天然产物全合成

ARTICLE

pubs.acs.org/jnp

TotalSynthesisoftheMarine(()-PolysiphenolviaHighlyRegioselectiveIntramolecularOxidativeTimN.Barrett,†D.ChristopherBraddock,*,†AnnaMonta,†MichaelR.andAndrewJ.P.White†

†

DepartmentofChemistry,ImperialCollegeLondon,London,SouthKensingtonSW72AZ,U.K.‡

GlaxoSmithKlineResearchandDevelopmentLtd,GunnelsWoodRoad,Stevenage,Hertfordshire,SG12NY,U.K.

SupportingInformationb

olysiphenol(1)1isoneofanumberofbromophenolsisolatedfromredmarinealgaeaceae,2À4withmembersofthisfamilyshowingcalactivitiesandotherproperties.5Polysiphenol,9,10-dihydrophenanthrene6tobeisolatedfromamarinesource,wasobtainedfromtheredalgaPolysiphoniaferulaceacollectedatJoal,Senegal,in1990.1Itwasfoundtoexistasastableatropisomeratroomtemperature,anditsRconfigurationwasestablishedfromitsCDspectrum.1Twomoreaxiallychiralbromophenol-9,10-dihy-drophenanthreneshaverecentlybeenisolatedfromPolysiphoniaurceolata.3bBiogenetically,itseemsreasonabletoproposethatthesebromophenolic9,10-phenanthrenescouldarisefromdihydrostil-benederivativesbyoxidativephenoliccoupling.7,8Indeed,dihy-drostilbene2,whichcouldserveasthebiogeneticprecursorfor1inthisfashion,hasbeenisolatedfromP.urceolata.9Suchacouplingwouldpresentadirectandattractivesyntheticroutetothesecompounds(Figure1).However,thereareonlyafewreportsonthesynthesis10ofnaturallyoccurringbromophenols,andnosynthesesofpolysiphenol(1)oroftheotherphenanthreneshavebeenreportedtodate.Herein,wereportonthefirstsynthesisof(()-polysiphenol(1)viaahighlyregioselectiveintramolecularoxidativecoupling.Wealsoreportonthesynthesisofdihydrostil-bene2andanaturallyoccurringhexabromide(videinfra).Finally,theoriginsofthehighregioselectivityoftheoxidativecouplingstepareexplored.

Attheoutsetofourinvestigationsweconsideredthatsuccessfuloxidativecouplingwouldrequireasubstratewiththetwobromineatomsalreadyinstalled,leadingnecessarily(becauseofthebulkybrominesubstituents)1toanonplanaratropisomericdihydrophe-nanthreneframework,wherefurtherundesirableoxidationtoaplanarfullyaromatizedphenanthrenecouldnotoccur.11

CopyrightrXXXXAmericanChemicalSocietyandAmericanSocietyofPharmacognosy

P

Moreover,wealsorecognizedtheneedtocontroltheregiochem-istryoftheproposedoxidativecoupling,suchthatCÀCbiarylbondformationoccurstoforma4,5-dibromodihydrophenan-threne(Figure2,modea)ratherthana2,7-dibromo-(modeb)or2,5-dibromodihydrophenanthrene(modec).Wepositedthatsuchcontrolcouldbegainedbyexploitingthewell-knowncoplanarconformationalpreferenceofortho-dimethoxybenzenes12tostericallyshieldtheundesiredsitesofmodesbandccoupling(Figure2).Thisinteractionwasexpectedtobeparticularlysevereinmodeb,wheretwomethoxygroupsmustapproacheachother.Further,wealsorecognizedtheneedforanoxidativecouplingthatwascompatiblewitharylbromides.

