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Studies toward a total synthesis of (±)-subergorgic acid Dragojlovic, Veljko 1993

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STUDIES TOWARD A TOTAL SYNTHESIS OF(±)-SUBERGORGIC ACIDbyVELJKO DRAGOJLOVICB. Sc., University of Belgrade, 1986A THESIS SUBMITTED IN PARTIAL FULFILLMENT OFTHE REQUIREMENTS FOR THE DEGREE OFDOCTOR OF PHILOSOPHYinTHE FACULTY OF GRADUATE STUDIESDEPARTMENT OF CHEMISTRYWe accept this thesis as conformingto the required standardTHE UNIVERSITY OF BRITISH COLUMBIAOctober 1993© Veljko Dragojlovic, 1993In 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  C 1.-te^s7 The University of British ColumbiaVancouver, CanadaDate ^jO^Oc- 701E- K^c16■3 DE-6 (2/88)ABSTRACTThis thesis describes synthetic studies directed towards the totalsynthesis of (±)-subergorgic acid (8) and the development ofmethodology for the conversion of cyclopentanones intocyclopentenones.In the synthetic studies directed towards the total synthesis of(±)-subergorgic acid (8), the known keto ketal 101 was converted intothe enone 100. Copper(I)-catalyzed conjugate addition of the Grignardreagent 91 to the enone 100, followed by intramolecular alkylation ofthe intermediate enolate anion, provided the triquinane 99. Sequentialdeoxygenation of the keto function in 99 and oxidative cleavage of thedouble bond provided the ketone 103. The ketone 103 was convertedinto dienedione 98 via a four step sequence, involving Saegusaoxidation to give 156, deketalization of the ketal function andbenzeneseleninic acid anhydride (BSA) mediated dehydrogenation of theintermediate 157. The dienedione 98 was alkylated to provide 107.Conversion of the enone 157 into the dienedione 98 required thedevelopment of new methodology for the conversion of cyclopentanonesinto the corresponding cyclopentenones. Reactions of di- andtriqiunanes such as 133 and 157 with BSA provided the correspondingenones 250 and 98, respectively.8CO2H1 0 2157 980=C:0(:_f\--V1330-vWO--/\1 0 1 99i vTABLE OF CONTENTSABSTRACTTABLE OF CONTENTSLIST OF TABLESpageiiivxLIST OF FIGURES xiiABBREVIATIONS xiiiACKNOWLEDGMENTS xviQUOTATION xvii1 INTRODUCTION 11.1 General 11.2 Silphiperfolene^Sesquiterpenes 21.3 Previous Synthetic Approaches 41.3.1 The Synthetic Problem 41.3.2 Total Synthesis by C. lwata and Coworkers 41.3.3 Total Synthesis by P. Wender and M. deLong 81.3.4 Synthetic Studies by M. Crimmins and Coworkers 111.3.5 Enantioselective Total Synthesis of(-)-Subergorgic Acid by L. Paquetteand Coworkers 141.4 Retrosynthetic^Analysis 191.5 Previous Work 201.6 Research Objectives 25V2 DISCUSSION 272.1 Retrosynthetic Analysis of (±)-Subergorgic^Acid 272.2 The Synthetic Plan 282.3 Studies Toward a Total Synthesisof (±)-Subergorgic Acid 352.3.1 Preparation of the Starting Materials 89 and 101 352.3.2 Preparation of the Enone Ketal 100 362.3.3 Preparation of the Tricyclic Ketone 99 362.3.4 Preparation of the Alcohols 135 and 136 452.3.5 Preparation of the Methyl Xanthates 137 and 138 462.3.6 Reduction of the Methyl Xanthates 137 and 138 472.3.7 Preparation of the PhenylThionocarbonates 148 and 149 502.3.8 Reduction of the PhenylThionocarbonates 148 and 149 502.3.9 Sterochemistry of the Alcohols 135 and 136,and the Phenyl Thionocarbonates 148 and 149 512.3.10 Preparation of the Tricyclic Keto Ketal 103 592.3.11 Preparation of the Diketone 104 622.3.12 Preparation of the Tricyclic Enone Ketal 156 632.3.13 Preparation of the Tricyclic Enedione 157 642.3.14 Preparation of the Tricyclic Dienedione 98 652.3.14.1 Saegusa Oxidation of theEnol Sily1 Ethers 105 and 164 65vi2.3.14.2 Reexamination of the Saegusa's Procedure 692.3.14.3 Attempted Saegusa Oxidation ofthe Enol Silyl Ether 168 712.3.14.4 Other Palladium Oxidations 722.3.14.5 Oxidation-Elimination of a-Phenylseleno Ketone 172a 732.3.14.6 Oxidation of the Enone 157 withBenzeneseleninic Acid Anhydride 752.3.15 Alkylation of the Dienedione 98 782.3.16 Lithium^Dimethylcuprate^Additionto 11-Methyl Dienedione 107 852.4 Preparation of Enones form Ketones: BSA Method 862.4.1 Introduction 862.4.2 Oxidation of Cyclopentanones 913 CONCLUSION 984 DESIGN OF AN ALTERNATIVE SYNTHETIC SEQUENCEFOR THE SYNTHESIS OF SUBERGORGIC ACID 1014.1 Recent Developments in Related Fields 1014.2 A Synthetic Plan Involving a [2+2+1] Cyclization 104 4.3 A Synthetic Plan for an EnantioselectiveSynthesis of (-)-Subergorgic Acid 1 085 EXPERIMENTAL 110 5.1 General 110 5.1.1 Data Acquisition and Presentation 11 05.1.2 Solvents and Reagents 11 2vii5.2 Experimental Procedures 1155.2.1 Synthetic Studies Toward the Total Synthesisof (±)-Subergorgic^Acid 1155.2.1.1 Preparation of the Trimethylsilyl Enol^Ether 130 1155.2.1.2 Preparation of the Enone Ketal 100 1175.2.1.3 Preparation of the Tricyclic Ketone 99 1195.2.1.4 Preparation of the Chloro Ketone 132 1225.2.1.5 Preparation of Tricyclic Ketone 99from Chloro Ketone 132 1245.2.1.6 Preparation of the Alcohol 135 1255.2.1.7 Preparation of the Alcohol 136 1275.2.1.8 Sodium Borohydride Reduction of the Ketone 99 1295.2.1.9 DIBAL-H Reduction of the Ketone 99 1305.2.1.10 Preparation of the Methyl Xanthate 137 and 138 1305.2.1.11 Preparation of the Phenyl Thiocarbonate 149 1325.2.1.12 Preparation of the Phenyl Thiocarbonate 148 1355.2.1.13 Preparation of the Alkene 102from the Xanthates 137/138 1375.2.1.14 Preparation of the Alkene 102 from the Phenyl Thionocarbonate 148 1395.2.1.15 Preparation of the Alkene 102 from the Phenyl Thionocarbonate 148 1405.2.1.16 Preparation of the Keto Ketal 103 1405.2.1.17 Preparation of the Diketone 104 142viii5.2.1.18 Preparation of the Enone Ketal 156via the Enol Silyl Ether 155^ 1 445.2.1.19 Preparation of the Enedione 157 1465.2.1.20 Preparation of the Dienedione 98^ 1485.2.1.21 Preparation of the Dienedione 98via the Enol Silyl Ether 164^ 1505.2.1.22 Preparation of the 11-Methyl Dienedione 107^1515.2.2^Preparation of Enones from Ketones: BSA Method^1555.2.2.1^General Procedure: Oxidation of theKeto Ketal 101 to the Enone Ketal 100^1555.2.2.2^Oxidation of the Keto Ketal 101to the Enone Ketal 100^ 1565.2.2.3^Oxidation of the Keto Ketal 101to the Enone Ketal 100^ 1565.2.2.4^Oxidation of the Keto Ketal 101to the Enone Ketal 100^ 1575.2.2.5^Oxidation of the Keto Ketal 101to the Enone Ketal 100^ 1575.2.2.6^Oxidation of the Keto Ketal 101to the Enone Ketal 100^ 1585.2.2.7^Preparation of the 5-Methyl Enone 250^1585.2.2.8^Preparation of the Enedione 157^ 1605.2.2.9^Preparation of the Dienedione 98from the Diketone 104^ 1615.2.2.10 Preparation of the Dienedione 98from the Enedione 157^ 1615.2.2.11 Preparation of the Enone Ketal 156^ 162i x5.2.3 Preparation of Enones from Ketones:Saegusa Oxidation 1 635.2.3.1 Preparation of the Methyl Enone 250via the Enol Silyl Ether 251 1635.2.3.2 Preparation of the Tricyclic Dieneone Ketal 252via the Enol Silyl Ether 253 1646 REFERENCES 167LIST OF TABLESTable 1^1H NMR (400 MHz, CDCI3) and COSY(200 MHz, CDCI3) data for thechloro ketone 132Table 2^Methylenecyclopentane annulationof the enone ketal 10040, 12342Table 3Table 41H NMR (400 MHz, CDCI3) and COSY(400 MHz, CDCI3) data forthe keto alkene 991H NMR (400 MHz, CDCI3) anddecoupling experiments (400 MHz, CDCI3)data for the keto alkene 9944, 12144, 121Table 5^Reduction of the tricyclic ketone 99^46Table 6^1H NMR (400 MHz, CDCI3), COSY(200 MHz, CDCI3) and nOe (400 MHz, CDCI3)data for the alcohol 135^ 52, 126Table 7^1H NMR (400 MHz, CDCI3), COSY(200 MHz, CDCI3) and nOe (400 MHz, CDCI3)data for the phenyl thionocarbonate 148^55, 136Table 8^1H NMR (400 MHz, CDCI3), COSY(200 MHz, CDCI3) and nOe (400 MHz, CDCI3)data for the phenyl thionocarbonate 149Table 9^1H NMR and COSY (400 MHz, CDCI3)data for the keto ketal 103Table 10^1H NMR (400 MHz, CDCI3) and COSY(200 MHz, CDCI3) data for the enedione 157Table 11^1H NMR (400 MHz, CDCI3) and COSY(200 MHz, CDCI3) data for the dienedione 9857, 13462, 14264, 14776, 149xiTable 12 1H NMR, COSY (200 MHz, CDCI3) and nOe(400 MHz, CDCI3-C6D6 (7:3)) data forthe 11-methyl dienedione 107 83, 153Table 13 Decoupling experiments(400 MHz, C6D6 and CDCI3)data for the 11-methyl dienedione 107 84, 154Table 14 BSA oxidation of the keto ketal 101 93Table 15 Preparation of enones from ketones 95Table 16 1H NMR (400 MHz, CDCI3) and COSY(200 MHz, CDCI3) data for the enone 100 118 Table 17 Decoupling experiments (400 MHz, CDCI3)data for the alcohol 135 1 27Table 18 1H NMR (400 MHz, CDCI3) and COSY(200 MHz, CDCI3) data for the alcohol 136 1 29Table 19 Decoupling experiments (400 MHz, CDCI3)data for the phenyl thionocarbonate 149 133 Table 20 Decoupling experiments (400 MHz, CDCI3)on the ketal alkene 102 138 Table 21 1H NMR (400 MHz, CDCI3) andCOSY (200 MHz, CDCI3)data for the 5-methyl enone 250 160 Table 22 1H NMR (400 MHz, CDCI3) andCOSY (200 MHz, CDCI3)data for the dienone ketal 252 166x i iLIST OF FIGURESFigure 1^The 1 H NMR spectrum (400 MHz, CDCI3)of the keto alkene 99^ 43Figure 2^nOe experiments on the alcohol 135^52Figure 3^nOe experiments on thephenyl thionocarbonate 148^ 54Figure 4^nOe experiments on thephenyl thionocarbonate 149^ 56Figure 5^The COSY (400 MHz, CDCI3) spectrumof the keto ketal 103^ 61Figure 6^The 1 H NMR spectrum (400 MHz, CDCI3)of the dienedione 98^ 77Figure 7^nOe experiments on the11-methyl dienedione 107^ 83LIST OF ABBREVIATIONSAc^ acetylAIBN 2,2'-azobis(isobutyronitrile)Anal. elemental analysisAPT^ attached proton testaq. aqueousBn benzylb.p.^ boiling pointbr broadBSA benzeneseleninic acid anhydrideBTA^ benzenetelurinic acid anhydrideBu butyln-Bu normal-butylt-Bu or But^tertiary-butylBz^ benzoylcalcd. calculatedcat. catalyticcm^ centimeterCOSY correlation spectroscopym-CPBA 3-chloroperoxybenzoic acidCSA^ 10-camphorsulfonic acidA heatd doubletDBU^ 1,8-diazabicyclo[5.4.0]undec-7-eneDCQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinoneDIBAL-H^-^diisobutylaluminum hydrideDIPHOS 1,2-bis(diphenylphosphino)ethaneDMAP 4-(N,N-dimethylamino)pyridineCMF^ N,N-dimethylformamideDMPU N,N'-dimethylpropyleneureaCMS° dimethyl sulfoxideequiv.^ equivalent(s)Et ethyl9 gram(s)x i vGLC^ gas-liquid chromatographyHMPA hexamethylphosphoramidehr hour(s)HRMS^ high resolution mass spectroscopyHz hertzIR infraredLDA^ lithium diisopropylamideLRMS low resolution mass spectroscopyL-Selectride^lithium tri-sec-butylborohydridemolarmultipletmetaMe^-^methylmg milligram(s)MHz megahertzmin^ minute(s)mL milliliter(s)- microliter(s)mmol^ millimole(s)mol mole(s)m.p. melting pointMs^ methanesulfonylmult. multiplicity- normalMAR^ nuclear magnetic resonancenOe nuclear Overhauser enhancementpageparaPCC^ pyridinium chlorochromatePDC pyridinium dichromatePh phenylpp^ pagesppm parts per millionPPTS pyridinium p-toluenesulfonatePROPHOS^1,3-bis(diphenylphosphino)propanePy^ pyridineX Vq^ quartetr t room temperatureS singlett^ triplett tertiaryTBDMS tertiary-butyldimethylsilylTf^ trifluoromethanesulfonylTf2NPh N-phenyltrifluoromethanesulfonimideTHF -^tetrahydrofuranTLC^ thin layer chromatographyTMEDA N,N,N',N'-tetramethylethylenediamineTMS tetramethylsilaneTMS-^ trimethylsilylp-Ts para-toluenesulfonylp-TSA para-toluenesulfonic acid-ve^ negativex v iACKNOWLEDGMENTSI would like to thank my research supervisor, Professor Ed Piers,for his guidance and patience throughout the course of this studies. Hisadvice on writing this thesis is greatly appreciated.In addition, thanks are extended to the past and present membersof the group for the intellectual and social interactions over the years.My thanks and best wishes to Dr. Livain Breau for many discussions,helpful suggestions and criticisms, and the care taken in proofreadingthis thesis. I would like to thank Professor Thomas Money and Mr. andMrs. Keith Ellis for their contribution in proofreading this thesis.Special thanks are also due to Dr. Betty-Anne Story, Mrs. ChantalSoucy-Breau, Dr. Miguel Romero (1. ...d5), Mr. Anthony Dotse and Mr.Timothy Wong.Financial assistance from the University of British Columbia in theform of a University Graduate Fellowship is also acknowledged.xvii"Never late were favors divine"N. Machiavelli, Letter to Vettori (1513).11^Introduction1.1 GeneralThe rapid growth of organic chemistry over the past severaldecades has led to the development of a broad repertoire of synthetictools. New methodologies, based on organoelement compounds, such asorganoboron, organosilicon, organosulfur, and organophosphorussubstances have contributed to a fundamental change in theunderstanding of synthetic organic chemistry. New concepts such as"umpolung"1 and retrosynthetic analysis2a,b have emerged from researchon the reactivity and properties of these reagents. In search for moreefficient reagents, a number of research groups have now focused onthe application of biochemical (enzymes, catalytic antibodies) andorganometallic reagents. The latter field of research is particularlypromising because it offers many advantages over the known methodswith regard to selectivity, efficiency, cost and broad range ofapplicability.3 Over the past decade alone, new developments in relatedfields, as well as development of adequate experimental techniquesnecessary to handle organometallic compounds, have made possible theintroduction of hundreds of new reagents.Until recently, the efforts of synthetic organic chemists werededicated to target structures such as naturally occurring ortheoretically interesting molecules. Due to the advances madeconcomitantly in medicinal and organometallic chemistry, and in partdue to the way that funding is allocated to chemists, much of today'ssynthetic efforts have been shifted from interesting target structures2to the synthesis of biologically active molecules.3,4 Following thetrend of modern research, this thesis is largely concerned with theexploratory use of a bifunctional reagent toward the synthesis of thenaturally occurring triquinane subergorgic acid.51.2^Silphiperfolane SesquiterpenoidsAmong synthetic organic chemists, triquinane molecules have beenparticularly popular targets.6 The triquinanes are molecules whichhave three connected five membered rings. Depending on thearrangement by which the rings are interconnected they are dividedinto angular triquinanes 1, linear triquinanes 2, and propellanes 3(Chart 1).icc9 c00)1^2^3Chart 1The angular sesquiterpene triquinanes are subdivided into thefollowing groups (represented as their parent hydrocarbons):isocomane (4), silphilinane (5), pentalenane (6), and silphiperfolane (7)(Chart 2).The chemistry of triquinane natural products has been an area ofextensive synthetic studies since the mid-1970s. This interest is inpart due to their biological properties. For instance, some of them arepharmacologically active,7 some are fragrant compounds.5 It has been3shown that subergorgic acid (8) exhibits cardiotoxic activity,5anticholinesterase activity,9a and activity against "Soman" toxicity inmice.9b4^5^6^7Chart 2In recent years, a considerable effort has been directed towardssynthesis of compounds with fused five-membered rings and thetriquinanes provide convenient targets for the development and testingof new methodologies. It is a continuing effort of many researchgroups to find a general and versatile cyclopentane annulation method,such as the Diels-Alder reaction for the assembly of six-memberedrings.19131214CO2H841.3 Previous Synthetic Approaches1.3.1 The Synthetic ProblemSeveral synthetic approaches to subergorgic acid (8) have appearedin the literature since 1988.The principal difficulty encountered in the synthesis ofsubergorgic acid is related to the unusual functionality present in themolecule as compared with the other silphiperfolanes. Subergorgicacid has a keto function at position C-2, a feature that is unknown inother silphiperfolane molecules. Also, the configurational orientationof the C-15 methyl group is noteworthy.1.3.2 A Total Synthesis of (±)-Subergorgic Acid (8) by C. lwata andcoworkersThe first total synthesis of (±)-subergorgic acid was reported in1988 by C. lwata and coworkers (Scheme 1).11In their approach, the Spiro enone 9 was utilized as the startingmaterial. The compound 9 had been previously prepared by lwata'sgroup and had been used in the synthesis of several other naturalproducts.12 Oxidation, and selective protection of the newly formedketo group with ethylene glycol, gave the ketal enone 10. Thephotochemical addition of allene to 10 afforded 11.L-Selectride (Aldrich) reduction of 11 provided the axial alcohol12. Oxidative cleavage of the double bond with a catalytic amount ofosmium tetraoxide in presence of sodium periodate as cooxidant8 2251)PCC, CH2Cl22)(CH2OH)2, p-TSA, C6H69H nom^H,,,.-- N100304, a 41 20 ,'Dioxane, Pyridine01311) MsCI, Pyridine2) NaBH4, Me0HH ,OH12L-Selectride,11-IF110010ihv, aliens, THF01)3 N HCI, THF2)MsCI, Et3N, al2c12-.4^Me02S0 017t-BuOK THFLi, liquid NH31921Scheme 1.1)PPTS, acetone, H202)CH3OCH2CI, (i-Pr)2NEt, CH2Cl23) LDA, PhSSPh, THF, HMPA^ D. MOMO0151 1) Na104, Me0H, H202) Et3N, CCI41)Mai, Et202)CiO3, Et20, H20 illI^.- eak20i0,, CH2Cl2;Zn, AcOHCHOCO2H0 NaC102CHO0^.^.pipend' ine acetate, CsFis6provided the hydroxy ketone 1 3.^Treatment of 1 3 withmethanesulfonyl chloride in pyridine followed by sodium borohydridegave compound 14. The transformation proceeds via a reduction ofketone 23, a 1,4-elimination-fragmentation, and reduction of the insitu generated aldehyde 25 (Scheme 2).•■•■^ I=MrM sCI, Pyridine_23^ 24-13HONaBH4 14Scheme 2With compound 14 in hand, it was necessary to conduct extensivefunctional group interconversions in order to prepare an intermediatesuitable for cyclization to the tricyclic molecule 18. The ketalfunction in 14 was removed by transketalization with PPTS in acetoneand the hydroxy group was protected by treatment with chloromethylmethyl ether in the presence of N,N-diisopropylethylamine.Deprotonation of the resultant ketone with LDA removed the lesssterically hindered proton to provide the kinetic enolate, which upon30% H202, 10% aq. NaOH,Me0H28 271) MsCI, Et3N, CH2Cl22) PCC, CH2Cl2 AI3) DBU, THF-.aa.Me2CuU, Et202 O7addition of diphenyldisulphide afforded the a-phenylthio ketone 15.Oxidation of 15 with sodium periodate gave the correspondingsulfoxide. The elimination of phenylsulphinic acid with triethylaminein carbon tetrachloride gave the enone 16. The alcohol function ofcompound 16 was deprotected with 3 N hydrochloric acid in THF andsubsequently treated with methanesulfonyl chloride and triethylaminein dichloromethane to afford 17. The tricyclic product 18 wasobtained from the treatment of compound 17 with potassium t-butoxide in THF.In order to introduce a methyl group at C-4 (corresponding to thesubergorgic acid numbering system), the compound 18 was treatedwith methyllithium to provide the tertiary alcohol, which uponchromium trioxide oxidation yielded the transposed enone 19.Reduction of 19 with lithium in ammonia gave the ketone 20 and its C-4 epimer in a ratio of 6:1.Scheme 38Alternatively, it is possible to prepare 20 in a morestereoselective manner via a lengthier route (Scheme 3). The enone18 was epoxidized with alkaline hydrogen peroxide to give 26 as anisomeric mixture. Upon lithium aluminum hydride reduction, thecompound 27 was obtained as a mixture of diastereoisomers. Thesiteselective mesylation of the less sterically hindered C-4 hydroxyfunction of 27, followed by a PCC oxidation of the C-2 hydroxy groupgave the corresponding 13-mesyloxyketone, which upon addition of DBUinduced elimination to gave the enone 28. Stereoselective addition oflithium dimethylcuprate to the enone 28 afforded the intermediate 20and its C-4 isomer in a ratio of 20:1.Preparation of dialdehyde 21 was accomplished by ozonolysis ofthe keto alkene 20 (Scheme 1). Treatment of dialdehyde 20 withpiperidine acetate in benzene gave the triquinane aldehyde 22. The IRand partial 1H NMR spectral data of 22 were reported as having beenrecorded in chloroform and deuterochloroform, respectively. Bothspectra were actually recorded in carbon tetrachloride.13 Oxidation ofaldehyde 22 with sodium chlorite provided (±)-subergorgic acid (8).1.3.3 A Total Synthesis of (±)-Subergorgic Acid (8) by P. Wender andM. deLongIn 1990 a considerably shorter synthesis of (±)-subergorgic acidwas published by P. Wender and M. deLong (Scheme 4).14 Althoughassembly of the triquinane skeleton was very expeditious, the sequenceproceeded in a low overall yield.1) Li, Et20; 3-Me-4-Pentenal2) PCC, CH2Cl23) (CH20F)2, CSA, C6H6, ANC31 32---NMgBr0^...''70%35i SOCl2Pyridine1 K, 18-C-6Toluene1) Benzoyl peroxideacetonitrile, A42% (1 : 1.8)1) m-CPBAHO92 9^ 3 01 hv, mecum press Hanovia,Vycor Fitter, CyclohexaneOHC DMSO, AgBF4; Et3NCI 85%^ 85%37 3 61 NaCIO2, 2-M e-2-Butene,NaH2PO4, t-BuOH, H208^ Scheme 410Their approach was based on the arene-alkene photocycloadditionstrategy previously applied in the synthesis of several polycyclicsesq u ite rp en es.15 The benzylic ketal 30 necessary for thecycloaddition step was prepared from the bromoxylene 29 and 3-methy1-4-pentenal.Photolysis of the benzylic ketal 30 provided two products 31 and32 in a 1:1.8 ratio and in 42% overall yield, the desired adduct beingthe minor product 31. According to the authors, the relatively lowyield of the reaction may be due in part to the introduction of threecontiguous quaternary centers. The preference for the formation of 32over 31 was claimed to be due to the greater strain in 31 arising froman increased steric interaction between the angular quaternary methylsubstituent and the ketal function relative to that in 32.Free radical addition of the C-centered radical prepared fromacetonitrile to the vinylcyclopropane 31 gave the nitrile 33, whichupon treatment with potassium metal afforded the decyanated product34. The preparation of the angular triquinane 34 completed theassembly of the carbon skeleton of subergorgic acid.Attempts to functionalize the allylic C-14 position in 34 withselenium dioxide, N-bromosuccinimide, and palladium acetate wereunsuccessful, and a lengthier sequence had to be developed. The alkene34 was epoxidized, and subsequently rearranged upon treatment withbromomagnesium N-cyclohexyl-N-isopropylamide to give the allylicalcohol 35. As expected, the transformation of alcohol 35 to thechloride 36 was accompanied by an allylic rearrangement and byhydrolysis of the ketal function. A formal synthesis of subergorgicacid was completed by oxidation of the chloride 36 to the aldehyde 