentrated under reduced pressure, and the crude oilthus obtained was flash chromatographed (8 g silica gel, 5.7:1 petroleum ether - ethyl acetate)to yield 17 mg (79%) of the ester 188b as a colourless oil.‘H nmr (400 MHz) 6: 0.79 (d, 3H, J = 7 Hz, secondary Me), 0.83-1.02 (m, 3H), 0.91, 0.92(d, d, 3H each, J = 6.5, 6.5 Hz, isopropyl Me groups), 1.27-1.36 (m, 1H), 1.56-1.67 (m, 2H),3221.94 (dd, 3H, J = 1, 1 Hz, vinyl Me), 2.03-2.15 (m, 3H), 2.26-2.34 (m, 2H), 2.36-2.44 (ddd,1H, J = 17, 10, 4.5 Hz), 2.52-2.58 (m, 1H), 3.15-3.21 (ddd, 1H, J = 10.5, 10.5, 4 Hz,-CHOCH2-), 4.11 (d, 1H, J = 16.5 Hz, one of -C(O)-Cjj2-O-), 4.21 (d, 1H, J = 16.5 Hz, oneof -C(O)-Cjj2-O-), 5.64-5.67 (dd, 1H, J = 7.5, 5, Hz, -CjjOC(O)-), 5.95 (br s, 1H, vinylproton).To a solution of the ester 188b in CDC13 was added 0.15 equivalents of a Eu(fod)3solution in CDC13. The ‘H nmr of this mixture indicated only one signal corresponding tothe vinyl methyl group, indicating an ee >99%. A similar experiment was performed on amixture of esters 188a and 188b and two distinct, baseline resolved vinyl methyl signalswere obtained for the two diastereomers.áMe Me°io.”188a 188b3233.1.2. PREPARATION OF THE ENANTIOMERICALLY HOMOGENEOUSBICYCLO[4.3.O] ENONE 177b3.1.2.1. Synthesis of (S)-(+)-4-(tert-Butyldiphenylsioxy)-3-methyl-2-cyclohexen-1-one(180b): 1580 0Me NMeAcO TBDPSO181b 180bTo a solution of the (-)-allylic acetate 181b (717 mg, 4.26 mmol, 1 equiv.) in dryMeOH (43 mL) at rt was added solid sodium carbonate (2.26 g, 21.3 mmol, 5 equiv.). Theheterogeneous reaction mixture was stirred at 11 for 1.5 h. The resultant pink mixture wasfiltered and concentrated under reduced pressure. The residue was subjected to flashchromatography (35 g silica gel, 3:1 ethyl acetate - petroleum ether) to afford 538 mg(quantitative yield) of the colourless (-)-allylic alcohol 186b which was used immediately inthe next step.To a solution of the (-)-allylic alcohol 186b (538 mg, 4.26 mmol, 1 equiv.) in dryDMF (8.5 mL) at rt was added sequentially imidazole (1.16 g, 17.1 mmol, 4 equiv.) and tertbutyldiphenylsilyl chloride (2.2 mL, 8.5 mmol, 2 equiv.). The reaction mixture was stirred atP for 15 h, at which time water (10 mL) was added. The aqueous phase was separated andextracted with diethyl ether (2 x 50 mL). The combined organic extracts were washed withwater (5 x 30 mL, in order to extract the DMF), dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The crude product mixture was subjected to flashchromatography (50 g silica gel, 9:1 petroleum ether - ethyl acetate) and the viscous oil thusobtained was heated to 70 °CI0.2 Torr for 1 h (to remove any residual solvent) to provide 1.2324g (80%, based on allylic acetate 181b) of the (+)-TBDPS ether 180b59 ([c} +8.7 (c 2.05,CHC13); lit.,124 +4.7 (c 1.03, CDC13)).JR (film): 1674, 1627, 1590, 1111,974, 704 cm’.‘H nmr (400 MHz) 3: 1.08 (s, 9H, -CMe3), 1.94 (dd, 3H, J = 1, 1 Hz, vinyl Me), 1.91-2.04(m, 2H), 2.08-2.16 (m, 1H), 2.46-2.53 (ddd, 1H, J = 17, 6.5, 4.5 Hz, one of H-6), 4.34 (brdd, 1H, J = 7.5, 4.5 Hz, -CUO-), 5.79 (br s, 1H, vinyl proton), 7.38-7.48 (m, 6H, aromaticprotons), 7.68-7.72 (m, 4H, aromatic protons).13C nmr (75.3 MHz) ö: 19.4, 21.5 (-ye), 27.0 (-ye, -C(H3)3), 32.2, 34.8, 70.5 (-ye, -CHO-),126.7 (-ye, C-2), 127.6 (-ye), 127.8 (-ye), 129.9 (-ye), 130.0 (-ye), 132.9, 133.6, 135.8 (-ye),135.9 (-ye), 163.6 (C-3), 198.7 (C-i).3253.1.2.2. Synthesis of (3S, 4S)- (+)-4- ( tert-Butyldiphenylsiloxy)-3-[2-(1 ,3-dioxan-2-yl)ethyl] -3-methyl-cyclohexanone (189):15Q)C:)TBDPSO 14 S’ 14189 190180b 16)( N%11516‘614ui.._i15To a stirred suspension of freshly ground magnesium turnings (1.01 g, 41.7 mmol, 5equiv.) and iodine (a few crystals) in dry THF (5 mL) at rt was added dropwise (via a largecannula) a solution of 2-(2-bromoethyl)-1,3-dioxane (4.06 g, 20.8 mmol, 2.5 equiv.) in dryTHF (5 mL). Formation of the Grignard reagent began immediately and the bromidesolution was added at such a rate that reflux of the reaction mixture was maintained. Afterthe addition was complete, the mixture was heated to reflux for an additional 35 mm. Themixture was cooled to rt, diluted with THF (90 mL), and further cooled to -78 °C. SolidCuBr•Me2S (1.07 g, 5.20 mmol, 25 mol% with respect to the Grignard reagent) was addedand the resultant cloudy mixture was stirred at -78 °C for 1 h. Addition of dry HMPA (3.7mL, 21 mmol, 2.5 equiv.) was followed by the dropwise addition (via a large cannula over 10mm) of a solution of the (+)-enone 180b (3.08 g, 8.45 mmol, 1 equiv.) and trimethylsilylchloride (2.7 mL, 21 mmol, 2.5 equiv.) in dry THF (8 mL). The resultant bright yellowsolution was stirred at -78 °C for 3 h and was then warmed to -50 °C over a period of 2.5 h,at which point the solution became colourless. Water (20 mL) was added and the mixturewas stirred at 11 for 2 h, open to the atmosphere, to hydrolyze the silyl enol ether. AqueousNH4C1-NH4OH (pH 8-9, 50 mL) and diethyl ether (50 mL) were added and the mixture wasstirred vigorously until the aqueous phase became bright blue in colour. The layers wereseparated and the aqueous phase was extracted with diethyl ether (3 x 100 mL). The326combined organic extracts were washed with water (5 x 75 mL, to extract the HMPA), driedover anhydrous magnesium sulfate, and concentrated under reduced pressure.16°The crudeoil thus obtained was subjected to chromatography161 (50 g tic grade silica gel, 5.7:1petroleum ether - ethyl acetate) which yielded 3.0 g of the solid (+)-acetal 189 as well as amixture of the acetal 189 and the byproduct 190. The acetal 189 was separated from thismixture by crystallization from petroleum ether. The combined acetal fractions were thenrecrystallized from petroleum ether to yield 3.6 g (88%) of the (+)-acetal 189, as a colourlesscrystalline solid, mp 99-101 °C, [cc] +15.72 (c 1.62, CHC13).IR(KBr): 1704,1588,1145,1111,1088,706cm-’.