T2003

DevelopmentofnovelLewisacidcatalyzedcycloisomerizations:

synthesisofbicyclo[3.1.0]hexenesandcyclopentenones

AubryK.Miller,MatthewR.Banghart,ChristopherM.Beaudry,JudyM.SuhandDirkTrauner*

DepartmentofChemistry,CenterforNewDirectionsinOrganicSynthesis,UniversityofCalifornia,

419LatimerHall,Berkeley,CA94720,USA

Received10February2003;accepted4April2003

Abstract—TheLewisacidcatalyzedcyclizationofhexatrienesandpentadienalstobicyclo[3.1.0]hexenesandcyclopentenones,respectively,wasinvestigated.Theapplicationoftheformerreactiontothetotalsynthesisofphotodeoxytridachione,amolluscanpolypropionate,isdescribed.

q2003ElsevierLtd.Allrightsreserved.

1.Introduction

Thermalandphotochemical6pelectrocyclizationsareubiquitouswithinthechemicalliterature(Scheme1).1Theirdevelopmentasapowerfulsynthetictoolhasbeengreatlyaidedbyadvancesintheory,culminatingintheWoodward–Hoffmannprincipleofconservationoforbitalsymmetry.2Thediscoveryofthesereactionsinmanybiosyntheticpathways,hasfurtheraddedtotheirimpor-tance.3[p4aþp2s]cycloadditions—antarafacialwithrespecttoonecomponentandsuprafacialwithrespecttotheother.Veryfewthermalisomerizationsofthistype,which,ifconcerted,necessarilyproceedas[p4aþp2a]cycloadditions,havebeenreported.Mostoftheseinvolvecycloocta-tetraenesassubstrates(Scheme2).6Tothebestofourknowledge,nointermolecular[p4aþp2a]cycloadditionshavebeenreported.Stericconstraintsusuallyfavorthe[p4sþp2s]pathwayfoundina‘regular’Diels–Alderreactionandprecludethedieneanddienophilefromapproachingeachotherinsuchafashionastoallowconcertedtwofoldantarafacialbondformation.

Scheme1.

Incomparison,theisomerizationofhexatrienestobicyclo-[3.1.0]hexeneshasreceivedrelativelylittleattention(Scheme1).Nevertheless,photochemicalversionsofthereactionarewellknown.4Oneexample,thephotolysisofvitaminD2toaffordamixtureofsuprasterolIandII,isshowninScheme2.5Inasense,theseisomerizationscanbeseenasintramo-lecular[4þ2]cycloadditionswithatetherconsistingofasinglebond.Hence,theyhavebeendubbedthe‘photo-chemicalDiels–Alderreaction’.2InaccordancewiththeWoodward–Hoffmannrules,theyproceedas[p4sþp2a]or

Keywords:Lewisacid;cycloisomerization;molluscanpolypropionate.*Correspondingauthor.Tel.:þ1-510-3-5507;fax:þ1-510-3-9480;e-mail:trauner@cchem.berkeley.edu

0040–4020/$-seefrontmatterq2003ElsevierLtd.Allrightsreserved.doi:10.1016/j.tet.2003.04.006

Scheme2.[4þ2]cycloadditionsaffordingbicyclo[3.1.0]hexenes.

20A.K.Milleretal./Tetrahedron59(2003)19–30

Scheme3.

Figure2.Polypropionatesfromsacoglossanmolluscs.

WenowreportthediscoveryofaLewisacidcatalyzedcycloisomerizationofsubstitutedhexatrienesthatresemblessuchathermal[p4aþp2a]cycloaddition.Followingitsinitialserendipitousdiscovery,thereactionwassystem-aticallystudiedandappliedtothetotalsynthesisofnaturalproductsfeaturingabicyclo[3.1.0]hexeneskeleton.7Afullaccountofthiswork,aswellasapreliminaryreportontheextensionofthemethodologytothecyclizationtopentadienals,isgivenherein.

Tooursurprise,treatmentof1withvariousLewisacidsdidnotresultintheformationof2butrathergavebicyclo[3.1.0]hexene3inmodesttogoodyields.Nootherdiastereomerswerefound.Underoptimizedconditions,i.e.inthepresenceof20%dimethylaluminumchloride,68%ofthebicyclicproductwasobtained.

Itwassoondiscoveredthatthetrimethylbicyclo[3.1.0]hex-enecoreofcompound3occursinseveralnaturalproductsproducedbysacoglossanmolluscs.9Theseunusualanimalslackaprotectiveshellandrelyonchemicaldefensesagainstpredators.Inaddition,theyharvestfunctionalchloroplastsfromalgaeandusetheseorganellestoliveautotrophicallythroughphotosynthesis.Thisfacthasprovokedinvesti-gationstodetermineifphotochemicalstepsplayaroleinthebiosynthesisofnaturalproductsisolatedfromtheirtissues.

Mostofthesemetabolitesfallintotwogeneralclasses:cyclohexadienederivativesandbicyclo[3.1.0]hexenes(Fig.2).Tridachione(4)wasisolatedfromTridachielladiomedea.10aTheisomers9,10-deoxytridachione(5)andphotodeoxytridachione(6)werebothfoundinthePacificmolluscPlacobranchusocellatus10bandlateridentifiedintheMediterraneanElysiatimida.10cPhotodeoxytridachionehasshownactivityinanichthyotoxicityassayat5ppm.

2.Discoveryandapplication

DuringourinvestigationsdirectedattheSNF4435classofimmunosupressants,3bitwasfoundthattrienoate1readilyunderwentdisrotatoryelectrocyclizationtoaffordcyclo-hexadiene2(Scheme3).TheX-raycrystalstructureofthisproductisshowninFigure1.Therelativelyslowrateofthereactionatroomtemperatureofferedanopportunitytoinvestigatewhetheritcouldbecatalyzed.Beingquiteawarethatsubstitutedtrienesoftype1maynotbeidealsubstrates,wewonderedwhatinfluence,ifany,aLewisacidwouldhave.Tothebestofourknowledge,electrocyclizationshavenotyetsuccumbedtoasymmetriccatalysisinstarkcontrasttootherpericyclicreactionssuchascycloadditionsorsigmatropicrearrangements.8A.K.Milleretal./Tetrahedron59(2003)19–3021

Crispatene(7)andtridachiapyroneE(8)wereisolatedfromElysiacrispata.10d,eCrispatenewasmoderatelyactiveinalymphocyticleukemiaassay(ED50¼3.7mg/mL).10eTheisomers9,10-deoxytridachioneandphotodeoxytri-dachionehavereceivedconsiderableattentionduetotheirinterestingbiogeneticrelationship.Inimportantstudies,Ireland,FaulknerandScheuerdemonstratedthat9,10-deoxytridachionecanbephotochemicallyconvertedinvivoandinvitrointophotodeoxytridachione.10b,dThusitappearsthatthebicyclo[3.1.0]hexeneclassisbiosyntheticallyderivedfromthecyclohexadieneclass.

Interestingly,despitetheirunusualandattractivechemicalstructures,noneofthenaturalproductsshowninFigure2havebeenpreviouslypreparedbytotalsynthesis.Withrapidsyntheticaccesstothebicyclo[3.1.0]hexenecoreofphotodeoxytridachione(6),crispatene(7)andtridachia-pyroneE(8)athand,wedecidedtolaunchaprogramaimedattheirtotalsynthesis,startingwiththesimplestmemberofthefamily,6.

Attheoutsetofourstudies,oneimportantissueremainedunresolved:thestereochemistryatoneofthequaternarycentersin3doesnotcorrespondtothenaturalproducts.Wereasonedthatthiscouldbepotentiallyovercomebyperformingthereactionwithageometricisomerofthestartingmaterial—apredictionthatultimatelyprovedcorrect(videinfra).

Oursynthesisofphotodeoxytridachionestartedwiththeconversionofknownunsaturatedaldehyde911intotetraene13(Scheme4).Still–Gennaricondensation12of9withtrifluoroethylphosphonate10yieldedthe(Z,E,E)-configured

ester11withhighdiastereoselectivity(.20:1).Thismaterialwassubsequentlyreducedtoallylicalcohol12.Oxidationgaveaverysensitivealdehyde,whichwassubjectedtoaHorner–Wadsworth–Emmonscondensationtoaffordcyclizationprecursor13.

Thestagewasnowsetfortheapplicationofthenewlydiscoveredreactiontowardthesynthesisofphotodeoxy-tridachione.Intheevent,treatmentof13withcatalyticamountsofdimethylaluminumchlorideeffectedthecycli-zationtoaffordcompound14,featuringthebicycliccoreofphotodeoxytridachione,ingoodyield.Scandiumtriflatealsopromotedthecycloisomerization,albeitinloweryields.Again,thebicyclo[3.1.0]hexeneproductwasformedasasinglediastereomer.Notethatallfourstereocentersofthetargetmoleculeweresetcorrectlyinarelativesense.Clearly,theuseofachiralLewisacidmightprovideawaytocontroltheabsolutestereochemistryofthereactionaswell.Wearecurrentlypursuingthispossibility.Compli-catingthistasksomewhat,theabsolutestereochemistryofthenaturalproductremainsunknown.