37.11Surprisingly, the data obtained from the 1H NMR and IR spectra and themelting point of the aldehyde 37 were different from those previouslyreported.13 Nonetheless, oxidation of the aldehyde 37 gave (±)-subergorgic acid, spectroscopically identical with the natural product.1.3.4 Synthetic Studies Towards the Synthesis of (±)-Subergorgic Acid(8) by M. Crimmins and coworkersA recent synthetic study towards the preparation of subergorgicacid was published by M. Crimmins.16 The approach by Crimmins' groupis based on a free-radical reduction-fragmentation reaction of a[4•5.5•51 fenestrane, of general structure 38.X= OC(S)SMe, OC(S)0PhY=o, (0)b38A strategy for the preparation of such fenestranes, involving anintramolecular photocycloaddition, was developed earlier.17n -Bu3SnH (1.0 eq.)Benzene, 80 °C 39^40Scheme 51 2Crimmins' approach had already been successfully applied to thetotal synthesis of (±)-silphinene (40) (Scheme 5).18 However, whenthe radical precursor 41 was subjected to the same reaction conditionsthe expected triquinane product was not isolated. Instead, the ringexpanded product 46 was obtained (Scheme 6).OC(S)0Ph,5=0n -Bu3SnH, AIBNBenzene, A63%Scheme 641 46The proposed mechanism for the formation of 46 is shown inScheme 7. Reaction of 41 with the tributyltin radical generates thecyclobutylcarbinyl radical 42, which fragments to produce a primaryradical 43. This latter species then undergoes cyclization to producethe cyclopropyl alkoxy radical 44. The radical species 44 rearrangesto the more stable secondary radical 45, which is in turn reduced withtributyltin hydride to provide the ring expanded product 46.In accordance with the proposed mechanism the methyl xanthate47 provided the cyclohexene 48. In contrast, the ketal 49 lacking a 7C-bond adjacent to the intermediate primary radical, undergoes a simplefragmentation to produce the triquinane 50 (Scheme 8), which may bea suitable precursor for the synthesis of (±)-subergorgic acid (8).n -Bu3SnH, AIBNCO2Me  Benzene, A-Do-94%^ CO2Me13 •45=04 204 1 43/451-0"4 6^ 45^ 44Scheme 7Although 46 was not the desired intermediate, it is similar instructure to the alkene 18, which was converted to subergorgic acid bylwata and coworkers. Furthermore, use of an appropriate free radicalprecursor should provide 18, thus accomplishing a formal synthesis ofsubergorgic acid.47OC(S)SMen -Bu3SnH, AIBN$0•1 Benzene, Afr --01^82%4849 50Scheme 81 41.3.5 Enantioselective Total Synthesis of (-)-Subergorgic Acid (8) byL. Paquette and coworkersThe first enantioselective total synthesis of (-)-subergorgic acid(8) has been accomplished by Paquette and coworkers (Scheme 9).19Their approach employed the readily accessible 2-methyl-1,3-cyclopentanedione (51) as the starting material. Alkylation of 51 with3-bromo-2-methylpropene gave the dione 52. This compound wasstereoselectively reduced with sodium borohydride in methanol, and thecorresponding racemic alcohol was converted to the chloroacetate.Enzymatic hydrolysis with Lipase P-30 of the racemic chloroacetateprovided the ketol 54 in 50% yield and 100% enantiomeric purity, andthe keto ester 53 in 45% yield (100% enantiomeric purity).The desired enantiomer 53, was converted into the enone 55 via afour-step sequence of reactions and in 52% overall yield.Copper(I)-catalyzed conjugate addition of the Grignard reagent to55 in the presence of TMSCI and DMAP gave the trimethylsilyl enolether 56. Treatment of 56 with titanium tetrachloride indichloromethane provided the cyclized products 57 as a mixture ofdiastereomers in 63% overall yield.The mixture of diastereomers was irradiated in presence ofphenyliodonium diacetate and iodine in benzene to provide the ketoketal 58 in 75% yield. The keto function in 58 was reduced to providethe alkane 59 by means of a three-step procedure and in 43% overallyield.The ketal 59 was hydrolyzed, and the ketone 60 was converted tothe corresponding enol triflate by treatment with potassium1 5bis(trimethylsilypamide and N-phenyltriflimide in the presence ofTMEDA in THF. The enol triflate was reduced to the correspondingalkene in a palladium-catalyzed reaction involving formic acid and tri-n-butylamine. The alkene thus obtained was deprotected upon exposureto hydrofluoric acid to provide the alcohol 61.Steric hindrance present in 61 resulted in some difficulties duringthe oxidation step. Several reagents (Swern's, Jones', PCC on Celite ormolecular sieves) failed to provide satisfactory results. However, thealcohol function was oxidized to the corresponding ketone in excellentyield (90%) using PCC on alumina. The a-methoxycarbonyl group incompound 62 was introduced according to Mander's procedure.2°Conversion of a ketone function in 62, into the corresponding enonemoiety was found to be difficult. Indeed, oxidation of 62 with DDQ inrefluxing benzene produced 63 in very low yield. Oxidation ofcompound 62 under milder conditions, DDQ in the presence of silica gelin benzene at room temperature, gave the enone 63 in 67% yield.Stereoselective conjugate addition of lithium dimethylcuprate to63 in the presence of DMAP and TMSCI in THF provided 64 as a singleisomer.The (3-keto ester function of 64 was converted to an ad3-unsaturated ester moiety (see 65) via a procedure previously used byCrimmins in the synthesis of pentalenic and deoxypentalenic acids.21In order to set the functionality for the introduction of the C-4methyl group by conjugate addition, an allylic oxidation of 65 wasrequired. However, presumably due to steric hindrance, the use of theusual reagents to affect such a transformation failed to produce thedesired compound 71, and instead caused decomposition of theOTBDMS^ OTBDMSTiCI4, CH2Cl21^1-(63% from 55)TMSOHO.,...,....0.,&)56^57165 1^521)NaBH4, Et0H (89%)12) CICH2COCI, Py, DMAP (97%)3) Lipase P-301)K2003, Me0H, THF (93%)2)TBDMSCI, lmidazole, DMAP,DMF, 60°C (88%)OTBDMS3) 03, CH2Cl2, Py;Zn, AcOH (86%)^04) t-BuOK, t-BuOH, r t (74%)-4Cl + H5 5^53^541 coyMgBr, CuBr2t/e2S,TMSCI, DMAP0I Ph1(0Ac)2, 12,hv, C6F16, A (75%)1) LiAIH4i......_ OTBDMSC.---t--1^..,12) MeS02C1, DMAP, Py3) LiEt3BH, THF, A(43% overall yield)\-0 —59 5 8Scheme 9OTBDMSPPTS, AAcetone-H20 (85%1 59601) KN(SiMe3)2, TMEDA,T1-1F, Tf2NPh2) HCOOH, n-Bu3N,Pd(OAc)2(PPh3)2, DMF3) HF, CH3CN, H20(84% overall yield)2 OH61NaBH4, Me0H,Me0H, -50°CCO2C H3:CO2C H3171 1) PCC, Al203,CH2Cl2 (90%)2) LDA, HMPA, ether,CH3OCOCN (71%)C 02C H3DDQ, Si02,C6H6, rt (67%) CO2C H3 63^62I Me2CuLi, DMAP,Me3S1CI, THF (74%)1) NaBH4, Me0H, 0°C (73%)2) MeS02C1, DMAP, Py (100%)CO2CH3 3) Al203 (basic), ether (87%) CO2CH364^651 PDC, Celite, t-BuO0HC6H6, rt (35%)CO2C H3 +HO'(79%)^ (14%)67 68^66Scheme 9 cont.186 7NSPh, Su3P, CsHs,rt (79%)CO2C H 3 PhS69(1) Na104, Me0H, H20 (97%)2) (Me0)3P, Et2NH, Me0H, A (91%)zMn02, CCI4,CO2CH3 r t (96%) CO2C H37 1^70I 1) Me2CuLi, ether, -10°C (88%)2) KOH, Me0H, H20, rt (93%)(-) - 8Scheme 9 endsubstrate. Alternatively, oxidation of 65 with PDC in the presence ofCelite and t-butylhydroperoxide produced 66 in satisfactory yield(35%, 69% based on recovered 65).The enone 66 was transposed into the enone 71 via a lengthyprocedure, involving five steps and in 53% overall yield.Chemoselective conjugate addition of lithium dimethylcuprate tothe enone 71 produced (-)-methylsubergorgate as a single isomer,which upon hydrolysis afforded the (-)-subergorgic acid (8).The sequence 66—)71 illustrates the difficulties encountered inthe introduction of C-2 keto group. The sequence 18-428 (Scheme 3,page 7) applied by the lwata's group also involved five steps and19proceeded in 47% yield. The more conventional sequence 18-420(Scheme 1, page 5) introduced the desired keto function and the C-4methyl group in three steps (73% yield), but with a modeststereoselectivity. Wender's group prepared the precursor 30 whichalready contained the C-4 methyl substituent and the required C-2carbonyl function (protected as a ketal moiety) (Scheme 4, page 9),and thus avoided later problems connected with functionalization ofthe A-ring (structure 8, page 3). However, due to steric congestioncaused by the generation of three contiguous quaternary centers duringthe cycloaddition, as well as sensitivity of the ketal function to thereaction conditions, the desired product 31, was obtained in only 15%yield. Crimmins' group did not report any attempt to introduce the C-2keto function.1.4^Retrosynthetic AnalysisIntroduced and developed by Corey,2 the retrosynthetic, orantithetic, analysis is a logical method for theoretically disconnectingthe target molecule into smaller fragments. Starting with the targetmolecule, bonds between carbon atoms are theoretically disconnected,in a process reverse of a synthetic reaction. Simpler fragments, thusobtained had been called synthons. Recently, the term synthon has beenapplied and misused to denote any intermediate, including the actualreagent (synthetic equivalent of a synthon). To alleviate the problem,Corey has introduced a more descriptive term retron instead ofsynth on •2b20The process of disconnecting the target molecule into smallerfragments is repeated until simple commercially or otherwiseavailable precursors are obtained. Steps reverse of synthetic reactionsare called transforms.In the course of an actual synthesis, a function obtained is often inthe wrong oxidation state, possesses the wrong polarity or isotherwise unsuitable for the next transformation. It is then necessaryto conduct functional group interchange (FGI), and introduce appropriatefunctionality for the next conversion.1.5 Previous WorkAn access to several triquinane natural products has been achievedby means of bifunctional conjunctive reagents. According to Trost, 22"The term conjunctive reagent is introduced to focus on those reagentswhich are simple building blocks that are incorporated in whole or inpart into a more complex system and to differentiate them fromreagents that operate on but are not normally incorporated into asubstrate." Therefore, a bifunctional conjunctive reagent is a reagentwith two reactive sites that is incorporated into a substrate moleculewith the exception of heteroatoms.Among the numerous bifunctional reagents developed as a result ofextensive research by a number of groups, the following are chosen forthe purpose of illustration.ad72OHrTMS7 3HBr (anhyd.) TBDMSCI77 763 steps(±)-hirsutene7 9I 1) Et3BzN+CI7KF.2H202) -OH —0– -OTS8 0(Me3Si)2NLi, etherN^.OH^ OTBDMS751 BuLi, ether-100°COTBDMS7 4OTBDMSF3B.Cu Cu(I)I.P(NMe2)3, LiBF3-Et20 (2 eq)-• HI8 121The reagent 77, a synthetic equivalent of the synthon 72, wasdeveloped by Magnus' group23 and was applied in the total synthesis of(±)-hirustene (Scheme 10). The starting material, 4-(trimethylsilyI)-3-butyn-1-ol (73), can be easily prepared from 3-butyn-1-ol,according to procedure of Boeckman.24 Reaction of 73 with anhydroushydrogen bromide provided the vinyl bromide 74. The alcohol functionof 74 was protected as the t-butyldimethylsily1 ether 75 and halogenmetal exchange with t-butyllithium gave the vinyllithium 76. Theintermediate 7 6 was treated with copper(I) iodide-hexamethylphosphorous triamide complex to give the vinylcopperreagent 77.Scheme 1082 83 84 a-cDBU, Benzene, e1) IMgBr-Cul2) Me3S1CI, Et3NOSiMe3Pd(OAc)2,Na0Ac22The 1,4-addition of the vinylcopper reagent to the enone 78 providedthe ketone 79. The latter substance was converted to the tosylate 80.The cyclized product 81 was obtained from treatment of compound 80with lithium bis(trimethylsilyl)amide.The work carried out by lkegami (Scheme 11)25 and Pattenden(Scheme 12)26 illustrates the increasing role of bifunctional reagents.84 a^84 b^84 cScheme 11Ikegami's group used copper (I) catalyzed addition of 3-butenylmagnesium bromide to 3-methyl-2-cyclopenten-1-one (82),followed by trapping of the intermediate enolate with trimethylsilylchloride to provide the trimethylsilyl enol ether 83. Palladium acetateinduced cyclization of 83 provided three diquinane isomers 84a-c.Interestingly, the major isomer was the diquinane 84c with anendocyclic bond in the 0,7-position with respect to the carbonyl group.Furthermore, DBU-catalyzed isomerization in refluxing benzeneconverted the mixture of products to the compound 84c.8 2 8 5 86C U^OAc snclis,moist cH2ci223The Pattenden approach utilized 1,4-addition of lithium bis(3-methy1-3-butenyl)cuprate to 3-methyl-2-cyclopenten-1-one, followedby trapping of the resulting intermediate enolate with acetic anhydride.Cyclization of 85 was accomplished by treatment with tintetrachloride in moist dichloromethane to provide the compound 86(Scheme 12).Scheme 12The bifunctional reagents 91 and 92, which have been developed inour laboratory, correspond to the 1-butene d2,a4-synthon 72 and, ineach case, include both a nucleophilic and an electrophilic centerwithin the same molecule. The required precursor to the bifunctionalreagents was prepared using organotin methodology.27 Reaction of 3-butyn-1-ol (87) with (trimethylstannypcopper(1)-dimethylsulphidecomplex provided 3-trimethylstanny1-3-buten-1-ol (88). Alcohol 88was subsequently converted to the corresponding chloro derivative 89,by treatment with triphenylphosphine in carbon tetrachloride (Scheme13). Transmetalation of 89 with methyllithium in THF at -78 °Cprovided the vinyllithium 90, and addition of magnesium bromide-etherate complex converts the vinyllithium intermediate to thevinylmagnesium bromide reagent 91. In the presence of a catalyticamount of copper bromide-dimethyl sulfide complex the reagent 9187 88BrMgCI^ CIMgBr2-Et2091^ 90^92Scheme 1389CuCN Li(CN)Cu24undergoes 1,4-conjugate addition to enones. Alternatively, the additionof copper cyanide to the vinyllithium 90 provides the organocupratereagent 92. The organocuprate reagent thus formed in situ is asynthetic equivalent of the bifunctional synthon 72. While there is asimilarity between the reagent 77 (Scheme 10, page 21), and thereagents 91 and 92 used in our work, the former reagent is lessefficient. After the first step (i.e. 1,4-addition), the protectedacceptor site in 77 must undergo two additional transformationsbefore annulation can be completed.OH OH^ CIPh3P, CCI4^Me3SnMe3SnCuBr, THF Me3SnThe reagent 91 undergoes efficient Cu(I)-catalyzed 1,4-addition toenones such as 93 to provide enolate anions such as 94 (Scheme14).28 The latter species can be cyclized by adding a suitable additive(HMPA is the most commonly used). Alternatively, the enolate 94 canbe protonated to give the chloro ketone 95. The compound 95 wascyclized upon treatment with potassium hydride in THE. Using eitherCI94/Om 1 HMPA025protocol, the cyclized product 96 is formed cleanly and in a goodoverall^yield.^The^naturally^occurring^triquinanes^(±) -9(12)ca pnellene28, (±)-pentalenene29, (±)-methyl cantabrenonate3° and(±)-methyl epoxycantabronate3° have already been successfullyprepared via routes in which the described annulation sequence played akey role.CIBrMgII^, CuBr-Me2S 9193^CIBrMg, CuBr-Me2S;work-up91 95^ 96Scheme 141.6 Research ObjectivesAs mentioned earlier, subergorgic acid (8) is a structurally uniquesilphiperfolene sesquiterpenoid, in that it is the only one having a ketofunction at 0-2.^Successful total synthesis have confirmed thepreviously assigned structure.5,11^Nonetheless, a shorter total26synthesis, which would produce subergorgic acid in a good yield,remains a challenge.In a retrosynthetic sense, access to the triquinane skeleton ofsubergorgic acid may be possible based on the describedmethylenecyclopentane annulation sequence. Furthermore, the desiredketo function at C-2 can be obtained by the oxidation of the methylenegroup derived from the bifunctional reagent 91. Thus, it was decidedto attempt the synthesis of (±)-subergorgic acid (8) via a syntheticroute which involves the annulation sequence as its key transformation.:C 02C H3BrMgCI8^918 989712V130:^ 0H + 100101 a^d7299272 DISCUSSION2.1^Retrosynthetic Analysis of (±)-Subergorgic Acid (8)The retrosynthetic analysis of (±)-subergorgic acid (8), as depictedin Scheme 15, was based on the methylenecyclopentane annulationmethodology, which would allow the assembly of an angular triquinaneskeleton. Once the skeleton had been assembled, the functionalitiesand substituents were to be introduced.Thus, disconnection of the carbon-carbon bond between 0-10 andC-14 in (±)-subergorgic acid (8) would lead to the diketone 97.Disconnections of the carbon-carbon bonds between C-4 and 0-12,between C-8 and C-13, and between C-11 and 0-15 would produce thedienedione 98, which should be accessible from the tricyclic keto ketal99 via functional group interconversions (FGI's).Scheme 15o109 110CI1) /---/MgBr , CuBr.Me2S912)KH, THE .s* H28Disconnections between C-1 and C-2 and between C-4 and C-5 inthe key intermediate, tricyclic keto ketal 99, leads to the bifunctionalsynthon 72 and the enone ketal 100. A synthetic equivalent of thebifunctional synthon 72 is the Grignard reagent 91 (Scheme 13, p 24),and the enone ketal 100 should be accessible from the known ketoketal 101.2.2 The Synthetic PlanIn accordance with the retrosynthetic analysis described above,the following synthetic plan was devised (Scheme 16).The readily available keto ketal 101 was chosen as startingmaterial. Saegusa oxidation31 of 101 via the corresponding enol silylether, was expected to provide the enone ketal 100.It was anticipated that the copper(I)-catalyzed reaction of thereagent 91 with the enone ketal 100, followed by intramolecularalkylation of the intermediate chloro ketone, would provide thetricyclic keto ketal 99. The methylenecyclopentane annulationsequence on the structurally similar enone 109 had been successfullyaccomplished in our laboratory (Scheme 17).29Scheme 1729i LDA-TMSCI,• Et3N, THFt9 8: 1) LDA, THE12) MelY105 106excess Me2CuLi,Et20; NH4CI-H20^ -.-:1 0 11) TMSI, Et3N, CH2Cl22) Pd(OAd)2, CH3CN^-11.-sk^.r7r\. ,C=0 --0.-- /CFI2lis^Ili,H0100CI^r'1) CMgB912) KH, THFt, CuBrMe2STHF102■ sssH1 0399HH3O+Cl-^ -0.-^........)1.00104%Pd(OAc)2 (2 eq.),0 CH3CN ^. •-Nal- OTMS +OTMSKOH/Me0H■11-^107897: 1) LDA, THE; PhN(SO2CF3)21 2) Pd(PPh3)4, CO, Me0H1CO2Me108Scheme 163 0Deoxygenation of the C-6 keto function in the keto ketal 99 wouldproduce the tricyclic ketal alkene 102. Barton's deoxygenationprocedure, involving a xanthate as an intermediate, is a method ofchoice to accomplish such a transformation.32Oxidative cleavage of the double bond in 102 would give the ketoketal 103, thus solving the problem of the introduction of the C-2carbonyl group (pp 18-19). Reagents commonly used for such atransformation in polyquinane chemistry are ozone,33 osmiumtetroxide-sodium periodate34 and ruthenium tetroxide-sodiumperiodate.35Acid-mediated deprotection of the keto ketal 103 would give thetricyclic diketone 104.Treatment of 104 with LDA followed by TMSCI could produce twopossible regioisomeric bisenol silyl ethers 105 and 106. It wasenvisioned that the double Saegusa oxidation31 of bisenol silyl ether105 would yield the dienedione 98. Based on an inspection ofmolecular models, it was concluded that the formation of the desired105 would be favoured in a kinetically controlled reaction (Scheme18). The presence of the A-ring enolate moiety, in the intermediate111, should prevent formation of the undesired enolate 113, due tosteric hindrance and electrostatic interaction with an approachingbase. Trapping of the "kinetic" enolate 112 with TMSCI would providethe bisenol silyl ether 105. Alternatively, one could usethermodynamically controlled reaction conditions to favour theformation of the bisenol silyl ether 105. Once formed the enolate 112should be more stable than 113 (Scheme 18), primarily due to aninteraction between the p-hydrogen at C-7 and a-hydrogen at C-9 in31113. The corresponding interaction in the enolate 112, i.e. betweenthe hydrogen at C-5 and the 13-hydrogen at C-11, is less severe.Furthermore, the distance between the angular proton at C-8 and theenolate oxygen at C-3 is shorter in 113 as compared to 112. Thus, thedienolate 11 2 was expected to be both kinetically andthermodynamically favoured. 111 1131121 TMSCI ITMSCIH106Scheme 18Removal of the most acidic C-11 proton in dienedione 98, in akinetically controlled reaction, followed by treatment withiodomethane should provide the compound 107. The relativeconfiguration of the newly introduced C-11 methyl group is expected tobe as drawn. A literature survey did not provide any examples of3 2alkylation on a substrate similar to the dienedione 98. Alkylations ofthe saturated diquinanes36,37 have shown that the approach of analkylating agent from the less hindered convex a-face should bepreferred, even in the presence of a methyl substituent at theneighboring angular position (Scheme 19).CI:._.0.\114NaH, Mel 115CHSRCli=0 Li, NH3 co118116 117Scheme 19The double addition of lithium dimethylcuprate to the dienedione107 should provide the diketone 97. The addition of both methylgroups in 97 should proceed to give the desired relativestereochemistry as shown in Scheme 16. Literature precedentsindicate that lithium dimethylcuprate addition provides cis-f useddiquinanes," and an addition to A-ring of enone 107 would take placefrom the less hindered convex face (Scheme 20, see also Scheme 3, p7).3933Me2CuLi, Et20119^120Me2Culi^NW. 121^122Scheme 20Kinetically controlled reaction of the diketone 97 with 2.2 equiv.of a base should provide the corresponding bisenolate. The siteselective transformation of the sterically less hindered C-10 enolatefunction of the bisenolate into a vinyl triflate moiety, followed by apalladium-catalyzed methoxycarbonylation," would produce methylsubergorgate 108. Hydrolysis of methyl subergorgate (108) upon basetreatment would give the target subergorgic acid (8).Some difficulties were anticipated in the execution of the planoutlined above. Specifically, it was felt that the double Saegusatransformation, i.e. from 104 --> 98, as well as the double lithiumdimethylcuprate addition, i.e. from 107 -4 97 (Scheme 16), could beproblematic. Therefore, an alternative route was devised.The following synthetic sequence was developed so that, should itbe necessary, these transformations could be conducted sequentially(Scheme 21). The plan was modified so that after the preparation ofthe keto alkene 123 from the ketal alkene 102, the difference inchemical reactivity between the keto and the alkene functions could be34exploited. Saegusa conversion of the keto alkene 123 would producethe keto diene 124. Generation of the "kinetic" enolate from 124 andsubsequent alkylation with methyl iodide would give 125. Lithiumdimethylcuprate addition followed by the previously described McMurryprocedure," would be expected to provide the compound 126.Chemoselective cleavage of the exocyclic double bond, followed by aSaegusa transformation, should provide the intermediate 71, whichwas recently converted to subergorgic acid by the Paquette's group.19H3O+Ci1)LDA-TMSCI, THF2) Pd(OAc)2, CH3CN0^-0.