‘H nmr (400 MHz) ö: 0.96 (s, 3H, Me-7), 1.09 (s, 9H, Me-iS), 1.27-1.47 (m, 5H, one ofwhich is H-12), 1.74-1.79 (br ddd, 2H, J = 7.5, 7.5, 5 Hz, H-5 and H-5’), 1.96-2.07 (m, 3H,H-2, H-6, and H-12’), 2.38-2.43 (br dt, 1H, J = 14, 7.5 Hz, H-6’), 2.47-2.5 1 (br d, 1H, J = 14Hz, H-2’), 3.65-3.72, 3.66-3.73 (ddd, 1H each, J = 12, 12, 2 Hz for each ddd, axial protonson C-il and C-13), 3.81-3.84 (dd, 1H, J = 5, 5 Hz, H-4), 4.03-4.07 (br ddd, 2H, J = 12, 5, 1Hz, equatorial protons on C-il and C-13), 4.34-4.36 (dd, 1H, J = 5, 4.5 Hz, H-b), 7.35-7.72(m, 6H, H-15), 7.66-7.72 (m, 4H, H-14).Detailed ‘H nmr data, derived from a COSY experiment, is given in Table 63.nmr (75.3 MHz) & 19.6, 21.2 (-ye, C-7), 25.7, 27.2 (-ye C-16), 28.8, 29.0, 33.1, 36.8,42.7, 49.2, 66.8, 73.9 (-ye, C-4), 102.4 (-ye, C-b), 127.5 (-ye), 127.6 (-ye), 129.7 (-ye),129.8 (-ye), 133.4, 134.3, 135.9 (-ye), 136.0 (-ye), 211.4 (C-i).Exact Mass calcd. for C29H41JO4Si: 480.2696; found: 480.2668.Anal. calcd. for C29H4004Si: C 72.46, H 8.39; found: C 72.57, H 8.52.327Table 63: iH nmr Data (400 MHz, CDC13) for the Keto Acetal 189: COSY Experiment0151515Q141,0 18914 Si 14C::16 161415Assignment ‘H nmr (400 MHz) COSY CorrelationsaH-x 8 ppm (mult., J (Hz))Me-7 0.96 (s)Me-16 1.09 (s)H-12 —1.30-1.40 (m), part of the m (5H) at H-il, H-il’, H-12’, H-13,1.27-1.47 H-13’H-5 and H-5’ 2.38-2.43 (br ddd, J =7.5,7.5,5) H-4, H-6, H-6’H-2 Part of m (3H) at 1.96-2.07 H-2’H-6 Part of m (3H) at 1.96-2.07 H-5, H-5’, H-6’H-12’ Partofm(3H) at 1.96-2.07 H-il, H-li’, H-12, H-13,H- 13’H-6’ 2.38-2.43 (dt, J = 14, 7.5) H-5, H-5’, H-6H-2’ 2.47-2.51 (br d, J = 14) H-2axial protons on C- 3.65-3.72, 3.66-3.73 (ddd, 1H each, equatorial protons on C-lillandC-13 J =12, 12,2) andC-13, H-l2,H-i2’H-4 3.81-3.84 (dd, J = 5, 5) H-5, H-5’equatorial protons 4.03-4.07 (ddd, 2H, J = 12, 5, 1) axial protons on C-li andon C-li and C-i3 C-i3, H-l2, H-l2’H-10 4.34-4.36 (dd, J =5, 4.5)H-15 7.35-7.72 (m) H-14H-i4 7.66-7.72 (m) H-15a- Only those COSY correlations that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-2’ is more downfield than H-2).3283.1.2.3. Synthesis of (5S, 6S)-(-)-5-( tert-Butyldiphenylsiloxy)-6-methylbicyclo[4.3.Ojnon-9-en-2-one 162TBDTo a stirred solution of the (+)-acetal 189 (2.04 g, 4.24 mmol, 1 equiv.) in 1,4-dioxane(57 mL) at rt was added 80% aqueous trifluoroacetic acid (28 mL: 5.5 mL H20 + 22.5 mL of100% CF3COOH). The mixture was heated to 80 °C for 16.5 h. The dark brown solutionwas neutralized by the careful, dropwise addition (via the condenser) of saturated aqueousNaHCO3. The aqueous phase was separated and extracted with diethyl ether (3 x 75 mL)and ethyl acetate (1 x 75 mL). The combined organic extracts were dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. Flash chromatography of thebrown oil thus obtained (125 g silica gel, 4:1 petroleum ether - diethyl ether) afforded 1.33 g(77%) of the (-)-enone 177b as a viscous, yellow oil.After recovery of the (-)-enone 177b, the column was flushed with diethyl ether (600mL). The eluate was concentrated, the residue was dissolved in a mixture of dioxane (16mL) and 100% CF3COOH (8 mL), and the solution was heated to 75 °C for 16 h. Thereaction mixture was neutralized with saturated aqueous NaHCO3. The aqueous layer wasseparated and extracted with diethyl ether (3 x 25 mL) and ethyl acetate (1 x 25 mL). Thecombined organic extracts were dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residual material was flash chromatographed (25 g silica gel,4:1 petroleum ether - diethyl ether) to yield a further 81 mg (5%) of the (-)-enone 17Th. Theresidual solvent was removed by heating the enone to 80 °C/0.2 Torr for 1 h; the total yieldof the (-)-enone 17Th was 2.14 g (82%), [o] -22.2 (c 0.92, CHC13).189 1 77b329JR (neat): 1687, 1618, 1428, 1111, 1069, 703 cm’.‘H nmr (400 MHz) 6: 1.09 (s, 9H, -C3), 1.20 (s, 3H, Me-lO), 1.70-1.75 (m, 2H), 1.99-2.08 (m, 3H), 2.26-2.50 (m, 3H), 3.76-3.80 (dd, 1H, J = 11, 4Hz, H-5), 6.42-6.43 (dd, 1H, J= 2.5, 2.5 Hz, H-9), 7.37-7.47 (m, 6H, aromatic protons), 7.68-7.72 (m, 4H, aromaticprotons).nmr (75.3 MHz) 6: 17.6 (-ye, Me-lO), 19.4, 27.0 (-ye, -C(H3)3), 29.2, 30.0, 38.1, 40.6,52.4, 78.2 (-ye, C-5), 127.5 (-ye), 127.6 (-ye), 129.6 (-ye), 129.8 (-ye), 133.4, 134.5, 135.8(-ye), 135.9 (-ye), 138.3 (-ye, C-9), 147.7 (C-i), 198.7 (C-2).Exact Mass calcd. for C26H32O2Si: 404.2171; found: 404.2178.Anal. calcd. for C26H32O2Si: C 77.18, H 7.97; found: C 76.88, H 7.91.3303.1.2.4. Synthesis of 2-methyl-3-(tri-n-butylstannyl)propene (194) :163,1M).....SnBu3195 194To a cold (0 °C), stirred suspension of freshly ground magnesium turnings (4.10 g,169 mmol, 2.2 equiv.) in dry THF (20 mL) was added dropwise, over a period of 1 h, asolution of 3-chloro-2-methylpropene (195) (15.2 mL, 154 mmol, 2 equiv.) and tn-nbutylstannyl chloride (20.9 mL, 77.0 mmol, 1 equiv.) in dry THF (50 mL). The gray slurrywas refluxed for 2 h, cooled to 0°C, and saturated aqueous ammonium chloride (10 mL) wasadded. The suspension was filtered (using water aspirator pressure) through Celite (10 g).The filter cake was washed with diethyl ether (700 mL) and the combined filtrates wereconcentrated. The concentrate was taken up in diethyl ether (500 mL) and the mixture waswashed with water (2 x 100 mL) and brine (1 x 100 mL). The organic layer was dried overanhydrous magnesium sulfate, concentrated under reduced pressure, and the oil thus obtainedwas distilled (100 °CI0.45 Torr) to provide 23.6 g (89%) of 2-methyl-3-(tni-n-butylstannyl)propene (194). 165‘H nmr (400 MHz) 6: 0.80-0.95 (m, 15H), 1.28-1.55 (m, 12H), 1.70 (s, 3H, vinyl Me), 1.78(s, 2H, -CU2SnBu3), 4.42-4.50 (m, 2H, vinyl protons).3313.1.3. PREPARATION OF THE BICYCLIC KETONE 176b3.1.3.1. Synthesis of (1 R, 55, 6S, 9S)- (- ) -5- (tert-Butyldiphenylsiloxy)-6-methyl-9-(methallyl)-bicyclo-[4.3 .0]nonan-2-one (196) and (iS, 5S, 65, 9S)-(-)-5-( tert-Butyldiphenyl -siloxy)-6-methyl-9-(methallyl)bicyclo[4.3.0]nonan-2-one (176b ):166p ,LCuTBDPSO e TBDPSO e TBDPSO e177b 196 17GbA suspension of flame dried lithium chloride167 (267 mg, 6.30 mmol, 3.1 equiv.) andfreshly recrystallized copper(I) iodide168 (1.20 g, 6.30 mmol, 3.1 equiv.) in dry THF (35 mL)was stirred at rt for 15 mm until a clear yellow solution resulted. The mixture was cooled to-78 °C. To a cold (-78 °C), stirred solution of 2-methyl-3-(tri-n-butylstannyl)propene (194)(2.12 g, 6.14 mmol, 3 equiv.) in dry THF (10 mL) was added a solution of n-butyllithium inhexanes (1.61 M, 3.6 mL, 5.8 mmol, 2.8 equiv.). The resultant yellow solution was stirred at-78 °C for 25 mm and was quickly cannulated (via a large cannula) into the LiCLICuIITHFsolution to produce a clear red solution containing the organocopper(I) reagent 179.Cannulation of trimethylsilyl bromide (2.20 g, 14.4 mmol, 7 equiv.) into the red solution wasfollowed by the addition of a solution of the (-)-enone 177b (829 mg, 2.05 mmol, 1 equiv.) indry THF (5 mL). The reaction mixture was stirred at -78 °C for 5.5 h. Water (20 mL) wasadded and the mixture was stirred at rt, open to the atmosphere, for 45 mm. Analysis by thinlayer chromatography confirmed the hydrolysis of the silyl enol ether products. AqueousNH4C1-NH4OH (pH 8-9, 50 mL) was added and the mixture was stirred rapidly until theaqueous layer became bright blue in colour. The phases were separated and the aqueouslayer was extracted with diethyl ether (3 x 75 mL). The combined organic extracts werewashed with brine (1 x 100 mL), dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure. ‘H nmr spectroscopic analysis of the crude oil thus obtained332indicated a 5:1 ratio of the two isomers 196 and 176b, as determined by the integration oftheir respective vinyl proton signals. The two isomers were easily separated by flashchromatography (125 g silica gel, 11.5:1 petroleum ether - diethyl ether). The firstcompound to be eluted was the addition product 176b bearing the trans ring junction.Concentration of the appropriate fractions, followed by recrystallization (from diethyl ether -petroleum ether) of the solid thus obtained provided 113 mg (12%) of the (-)-trans-fusedcompound 176b, a colourless crystalline solid, mp 98-99 °C, [a] -37.1 (c 1.27 in CHC13).IR(KBr): 1716, 1649, 1590, 1112, 1094, 704 cm1.