Thecompletionofthesynthesisrequiredelaborationofthea-methoxy-g-pyronemoietyfromanethylester—aseeminglystraightforwardtask.However,duetothestericallyhinderednatureofthisneopentylicester,thistransformationprovedtobemoredifficultthananticipated.Forinstance,14couldnotbeconvertedtothedesiredtricarbonylcompound18bycrossClaisencondensationwiththecorrespondingdianion.Therefore,anindirectstrategywaschosen.TheWeinrebamide15wasobtainedingoodyieldundercarefullycontrolledconditions.13Exposureof15toethylmagnesiumbromidethenaffordedethylketone16.Deprotonationof16withexcessbaseand

Scheme4.Totalsynthesisof(^)-photodeoxytridachione.Reagentsandconditions:(a)9,KHMDS,18-C-6,THF,2788C,79%;(b)DIBAH,CH2Cl2,08C,

˚molsieves,CH2Cl2;(d)(EtO)2P(O)CH(Me)COOEt,LiCl,DBU,MeCN,43%from12;(e)Me2AlCl(0.2equiv.),CH2Cl2,73%;93%;(c)TPAP,NMO,4A

(f)MeHNOMe·HCl,i-PrMgCl,THF,08C,63%;(g)EtMgBr,THF,87%;(h)LiHMDS(3equiv.),17,THF,hexanes,2788C,59%(95%borsm);(i)DBU,PhH,rflx.,78%;(j)FSO2OMe,CH2Cl2,77%.

22A.K.Milleretal./Tetrahedron59(2003)19–30

additionofmalonylchloride17gave18asaninconse-quentialmixtureofdiastereomers14inverygoodyieldbasedonrecoveredstartingmaterial.Thisreactionpresumablyproceedsviaanacylketeneintermediate.Cyclizationof18underbasicconditionsresultedinformationofthedesiredpyrone19.15Finally,regioselectivemethylationundertheconditionsdescribedbyBeak16affordedphotodeoxy-tridachioneingoodyield.Althoughasampleofthenatural1productwasnotavailabletous,comparisonoftheH-,13C-,IR-andMSspectrawiththepublisheddataconfirmedtheidentity7,10cofoursyntheticmaterialwiththenaturalproduct.Itisinterestingtospeculatetowhichextentoursynthesisisbiomimetic.Asmentionedabove,Ireland,Faulkner,andScheuer’sworkpointstoaphotochemicaloriginofphotodeoxytridachione(6)from9,10-deoxytridachione(5),atleastinP.ocellatus.10b,dHowever,accordingtoGavagninandCimino,therelativeamountof5and6inE.timidaisindependentonthelevelofexposuretolightandthecollectionseason.9a,10cVeryrecently,Baldwinsuggestedthatthebicyclo[3.1.0]hexenecoreofcrispateneisbiosyntheticallyformedfromalinearall-transpolyenethroughaseriesofdoublebondisomerizationsfollowedby[p4sþp2a]cycloaddition.17TheeaseofourLewisacidcatalyzedcyclizationatlowtemperaturesraisesthequestionwhetherasimilarreactioncouldoccurinnature—perhapsproceedingthroughpyryliumion21(Scheme5).Notethatthermal6p-electrocyclizationoftheputativepolyeneprecursor20leadstothecyclohexadieneclassofmolluscanpolypropionates.

Scheme5.

3.Scopeandmechanism

Severalexperimentswereperformedtogainmoreinsightintothescopeandmechanismofthecycloisomerization.First,itisimportanttonotethatintheabsenceofaLewisacidtetraene13undergoesdisrotatory6pelectrocyclizationtoaffordcyclohexadiene22(Scheme6).Thismaterialmayserveasanintermediateinthetotalsynthesesof9,10-deoxytridachione(5)andtridachione(4),bothofwhicharecurrentlyunderwayinourlaboratories.Con-versiontotheWeinrebamide23setsthestagefortheinstallmentofthepyronemoietyanalogoustothesynthesisofphotodeoxytridachione.

Scheme6.Reagentsandconditions:(a)PhH,rflx.,98%(b)MeHNO-Me·HCl,i-PrMgCl,THF,08C,28%(91%borsm).

Next,thestereospecificityofthereactionwasprobed(Scheme7).The(Z,Z,E,E)-configuredester24andthe(E,Z,E)-configuredester26werepreparedusingstereo-selectiveolefinationmethodsasbefore(seeSection5).Eachunderwentstereospecificcyclizationtoafford25and27,respectively,assinglediastereomers.Hence,thestereo-chemistryofthea,b-unsaturatedestermoietyisreflectedinthecyclizationproduct.

Scheme7.Reagentsandconditions:(a)Me2AlCl(0.2equiv.),CH2Cl2,61%.(b)Me2AlCl(0.8equiv.),CH2Cl2,84%.

Ester24wasneverfullypurifiedduetorapid6p-electro-cyclizationatroomtemperatureaffordinganepimerof22.Generally,weobservedthatcompounds1and24underwentboththeelectrocyclizationsandLewisacidcatalyzedcycloisomerizationsnoticeablyfasterthantheirstereo-isomers26and13.

Thestereochemistryofthebicyclo[3.1.0]hexenes14and3waselucidatedbyreductiontothecorrespondingprimaryalcohols28and29,respectively,andextensiveNOEmeasure-ments.SelectedNOEsignalsareshowninScheme8.

Scheme8.Reagentsandconditions:(a)DIBAH,CH2Cl2,2788C,76%.(b)DIBAH,CH2Cl2,2788C,42%.

Withrespecttothemechanismofthecyclization,twoscenariosareconceivable.Thereactioncouldeitherproceedinaconcertedfashion,involvingonlyonetransitionstate,orinastepwisefashionthroughzwitterionicintermediates.Formally,theisomerizationhasthehallmarksofaconcerted

A.K.Milleretal./Tetrahedron59(2003)19–3023

[4þ2]cycloaddition:twos-bondsareformedattheexpenseoftwop-bonds,whichaccountsforitsthermodynamicdrivingforcedespitetheformationofastrainedbicyclicframework.Fournewstereocenters,twoofthemquater-nary,arecreatedfromanacyclicprecursor.InanalogytoanintramolecularDiels–Alderreaction,tworingsarecreatedinasinglestep.

InatraditionalDiels–Alderreaction,i.e.a[reactionofdieneanddienophilep4proceedssþp2s]cycloaddition,thethroughatransitionstatewhereinbothcomponentsarealignedparalleltoeachother.CatalysisisachievedbyloweringtheenergyoftheLUMOandclosingtheHOMO–LUMOgap.Bycontrast,inthecaseoftrienesoftype1,thisapproachisgeometricallyimpossiblesincethe‘tether’connectingthedieneanddienophileconsistsofasinglebond.Nevertheless,cycloadditioncouldoccur,providedthereactionproceedsthroughatransitionstate30whereinthedieneanddienophileareorientedmoreorlessperpendiculartoeachother(Scheme9).Theconformationalconstraintsofthemethylsubstitutedtrienesystemworkinfavorofsuchatransitionstate(30).DuetosevereA1,3-strainbetweenthemethylgroupsatC2andC4,thetrieneiseffectivelydissectedintoadieneandadienophilemoiety.TheC6methylgroupassuresthatthedienecanassumeans-cisconformationwithoutpayingtoohighanenergycost.Concertedbondformationthenoccursina[p4aþtoaffordabicyclo[3.1.0]hexene.TheLUMO-p2a]fashionloweringeffectofaLewisacidaccountsfortherateacceleration,allowingthisreactiontoeffectivelycompetewitha6pelectrocyclization.Notethatthestereospecificityofthereactionisnicelyexplainedbythisconcertedmechanism.

Scheme9.The[p4aþp2a]mechanism.

Alternatively,astepwisemechanismcouldoperate(Scheme10).CoordinationoftheLewisacidtothecarbonylgroupoftrienoicester31aoritsisomer31btriggersaconrotatorycyclization,placingthetwosubstituentsonthefive-memberedringantiwithrespecttoeachother.Theresultingzwitterionicintermediates32a,bstabilizethem-selvesbyC,C-bondformationtoyield33aor33b.Provided

Scheme10.Stepwisemechanismofthecyclization.thislaststepisconsiderablyfasterthanrotationaroundtheC2–C3bond,thereactionscouldproceedwithcompletestereocontrol.Inthismechanism,themethylsubstituentsnotonlyconformationallypreorganizethesubstratebutalsostabilizetheintermediaryallylcation32a,b.

AlthoughtheLewisacidcatalyzedcycloisomerizationoftrienestobicyclo[3.1.0]hexeneshasbeenpresentedinthecontextofpericyclicreactions,itisbynomeansimpliedthatwebelieveitproceedsinaconcertedfashion.Basedontheavailableexperimentaldata,weareunabletodeterminewhichmechanismapplies.Theconcertedpathwayiscurrentlybeingprobedbycomputationalstudies.4.Extensiontopentadienals:towardsan‘iso-Nazarov

cyclization’Withtheabovemechanismsinmind,wewonderedwhetherthereactioncouldbeextendedtopentadienalsbyreplacingtheelectrophilicdoublebondwithacarbonylgroup(Scheme11).Inprinciple,suchasubstitutionshouldleadtocyclopentadieneepoxidesthatwouldpossiblyundergofurtherisomerizationsinthepresenceofaLewisacid.IntheabsenceofaLewisacid,pentadienalswithappropriatedoublebondgeometryarewellknowntoundergoreversible6pelectrocyclizationstoafford2H-pyrones.1Scheme11.

Again,astepwiseoraconcertedmechanismcouldbeformulated(Scheme12).Inthelatterscenario,hetero[p4aþp2a]cycloadditiondirectlyleadstocyclopentadieneepoxide35.UndertheLewisacidicreactionconditions,thisintermediateislikelytoundergofurtherisomerizationstocyclopentenones36andultimately37.Alternatively,aNazarov-likemechanisminvolvingtheconrotatorycycliza-tionofanoxy-pentadienylcation38couldbeoperating.Theresultingzwitterion39reactsfurthertoaffordcyclopenta-dieneepoxidesorcyclopentenones.Notethatcompoundsoftype34areisomersofthedivinylketonesusedintheclassicalNazarovcyclization.18Remarkably,theisomeri-zationofpentadienalstocyclopentenonesappearstobelargelyunknown.19 Scheme12.Extensiontopentadienals.