-102 123 1241: LDA, THF; Meltae.....1) Me2CuLi, THF2) LDA, THF, PhN(SO2CF3)23) Pd(PPh3)4, CO, Me0HCO2Me ...... ^^126^ 1251))^--IN-^02) TMSI, Et3N, CH2Cl23) Pd(OAc)2, CH3CNCO2Me 2 steps (Scheme 9) -MIN- 87 1Scheme 21CO2MeHOCO2Me CO2MeOHNaOH, Me0HrefluxCHO +CHOo=C0e)(oHO—\#..,HO-1\ , p-Ts0H,benzene, reflux....." ^0^01 aq. HCI, AcOHreflux352.3 Studies Toward a Total Synthesis of (±)-Subergorgic Acid2.3.1 Preparation of the Starting Materials 89 and 101The diketone 1 2 9 was prepared from dimethyl 1,3-acetonedicarboxylate (127) and glyoxal according to the Weiss andCook's procedure.41 The substrate 129 was converted into the ketoketal 101, using a procedure developed previously in our laboratory(Scheme 22).42CO2Me^ CO2Me CO2Me127 128101^ 129Scheme 224-Chloro-2-trimethylstanny1-1-butene^(89) was synthesizedfollowing a well established method from our laboratory (Scheme 13,page 23).27CISnMe3893 62.3.2 Preparation of the Enone Ketal 100The known keto ketal 101 was converted into the enol silyl ether130, by treatment with trimethylsilyl iodide and triethylamine indichloromethane." The compound 130 was oxidized with palladiumacetate in acetonitrile31 to give the enone ketal 100 in 72% overallyield (Scheme 23).H^TMSI, Et3N,^H^Pd(OM)2,0 _Ft...\10 —V CH2Cl2TMSOCH3CN0WO—/\H^ H101 130 100Scheme 232.3.3 Preparation of the Tricyclic Ketone 99With the enone 100 in hand we were prepared to undertake one ofthe key transformations of the sequence, namely the assembly of thetriquinane skeleton.In order to optimize the efficiency of methylenecyclopentaneannulation sequence, the Grignard reagent 91, as well as the lower(92) and the higher (131) order cuprate reagents were prepared from4-chloro-2-trimethylstanny1-1-butene (89) via 2-lithio-4-chloro-1-butene (90). 2-Lithio-4-chloro-1-butene (90) was generated by thetransmetallation of 4-chloro-2-trimethylstanny1-1-butene (89) withmethyllithium (Scheme 24).37CIit■AgBrCI1) Melj (1 eq.)2) MgBr.B20SnMe38 9^c°14149‘ .Cl/C4114°Elp.) CICu(Me)(CN)Li2Scheme 24Usually, one equivalent of methyllithium is added to a solution ofthe vinylstannane reagent to provide the corresponding vinyllithiumreagent. If two equivalents of methyllithium are used, an equimolarsolution of the vinyllithium and methyllithium is obtained. Addition ofcopper(I) cyanide to this solution generates a higher order cupratereagent. Such reagents readily undergo 1,4-conjugate additionreactions, generally transferring a specific group selectively. "Dummy"ligands such as the cyano and alkyne groups are not transferred." Themethyl group in higher order cuprates is considered to be a "dummy"ligand as often vinyl or other alkyl groups are transferredpreferentially. Thus, we expected reagent 131 to transfer the vinylgroup selectively. To our surprise, the methyl group transferred withequal ease to the enone 100, producing a 1:1 mixture of the chloroketone 132 and the 1-methyl ketone 133 (Scheme 25). A literaturesearch has revealed that although in most cases a vinyl group istransferred preferentially, in a few examples competitive transfer of9113138the methyl group was observed.45 The reason for such an anomalousbehavior is not known. Attempts to suppress the side reaction usingdifferent reaction conditions failed. Therefore, the use of the higherorder cuprate reagent 131 was abandoned.We next tried using the lower order cuprate reagent 92. Thisreagent underwent efficient 1,4-addition to the ketal enone 100,providing chloro ketone 132 in good yield. However, reproducibility ofthe reaction was poor as several trials led to the recovery of largequantities of the starting ketal enone 100. This leads one to speculatethat the stability of the vinylcuprate reagent 92 may be questionable.D<H91 or 92^E^0^ °WO<CI 132131^133^132^(1 1)Scheme 25It was decided to investigate a copper(I)-catalyzed 1,4-addition ofthe Grignard reagent 91 to the enone 100. Thus, treatment of thevinyllithium 90 with magnesium bromide-etherate complex, provided100139the corresponding Grignard reagent 91. The Grignard reagent wassubsequently employed in the copper bromide-dimethyl sulfidecatalyzed 1,4-addition to the ketal enone 100, consistently providingthe chloro ketone 132 in good yield (77%).Incidentally, when reagents 91 or 92 were employed, a smallamount of the 1-methyl keto ketal 133 was isolated, indicating that asmall amount of methyllithium was present in the reaction mixture.Therefore, transmetallation of 4-chloro-2-trimethylstanny1-1-butene(89) with methyllithium does not proceed to completion and instead anequilibrium must have been established (Scheme 26). Studies byRoberge have confirmed the existence of such equilibria."CISnMe3+ MeLi CI+ Me4Sn8 9^90Scheme 26The IR spectrum of the chloro ketone 132 indicated the presence ofa five-membered cyclic ketone (1742 cm-1), a double bond (1638 cm-1),and a C-0 bond (1116 cm-1). The 1H NMR spectrum of 132 was assignedwith the aid of homonuclear correlation (COSY) experiments (Table 1).The singlets at 0.96 and 0.97 indicate the presence of gem-dimethylmoiety. Signals at 3.45 and 3.48 are due to the ketal methyleneprotons, and a triplet at 3.67 is assigned to the protons of the chloromethylene moiety. The olefinic protons exhibit signals at 4.91 and5.01.4 0132Table 1. 1H NMR (400 MHz, CDCI3) and COSY (200 MHz, CDCI3) data forthe chloroketone 132.H-x(assignment)1H NMR(400 MHz, CDCI3) 8COSY CorrelationsaH-4a or p 2.43 H-5H-5 2.89 H-4a or p,H-6« and 13H-6r3 2.36 H-5, H-6aH-6a 1.87 H-5, H-613ketal CH21s 3.45 & 3.48 H-16 & H-17H-16 & H-17 0.96 & 0.97 ketal CH2'S^.a) Only those COSY correlations that could be unambigously assignedare recordedAfter preparation of the chloro ketone 132 was made efficient, ourattention turned to the one-pot conversion of 100 to 99. It is knownthat the enolates obtained after conjugate addition can be trapped withelectrophiles, and that such reactions are aided by complexing agents.47Thus, after 134 was formed in situ (Scheme 27), subsequent additionof a complexing agent provided tricyclic keto ketal 99. The role of anadditive is to complex with the metal ion in the intermediate enolate134 and thus promote intramolecular alkylation of the carbanion. Theratio of cyclized product 99 to the uncyclized product 132 dependedon whether or not an additive was employed prior to warming up of the1 0 0CI1) SMgBr912) KH, THF, CuBrMe2STHF, -78°CCMgBr , CuBrMe2STHF, -78°C9 1^WO'^•CI141reaction mixture. Results are summarized in the Table 2. The bestresults were obtained when 2 equivalents of either HMPA or DMPU wereused as an additive. Due to the high toxicity of HMPA, DMPU was chosenas the additive in subsequent reactions. Under these conditions, theisolated yield of the cyclized product 99 was 81% and wasaccompanied by 4% of the uncyclized chloro ketone 132, which could beefficiently cyclized upon treatment with potassium hydride in THE.99Scheme 27Alternatively, the chloro ketone 132 could be isolated in 77%yield, and then cyclized in 94% yield upon treatment with potassiumhydride.42Table 2. Methylenecyclopentane annulation of the enone ketal 100 Entry^Additive^99/132a^yield of 99(%) (1) (none) 50/50 74b(2) TMEDA (4 eq.)^90/10^ 75(3) HMPA (2 eq.)^95/5 80(4) DMPU (2 eq.)^95/5^ 81a) GLC ratio; b) Isolated yield of 99 after treatment of a mixture withKH/THF.The IR spectrum of the ketone 99 indicated the presence of a five-membered cyclic ketone (1741 cm-1), a double bond (1651 cm-1) and aC-0 single bond (1119 cm-1). The 1H NMR spectrum (400 MHz, CDCI3)(Figure 1) of the ketone 99 is consistent with the proposed structure.The signals were assigned with the aid of homonuclear correlation(COSY, 400 MHz CDCI3) experiments (Table 3), as well as decouplingexperiments (400 MHz) (Table 4). The doublets at 2.19 and 2.32 aredue to two isolated protons at the C-11. The olefinic protons at C-12exhibit resonances at 4.97 and 5.02, while the angular protons at C-8and C-5 exhibit signals at 2.57 and 2.61, respectively. The ketal groupremained intact as evidenced by the presence of singlets at 0.90 and0.92 which are due to the protons at the two geminal methyl groups C-16 and C-17. They exhibit long range coupling with the signals at 3.40and 3.47, due to the four ketal methylene protons at C-12 and C-14.I^•• •T • '• '1 •" • 1.5.0^4.5^4.0^3.5^3.0^2.5^2.0^1.5^1.0^.5Fp"Figure 1. The 1H NMR Spectrum (400 MHz, CDCI3) of the keto alkene 99.44Table 3. 1H NMR (400 MHz, CDCI3) and COSY (400 MHz, CDCI3) data forthe keto alkene 99.•H-x(assignment)1H NMR(400 MHz, CDCI3) 8COSY correlationsH-4a & AH-9a or p1.80-1.96 H-5, H-8H-5 and H-8 2.57 & 2.61 H-4«. & A, H-7a & p,H-9a & AH-7a or p 2.47 H-7p or a, H-8ketal CH2's 3.42, 3.46 & 3.50 H-16 & H-17H-16 & H-17 0.90 & 0.93 ketal CH2'sa) Only those COSY correlations that could be unambigously assignedare recordedTable 4. 1H NMR (400 MHz, CDCI3) and decoupling experiments (400MHz CDCI data for the keto alkene 99.irradiated^signals observed signalsassignmentH-x1H NMR (400MHz, CDCI3)s ppm (mult. J, H-x) mult.^afterirradiationH-4« and p(H-9 alsoirradiated)1.80-1.96 2.18-2.42 (m, 4H,H-3a and p, H-7, H-9)2.57 (m, H-8)2.61^(m, H-5)sharpened mdd (J=9.0, 3.0)sH-11« or 0 2.19 2.32 (m, H-11p or a) sH-5 & H-8 2.57 and 2.61 1.80-1.96 (m, 3H,H-4a & fl ,H-9a or p)2.18-2.42 (m, 4H,H-3a and fi , H-7, H-9)sharpened msharpened mH-12_4.98 and 5.01 2.18-2.42 (m, 4H,H-3a and p, H-7, H-9)sharpened m452.3.4. Preparation of the Alcohols 135 and 136Extensive use has been made of the Barton-McCombiedeoxygenation for the removal of secondary hydroxyl groups inpolyquinanes.23,29,48 The alcohols are easily converted in a good yieldto the corresponding xanthates. In order to deoxygenate the tricyclicketo ketal 99, via the Barton-McCombie procedure,32 the correspondingalcohols 135 or 136 are required as precursors. Ketone 99 wasreduced by sodium borohydride to provide a mixture of the epimericalcohols 135 and 136. These were converted to the correspondingmethyl xanthates for our initial trials (vide infra).Later in our work, in order to improve the yield of thedeoxygenation sequence, the corresponding phenyl thionocarbonateswere investigated instead of the xanthates 137 and 138. Results fromearlier work in our laboratory indicated that the stereochemistry ofalcohols may have an effect on the yield and ease of preparation ofphenyl thionocarbonate derivatives, and subsequently on the yield ofdeoxygenated product.43 H LiAIH4,0°CL-Selectride6,-78 °C^HOHHO135^99^136Scheme 28Several reducing agents were investigated in order to obtain, in apure form, each of the stereoisomeric alcohols 135 and 136. Resultsof the reductions are summarized in the Table 5. The best results46were obtained when lithium aluminum hydride and L-Selectride(Aldrich) were used as reducing agents (Scheme 28). Isolated yieldsof the isomeric alcohols 135 and 136 were 97% and 92%, respectively.Table 5. Reduction of the tricyclic ketone 99Entry Reducing Agent 135/136a Yield^(%)(1) LiAIH4 >981<2 97c(2) NaBH4 75/25 9713(3) DIBAL-H 20/80 96b(4) L-Selectride 4/96 92Ca) 1H NMR ratio; b) Isolated yield of the mixture of epimeric alcohols;c) Isolated yield of the major epimer.2.3.5 Preparation of the Methyl Xanthates 137 and 138The Barton-McCombie procedure required the conversion ofalcohols 135 and 136 to their corresponding methyl xanthates 137 and138An isomeric mixture of alcohols 135 and 136 (3:1 ratio), wasdeprotonated with potassium hydride in THF. Treatment of thecorresponding mixture of potassium alkoxides with carbon disulfidefollowed by methyl iodide, gave (78%) a mixture of the methylxanthates 137 and 138, in a ratio of approximately 3:1 (as determinedfrom the 1H NMR spectrum of the isolated product) (Scheme 29).47HO1) KH, THF2) CS2; MelMeSC(S)0 135/136 137/138Scheme 292.3.6 Reduction of the Methyl Xanthates 137 and 138The mixture of methyl xanthates 137 and 138 was reduced withtributyltin hydride in refluxing benzene in the presence of a catalyticamount of AIBN as a radical initiator (Scheme 30). The deoxygenatedproduct 102 was obtained in 50% yield.MeSC(S)0n-Bu3SnH, benzene,AIBN, 80°C).137/138^102Scheme 30The reason for the relatively low yield is probably due to the competingreactions in which the intermediate 140 can be involved (Scheme 31).Extensive studies on Barton-McCombie deoxygenation have establisheda radical chain mechanism.5° Addition of a tributyltin radical to thethiocarbonyl bond provides the adduct radical 140 which can thenundergo 0-fragmentation via pathway A to generate an alkyl radical andthe compound 141. The alkyl radical then abstracts a hydrogen atomfrom tributyltin hydride propagating the free radical chain reaction.Alternatively, the intermediate 140 can undergo 0-fragmentation of48the methyl-sulfur bond (pathway B) to provide a methyl radical andcompound 142. In this case the methyl radical abstracts a hydrogenfrom tributyltin hydride to propagate the chain reaction. Compound142 hydrolyzes during work up to provide the starting alcohol (pathwayC). Alternatively, it may undergo further reduction (pathway D) toprovide the hemithioacetal 144. The existence of pathway D has notbeen confirmed by mechanistic studies, and an alternative suggestionis that the compound 144 may arise from the participation of analternative pathway in the reduction of the xanthate 139.(B)S^ SSnBu3)..R *0AS + Bu3Sn.^R *0 S139 140S+ Me.R '0A SSnBu3142 1 (C)ROH\D)RH + Bu3Sn.Bu3SnH^SSnBu3R+ A0 S141R -0 SSnBu3143/ROCH2SH144Scheme 31From a synthetic point of view, the low yield obtained in thedeoxygenation of xanthates 137 and 138 was not satisfactory. Inorder to improve yield of Barton-McCombie deoxygenation procedure,Robins and coworkers investigated the use of a number ofthionocarbonate derivatives of the corresponding alcohols.51 The49phenyl thionocarbonates have shown to be suitable intermediates forthis transformation.It is claimed that the main advantage in using phenylthionocarbonates instead of methyl xantates in a such deoxygenationprocesses is that the former substrates limit side reactions (Scheme32). Phenyl thionocarbonates have an unreactive phenyloxy functioninstead of the thiomethyl group. Thus, the pathway B (Scheme 31)does not participate in evolution of the intermediate 146. The onlypathway available is the p-fragmentation between the alkyl group andone of the oxygen atoms. The bond between the phenyl group and theother oxygen is stronger and thus does not fragment under the reactionconditions.SR *0AO' Ph + Bu3Sn.145 SSnBu3RA Ph*0 • 0'146iSSnBu3Bu3SnHR. + 0A0-Ph147RH + Bu3Sn.Scheme 32Therefore, it was decided to investigate deoxygenation of thecorresponding phenyl thionocarbonates 148 and 149.HPh0C(S)0W(0)(^HHs^ ‘... 0^Ph0C(S)0L148502.3.7 Preparation of the Phenyl Thionocarbonates 148 and 149The phenyl thionocarbonates 148 and 149 were prepared in 76%and 71% yield, respectively, from the reaction between thecorresponding alcohols 135 and 136 and phenyl chlorothionoformate,in the presence of DMAP (Scheme 33).51Ph0C(S)C1, DMAP,.• i^..-)<Yl^ CH3CN, it^ Y1Y2' NiS^0135: Y1=-OH; V2= -H^148: Y1= -0C(S)0Ph; Y---H (71%)136: Y1= -H; Y2= -OH 149: Y1= -H; 4.- -0C(S)0Ph (76%)Scheme 332.3.8 Reduction of the Phenyl Thionocarbonates 148 and 149Following the deoxygenation procedure developed by Robins et al.,51the phenyl thionocarbonates 148 and 149 were reduced in refluxingbenzene with tributyltin hydride and a small amount of AIBN, as aradical initiator (Scheme 34). The yield of the alkene ketal 102 thusobtained was 87% from 148 (83% from 149), and, thus, the overallyield for the three step deoxygenation procedure via the phenylthionocarbonate 148 was 60% (58% via 149). This is a significantimprovement over the deoxygenation procedure utilizing the methylxanthates, which provided the tricyclic ketal 102 in only 37% overallyield.51H n-Bu3SnH, benzene,AIBN, 80°CHWe0)< ^INN-148:Y1= -0C(S)0Ph;Y-H149:Y1= -H; Y -0C(S)0PhScheme 34102 (87%)(83%)2.3.9 Stereochemistry of the Alcohols 135 and 136, and the PhenylThionocarbonates 148 and 149Both of the epimeric alcohols 135 and 136 underwent phenylthionocarbonate formation, and subsequent deoxygenation with equalease. Nonetheless, the relative stereochemistry of each epimer was ofinterest and 1H NMR studies were carried out to determine theconfiguration at the hydroxy bearing center in each of these substances.The tentative assignment of the signals in the proton NMR spectrawere confirmed with the aid of homonuclear correlation (COSY)experiments (Table 6).The nOe difference spectra of the alcohol 135 were obtained todetermine the relative stereochemistry of protons at C-5, C-6 and C-8.The absence of nOe enhancement between the H-5 and H-6 suggests thatthese protons are in a trans relationship (Figure 2). Furthermore,irradiation of the signal due to H-6 led to enhancement of the signalsassigned to H-4a, H-7a and H-8 protons. The reciprocal enhancementbetween H-4a and H-6 indicate that the stereochemistry of H-6 protoniS a.HOH'(HH .....(HFigure 2. nOe experiments on the alcohol 13552Table 6. 1H NMR (400 MHz, CDCI3), COSY (200 MHz, CDCI3) and nOe (400MHz CDCh data for the alcohol 135._^_.AssignmentH-x1FINMR(400MHz, CDCI3) 6ODSYcorrelationsanOecorrelationsH-413 1.85 H-4a, H-5H-4a 1.37 H-40, H-5 1.85 (H-40)3.84 (H-6)H-5 2.20 H-4a & fi , H-6H-6 3.84 -OH, H-5,H-7a & f31.37 (H-4a)2.14 (H-7a or p)2.30 (H-8)3.06 (-OH)-OH 3.06 H-6 3.84 (H-6)H-7a or 0 1.67 H-6, H-7a or 0 2.14 (H-7a or p)3.84 (H-6)H-7a or p 2.14 H-6, H-7a or pH-11a or p 2.06 H-110 or a 2.45^(H-11)H-1113 or a 2.45 H-11a or p 2.06^(H-11)H-13 & H-15 3.44 & 3.51 H-16 & H-17H-16 & H-17 0.91 & 0.99 H-13 & H-15a) Only those COSY correlations that could be unambigously assignedare recordedUnfortunately, it was not possible to selectively conduct nOeexperiments on the alcohol 136 as the signals of interest (signals due53to protons at C-4, C-5, C-7 and C-8) in the proton NMR spectrum wereoverlapping. Although results of nOe experiments on the alcohol 135indicated that the stereochemistry of the hydroxyl group is p, furtherstudies on the corresponding phenyl thionocarbonates were carried out.The proton NMR spectra of the corresponding phenyl thionocarbonatesgave better signal dispersion and thus were more suitable for thisstudy.To verify that the preparation of the phenyl thionocarbonatederivative occurs with the retention of stereochemistry, a lithiumaluminum hydride reduction of 148 was carried out. The alcohol thusobtained displayed spectral data which were identical with those ofthe starting alcohol 135 (Scheme 35). Ph0C(S)C1, DMAP,CH3CNHOEt20Ph0C(S)0135^148Scheme 35The results of nOe difference experiments on the phenylthionocarbonate 148 are summarized in the Figure 3 and Table 7.Irradiation of the signal due to H-6 caused enhancement of the signalsassigned to H-3«, H-4a, H-5 and H-7«. Irradiation of the signals due toH-4« and H-5 caused enhancement of the signal due to H-6. Thereciprocal enhancement between H-6 and H-4« indicates that thestereochemistry of C-6 proton is a.54Y.-0C(S)0PhFigure 3. nOe experiments on the phenyl thionocarbonate 148The nOe enhancement between H-5 and H-6 protons is probably dueto a conformation of the triquinane skeleton of 148 in which the H-5and H-6 protons are relatively close to one another. However, themagnitude of the nOe (3.6%) at proton H-6 when proton H-5 wasirradiated is much smaller compared with the correspondingenhancement in compound 149 (11.2%).55Table 7. 1H NMR (400 MHz, CDCI3), COSY (200 MHz, CDCI3) data and nOeex eriments 400 MHz CDC' for the phenyl thionocarbonate 148..^.AssignmentH-x1H NMR(400 MHz, CDCI3) aCOSYcorrelationsanOecorrelationsH-4a 1.60 H-4p, H-5 1.87 (H-4p)5.32 (H-6)H-4p 1.87 H-4a, H-5 1.60 (H-4a)2.69 (H-5)H-5 2.69 H-4a & p, H-6 1.87 (H-40)2.20 (H-11p)5.32 (H-6)H-6 5.32 H-5, 1.60 (H-4a)H-7a and 13 2.32-2.50(H-3a & H-7a)2.69 (H-5)H-7p 1.93 H-6, H-7aketal CH2's 3.49 H-16 & H-17H-16 & H-17 0.93 & 1.02 ketal CH2'sa) Only those COSY correlations that could be unambigously assignedare recordedThe nOe difference experiments on the phenyl thionocarbonate 149(Figure 4 and Table 8) have shown that irradiation of the signal dueto the H-6 proton caused enhancement of the H-5, H-7p and H-9p protonresonances. The irradiations of H-5 and H-9p protons caused nOeenhancement of the H-6 proton. Thus we concluded that thestereochemistry of the latter proton is I.56Y. -0C(S)0PhFigure 4. nOe experiments on the phenyl thionocarbonate 149Additional support for the assigned stereochemistry of the phenylthionocarbonates was obtained from GLC analysis. Retention times forthe phenyl thionocarbonates 148 and 149 were close to that of thedeoxygenated product 102. Thus, it was concluded that under theconditions of GLC analysis the phenyl thionocarbonates 148 and 149underwent elimination to provide the corresponding alkenes 150 and151 (Scheme 36). Phenyl thionocarbonates undergo pyrolyticelimination in a mechanism which involves a six-membered transitionstate (El mechanism).52 Such eliminations are syn and, therefore, theposition of the double bond will be determined by the available cis p-hydrogens. The compound 148 has two fi• -hydrogens cis to the phenylthionocarbonate moiety and is expected to provide two alkenes 150 and151. On the other hand, phenyl thionocarbonate 149 has only one p-hydrogen cis to the phenyl thionocarbonate moiety and is expected to57provide only the alkene 150. As expected, GLC analysis of the phenylthionocarbonate 148 exhibited two peaks with very similar retentiontimes corresponding to the two isomeric alkenes 150 and 151, whileGLC analysis of phenyl thionocarbonate 149 exhibited a single peak dueto the alkene 150 that can be produced by elimination.Table 8. 