‘H nmr (400 MHz) 6: 0.89 (s, 3H, Me-lO), 1.06 (s, 9H, -C3), 1.14-1.34 (m, 2H, one ofwhich is H-8), 1.65-1.80 (m, 1H, H-il), 1.71 (s, 3H, Me-14), 1.81-1.95 (m, 5H, one of whichis H-i (d, J = 11 Hz), one of which is H-4, and one of which is H-4’), 2.01-2.19 (m, 2H),2.14-2. 19 (br dd, 1H, J = 14, 4.5 Hz, H-il’), 2.44-2.51 (m, 1H, H-9), 3.33-3.40 (dd, 1H, J =10.5, 5 Hz, H-5) 4.59 (br s, 1H, H-13), 4.64 (br s, 1H, H-13’), 7.36-7.52 (m, 6H, aromaticprotons), 7.66-7.73 (m, 4H, aromatic protons).Detailed ‘H nmr data, derived from COSY and NOE experiments, are given in Table 64.13C nmr (75.3 MHz) 6: 13.3 (-ye, Me-6), 19.4, 22.4 (-ye), 27.0 (-ye, -C(H3)3), 27.1, 32.0,32.6 (-ye), 38.4, 39.5, 44.5, 52.4, 62.9 (-ye), 78.8 (-ye, C-5), 110.6 (C-13), 127.5 (-ye), 127.6(-ye), 129.6 (-ye), 129.8 (-ye), 133.6, 134.5, 135.9 (-ye), 136.0 (-ye), 145.2 (C-12), 209.7 (C-2).Exact Mass calcd. for C3HijOSi: 460.2798; found: 460.2792.AnaL calcd. for C30H4O2Si: C 78.21, H 8.75; found: C 78.25, H 8.78.333Table 64: 1H nmr Data (400 MHz, CDC13) for the Trans-Fused Compound 176b: COSYand NOE Experimentsi9lTBDPSO e176bAssignment ‘H nmr (400 MHz) COSY Correlationsa NOEH-x ppm (mult., J (Hz)) CorrelationsaMe-lO 0.89 (s) H-9-C(j3) 1.06 (s)H-8 Partofthematl.14-l.34 11-9H-li 1.65-1.80 (m) H-9, Hil’b, H-13, H-13’Me-14 1.71 (s) H-9, H-il’, H-13’H-4 Partofthemati.81-i.95 H-5H-4’ Partofthematl.81-l.95 H-5H-i —1.87-1.90 (d, J = 11), part of H-9them at 1.81-1.95H-il’ 2.14-2.19 (br dd, J = 14, 4.5) 11-9, H-li, H-i3 H-li, Me-14H-9 2.44-2.51 (m) H-i, H-8, H-li, H-il’ H-il’, Me-lO,Me-i4H-S 3.33-3.44 (dd, J = 10.5,5) H-4, 11-4’ H-iH-i3 4.59(brs) H-li,H-ll’,H-13’ 11-13’H-13’ 4.64 (brs) H-li, H-13 H-i3,Me-14a- Only those COSY correlations and NOE data that could be assigned are recorded.b- H indicates the hydrogen of a pair which is more downfield (H-il’ is more downfield than H-i 1).334The second compound to be eluted was the conjugate addition product 196 bearingthe cis ring junction. Concentration of the appropriate fractions, followed by removal oftraces of solvent (vacuum pump) from the oil thus obtained, provided 763 mg (8 1%) of the(-)-cis-fused product 196, as a colourless oil, [a] -73.0 (c 1.79, CHC13).IR(neat): 1702, 1648, 1590, 1112, 704cm-1.‘H nmr (400 MHz) 6: 1.02-1.21 (m, 1H), 1.07 (s, 9H, -C3), 1.18 (s, 3H, Me-lO), 1.30-1.38 (m, 1H), 1.41-1.47 (br dd, 1H, J = 13, 10.5 Hz, H-9), 1.59 (s, 3H, Me-14), 1.56-1.70(m, 1H, H-il), 1.79-1.95 (m, 5H, two of which are H-4 and H-il’), 2.29-2.38 (m, 1H, H-4’),2.40-2.48 (m, 1H), 2.49-2.52 (dd, 1H, J = 10.5, 2 Hz, H-i), 3.74-3.77 (dd, 1H, J = 8.5, 3.5Hz, H-5), 4.48 (br s, 1H, H-l3), 4.65 (br s, 1H, H-13’), 7.28-7.50 (m, 6H, aromatic protons),7.66-7.73 (m, 4H, aromatic protons).Detailed ‘H nmr data, derived from COSY and NOE experiments, are given in Table 65.‘3C nmr (75.3 MHz) 6: 19.4, 21.9 (-ye), 23.5 (-ye), 27.1 (-ye, -C(H3)3), 27.9, 30.2, 37.9,39.3, 40.4 (-ye), 40.7, 49.5, 62.8 (-ye), 74.1 (-ye), 111.4 (C-13j, 127.5 (-ye), 127.7 (-ye),129.7 (-ye), 129.8 (-ye), 133.3, 134.4, 135.9 (-ye), 136.0 (-ye), 143.9 (C-12), 213.5 (C-2).Exact Mass calcd. for C3OH4002Si: 460.2797; found: 460.2804.Anal. calcd. for C30H4002Si: C 78.21, H 8.75; found: C 77.88, H 8.68.335Table 65: ‘H nmr Data (400 MHz, CDC13) for the Cis-Fused Compound 196: COSY andNOE ExperimentsTBDPSO Me196Assignment ‘H nmr (400 MHz) COSY Correlationsa NOEH-x 6 ppm (mull., J (Hz)) Correlationsa-CIyk3 1.07(s)Me-lO 1.18 (s) H-iH-9 1.41-1.47 (br dd, J 13, Hi,H11’b H-il’, H-1310.5)Me-14 1.59 (s) H-13’H-il 1.56-1.70 (m) H-il’, H-i3, H-13’H-4 Part of the m at 1.79-1.95 H-4’, H-5H-il’ Part of themat 1.79-1.95 H-li, H-13, H-13’H-4’ 2.29-2.38 (m) H-4, H-5 H-4H-i 2.49-2.52 (dd, J = 10.5, 2) H-9 Me-lOH-5 3.74-3.77 (dd, J = 8.5, 3.5) H-4, H-4’ H-4, H-liH-13 4.48(brs) H-11,H-ll’,H-13’ H-9H-13’ 4.56 (br s) H-il, H-il’, H-13 H-13, Me-14a- Oniy those COSY correlations and NOE data that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-il’ is more downfield than H-il).3363.1.3.2. Epimerization of compound 196:TBDPSO e TBDPSO Me196 176b1 7To a cold (-78 °C), stirred solution of the (-)-cis-fused compound 196 (264 mg, 0.573mmol, 1 equiv.) in dry MeOH (11.5 mL) was added a solution of NaOMe in MeOH (0.4 M,1.1 mL, 0.44 mmol, 0.8 equiv.). The pale yellow solution was warmed to rt and stirred for 19h. The MeOH was removed by rotary evaporation and water (10 mL) and diethyl ether (20mL) were added to the residue. The layers were separated and the aqueous phase wasextracted with diethyl ether (3 x 25 mL). The combined organic extracts were dried overanhydrous magnesium sulfate and concentrated under reduced pressure. nmrspectroscopic analysis of the oil thus obtained indicated a 7:1 ratio169 of trans- to cis-fusedcompounds (176b and 196, respectively). Flash chromatography of the crude oil (25 g silicagel, 19:1 petroleum ether - diethyl ether) yielded 223 mg (84%) of the (-)-trans-fusedcompound 176b, followed by 35 mg (13%) of the (-)-cis-fused compound 196.The recovered (-)-cis-fused compound 196 (35 mg, 0.076 mmol) was subjected to theabove epimerization conditions (2.0 mL MeOH, 0.15 mL of a 0.4 M NaOMe/MeOHsolution, 0.8 equiv.). Flash chromatography (8 g silica gel, 19:1 petroleum ether - diethylether) of the crude product provided a further 24 mg of the (-)-trans-fused compound 176b.After two such epimerizations, 247 mg (94%) of the crystalline (-)-trans-fused compound176b was obtained.3373.1.4. SYNTHESIS OF (-)-HOMALOMENOL B (169b)3.1.4.1. Synthesis of (iS, 2R, 5 S, 6 S, 9S)-(-)-5-( tert-Butyldiphenylsiloxy)-2,6-dimethyl-9 -(methallyl)-bicyclo[4.3.0]nonan-2-ol (197): 170TBDPSO Me 11176b 197To a cold (-20 °C), stirred solution of the (-)-trans-fused compound 176b (61 mg,0.13 mmol, 1 equiv.) in dry diethyl ether (2.6 mL) was added a solution of methyllithium indiethyl ether (1.4 M, 140 pL, 0.20 mmol, 1.5 equiv.). The solution was warmed to -5 °Cover the course of 1.5 h. A few drops of water were added to quench the excessmethyllithium. The solution was dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure. The crude product was flash chromatographed (8 gsilica gel, 9:1 petroleum ether - diethyl ether) and after removal of trace amounts of solvent(vacuum pump) from the resultant oil, there was obtained 55 mg (87%) of the (-)-tertiaryalcohol 197, as a colourless oil, [ct] -75.2 (c 0.04, CHC13).IR (film): 3583, 3481, 3071, 1650, 1590, 1111, 1052, 703 cm4.