’RESULTSANDDISCUSSION

Totestthevalidityofthesepropositions,weinitiallyexploredthechemistryofsomemodelcompounds.Thusstilbene511cwaspreparedinanovelone-potprocedurefromcommerciallyavailable3,4-dimethoxybenzylalcohol(3)involv-ingAppelbrominationandinsituphosphoniumsaltformationwithexcesstriphenylphosphine,ylidformationbysubsequentadditionofbase,andfinallyWittigreactionwithcommerciallyavailablealdehyde4(Scheme1).Subsequenthydrogenationofalkene511cgavetetramethoxydihydrostilbene6.TheX-raycrystalstructureofdihydrostilbene6clearlyshowsthecoplanarconformationineachoftheortho-dimethoxybenzenesubunits(Figure3).13

Dihydrostilbene6isknowntoundergohighlyregioselec-tiveoxidativebiarylcouplingwithhypervalentiodinereagent

Received:

July15,2011

A

dx.doi.org/10.1021/np200596q|J.Nat.Prod.XXXX,XXX,000–000

Figure

1.Proposedbiogenesisofpolysiphenol.

Figurepossible2.Considerationsforregioselectivebiarylmethoxymodesbenzeneofmotif.

coupling;(ii)possibleinfluencebondofformation:coplanar(i)di-Scheme

1.PreparationofModelCompound6

phenyliodinebis(trifluoroacetate)(PIFA)inconjunctionwithBF33OEt2withunavoidablearomatizationtogivephenan-threne7inexcellentyield(Scheme2).11Twoaspectsofthisreactiondeservefurthercomment.Althoughtherehasbeennospeculationintheliterature,theobservedregioselectivitymay,inpart,becontrolledbytheconformationofthemethoxygroupsineachdimethoxybenzenesubunit,withtheirpreferredcoplanarortho-dimethoxybenzeneconformationsdisfavoringcouplingbymodesborc(cf.Figure2).Second,thedihydrophenanthrene(intemediateA,Scheme2)that

ARTICLE

Figure3.Molecularstructureof6.

Scheme2.Proposed

PIFA-MediatedOxidative

CouplingÀAromatizationMechanism

Scheme3.

SynthesisofNaturallyOccurringHexabromide9

mustbeinitiallyformedissubjecttofurtheroxidation.ThecoplanarnatureofthisinitialbiaryladductAevidentlyleadstoextendedconjugationoftheπ-systemandahigherenergyHOMO,thusfacilitatingcompetitiveoxidation.14InourhandstheoxidativecyclizationÀaromatizationof6withPIFAproceededaspreviouslyreportedtogivearomatic7

ingoodisolatedyield(81%).

B

dx.doi.org/10.1021/np200596q|J.Nat.Prod.XXXX,XXX,000–000

Scheme4.RegioselectiveDibromination

Scheme5.TotalSynthesisof(

()-Polysiphenol

1andDibromodihydrostilbene2

Tetramethoxydihydrostilbene6couldalsobedeprotectedtotetrol8(Scheme3).15Electrophilicbrominationatalltheavailablearomaticpositionsgavethenaturallyoccurringhexabromide9.16Thisconstitutesthefirstsynthesisofthismetabolite.

Tetramethoxydihydrostilbene6wasdibrominatedusingNBSinDMFwiththeexpectedselectivity17togivedibromide1018inexcellentyield(Scheme4).

Incompound10,thetwobrominesubstituentsareincorrectlypositionedonthearomaticringstoleadtopolysiphenol(1)byoxidativecoupling.However,thissubstratewaspurposefullypreparedfora2-foldtestoftheoxidativecoupling.First,would

ARTICLE

Figurearrangement5.Molecularofthe4-methoxy

structuregroups.

ofE-13showingthenowout-of-planeScheme6.RegioselectivityExperiments

aromaticbromidessurvivethePIFAoxidative-couplingcondi-tions?Second,withthetwobrominesnowblockingthepre-viouslypreferredpositionsofcoupling(cf.compound6,Scheme2),wouldcouplingoccurinsteadbetweentheothertwofreeorthopositions?AnX-raycrystalstructureofcompound10(Figure4)clearlyshowsthecoplanararrangementofthetwopairsofmethoxygroups,19whichmaybeafactorincontrollingregioselectivecoupling.

Intheevent,subjectingcompound10toidenticaloxidative-couplingconditionsasusedfor6gavecompletereturnofunreactedstartingmaterialuponworkup.Thisexperimentthusdemonstratesthat(a)thearomaticbromidefunctionalityistolerantoftheseconditionsand(b)thattheoxidativecouplingdoesnotproceedwhenthispositionisblocked.