1H NMR (400 MHz, CDCI3), COSY (200 MHz, CDCI3) and nOe (400MHz CDCI) data for the Dhenvl thionocarbonate 149._.AssignmentH-x1HNMR(400 MHz, CDCI3) 8,COSYcorrelationsanOecorrelationsH-43 1.71 H-5 1.61^(H-4a)2.79 (H-5)H-4a 1.61 H-5H-5 2.79 H-4a & (3, H-6^1.71^(H-40)2.19^(H-1113)5.81^(H-6)H-6 5.81 H-5,H-7a & 131.90 (H-9(3)2.07-2.15(H-7a & 0)2.79 (H-5)H-7a & ii 2.07-2.15 H-6H-9p 1.90 H-9a 2.19 (H-9a)5.81^(H-6)H-9a 2.19 H-9f3ketal CH2's 3.46 H-16 & H-17H-16 & H-17 0.91 & 0.98 ketal CH2'sa) Only those COSY correlations that could be unambigously assignedare recordedPh0C(S)0148H..Ph0C(S)0...A150AW(0-)C15158149^ 150Scheme 36It is interesting to note the complete reversal in stereochemistryresulting from the reduction of ketone 99 with L-Selectride andlithium aluminum hydride, as compared with that obtained by thereduction of ketone 152 mentioned previously (Scheme 37).8 This canbe attributed to the presence of an angular methyl group in thecompound 152, as opposed to a proton in ketone 99. It has beenproposed that the reduction of ketones with nonsterically demandingmetal hydrides (such as lithium aluminum hydride) is controlledprimarily by torsional strain in the transition state, while reductionwith bulky reagents (such as L-Selectride) is controlled primarily bythe degree of steric hindrance of the carbonyl group.5359HOLiAIH4,0°CL-Selectridee,-78 °C^HO 135^99^136HOLimia, n L-Selectridee, -78 °C^0.- HO153^152^154Scheme 372.3.10^Preparation of the Tricyclic Keto Ketal 103The keto ketal 103 was synthesized by a ruthenium(VIII) catalyzedoxidation of the ketal alkene 102. Ruthenium tetroxide was usedinstead of osmium tetroxide, the usual reagent used in such reaction,because ruthenium tetroxide is less expensive and less toxic. Thereaction was carried out in a mixture of solvents (2:2:3 carbontetrachloride/acetonitrile/water), according to Sharpless' procedure.54As the newly formed keto ketal 103 has an acid sensitive ketalgroup, the reaction must be carefully monitored to prevent ketalhydrolysis. If the reaction is carried out at room temperature for 1 hrthe keto ketal 103 is obtained in 79% yield, accompanied by 3% (asdetermined by GLC analysis of the crude product) of the diketone 104.However, if the reaction time was extended to 24 hr, the only productwas the diketone 104, obtained in 71% yield (Scheme 38).60Ru02/Na104,CCI4/MeCN/H20 102^103^104reaction time:^1 hr^(97% 3%)79% isolated yield24 hr^0%^71%Scheme 38It is possible to completely suppress hydrolysis of the ketal groupby using a phosphate buffer (pH 7.2). However, the use of a bufferedsolution decreased the solubility of sodium periodate, thus a greatervolume of water was necessary and the work-up was complicated bypresence of a large amount of precipitated salts. For these reasons theprocedure using a buffered system of solvents was abandoned.The IR spectrum of the keto ketal 103 indicated presence of afive-membered cyclic ketone (1731 cm-1) and a C-0 single bond (1114cm-1). The HRMS of 103 gave an exact mass of 264.1728 mass units.The calculated exact mass for 103 is 264.1726. The 1H NMR spectrumis consistent with the assigned structure and the resonances wereassigned with the aid of homonuclear correlation (COSY, 400 MHzCDCI3) experiments (Table 9).The COSY spectrum of the keto ketal 103 is shown in Figure 5.:A.zI• •0^*• •,,,t^+ ..-^0^0• . ,^-'/-U 421hc'e,7'41.ilt-'^4-,-. ,' •^•^i^, =1(. j;-:'415*,,,-.;;;::,:k.*■,.;SII7^14 .,•-'^/L. 81.52. 0253835611033 5^3 8^2.5^2.8^1. 5PPM 185PPM. Figure 5. The COSY (400 MHz, CDCI3) spectrum of the keto ketal 103.62Table 9. 1H NMR and COSY (400 MHz, CDCI3) data for the keto ketal103.H-x(assignment)1H NMR(400 MHz, CDCI3) 5COSY correlationsaH-3a or p 2.23 H-3a or [3, H-4a & pH-3a or p 2.39 H-3a or 13, H-4a & 13H-4a or 0 1.64 H-3a & p, H-4a or p, H-5H-5 2.55 H-4a and p, H-6a and 13H-713 1.38 H-7a, H-93H-9P 1.54 H-7p, H-8, H-9aH-8 2.50 H-7a, H-9a and pH-9a 1.87 H-7a, H-8, H-9Pketal CH21s 3.48 H-15 & H-16H-15 & H-16 0.92 & 0.93 ketal CF12' Sa) Only those COSY correlations that could be unambigously assignedare recorded2.3.11 Preparation of the Diketone 104The keto ketal 103 was deketalized by treatment with a 1:1mixture of 5% hydrochloric acid and acetone to provide the diketone104, which was obtained in 93% yield (Scheme 39). The diketone 104was subsequently used in studies directed towards preparation of thedienedione 98. The diketone 104 exhibited expected spectralcharacteristics, including a high resolution mass spectrum, which gavean exact mass of 178.0994 mass units (calculated exact mass for 104is 178.0994). Absence of the C-0 bond absorption in the IR spectrumindicated that the ketal function had been removed.Pd(OAc)2,CH3CNTMSI, Et3N,CH2CI3. .^0LrOTMS155Scheme 401036 3HCI (aq.)/ acetone)._103^104Scheme 39It is interesting to note that compound 104 is relatively unstable,as compared with other compounds prepared during the execution ofthis synthetic sequence. Even when stored in a freezer (-4 °C) under anargon atmosphere, the diketone 104 quickly darkened, and turned blackin a few days. Thus, the diketone 104 was used immediately afterpreparation or was freshly distilled before use.2.3.12 Preparation of the Tricyclic Enone Ketal 156The tricyclic keto ketal 103 was converted to the enol silyl ether155 using trimethylsilyl iodide and triethylamine in methylenechloride. Oxidation of the enol silyl ether 155 with palladium acetatein acetonitrile31 gave the enone ketal 156 in 74% overall yield(Scheme 40). The IR spectrum of 156 exhibited absorptions at 1697and 1584 cm-1 due to the enone moiety, and an absorption at 1122 cm-1due to the C-0 single bond. In the 1H NMR spectrum of 156, resonancesat 6.14 (dd, 1H, J=5.5, 2.0 Hz) and 7.43 (dd, 1H, J=5.5, 2.5 Hz) are due tothe enone protons H-3 and H-4, respectively.642.3.13 Preparation of the Tricyclic Enedione 157Acid-mediated deketalization of the tricyclic enone ketal 156, asdescribed in section 2.3.11 (pp 62-63), provided the tricyclic enedione157 in 93% yield. The IR spectrum of the enedione 157 indicated thepresence of five-membered cyclic ketone (1739 cm-1) and enone (1702,1584 cm-1). The 1H NMR spectrum was assigned with the aid ofhomonuclear correlation (COSY, 200 MHz CDCI3) experiments (Table10). Enone protons H-3 and H-4 exhibited resonances at 6.24 (dd, 1H,J=5.7, 1.7 Hz) and 7.55 (dd, 1H, J=5.7, 2.6 Hz), respectively.D‹  HCI (aq.)/ acetone 3156^157Scheme 41Table 10. 1H NMR (400 MHz, CDCI3) and COSY (200 MHz, CDCI3) data forthe enedione 157.H-x(assignment)1H NMR(400 MHz, CDCI3) 8,COSY correlationsaH-3 6.24 H-4, H-5H-4 7.55 H-3, H-5H-5 3.19 H-3, H-4, H-60H-8,H-9a or ri2.70 H-7a & 13,H-11a or §H-11a or fi 2.33 H-11a or13H-11a or p 2.86 H-11a or 13a) Only those COSY correlations that could be unambigously assignedare recordedLDA-TMSCI,THF, -78°C OTMS +OTMS105(1104HOTMS65In contrast to the diketone 104, the enedione 157 is quite stableand can be kept at room temperature for weeks without any observabledeterioration.2.3.14 Preparation of the Tricyclic Dienedione 982.3.14.1 Saegusa Oxidation of the Enol Silyl Ethers 105 and 164The diketone 104 was converted to a mixture of the bisenol silylethers 105 and 106 upon treatment with LDA-TMSCI according to theprocedure of Corey et al.55 A GLC analysis of the crude productindicated that the two bisenol silyl ethers were formed in a ratio of about1:1. Oxidation of this 1:1 mixture of 105 and 106 with palladiumacetate gave the dienedione 98 and enedione 157 in 20% and 10% yield,respectively (Scheme 42).1 Pd(OAc)2, CH3CNHo98^157am 10%Scheme 4266Our first attempts to improve the conversion yield of 104 into 98using this procedure were directed towards the regioselectiveformation of the bisenol silyl ether 105. A variety of more hinderedbases were used instead of LDA. These include both lithium andpotassium bis(trimethylsilyl)amides, lithium tetramethylpiperidideand lithium bis(phenyldimethylsilyl)amide. The reactions were carriedout in THE at -78 °C, in an attempt to prepare the kinetically favoredbisenol silyl ether.Alternatively, we attempted to prepare the bisenol silyl ether 105under thermodynamic conditions, by treatment of the diketone 104with TMSBr-Et3N in DMF,56 or TMSI-Et3N in CH2Cl2.43 The mixture ofbisenol silyl ethers was unstable and did not provide a useful 1H NMRspectrum (LRMS: 322, M+; 307, [M-15]+). In all cases, the results weresimilar in that the ratio of regioisomers 105 and 106 was close to1:1, as determined by GLC analysis. The subsequent oxidation withpalladium acetate produced consistently the dienedione 98 and theenedione 157 in 2:1 ratio and in a low yield.Formation of a relatively large amount of the bisenol silyl ether106 may be rationalized by proposing the following pathway, whichmay compete with the pathway described in Scheme 18 (p 31). Thebase first abstracts the least hindered C-3 proton to give the lithiumenolate 158 (Scheme 43). This enolate may then, in an intramolecularreaction, abstract the C-11 proton and thus produce the undesiredenolate 159. Deprotonation of 159 with a second equivalent of base,followed by treatment with trimethylsilyl chloride, would produce106.OTMS^IMSCI (excess)-■10667H 9 0 LDA 0-1 0 41 LDAScheme 43If this rationale is correct then the use of a more hindered base isof no benefit as it would only increase the difference in reactivitybetween the C-9 and C-3 protons, and thus favor the pathway describedin Scheme 43.Therefore, it was decided to execute the oxidation stepssequentially. It was assumed that the A-ring enone functionality ofenedione 157 would not react with a base, since the resulting enolate160 would be very strained (Scheme 44).The enedione 157 was treated with a variety of bases (LDA,lithium and potassium bis(trimethylsilyl)amides and lithiumbis(phenyldimethylsilyl)amide) in THE at -78 °C. Unfortunately, GLCanalysis of the crude mixture indicated that two products were formedin a 1:1 ratio. These products were concluded to be the tworegioisomeric enol silyl ethers 163 and 164. Subsequent oxidation ofthis mixture of enol silyl ethers 163 and 164 with palladium acetateOTMS TMSCI a •.41(-68met with no more success than the previous attempts to oxidizebisenol silyl ethers 105 and 106.- -base—X-0,--o- 160 161- MELii163^162Scheme 44The material balances in the conversions of the diketone 104 orthe enedione 157 to the dienedione 98 were very low. The low yieldmay in part be attributed to overoxidation of the products, toadsorption or occlusion of reaction products by the precipitatedpalladium, or possibly to the irreversible complexation of the productsto palladium(0).Assuming that the loss of material is due to the complexation ofthe product to the palladium(0), several modifications were attemptedto minimize this interaction. Reactions were conducted under higherdilution (5-30 mmol/L of the substrate) than normal (250 mmol/L ofthe substrate). Under such conditions, it was necessary to extend thereaction time from 2 to 24 hr. Higher dilutions were consideredimpractical.Various phosphine ligands, such as triphenylphosphine, DIPHOS,PROPHOS were added to the reaction mixture in hope that these ligands6 9would replace any dienedione 98 that may be complexed topalladium(0). Also, sonication of the precipitated palladium(0)obtained from the reaction mixture with various solvents wasinvestigated.Unfortunately, all of these attempts failed to significantlyimprove the yield of 98. Oxidation of the enol silyl ether 164 (in amixture with the enol silyl ether 163) (Scheme 45) under higherdilution conditions provided only a moderate improvement and a 28%overall yield of the dienedione 98 was achieved after reoxidation ofthe recovered enedione 157.^ 0*LDA-TMSCI, THF, -78 °C^OTMS +"soOTMS157^164^1631 Pd(OAc)2 (5-30 mmol/L),CH3CNHo98^15725% 14%28% -0 ^1Scheme 452.3.14.2 Reexamination of the Saegusa ProcedureIt was later found from a study on the alkylation of the dienedione98 that the 1,4-addition of amide bases to the A-ring enoneHLDAE^ ).....1"0.10(i-Pr)2No157 165 o-1 TMSCI70functionality occurs with ease (Section 2.3.15, p 80). We speculatedthat the reason for the lack of selectivity in formation of the enol silylether 164 was that the intermediate enolate obtained after theaddition, would abstract a C-11 proton yielding the undesired enol silylether 163 after the treatment with trimethylsilyl chloride (Scheme46). The results from the alkylation of dienedione 98 indicated that itmight be possible to prevent 1,4-addition of a base to the enonefunction of 157 by use of lithium tetramethylpiperidide undercarefully controlled conditions.OTMS work up OTMSi....p.  0(i-Pr)2Ne167163Scheme 46Thus, treatment of the enedione 157 with 1.1 equivalent of lithiumtetramethylpiperidide at -78 °C, followed by an excess oftrimethylsilyl chloride provided predominantly the enol silyl ether 164(97% by GLC analysis of the crude product). Treatment of the enedione157 with a larger excess of lithium tetramethylpiperididesignificantly reduced selectivity of the formation of 164. Subsequent71oxidation of 164 with palladium acetate, in DMF, provided thedienedione 98. Application of this sequence successively on 5.6 and 8.2mg of the enedione 157 gave the dienedione 98 in 42% and 46% yieldsrespectively. Thus, one may assume that if the reactions wereperformed on a larger scale better yields would be obtained, and thismay represent a more convenient procedure for preparation of largequantities of 98.Unfortunately, this development occurred toward the end of ourresearch, after the study on the preparation of the dienedione 98 wasconcluded. For this reason, only limited quantities of the enedione 157were available for reexamination of the Saegusa procedure. Therefore,this route was not fully evaluated.2.3.14.3 Attempted Saegusa Oxidation of the Enol Silyl Ether 168As the yields of conversion of compounds 104 and 157 into thedienedione 98 were unsatisfactory, it was decided to attempt theintroduction of the enone functionality earlier on in the synthesis, asshown in Scheme 21 (p 34). To this end, the tricyclic ketal alkene102 was deketalized and the resulting keto alkene 123 was convertedto a mixture of the corresponding enol silyl ethers 168 and 169. A GLCanalysis of the crude product mixture indicated that the two enol silylethers were formed in a ratio of about 2:1. This mixture was treated withpalladium acetate to provide a complex mixture of products (Scheme47), none of which was the desired enone 124 (Scheme 21, p 34).-^Pd(II)Pd(II)mixture ofproducts 72OSiMe3 OSiMe3123^168^169170^171Scheme 472.3.14.4 Other Palladium OxidationsAfter our attempts to prepare 98 by means of the enol silylether/palladium acetate procedure proved unsatisfactory, otherprocedures involving palladium(II) salts were investigated.The diketone 104 was converted to the corresponding bisenol silylethers, and subjected to the palladium(II)-catalyzed oxidation,according to the procedure of Tsuji.57 A mixture of products wasobtained, none of which was the desired dienedione 98 (Scheme 48).When the enedione 157 was used as the starting material thedienedione 98 was obtained in 11% yield, accompanied with a mixtureof other products which were not identified.731)LDA-TMSCI,THF, -78 °C2) OCO2MePd(OAc)2 (5 mol%),DIPHOS, MeCNI^.-104 157^ aePdC12, t-BuOH<10%98Scheme 491041)LDA-TMSCI,THF, -78 °C2) .0CO2MePd(OAc)2, (5 mol°/0),DIPHOS, MeCN-.I^11%Scheme 48The diketone 104 was consumed within 2 hr when treated withpalladium(11) chloride in hot t-butano1;58 however, the dienedione 98was produced in a very low yield (<10%) (Scheme 49).2.3.14.5 Oxidation-Elimination of the a-Phenylseleno Ketone 172aAfter the palladium based methods failed to achieve satisfactoryconversion of the diketone 104 or the enedione 157 to the dienedione98, our attention turned to selenium-based reagents.Conversion of the enedione 157 into the a-phenylseleno ketone172a, using an excess of lithium tetramethylpiperidide followed byphenylselenyl bromide," was attempted (Scheme 50). A mixture offour products was obtained (as determined by a TLC analysis of thecrude product mixture). The mixture may be composed of all the fourpossible isomers 172a-d. This result was not completely surprisingin view of the lack of selectivity observed in formation of the enolSePhH202,0^CH2Cl2, rt74sily1 ethers 105 and 106 (p 65), as well as in the formation of 163and 164 (when using an excess of lithium tetramethylpiperidide, p 70).Separation of this mixture by gravity column chromatography providedone pure compound tentatively assigned as 172a (21%), and a mixtureof the three remaining products. Assuming that these three productswere all phenylseleno ketones, their combined yields would be 31%.This mixture was separated by a second gravity column chromatographyto provide another pure compound and a mixture of the other two. Itshould be noted that the conclusion that all of the products are a -phenylselenyl ketones is only tentative, and no analytical studies wereperformed on any of the products. All three fractions wereindependently subjected to hydrogen peroxide oxidation-eliminationsequence. The major product 172a provided the dienedione 98.In conclusion, although there are problems in the selectivepreparation of the desired a-phenylseleno ketone 172a, the subsequentphenylselenenic acid elimination is a feasible method foraccomplishing the desired transformation.1)..1■1Li+THF, -78 °C^oSePh^SePh2) PhSeBr 0 +^0^0 +^00 SePh i.......6SePh157^ 172a^172b^172c^172d172a^ 98Scheme 50752.3.14.6^Oxidation of the Enone 157 with Benzeneseleninic AcidAnhydrideIn the late-1970s and early-1980s, Barton's group reported, in aseries of papers, the use of benzeneseleninic acid anhydride (BSA) tooxidize steroidal ketones to enones.66-62 An interesting feature of thisreaction is that the a-phenylselenoxy ketone is formed directly and, ifappropriately positioned, undergoes syn-elimination immediately.Furthermore, the formation of the a-phenylselenoxy ketone isreversible. This allows for the equilibration of intermediates thatcannot eliminate.The drawback of this method is that benzeneseleninic anhydrideand other selenium byproducts are powerful oxidants which may reactfurther with the enone produced, thus diminishing the yield of thelatter substance.The enedione 157 was subjected to BSA oxidation under variousreaction conditions. After extensive research, optimal conditions forconversion of the enedione 157 to the dienedione 98 were found. Thereaction was allowed to proceed until consumption of approximately50% of the starting enedione 157 (by GLC analysis of the reactionmixture) had been achieved (Scheme 51). Attempted separation, bydrip column chromatography, of the mixture thus obtained resulted in apoor resolution due to tailing of dienedione 98 and a modifiedprocedure had to be applied. Separation of the mixture was achieved bygravity column chromatography using TLC grade silica gel withoutbinder.63 Under these conditions, the dienedione 98 and the recoveredenedione 157 were obtained in yields of 38% and 43%, respectively.0+BSA (1.4 equiv.),benzene, 80 °C 0...76Recycling the enedione 157 twice provided the dienedione 98 in 59%overall yield.157^98^15738% 43%Scheme 51The IR spectrum of the dienedione 98 indicated the presence oftwo five-membered cyclic enones (1713, 1630, 1585 cm-1). The 1H NMRspectrum of 98 was assigned with the aid of homonuclear correlation(COSY) experiments (Table 11). The presence of signals due toolefinic protons (8 6.02 (d, 1H, H-9, J.1.9 Hz), 6.32 (dd, 1H, H-3, J=5.6,1.3 Hz) and 7.78 (dd, 1H, H-4, J.5.6, 3.0 Hz)) was consistent with thestructural formula 98.The 1H NMR (400 MHz, CDCI3) spectrum of the dienedione 98 isshown in Figure 6.Table 11. 1H NMR (400 MHz, CDCI3) and COSY (200 MHz, CDCI3) data forthe dienedione 98.H-x(assignment)11-I NMR(400 MHz, CDCI3) 8COSY correlationsaH-3 6.32 H-4H-4 7.78 H-3H-6a 2.27 H-7aH-7a 2.59 H-6aH-11aorp 2.39 H-11p or aH-11p or a 2.63 H-11a or pa) Only those COSY correlations that could be unambigously assignedare recorded7. III^LS^C. 8^5. 5^5.1^4.5^q.l^3.5^3. 11^2:5^2.9^1.5^1.11^.5^$.9PPM Figure 6. The 1H NMR Spectrum (400 MHz, CDCI3) of the dienedione 98.1071) LDA, TFIF,-78°C° 2) Mel90+ 0.1112^0o+o+ 9813 1298^ 107^174^175782.3.15 Alkylation of the Dienedione 98In order to prepare the 11-methyl dienedione 107, the dienedione98 was subjected to alkylation under kinetically controlled conditions.Treatment of 98 with LDA was expected to provide the "kinetic"enolate 173 (Scheme 52) by removal of the kinetically most acidicproton at C-11 (subergorgic acid numbering). Treatment of the enolate173 with iodomethane was expected to provide the alkylated product107.98o LDA, THE, -78 °Co173Scheme 520' MelAlkylation of the dienedione 98 with LDA-Mel was very capricious.Mixtures of mono- and dialkylated products, some recovered dienedione98, as well as other unidentified products, which proved to be verydifficult to separate from the 11-methyl dienedione 107, wereobserved in the crude product mixtures (Scheme 53).Scheme 530121) (Me3Si)2NLi0 2) Mel(Me3Si) N97 9The isolated byproducts 174 and 175 were identified on the basisof their 1H NMR spectra (CDCI3, 200 MHz). The 3,11-dimethyldienedione 174 exhibited resonances due to Me-12 (8 1.08, d, 3H), Me-13 (8 1.81, s, 3H), H-5 (8 3.28, br d, 1H), H-9 (8 5.94, d, 1H) and H-4 (87.33, d, 1H). The 3-methyl dienedione 175 exhibited resonances due toMe-12 (8 1.82, s, 3H), H-11a or j3 (8 2.36, d, 1H), H-1 1a or 0 (8 2.61, d,1H), H-5 (8 3.18, m, 1H), H-9 (8 6.00, d, 1H) and H-4 (8 7.35, d, 1H).It was difficult to rationalize the significant amount ofdialkylated product 174 obtained. In an attempt to improve selectivityof the alkylation a more bulky base, lithium bis(trimethylsily0amide,was employed. The mixture of products thus obtained was separated byradial chromatography and the components were characterized. A newproduct was isolated along with the desired 11-methyl dienedione 107,and the 3,11-dimethyl dienedione 174.  