24A.K.Milleretal./Tetrahedron59(2003)19–30

Treatmentofpentadienal40withdimethylaluminumchlorideindeedaffordedtheknowncyclopentenone41,19ainmoderateyield(notoptimized).Apparently,thedoublebondisomerizesintothethermodynamicallymoststablepositionunderthereactionconditions.Similarly,42gavecyclopentenone43.Inthiscase,thesecondaryalcohol44bearinganextramethylgroupwasisolatedasabyproduct.Thiscompoundpresumablystemsfromnucleophilicopeningofthevinylepoxideintermediate35withadimethylaluminateorfrominterceptionoftheallyliccationcorrespondingto39.Pentadienal45affordedtheknowncyclopentenone46.20Compound47,however,onlyunder-wentE,Z-isomerizationtotheall-transaldehyde48,indicatingapotentiallimitationofthemethod(Scheme13).

Scheme13.Reagentsandconditions:Me2AlCl(0.2equiv.),CH2Cl2,08C;(a)47%;(b)43:25%,44:17%;(c)28%;(d)80%.

Thepentadienals40,42,45and47weresynthesizedusingacombinationofstereoselectiveolefinations,reductionsandoxidationsteps.Thissyntheticstrategyisfurtherillustratedinthesynthesisofhexahydroindanone53(Scheme14).Still–Gennariolefinationof(2)-perillaldehyde(49)affordedunsaturatedester50.Reductionofthismaterialwithdiisobutylaluminumhydride,followedbyallylicoxidationthengavepentadienal52.Exposureofthismaterialtodimethylaluminumchlorideorborontrifluorideetherateresultedinacomplexmixtureofproductsfromwhichcyclopentenone53couldbeisolatedinlowyields.Interestingly,therelativeamountof53appearedtoincreaseovertime,suggestingthatthecomplexmixtureconsisted

Scheme14.Reagentsandconditions:(a)KHMDS,(CF3CH2O)2P(O)CH2-COOEt,18-C-6,THF,2788C,85%;(b)DIBAH,CH2Cl2,08C,88%;(c)MnO2,CH2Cl2,56%.(d)Me2AlCl(0.2equiv.),CH2Cl2,08C,22%.

mainlyofisomericvinylepoxidesandcyclopentenonesanalogousto35and36.

Arathercuriousresultwasobtainedwiththesensitivealdehyde54,anintermediateinoursynthesisofphoto-deoxytridachione.Attemptedolefinationofthismaterialwithtriethylphosphonopropionate21usingtheconditionsdescribedbyPetroskigaveverylittleoftheintendedproduct13.Instead,aconsiderableamountofcyclopente-none55wasisolated.Presumably,theLewisacidicpropertiesofthelithiumphosphateformedasaby-productoftheHorner–Wadsworth–Emmonsreactionaccountforitsformation.Abase-mediatedalternativemechanismisdifficulttoimagineandwasexcludedbycontrolexperi-ments.Interestingly,attemptstoisomerize54to55usingdimethylaluminumchlorideasacatalystfailed(Scheme15).

Scheme15.

ThesepreliminaryresultssuggestthatdimethylaluminumchloridemaynotbetheoptimalLewisacidforthistypeofreactionandthatathoroughsurveymightyieldabettercatalyst.Furtherinvestigationswillalsoshowwhetherthecorrespondingketonesandsilylketoneswillundergotheisomerizationperhapsleadingtomorestablevinylepoxidesandsilylenolethers.TheLewisacidcatalyzedisomeriza-tionof2H-pyrones,whoseelectrocyclicringopeningaffordspentadienals,tocyclopentenonesisalsounderinvestigation.

Insummary,wehavedemonstratedhowtheserendipitousdiscoveryofareactioncanformthebasisofawide-rangingsyntheticprogram.TotalsynthesesofallthemolluscanpolypropionatesshowninFigure2arecurrentlypursuedinourlaboratories.Inthiscontext,theasymmetriccontrolof6pelectrocyclizationsandthenewlydiscoveredcyclo-isomerizationwillreceivespecialattention.Furthermore,theextensionofthecyclizationtoothersubstrateclasseswillbeexplored.

5.Experimental

5.1.General

Unlessotherwisenoted,allreagentswerepurchasedfromcommercialsuppliersandusedwithoutfurtherpurification.

MeltingpointsweremeasuredonaBu

¨chimeltingpointapparatusandareuncorrected.1Hand13CNMRspectrawererecordedonaBrukerDRX500,aBrukerAM400oraBrukerAMX300.OpticalrotationsweremeasuredonaPerkin–Elmer241polarimeter.MassspectrawererecordedonaVGProSpec.SilicagelchromatographywasoutusingICNSiliTech32–63D60A

˚carried

.Thinlayerchromatography(TLC)wasperformedwithMerckSilicaGel60plates.Elementalanalysiswasperformedbythe

A.K.Milleretal./Tetrahedron59(2003)19–3025

MicroanalyticalLaboratoryoperatedbytheUCBCollegeofChemistry.X-RayanalysiswasperformedonaBrukerSMARTCCDarea-detectordiffractometer.AllreactionswerecarriedoutunderanatmosphereofArorNdriedglassware.Externalbathtemperatureswere2inoven-usedtorecordallreactionmixturetemperatures.Tetrahydrofuran(THF),methylenechloride(CHdriedbypassingthroughactivated2Cl2),andtoluenewerealuminacolumns.Benzene,hexanesandDBUweredistilledfromcalciumhydride.n-ButyllithiumwastitratedusingdiphenylaceticacidinTHF.5.2.Compounds

5.2.1.2,4,6-Trimethyl-7-(4-nitro-phenyl)-hepta-(Z)-2,(Z)-4,(E)-6-trienoicacidethylester(1).Toamixtureof18-crown-6(2.09g,7.91mmol)and10(770mg,2.22mmol)in5.0mLofTHFwasaddedasolutionofpotassiumbis(trimethylsilyl)amide(4.40mL,2.20mmol,0.5Mintoluene)at2788Cundernitrogen.After5min,asolutionof40(462mg,2.01mmol)in5.0mLofTHFwasadded.After2.5h,thereactionmixturewasquenchedwith20mLofa1:1mixtureofsaturatedNH4ClandHwith10mLofEtOAc.Thetwolayers2O,anddilutedwereseparatedandtheaqueouslayerwasextractedwithEtOAc(2£10mL).Thecombinedorganiclayersweredried(MgSO4),filtered,andconcentratedinvacuo.Theproductwaspurifiedbycolumnchromatography(10%EtOAcinhexanes)toafford570mg(90%)of1asayellowoil:Rf¼0.35(silica,20%EtOAcinhexanes);IR(thinfilm)nmax¼2926,1711,1516,1342cm21;1HNMR(400MHz,CDCl3):d8.16(d,J¼8.8Hz,2H),7.83(d,J¼8.8Hz,2H),6.51(s,1H),6.40(s,1H),5.96(s,1H),4.18(q,J¼7.2Hz,2H),1.98(d,J¼1.2Hz,3H),1.97(d,J¼1.2Hz,3H),1.94(s,3H),1.27(t,J¼7.2Hz,3H);13CNMR(100MHz,CDCl3):d168.9,146.0,145.0,139.6,136.8,135.9,133.0,129.8,129.6,128.9,123.6,60.8,24.0,21.1,19.2,14.2;HRMS(EI):calcdforCAnal.calcdforC18HH21NO4:315.1470;found:315.1466;4.44;found:C68.41,H6.80,18N21NO4.47.

4:C68.55,H6.71,N5.2.2.(1Rp,6Rp)1,3,5-Trimethyl-6-(4-nitro-phenyl)-cyclohexa-2,4-dienecarboxylicacidethylester(2).Asolutionof1(100mg,0.317mmol)in3.0mLoftoluenewasheatedat608Cundernitrogenfor16h.Thesolutionwasconcentratedinvacuoandtheproductwaspurifiedbycolumnchromatography(10%EtOAcinhexanes)toafford98.0mg(98%)of2asayellowsolid:Rf¼0.37(silica,20%EtOAcinhexanes);mp105–1068C;IR(KBrpellet)nmax¼2979,1715,1521,1348cm21;1HNMR(400MHz,CDCl3):d8.10(d,J¼8.4Hz,2H),7.33(d,J¼8.4Hz,2H),5.72(s,1H),5.07(s,1H),4.18(dq,J¼10.4,7.2Hz,1H),4.10(dq,J¼10.4,7.2Hz,1H),3.83(s,1H),1.85(d,J¼1.2Hz,3H),1.66(s,3H),1.23(t,J¼7.2Hz,3H),0.95(s,3H);13CNMR(125MHz,CDCl139.4,133.5,130.7,123.6,123.5,3):d176.7,147.4,145.8,121.9,61.2,51.0,47.5,23.2,22.2,21.2,14.3;HRMS(EI):calcdforCfound:315.1463;Anal.calcdforC18H21NO4:315.1470;68.55,H6.71,N4.44;found:C68.69,H6.78,18HN21NO4.30.4:C5.2.3.(1Sp,4Sp,5Rp,6Rp)1,3,6-Trimethyl-4-(4-nitro-phenyl)-bicyclo[3.1.0]hex-2-ene-6-carboxylicacidethylester(3).Toasolutionof1(103mg,0.33mmol)in3.0mL