‘H nmr (400 MHz) c5: 0.79 (br d, 1H, J = 11 Hz, H-i), 1.05 (s, 9H, -CM3), 1.00-1.10 (m,1H), 1.11-1.20 (m, 2H, one of which is H-3), 1.17 (s, 3H, Me-lO), 1.20 (d, 3H, J = 0.6 Hz,Me-il), 1.23-1.36 (m, 2H, H-4 and H-8), 1.42-1.47 (m, 1H, H-3’), 1.61-1.73 (m, 2H, one ofwhich is H-12), 1.71 (s, 3H, Me-iS), 1.80-1.93 (m, 2H, one of which is H-4’), 2.24-2.32 (m,1H, H-9), 2.52 (br d, 1H, J = 14Hz, H-12’), 3.37-3.41 (dd, 1H, J = 11.5, 4.5, H-5), 4.66 (br338s, 1H, H-14), 4.71 (br s, 1H, H-14’), 7.34-7.45 (m, 6H, aromatic protons), 7.65-7.7 1 (m, 4H,aromatic protons).Detailed ‘H nmr data, derived from COSY and NOE experiments, are given in Table 66.13C nmr (75.3 MHz) & 15.2 (-ye), 19.5, 22.6 (-ye), 27.0 (-ye, -C(H3)3), 27.9, 28.2, 31.6(-ye), 33.4 (-ye), 39.1, 40.9, 45.8, 48.4, 58.8 (-ye), 71.8 (C-2), 81.0 (-ye, C-5), 110.7 (C-14),127.3 (-ye), 127.4 (-ye), 129.3 (-ye), 129.5 (-ye), 134.1, 135.2, 135.9 (-ye), 136.0 (-ye), 145.5(C-13).Exact Mass calcd. for C27H35O2Si (J4 - C(CH3)3) : 419.2406; found: 419.2409.Anal. calcd. for C31H44O2Si: C 78.10, H 9.30; found: C 78.12, H 9.41.339Table 66: 1H nmr Data (400 MHz, CDC13) for the Tertiary Alcohol 197: COSY and NOE10MeOH321545 14TBDPSO e197Assignment ‘H nmr (400 MHz) COSY Correlationsa NOEH-x 6 ppm (mult., J (Hz)) CorrelationsaH-i 0.79 (br d, J 11) H-9 H-5-CI3 1.05 (s)H-3 Part of the m at 1.10-1.20 HYb, H-4, H-4’Me-lO 1.17 (s) H-i, H-3’, H-9,H-12’Me-li 1.20 (d, J = 0.6) H-9H-8 Partofthemati.23-1.36 H-9H-4 Part of the m at 1.23-1.36 H-3, H-3’, H-4’, H-5H-Y 1.42-1.47 (m) H-3, H-4, H-4’H-12 Part of them at 1.61-1.73 H-9, H-i2’, H-14, H-14’Me-15 1.71 (s)H-4’ Part of them at 1.80-1.93 H-3, H-3’, H-4H-9 2.24-2.32 (m) H-i, H-8, H-12, H-i2’ Me-lO, Me-il,H-14, Me-i5H-i2’ 2.52 (brd, J = 14) H-9, H-i2, H-i4 H-9, Me-lO, H-12H-5 3.37-3.41 (dd, J = 11.5, 4.5) H-4, H-4’ H-iH-i4 4.66 (br s) H-12, H-i2’, H-14’H-14’ 4.71 (br s) H-12, H-14a- Only those COSY correlations and NOE data that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-3’ is more downfield than H-3).Experiments3403.1.4.2. Synthesis of (-)-Homalomenol (169b):10MeOH-! H 15•12kJJ14kAHO ivie1 69bHOMALOMENOL BTo a stirred solution of the (-)-tertiary alcohol 197 (52 mg, 0.11 mmol, 1 equiv.) indry THF (2.2 mL) at a was added a solution of TBAF in THF (1 M, 550 iL, 0.55 mmol, 5equiv.). The mixture was refluxed for 17 h. The solution was cooled to a and water (5 mL)and diethyl ether (10 mL) were added. The layers were separated and the aqueous layer wasextracted with diethyl ether (2 x 10 mL) and ethyl acetate (2 x 10 mL). The combinedorganic extracts were dried over anhydrous magnesium sulfate, concentrated under reducedpressure, and the oil thus obtained was flash chromatographed (8 g silica gel, 3:2 petroleumether - ethyl acetate). Concentration of the appropriate fractions and recrystallization (fromethyl acetate - petroleum ether) of the solid thus obtained yielded 25 mg (95%) of (-)-homalomenol B (169b), a colourless crystalline solid, mp 94-95 °C, [cc] -43.0 (c 1.71,CHC13); lit.121 [a] of (+)-homalomenol B (169a) +20.4 (c 1.745, CHC13). (-)-Homalomenol B (169b) was sublimed at 80 °CI0.2 Torr to afford needle-like crystals, mp 94-95 °C.JR (KBr): 3632, 3371, 3070, 1649, 1194, 1024, 894 cm’.‘H nmr (400 MHz, referenced at 7.24) & 0.92 (d, 1H, J = 11 Hz, H-i), 1.02 (br d, 3H, J =0.9 Hz, Me-li), 1.09 (br s, 1H, 30 Oa; this signal exchanges upon treatment with D20),1.15-1.27 (m, 2H), 1.25 (s, 3H, Me-lO), 1.30-1.37 (m, 2H, H-8 and 2° Off; this signal341exchanges upon treatment with D20), 1.41-1.66 (m, 3H, one of which is H-4), 1.70 (s, 3H,Me-15), 1.72-1.83 (m, 2H, H-4’ and H-12), 1.84-1.94 (m, 1H), 2.24-2.34 (m, 1H, H-9), 2.56(br d, 1H, J = 14 Hz, H-12’), 3.34-3.38 (ddd, 1H, J = 11.5, 4.5, 4.5 Hz, H-5; this signalcollapses to add (J = 11.5, 4.5 Hz) upon treatment with D20), 4.66 (br s, 1H, H-14), 4.71(br s, H-14’).Detailed ‘H nmr data, derived from COSY and NOE experiments, are given in Table 67.13C nmr (75.3 MHz) 6: 14.5 (-ye), 22.6 (-ye), 27.7, 28.0, 31.7 (-ye), 33•3 (-ye), 38.3, 41.0,45.8, 47.7, 59.1 (-ye), 71.8 (C-2), 79.7 (-ye, C-5), 110.8 (C-14), 145.4 (C-13).Exact Mass calcd. for C15H2602: 238.1933; found: 238.1927.Anal. calcd. for C15H2602: C 75.58, H 10.99; found: C 75.80, H 11.14.Comparison of the reported spectral data for (+)-homalomenol B (169a) with that of thesynthetic (-)-homalomenol B (169b) is shown in Table 68.342Table 67: ‘H nmr Data (400 MHz, CDC13) for (-)-Homalomenol B (169b): COSY andNOE Experiments10MeOH49YHO Me11I 69bAssignment ‘H nmr Data (400 MHz) COSY Correlationsa NOEH-x 6 ppm (mult., J (Hz)) CorrelationsaH-i 0.92 (d, J = ii) H-9 H-5, Me-lO,H-12Me-li 1.02 (brd, J =0.9) H-93°OH 1.09(brs)Me-lO 1.25(s) H1,H12’bH-8 Part of the m at 1.30-1.37 H-92° OH Part of them at 1.30-1.37 H-5H-4 Part of them at 1.41-1.66 H-4’, H-5Me-15 1.70(s)H-4’ Part of the m at 1.72-1.83 H-4, H-5H-i2 Part of them at 1.72-1.83 H-9, H-12’, H-14, H-14’11-9 2.24-2.34 (m) H-i, H-8, H-12, H-12’; Me-li, H-i2’,H-i4, Me-i5H-i2’ 2.56 (brd, J = 14) H-9, H-12, H-i4, H-i4’ H-9, Me-iO,H- 12H-5 3.34-3.38 (ddd, J = 11.5, 4.5, 2° O H-i4.5)H-i4 4.66 (br s) H-i2, H-i2, H-i4’H-14’ 4.71 (br s) H-12, H-12’, H-14a- Oniy those COSY correlations and NOE data that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-12’ is more downfield than H-12).343Table 68: Comparison of the Reported Spectral Data for (+)-Homalomenol B (169a) withthat of the Synthetic (-)-Homalomenol B (169b)Data Synthetic I ReportedaMP 94-95 °C 78-8 1 °C3632 36103371 34603070 3080IR (-1) 1649 16501194 —1024 —894 9001.02 (br d, 3H, J = 0.9 Hz) 1.03 (d, 3H, J = 0.9 Hz)1.25 (s, 3H) 1.27 (s, 3H)1.70 (s, 3H) 1.71 (m, 3H)2.24-2.34 (m, 1H) 2.30 (m, 1H)1H NM.Rb 2.56 (br d, 1H, J 14 Hz) 2.57 (br d, 1H, J = 15 Hz)(6) 3.34-3.38 (dd, 1H, J = 11.5, 4.5, 4.5 Hz) 337C (dd, 1H, J = 10.8, 4.5 Hz)4.66 (br s, 1H) 4.67 (m, 1H)4.71 (br s) 4.72 (m, 1H)14.5 14.622.6 22.727.7 27.828.0 28.131.7 31.233.3 33.413C NMR 38.3 38.4(6) 41.0 41.045.8 45.947.7 47.859.1 51.971.8 71.979.7 79.8110.8 110.9145.5 145.5HRMS(238.1933)d 238.1927 238.1926ElementalAnalysis C15H2602(Q3) -43.0 (c 1.71) +20.4 (c 1.745)a- Spectral data br (+)-homalomenol B as reported in reference 121.b- Only the selected 1H nmr signals for the synthetic (-)-homalomenol B which correspond to those reported forthe natural (+)-homalomenol B are listed.c- Reference 121 lists this signal at 4.62 ppm; however, the spectrum of (+)-homalomenol B provided by Dr.Sung indicates that this signal appears at 3.37 ppm.d- Calculated value for C15H2602.e- Not reported.3443.2. ROUTE TO THE SYNTHESIS OF (-)-HOMALOMENOL A (168b)3.2.1. PREPARATION OF THE