This new product wasidentified as the 4-bis(trimethylsilyl)amino-3,11-dimethyl dienedione176 (Scheme 54). The 1H NMR spectrum (CDCI3, 200 MHz) of compound176  exhibited a signal at 60.25 (d, 18 H) due to the protons intrimethylsilyl groups. The resonances due to two methyl groups wereoverlapping at 8 1.05 (m, 6H, Me-12 and Me-13), and the olefinic protonexhibited a resonance at 8 5.98 (d, 1H, H-9).98^ 107^174^176Scheme 5498 177 176-(Me3S1)2NH(Me3Si)2N+LI(excess) 0" Mel80The products 174 and 176 are a result of 1,4-addition of the baseto the A-ring enone of 98 (Scheme 55), followed by subsequenttrapping of the intermediate enolate 177 with iodomethane. This wasan unexpected outcome, as lithium bases do not usually add in a 1,4-fashion to enones in THE at -78 oc.64a174Scheme 55Compound 176 was moderately stable with a half life ofapproximately 24 hr in deuteriochloroform solution at roomtemperature. This material eliminated hexamethyldisilazane (Scheme56) to provide the 3,11-dimethyl dienedione 174. o 0(Me3S02N-(Me3Si)2NH176^175Scheme 5681Lithium tetramethylpiperidide was used next as a non-nucleophilicbase.6" The 11-methyl dienedione 107 was obtained in acceptableyield (53%) when 1.1 equivalent of base was used. Surprisingly, whenlarger excesses of base was employed, significant amounts ofdialkylated product 174 was obtained. With these results in hand wereexamined the formation of enol silyl ethers from the enedione 157(section 2.3.14.2, pp 69-71), and the subsequent palladium acetateoxidation.The initial stereochemical assignment on the 11-methyl dienedione107 was based upon the previously described prediction regarding thestereocontrol in the alkylation of the enolate anion 173 (pp 31-32).NOe difference experiments were performed in order to determine theconfiguration of the methyl group (Figure 7). The signals in the 1H NMRspectrum were assigned with the aid of homonuclear correlation (COSY)(Table 12) and homonuclear decoupling experiments (Table 13). Thepresence of signals due to the C-11 methyl group (8 1.10, d, 3H, J=8.0Hz), and the C-11 proton (8 2.60, q, 1 H, J=8.0 Hz, overlaps with H-6a (82.60, dd, 1H, J=13.0, 6.5 Hz)), as well as the olefinic protons (8 5.96 (d,1H, H-9, J=2.0 Hz), 6.27 (dd, 1H, H-3, J=5.8, 1.5 Hz) and 7.74 (dd, 1H, H-4, J=5.8, 3.0 Hz)) are consistent with the assigned structure.As there is an overlap between the signals due to H-6 and H-11protons, a titration of the CDCI3 solution of 107 with C6D6 wasperformed, in order to obtain a spectrum with signal dispersionsuitable for nOe difference experiments.Irradiation of the signal due to Me-12 caused enhancement of thesignals due to H-11 (3.6%) and H-5 (2.4%). Irradiation of the signal dueto H-11 provided some surprising results. Saturation of H-11 caused8 2negative enhancement of the H-4 and H-5 signals and, as expected, thereciprocal enhancement of the signal due to Me-12 was observed. Thedetection of a negative nOe could be characteristic of nuclei having aroughly linear arrangement.65 Irradiation of the resonance due to theH-5 proton caused enhancement of the signal due to Me-12, and noenhancement of the signal due to H-11. An absence of nOe enhancementat H-11 when H-5 was irradiated, may be due to the cancellationbetween the direct positive and indirect (through Me-12) negative nOe.The results of nOe experiments indicate that the protons H-5, H-11 andMe-12, as well as H-4, H-11 and Me-12 exhibit "three spin effects1.65bTherefore, nOe between those nuclei depends not only on the distancebetween the protons, but also on their geometry, and additionalexperiments are needed to determine their relative stereochemistry.Thus, it was not possible to unequivocally prove that this substancehad the relative stereochemistry as depicted in 107 (Scheme 16, p29).Molecule 107 has three sp2 carbons in each of the A and C rings.This flattens the molecule and changes the orientation of the protonsof interest and the distances between them, as compared to a saturatedtriquinane ring system. Thus, usual nOe experiments which weresuccessfully applied in determination of the stereochemistry of C-11methyl group in other silphiperfolanes,19,66,82b did not provide aconclusive result in this case.8303.1%Figure 7. nOe experiments on the 11-Methyl Dienedione 107Table 12. 1H NMR, COSY(200 MHz, CDCI3) and nOe (400 MHz, CDCI3-C6D67:3 data for the 11-methyl dienedione 107H-x(assign.)1H NMR(200 MHz,CDCI3)COSYcorrelationa1H NMR(400 MHz,CDCI3-C6D6(7:3)nOecorrelationsH-3 6.27 H-4 - -H-4 7.74 H-3 - -H-5 - - 3.05 0.94^(H-12)1.62 (H-6f3)7.30 (H-4)H-11 2.60 H-12 2.53 0.94 (H-12)3.05 (-ye, H-5)7.30 (-ye, H-4)H-12 1.10 H-11 0.94 2.53^(H-11)3.05 (H-5)a) Only those COSY correlations that could be unambigously assignedare recorded84Table 13. Decoupling experiments (400 MHz, C6D6 and CDCI3) data forthe 11-methyl dienedione 107.irradiated^signals observed signalsassignment 1H NMR (400 8 ppm (mutt., J, H-x) mutt.^afterH-x MHz, C6D6) irradiationH-5 2.45 1.05 (m, H-6a or 0) sharpened m1.10 (m, H-6a or 13) sharpened m5.75 (dd, (J=5.8, 1.5, d (J=5.8)H-3)6.60 (dd, (J=5.8, 3.0 d (J=5.8)H-4)H-11 2.60 0.75 (q,^H-12) sassignment H NMR(400 8 ppm (mult., J , H-x) mutt.^afterH-x MHz, CDCI3) irradiationH-4 7.74 3.42 (ddd, br dJ=9.5, 3.0, 1.5, H-5)6.27 (dd, J=5.8, 1.5, d (J=1.5)H-3)H-5 3.42 1.97 (ddd, J=13.0, dd9.5, 6.5, H-6f3) (J=13.0, 6.5))6.27 (dd, J=5.8, 1.5, d (J=5.8)H-3)7.74 (dd, J=5.8, 3.0, d (J=5.8)H-4)H-60 1.97 2.09 (m, H-7j3) sharpened m2.27 (m, H-7a) sharpened m2.60 (m, H-6a) sharpened m3.42 (ddd, br dJ=9.5, 3.0, 1.5, H-5)H-9 5.96 2.27 (m, H-7a) sharpened mH-12 1.10 2.60 (q, J=8.0,^H-11) s8 52.3.16 Lithium Dimethylcuprate Addition to 11-Methyl Dienedione 107The 11-methyl dienedione 107 was treated with an excess ofdilithium dimethylcyanocuprate reagent in THF at -78 °C (Scheme 57).107^97Scheme 57The major isolated product provided satisfactory IR (2928, 1708cm-1) and LRMS (220, M-F; 219, [M-H]; 205, [M-Me]; 191, [M-CHO]; 177,[M-MeCO]). Unfortunately, we were unable to obtain a sufficiently puresample for proton NMR analysis. Thus, although it appears that thedesired diketone 97 had been prepared, it was not possible tosatisfactorily characterize the isolated compound. The reactions werecarried out on a very small scale (less than 5 mg) and this may be thereason why a sufficient amount of pure product was not obtained.Since the product of this transformation was obtained in a smallquantity and was impure, the following transformations could not becarried out. Therefore, we decided to conclude our research.178 1792 eq. BSA, C6H5CI,132°C, 50 mini, 91%Ac0862.4 Preparation of Enones from Ketones: BSA Method2.4.1^IntroductionIn the course of this work, it became necessary to find a suitableprocedure for the preparation of cyclopentenones from cyclopentanones.This led us to study the elimination of benzeneselenenic acid from a-phenylselenoxy ketones.Barton's group dehydrogenated a number of steroidal and triterpenoidketones using benzeneseleninic anhydride (BSA) in chlorobenzene at 95-132 °C (Scheme 58). 6o,612 eq. BSA, C6H5CI132°C, 3hr 1,...83%180^181Scheme 58It should be noted that all the oxidations were performed oncyclohexanones. While in most cases yields were acceptable, thereaction was limited to the ketones with no acidic protons at one of the182 1811 eq. BSA, C6H5CI,95°C, 45 min.^0._92%(1)183 181184 185(4)180 1851 eq. BSA, C6H5CI,95°C, 1 hr50%(3)87a positions. In the cases of ketones with acidic protons at both apositions, 1,4-dien-3-ones were obtained (Schemes 58 and 59). Also,if there are protons at the y position, the dehydrogenation could becarried further. In some cases such a transformation is not ofpreparative value (Scheme 59, entry 4).6ob1 eq. BSA, C6H5CI,132°C, 40 min. w76%^0(2)Scheme 59Pummerer-typeBSA PhSe(0)^reactionPhSe(0)BSA^PhSe1^.-oS. Ph esyn-elimination19288Due to the high reactivity of the reagent, as well as the vigorousreaction conditions employed (95-132 °C), the starting ketone oftenunderwent side reactions (Scheme 60). An intermediate phenylselenoxyketone can undergo Pummerer-type rearrangement to provide an a-diketone. Reaction of a ketone with BSA gives phenylselenoxy ketone andbenzeneseleninic acid. Fragmentation of phenylselenoxy ketone providesan enone and benzeneselenenic acid. Condensation of benzeneseleninicwith benzeneselenenic acid provides 189. The latter compound couldreact with the starting ketone to give undesired products such as 192.186^187^1881 PhSe(0)0SePh189190^191Scheme 60In some cases A-nor steroidal ketones were also observed. It hasbeen suggested that these ketones were formed via a sequence ofreactions involving nucleophilic addition to enone formed in situ,Pummerer rearrangement and benzylic acid rearrangement. Thisrationale is shown in Scheme 61.6"BSA PhSe(0)^syn-elimination191 192[0]196 195 194BSA198Scheme 61197benzylic acidrearrangement193PhSe02HPhSe(0)0[0]89It is known that BSA has a lower reactivity toward olefins,compared to selenium dioxide. In a few reported examples, the allylicoxidation of olefins with BSA proceeded in a low yield after longreaction times (24 hr or longer).61,62 It has been proposed that the lower"enephilicity" of BSA as compared to selenium dioxide is the reason forthe higher chemoselectivity of the BSA reagent.61 Thus, the presence ofolefinic functional groups should not significantly affect the yields ofenone formation.Oxidation of lactones with BSA has also been reported.67 Forexample, the steroidal 6-lactone 199 was successfully dehydrogenatedto the a,-unsaturated lactone 200. As expected, the lactone functions199 200BSA, C6H5CI,100°C 84%201 202BSA, C6H5C1,100°C90%90are less reactive than the keto groups and the 7-lactone moiety of thecompound 201 failed to react under the conditions employed (Scheme62).Scheme 62In another example, the lactone 203 with a proton in the y positionunderwent further allylic oxidation, and as a result the desired 204and two epimeric alcohols 205 and 206 were obtained (Scheme 63).The proposed rationale for their formation is shown below.67191203^207^2040 0 BSA^, .0^ 0't jSePh210 )PhSe021^L./^1+60H^60H205 206,Se Ph209 208Scheme 632.4.2 Oxidation of CyclopentanonesFrom the initial research described in section 2.3.14.6 (pp 74-75),it would seem that the phenylselenenic acid elimination is a feasiblemethod for the preparation of dienedione 98, provided that the a-phenylselenoxy ketone is easily available. The process involving BSA isparticularly attractive since the elimination of benzeneselenenic acid92proceeds with equilibration of the intermediates that cannot eliminate.It has been shown from the research on cyclohexanones thatdehydrogenation occurs, for as long as there are acidic hydrogen atoms(a, a', or y) available to react with BSA, to produce dienones andtrienones (Schemes 58 and 59). The enones thus formed oftenundergo further side reactions (Scheme 61).Since the work of this thesis is restricted to cyclopentanones it isanticipated that difficulties associated with further dehydrogenationwill not occur. The first elimination of benzeneselenenic acid wouldyield a cyclopentenone (Scheme 64), and the subsequent elimination ofbenzeneselenenic acid would lead to an antiaromaticcyclopentadieneone, which would be strongly disfavored.o=CD BSA + PhSe0HH211^ 212^93BSAPhfTh i ,-------0=Se^0-Li I-.1 X^0^+ 0'Se 'Ph2131 -BSA214H+93^215Scheme 649 3For that reason any formed a'-selenoxy enone would react withnucleophiles present (most likely benzeneseleninic acid) to regeneratethe enone 93.Barton has shown that the five membered rings are much lessreactive towards BSA than the six membered ring analogs.67,68 Thereason for a lower reactivity may be the smaller amount of enoltautomer present. For that reason there was some concern as toweather it would be possible to conduct the reaction under conditionsthat would be vigorous enough to affect the desired transformationwithout significant side reactions.Surprisingly, the first experiments on the keto ketal 101 revealedthat Barton's conditions (BSA in refluxing chlorobenzene) were toovigorous and that the reaction could proceed with a reasonable rate atmuch lower temperatures. The results of several reactions carried outunder various conditions are listed in Table 14. )<H1 0 1Table 14. BSA oxidation of the keto ketal 101. Entry^equiv.^solvent^temperature^reaction^yield ofof BSA (°C)^time (hr)^100 WO (1) 1.1^C6H5CI^135 1.5^49(18)a(2) 2.0^C6H5CI 135^4.0 20(3) 2.0^C6H6^80 2.0^55(15)(4) 2.0^CHCI3 60^3.5 49(24)b(5) 2.0^CH2Cl2^40 4.5^44(22)b(6) 1.5^CH2Cl2 17^72.0 15 a) yield of the recovered keto ketal 101 is given in brackets; b) twoadditional unidentified products were obtained.94Optimum conditions for this oxidation reaction are shown in entry3. The reactions in entries 4 and 5 provided similar mass balance.However two byproducts, which had to be separated from the enone,were obtained. The reaction described in entry 1 also deservesconsideration, but was complicated by removal of high boilingchlorobenzene (b.p. 135 °C). Thus, the best yield of the enone 100 wasobtained when 2.0 equivalents of BSA in benzene at 80 °C were used.The results of the oxidations of other cyclopentanones, conducted undersimilar reaction conditions, are listed in the Table 15.This transformation is an example of what Turner called a "pointreaction".69 It provided an acceptable yield only within a relativelynarrow range of conditions, and an excess of reagent or extendedreaction times significantly lowered the yield. For that reason, thegiven conditions may not be optimal for other substrates, and moreresearch could improve the yield of individual reactions. It is possiblethat the reaction conditions for the oxidation of substrates 99 and 132(Table 15, entries 3 and 4 could be found. Indeed, the optimalprocedure for the oxidation of enedione 157 is different (pp 74-75),and when using the procedure described in entry 3 (Table 14), thedienedione 98 was obtained in only 32% yield (Table 15, entry 7).In the course of this work, several polyquinane ketones wereoxidized using Saegusa's procedure.31 The results are listed in Table15. A comparison between the results obtained by the BSA oxidationand those obtained by Saegusa's method shows that the latter generallyprovides a higher yield (entries 1,3,8). However, in several specificexamples the BSA method was superior (entries 2,5). Therefore it(1) WO<o101(2) o<b(c)--\'o--/133o--\,,,(3) o--/^2.099Op<1322.02.0(4) 2.0(5) 2.0104(6) 4.0104(7) 6.0(8)^oo)<^2.095Table 15. Preparation of Enones from Ketones.entry^substrate^BSA(equiv.)producto1000250252)(2541579898)<solventt (°C)yield (%)(a)^(b)C6H680 °C 55(15)c 72C61-1680 °C 51(35)c 42(9)cC6H680°C Od 73C6H680°C OdCHCI360 °C 40 10eCHCI360 °C 17 20eC6H680°C 32 42C6H680°C 62 74103 156a) BSA method; b) Saegusa's method; c) yield of recovered startingketone is given in brackets; d) a mixture of unidentified products wasobtained; e) A single conversion of 104 provided 98 and 157 in yieldsof 20% and 10%, respectively.96represents a complementary method to Saegusa's procedure when pooryields are obtained, or when Saegusa's method cannot be applied due tothe presence of incompatible functional groups elsewhere in themolecule.It should be noted that BSA was prepared by ozonization ofdiphenyldiselenide.7° The commercially available BSA reagent71 cannotbe used in this reaction because it contains up to 30% benzeneseleninicacid.03, CH2Cl2, -10 °CPhSeSePh ^ PhSe(0)0Se(0)PhBenzenetelurinic anhydride (BTA) was used as a substitute for BSAin an attempt to improve formation of the enone 100 from the ketone101.72 However, instead of improving the yield of the desired enone,BTA failed to react with the keto ketal 101, under the same reactionconditions (refluxing benzene, 80 °C). Under more vigorous reactionconditions (i.e. chlorobenzene, 135 °C), rapid reaction occurred, asindicated by the appearance of the deep red color of diphenyl diteluride.While the substrate 101 was consumed, no enone 100 could beobserved. The GLC analysis of the reaction mixture indicated thepresence of diphenylditeluride, the starting keto ketal 101, and fouradditional products. After the work-up, 22% of the keto ketal 101 wasrecovered while byproducts were not isolated. It appears that thereaction between the benzeneteluric anhydride and the enol tautomer216 to provide a-phenylteluroxy ketone is slower compared to thereaction using BSA, and it is possible that the starting material or theintermediate 217 underwent side reactions with benzeneteluricHOri216I (PhTe0)20slow1:1D<PhTe(0)..217101decompositionproducts o97compounds (Scheme 65), similar to those described in Schemes 60and 61 (pp 86-87).Scheme 65983 ConclusionThe work described herein represents a new approach to theconstruction of the silphiperfolane carbon skeleton. Themethylenecyclopentane annulation was a key step in our sequencedirected towards the total synthesis of (±)-subergorgic acid (8). Thismethylenecyclopentane annulation was readily accomplished via a onepot process involving a copper(I)-catalyzed reaction of the enone ketal100 with the bifunctional reagent 91.H CICO2HD< MgBr100^91^8Oxidation of the alkene 102 provided efficiently the ketone 103 withthe desired C-2 keto function. On the other hand, preparation andsubsequent alkylation of the dienedione 98 provided 107 in less thansatisfactory yields. An improvement in the yields of these two stepswould substantially increase the overall efficiency of this route. Tothis end some improvements can be made in optimizing the modifiedSaegusa procedure described in section 2.3.14.2 (pp 69-71).A brief study on the preparation of cyclopentenones disclosed thatBSA can be used effectively for the synthetically useful conversion ofcyclopentanones into cyclopentenones (Scheme 66). The proceduredescribed herein has some advantages over those reported earlier interms of reaction efficacy.Ca,b o72% 81%100)<99H0—f-±\/0—\/WO—/\H101g79%a,b74%Id,e,f60% overallH0--v0—/\99=6.E.N. BSA, benzene,0^reflux/Scheme 66 The compound 107 was thus prepared in 12 steps and an overallyield of 6% from the known keto ketal 101 (Scheme 67).156^103^ 1021 hHi i59% 53%157 98 107a) TMSI, Et3N, CH2Cl2, -78 °C; b) Pd(OAc)2, MeCN, rt; c) 91,CuBr.Me2S, DMPU, THF, -78 °C; d) LiAIH4, Et20, 0 °C; e) Ph0C(S)C1, DMAP,MeCN, rt; f) n-Bu3SnH, AIBN, benzene, 80 °C; g) Ru02-xH20, Na104.H20,(2:2:3) CCI4/MeCN/H20, rt; h) H3O+Cliacetone, rt; i) BSA, benzene, 80°C;j) Li-tetramethylpiperidide, THF, -78 °C; followed by Mel.Scheme 671 00The employed methodology allowed for an efficient construction ofthe triquinane skeleton. Therefore this appears to be a viable generalroute towards the total synthesis of various molecules containing atriquinane skeleton. Future work involving a [2+2+1]-cyclization, asdescribed in the Section 4 is also worth considering..._""". ...=--220:T.4Me H2182191 014^Design of an Alternative Sequence for the Synthesis ofSubergorgic Acid4.1 Recent Developments in Related FieldsAn alternative and possibly enantioselective route for thepreparation of subergorgic acid (8) can be based on recentdevelopments in synthetic methodology and polyquinane chemistry.Developments in the field of free radical chemistry have foundsome application as a cyclopentane annulation method.73 The work ofCurran's group in the preparation of polyquinane molecules via a radicalcyclization cascade is particularly noteworthy (Scheme 68).74 In thiscase, the triquinane skeleton is assembled efficiently in one step andno protective groups are necessary. However, a serious drawback ofthis procedure is the lack of stereoselectivity at the C-4 center.74b221^222Scheme 68(Me3Ge223 224225 226109 1101) 91, CuBr.Me2S2) KH, THFBrMg^CI9.1CuCN)Li1) 2232)12, CH2C123) (Ph3P)413c1, t-BuOK,t-BuOH/THF1 02Recent work in our laboratory has produced the bifunctionalreagent 223 which corresponds to an a2,d4-synthon 224 (Scheme 69).Addition of the reagent 223 to a cyclopentenone such as 225, followedby cyclization provides a methylenecyclopentane moiety in whichexocyclic methylene group is in different position,75 as compared withthe product of methylenecyclopentane annulation sequence using thebifunctional reagent 91.28,29Scheme 69Assembly of the silphiperfolane skeleton may be more efficientwith the reagent 223 than 91, because all the carbon atoms from thesubstrate and the reagents would become part of the target molecule.A possible sequence for the synthesis of such a system is presented inthe Scheme 70. The diketone 97 is an advanced intermediate in ouroriginal synthetic plan (Scheme 16, p 29).1...,...,%e„.0,0Li^several steps+-IN.-o227 2281031) 2232) 12, CH2C12t3) (P11313)4Pd, t-BuOK,t-E3u0H/THFM.:■•■+I-1)Se022)Li, NH3 97^229Scheme 70Finally, the recent disclosure of a Pauson-Khand reaction appliedto an intramolecular [2+2+1] cyclization of alkynes, enones and carbonmonoxide is of significance to the field of polyquinanes (Scheme71).76The methodologies presented above lead to a large number ofalternative sequences for the synthesis of subergorgic acid. Asequence, considered to be most promising, is discussed in thefollowing chapters.