Havingestablishedtheabove,attentionnowturnedtoasynthesisofpolysiphenol(1).Commerciallyavailable5-bromo-veratraldehyde11wasreducedtothecorrespondingalcohol1220(Scheme5).Alcohol12wasconvertedintoolefin1321inatelescopedone-potreactionsequenceviathebromide,phospho-niumsalt,ylid,andWittigreactionwith11.E-13provedtobecrystalline,andanX-raycrystalstructurewasobtained(Figure5).Althoughthebromineatomsbuttresstheiradjacentmethoxygroups,theremotemethoxygroupsmaintaintheirpreferredplanararrangementwiththearomaticring.22

Subsequent23hydrogenationofolefin13affordeddibromide14asthesubstrateforoxidativecoupling.Toourdelight,oxidativecouplingproceededsmoothlytodibromodihydro-phenanthrene15inexcellentyield(90%)andwithperfectregioselectivity.Evidently,thisdihydrophenanthrene,withthetwobromineatomspreinstalledatthe4-and5-positions(phenanthrenenumbering),cannotaromatizetoaplanarphenanthrene.Finally,themethoxygroupswereremoved

from

C

dx.doi.org/10.1021/np200596q|J.Nat.Prod.XXXX,XXX,000–000

15togive(()-polysiphenol(1).1,24Dibromide14couldalsobedeprotected9,25

toprovidenaturallyoccurringdibromodihy-drostilbene2.Tofurtherprobetheregioselectivityoftheoxidativecoupling,weexaminedthePIFA-mediatedreactionofmethylenedioxycompounds16and17.Dihydrostilbene1626waspreparedfromtetrol8,anddibromide17waspreparedbyregioselectivebrominationof16(Scheme6).While16underwentefficientcyclization(andaromatization)to18,27dibromide17returnedonlystartingmaterialundertheseconditions.Theseexperimentsprovethattheregioselectivityoftheoxidativecouplingisnotcontrolledbystericeffectsduetoenforcedcoplanardimethox-ybenzeneconformationsincompounds6,10,and14andmustinsteadbeunderelectroniccontrol.Wesuggestthattheobservedregioselectivityofcouplingissuchthatcross-conjugation28ismaximizedinthetransitionstateleadingtointermediateX(viamodea,cf.,Figure2)ratherthanintermediatesY(modec)orZ(modeb)(Figure6).

Inconclusion,wehavereportedthefirsttotalsynthesesofnaturallyoccurring(()-polysiphenol1,dibromodihydrostil-bene2,andhexabromide9.Thesynthesisof(()-polysiphenol1isbroughtaboutinfourstepswithanoverallyieldof70%.Thekeystepinvolveshighlyregioselectiveoxidativecouplingofadibrominateddihydrostilbene,asinspiredbytheprobablebiogenesisofpolysiphenol.

’EXPERIMENTALSECTION

General0ExperimentalProcedures.SeeSupportingInformation.

5,516-(Ethane-1,2-diyl)bis(3,4,6-tribromobenzene-1,2-diol)(9).Toastirredsolutionoftetrol8(0.10g,0.41mmol)inaceticacid

(5mL)wasaddedbromine(2.1mL,4.1mmol,10equiv),andthemixturewasstirredfor48h.ThemixturewasdilutedwithCH(10mL),quenchedwithsaturatedaqueoussodiumsulfitesolution2Cl2(25mL),andextractedwithCHlayerswerewashedwithH2Cl2(3Â25mL).ThecombinedorganicMgSO2O(2Â25mL)andbrine(20mL),driedover4,andconcentrated,affordingtitlecompound,9(0.19g,65%),asayellow1solid:mp228°C;lit.16230À232°C;IR(neat)3550À2700cmÀ;1HNMR(400MHz,acetone-dH),8.56(2H,brs,ArOH),3.45(4H,s,ArC6)δ138.69(2H,brs,ArO2H4Ar);CNMR(100MHz,acetone-d6)δ144.0,143.9,132.5,118.0,113.9,37.3;MS(EI+)m/z714,716,718,720,722,724,726[M]+;HREIMSm/z713.5522[M]+(calcdforC14H8O479Br6,713.5523).