BICYCLIC KETONE 175b3.2.1.1. Synthesis of 1-Iodo-2-methylpropene (202): 171202 202aTo 2.0 g of zinc dust in a cintered glass funnel was added 10 mL of 1.0 Mhydrochloric acid. The resultant flocculent solid was triturated with a glass rod and the acidsolution was removed using water aspirator pressure. This was repeated twice. The zinc dustwas then washed with water (3 x 10 mL), MeOH (3 x 10 mL), and diethyl ether (3 x 10 mL)to provide —2.0 g of activated zinc dust.To a stirred, colourless solution of 1-bromo-2-methylpropene (19.0 mL, 185 mmol, 1equiv.) in HMPA (135 mL) at rt was added solid potassium iodide (77.0 g, 464 mmol, 2.5equiv.). The suspension turned dark orange. Cannulation of a solution of NiBr2 in DMF(0.3 M, 50.0 mL, 14.8 mmol, 8 mol%) into the suspension was followed by the addition offreshly activated zinc dust (1.21 g, 18.5 mmol, 10 mol%). The dark green slurry was cooledto -20 °C and purged with an argon stream for 10 mm. The mixture was heated to 70 °C andstirred at this temperature for 48 h. Diethyl ether (100 mL) and 5% hydrochloric acid (50mL) were added. The organic layer was separated, washed with aqueous Na2S 207 (2 x 100mL) and water (2 x 100 mL), dried over anhydrous sodium sulfate, and concentrated bydistillation of the solvent at atmospheric pressure through a jacketed Vigreux column (20cm). The product was fractionally distilled at 61 °C190 Torr to afford 23.7 g (70%) of 1-iodo-2-methylpropene (202). ‘H nmr spectroscopic analysis of the product revealed a 12:1mixture of the desired compound 202 and 2,5-dimethyl-2,4-hexadiene (202a), as determined345by the integration of the respective vinyl proton signals. Since the latter compound does notinterfere with the subsequent conjugate addition reaction, the mixture was used as obtained.‘H nmr (400 MHz) of a mixture of 1-iodo-2-methylpropene (202) and 2,5-dimethyl-2,4-hexadiene (202a):Signals attributed to l-iodo-2-methylpropene (202) 172 6: 1.83 (s, 3H, vinyl Me), 1.91(s, 3H, vinyl Me), 5.82 (s, 1H, vinyl proton).Signals attributed to 2,5-dimethyl-2,4-hexadiene (202a) 6: 5.98 (s, 2H, vinyl proton),1.72 (s, 6H, vinyl Me), 1.78 (s, 6H, vinyl Me).Analysis of the mixture by glc-mass spectrometry showed:M (1 -iodo-2-methylpropene (202)): 182; M (2,5-dimethyl-2,4-hexadiene (202a)):110.3463.2.1.2 Synthesis of (1 R, 5 S, 6S, 9R)-(-)-5-( tert-Butyldiphenylsiloxy)-6-methyl-9-(2-methyl-1 -propenyl)bicyclo [4.3 .0]nonan-2-one (213), (iS, 55, 6S, 9S)-(-)-5-(tert-Butyldiphenyl-siloxy)-6-methyl-9-(2-methyl- 1 -propenyl)bicyclo[4.3.O]nonan-2-one (175b), and (1 R, 55, 6S,9S)-(-)-5-(tert-Buty1dipheny1siloxy)-6-methyl-9-(2-methyl-1-propenyl)bicyclo[4.3.0]nonan-2-one (212):? HX H H++ ct:JtDu(CN)LiTBDPSQ TBDPSO e TBDPSO Me 178213 175b 212a. Via Conjugate Addition of the Cuprate Reagent 178 to the Enone 177b in thePresence of TMSBr and BF3•Et20; General Procedure 5:To a cold (-78 °C), stirred solution of tert-butyllithium (1.62 M in pentane, 4.8 mL,7.8 mmol, 12.8 equiv.) in dry THF (40 mL) was added slowly (over -.1 h via a small cannula)a solution of 1-iodo-2-methylpropene (202) (701 mg, 3.85 mmol, 6.4 equiv.) in dry THF (8mL). The clear yellow solution became a cloudy, colourless mixture. To the cold (-78 °C),stirred mixture was added (via a large cannula) a clear yellow solution of LiC1 (326 mg, 7.69mmol, 12.8 equiv.) and CuCN (345 mg, 3.85 mmol, 6.4 equiv.) in dry THF (13 mL).139BF3•Et20 (450 .tL, 3.6 mmol, 6 equiv.) was added to the resultant orange/red solutioncontaining the organocopper(I) reagent 178. Cannulation of trimethylsilyl bromide (558 mg,3.64 mmol, 6 equiv.) into the red solution was followed by the addition of a solution of the(-)-enone 17Th (245 mg, 0.605 mmol, 1 equiv.) in dry THF (5 mL). The mixture was stirredat -78 °C for 6.5 h. The solution was quenched at -78 °C with water (15 mL) and the mixturewas stirred, open to the atmosphere, for 1 h. Aqueous NH4C1-NH4OH (pH 8-9, 50 mL) anddiethyl ether (50 mL) were added and the mixture was stirred vigorously until the aqueouslayer became bright blue in colour. The layers were separated and the aqueous phase wasextracted with diethyl ether (3 x 50 mL). The combined organic extracts were washed with347brine (1 x 75 mL), dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The ‘H nmr spectrum of the crude oil thus obtained indicated that the startingmaterial had been consumed and that the ratio of isomers 213: 175b: 212 was 34:4:62.173213 + 175b + 21234 : 4 : 621 : 1.9Flash chromatography (25 g silica gel, 19:1 petroleum ether - diethyl ether) of thecrude oil provided 9.4 mg (3.4%) of compound 175b and 220 mg (78%) of a mixture ofcompounds 213 and 212. The mixture of addition products (218 mg, 0.47 mmol, 1 equiv.)was dissolved in MeOH (9 mL) and the solution was cooled to -78 °C. A solution of NaOMein MeOH (0.4 M, 1.2 mL, 0.48 mmol, 1 equiv.) was added and the solution was warmed to rtand stirred for 17.5 h. The mixture was worked up (see epimerization procedure on page180) and analysis of the ‘H nmr spectrum of the crude product indicated that the ratio ofisomers 213:175b:212 was 36:36:28.173 Flash chromatography (15 g silica gel, 19:1petroleum ether - diethyl ether) of the crude product provided 64 mg (23 % with respect tothe (-)-enone 17Th) of compound 175b and 140 mg of a mixture of compounds 213 and 212.The remaining mixture (140 mg of compounds 213 and 212) was resubjected to theepimerization conditions and the desired isomer 175b was derived by flash chromatographyof the mixture. This process was repeated twice (i.e. three epimerizations in total). Theoverall yield of the desired (-)-isomer 175b, based on the (-)-enone substrate 17Th, was 120mg (43%). It is interesting to note that the compound 213 does not undergo epimerization(i.e. compound 213 is thermodynamically more stable than the corresponding trans-fusedepimer).348The original mixture of compounds 213 and 212 was further purified by flashchromatography and the first few fractions eluted from the column chromatography wereconcentrated to provide pure compound 213, a solid. The solid thus obtained wasrecrystallized from petroleum ether - diethyl ether to provide compound 213 as a colourlesscrystalline solid, mp 72-74 °C, [cx] -30.0 (c 1.94, CHC13).JR (KBr): 1709, 1589, 1109, 1093, 704 cm-1.