[2+2+1]73%00 m2cif 2 (c 0 )602301 04[2+2+1]- Me0H53%0231Co2(C0)6Me0(.1oAl(0But)3, Quinone,Se02, Dioxane/ H20 H•••^"'OH CO*57% 79%232^233Co2(C0)6Me0 ^lo- no reaction0234Scheme 714.2 A Synthetic Plan Involving a [2+2+1] CyclizationThe readily available cyclopentadiene dimer 235 was chosen as astarting material. The dieneone 237 can be prepared in two steps,according to published procedures (Scheme 72).77235^236^237Schemee 72The organocuprate reagent 241, can be efficiently prepared from3-butyn-1-ol (87) (Scheme 73). Reaction of 87 with 2.2 equiv. of105methyllithium followed by addition of an excess of trimethylsilylchloride would produce 238.23 Conversion of trimethylsilyl ether tothe corresponding iodide 239 can be accomplished according to aliterature procedure.75 Halogen metal exchange between the iodide239 and 2.2 equiv. of t-butyllithium followed by addition of copper(I)cyanide would produce the organocuprate reagent 241.75OH^ OTMS^1MeLi (2.2 equiv.);TMSCI (excess),Et20, 0 °C^ -0--TMSCI, Nal,CH3CN, rtI ^TMS^ TMS87 238 239Cu(CN)Lii t -BuLi1 (2.2 equiv.)tLiCuCNITMS^ TMS241 240Scheme 73Addition of the organocuprate reagent 241 to the dieneone 237(Scheme 74), followed by trapping of the resulting enolate withacetaldehyde would produce the corresponding alcohol. Thisintermediate alcohol is expected to undergo an elimination of waterduring the acidic work up to provide the enone 242.47 Alternatively,the intermediate keto alcohol can be isolated, the hydroxyl functiontransformed into a good leaving group (-0S02CH3) and eliminated bytreatment with DBU. According to literature precedents, the vinylicmethyl group will be placed in a trans configuration relative to the106keto function.79^This is not the desired orientation, since [2+2+1]addition proceeds with the retention of stereochemistry (i.e. transsubstituents on the double bond will become trans substituents on thenewly formed five-membered ring).80c The [2+2+1] cyclization of 242using cobalt octacarbonyl as a promoter, is expected to produce thepolyquinane 243.78,80c In addition to cobalt octacarbonyl, several othermetal complexes (e.g. Zr, Ti)8° are known to mediate this cyclization.Their use could be investigated should the cyclization involving cobaltoctacarbonyl provide an unsatisfactory yield of 243. Alternatively, ifthe enone 242 fails to undergo an intramolecular Pauson-Khandreaction, the intermediate complex could be reduced to an allylicalcohol by treatment with NaBH4/CeCI3, and cyclized in a [2+2+1]reaction.81 Upon completion of the [2+2+1] cyclization, the methylgroup is expected to be in the p-position opposite to that in thenaturally occurring subergorgic acid. Interestingly, severalsilphiperfolanes have a C-11 methyl group with p-stereochemistry.82Therefore, this sequence could be useful for an expedient synthesis ofsilphiperfolanes. The dienedione 244 can be prepared, in a retro DieIs-Alder reaction, by treatment of the ketone 243 with boron trifluoride-etherate complex." Base promoted equilibration of the C-11 methylgroup in compound 244 (subergorgic acid numbering) would give 245.Based on an inspection of molecular models, it was concluded that a-orientation of the C-11 methyl group (as in 245) would bethermodynamically favored. Removal of the trimethylsilyl group,followed by the addition of lithium dimethylcuprate should yield 97, aproposed intermediate in our original synthetic sequence (Scheme 16,p 29).TMS BF3*E120,0^CH2Cl2-...e. ^1 07Cu(CN)Li1) I^241TMS2)CH3CHO; NH4CI (aq.) -0.- H 2 3 7^242i Co(C0)8i244^243,: KOBut , THFtTMS 1) Bu4NF^.7.10 2) Me2CuLi 00^ 0245 97Scheme 74Alternatively, the trimethylsilyl group in intermediate 243, couldbe removed and the C-11 methyl group equilibrated under basicconditions to provide 246 (Scheme 75). The lithium dimethylcuprateaddition followed by trapping of the intermediate enolate as vinyltriflate should provide 247.  The palladium catalyzedmethoxycarbonylation of the vinyl triflate 247 would provide the esterOTfMe2CuLi;° Tf2NPh1) Bu4NF2) KOBut , THF 411011-11.-^...H." It:.1 08248. The retro DieIs-Alder reaction, catalyzed by boron trifluoride-etherate complex, of the compound 248 would give the enone 71. Thisenone was converted to subergorgic acid, via the ester 108, byPaquette et al.19243^246^247i: Pd(PPh3)4,I CO, Me0HI:.:.CO2Me Me2CuLi ego,....,_BF3* Et20,CO2Me C C _ H2 _ 12 HCO2Me 108^71^248Scheme 754.3 A Synthetic Plan for an Enantioselective Synthesis of(-)-Subergorgic AcidThe synthetic sequence previously described in the section 4.2which involves a [2+2+1] cycloaddition, could represent a convenientroute for an asymmetric synthesis of (-)-subergorgic acid.The synthetic sequence would begin with a resolution of thereadily available cyclopentadienol 236 (Scheme 76). The racemicalcohol 236 could be converted to diastereomeric esters by1) Na0Me, Me0H0 2) Cr03, H2SO4/ Acetone H"^'"0C(0)R....1-'HH1 09esterification with (+)-mandelic acid (or some other readily availablechiral acid). Separation of these diastereomers by fractionalcrystallization or chromatography, followed by hydrolysis of the estershould provide the (+) and (-)-enantiomers of cyclopentadienol 236.Jones' oxidation of a single enantiomer of alcohol 236 would providethe ketone 237 in its enantiomerically pure form. Upon completion ofthe synthetic sequence described in section 4.2 (Schemes 74 and 75),one enantiomer of dienone 237 would provide enantioselectively (-)-subergorgic acid. The enantiomer of dienone 237 would lead to thepreparation of the unnatural (+)-subergorgic acid.Se02 racemate235racemate2361) Mandelic Acid,2) Separation ofdiasteroisomers2 3 7^ singleenantiomer249Scheme 761105 Experimental5.1 General5.1.1 Data Acquisition and PresentationInfrared (IR) spectra were recorded on liquid films (sodiumchloride plates) or on potassium bromide discs, by means of a Perkin-Elmer model 1710 Fourier transform spectrophotometer (internalcalibration).Proton nuclear magnetic resonance (1H NMR) spectra were recordedon deuteriochloroform solutions (unless otherwise stated) using Varianmodel XL-300 or Bruker models AC-200 or WH-400 spectrometers.Signal positions are given in parts per million (s) fromtetramethylsilane (TMS) as the internal standard. Coupling constants(J-values) are reported in Hz and were measured on spectra judged tobe first order. Data are reported in the format: chemical shift (s) inppm (multiplicity, number of protons, assignment (if possible),coupling constants). Assigned protons are reported in the form H-x,where x is the number of the hydrogen bearing carbon. The protons maylie either below the plane of the drawing (denoted by the letter a) orabove it (0).Carbon nuclear magnetic resonance (13C NMR) spectra and theattached proton test (APT)84 experiments were recorded ondeuteriochloroform solutions at 75.3 MHz using the Varianspectrometer noted above, or the Bruker models AC-200 (50.5 MHz) orAMX-500 (125.8 MHz). Signal positions are given in parts per million111(8) relative to deuteriochloroform (8 77.0).^Signals with negativeintensities in the attached proton test (APT) experiments are indicatedby (-ye) following the chemical shift.Nuclear Overhauser enhancement (n0e)85 difference experimentswere recorded on a Bruker model WD-400 spectrometer.1H-1H Homonuclear correlation (COSY)86 experiments were recordedon Bruker models AC-200 or WD-400 spectrometers.Low resolution and high resolution mass spectra were recordedwith a Kratos/AEI MS 50 (70 eV) mass spectrometer. All compoundssubjected to high resolution mass measurements were homogeneous byGLC and/or TLC analysis.Microanalysis were performed on a Carlo Erba CHN elementalanalyzer (Model 1106) in the microanalytical laboratory at theUniversity of British Columbia.Gas-liquid chromatography (GLC) analyses were performed onHewlett-Packard models 5880 or 5890 capillary gas chromatographs,employing 25 m x 0.21 mm fused silica columns coated with cross-linked SE-54 and equipped with flame ionization detectors.Thin layer chromatography (TLC) analyses were done on commercialaluminium-backed silica gel plates (E. Merck 5554). Visualization wasaccomplished with ultraviolet light, iodine vapor and/or heating thechromatogram under a hot air gun after immersion in 5% ammoniummolybdate in 10% aqueous sulfuric acid. Conventional (drip) and flashcolumn chromatography" were performed on 230-400 mesh silica gel(grade 60). In addition to column chromatography, separations werecarried out on a centrifugally accelerated, radial, thin-layer112chromatograph (Chromatotron, Model 7924) using 1, 2 or 4 mm silicagel plates (grade 60, E. Merck 7749).Concentration of the solvent under reduced pressure (wateraspirator) refers to solvent removal on a Biichi rotary evaporator at 15mm Hg.Distillation temperatures (uncorrected) were recorded as air-bathtemperatures required for short-path bulb-to-bulb (Kugelrohr)distillation. Melting points were measured on a Fisher-Johns apparatusand are uncorrected.Temperatures of reaction mixtures refer to bath temperatures.Cold bath temperatures were obtained by the following mixtures ofsolvents and coolants: 0 °C: ice/water; -10 °C: ice/acetone; -20 °C:27g CaCl2/100 mL H20/dry ice; -48 °C: 46g Ca012/100 mL H20/dry ice;-63 °C: chloroform/dry ice; -78 °C: acetone/dry ice.All reactions were carried out under an atmosphere of dry argonusing flame dried glassware unless stated otherwise.5.1.2 Solvents and ReagentsSolvents and reagents were purified and dried using establishedprocedures. THF and diethyl ether were distilled from sodiumbenzophenone ketyl. Carbon tetrachloride was distilled from P205.Acetonitrile, diisopropylamine, triethylamine, HMPA, DMPU, benzene,trimethylsilyl chloride, chloroform and dichloromethane were distilledfrom calcium hydride. Petroleum ether refers to a hydrocarbon fractionboiling between 30-60 °C.1 1 3lodomethane was passed through a short column of flame driedbasic alumina (activity I) before use.Boron trifluoride-etherate was distilled under reduced pressure(55 °C/15 mmHg).Solutions of methyllithium (LiBr complex) in diethyl ether, n-butyllithium in hexane and t-butyllithium in pentane were obtainedfrom Aldrich Chemical Co. Inc. and were standardized using the methodof Kofron and Baclawski.87Magnesium bromide-etherate complex was prepared by the reactionof freshly distilled 1,2-dibromoethane with magnesium turnings (flamedried under argon atmosphere) in dry ether, with subsequent removal ofether under vacuum (0.1 mmHg) at room temperature.Cuprous bromide-dimethyl sulfide complex was prepared by themethod of Wuts.88Benzeneseleninic acid anhydride was prepared by ozonization ofdiphenyl diselenide, and was recrystallized from benzene.7°Lithium diisopropylamide (LDA) and other lithium dialkylamideswere prepared by the addition of a solution of methyllithium (1.0equiv.) in diethyl ether to a solution of the appropriate amine (1.1equiv.) in dry THF at -78 °C. The resulting solution was then stirred at0 °C for 5 min before use.Potassium hydride was obtained as 35% suspension in mineral oilfrom the Aldrich Chemical Company, inc. and was rinsed free of oil(with dry THF) and dried under stream of argon before use.Aqueous NH4CI-NH4OH (pH 8) was prepared by the addition of 50 mLof aqueous ammonium hydroxide (58%) to 1L of saturated aqueousammonium chloride.1 1 4All other reagents were commercially available and were utilizedwithout purification unless stated otherwise.07^1014(CH3)351012111301155.2 Experimental Procedures5.2.1 Synthetic Studies Toward the Total Synthesis of (±)-SubergorgicAcid (8)5.2.1.1 Preparation of the Enol Silyl Ether 1301:1^9^ 90^1312101To a cold (-78 °C), stirred solution (argon atmosphere) of the ketoketal 101 (1.80 g, 8.0 mmol) in dry CH2Cl2 (100 mL), were added Et3N(3.44 m L, 24 mmol) and Me3Sil (2.35 mL, 16 mmol). After the mixturehad been stirred at -78 °C for 30 min, saturated aqueous NaHCO3 (10mL) was added, and the mixture was allowed to warm to roomtemperature. The phases were separated, and the aqueous phase wasextracted with Et20 (3 x 10 mL). The organic extracts were combinedand dried over anhydrous MgSO4. Evaporation of the solvent gave theenol silyl ether 130 (2.19 g, 92%), as a colorless oil.The product was used without further purification. The productwas characterized with a sample obtained by distillation (120 °C/0.1mm Hg).1 1 6IR (neat): 2957, 1645, 1114 cm-1.1H NMR (400 MHz, CDCI3) 8: 0.12 (s, 9H, Me3Si-), 0.90 (s, 6H, Me-12and Me-13), 1.49 (m, 2H), 1.94 (dd, 1H, J=4.2, 2.4 Hz), 2.18-2.32 (m, 2H),2.36-2.62 (m, 2H), 3.03 (m, 1H, H-1), 3.38 (s, 2H, ketal CH2), 3.42 (s, 2H,ketal CH2), 4.55 (d, 1H, H-2, J=1.8 Hz).Mass Spectrum, m/z (relative intensity): 296 (M+, 37.8), 224 (6.3),210 (24.6), 209 (73.7), 206 (59.0), 168 (28.7), 167 (100.0), 128 (87.0).Exact Mass Calcd. for C16H2803Si: 296.1807, found: 296.1804.1 1 75.2.1.2 Preparation of the Enone Ketal 1001312100To a solution of Pd(OAc)2 (1.59 g, 7.1 mmol) in 90 mL of dryacetonitrile at rt was added a solution of 2.09 g (7.1 mmol) of thecrude enol silyl ether 130 in dry acetonitrile (10 mL). After themixture had been stirred at rt for 2 hr, it was filtered through a shortcolumn of Florisil (2 cm x 5 cm). The column was washed with Et20 andthe combined filtrate was concentrated under reduced pressure. A GLCanalysis of the residual oil showed that the enone 100 and ketone 101were present in a ratio of 94:6. Flash chromatography (4 cm x 25 cmsilica gel column, elution with 2:1 petroleum ether/Et0Ac) of theresidual material gave 1.29 g (72%) of enone 100  as a white solid.Recrystallization (hexane) provided long white needles that exhibitedm.p. 84-86 °C.IR (KBr): 2959, 1704, 1635, 1103 cm-1.1H NMR (400 MHz, CDCI3) 8: 0.94, 1.01 (s, s, 3H each, Me-12 and Me-13), 1.40 (dd, 1H, H-6a or p, J=6.2, 6.2 Hz), 2.08 (dd, 1H, H-4a or p, J=9.0,1.7 Hz), 2.60 (dd, 1H, H-4a or 13, J=9.0, 3.0 Hz), 2.65 (dd, 1H, H-6a or 13,J=6.2, 4.0 Hz), 2.87 (d, 1H, H-8a or fS, J=9.0 Hz), 2.99 (d, 1H, H-8a orJ=9.0 Hz), 3.12 (m, 1H, H-5), 3.47 (dd, 2H, ketal CH2, J=5.0 Hz), 3.52 (dd,2H, ketal CH2, J=5.0 Hz), 5.89 (s, 1H, H-2).1 1 8Detailed 1H NMR data, including those derived from COSYexperiments, are given in Table 16.13C NMR (75 MHz, CDCI3) 8: 22.36 (C-12), 22.40 (C-13), 30.08 (C-10), 38.15 (C-4), 42.05 (C-6 or C-8), 42.09 (C-6 or C-8), 43.42 (C-5),71.65 (C-9), 72.55 (C-11), 109.01 (C-7), 125.76 (C-2), 185.62 (C-1),209.66 (C-3).Mass Spectrum, m/z (relative intensity): 222 (M+, 100.0), 193(5.2), 181 (6.4), 154 (21.7), 137 (30.8), 128 (28.8), 109 (71.7).Exact Mass Calcd. for C13H1803: 222.1256, found: 222.1255.Anal. Calcd. for C131-11803: C, 70.25; H, 8.16, found: C, 70.36; H,8.30.Table 16. 1H NMR (400 MHz, CDCI3) and COSY (200 MHz, CDCI3) data forthe enone 100.H-x(assignment)11-1 NMR(400 MHz, CDCI3) 8COSY correlationsH-2 5.89 H-8a & pH-4a or 0 2.60 H-5, H-4a or 13H-4a or 0 2.08 H-5, H-4a or 13H-5 3.12 H-4a & 13, H-6a & pH-6a or 13 2.65 H-5, H-6a or 8H-6« or p 1.40 H-5, H-6a or 0H-8a & 13 2.87 & 2.99 H-2ketal CH2's 3.47 & 3.52 H-12 & H-13H-12 & H-13 0.94 & 1.01 ketal CH2'S1 1 95.2.1.3 Preparation of the Tricyclic Ketone 999^15613129917To a cold (-78 °C), stirred solution of the freshly distilled 4-chloro-2-trimethylstanny1-1-butene (89) (1.09 g, 4.28 mmol, 1.4equiv.) in 100 mL of dry THE was added a solution of MeLi in Et20 (2.85mL, 1.5 M, 4.28 mmol, 1.4 equiv.). After the solution had been stirred at-78 °C for 15 min, solid MgBr2.Et20 (1.10 g, 4.28 mmol, 1.4 equiv.) wasadded in one portion. After stirring at -78 °C had been continued foranother 10 min period, solid CuBr-Me2S (102 mg, 0.43 mmol, 0.14 equiv.)was added in one portion, followed by a solution of the enone 100 (678mg, 3.05 mmol, 1.0 equiv.) in dry THF (5 mL). The mixture was stirredat -78 °C for 10 min and dry DMPU (0.74 ml, 6.1 mmol, 2.0 equiv.) wasadded. The solution was stirred for an additional 15 min at -78 °C andwas allowed to warm up to rt. After stirring for 3 hr at rt, aqueousNH4CI-NH4OH (pH 8) and Et20 (50 mL) were added and the mixture wasfiltered through a short column of Florisil. The column was washedwith Et20 and the combined filtrate was concentrated under reducedpressure. Flash chromatography (2 cm x 15 cm silica gel column,elution with 3:1 petroleum ether/Et20) of the residual material, gave683 mg (81%) of the tricyclic ketone 99 as a white solid.Recrystallization (methanol) provided a white cubic crystals thatexhibited m.p. 59-61 °C.120IR (KBr): 2927, 1741, 1651, 1119 cm-1.1H NMR (400 MHz, CDCI3) s: 0.90, 0.93 (s, s, 3H each, Me-16 and Me-17), 1.80-1.96 (m, 3H, H-4a and 0, H-9a or p), 2.19 (d, 1H, H-11 a or 0,J=13.9 Hz), 2.32 (d, 1 H, H-11 a or 13 , J=13.9 Hz), 2.18-2.42 (m, 4H, H-3aand p, H-7a or p, H-9a or p), 2.47 (dd, 1H, H-7a or 0, J=18.5, 9.0 Hz), 2.57(m, 1H, H-8), 2.61 (m, 1H, H-5), 3.42 (d, 1H, ketal CH2, J=11.2 Hz), 3.46(d, 1H, ketal CH2, J=11.2 Hz), 3.50 (s, 2H, ketal CH2), 4.98 (t, 1H, H-12,J=1.8 Hz), 5.01 (t, 1H, H-12, J=1.8 Hz).Detailed 1H NMR data, including those derived from COSY anddecoupling experiments, are given in Tables 3 and 4.13C NMR (75 MHz, CDCI3) s: 22.39 (C-16, -ve), 22.43 (C-17, -ve),27.59 (C-4), 30.03 (C-14), 33.74 (C-3), 42.06 (C-7), 44.25 (C-8, -ve),45.02 (C-9 or C-11), 47.73 (C-9 or C-11), 58.80 (C-1), 60.21 (C-5, -ve),71.55 (C-13), 72.41 (C-15), 105.37 (C-12), 108.76 (C-10), 159.79 (C-2), 221.90 (C-6).Mass Spectrum, m/z (relative intensity): 276 (M+, 12.3), 207 (37.5),154 (8.6), 128 (100.0), 93 (27.1), 69 (64.0).Exact Mass Calcd. for C17H2403: 276.1725, found: 276.1725.Anal. Calcd. for C17H2403: C, 73.88; H, 8.75, found: C, 74.04; H,8.69.121Table 3. 1H NMR (400 MHz, CDCI3) and COSY (400 MHz, CDCI3) data forthe Keto Alkene 99.H-x(assignment)1H NMR(400 MHz, CDCI3) 8COSY correlationsaH-4a & 13H-9a or 131.80-1.96 H-5, H-8H-5 and H-8 2.57 & 2.61 H-4a & p, H-7a & ii,H-9a & 15H-7a or p 2.47 H-7f3 or a, H-8ketal CH2's 3.42, 3.46 & 3.50 H-16 & H-17H-16 & H-17 0.90 & 0.93 ketal CH2' Sa) Only those COSY correlations that could be unambigously assignedare recordedTable 4. 1H NMR (400 MHz, CDCI3) and decoupling experiments (400MHz CDC! data for the Keto Alkene 99.irradiated^signals observed signalsassignmentH-x1H NMR (400MHz, CDCI3)8 ppm (mult. J, H-x) mult.^afterirradiationH-4a and 13(H-9 alsoirradiated)1.80-1.96 2.18-2.42 (m, 4H,H-3a and I-3, H-7, H-9)2.57 (m, H-8)2.61^(m, H-5)sharpened mdd (J=9.0, 3.0)sH-1 1a or 13 2.19 2.32 (m, H-11r3 or a) sH-5 & H-8 2.57 and 2.61 1.80-1.96 (m, 3H,H-4a & 13,H-9a or 13)2.18-2.42 (m, 4H,H-3a and p, H-7, H-9)sharpened msharpened mH-12 4.98 and 5.01 2.18-2.42 (m, 4H,H-3a and p, H-7, H-9)sharpened m1225.2.1.4 Preparation of the Chloro Ketone 132132To a cold (-78 °C), stirred solution of the freshly distilled 4-chloro-2-trimethylstanny1-1-butene (89) (101 mg, 0.42 mmol, 1.35equiv.) in 20 mL of dry THF was added a solution of MeLi in Et20 (0.33mL, 1.5 M, 0.5 mmol, 1.6 equiv.). After the solution had been stirred at-78 °C for 15 min, solid MgBr2.Et20 (129 mg, 0.5 mmol, 1.6 equiv.) wasadded in one portion. After stirring for another 10 min solid CuBr.Me2S(23 mg, 0.09 mmol, 0.03 equiv.) was added in one portion, followed by asolution of the enone 100 (70 mg, 0.31 mmol, 1.0 equiv.) in dry THE (2mL). The reaction mixture was stirred at -78 °C for another 30 min.Aqueous NH4CI-NH4OH (pH 8) was added, followed by Et20 and theresultant mixture was opened to the atmosphere and was stirredvigorously until the aqueous layer was blue. The phases wereseparated, and the aqueous layer was extracted with Et20 (3 x 10 mL).The combined organic extracts were washed with brine, dried (MgSO4),and concentrated under reduced pressure. Flash chromatography (1 cmx 12 cm column, 2:1 petroleum ether/Et20) of the residual material,followed by distillation (120 °C/0.1 mmHg) of the liquid thus obtained,give 74.5 mg (77%) of the chloro ketone 135 as a colorless oil.IR (neat): 2956, 1742, 1638, 1116 cm-1.1231H NMR (400 MHz, CDCI3) s: 0.96, 0.97 (s, s, 3H each, Me-16 and Me-17), 1.87 (dd, 1H, H-6a, J=14.5, 8.0 Hz), 2.22 (m, 3H, H-4a or 0, H-8a &13),2.36 (d, 1H, H-60, J=14.5 Hz), 2.43 (m, 1H, H-4a or fis ) , 2.54 (m, 4H, H-2« & [3 , H-10), 2.89 (ddd, 1H, H-5, J=16.0, 8.0, 2.5 Hz), 3.45 (s, 2H, ketalCH2), 3.48 (s, 2H, ketal CH2), 3.67 (t, 2H, H-11, J=8.0 Hz), 4.91 (s, 1H, H-12), 5.01 (s, 1H, H-12).Detailed 1H NMR data, including those derived from COSYexperiments, are given in Table 1.13C NMR (50 MHz, CDCI3) 8: 22.37 (C-16 and C-17, -ve), 30.02 (C-14), 35.25, 40.72 (C-5, -ve), 41.53, 43.07, 43.49, 46.06, 49.50, 53.70(C-1), 71.94 (C-13), 72.04 (C-15), 108.36 (C-7), 109.87 (C-12), 148.91(C-9), 218.15 (C-3).Mass Spectrum, m/z (relative intensity): 312 (M+, 3.8), 277 (5.4),243 (10.6), 155 (10.8), 129 (15.8), 128 (100.0), 69 (96.6).Table 1. 1H NMR (400 MHz, CDCI3) and COSY (200 MHz, CDCI3) data forthe chloroketone 132.H-x(assignment)1H NMR(400 MHz, CDCI3) 8COSY CorrelationsaH-4a or 13 2.43 H-5H-5 2.89 H-4a or 0,H-6a and 13H-613 2.36 H-5, H-6aH-6a 1.87 H-5, H-6(3ketal CH21s 3.45 & 3.48 H-16 & H-17H-16 & H-17 0.96 & 0.97 ketal CF121Sa) Only those COSY correlations that could be unambigously assignedare recorded1245.2.1.5 Preparation of Tricyclic Ketone 99 from Chloro Ketone 13299To a stirred suspension of KH (13.2 mg, 0.33 mmol, 3 equiv.) in 2.5mL of dry THF, was added a solution of the chloro ketone 132 (33 mg,0.11 mmol, 1 equiv.) in dry THF. After the mixture had been stirred atrt for 3 hr, aqueous NH4CI was added, followed by Et20. The phaseswere separated, and the aqueous phase was extracted with Et20 (3 x 2mL).^The combined organic extracts were dried (MgSO4) andconcentrated under reduced pressure.^The residual material thusobtained was distilled (120 °C/0.1 mm Hg) to give 27.4 mg (94%) of theketone 99 as a colorless oil which solidified upon cooling to rt. Thespectral properties observed for this material were identical withthose described for the compound 99 obtained previously (pp 119-121).1255.2.1.6 Preparation of the Alcohol 13511:HO1615135To a cold (0 °C), stirred suspension of L1AIH4 (30 mg, 0.75 mmol,1.5 equiv.) in 20 mL of dry THE was added a solution of the ketone 99(158 mg, 0.57 mmol, 1 equiv.) in 2 mL of dry THF. After the mixture hadbeen stirred at 0 °C for 30 min, solid Na2SO4.10H20 was added in oneportion. The slurry thus formed was filtered through a sintered glassfunnel and the collected material was rinsed with Et20. The combinedfiltrates were dried (MgSO4) and concentrated under reduced pressureto provide a crude product as a white solid. Recrystallization (pentane)provided 155 mg (97%) of the alcohol 135 as white cubic crystals thatexhibited m.p. 80-81 °C.IR (KBr): 3296, 2956, 1647, 1111 cm-1.1H NMR (400 MHz, CDCI3) 8: 0.91, 0.99 (s, s, 3H each, Me-16 and Me-17), 1.37 (m, 1H, H-4a), 1.67 (dt, 1H, H-7a or 13, J.13.3, 4.9 Hz), 1.85 (m,1H, H-413), 2.06 (d, 1H, H-11 a ore, J=14 Hz), 2.14 (m, 1H, H-7a or e), 2.20(m, 1H, H-5), 2.12-2.42 (m, 5H, H-3a and 13, H-8, H-9a and 0), 2.45 (d, 1H,H-11a or 0, J=14 Hz), 3.06 (br, 1H, -OH, exchanges with D20), 3.44 (s,2H, ketal CH2), 3.51 (s, 2H, ketal CH2), 3.84 (br, 1H, H-6), 4.84 (s, 1H, H-12), 4.86 (s, 1H, H-12).Detailed 1H NMR data, including those derived from COSY, nOe anddecoupling experiments, are given in Tables 6 and 17.1317126130 NMR (100 MHz, CDCI3) 8: 22.43 (C-16, -ve), 22.59 (C-17, -ve),28.35 (C-4), 30.02 (0-14), 33.44 (0-7), 41.76 (C-9 or C-11), 41.96 (C-9or C-11), 48.20 (0-3), 48.32 (C-8, -ve), 61.56 (C-1), 61.87 (C-5, -ve),71.40 (C-13), 72.63 (0-15), 79.07 (0-6, -ve), 104.07 (0-10), 110.45 (C-12), 162.76 (0-2).Mass Spectrum, m/z (relative intensity): 278 (M+, 0.9), 260 (8.0),240 (6.5), 207 (105), 128 (100.0).Exact Mass Calcd. for C17H2603: 278.1882, found: 278.1884.Table 6. 