ofCHchloride2Cl(652wasaddedasolutionofdimethylaluminummL,0.065mmol,1.0Minhexanes)at08Cunderablanketofnitrogen.After30min,thereactionmixturewasallowedtowarmto238Candafter3hwasquenchedwith3.0mLofH2O.ThetwolayerswereseparatedandtheaqueouslayerwasextractedwithCHdried2Cl(MgSO2(2£2mL).Thecombinedorganiclayerswere4),filtered,andconcentratedinvacuo.Theproductwaspurifiedbycolumnchromatography(5%EtOAcinhexanes)toyield70mg(68%)of3asayellowoil:Rf¼0.25(silica,10%Et¼2978,2934,1725,1520,2Oinhexanes);IR(thinfilm)nmax1346cm21;1HNMR(400MHz,C5.326D6):d7.85(d,J¼8.8Hz,2H),6.77(d,J¼8.8Hz,2H),(d,J¼0.8Hz,1H),4.05(s,1H),4.05(dq,J¼10.4,7.2Hz,1H),3.90(dq,J¼10.4,7.2Hz,1H),1.33(s,3H),1.18(s,3H),1.16(s,3H),0.99(t,J¼7.2Hz,3H),0.87(s,1H);13CNMR(125MHz,C141.8,132.3,129.0,124.2,60.4,6D55.8,6):d171.9,151.3,147.6,41.3,40.3,37.1,18.1,14.8,14.3,14.1;HRMS(EI):calcdforC18H21NO4:315.1470;found:315.1471;Anal.calcdforC68.55,H6.71,N4.44;found:C68.55,H6.76,18HN21NO4.30.4:C5.2.4.2,4,6-Trimethyl-nona-(Z)-2,(E)-4,(E)-6-trienoicacidethylester(11).Toamixtureof18-crown-6(12.60g,47.67mmol)and10(6.06g,17.5mmol)in160mLofTHFwasaddedasolutionofpotassiumbis(trimethylsilyl)amide(35.0mL,17.5mmol,0.5Mintoluene)at2788Cunderablanketofargon.After5min,asolutionof9(2.19g,15.8mmol)in25mLofTHFwasaddeddropwise.After45min,thereactionmixturewasallowedtowarmto08C.Uponreaching08C,themixturewasquenchedwith200mLofa3:1mixtureofHanddilutedwith100mLofEt2OandsaturatedNHwereseparated4Clandtheaqueouslayerwas2O.ThetwolayersextractedwithEt2O(2£100mL).Thecombinedorganiclayerswerewashedwith100mLofbrine,dried(MgSOvacuo.Theproductwaspurified4),filtered,andconcentratedinbycolumnchromatography(5–10%Et2Oinhexanes)toafford2.78g(78.9%)of11asacolorlessoil:Rf¼0.56(silica,10%Et2Oinhexanes);21IR(thinfilm)n;1HNMR(400MHz,max¼2965,2933,2873,1723cmCDCl3):d6.12(s,1H),5.85(s,1H),5.36(t,J¼7.2Hz,1H),4.18(q,J¼7.2Hz,2H),2.10(quint,J¼7.2Hz,2H),1.97(d,J¼1.6Hz,3H),1.85(s,3H),1.7313(s,3H),1.28(t,J¼7.2Hz,3H),0.98(t,J¼7.2Hz,3H);CNMR(100MHz,CDCl134.2,131.9,131.6,127.2,60.6,21.8,3):d170.7,138.6,136.3,21.7,16.9,16.8,14.3,14.2;HRMS(EI):calcdforC14H22O2:222.1619;found:222.1615;Anal.calcdforC75.60,H10.13.

14H22O2:C75.63,H9.97;found:C5.2.5.2,4,6-Trimethyl-nona-(Z)-2,(E)-4,(E)-6-trien-1-ol(12).Toasolutionof11(2.78g,12.5mmol)in120mLofCH2Cl2wasaddedasolutionofDIBAH(30.0mL,30.0mmol,1.0Mintoluene)at08Cunderablanketofargon.Aftertheadditionwascomplete,thereactionmixturewasallowedtowarmto238C.After1h,thereactionmixturewascooledto08Candquenchedwith150mLofa4:1mixtureofH2OandsaturatedRochelle’ssaltandstirredvigorouslyfor2h.ThetwolayerswereseparatedandtheaqueouslayerwasextractedwithCHcombinedorganiclayersweredried(MgSO2Cl2(2£100mL).Thevacuo.Theproductwaspurified4),filtered,andconcentratedinbycolumnchromatography(20%Et2Oinhexanes)toafford2.09g

26A.K.Milleretal./Tetrahedron59(2003)19–30

(92.8%)of12asacolorlessoil:Rf¼0.30(silica,15%EtOAcinhexanes);IR(thinfilm)nmax¼3324(br)2963,2933,2872,1447cm21;1HNMR(400MHz,CDCl5.82(s,1H),5.(s,1H),5.32(t,J¼7.2Hz,1H),4.263):d(s,2H),2.10(quint,J¼7.2Hz,2H),1.86(d,J¼1.6Hz,3H),1.84(s,3H),1.73(s,3H),0.99(t,J¼7.2Hz,3H);13CNMR(100MHz,CDCl3):d135.2,133.4,133.3,133.0,131.9,131.6,62.7,22.8,21.7,19.0,17.0,14.3;HRMS(EI):calcdforC12H20O:180.1514;found:180.1517.

5.2.6.2,4,6,8-Tetramethyl-undeca-(E)-2,(Z)-4,(E)-6,(E)-8-tetraenoicacidethylester(13).Toamixtureof12(1.39g,7.71mmol),3.50gof4A

˚NMO(1.40g,12.0mmol),and

molecularsievesin30mLofCHaddedTPAP(84.0mg,0.239mmol)at08Cunder2Clablanket2wasofargon.Immediatelyaftertheaddition,thereactionflaskwaswrappedinaluminumfoilandallowedtowarmto238C.After4h,thereactionmixturewasfilteredthroughathinpadofsilicaandwashedwithCH2Cl2(3£30mL).Thecombinedfiltratewasconcentratedinvacuotogive995mgofcrudealdehyde54asayellowoilthatwasusedinthenextstepwithoutfurtherpurification.ToamixtureofLiCl(338mg,7.97mmol),DBU(0.90mL,6.02mmol),andtriethylphosphonopropionate(4.16g,17.5mmol)in25mLofCH3CNwasaddedasolutionofcrudealdehyde(995mg,5.58mmol)in35mLofCH3CNat238Cunderablanketofargon.After5h,themixturewasconcentratedinvacuoanddilutedwith200mLofH2Oand100mLofEtaqueouslayerwas2O.ThetwolayerswereseparatedandtheextractedwithEt2O(2£50mL).Thecombinedorganiclayerswerewashedwith50mLofbrine,dried(MgSOinvacuo.Theproductwaspurified4),filtered,andconcentratedbycolumnchromatography(1–5%Et2Oinhexanes)toafford860mg(42.5%from12)of13asacolorlessoil:REt(thinfilm)nf¼0.45(silica,5%2Oinhexanes);IR;1HNMR(400MHz,CDClmax¼2954,2932,2873,1709cm217.23):d7.45(s,1H),6.01(s,1H),5.78(s,1H),5.34(t,J¼Hz,1H),4.20(q,J¼7.2Hz,2H),2.10(quint,J¼7.2Hz,2H),1.95(s,3H),1.(d,J¼1.2Hz,3H),1.83(s,3H),1.73(s,3H),131.29(t,J¼7.2Hz,3H),0.98(t,J¼7.2Hz,3H);CNMR(100MHz,CDCl3):d168.9,140.6,137.5,136.4,133.4,132.3,132.1,131.1,127.2,60.7,31.8,24.2,21.8,18.4,17.0,14.4,14.2;HRMS(EI):calcdforCfound:262.1930.

17H26O2:262.1932;5.2.7.(1Sp,d4Sp,5Rp,6Sp)1,3,6-Trimethyl-4-(1-methyl-but-1-enyl)-bicyclo[3.1.0]hex-2-ene-6-carboxylicacidethylester(14).Toasolutionof13(425mg,1.62mmol)in16mLofCH2Cl2wasaddedasolutionofdimethyl-aluminumchloride(0.35mL,0.35mmol,1.0Minhexanes)at08Cunderablanketofargon.Thereactionmixturewasallowedtowarmto238Candwaswrappedinaluminumfoil.After8h,thereactionmixturewasquenchedwith15mLofH2O.ThetwolayerswereseparatedandtheaqueouslayerwasextractedwithCH2Cl2(2£15mL).Thecombinedorganiclayersweredried(MgSO4),filtered,andconcentratedinvacuo.Theproductwaspurifiedbycolumnchromatography(5%Etof14asacolorless2Oinhexanes)toafford312mg(73.4%)oil:Rf¼0.34(silica,5%Etinhexanes);IR(thinfilm)n2930,2872,2O1717cm21;1HNMR(400MHz,max¼2961,CDClHz,2H),2.60(s,1H),2.023):d5.25(m,2H),4.13(q,J¼7.2(quint,J¼7.6Hz,2H),1.92(s,1H),1.53(s,3H),1.47(s,3H),1.30(s,3H),

131.26(t,J¼7.2Hz,3H),1.05(s,3H),0.96(t,J¼7.6Hz,3H);CNMR(100MHz,CDCl43.1,37.9,3):d174.2,144.1,134.1,129.3,128.9,60.5,59.1,33.7,21.4,14.6,14.5,14.5,13.8,12.5,10.1;HRMS(EI):calcdforC262.1936;Anal.calcdforC17H26O2:262.1932;found:17H26O2:C77.82,H9.99;found:C78.16,H10.20.