‘H nmr (400 MHz) 6: 1.02-1.16 (m, 1H), 1.07 (s, 9H, -C3), 1.16 (s, 3H, Me-i0), 1.23-1.40 (m, 1H), 1.42 (d, 3H, J = 1 Hz, Me-14), 1.61 (d, 3H, J = 1 Hz, Me-13), 1.57-1.70 (m,1H), 1.82-1.96 (m, 3H), 2.00 (d, 1H, J = 11.5 Hz, H-i), 2.12-2.28 (m, 2H), 2.79-2.88 (m,1H, H-9), 3.86-3.91 (dd, iH, J =10.5,4Hz, H-5), 4.92 (br d, 1H, J = 9 Hz, H-il), 7.36-7.48(m, 6H, aromatic protons), 7.66-7.73 (m, 4H, aromatic protons).NOE difference experiments: irradiation of the signal at 6 2.00 (H-i) caused an enhancementof the signals at 6 1.16 (Me-lO) and 4.92 (H-il); irradiation at 6 4.92 (H-il) caused anenhancement of signals at 6 1.61 (Me-i3) and 2.00 (H-i); irradiation of the signal at 6 3.86-3.91 (H-5) caused an enhancement of the signal at 6 2.79-2.88 (H-9).L3c nmr (75.3 MHz) 6: 18.0 (-ye), 19.5, 21.2 (-ye), 25.6 (-ye), 27.0 (-ye, -C(H3)3), 29.7,31.6, 35.9, 37.6, 42.9 (-ye), 51.7, 67.8 (-ye), 73.1 (-ye, C-5), 127.5 (-ye), 127.7 (-ye), 129.6(-ye), 129.8 (-ye), 132.1 (C-i2), 133.4, 134.4, 135.9 (-ye), 136.0 (-ye), 212.2 (C-2).Exact Mass calcd. for C30H4002Si: 460.2797; found: 460.2799.Anal. calcd. for C30H4(JO2Si: C 78.21, H 8.75; found: C 78.28, H 8.64.349Compound 175b was the first compound to be eluted from the flash chromatographyof the epimerization mixture. The oil thus obtained was heated at 80- 100 °CI0.2 Torr for 1 hto remove any residual solvent, thereby providing pure compound 175b, [CL] -8.0 (c 1.05,CHC13).IR (ifim): 1723, 1590, 1112, 1064, 703 cm’.‘H nmr (400 MHz) 6: 0.91 (s, 3H, Me-lO), 1.06 (s, 9H, -C3), 0.97-1.48 (m, 4H, one ofwhich is H-8), 1.60 (br s, 3H, Me-13), 1.70 (br s, 3H, Me-14), 1.73-2.07 (m, 5H, three ofwhich are H-i (d, J = 10.5 Hz), H-4, and H-4’), 3.03-3. 10 (dddd, 1H, J 10.5, 10.5, 10.5,6.5 Hz, H-9), 3.87-3.91 (dd, 1H, J = 10.5, 5 Hz, H-5), 4.78 (br d, 1H, J = 10.5 Hz, H-li),7.36-7.48 (m, 6H, aromatic protons), 7.66-7.72 (m, 4H, aromatic protons).Detailed ‘H nmr data, derived from COSY and NOE experiments, are given in Table 69.13C nmr (75.3 MHz) 6: 13.4 (-ye), 18.2 (-ye), 19.4, 25.8 (-ye), 27.0 (-ye, -C(H3)3), 28.9,32.1, 33.8 (-ye), 38.7, 39.6, 52.5, 63.5 (-ye), 78.8 (-ye, C-5), 127.5 (-ye), 127.6 (-ye), 128.7(-ye, C-il), 129.6 (-ye), 129.8 (-ye), 131.5 (C-12), 133.6, 134.5, 135.9 (-ye), 136.0 (-ye),209.4 (C-2).Exact Mass calcd. for C3OH4002Si: 460.2797; found: 460.2793.Anal. calcd. for C3H4tjOSi: C 78.21, H 8.75; found: C 78.15, H 8.81.350Table 69: 1H nmr Data (400 MHz, CDC13) for Compound 175b: COSY and NOE14 12 13TBDPSO Me1 75bAssignment ‘H nmr (400 MHz) COSY Correlationsa NOEH-x 6 ppm (mult., (Hz)) CorrelationsaMe-lO 0.91 (s) H-9-CMe3 1.06(s)H-8 Part of the m at 0.97-1.48 H-9Me-13 1.60 (br s) H-li H-liMe-i4 i.70(brs) H-liH-i —2.01 (d, J = 10.5), part of H-9 H-5, H-ilthe m at 1.37-2.07H-4 Part of them at 1.37-2.07 H-5H-4’1’ Part of the m at 1.37-2.07 H-5H-9 3.03-3.10 (dddd, J = 10.5, H-i, H-8, H-li Me-lO, Me-1410.5, 10.5, 6.5)H-5 3.87-3.91 (dd, J = 10.5, 5) H-4, H-4 H-i, -CM3H-u 4.78 (br d, J = 10.5) H-9, Me-l3, Me-i4 H-i, Me-i3a- Only those COSY correlations and NOB data that could be assigned are recorded.b- H’ indicates the hydrogen of a pair which is more downfield (H-4’ is more downfield than H-4)Experiments351Compound 212 was obtained in a pure form from further purification (flashchromatography) of the original mixture of compounds 213 and 212. The late fractionseluted from the column chromatography were concentrated and the oil thus obtained washeated at 80-100 °C/0.2 Torr for 1 hour (to remove any residual solvent) to provide purecompound 212, [cc] -33.5 (c 0.84, CHC13).IR (film): 1704, 1590, 1112, 1089, 704 cm_i.‘H nmr (400 MHz) & 1.08 (s, 9H,-3), 1.08-1.17 (m, iH), 1.17 (s, 3H, Me-lO), 1.31-1.39 (m, 1H), 1.43 (d, 3H, J = 0.8 Hz, Me-i4), 1.50 (br s, 3H, Me-i3), 1.74-2.00 (m, 5H,three of which are H-3, H-4, H-4’), 2.15-2.19 (m, 1H, H-3’), 2.48-2.51 (br dd, iH, J = 10, 2Hz, H-i), 3.12-3.21 (m, 1H, H-9), 3.77-3.81 (br dd, 1H, J = 10.5, 4 Hz, H-5), 4.51 (br d, iH,J = 10 Hz, H-i 1), 7.37-7.49 (m, 6H, aromatic protons), 7.66-7.75 (m, 4H, aromatic protons).Detailed iH nmr data, derived from COSY and NOE experiments, are given in Table 70.nmr (75.3 MHz) 6: 18.0 (-ye), 19.4, 21.6 (-ye), 25.7 (-ye), 27.0 (-ye, -C(H3)3), 29.0,31.8, 38.5, 39.6, 41.4 (-ye), 495, 64.8 (-ye), 73.6 (-ye, C-5), 126.6 (-ye, C-li), 127.4 (-ye),127.7 (-ye), 129.6 (-ye), 129.8 (-ye), 133.4, 133.5, 134.5, 135.9 (-ye), 136.0 (-ye), 212.7 (C-2).Exact Mass calcd. for C3OH4002Si: 460.2797; found: 460.2797.352Table 70: 1H nmr Data (400 MHz, CDC13) for Compound 212: COSY and NOEExperimentso14jf13c:$h11Me’°TBDPSO212Assignment ‘H nmr (400 MHz) COSY Correlationsa NOEH-x ö ppm (mult., (Hz)) Correlationsa-CM3 1.08 (s)Me-lO 1.17(s) H-iMe-l4 1.43 (d, J = 0.8) H-ilMe-13 1.50(brs) H-liH-3 Part of the m at 1.74-2.00 HYbH-4 Part of the m at 1.74-2.00 H-3’H-4 Part of the m at 1.74-2.00 H-YH-3’ 2.15-2. 19 (m) H1C, H-3, H-4, H-4’, H-5H-i 2.48-2.5 1 (br dd, J = 10, 2) H3’C, H-9 H-9, Me-lOH-9 3.12-3.21 (m) H-i, H-li H-i, Me-14H-5 3.77-3.8 1 (br dd, J = 10.5, H-3’, H-4, H-4’ H-il5)H-li 4.51 (brd, J = 10) H-9, Me-13, Me-i4 H-5, Me-13a- Only those COSY correlations and NOE data that could be assigned are recorded.b- H indicates the hydrogen of a pair which is more downfield (H-3’ is more downfield than H-3).c-W coupling353b. Via Conjugate Addition of the Cuprate Reagent 178 to the Enone 17Th in thePresence of TMSBr at -78 °C:Following the general procedure 5, the enone 177b (224 mg, 0.553 mmol) wassubjected to the cuprate addition reaction in the presence of TMSBr (i.e. BF3’Et20 was notused as a co-additive). The reaction mixture was stirred at -78 °C for 9.5 h. ‘H nmrspectroscopic analysis of the crude product indicated that —25% of the starting materialremained and that the ratio of compounds 213:175b :212 was 15:3:57.17417Th + 213 + 175b + 21226 : 15 : 3 : 571 : 4Flash chromatography (25 g silica gel, 12.3:1 petroleum ether - diethyl ether) of thecrude product produced 7.2 mg (3%) of compound 175b, 137 mg (54%) of a mixture ofcompounds 213 and 212, and 73 mg (33%) of recovered starting material 17Th. The mixtureof addition products 213 and 212 was subjected to three epimerizations with NaOMeIMeOH(workup and column chromatography were performed after each epimerization to isolate thedesired trans-fused isomer 175b) to afford 97 mg (38% or 56% based on recovered startingmaterial) of the desired epimer 175b.c. Via Conjugate Addition of the Cuprate Reagent 178 to the Enone 177b in thePresence of TMSBr at -78 °C to -10 °C:Following the general procedure 5, the enone 177b (278 mg, 0.687 mmol) wassubjected to the conjugate addition reaction employing trimethylsilyl bromide as the soleadditive. The reaction mixture was stirred at -78 °C for 6.5 h and then was warmed to -10 °Cover the course of 2 h. After the workup described in general procedure 5, the ‘H nmrspectrum of the crude product indicated that all of the starting enone 1 77b had beenconsumed, but that the product ratio now favored the undesired isomer 213. The ratio of theaddition products 213:175b :212 was found to be 59:3:38.173213 + 175b + 21259 3 : 38____-J1.4 : 13543553.2.2. SYNTHESIS OF (-)-HOMALOMENOL A (168b)3.2.2.1. Synthesis of (iS, 2R, 5S, 6S, 9S)-(-)-5-(tert-Butyldiphenylsiloxy)-2,6-dimethyl-9-(2-methyl- l-propenyl)bicyclo[4.3.0]nonan-2-ol (214) :170%% 10 1514T MeOHTBDPSO e TBDPSO175b 214To a cold (-20 °C), stirred solution of the (-)-trans-fused compound 175b (170 mg,0.369 mmol, 1 equiv.) in dry diethyl ether (7 mL) was added a solution of methyllithium indiethyl ether (1.4 M, 530 giL, 0.74 mmol, 2 equiv.). The solution was warmed to -5 °C overthe course of 1 h. Water (10 mL) was added and the layers were separated. The aqueousphase was extracted with diethyl ether (3 x 15 mL) and the combined organic extracts weredried over anhydrous magnesium sulfate and concentrated under reduced pressure. Thecrude oil thus obtained was flash chromatographed (8 g silica gel, 9:1 petroleum ether -diethyl ether) to afford, after recrystallization of the acquired solid from diethyl ether -petroleum ether, 141 mg (80%) of the desired (-)-tertiary alcohol 214, as a colourlesscrystalline solid, mp 98-100 °C, [c] -43.0 (c 1.71, CHC13).JR (KBr): 3602, 3072, 1590, 1111, 703 cm-1.