1H NMR (400 MHz, CDCI3), COSY (200 MHz, CDCI3) and nOe (400MHz CDCI data for the alcohol 135.AssignmentH-x1H NMR(400MHz, CDCI3) 8COSYcorrelationsanOecorrelationsH-413 1.85 H-4a, H-5H-4a 1.37 H-413, H-5 1.85 (H-40)3.84 (H-6)H-5 2.20 H-4a & 13, H-6H-6 3.84 -OH, H-5,H-7a & 131.37 (H-4a)2.14 (H-7a or 13)2.30 (H-8)3.06 (-OH)-OH 3.06 H-6 3.84 (H-6)H-7a or 13 1.67 H-6, H-7a or 13 2.14 (H-7a or 13)3.84 (H-6)H-7a or 13 2.14 H-6, H-7a or 13H-11a 01'13 2.06 H-1113 or a 2.45^(H-11)H-1 1i3 or a 2.45 H-11a or ft 2.06^(H-11)H-13 & H-15 3.44 & 3.51 H-16 & H-17H-16 & H-17 0.91 & 0.99 H-13 & H-15a) Only those COSY correlations that could be unambigously assignedare recorded127Table 17. Decoupling experiments (400 MHz, CDCI3) data for thealcohol 135irradiated^signals observed signalsassignmentH-x1H NMR (400MHz, CDCI3)6 ppm (mult., H-x) mult.^afterirradiationH-4a 1.37 1.85 (m, H-413) sharpened mH-7a or p 1.67 2.14 (m, H-7« or p)_ sharpened mH-4p 1.85 1.37 (m, H-4a)2.30 (m, H-3)2.36 (m, H-3)sharpened msharpened msharpened m-OH 3.06 3.84 (m, H-6) q (J=4.9 Hz)5.2.1.7 Preparation of the Alcohol 136HO1716136To a cold (-78 °C), stirred solution of L-Selectride (Aldrich) (400of a 1.0 M solution in THF, 0.4 mmol, 2.0 equiv.) in 5 mL of dry THFwas added a solution of the ketone 99 (55 mg, 0.20 mmol, 1 equiv.) in 2mL of dry THF. After the solution had been stirred at -78 °C for 3 hr, a5% solution of KOH in Me0H (30 pl) was added followed by 60 pt ofH202 (30% wt. solution in water). The reaction mixture was filteredthrough a short column of Florisil, and eluted with Et20. The combinedfiltrates were dried (MgSO4) and concentrated under reduced pressure.Flash chromatography (1 cm x 6 cm silica gel column, eluting with 3:1128petroleum ether/ether) of the crude material produced 51 mg (92%) ofthe alcohol 136 as a white solid. Recrystallization (pentane) providedwhite needles that exhibited m.p. 80-82 °C.IR (KBr): 3213, 2956, 1655, 1109 cm-1.1H NMR (400 MHz, CDCI3) 8: 0.89, 0.98 (s, s, 3H each, Me-16 and Me-17), 1.33 (br s, 1H, -OH, exchanges with D20), 1.61 (m, 1H, H-4a or 13),1.68 (m, 1H, H-4a or p), 1.80 (m, 3H, H-7a and p, H-9a or p), 2.07 (d, 1H,H-11a or 13 , J=13.8 Hz), 2.17 (d, 1H, H-9a or fi , J=12.1 Hz), 2.19 (d, 1H, H-11 a or 0, J=13.8 Hz), 2.33-2.47 (m, 4H, H-3a and (3 , H-5, H-8), 3.44 (dd,4H, ketal CH2's, J=11.5 Hz), 4.43 (q, 1H, H-6, J=6.6 Hz), 4.81 (s, 1H, H-12), 4.88 (s, 1H, H-12).Detailed 1H NMR data, including those derived from COSYexperiments, are given in Table 18.13C NMR (100 MHz, CDCI3) 8: 22.45 (C-16, -ye), 22.63 (C-17, -ye),23.83 (C-4), 29.95 (C-14), 35.06 (C-7), 40.11 (C-9 or C-11), 41.81 (C-9or C-11), 46.73 (C-8, -ve), 48.13 (0-3), 57.46 (C-5, -ye), 60.67 (0-1),72.05 (0-13 and C-15), 74.86 (C-6, -ve), 103.57 (0-12), 109.34 (0-10),163.34 (C-2).Mass Spectrum, m/z (relative intensity): 278 (M+, 2.6), 260 (18.2),240 (8.0), 207 (15.7), 128 (100.0).Exact Mass Calcd. for C17H2603: 278.1882, found: 278.1883.1 29Table 18. 1H NMR (400 MHz, CDCI3) and COSY (200 MHz, CDCI3) data forthe alcohol 136AssignmentH-x1H NMR(400 MHz, CDCI3) 8COSY correlationsaH-4a or p 1.61 H-4a or pH-4a Or 13 1.68 H-4a or pH-6 4.43 H-7a & 13H-7a & 13,H-9a or p1.80 H-6, H-9a or DH-9a or 13 2.17 H-8, H-913 or aH-11a or p 2.07 H-11p or aH-11p or a 2.19 H-11a or pketal CH2's 3.44 H-16 & H-17H-16 & H-17 0.89 & 0.98 ketal C Hi Sa) Only those COSY correlations that could be unambigously assignedare recorded5.2.1.8 Sodium Borohydride Reduction of the Ketone 99To a cold (0 °C), stirred solution of the ketone 99 (352 mg, 1.28mmol, 1.0 equiv.) in 1% KOH in Me0H (25 mL) was added solid NaBH4(75.2 mg, 1.9 mmol, 1.5 equiv.). After the reaction mixture had beenstirred at 0 °C for 20 min, the Me0H was evaporated under reducedpressure and the residue partitioned between brine and Et20. Thephases were separated and the aqueous layer was extracted with Et20(3 x 10 mL). The combined organic extracts were dried (MgSO4) andconcentrated under reduced pressure to yield 345.1 mg (97%) ofalcohols 135 and 136, as a 3:1 mixture of epimers."F.4^411. 0^1711i^•^0^151219^18CH3SC(S)017 19^18CH3SC(S)01305.2.1.9 DIBAL-H Reduction of the Ketone 99To a cold (-78 °C), stirred solution of DIBAL-H (420 gl_ of 1.0 Msolution in hexanes, 0.42 mmol, 2.0 equiv.) in 10 mL of dry THF wasadded a solution of the ketone 99 (58.6 mg, 0.21 mmol, 1 equiv.) in 2mL of dry THE. After the solution had been stirred at -78 °C for 3 hr, a5% solution of KOH in Me0H (30 I.LL) was added followed by 60 pt ofH202 (30% wt. solution in water). The mixture was filtered through ashort column of Florisil, and eluted with Et20. The combined filtrateswere dried (MgSO4) and concentrated under reduced pressure to provide55.5 mg (95%) of alcohols 135 and 136, as a 1:4 mixture of epimers."5.2.1.10 Preparation of the Methyl Xanthates 137 and 138137^13816To a cold (0 °C), stirred solution of the alcohols 135  and 1 36(approx. 3:1 mixture of epimers) (217 mg, 0.78 mmol, 1.0 equiv.) in 10mL of dry THF was added solid KH (56.2 mg, 2.34 mmol, 3.0 equiv.) inone portion. After the mixture had been stirred at rt for 2 hr, freshlydistilled CS2 (59 111.., 0.98 mmol, 1.25 equiv.) was added and theresulting mixture was stirred for an additional 1 hr. Freshly distilled131Mel (61 4, 0.98, 1.25 equiv.) was added and the mixture was stirredfor an 18 hr period. The reaction mixture was treated with 2 mL ofwater and 10 mL of Et20. The phases were separated and the aqueouslayer was extracted with Et20 (3 x 5 mL). The organic extracts werecombined, dried (MgSO4) and concentrated under reduced pressure. Dripcolumn chromatography (2 cm x 15 cm silica gel column, 3:1 petroleumether/Et20) of the crude product gave 223.8 mg (78%) of the xanthates137 and 138 as a 3:1 mixture of epimers.89IR (film): 2952, 1651, 1226 cm-1.1H NMR (400 MHz, CDCI3) 8 (signals due to the minor isomer aregiven in brackets): 0.91, 1.02 (0.92, 1.00) (s, s, 3H each, Me-16 and Me-17), 1.48 (1.60) (m, 1H), 1.90 (1.70) (m, 2H), 2.01-2.12 (m, 2H, bothisomers), 2.12-2.50 (m, 7H, both isomers), 2.53 (2.51) (s, 3H, H-19),2.67 (2.81) (m, 1H, H-6), 3.46-3.55 (m, 4H, ketal CH2's, both isomers),4.89 (s, 1H, H-12, both isomers), 4.99 (4.94) (s, 1H, H-12).Mass Spectrum, rrilz (relative intensity): 368 (M+, 7.8), 261 (78.9),175 (79.9), 149 (55.3), 128 (100.0), 91 (35.2).18Ph OC(S)0151491325.2.1.11 Preparation of the Phenyl Thionocarbonate 149To a stirred solution of the alcohol 136 (45.3 mg, 0.16 mmol, 1.0equiv.) in 8 mL of dry acetonitrile were added DMAP (80 mg, 0.65 mmol,4.0 equiv.) and phenyl chlorothionocarbonate (33 j.L, 0.24 mmol, 1.5equiv.). After the reaction mixture had been stirred for 24 hr at rt, itwas concentrated under reduced pressure The residue was partitionedbetween water (2 mL) and Et0Ac (5 mL), and the phases were separated.The aqueous layer was extracted with Et0Ac (2 x 2 mL). The combinedorganic extracts were washed with 0.1 M HCI, followed by aqueousN a HCO3 and brine. The organic extracts were dried (MgSO4) andconcentrated under reduced pressure. Two sequential flashchromatographies (1 cm x 15 cm silica gel column, 3:1 hexanes/Et20; 1cm x 12 cm silica gel column, 5:1 hexanes/Et20) of the residue thusobtained, provided 51 mg (76%) of the phenyl thionocarbonate 149 as awhite solid that exhibited m.p. 89-91 °C (decomposes).IR (KBr): 2955, 1775, 1737, 1650, 1594, 1491, 1112 cm-1.1H NMR (400 MHz, CDCI3) 8: 0.91, 0.98 (s, s, 3H each, Me-16 and Me-17), 1.61 (m, 1H, H-4a), 1.71 (m, 1H, H-4I3), 1.90 (dd, 1H, H-913, J=13.4,5.5 Hz), 2.07-2.15 (m, 2H, H-7a and f3), 2.19 (m, 3H, H-9a, H-11a and p),1332.31-2.48 (m, 3H, H-3« and p, H-8), 2.79 (q, 1H, H-5, J=7.4 Hz), 3.46 (m,4H, ketal CH2's), 4.86 (s, 1H, H-12), 4.90 (s, 1H, H-12), 5.81 (q, 1H, H-6,J=7.4 Hz), 7.07 (m, 2H, Ph), 7.26 (m, 1H, Ph), 7.38 (m, 2H, Ph).Detailed 1H NMR data, including those derived from COSY, nOe anddecoupling experiments, are given in Tables 8 and 19.13C NMR (75 MHz, CDCI3) s: 22.47 (C-16, -ye), 22.61 (C-17, -ve),25.05, 30.03 (C-14), 34.81, 36.30, 41.44, 46.46 (C-5 or C-8, -ve),48.45, 54.77 (C-5 or C-8, -ye), 60.76, 71.83 (C-13), 72.32 (C-15), 87.37(C-6, -ye), 104.22, 109.03, 121.87, 121.91 (-ye), 126.40 (-ye), 129.44(-ye), 153.31, 162.39, 194.64 (C-18).Mass Spectrum, m/z (relative intensity): 260 (M-PhOC(S)OH, 13.0),174 (13.3), 128 (79.5).Exact Mass Calcd. for C24H30SO4: 414.1865, found: 414.1860.Table 19.^Decoupling experiments (400 MHz, CDCI3) data for thehen vi thionocarbonate 149irradiated^signals observed signalsassignment 1H 11-I NMR mult.^afterH-x lIvil (mult., J, H-x) 8 irradiationH-5 2.79 1.61^(m, H-4a) sharpened m1.71 (m, H-4p) sharpened m5.81 (q, J= 7.4, H-6) t (J=7.4)H-6 5.81 2.79 (q, J= 7.4, H-5) t (J=7.4)2.07-2.15 (m,^H-7« & p) sharpened mH-8 2.31 1.71 (m, H-4p) sharpened m(H-3« and 0 -2.48 1.90 (dd, J=13.4, 5.5, H-9p) d (J=13.4)also 2.07-2.15 (m, H-7) br dirradiated) 2.19 (m, H-9a) sharpened mH-9p 1.90 2.19 (m, H-9a) sharpened mH-9a 2.19 1.90 (dd, J=13.4, 5.5, s(H-11^also H-9p) sharpened mirradiated) 2.31-2.48 (m, H-8)134Table 8. 1H NMR (400 MHz, CDCI3), COSY (200 MHz, CDCI3) and nOe (400MHz CDCI) data for the Dhenyl thionocarbonate 149.AssignmentH-x1H NMR(400 MHz, CDCI3) sCOSYcorrelationsanOecorrelationsH-4i3 1.71 H-5 1.61^(H-4a)2.79 (H-5)H-4a 1.61 H-5H-5 2.79 H-4a & 0, H-6^1.71^(H-413)2.19 (H-11p)5.81^(H-6)H-6 5.81 H-5,H-7a & f 31.90 (H-90)2.07-2.15(H-7a & 13)2.79 (H-5)H-7a & 0 2.07-2.15 H-6H-9p 1.90 H-9a 2.19 (H-9a)5.81^(H-6)H-9a 2.19 H-913ketal CH21s 3.46 H-16 & H-17H-16 & H-17 0.91 & 0.98 ketal CH21sa) Only those COSY correlations that could be unambigously assignedare recorded1355.2.1.12 Preparation of the Phenyl Thionocarbonate 14818Ph OC(S)0148Using the previously described procedure, the alcohol 135 (1.49 g,5.36 mmol) was converted to the corresponding phenyl thionocarbonate148 in 1.57 g (71%) isolated yield. The white solid thus obtainedexhibited m.p. 83-86 °C (decomposes).IR (KBr): 2953, 1784, 1652, 1592, 1491, 1123 cm-1.1H NMR (400 MHz, CDCI3) a: 0.93, 1.02 (s, s, 3H each, Me-16 and Me-17), 1.60 (m, 1H, H-4a), 1.87 (m, 1H, H-413), 1.93 (m, 1H, H-713), 2.07 (m,1H, H-9a or 0), 2.20 (m, 3H, H-11a and 0, H-8), 2.32-2.50 (m, 4H, H-3aand 0, H-7«, H-9« or 13), 2.69 (m, 1H, H-5), 3.49 (m, 4H, ketal CH2's), 4.91(m, 1H, H-12), 4.98 (s, 1H, H-12), 5.32 (dd, 1H, H-6, J.11.3, 5.7 Hz),7.10 (m, 2H, Ph), 7.28 (1H, Ph), 7.40 (m, 2H, Ph).Detailed 1H NMR data, including those derived from COSY and nOeexperiments, are given in Table 7.13C NMR (75 MHz, CDCI3) 8: 22.50 (C-16, -ve), 22.64 (C-17, -ye),27.48, 30.06 (C-14), 33.24, 36.70, 41.06, 47.96 (C-3), 48.02 (C-8, -ve),58.22 (C-5, -ve), 60.42 (C-1), 71.97 (C-13), 72.10 (C-15), 90.53 (C-6,-ye), 105.31 (C-12), 109.59 (C-10), 122.00 (Ph, -ve), 126.43 (Ph, -ye),129.47 (Ph, -ve), 153.34 (Ph), 161.71 (C-2), 194.81 (C-18).136Mass Spectrum, m/z (relative intensity): 414 (M+, 0.2); 260 (23.9);175 (24.3); 141 (17.5); 128 (100.0).Exact Mass Calcd. for C24H30SO4: 414.1864, found: 414.1864.Table 7. 1H NMR (400 MHz, CDCI3), COSY (200 MHz, CDCI3) data and nOeexperiments 400 MHz, CDC! for the phenyl thionocarbonate 148.AssignmentH-x1H NMR(400 MHz, CDCI3) 8COSYcorrelationsanOecorrelationsH-4a 1.60 H-4(3, H-5 1.87 (H-4(3)5.32 (H-6)H-4f3 1.87 H-4a, H-5 1.60 (H-4a)2.69 (H-5)H-5 2.69 H-4a & 11, H-6 1.87 (H-413)2.20^(H-1113)5.32 (H-6)H-6 5.32 H-5, 1.60 (H-4a)H-7a and 13 2.32-2.50(H-3a & H-7a)2.69 (H-5)H-7r3 1.93 H-6, H-7aketal CH2's 3.49 H-16 & H-17H-16 & H-17 0.93 & 1.02 ketal CH2ISa) Only those COSY correlations that could e unambigously assignedare recorded1375.2.1.13 Preparation of the Alkene 102 from the Xanthates 137/138102To a stirred solution of the methyl xanthates 137 and 138 (3:1ratio, 190 mg, 0.52 mmol, 1.0 equiv.) in 10 mL of dry benzene wereadded tributyltin hydride (210 pi, 0.78 mmol, 1.5 equiv.) and solid AIBN(10 mg, 0.06 mmol, 0.12 equiv.). After the reaction mixture had beenheated to reflux for a 2 hr, the solution was concentrated under reducedpressure. Two consecutive flash chromatographies (2 cm x 15 cmsilica gel column, eluting with 50 mL of petroleum ether followed by a1 cm x 15 cm silica gel column eluting with 10:1 petroleum ether/Et20)of the residue thus obtained, produced a colorless oil. Distillation (80°C/0.1 mmHg) of the crude product provided 67.8 mg (50%) of the ketalalkene 102 as a colorless oil.IR (neat): 2954, 1728, 1650, 1123 cm-1.1H NMR (400 MHz, CDCI3) 8: 0.91, 1.02 (s, s, 3H each, Me-16 and Me-17), 1.28 (m, 1H), 1.37 (m, 1H), 1.46 (m, 1H), 1.69-1.82 (m, 3H), 1.88 (m,1H), 2.02 (d, 1H, H-110, J=14.0 Hz), 2.16 (ddd, 1H, H-9a, J=13.5, 8.7, 1.8Hz), 2.25 (d, 1H, H-11a, J=14.0, 1.8 Hz), 2.24-2.42 (m, 4H, H-3a and 0, H-913), 3.45 (s, 2H, ketal CH2), 3.46 (d, 1H, ketal CH2, J=11.0 Hz), 3.52 (d,1H, ketal CH2, J=11.0 Hz), 4.83 (br s, 1H, H-12), 4.91 (br s, 1H, H-12).1 3 8Detailed 1H NMR data, including those derived from COSY and nOeexperiments, are given in Table 20.13C NMR (75 MHz, CDCI3) 8: 22.47 (C-16, -ve), 22.68 (C-17, -ve),29.66, 30.02 (C-14), 30.92, 31.40, 34.35 (C-9 or C-11), 47.98 (C-3),50.80 (C-8, -ve), 53.69 (C-5, -ye), 61.84 (C-1), 71.89 (C-13), 72.13 (C-15), 104.07 (C-12), 109.61 (C-10),163.42 (C-2).Mass Spectrum, m/z (relative intensity): 262 (M+, 8.6), 167 (11.5,(128, 100.0), 119 (10.9).Exact Mass Calcd. for C17H2602: 262.1932, found: 262.1930.Table 20. Decoupling experiments (400 MHz, CDCI3) on the ketalalkene 102irradiated^signals observed signalsassignmentH-x1H NMR (400MHz, CDCI3) 81H NMR(MUlt.,^J,^H-x)mutt.^afterirradiation1.88 1.37 (m) sharpened m1.46 (m) sharpened m1.69-1.82 (m, 3H) sharpened mH-1113 2.02 2.25 (dd, H-11 a, d (J.1.8)(d, J=14.0) J=14.0, 1.8)H-9a 2.16 (ddd, 1.69-1.82 (m, 3H) sharpened mJ=13.5, 8.7, 1.8) 2.24-2.42 (m, 4H) sharpened m2.25 (dd, H-11 a, d(J=14.0)J=14.0, 1.8)H-11 a 2.25 (d, 2.02 (d, H-11p, sJ=14.0, 1.8) J=14.0)2.16 (ddd, H-9a, dd (J=13.5, 8.7)J.13.5, 8.7, 1.8)H-12 4.91^(br s) 2.24-2.42 sharpened m1395.2.1.14^Preparation of the Alkene 102 from the PhenylThionocarbonate 148102To a stirred solution of the phenyl thionocarbonate 148 (772 mg,1.87 mmol, 1 equiv.) in dry benzene (50 mL) were added tributyltinhydride (1.0 mL, 3.73 mmol, 2 equiv.) and solid AIBN (15 mg, 0.1 mmol).After the reaction mixture had been heated to reflux for 2 hr, thesolution was cooled to rt and concentrated under reduced pressure.Two consecutive column chromatographies (3 cm x 15 cm silica gelcolumns, eluting the first column with petroleum ether, and the secondcolumn with 5:1 petroleum ether/Et20) of the material thus obtainedgave a colorless oil. The crude product thus obtained was distilled (80°C/0.1 mm Hg) to provide 425 mg (87%) of the alkene 102. Thespectral properties observed for this material were identical withthose described for the compound 102 obtained previously (pp 137-138).1405.2.1.15^Preparation of the Alkene 102  from the PhenylThionocarbonate 149102Using the previously described procedure, the phenylthionocarbonate 149 (193.4 mg) was converted to the alkene 102 in102.2 mg (83%) isolated yield. The spectral properties observed forthis material were identical with those described for the compound102 obtained previously (pp 137-138).5.2.1.16 Preparation of the Keto Ketal 103103To a stirred solution of the alkene 102 (101 mg, 0.39 mmol, 1equiv.), in 6 mL of CCI4, 6 mL of acetonitrile and 9 mL of water wereadded solid Na104.H20 (329 mg, 1.54 mmol, 4 equiv.) and solid Ru02.xH20(5.5 mg, 0.04 mmol, 0.03 equiv.). After the reaction mixture had been141stirred at rt for 1 hr, the phases were separated and the aqueous layerwas extracted with 2 mL CCI4. lsopropanol (0.5 mL) was added to thecombined organic extracts and stirring was continued at rt for another1 hr period. The slurry was filtered through a column of Florisil (2 cmx 10 cm, eluting with Et20 (50 mL)). The combined filtrates wereconcentrated under reduced pressure. Flash chromatography (1 cm x 12cm silica gel column, 3:1 petroleum ether/Et20) and distillation (100°C/0.1 mmHg) of the crude product produced 79 mg (79%) of the ketoketal 103 as a colorless oil.IR (neat): 2952, 1732, 1114 cm-1.1H NMR (400 MHz, CDCI3) 8: 0.92, 0.93 (s, s, 3H each, Me-15 and Me-16), 1.38 (m, 1H, H-70), 1.54 (m, 1H, H-9p), 1.64 (m, 1H, H-4a or 13), 1.87(m, 1H, H-9a), 1.93-2.07 (m, 5H, H-11a or 13 , H-4a or 13 , H-6a and p, H-7a), 2.16 (m, 1H, H-11a or p), 2.23 (m, 1H, H-3a or 8), 2.39 (m, 1H, H-3aor 0), 2.50 (m, 1H, H-8), 2.55 (m, 1H, H-5), 3.48 (m, 4H, ketal CH2's).Detailed 1H NMR data, including those derived from COSYexperiments, are given in Table 9.13C NMR (75 MHz, CDCI3) 8 : 22.52 (C-15, -ve), 22.54 (C-16, -ve),24.00, 29.94 (C-13), 32.48, 33.02, 36.58 (C-3), 39.95 (C-9 or C-11),42.68 (C-9 or C-11), 47.68 (C-5 or C-8, -ye), 49.35 (C-5 or C-8, -ye),64.74 (C-1), 71.45 (C-12), 72.67 (C-14), 109.84 (C-10), 224.47 (C-2).Mass Spectrum, m/z (relative intensity): 264 (M+, 4.3), 208 (21.6),128 (100.0), 123 (24.2), 95 (13.5).Exact Mass Calcd. for C16H2403: 264.1726, found: 264.1728.Anal. Calcd. for C16H2403: C 72.69%; H 9.15%, found: C 72.43%; H9.04%.0.5.2.1.17 Preparation of Diketone 104001104142Table 9. 1H NMR and COSY (400 MHz, CDCI3) data for the keto ketal103.H-x(assignment)1H NMR(400 MHz, CDCI3) 8COSY correlationsaH-3a or 13 2.23 H-3a or 13 , H-4a & 13H-3a or 13 2.39 H-3a or p, H-4a & 13H-4a or 13 1.64 H-3a & p, H-4a or 13, H-5H-5 2.55 H-4a and p, H-6« and pH-713 1.38 H-7a, H-913H-913 1.54 H-713, H-8, H-9aH-8 2.50 H-7a, H-9a and pH-9a 1.87 H-7a, H-8, H-913ketal CH21s 3.48 H-15 & H-16H-15 & H-16 0.92 & 0.93 ketal CH2'sa) Only those COSY correlations that could be unambigously assignedare recordedA solution of the keto ketal 103 (46 mg, 0.17 mmol) in a mixtureof acetone and 5% aqueous HCI (1:1, 10 mL) was stirred at rt for 20min. Diethyl ether (5 mL) was added and the phases were separated.The aqueous layer was extracted with Et20 (3 x 3 mL). The combinedorganic extracts were washed with water, aqueous NaHCO3, brine, anddried (MgSO4). The mixture was concentrated under reduced pressure,143and the residual material distilled (90 °C/0.1 mmHg) give 28.9 mg(93%) of the diketone 104 as colorless oil.IR (neat): 2955, 1741 cm-1.1H NMR (400 MHz, CDCI3) 8: 1.48 (dd, 1H, J.12.0, 6.0 Hz), 1.66 (m,2H), 2.02-2.18 (m, 5H), 2.32 (ddd, 1H, J.18.5, 9.0, 6.0 Hz), 2.50 (ddd, 1H,J.16.5, 9.0, 0.5 Hz), 2.56 (m, 1H), 2.65 (dd, 1H, H-11a or p, J.18.5, 1.4Hz), 2.68 (m, 1H), 2.72 (dd, 1H, H-11a or f3, J=18.5, 1.5 Hz).13C NMR (75 MHz, CDCI3) 8: 25.21, 32.41, 33.40, 37.12 (C-3), 44.05(C-9 or C-11), 45.77 (C-8, -ve), 46.26 (C-9 or C-11), 49.01 (C-5, -ve),62.87 (C-1), 217.08 (C-10), 222.01 C-2).Mass Spectrum, m/z (relative intensity):^178 (M+, 60.6), 150(13.9), 136 (100.0), 123 (85.9).Exact Mass Calcd. for Ci1H1402: 178.0994, found: 178.0994.15512 161445.2.1.18 Preparation of the Enone Ketal 156 via the Enol Silyl Ether1 5 51 5 6To a cold (-78 °C), stirred solution of the keto ketal 103 (360 mg,1.36 mmol, 1.0 equiv.) in 100 mL of dry CH2Cl2 were added freshlydistilled Et3N (568 gL, 4.08 mmol, 3.0 equiv.) and Me3Sil (387 pt, 2.7mmol, 2.0 equiv.). After the mixture had been stirred at -78 °C for 2hr, a saturated aqueous NaHCO3 solution (20 mL) was added. The phaseswere separated, and the aqueous layer was extracted with Et20 (3 x 10mL). The combined organic extracts were dried (MgSO4) andconcentrated under reduced pressure to gave the enol silyi ether 155.IR (neat): 2953, 1645, 1113 cm-1. This product was used withoutfurther purification.To a stirred solution of Pd(OAc)2 (305 mg, 1.36 mmol) in 100 mL ofdry acetonitrile was added a solution of the crude enol silyl ether 155in dry acetonitrile (5 mL). After the mixture had been stirred at rt for2 hr, it was filtered through a short column of Florisil (1 cm x 5 cm,elution with Et20 (50 mL)). Concentration of the filtrate under reducedpressure, followed by a flash chromatography (2 cm x 12 silica gelcolumn, elution with 10:1 petroleum ether-Et0Ac) of the residual145material, gave 264.2 mg (74%) of the enone ketal 156 as a white solid.Recrystalization (hexane) provided material that exhibited m.p. 87-88°C.IR (KBr): 2949, 1697, 1584, 1122 cm-1.1H NMR (400 MHz, CDCI3) 8: 0.95, 1.01 (s, s, 3H each, H-15 and H-16), 1.52 (m, 3H), 1.79 (ddd, 1H, H-9a or [3 J=14.0, 7.0, 1.5 Hz), 2.11 (d,1H, H-11a or (3 , J.14.0 Hz), 2.15 (m, 1H), 2.26 (ddd, 1H, H-9a or fl ,J=14.0, 10.0, 1.0 Hz), 2.43 (d, 1H, H-11a or 13 , J.14.0 Hz), 2.54 (m, 1H, H-8), 3.08 (br d, 1H, H-5, J=9.0 Hz), 3.50 (s, 2H, ketal CH2), 3.47 (d, 1H,ketal CH2, J=11.5 Hz), 3.56 (d, 1H, ketal CH2, J=11.5 Hz), 6.14 (dd, 1H, H-3, J=5.5, 2.0 Hz), 7.43 (dd, 1H, H-4, J=5.5, 2.5 Hz).13C NMR (75 MHz, CDCI3) 6: 22.42 (C-15, -ye), 22.56 (C-16, -ve),27.05 (C-6 or C-7), 29.71 (C-6 or C-7), 30.00 (C-13), 40.94 (C-9 or C-11), 41.51 (C-9 or C-11), 46.35 (C-8, -ve), 55.26 (C-5, -ye), 63.29 (C-1), 71.97 (C-12), 72.38 (C-14), 109.27 (C-10), 133.17 (C-3, -ve),166.39 (C-4, -ve), 212.83 (C-2).Mass Spectrum, m/z (relative intensity):^262 (M+, 81.6), 234(16.6), 221 (11.7), 208 (11.9), 177 (27.1), 167 (59.1), 128 (100.0).Exact Mass Calcd. for C16H2203: 262.1571, found: 262.1570.Anal. Calcd. for C16H2203: C 73.25%; H 8.45%, found: C 73.06%; H8.38%.1465.2.1.19 Preparation of the Enedione 1570.157A solution of the enone ketal 156 (26.4 mg, 0.1 mmol) in a mixtureof acetone and 5% aqueous HCI (1:1, 4 mL) was stirred at rt overnight.The reaction mixture was diluted with Et20 (2 mL). The phases wereseparated and the aqueous layer extracted with Et20 (3 x 3 mL). Thecombined extracts were washed with water, aqueous NaHCO3, brine, anddried (MgSO4). The mixture was concentrated under reduced pressure togave 16.4 mg (93%) of the desired enedione 157 as a white solid.Recrystalization (hexane) provided white needles that exhibited m.p.82-83 °C.IR (KBr): 2929, 1739, 1702, 1584 cm-1.1H NMR (400 MHz, CDCI3) 8: 1.70 (m, 3H, H-7a and 13, H-6a), 2.05 (m,2H, H-60, H-9a or 13), 2.33 (d, 1H, H-11a or fi, J=18.7 Hz), 2.70 (m, 2H, H-8 and H-9a or 0), 2.86 (d, 1H, H-1 la or p, J=18.7, 1.1 Hz), 3.19 (br d, 1H,H-5, J=9.0 Hz), 6.24 (dd, 1H, H-3, J=5.7, 1.7 Hz), 7.55 (dd, 1H, H-4,J=5.7, 2.6 Hz).Detailed 1H NMR data, including those derived from COSY and nOeexperiments, are given in Table 10.14713C NMR (75 MHz, CDCI3) 8: 27.04 (C-6 or C-7), 29.82 (C-6 or C-7),42.70 (C-9), 44.11 (C-8, -ye), 46.39 (C-11), 54.47 (C-5, -ve), 61.57 (C-1), 133.28 (C-3, -ve), 166.06 (C-4, -ve), 212.00 (C-2), 217.50 (C-10).Mass Spectrum, m/z (relative intensity):^176 (M+, 81.6), 148(23.0), 135 (77.2), 122 (30.4), 107 (65.1), 91 (100).Exact Mass Calcd. for C11E11202: 176.0837, found: 176.0839.Table 10. 1H NMR (400 MHz, CDCI3) and COSY (200 MHz, CDCI3) data forthe enedione 157.H-x(assignment)1H NMR(400 MHz, CDCI3) 8COSY correlationsaH-3. 