5.2.8.(1Sp,4Sp,5Rp,6Sp)1,3,6-Trimethyl-4-(1-methyl-but-1-enyl)-bicyclo[3.1.0]hex-2-ene-6-carboxylicacidmethoxy-methyl-amide(15).Toaslurryof14(120mg,0.457mmol)andN,O-dimethylhydroxylaminehydro-chloride(226mg,2.32mmol)in2.0mLofTHFwasaddedasolutionofisopropylmagnesiumchloride(2.1mL,4.2mmol,2.0MinEt2O)at2108Cunderablanketofargon.Thereactionmixturewasallowedtowarmto238Cand,after1h,wasquenchedwith20mLofa1:1mixtureofsaturatedNH4ClandH2Oanddilutedwith20mLofEt2O.ThetwolayerswereseparatedandtheaqueouslayerwasextractedwithEtwashedwith2O(2£20mL).Thecombinedorganiclayerswere20mLofbrine,dried(MgSOconcentratedinvacuo.Theproductwaspuri-4),filtered,andfiedbycolumnchromatography(25%Et15asacolorless2Oinhexanes)toyield80.0mg(63.1%)ofoil:REtf¼0.13(silica,25%2931,2870,16582Oinhexanes);IR(thinfilm)ncm21;1HNMR(500MHz,max¼2963,CDCl5.25(t,J¼7.5Hz,1H),5.23(s,1H),3.71(s,3H),3.233):d(s,3H),2.62(s,1H),2.01(quint,J¼7.5Hz,2H),1.69(s,1H),1.53(s,3H),1.45(s,3H),1.22(s,3H),1.03(s,3H),0.95(t,J¼7.5Hz,3H);13CNMR(100MHz,CDCl58.8,40.3,34.9,3):d210.0,144.3,134.1,128.8,128.0,60.6,34.6,34.3,21.4,16.2,14.5,13.8,12.6,11.0;HRMS(EI):calcdforCfound:277.2044;Anal.calcdforC17H27NO:2:277.2041;17H27NO2C73.61,H9.81,N5.05;found:C73.72,H9.98,N4.90.5.2.9.(1Sp,4Sp,5Rp,6Sp)1-[1,3,6-Trimethyl-4-(1-methyl-but-1-enyl)-bicyclo[3.1.0]hex-2-en-6-yl]-propan-1-one(16).Toasolutionof15(16.9mg,0.061mmol)in0.8mLofTHFwasaddedasolutionofethylmagnesiumbromide(0.20mL,0.60mmol,3.0MinEt2O)at08Cunderablanketofargon.After3h,thereactionmixturewasquenchedwith2.0mLofa1:1mixtureofsaturatedNHofEt4ClandH2Oanddilutedwith2.0mLlayerwas2O.ThetwolayerswereseparatedandtheaqueousextractedwithEtThecombinedorganiclayersweredried(MgSO2O(2£2mL).invacuo.Theproductwaspurified4),filtered,andconcentratedbycolumnchromatography(5%Et13.0mg(86.6%)of16asacolorless2Oinhexanes)toyieldoil:ROinhexanes);IR(thinfilm)nf¼0.71(silica,25%Et2872,162cm21;1HNMR(400MHz,max¼2963,2932,CDCl1H),5.23(t,J¼7.2Hz,1H),2.65(dq,J¼17.6,3):d5.25(s,7.2Hz,1H),2.55(s,1H),2.49(dq,J¼17.6,7.2Hz,1H),2.07(s,1H),2.01(quint,J¼7.2Hz,2H),1.55(s,3H),1.45(s,3H),1.13(s,3H),1.1113(s,3H),1.04(t,J¼7.2Hz,3H),0.94(t,J¼7.2Hz,3H);CNMR(100MHz,CDCl134.2,129.2,128.8,59.1,45.2,40.6,37.1,3):d211.0,144.8,34.6,21.4,14.5,14.0,13.9,12.6,10.6,8.3;HRMS(EI):calcdforC17H26O:246.1985;found:246.1983.

5.2.10.(1Sp,4Sp,5Rp,6Sp)2,4-Dimethyl-3,5-dioxo-5-[1,3,6-trimethyl-4-(1-methyl-but-1-enyl)-bicyclo[3.1.0]-hex-2-en-6-yl]-pentanoicacidmethylester(18).Toasolutionof16(75.0mg,0.304mmol)in5.0mLofTHFwasaddedasolutionoflithiumbis(trimethylsilyl)amide

A.K.Milleretal./Tetrahedron59(2003)19–3027

(1.30mL,1.30mmol,1.0Minhexanes)at2788Cunderablanketofargon.Afteraddition,themixturewasallowedtowarmto238Cfor5minbeforebeingcooledto2788Canddilutedwith5.0mLofhexanes.Tothismixturewasaddedasolutionofmalonylchloride17(63.2mg,0.420mmol)in5.0mLofhexanesover20min.Thereactionmixturewasstirredat2788Cfor45minandthenallowedtowarmto238C.After2h,thereactionmixturewasquenchedwith10mLofa1:1mixtureofH2OandsaturatedNHofEt4Clanddilutedwith10mLaqueouslayerwas2O.ThetwolayerswereseparatedandtheextractedwithEt2O(2£10mL).Thecombinedorganiclayersweredried(MgSOandconcentratedinvacuo.Theproductwaspurified4),filtered,bycolumnchromatography(10–30%Etbasedon2Oinhexanes)toafford.8mg(59.1%,95%recoveredstartingmaterial)of18asamixtureofdiastereomersasacolorlessoil:Rf¼0.19(silica,10%EtH2Oinhexanes);HRMS(EI):calcdforC2232H4:360.2301;found:360.2302.

5.2.11.(1Sp,4Sp,5Rp,6Sp)4-Hydroxy-3,5-dimethyl-6-[1,3,6-trimethyl-4-(1-methyl-but-1-enyl)-bicyclo[3.1.0]-hex-2-en-6-yl]-pyran-2-one(19).Amixtureof18(100mg,0.277mmol)andDBU(50mL,0.334mmol)in3.0mLofbenzenewasheatedtorefluxunderargon.After3h,thereactionmixturewasconcentratedinvacuoandtheproductwaspurifiedbycolumnchromatography(CHtoyield71.0mg(77.9%)2ClAcOH¼97.5:2.5:0.125)2/MeOH/of19asawhitefoam:RIR(CDCl)nf¼0.38(silica,5%MeOHinCH3032,2962,2928,2Cl2870,2);1665cm213;1Hmax¼3136(br),NMR(400MHz,CDCl(m,2H),2.69(s,1H),2.03(quint,J3):d6.82(bs,1H),5.28¼7.5Hz,2H),2.01(s,3H),1.99(s,3H),1.55(s,1H),1.54(s,3H),1.45(s,3H),1.16(s,3H),1.07(s,3H),0.96(t,J¼7.5Hz,3H);13CNMR(100MHz,CDCl109.4,3):d167.2,166.2,161.3,144.3,134.1,129.0,128.6,98.9,58.7,40.9,31.9,29.9,21.4,17.0,14.5,13.8,13.3,12.7,10.7,8.8;HRMS(EI):calcdforC21H28O3:328.2038;found:328.2035.

5.2.12.(6)-Photodeoxytridachione(6).Toasolutionof19(12.5mg,0.038mmol)in0.3mLofCHL,0.38mmol)2Clat2wasaddedmethylfluorosulfonate(30m238Cunderablanketofargon.After3h,thereactionmixturewasconcentratedinvacuo,dissolvedin2mLofCHThecrudematerialwastakenupin2Cl2mL2andconcentrated.ofCH2Cl2and2mLof1NNaOH.ThetwolayerswereseparatedandtheaqueouslayerwasextractedwithCH(2£2mL).Thecombinedorganiclayersweredried2Cl2(MgSOwasfurther4),filtered,andconcentratedinvacuo.Theproductpurifiedbycolumnchromatography(2%MeOHinCH2Cl2)toyield10.0mg(76.7%)of6asawhitesolid:Rf¼0.50(silica,5%MeOHinCH1661cm21;1HNMR(400MHz,2Cl2);IR(thinfilm)n1H),max¼CDCl5.30(t,J¼7.2Hz,1H),3.96(s,3H),2.73(bs,3):d5.33(s,1H),2.04(dq,J¼7.6,7.2Hz,2H),1.97(s,3H),1.84(s,3H),1.57(s,3H),1.48(s,3H),1.42(bs,1H),1.19(s,3H),1.10(s,3H),0.97(t,J¼7.6Hz,3H);13CNMR(100MHz,CDCl181.8,162.5,160.7,144.2,134.2,129.0,128.8,120.6,99.7,3):d58.6,55.5,40.9,37.0,32.0,21.4,17.3,14.5,13.9,12.9,11.0,7.1;HRMS(EI):calcdforCfound:343.2248.

21H30O3:343.2228;5.2.13.(1Sp,6Rp)1,3,5-Trimethyl-6-(1-methyl-but-1-enyl)-cyclohexa-2,4-dienecarboxylicacidethylester

(22).Asolutionof13(100.0mg,0.381mmol)in38mLofbenzenewasheatedat608Cunderargon.After2d,thereactionmixturewasconcentratedinvacuotoyield98.3mg(98.3%)of22asacolorlessoil:R21IR(thinfilm)nf¼0.71(silica,15%EtOAcinhexanes);;1HNMR(300MHz,CDClmax¼2963,2933,2874,1719cm2.93(t,J¼7.53):d5.39(s,1H),5.00(s,1H),4.07(m,2H),Hz,1H),2.34(s,1H),1.65(d,J¼1.2Hz,3H),1.63(s,3H),1.40(m,2H),1.38(s,3H),1.21(t,J¼7.2Hz,3H),1.05(s,3H),0.84(t,J¼7.3Hz,3H);13CNMR(100MHz,CDCl3):d176.1,131.9,127.2,126.6,123.2,60.5,55.0,54.1,51.6,36.3,23.9,22.4,22.0,21.7,19.6,14.4,13.5;HRMS(EI):calcdforC17H26O2:262.1933;found:262.1935.