‘H nmr (400 MHz) & 0.86 (d, 1H, J = 11.5 Hz, H-i), 0.97 (s, iH, -011; this signalexchanges upon treatment with D20), 1.01 (s, 3H, Me-li), 1.04 (s, 9H, -C3), 1.01-1.20(m, 3H), 1.21 (s, 3H, Me-iO), 1.26-1.35 (m, 1H), 1.41-1.45 (ddd, iH, J = 14.5, 4.5, 2.5 Hz),1.62-1.65 (m, iH), 1.62, 1.63 (d, d, 3H each, J = 1 Hz for each d, Me-13 and Me-14), 1.79-1.90 (ddd, 1H, J = 18, 14, 4.5 Hz), 1.98-2.08 (m, iH), 2.86-2.95 (m, 1H, H-9), 3.35-3.39 (dd,3561H, J = 11.5, 4 Hz, H-5), 5.00 (br d, 1H, J = 9.5 Hz, H-12), 7.34-7.42 (m, 6H, aromaticprotons), 7.68-7.70 (m, 4H, aromatic protons).nmr (75.3 MHz) & 14.9 (-ye), 18.1 (-ye), 19.5, 25.7 (-ye), 27.0 (-ye, -C(H3)3), 28.4,29.5, 30.5 (-ye), 35.0 (-ye), 39•4, 40.4, 47.8, 58.8 (-ye), 71.7 (C-2), 81.3 (-ye, C-5), 127.3(-ye), 127.4 (-ye), 128.4 (C-13), 129.3 (-ye), 129.5 (-ye), 132.4 (-ye, C-12), 134.1, 135.3,135.9 (-ye), 136.0 (-ye).ExactMass calcd. for C31H44O2Si: 476.3110; found: 476.3103.Anal. calcd. for C31H44O2Si: C 78.10, H 9.30; found: C 78.12, H 9.34.3573.2.2.2. Synthesis of (-)-Homalomenol A (168b):Me OH15(14‘..I.12rThL7I tA jHO ivieI 68bHOMALOMENOL ATo a stirred solution of the (-)-tertiary alcohol 214 (141 mg, 0.296 mmol, 1 equiv.) indry THF (6 mL) at rt was added a solution of TBAF in THF (1 M, 2.4 mL, 2.4 mmol, 8equiv.). The mixture was refluxed for 18 h. The solution was cooled to ii; water (25 mL)and diethyl ether (25 mL) were added and the layers were separated. The aqueous layer wasextracted with diethyl ether (2 x 20 mL) and ethyl acetate (2 x 20 mL). The combinedorganic extracts were dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The crude oil was flash chromatographed (8 g silica gel, 3:2 petroleumether - ethyl acetate) to yield 61 mg (87%) of (-)-homalomenol A (168b), a white solid.Recrystallization of the solid from diethyl ether - petroleum ether provided (-)-homalomenolA (168b) as thin, needle-like plates, mp 99-100 °C, [a] -51.5 (c 1.30, CHC13); lit,121 for(+)-homalomenol A (168a): oil, [a] +33.2 (c 1.205, CHC13).IR (KBr): 3617, 3434, 1581, 1023 cm’.‘H nmr (400 MHz, referenced at 7.24) ö: 0.93 (s, ill, -011; this signal exchanges upontreatment with D20), 0.99 (d, 1H, J = 11.5 Hz, H-i), 1.04 (d, 3H, J =0.7 Hz, Me-il), 1.10(s, 3H, Me-lO), 1.19-1.39 (m, 3H, one of which is H-8), 1.41-1.46 (dd, 1H, J = 14, 5 Hz),1.52-1.64 (m, 3H, one of which is H-4), 1.63, 1.64 (d, d, 3H each, J = 1.5 Hz for each d, Me-35814 and Me-15), 1.73-1.84 (m, 1H, H-4’), 2.00-2.11 (m, 1H, H-8’), 2.88-2.98 (m, 1H, H-9),3.35-3.38 (dd, 1H, J = 11.4, 4.1 Hz, H-5), 5.05 (br d, 1H, J = 9.5 Hz, H-12).Detailed ‘H nmr data, derived from COSY and NOE experiments, are given in Table 71.nmr (75.3 MHz) 6: 14.1 (-ye), 18.1 (-ye), 25.7 (-ye), 27.9, 29.6, 30.7 (-ye), 34•9 (-ye),38.6, 40.6, 47.1, 59.0 (-ye), 71.7 (C-2), 80.0 (-ye, C-5), 128.7 (C-13), 132.1 (-ye, C-12).ExactMass calcd. for C15H2602: 238.1933; found: 238.1930.Anal. calcd. for C15H2602: C 75.58, H 10.99; found: C 75.29, H 11.12.Comparison of the reported spectral data for (+)-homalomenol A (168a) with that of thesynthetic (-)-homalomenol A (168b) is shown in Table 72.359Table 71: 1F1 nmr Data (400 MHz, CDC13) for (-)-Homalomenol A (168b): COSY andNOE Experiments10 15’14MeOH‘ •..“12HO e1 68bAssignment ‘H nmr (400 MHz) COSY Correlationsa NOEH-x ppm (mult., J (Hz)) CorrelationsaH-i 0.99 (br d, J = 11.5) H-9 H-5, H-12Me-li 1.04 (d, J = 0.7) H-9Me-lO 1.10(s) H-12H-8 Part of them at 1.19-1.39 H8’b, H-9H-4 Part of them at 1.52-1.64 H-4’, H-5Me-14 1.63 (d, J = 1.5) H-12Me-15 1.64 (d, J = 1.5) H-12H-4’ 1.73-1.84 (m) H-4, H-5H-8’ 2.00-2.11 (m) H-8, H-9 H-8, H-9H-9 2.88-2.98 (m) H-i, H-8, H-8’, H-12 H-8’, Me-il,Me- 15H-5 3.35-3.38 (dd, J = 11.4, 4.1) H-4, H-4’ H-iH-12 5.05 (br d, J = 9.5) H-9, Me-14, Me-15 Me-14a- Only those COSY correlations and NOE data that could be assigned are recorded.b- H indicates the hydrogen of a pair which is more downfield (H-8’ is more downfield than H-8).360Table 72: Comparison of the Reported Spectral Data for (+)-Homalomenol A (168a) withthat of the Synthetic (-)-Homalomenol A (168b)Data Synthetic ReportedaIvIP 99-100°C3617 3600IR (cm1) 3434 34501581 —-1023 —-1.04 (d, 3H, J = 0.7 Hz) 1.03 (d, 3H, J = 0.9 Hz)1.10 (s, 3H) 1.10 (s, 3H)1.63 (d, 3H, J = 1.5 Hz) 1.63 (m, 3H)1.64 (d, 3H, J = 1.5 Hz) 1.63 (m, 3H)1HNMRC(6) 2.88-2.98 (m, 1H) 2.92 (16 lines, 1H)3.35-3.38 (dd, 1H, J = 11.4, 4.1 Hz) 3.36 (dd, 1H, J = 11, 4.1 Hz)5.05 (br d, 1H, J = 9.5 Hz) 5.05 (d spd, 1H, J = 9.3, 1.4 Hz)14.1 14.218.1 18.125.7 25.827.9 28.029.6 29.630.7 30.713C NIvIR (3) 34.9 35.038.6 36.740.6 40.747.1 47.259.0 59.171.7 71.880.0 80.0128.7 128.7132.1 132.2HRMS(238.19 3)e 238.1930 238.1933ElementalAnalysis C15H2602(CHC1) -51.5(cl.30) +33.2(cl.205)a- Spectral data for (+)-homalomenol A as reported in reference 121.b- Reported as an oil.c- Only the selected ‘H nmr signals for the synthetic (-)-homalomenol A which correspond to those reported forthe natural (+)-homalomenol A are listed.d- d sp: doublet of septetse- Calculated value for Cl5HO2f-Not reported3613.2.3. SYNTHESIS OF (is, 2R, 5S, 65, 9S)-(-)-5-ACETOXY-2,6-DIMETHYL-9-(2-METHYL-i -PROPENYL)-BICYCLO[4.3.0]NONAN-2-OL (215):eOH15(14‘. I:! ..12AcO Me215To a stirred solution of homalomenol A (168b) (13 mg, 0.054 mmol, 1 equiv.) in drypyridine (0.30 mL, 3.7 mmol, 68 equiv.) at rt was added acetic anhydride (0.30 mL, 3.2mmol, 59 equiv.). The resultant solution was stirred at rt for 24 h and 0.1 M hydrochloricacid (5 mL) was then added. Diethyl ether was added (10 mL) and the layers were separated.The aqueous phase was extracted with diethyl ether (2 x 10 mL) and the combined organiclayers were washed with saturated aqueous NaHCO3 (2 x 10 mL), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The crude product was flashchromatographed (3 g silica gel, 9:1 petroleum ether - ethyl acetate) to