6.24 H-4, H-5H-4 7.55 H-3, H-5H-5 3.19 H-3, H-4, H-613H -8,H -9a or 132.70 H -7a & i3,H-11a or pH-11a or p 2.33 H-11 a or p,^H-11a or p 2.86 H-11a or [3a) Only those COSY correlations that could be unambigously assignedare recorded1485.2.1.20 Preparation of the Dienedione 9898To a stirred solution of the enedione 157 (94.5 mg, 0.54 mmol, 1.0equiv.) in dry benzene (20 mL) heated to reflux, was added solidbenzeneseleninic anhydride (272 mg, 0.76 mmol, 1.4 equiv.) in smallportions (every 5-7 min.) over a period of 3 hr and 15 min. After thereaction mixture had been stirred at 80 °C for a further 15 min, it wascooled and concentrated to a small volume under reduced pressure. Dripcolumn chromatography (TLC grade silica gel without binder,63 10 g,(2.5 cm x 5 cm column), elution first with hexane until PhSeSePh waseluted, then with Et20 until the enedione 157 was eluted, and finallywith Et0Ac to elute the dienedione 98) of the residual material, gave35.2 mg (38%) of the dienedione 98 as a white solid that exhibited m.p.125-128 °C, and 40.5 mg (43%) of the recovered enedione 157 as awhite solid.The overall yield of the dienedione 98 was 54.8 mg (59%) afterrecycling twice the enedione 157.IR (KBr): 2926, 1713, 1630, 1585 cm-1.1H NMR (400 MHz, CDCI3) s: 2.10 (m, 2H, H-613 and H-70), 2.27 (m,1H, H-6a), 2.39 (d, 1H, H-11a or 0, J=16.8 Hz), 2.59 (m, 1H, H-7a), 2.63(d, 1H, H-11a or 0, J=16.8 Hz), 3.33 (ddd, 1H, H-5, J=3.0, 1.3, 1.2 Hz),1496.02 (d, 1H, H-9, J=1.9 Hz), 6.32 (dd, 1H, H-3, J=5.6, 1.3 Hz), 7.78 (dd,1H, H-4, J=5.6, 3.0 Hz).Detailed 1H NMR data, including those derived from COSYexperiments, are given in Table 11.13C NMR (75 MHz, CDCI3) 8: 25.77 (C-6 or C-7), 29.85 (C-6 or C-7),46.36 (C-11), 48.34 (C-5, -ve), 67.42 (C-1),^125.65 (C-9, -ye),^132.80(C-3, -ve),^166.45 (C-4,^-ye),^182.81 (C-8),^207.65^(C-2^or C-10),208.35 (C-2 or C-10).Mass Spectrum, m/z (relative intensity):^174 (M+, 91.7), 146(59.0), 117 (100.0), 91 (74.9).Exact Mass Calcd. for C13H1803: 174.0681, found: 174.0681.Table 11. 1H NMR (400 MHz, CDCI3) and COSY (200 MHz, CDCI3) data forthe dienedione 98.H-x(assignment)1H NMR(400 MHz, CDCI3) 8COSY correlationsaH-3 6.32 H-4H-4 7.78 H-3H-6a 2.27 H-7aH-7a 2.59 H-6aH-11a or 13 2.39 H-110 or aH-1113 ora 2.63 H-11a or [3a) Only those COSY correlations that could be unambigously assignedare recorded1505.2.1.21 Preparation of Dienedione 98 via the Enol Silyl Ether 164OTMS98^164To cold (-78 °C) solution of lithium tetramethylpiperidide (0.033mmol; 1.1 eq) in 2.5 mL THF was added the enedione 157 (5.6 mg, 0.03mmol, 1 eq.), followed by Me3SiCI (38 mL, 0.3 mmol, 10 eq.). After themixture had been stirred at -78 °C for 10 min, the reaction wasquenched by addition of Et3N (0.5 mL), followed by a saturated aqueousNaHCO3 solution (0.5 mL). The phases were separated, and the aqueousphase was extracted with Et20 (2x1 mL). The organic extracts weredried over anhydrous MgSO4 and concentrated under reduced pressure.This material was used immediately in the following step.To a solution of Pd(OAc)2 (7.1 mg; 0.03 mmol) in 4 mL of dry DMFat rt was added a solution of the crude enol silyl ether 163 in dry DMF(1 mL). After the reaction mixture had been stirred at rt for 2 hr, itwas filtered through a short column of Florisil (1 cm x 3 cm). Thecolumn was eluted with Et20 (15 mL) and the combined filtrate wasconcentrated under reduced pressure. The resultant crude productwas purified on silica gel (chromatotron, 1 mm plate, eluting with90:10 CH2C12/Et20) to give 2.3 mg (42%) of diendione 98. The spectralproperties observed for this material were identical with thosedescribed for the compound 98 obtained previously (pp 148-149).1515.2.1.22 Preparation of the 11-Methyl Dienedione 107107To^a^cold^(-78^°C),^stirred^solution^of^lithiumtetramethylpiperidide (0.046 mmol, 1.1 equiv.) in 3 mL of dry THF, wasadded a solution of the dienedione 98 (7.3 mg, 0.042 mmol, 1.0 equiv.)in 2 mL of dry THF. After the solution had been stirred at -78 °C for 10min, freshly distilled iodomethane (103 .LL, 2.1 mmol, 50 eq.) wasadded. The reaction mixture was stirred at -78 °C for an another 10min period and 1 mL of aqueous NaHCO3and 1 mL Et20 were added. Themixture was allowed to warm to rt, the phases were separated and theaqueous layer was extracted with CH2Cl2 (5 x 1 mL). The combinedorganic extracts were washed with brine, dried (MgSO4) andconcentrated under reduced pressure. The residual material wasdissolved in 0.5 mL of CH2Cl2 and purified on silica gel (chromatotron,1 mm plate, eluting with 45:45:10 hexane/CH2C12/Et20) to give 4.2 mg(53%) of the 11-methyl dienedione 107 as a white solid that exhibitedm.p. 134-135 °C.IR (KBr): 2922, 1710, 1632, 1584 cm-1.1H NMR (400 MHz, CDCI3) 8: 1.10 (d, 3H, H-12, J=8.0 Hz), 1.97 (ddd,1H, H-613, J=13.0, 9.5, 6.5 Hz), 2.09 (m, 1H, H-7(3), 2.27 (m, 1H, H-7«,shows coupling with H-9 J.2.0 Hz), 2.60 (dd, 1H, H-6«, J=13.0, 6.5 Hz),1522.60 (q, 1H, H-11, J=8.0 Hz), 3.42 (ddd, 1H, H-5, J=9.5, 3.0, 1.5 Hz), 5.96(d, 1H, H-9, J=2.0 Hz), 6.27 (dd, 1H, H-3, J=5.8, 1.5 Hz), 7.74 (dd, 1H, H-4, J=5.8, 3.0 Hz).Detailed 1H NMR data, including those derived from decouplingexperiments, are given in Table 13.1H NMR (400 MHz, CDCI3-benzene (7:3)) s: 0.94 (d, 3H, H-12), 1.62(m, 1H), 1.72 (dd, 1H), 1.98 (m, 1H), 2.26 (dd, 1H), 2.53 (q, 1H, H-11),3.05 (br d, 1H, H-5), 5.84 (d, 1H, H-9), 6.05 (dd, 1H, H-3), 7.30 (dd, 1H,H-4).Detailed 1H NMR data, including those derived from COSY and nOeexperiments, are given in Table 12.13C NMR (125 MHz, CDCI3) s: 15.74 (C-12, -ve), 25.88 (C-6 or C-7),30.11 (C-6 or C-7), 44.22 (0-5 or C-8, -ve), 50.46 (C-5 or C-8, -ve),69.61 (C-1), 123.3 (C-9, -ve), 132.68 (C-3, -ye), 166.45 (0-4, -ve),182.06 (C-8), 207.98 (C-2 or 0-10), 212.63 (C-2 or 0-10).Mass Spectrum, m/z (relative intensity):^188 (M+, 100); 173(11.1); 160 (95.4); 145 (38.5).Exact Mass Calcd. for C12111202: 188.0838, found: 188.0841.1 53Table 12. 1H NMR, COSY(200 MHz, CDCI3) and nOe (400 MHz, CDCI3-C6D67:3)) data for the 11-methyl dienedione 107,H-x(assign.)1H NMR(200 MHz,CDCI3)COSYcorrelationa1H NMR(400 MHz,CDCI3-C6D6(7:3),nOecorrelationsH-3 6.27 H-4 - -H-4 7.74 H-3 - -H-5 - - 3.05 0.94 (H-12)1.62 (H-613)7.30 (H-4)H-11 2.60 H-12 2.53 0.94 (H-12)3.05 (-ye, H-5)7.30 (-ye, H-4)H-12 1.10 H-11 0.94 2.53^(H-11)3.05 (H-5)a) Only those COSY correlations that could be unambigously assignedare recorded154Table 13. Decoupling experiments (400 MHz, C6D6 and CDCI3) data forthe 11-methyl dienedione 107.irradiated^signals observed signalsassignmentH-x1H NMR (400MHz, COOs ppm (mult., J, H-x) mutt.^afterirradiationH-5 2.45 1.05 (m, H-6a or ft)1.10 (m, H-6a or p)5.75 (dd, (J.5.8, 1.5,H-3)6.60 (dd, (J=5.8, 3.0H-4)sharpened msharpened md (J.5.8)d (J=5.8)H-11 2.60 0.75 (q, H-12) sassignmentH-xH NMR(400MHz, CDCI3)8 ppm (mult., J, H-x) mult.^afterirradiationH-4 7.74 3.42 (ddd,J.9.5, 3.0, 1.5, H-5)6.27 (dd, J=5.8, 1.5,H-3)br dd (J.1.5)H-5 3.42 1.97 (ddd, J=13.0,9.5, 6.5, H-6p)6.27 (dd, J=5.8, 1.5,H-3)7.74 (dd, J.5.8, 3.0,H-4)dd(J=13.0, 6.5))d (J=5.8)d (J.5.8)H-6p 1.97 2.09 (m, H-7p)2.27 (m, H-7a)2.60 (m, H-6a)3.42 (ddd,J.9.5, 3.0, 1.5, H-5)sharpened msharpened msharpened mbr dH-9 5.96 2.27 (m, H-7a) sharpened mH-12 1.10 2.60 (q, J=8.0, H-11) s1555.2.2 Preparation of Enones from Ketones: BSA Method5.2.2.1 General Procedure: Oxidation of the Keto Ketal 101 to the EnoneKetal 100 (Table 14, entry 3)100To a heated (80 °C), stirred solution of the keto ketal 101 (27.9mg, 0.125 mmol, 1 equiv.) in dry benzene (10 mL) was added solid BSA(90 mg, 0.25 mmol, 2 equiv.) in small portions. A few minutes after thefirst addition, the mixture become yellow due to the formation ofPhSeSePh. The reaction was monitored by GLC and was complete uponaddition of 2 equivalents of BSA. The reaction mixture was cooled, andconcentrated under reduced pressure. The residual material wasdissolved in 1 mL of CH2C12, and purified by a gravity columnchromatography (1 cm x 12 cm silica gel column, 1:1 petroleumether/Et20) to give 15.2 mg (55%) of the enone ketal 100 as a whitesolid, and 4.1 mg (15%) of the recovered ketone 101. The spectralproperties observed for this material were identical with thosedescribed for the compound 100 obtained previously (pp 117-118).1565.2.2.2 Oxidation of the Keto Ketal 101 to the Enone Ketal 100 (Table14, entry 1)To a heated (135 °C), stirred solution of the keto ketal 101 (33mg, 0.15 mmol, 1 equiv.) in chlorobenzene (10 mL) was added solid BSA(55 mg, 0.16 mmol, 1.1 equiv.) in one portion. The mixture becomeyellow due to the formation of PhSeSePh. After the reaction mixturehad been refluxed for 1.5 hr, it was cooled and concentrated underreduced pressure. The residual material was dissolved in 2 mL ofCH2Cl2 and purified by a gravity column chromatography (1 cm x 12 cmsilica gel column, 1:1 petroleum ether/Et20) to give 16 mg (49%) of theenone ketal 100 as a white solid, and 6 mg (18%) of the recoveredketone 101. The spectral properties observed for this material wereidentical with those described for the compound 100 obtainedpreviously (pp 117-118).5.2.2.3 Oxidation of the Keto Ketal 101 to the Enone Ketal 100 (Table14, entry 2)To a heated (135 °C), stirred solution of the keto ketal 101 (22mg, 0.1 mmol, 1 equiv.) in chlorobenzene (10 mL) was added solid BSA(72 mg, 0.2 mmol, 2 equiv.) in one portion. The mixture become yellowdue to the formation of PhSeSePh. After the reaction mixture had beenrefluxed for 4 hr, it was cooled and concentrated under reducedpressure. The residual material was dissolved in 2 mL of CH2Cl2 andpurified by a gravity column chromatography (1 cm x 12 cm silica gel157column, 1:1 petroleum ether/Et20) to give 4.5 mg (20%) of the enoneketal 100 as a white solid. The spectral properties observed for thismaterial were identical with those described for the compound 1 00obtained previously (pp 117-118).5.2.2.4 Oxidation of the Keto Ketal 101 to the Enone Ketal 100 (Table14, entry 4)To a heated (60 °C), stirred solution of the keto ketal 101 (20.3mg, 0.09 mmol, 1 equiv.) in chloroform (8 mL) was added in smallportions BSA (66 mg, 0.18 mmol, 2 equiv.) over a period of 30 min.After the reaction mixture had been refluxed for another 3 hr, it wascooled and concentrated under reduced pressure. A GLC analysis of themixture showed the presence of the enone ketal 100, the keto ketal101, and two additional products. The residual material was dissolvedin 2 mL of CH2Cl2 and purified by a gravity column chromatography (1cm x 12 cm silica gel column, 1:1 petroleum ether/Et20) to give 9.9 mg(49%) of the enone ketal 100 as a white solid, and 4.9 mg (24%) of therecovered ketone 101. The spectral properties observed for thismaterial were identical with those described for the compound 1 00obtained previously (pp 117-118).1585.2.2.5 Oxidation of the Keto Ketal 101 to the Enone Ketal 100 (Table14, entry 5)To a heated (40 °C), stirred solution of the keto ketal 101 (30 mg,0.13 mmol, 1 equiv.) in dichloromethane (10 mL) was added solid BSA(49 mg, 0.14 mmol, 1.1 equiv.) in small portions over a period of 4.5 hr.The reaction mixture was cooled and concentrated under reducedpressure. A GLC analysis of the mixture showed the presence of theenone ketal 100, the keto ketal 101, and two additional products. Theresidual material was dissolved in 2 mL of CH2Cl2 and purified by agravity column chromatography (1 cm x 12 cm silica gel column, 1:1petroleum ether/Et20) to give 13 mg (44%) of the enone ketal 100 as awhite solid, and 6.7 mg (22%) of the recovered ketone 101. Thespectral properties observed for this material were identical withthose described for the compound 100 obtained previously (pp 117-118).5.2.2.6 Oxidation of the Keto Ketal 101 to the Enone Ketal 100 (Table14, entry 6)To a stirred solution of the keto ketal 101 (21 mg, 0.09 mmol, 1equiv.) in dichloromethane (8 mL) at rt was added solid BSA (51 mg,0.14 mmol, 1.1 equiv.) in small portions over a period of 1.5 hr. Afterthe reaction mixture had been stirred for 72 hr at 17 °C, it wasconcentrated under reduced pressure. The residual material wasdissolved in 2 mL of CH2Cl2 and purified by a gravity column159chromatography (1 cm x 12 cm silica gel column, 1:1 petroleumether/Et20) to give 3.2 mg (15%) of the enone ketal 100 as a whitesolid. The spectral properties observed for this material wereidentical with those described for the compound 100 obtainedpreviously (pp 117-118).5.2.2.7 Preparation of the 5-Methyl Enone 2501314250To a heated stirred solution of the ketone 133 (18.9 mg, 0.08mmol, 1.0 equiv.) in 3 mL of dry chloroform at reflux (60 °C) was addeda solution of BSA 60.8 mg (0.17 mmol, 2.0 equiv.) in chloroform (15 ml)over the period of 30 min, using a syringe pump. Reflux (60 °C) wascontinued for another 3 hr period. The material obtained afterevaporation of the reaction mixture was dissolved in 1 mL of CH2Cl2,and was purified by a gravity column chromatography (1 cm x 12 cmsilica gel column, eluting with hexane, followed by 1:1 hexane/Et20) togave 9.6 mg (51%) yield of the enone 250 as a white solid, accompaniedwith 6.7 mg (35%) of the starting keto ketal 133.IR (KBr): 2955, 1708, 1642, 1102 cm-1.1H NMR (400 MHz, CDCI3) 6: 0.96, 1.03 (s, s, 3H each, Me-13 and Me-14), 1.29 (s, 3H, H-9), 1.78 (d, 1H, H -6a or , fi, J=13.3 Hz), 2.34 (d, 1H, H-1604a or 0, J=18.7 Hz), 2.38 (d, 1H, H-4a or 0, J=18.7 Hz), 2.45 (d, 1H, H-6aor ft, J=13.3 Hz), 2.99 (dd, 1H, H-8a, J=17.2, 1.8 Hz), 3.08 (d, 1H, H-813,J=17.2 Hz), 3.46 (d, 2H, ketal CH2, J.7.4 Hz), 3.52 (d, 1H, ketal CH2,J.11.4 Hz), 3.55 (d, 1H, ketal CH2, J.11.4 Hz), 5.83 (d, 1H, H-2, J.1.8Hz)Detailed 1H NMR data, including those derived from COSYexperiments, are given in Table 21.13C NMR (50 MHz, CDCI3) 8: 22.32 (C-12 and C-13, -ve), 26.67 (C-9,-ve), 29.94 (C-11), 37.66 (C-4), 48.83 (C-5), 49.23 (C-8), 51.92 (C-6),72.08 (C-10), 72.18 (C-12), 109.19 (C-7), 124.78 (C-2, -ve), 188.81 (C-1), 209.50 (C-3).Mass Spectrum, m/z (relative intensity):^236 (Mt, 76.5); 221(11.9); 151 (23.7); 79 (100).Exact Mass Calcd. for C14H2003: 236.1413, found: 236.1413.Table 21. 1H NMR (400 MHz, CDCI3) and COSY (200 MHz, CDCI3) data forthe 5-methyl enone 250.H-x 1H NMR COSY correlationsa(assignment) (400 MHz, CDCI3) 8H-2 5.83 H-8aH-6a or 13 1.78 H-613 or aH-613 or a 2.45 H-6« or iiH-8a 2.99 H-813, H-2H-813 3.08 H-8aketal CH2's 3.46, 3.52 & 3.55 H-13 & H-14H-13 & H-14 0.96 and 1.03 ketal CH2ISa) Only those COSY correlations that could be unambigously assignedare recorded1615.2.2.8 Preparation of the Enedione 157157To a heated stirred solution of the diketone 104 (12 mg, 0.7 mmol,1 equiv.) in 10 mL of dry CHCI3 at reflux (60 °C) was added BSA (49 mg,0.14 mmol, 2 equiv.) over the period of 30 min. The material obtainedafter concentration of the reaction mixture was dissolved in 1 mL ofCH2Cl2, and purified by a gravity column chromatography (1 cm x 12 cmsilica gel column, eluting with hexane, followed by 1:1 hexane/Et20) togive 4.7 mg (40%) of the enedione 157 as a white solid. The spectralproperties observed for this material were identical with thosedescribed for the compound 157 obtained previously (pp 146-147).5.2.2.9 Preparation of the Dienedione 98 from the Diketone 10498To a heated stirred solution of the diketone 104 (8.3 mg, 0.05mmol, 1 equiv.) dissolved in 10 mL of dry CHCI3 at reflux (60 °C), was162added BSA (78 mg, 0.2 mmol, 4 equiv.) over a 1 hr period. The materialobtained after concentration of the reaction mixture was dissolved in 1mL of CH2Cl2 and purified by a gravity column chromatography (1 cm x15 cm silica gel column, eluting with 1:1 petroleum ether/Et20 ,followed by Et20, and finally with Et0Ac) to give 1.4 mg (17%) of thedienedione 98 as a white solid. The spectral properties observed forthis material were identical with those described for the compound 98obtained previously (pp 148-149).5.2.2.10 Preparation of the Dienedione 98 from the Enedione 15798Using the general procedure 5.2.2.1, the enedione 157 (7.8 mg,0.044 mmol, 1 equiv.) dissolved in 5 mL of dry benzene at reflux (80°C), was treated with BSA (96 mg, 0.27 mmol, 6 equiv.) over a 3 hrperiod. The material obtained after concentration of the reactionmixture was dissolved in 1 mL of CH2Cl2, and purified by a gravitycolumn chromatography (1 cm x 23 cm silica gel column, eluting withhexane, followed by 1:1 hexane/Et20, and finally with Et0Ac) to give 2.5mg (32%) of the dienedione 98 as a white solid. The spectralproperties observed for this material were identical with thosedescribed for the compound 98 obtained previously (pp 148-149).1635.2.2.11 Preparation of the Enone Ketal 156156Using the general procedure 5.2.2.1, the keto ketal 103 (28 mg,0.11 mmol, 1.0 equiv.) dissolved in 10 mL of dry benzene at reflux (80°C), was treated with BSA (78 mg, 0.22 mmol, 2.0 equiv.). The materialobtained after concentration of the reaction mixture was dissolved in 1mL of CH2Cl2, and purified by a gravity column chromatography (2 cm x5 cm TLC grade silica gel without binder, 63 eluting with hexanes untilPhSeSePh was removed, then with 3:1 hexanes/Et20) to give 17.2 mg(62%) of the enone ketal 156 as a white solid. The spectral propertiesobserved for this material were identical with those described for thecompound 156 obtained previously (pp 144-145).1645.2.3 Preparation of Enones from Ketones: Saegusa Oxidation5.2.3.1 Preparation of the Enone 250 via the Enol Silyl Ether 251TMSO250^251To a cold (-78 °C), stirred solution of LDA (0.14 mmol, 1.5 equiv.)in dry THF (4 mL) were added freshly distilled Me3SiCI (120 gL, 0.9mmol, 10 equiv.) and a solution of the keto ketal 133 (22 mg, 0.09mmol, 1 equiv.) in dry THE (1 mL). After the mixture had been stirred at-78 °C for 5 min, freshly distilled Et3N (1 mL) and saturated aqueousN aH CO3 (1 mL) were added. The mixture was diluted with Et20 (2 mL)and the phases were separated. The organic layer was dried (MgSO4)and concentrated under reduced pressure. The enol silyl ether 251(91% by GLC analysis of the crude product) thus obtained was distilledin vacuo (110 °C/0.1 mmHg).To a stirred solution of Pd(OAc)2 (21 mg, 0.09 mmol) in 7 mL of dryacetonitrile was added a solution of the distilled enol silyl ether 251in dry acetonitrile (1 mL). After the reaction mixture had been stirredfor 5 hr and 30 min, the solution was filtered through a short column ofFlorisil (2 cm x 5 cm, eluting with 40 mL Et20). The combined filtrateswere concentrated under reduced pressure. Flash chromatography (1 cmx 20 cm silica-gel column, 1:1 petroleum ether/Et20) of the residual2527 H 9^15TMSO 6 1101.11 0^1712253165material, gave 9.2 mg (42%) of the enone 250 as a white solid and 2 mg(9%) of the recovered keto ketal 133. The spectral properties observedfor this material were identical with those described for the compound250 obtained previously (pp 159-160).5.2.3.2 Preparation of the Tricyclic Dieneone Ketal 252 via the EnolSilyl Ether 253To a cold (-78 °C), freshly prepared LDA solution (0.15 mmol, 1.5equiv.) in dry THF (4 mL) were added freshly distilled Me3SiCI (126 gL,1.0 mmol, 10 equiv.) and a solution of the ketone 99 (28 mg, 1.0 mmol,1 equiv.) in dry THF (1 mL). After the reaction mixture had been stirredat -78 °C for 5 min, freshly distilled Et3N (1 mL) and saturated aqueousNaHCO3 (1 mL) were added. The mixture was diluted with Et20 (2 mL).The phases were separated, and the organic phase was dried (MgSO4)and concentrated under reduced pressure. The enol silyl ether 253 thusobtained was distilled in vacuo (125 °C/0.1 mmHg). GLC analysisshows the presence of a single enol silyl ether (IR (neat): 2954, 1651,1120 cm-1). This material was used immediately in the following step.166To a stirred solution of Pd(OAc)2 (23 mg, 1.0 mmol) in 9 mL of dryacetonitrile, was added a solution of the freshly distilled enol silylether 253 in dry actetonitrile (1 mL). After the reaction mixture hadbeen stirred for 3 hr, the mixture was filtered through a short columnof Florisil (2 cm x 5 cm eluting with 40 mL of Et20). Concentration ofthe filtrate, followed by flash chromatography (1 cm x 20 cm silica gelcolumn, elution with 1:1 petroleum ether/Et20) of the residualmaterial, gave 20.3 mg (73%) of the enone 252 as a white solid.1H NMR (400 MHz, CDCI3) 8: 0.97, 1.01 (s, s, 3H each, Me-16 and Me-17), 1.73 (m, 1H, H-413), 2.07 (m, 1H, H-4a), 2.19 (d, 1H, H-11a or ii,J=14.5 Hz), 2.22 (m, 2H, H-3a and 13), 2.61 (d, 1H, H-11a or 0, J=14.5 Hz),2.62 (br s, 1H, H-5), 2.94 (dd, 1H, H-9a, J=15.5, 2.0 Hz), 3.17 (d, 1H, H-913, J=15.5 Hz), 3.49 (s, 2H, ketal CH2), 3.53 (d, 1H, ketal CH2, J=11.5 Hz),3.58 (d, 1H, ketal CH2, J=11.5 Hz), 5.00 (br s, 1H, H-12), 5.25 (br s, 1H,H-12), 5.91 (d, 1H, H-7, J=2.0 Hz).Detailed 1H NMR data, including those derived from COSYexperiments, are given in Table 22.130 NMR (75 MHz, CDCI3) 8: 22.26 (C-16, -ve), 22.35 (C-17, -ve),26.66, 29.97 (0-14), 32.63, 38.00, 47.73, 60.92 (C-5, -ye), 61.85 (C-1),71.92 (C-13), 72.54 (C-15), 108.38 (C-12), 109.12 (C-10), 125.74 (C-7,-ve), 155.12 (C-2), 184.92 (C-8), 212.70 (C-6).Mass Spectrum, m/z (relative intensity): 274 (M+, 100); 246 (8.9);189 (18.0); 186 (18.5); 159 (32.5); 146 (37.9); 128 (56.7); 117 (76.8).Exact Mass Calcd. for C17H2203: 274.1569, found: 274.1569.167Table 22. 1H NMR (400 MHz, CDCI3) and COSY (200 MHz, CDCI3) data forthe dienone ketal 252.H-x(assignment)_1H NMR(400 MHz, CDCI3)8COSY correlationsaH-3a and p 2.22 H-4a and p, H-12H-43 1.73 H-3a and p, H-5H-5 2.62 H-4pH-7 5.91 H-9aH-9a 2.94 H-913, H-7H-913 3.17 H-9aH-1 1 a or (3 2.19 H-11p or aH-11p or a 2.61 H-11a or pketal CH2's 3.49, 3.53 and 3.58 H-16 & H-17H-16 & H-17 0.97 and 1.01 ketal C Fli Sa) Only those COSY correlations that could be unambigously assignedare recorded1686 References1. a) G. Wittig, P. Davis, G. Koenig, Chem. Ber. 84, 627 (1951).b) D. Seebach, Angew. Chem. Mt. Ed. Engl. 18, 239 (1979).2. a) E.J. Corey, Chem. Soc. Rev. 17, 111 (1988).b) E. J. Corey, X.-M. Cheng, The Logic of Chemical Synthesis; Wiley:New York, 1989.3. B. M. Trost, Science 254, 1471 (1991).4. D. Seebach, Angew. Chem. Mt. Ed. EngL 29, 1320 (1990).5. A. Groweiss, W. Fenical, H. Cun-heng, J. Clardy, W. Zhongde,Y. Zhongnian, L. Kanghou, Tetrahedron Lett. 26, 2379 (1985).6. Reviews: a) L. A. Paquette, Top. Curr. Chem. 79, 41(1979); 119, 1(1984).b) L. A. Paquette, A. M. Doherty, Reactivity and Structure Conceptsin Organic Chemistry 26, 1 (1987).7. S. Hartmann, J. Neeff, U. Heer, D. Mecke, FEBS Lett. 93, 339 (1978).8. J. Brendel and P. 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