5.2.14.(1Sp,6Rp)1,3,5-Trimethyl-6-(1-methyl-but-1-enyl)-cyclohexa-2,4-dienecarboxylicacidmethoxy-methyl-amide(23).Toasolutionof22(55.0mg,0.210mmol)in4.0mLofTHFwasaddedN,O-dimethylhydroxylaminehydrochloride(204mg,2.09mmol).Tothismixturewasaddedisopropylmagnesiumchloride(1.78mL,3.56mmol,2.0MinEt2O)at08Cunderablanketofargon.After4h,thereactionmixturewasquenchedwith4.4mLofa1:1mixtureofsaturatedNHmLofEt4ClandH2Oanddilutedwith2.22O.ThetwolayerswereseparatedandtheaqueouslayerwasextractedwithEt2O(2£4.4mL).Thecombinedorganiclayersweredried(MgSO4),filtered,andconcentratedinvacuo.Theproductwaspurifiedbycolumnchromatography(20%EtOAcinhexanes)toyield16.7mg(28.8%,91%basedonrecoveredstartingmaterial)of23asacolorlessoil:Rf¼0.29(silica,15%EtOAcinhexanes);IR(thinfilm)nmax¼2961,2933,2873,1668cm21;1HNMR(300MHz,CDCl3):d5.42(s,1H),4.97(s,1H),3.63(s,3H),3.08(s,3H),2.66(dd,J¼6.0,4.8Hz,1H),2.36(s,1H),1.79(s,3H),1.65(d,J¼1.2Hz,3H),1.51(m,2H),1.39(s,3H),1.04(s,3H),0.(t,J¼7.2Hz,3H);13CNMR(100MHz,CDCl3):d178.4,133.5,127.4,127.0,122.4,60.2,56.1,54.5,52.9,36.4,34.0,23.8,23.5,22.2,21.9,19.5,13.8;HRMS(EI):calcdforCfound:277.2041.

17H27NO2:277.2042;5.2.15.2,4,6,8-Tetramethyl-undeca-(E)-2,(Z)-4,(E)-6,(Z)-8-tetraenoicacidethylester(24).Toamixtureof10(343mg,0.991mmol)and18-crown-6(700mg,2.65mmol)in10mLofTHFwasaddedasolutionofpotassiumbis(trimethylsilyl)amide(2.0mL,1.0mmol,0.5Mintoluene)at2788Cunderargon.After5min,asolutionof54(150mg,0.84mmol)in2.0mLofTHFwasadded.After2h,thereactionmixturewasquenchedwith10mLofa4:1mixtureofH2O:saturatedNH4Cl.Thetwolayerswereseparatedandtheaqueouslayerwasextractedwith10mLofEt2O.Thecombinedorganiclayersweredried(MgSO4),filtered,andconcentratedinvacuo.Theproductwaspurifiedbycolumnchromatography(5–10%Et2Oinhexanes)toyield180mgofa3:1mixtureof24andtheproductof6pelectrocyclization(51%).Compound24wasusedimmediatelyinthenextstepwithoutfurtherpurification.

5.2.16.(1Sp,4Sp,5Rp,6Rp)1,3,6-Trimethyl-4-(1-methyl-but-1-enyl)-bicyclo[3.1.0]hex-2-ene-6-carboxylicacidethylester(25).Toasolutionof24(21.0mg,0.083mmol)in1.0mLofCH2Cl2wasaddedasolutionofdimethylaluminumchloride(30mL,0.030mmol,1.0Min

28A.K.Milleretal./Tetrahedron59(2003)19–30

hexanes)at08Cunderablanketofargon.Thereactionmixturewaswarmedto238Cover2hatwhichtimeitwasquenchedwith5mLofH.Thetwolayerswere2Oanddilutedwith4mLofCH2Cl2separatedandtheaqueouslayerwasextractedwithCH2Cl2(2£2mL).Thecombinedorganiclayersweredried(MgSOtratedinvacuo.Theproductwas4),filtered,andconcen-purifiedbycolumnchromatography(50%benzeneinhexanes)toyield13.0mg(61%)of25asacolorlessoil:Rinhexanes);IR(thinfilm)nf¼0.34(silica,5%Et2O1729cm21;1HNMR(400MHz,max¼2961,2928,2872,CDCl3):d5.30(t,J¼7.2Hz,1H),5.28(s,1H),4.08(dq,J¼10.8,7.2Hz,1H),3.99(dq,J¼10.8,7.2Hz,1H),3.24(s,1H),2.01(dq,J¼7.6,7.2Hz,2H),1.43(bs,6H),1.30(s,3H),1.28(s,3H),1.18(t,J¼7.2Hz,3H),0.97(s,1H),0.95(t,J¼7.6Hz,3H);13CNMR(100MHz,CDCl60.1,59.3,39.4,3):d173.0,140.5,134.9,131.2,128.7,39.1,36.1,29.9,21.4,18.2,14.6,14.0,13.9,12.2;HRMS(EI):calcdforC17H26O2:262.1932;found:262.1928.

5.2.17.2,4,6-Trimethyl-7-(4-nitro-phenyl)-hepta-(E)-2,(Z)-4,(E)-6-trienoicacidethylester(26).Toasuspen-sionofsodiumhydride(72mg,1.80mmol,60%inoil)in3.0mLofTHFwasaddedasolutionoftriethylphosphono-propionate(423mg,1.78mmol)in5.0mLofTHFat238Cunderablanketofargon.After2h,asolutionof40(1.72mmol)in9.0mLofTHFwasadded.After3h,thereactionmixturewasquenchedwith25mLofHlayerswereseparated2Oanddilutedwith20mLofEtandtheaqueouslayerwas2O.ThetwoextractedwithEtThecombinedorganiclayersweredried(MgSO2O(2£25mL).concentratedinvacuo.Theproductwas4),filtered,andpurifiedbycolumnchromatography(10–20%Etaffordmg(16%)of26asayellow2Oinhexanes)tooilwhichslowlysolidifiedinthefreezer:R(thinfilm)nf¼0.48(silica,25%Et2932,1707,2Oinhexanes);IRmax¼2980,1591,1515cm21;1HNMR(400MHz,CDCl2H),7.45(s,1H),7.39(d,J¼8.83):d8.18(d,J¼8.8Hz,Hz,2H),6.42(s,1H),6.13(s,1H),4.20(q,J¼7.2Hz,2H),2.02(s,3H),1.98(s,3H),1.92(s,3H),1.27(t,J¼7.2Hz,3H);13CNMR(100MHz,CDCl3):d209.8,168.4,144.7,139.7,139.3,135.4,134.7,129.7,129.4,128.5,123.6,60.9,24.4,18.6,14.4,14.2;HRMS(EI):calcdforCfound:315.1469.

18H21NO4:315.1471;5.2.18.(1Sp,4Sp,5Rp,6Sp)1,3,6-Trimethyl-4-(4-nitro-phenyl)-bicyclo[3.1.0]hex-2-ene-6-carboxylicacidethylester(27).Toasolutionof26(75mg,0.24mmol)in2.4mLofCH2Cl2wasaddedasolutionofdimethylalumi-numchloride(0.10mL,0.10mmol,1.0Minhexanes)at08Cunderablanketofargon.Thereactionmixturewasallowedtowarmto238C,andafter8hadditionaldimethylaluminumchloride(0.10mL,0.10mmol)wasadded.After16h,thereactionmixturewasquenchedwith4mLofa1:1mixtureofHanddilutedwith3mLof2OandsaturatedRochelle’ssaltCHtheaqueouslayer2Clwas2.ThetwolayerswereseparatedandextractedwithCH£2mL).Thecombinedorganiclayersweredried2Cl(22(MgSO4),filtered,andconcentratedinvacuo.Theproductwaspurifiedbycolumnchromatography(5–10%Et(84%)of27asayellow2Oinhexanes)toyield63mgoil:Rf¼0.38(silica,10%EtOAcinhexanes);IR(thinfilm)nmax¼2975,2932,2873,1712,1604,1520cm21;1HNMR

(500MHz,C6D5.136):d7.82(d,J¼7.0Hz,2H),6.71(d,J¼7.0Hz,2H),(s,1H),4.02(m,2H),2.(s,1H),2.27(s,1H),1.44(s,3H),1.25(s,3H),1.21(s,3H),1.00(t,J¼7.0Hz,3H);13CNMR(100MHz,C124.3,61.0,6D6):d173.1,150.0,147.6,144.4,131.0,129.0,55.5,43.7,40.6,35.3,14.8,14.8,13.9,10.6;HRMS(EI):calcdforC18H21NO4:315.1471;found:315.1468.

5.2.19.(1Sp,4Sp,5Rp,6Sp)[1,3,6-Trimethyl-4-(1-methyl-but-1-enyl)-bicyclo[3.1.0]hex-2-en-6-yl]-methanol(28).Toasolutionof14(25mg,0.095mmol)in1.0mLofCH2Cl2wasaddedasolutionofDIBAH(0.25mL,0.25mmol,1.0Mintoluene)at2788Cunderablanketofargon.After5min,thereactionmixturewasquenchedwith4mLofa1:1mixtureofsaturatedRochelle’ssaltandHanddilutedwith4mLofhexanes.Thelayerswere2OseparatedandtheaqueouslayerwasextractedwithEt2O(2£5mL).Thecombinedorganiclayersweredried(MgSOpurified4),filtered,andconcentratedinvacuo.Theproductwasbycolumnchromatography(25%Ethexanes)toafford16mg(76%)of28asacolorless2Oinoil:Rnf¼0.20(silica,25%Et2Oinhexanes);IR(thinfilm)max¼3350(br),2961,2929,2871,1449,1376cm21;1HNMR(400MHz,C6D6):d5.32(t,J¼6.8Hz,1H),5.19(s,1H),3.49(d,J¼11.2Hz,1H),3.20(d,J¼11.2Hz,1H),2.68(s,1H),2.03(quint,2H),1.51(s,6H),1.28(s,3H),1.05(s,3H),0.97(t,J¼7.2Hz,3H),0.81(s,1H),0.76(s,1H);13CNMR(100MHz,CDCl58.4,38.8,36.4,31.7,3):d141.8,135.1,130.8,128.3,69.3,21.4,15.5,14.6,13.8,12.5,11.1;HRMS(EI):calcdforC15H24O:220.1827;found:220.1830.