provide 15 mg (98%)of the monoacetate 215,175 a solid. The monoacetate 215 was recrystallized from petroleumether - ethyl acetate to provide a colourless crystalline solid, mp 89-92 °C.IR(KBr): 3498, 1717, 1455, 1262, 1027 cm-1.nmr (400 MHz, referenced at 6 7.24) 6: 1.08 (br s, 3H, Me), 1.11 (s, 3H, Me), 1.18-1.51(m, 6H), 1.62 (br d, 3H, J = 1 Hz, vinyl Me), 1.63 (br d, 3H, J = 1 Hz, vinyl Me), 1.57-1.66(m, 2H), 1.80-1.90 (m, 1H), 1.95-2.05 (m, in), 2.01 (s, 3H, -OC(O)M), 2.87-2.96 (m, 1H,H-9), 4.57-4.61 (dd, 1H, J = 11.5, 4Hz, H-5), 5.06 (br d, 1H, J = 9.5 Hz, H-12).13C nmr (75.3 MHz) 6: 15.2 (-ye), 18.1 (-ye), 21.3 (-ye), 24.5, 25.7 (-ye), 29.3, 30.7 (-ye),34.8 (-ye), 38.5, 40.3, 45.9, 59.1 (-ye), 71.6, 81.1 (-ye, C-5), 128.8 (C-i3), 131.9 (-ye, C-12),170.9 (-OOMe).362Exact Mass calcd. for C17H2803: 280.2039; found: 280.2035.Anal. calcd. for C17H2803: C 72.82, H 10.06; found: C 72.70, H 9.91.Table 73: Comparison of the Reported Spectral Data for the (+)-Monoacetate 215 with thatof the Synthetic Monoacetate 215Data Synthetic ReportedaMP 89-92 °C 92-95 °C3498 3600IR (cm’) 1717 17201455 —1262 12601.08 (br s, 3H) 1.09 (d, 3H, J = 0.8 Hz)1.11 (s, 3H) 1.11 (s, 3H)1.62 (br d, 3H, J = 1Hz) 1.62 (d, 3H, J = 1.5 Hz)1.63 (br d, 3H, J = 1Hz) 1.63 (d, 3H, J = 1.5 Hz)‘H NMRb 2.01 (s, 3H) 2.02 (s, 3H)2.87-2.96 (m, 1H) 2.91 (16 lines, 1H)4.57-4.61 (dd, 1H, J = 11.5, 4 Hz) 4.58 (dd, 1H, J = 11.4,4 Hz)5.06 (hr d, 1H, J = 9.5 Hz) 5.04 (d spC, 1H, J = 9.6, 1.5 Hz)15.2 15.218.1 18.221.3 21.424.5 24.625.7 25.829.3 29.430.7 30.7l3 NMR (3) 34.8 34.838.5 38.540.3 40.445.9 46.059.1 59.171.6 71.781.1 81.2128.8 128.8131.9 132.0170.9 171.0HRMS(280.039)d 280.2035 280.2042ElementalAnalysis C17H2803a- Spectral data for the monoacetate 215 as reported in reference 121.b- Only the selected ‘H nmr signals for the synthetic monoacetate 215 which correspond to those reported forthe (+)-monoacetate 215 are listed.c- d sp: doublet of septetsd- Calculated value forC17H2803e- Not reported363IV. REFERENCES AND FOOTNOTES1. Trost, B. M. Acc. Chem. Res. 1978, 11, 453. The bifunctional conjunctive reagentshave also been termed “multiple coupling reagents”. See Seebach, D.; Knochel, P.Helv. Chim. Acta 1984, 67, 261.2. Seebach, D. Angew. Chem. mt. Ed. Eng!. 1979, 18, 239.3. For examples of how bifunctional reagents are utilized in annulation sequences seethe following references: (a) Trost, B. M.; Urabe, H. J. Am. Chem. Soc. 1990, 112,4982; (b) Trost, B. M.; Matelich, M. C.; J. Am. Chem. Soc. 1991, 113, 9007; (c)Paquette, L. A.; Galemmo, R. A. Jr.; Caille, J.-C.; Valpey, R. S. J. Org. Chem. 1986,51, 686.4. Helquist, P.; Bal, S. A.; Marfat, A. J. Org. Chem. 1982,47, 5045.5. Corey has defined synthons as “structural units within a molecule which are related topossible synthetic operations”. See Corey, E. J. Pure App!. Chem. 1967, 14, 19.6. Piers, E.; Karunaratne, V. Tetrahedron 1989,45, 1089.7. Piers, E.; Marais, P. C. J. Org. Chem. 1990,55, 3454.8. Seebach states that reactivity umpolung is present in a reagent in which acceptor anddonor centers are reversed. See reference 2. For example, route A employs ad2,a4-synthon whereas route B employs an2,d4-synthon.9. Piers, E.; Marais, P. C. J. Chem. Soc., Chem. Commun. 1989, 1222.10. Piers, E.; Chong, J. M. Can. J. Chem. 1988, 66, 1425.11. Piers, E.; Karunaratne, V. Can. J. Chem. 1989, 67, 160.12. Piers, E.; Renaud, J. J. Chem. Soc., Chem. Commun. 1990, 1325.13. (a) Piers, E.; Yeung, B. W. A.; Fleming, F. F. Can. J. Chem. 1993, 71, 280; (b) Piers,E.; Yeung, B. W. A. J. Org. Chem. 1984, 49, 4567; (c) Piers, E.; Wai, J. S. M. Can. J.Chem. 1994, 72, 146; (d) Piers, E.; Roberge, J. Y. Tetrahedron Lett. 1991, 32, 5219;(e) Piers, E.; Roberge, J. Y. Tetrahedron Lett. 1992,33, 6923.14. The average carbon-tin bond length is 2.18 A while the average carbon-germaniumbond length is 1.98 A (Weast, R. C. (Ed.) “CRC Handbook of Chemistry andPhysics”, CRC Press, Boca Raton, 66th Edition, 1985, p F-165.). Since shorter bondsare associated with higher bond dissociation energies (Jackson, R. A. J. Organomet.Chem. 1979, 166, 17.), the trimethylgermyl functionality should be more resistant totransmetallation than the corresponding trimethyistannyl moiety.15. Piers, E.; Renaud, J. J. Org. Chem. 1993,58, 11.16. Piers, E.; Marais, P. C. Tetrahedron Lett. 1988,29, 4053. Although the bifunctionalreagents used in this paper are the corresponding vinyistannane reagents (i.e. 4-iodo-2-trimethyistannyl- 1 -butene vs. 4-iodo-2-trimethylgermyl- 1 -butene and 5-iodo-2-364trimethyistannyl- 1 -pentene vs. 5-iodo-2-trimethylgermyl- 1 -pentene), the final ringclosure step is identical with that described in reference 9. As a result, the productresulting from this annulation sequence is a bicyclic compound bearing a tertiaryallylic alcohol. See below.I,.n-BuLi (2 equiv.)THF, -78 °Cn=1,R=H 1 : 1n=1,R=Me >99 : <1n=2,R=H 1 : 15n=2, R=Me >99 : 117. There is, however, ample precedent for the closure of a vinyl iodide functionality ontoa carbonyl carbon to generate bicyclic compounds bearing a tertiary allylic alcoholmoiety. See reference 16.18. (a) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6015 and 6019.; (b)Alexakis, A.; Berlan, J.; Besace, Y. Tetrahedron Lett. 1986, 27, 1047.; (c) Kuwajima,I.; Nakamura, E.; Matsuzawa, S.; Horiguchi, Y. Tetrahedron Lett. 1986, 27, 4029.;(d) Kuwajima, I.; Nakamura, E.; Matsuzawa, S.; Horiguchi, Y. Tetrahedron 1989,45,349.19. Marais, P. C. Ph. D. Thesis, University of British Columbia, April 1990, pages 80-82.20. (a) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033; (b) Marais, P. C. Ph.D. Thesis, University of British Columbia, April 1990, page 86.21. Piers, E.; Chong, J. M. Can J. Chem. 1988, 66, 1425.22. Piers, E.; Lemieux, R. I Chem. Soc., Perkin Trans. 1 1995, 3.23. Trimethylgerinane (Me3GeH) was prepared by René Lemieux in 95% yield by use ofa procedure modified from that reported: Coates, D. A.; Tedder, J. M. J. Chem. Soc.,Perkin Trans. 2, 1978, 725. Thus, treatment of Me3GeBr with LiAIH4 in n-Bu20 at0 °C, followed by direct distillation via heating of the reaction mixture to —110 °C for3 h (collection flask cooled to -78 °C), gave the product containing —5-10% of nBu20. Redistillation (bulb to bulb) of this material at —30 °C gave essentially pureMe 3GeH, which was stored under an atmosphere of argon in a freezer.LIAIH4Me3GeBr Me3GeHn-Bu20, 110°C (95%)24. Millar, J. G.; Underhill, E. W. J. Org. Chem. 1986,51,4726.36525. Deslongchamps, P.; Ruest, L.; Blouin, G. Synth. Commun. 1976, 6, 169.26. The procedure for the synthesis of the enone 57 was modified from that reported inthe following paper: Liotta, D.; Barnum, C.; Puleo, R.; Zima, G.; Bayer, C.; Kezar,H. S. J. Org. Chem. 1981,46, 2920.27. 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