5.2.20.(1Sp,4Sp,5Rp,6Rp)(1,3,6-Trimethyl-4-phenyl-bicyclo[3.1.0]hex-2-en-6-yl)-methanol(29).Toasolutionof3(41.3mg,0.13mmol)in1.5mLofCH2Cl2wasaddedasolutionofDIBAH(0.35mL,0.35mmol,1.0Mintoluene)at2788Cunderablanketofargon.After5min,thereactionmixturewasquenchedwith4mLofa3:1mixtureofHRochelle’ssaltanddilutedwith5mL2OandsaturatedofCH2Cl2.ThetwolayerswereseparatedandtheaqueouslayerwasextractedwithCH2Cl2(2£5mL).Thecombinedorganiclayersweredried(MgSOtratedinvacuo.Theproductwas4),filtered,andconcen-purifiedbycolumnchromatography(30%EtOAcinhexanes)toyield15mg(42%)of29asayellowoil:R(thinfilm)nf¼0.47(silica,33%EtOAcinhexanes);IRcm21;1HNMR(500max¼3401(br),2931,2872,1603,1517MHz,CDCl3):d8.16(d,J¼8.5Hz,2H),7.30(d,J¼6.8Hz,2H),5.47(s,1H),3.56(d,J¼11.5Hz,1H),3.53(d,J¼11.5Hz,1H),3.34(s,1H),1.47(s,3H),1.41(s,3H),1.22(s,3H),1.04(s,1H);13C(125MHz,CDCl3):d151.7,146.9,142.1,131.2,128.9,124.0,63.7,55.2,42.1,40.1,32.8,18.7,15.4,14.0;HRMS(EI):calcdforC16H19NO3:273.1365;found:273.1370.5.2.21.2,4-Dimethyl-5-(4-nitro-phenyl)-penta-(Z)-2,(E)-4-dienal(40).To2,4-Dimethyl-5-(4-nitro-phenyl)-penta-2,4-dien-1-ol3b(468mg,2.01mmol)in20mLofCHwasaddedDess–Martinperiodinane(1.07g,2.52mmol)2Clat2238C.After30min,thereactionmixturewasquenchedwith30mLofa1:1:1mixtureofsaturatedNaHCOandH3,saturatedNa2S2O3,2O,anddilutedwith20mLofEt2O.Thetwolayerswereseparatedandtheaqueouslayerwasextractedwith20mLofEt2O.Thecombinedorganiclayers

A.K.Milleretal./Tetrahedron59(2003)19–3029

werewashedwith30mLofbrine,dried(MgSO4),filtered,andconcentratedinvacuo.Thecrudeproductwasusedwithoutfurtherpurificationinthenextstep.

5.2.22.3,5-Dimethyl-2-(4-nitro-phenyl)-cyclopent-2-enone(41).19aToasolutionof40(53mg,0.23mmol)in2.3mLofCH2Cl2wasaddedasolutionofdimethylalumi-numchloride(0.07mL,0.07mmol,1.0Minhexanes)at2108Cunderablanketofargon.After1h,thereactionmixturewasquenchedwith5mLofa1:1mixtureofHsaturatedRochelle’ssaltanddilutedwith5mL2OandofCH2Cl2.ThetwolayerswereseparatedandtheaqueouslayerwasextractedwithCHorganiclayersweredried(MgSO2Cl2(2£5mL).Thecombinedtratedinvacuo.Theproductwas4),filtered,andconcen-purifiedbycolumnchromatography(25%Etof41asayellowsolid:2Oinhexanes)toyield25mg(47%)Rf¼0.16(silica,20%EtOAcinhexanes);IR(CDCl1;1H3)n(400max¼2967,2931,1702,1637,1598,1518cm2MHz,CDClJ¼9.2Hz,2H),7.48(d,J¼9.2Hz,2H),2.973):d8.24(d,(dd,J¼18.8,6.8Hz,1H),2.52–2.63(m,1H),2.32(d,J¼18.8Hz,1H),2.21(s,3H),1.26(d,J¼7.2Hz,3H);13CNMR(100MHz,CDCl3):d209.8,172.5,145.1,139.1,137.5,130.2,123.6,41.4,40.4,18.6,16.7;HRMS(EI):calcdforC231.05;found:231.09.

13H13NO3:5.2.23.3,5-Dimethyl-2-phenyl-cyclopent-2-enone(43)and2,2,4-Trimethyl-5-phenyl-cyclopent-3-enol(44).Toasolutionof42(230mg,1.24mmol)inCH2CladdedasolutionofMe2(10mL)wasat2788C2AlCl(0.37mL,0.37mmol,1.0Minhexanes)underablanketofnitrogen.Themixturewaswarmedto238C.After16h,thereactionmixturewasquenchedwithsaturatedNaHCO3andwasextractedwithCH2Cl2.Thecombinedorganiclayerswerewashedwithbrine,dried(MgSO4),filteredandconcentratedinvacuo.Theproductwaspurifiedbycolumnchromato-graphy(silica,hexanes/EtOAc¼15:1)toyield58mg(25%)of43ascolorlessoil.Furtherelutiongave43mg(17%)of44asacolorlessoil.

Datafor43:IR(thinfilm)nMHz,max¼2927,1700,1494,1379cm21;1HNMR(300CDCl1H),2.51–2.59(m,3):d7.28–7.43(m,5H),2.88–2.95(m,1H),2.23–2.30(m,1H),2.17(s,3H),1.26(d,J¼7.5Hz,3H);13CNMR(125MHz,CDCl128.2,127.5,40.9,3):d209.9,169.8,139.0,131.9,129.1,40.0,18.2,16.7;HRMS(EI):calcdforC13H14O:186.1045;found:186.1048.

Datafor44:IR(thinfilm)nmax¼3399,2957,1453cm21;1HNMR(300MHz,CDCl(d,J¼7.9Hz,3):d7.16–7.43(m,5H),5.38(m,1H),3.841H),3.54(d,J¼7.9Hz,1H),1.46(m,3H),1.13(s,3H),1.04(s,3H);13CNMR(125MHz,CDCl3):d141.9,136.6,135.9,128.5,128.4,126.5,.6,61.1,45.2,27.1,20.5,15.4;HRMS(EI):calcdforC202.1358;found:202.1363.

14H18O:5.2.24.2-Phenyl-3-methyl-cyclopent-2-ene-1-one(46).20Toasolutionof45(65mg,0.38mmol)inCHasolutionofMeAlCl(0.076mL,0.0762Cl2(3mL)wasadded408C2mmol,1.0Minhexanes)at2underablanketofnitrogen.Thesolutionwaswarmedto238C.After16h,thereactionmixturewasquenchedwithsaturatedNaHCOwithCH3andextracted2Cl2.Thecombinedorganiclayerswere

washedwithbrine,dried(MgSOinvacuo.Purificationbycolumn4),filteredandconcentratedchromatography(silica,hexanes/EtOAc¼6:1)1afforded18mg(28%)of46asacolorlessoil.IR,HNMR,13CNMRandMSdataareconsistentwiththeliterature.205.2.25.(4S)-3-(4-Isopropenyl-cyclohex-1-enyl)-acrylicacidethylester(50).Toasolutionof[bis-(2,2,2-tri-fluoroethoxy)phosphoryl]aceticacidethylester(3.22g,8.70mmol)and18-crown-6(4.95g,18.72mmol)inTHF(60mL),wasaddedasolutionofpotassiumbis(trimethyl-silyl)amide(19.08mL,9.54mmol,0.5Mintoluene)at2788Cunderablanketofnitrogen.After5min,asolutionof49(1.0g,6.1mmol)inTHF(4mL)wasadded.After1h,thereactionmixturewasquenchedwithsaturatedNHThemixturewasdilutedwithH4Cl.Thecombinedorganiclayers2OandextractedwithEt2O.werewashedwithbrine,dried(MgSO4),filteredandconcentratedinvacuo.Purifi-cationbycolumnchromatography(silica,hexanes/Et40:1)afforded1.15g(85%)of50asayellowoil.[a2O¼]21418(c¼0.33);IR(thinfilm)nD¼;1HNMR(500MHz,max¼2934,1723,1625,1434,1177cm21CDCl5.46(d,J¼12.53):d6.19(d,J¼12.5Hz,1H),5.88(sbr,1H),Hz,1H),4.60(s,1H),4.59(s,1H),3.98–4.06(m,2H),2.28–2.38(m,1H),2.11–2.20(m,2H),1.91–2.09(m,2H),1.69–1.76(m,1H),1.60(s,3H),1.31(dq,J¼11.5,5.2Hz,1H),1.14(t,J¼7.2Hz,3H);13CNMR(125MHz,CDCl143.7,134.9,134.7,116.3,108.7,59.8,3):d166.4,148.9,40.2,31.5,27.4,27.2,20.5,14.0;HRMS(EI):calcdforCfound:220.1465.

14H20O2:220.1463;5.2.26.(4S)-3-(4-Isopropenyl-cyclohex-1-enyl)-prop-2-enol(51).Toasolutionof50(500mg,2.3mmol)inCH2Cl2(20mL)wasaddedasolutionofDIBAH(4.60mL,4.60mmol,1.0Minhexanes)at2788Cunderablanketofnitrogen.After20min,thereactionmixturewasquenchedwithaqueoussaturatedRochelle’ssaltandextractedwithEtOAc.Thecombinedorganiclayerswerewashedwithbrine,dried(MgSO4),filteredandconcentratedinvacuo.Purificationbycolumnchromatography(silica,hexanes/EtOAc¼10:1)toafford360mg(88%)of51asayellowoil.[a]D¼21028(c¼0.51);IR(thinfilm)nHNMR(500max¼3325,2919,14,1435,1029cm21;1MHz,CDClJ¼11.9Hz,1H),5.59(sbr,1H),5.45(dt,J¼3):d5.(d,12.5,6.5Hz,1H),4.70(s,1H),4.68(s,1H),3.98–4.06(m,2H),2.12–2.28(m,4H),1.91–2.09(m,1H),1.82–1.88(m,1H),1.74(s,3H),1.44–1.53(m,1H);13CNMR(125MHz,CDCl3):d149.5,134.4,132.6,128.5,128.0,108.7,59.6,40.5,31.0,29.1,27.6,20.7;HRMS(EI):calcdforCfound:178.1358.

12H18O:178.1358;5.2.27.(4S)-3-(4-Isopropenyl-cyclohex-1-enyl)-prop-2-enal(52).ToasuspensionofactivatedMnOmmol)inCH(25mL),wasaddedasolution2(3.30g,37.92Cl2of51(340mg,1.90mmol)inCH2Cl2(3mL)at08Cunderablanketofargon.Afterstirringfor2h,thereactionmixturewasfilteredandthesolutionwasconcentratedinvacuo.Purificationbycolumnchromatography(silica,hexanes/EtOAc¼12:1)provided180mg(56%)of52asayellowoil.Duetoitssensitivity,thealdehydewasimmediatelyusedinthenextstep.[a]D¼2418(c¼0.95);IR(thinfilm)n(500MHz,CDClmax¼2925,1663,1436cm21;1HNMRHz,1H),6.88(d,J¼11.8Hz,1H),6.103):d10.05(d,J¼8.2(s

30A.K.Milleretal./Tetrahedron59(2003)19–30

br,1H),5.84(dd,J¼11.8,8.2Hz,1H),4.69–4.79(m,2H),2.28–2.42(m,3H),2.05–2.27(m,2H),1.88–1.97(m,1H),1.75(s,3H),1.49–1.60(m,1H);13CNMR(125MHz,CDCl3):d192.0,150.5,148.5,137.7,134.8,128.3,109.2,39.9,31.6,29.2,27.2,20.7.

5.2.28.(6S)-6-Isopropenyl-2,3,4,5,6,7-hexahydro-inden-1-one(53).Toasolutionof52(100mg,0.57mmol)inCH2Cl2(25mL),wasaddedasolutionofMe(0.11mL,0.11mmol,1.0Minhexanes)at2788C2AlClunderablanketofnitrogen.Thesolutionwaswarmedto238C.After16h,thereactionmixturewasquenchedwithsaturatedNaHCO3thenextractedwithCHwashedwithbrine,2Cl2.Thecombinedorganiclayersweredried(MgSO4),filteredandconcentratedinvacuo.Purificationbycolumnchromatography(silica,Hex/EtOAc¼15:1)afforded22mg(22%)of53.[a]¼2921,1696,1650,D¼2948(c¼0.30);IR(thinfilm)nmax1439cm21;1HNMR(400MHz,CDCl3):d4.74(s,1H),4.71(s,1H),2.31–2.57(m,6H),2.08–2.19(m,1H),1.86–1.99(m,2H),1.76(s,3H),1.49–1.65(m,2H);13CNMR(100MHz,CDCl109.4,40.6,35.0,29.8,28.8,3):d208.9,173.3,148.5,138.6,27.2,25.4,21.0;HRMS(EI):calcdforCfound:176.1202.

12H16O:176.1201;5.2.29.3,5-Dimethyl-2-(1-methyl-but-2-enyl)-cyclopent-2-enone(55).Toasolutionoftriethylphosphonopropionate(2.98g,12.5mmol)inhexanes(25mL)wasaddedasolutionoflithiumt-butoxide(13.0mL,13.0mmol,1.0Minhexanes)at238Cunderablanketofargon.After4h,asolutionofcrude54(1.78g,10.0mmol)in10mLofhexaneswasadded.After30min,thereactionmixturewasquenchedwith50mLofHlayer2Oandthetwolayerswereseparated.Theorganicwaswashedwith25mLofbrine,dried(MgSOproductwas4),filtered,andconcentratedinvacuo.Thepurifiedbycolumnchromatography(5–20%Et2Oinhexanes)toyield500mg(28%)of55asacolorlessoil:Rnf¼0.55(silica,20%EtOAcinhexanes);IR(thinfilm)max¼2963,1703,1629cm21;1HNMR(400MHz,CDCl3):d5.23(tq,J¼7.2,1.6Hz,1H),2.76(dd,J¼18.4,6.8Hz,1H),2.37(m,1H),2.20–2.08(m,3H),2.04(s,3H),1.7713(s,3H),1.66(d,J¼7.2Hz,3H),1.01(t,J¼7.6Hz,3H);CNMR(100MHz,CDCl3):d211.1,168.0,143.2,133.6,127.0,40.8,39.9,21.4,18.0,16.7,15.7,14.1;HRMS(EI):calcdforC12H18O:178.1358;found:178.1358.

Acknowledgements

WethankProfessorRickL.Danheiser(MIT)forstimu-latingdiscussions.FinancialsupportbyMerckandCo.andtheACSPetroleumResearchFund(PRF#37520-AC1)isgratefullyacknowledged.ThecenterofNewDirectionsinOrganicsynthesisissupportedbyBristol-MyersSquibbasasponsoringandNovartisasasupportingmember.WethankDrFrederickJ.HollanderandDrAllenG.Oliverforthecrystalstructuredeterminationofcompound2.

References

1.Okamura,W.H.;DeLera,A.R.ComprehensiveOrganic

Synthesis;Trost,B.,Ed.;Pergamon:Oxford,1991;Vol.5,p699ff.

2.Woodward,R.B.;Hoffmann,R.TheConservationofOrbitalSymmetry;VCH:Weinheim,1970.

3.

Forexamplessee:(a)Nicolaou,K.C.;Sorensen,E.J.ClassicsinTotalSynthesis;VCH:Weinheim,1996;p265;andreferencescitedtherein(endiandricacids).(b)Beaudry,C.M.;Trauner,D.Org.Lett.2002,4,2221.(SNF4435CandD).(c)Lee,J.C.;Strobel,G.A.;Lobkovsky,E.;Clardy,J.J.Org.Chem.1996,61,3232.torreyanicacid.

4.

(a)Padwa,A.;Brodsky,L.;Clough,C.J.Am.Chem.Soc.1972,94,6767.(b)Dauben,W.G.;Smith,J.H.J.Org.Chem.1967,32,3244.(c)Dauben,W.G.;Kellogg,M.S.;Seemann,J.I.;Vietmeyer,N.D.;Wendschuk,P.H.PureAppl.Chem.1973,33,197.(d)Barton,D.H.R.;Kende,A.S.J.Chem.Soc.1958,688.(e)George,M.V.;Mitra,A.;Sukumaran,K.B.Angew.Chem.Int.Ed.1980,19,973.

5.

Okamura,W.H.;DeLera,A.R.ComprehensiveOrganicSynthesis;Trost,B.,Ed.;Pergamon:Oxford,1991;Vol.5,p79f.

6.Criegee,R.;Askani,R.Angew.Chem.Int.Ed.1968,7,537.7.Miller,A.K.;Trauner,D.Angew.Chem.Int.Ed.2003,42,549.

8.ComprehensiveAsymmetricCatalysis;Ojima,I.,Ed.;Wiley:NewYork,2000.

9.

(a)Cimino,G.;Fontana,A.;Gavagnin,M.Curr.Org.Chem.1999,3,327.(b)Davies-Coleman,M.T.;Garson,M.J.Nat.Prod.Rep.1998,15,477.

10.

(a)Ireland,C.;Faulkner,D.J.;Solheim,B.A.;Clardy,J.J.Am.Chem.Soc.1978,100,1002.(b)Ireland,C.;Scheuer,P.J.Science1979,205,922.(c)Gavagnin,M.;Spinella,A.;Castelluccio,F.;Cimino,G.J.Nat.Prod.1994,57,298.(d)Ireland,C.;Faulkner,D.J.Tetrahedron1981,37(Suppl.1),233.(e)Ksebati,M.B.;Schmitz,F.J.J.Org.Chem.1985,50,5637.

11.Dahmann,G.;Hoffmann,R.W.LiebigsAnn.Chem.1994,837.

12.Still,W.C.;Gennari,C.TetrahedronLett.1983,24,4405.13.

Williams,J.M.;Jobsen,R.B.;Yasuda,N.;Marchesini,G.;Dolling,U.H.;Grabowski,E.J.J.TetrahedronLett.1995,36,5461.

14.Garey,D.;Ramirez,M.L.;Gonzales,S.;Wertsching,A.;Tith,S.;Keefe,K.;Pena,M.R.J.Org.Chem.1996,61,4853.15.

(a)Oppolzer,W.;Moretti,R.;Bernardinelli,G.TetrahedronLett.1986,27,4713.(b)Birkbeck,A.A.;Enders,D.TetrahedronLett.1998,39,7823.

16.Beak,P.;Lee,J.K.;McKinnie,B.G.J.Org.Chem.1978,43,1367.

17.Moses,J.E.;Baldwin,J.E.;Marquez,R.;Adlington,R.M.;Claridge,T.D.W.;Odell,B.Org.Lett.2003,5,661.

18.Habermas,K.L.;Denmark,S.E.;Jones,T.K.Org.React.1994,45,1.

19.

Forrelatedcyclizationsthatpresumablyproceedthroughpentadienalintermediatessee(a)Ogawa,H.;Taketugu,Y.;Imoto,T.;Taniguchi,Y.;Kato,H.TetrahedronLett.1979,20,3457.(b)Padwa,A.;Au,A.;Lee,G.A.;Owens,W.J.Org.Chem.1975,40,1142.

20.

Takahashi,T.;Xi,Z.;Nishihara,Y.;Huo,S.;Kasai,K.;Aoyagi,K.;Denisov,V.;Negishi,E.-I.Tetrahedron1997,53,9123.

21.

Petroski,R.J.;Weisleder,D.Synth.Commun.2001,31,.