(()-4,5-Dibromo-2,3,6,7-tetramethoxy-9,10-dihydrophe-nanthrene(15).Toastirredsolutionofdiarylethane14(0.20g,0.43

mmol)inCH2Cl2(10mL)atÀ40°CwereaddedPIFA(0.24g,0.52mmol)andBFallowedtowarm33OEttoroom2(0.13mL,1.04mmol),andthemixturewastemperature(rt)andstirredfor24h.Thesolutionwasfilteredthroughasilicaplug,andthesolventevaporatedinvacuo.Theresiduewassubjectedtocolumnchromatography

ARTICLE

(petroleumspirit/EtOAc,2:1)toprovidethetitlecompound,15(0.18g,90%),asawhitesolid:mp215°C;IR(neat)2939,2837,1594,δ6.841464,(2H,1401,s,Ar1257,H),3.941059,(6H,996s,cmÀ1ArOC;1HHNMR(400MHz,CDCl3)À2.57(4H,m,ArCCNMR(1253),3.92(6H,s,ArOCHMHz,CDCl3),2.752H4Ar);13110.2,60.7,56.2,31.6;MS(CI+,3)δ152.1,145.7,137.9,128.8,119.1,NH3)m/z474,476,478[M+NH(calcdforC4]+;HRCIMS(NH3)m/z473.9931[M+NH4]+18H2279Br2NO4,473.9916).

(()-Polysiphenol(1).1Toastirredsolutionoftetramethoxyphe-nanthrene15(0.20g,0.51mmol)inCHCH2Cl2(5mL)atÀ78°CwasaddedasolutionofBBrwas3inallowed2Clto2(1M,3.06mL,3.06mmol)dropwise.Themixturewarmtortandwasstirredfor16h.ThereactionmixturewasquenchedbytheadditionofMeOH(25mL),andthesolventevaporatedinvacuo.Thesolidwasplacedunderhighvacuumat60°Cfor16htogivethetitlecompound,1(0.18g,100%),asanoff-whitesolid:mp133°C;29IR(neat)3550À2800,2942,1608,1578,1520,1471,1421,1261,1232,1199,1152cmÀ1;1HNMR(400MHz,CDCl13

H),5.49(2H,s,ArOH),2.693)δ6.85(2H,s,ArH),5.58(2H,s,ArOÀ2.47(4H,m,ArCCNMR(125MHz,CDCl)δ143.2,139.3,135.6,127.1,113.5,2H110.1,4Ar);31.2;MS(CI+,NH33)m/z400,402,404[M]+;HRCIMS(NH399.8944[M]+(calcdforCH3)m/z5,50-(Ethane-1,2-diyl)bis(3-bromobenzene-1,2-diol)141079Br2O4,399.8946).

(2).9

Toastirredsolutionofdihydrostilbene14(0.10g,0.22mmol)inCH1.302ClmL,2(2mL)atÀ78°CwasaddedasolutionofBBr1.30mmol)dropwise.Thereactionmixture3inCHwasallowed2Cl2(1M,towarmtortandwasstirredfor16h.ThereactionmixturewasquenchedbytheadditionofMeOH(10mL),andthesolventevaporatedinvacuo.Thesolidwasplacedunderhighvacuumat60°Covernighttoremovevolatileimpurities,givingthetitlecompound,2(0.18g,100%),asanoff-whitesolid:mp1981°C,lit.9205À206°C;IR(neat)3529,3448,3240,2925,2852cmÀ;1HNMR(400MHz,DMSO-d6)δ9.49(2H,s,ArOH),8.72(2H,s,ArOH),6.73(2H,d,J=2Hz,ArH),6.54(2H,d,J=2δHz,146.0,ArH140.8,),2.58133.5,(4H,122.2,s,ArC114.8,2H4Ar);13109.6,CNMR36.1;MS(100(EIMHz,+DMSO-d)m/z402,404,6)406[M]+79;HRCIMS(NH3)m/z419.9426[M+NHBr4]+(calcdforC14H162NO4,419.9946).

’ASSOCIATEDCONTENT

b

SupportingInformation.

Generalexperimentalproce-duresandcharacterizationdatafor5À8,10,12À14,and16À18,copiesof1Hand13CNMRspectrafor15,1,2,9,17,and18,acomparisonofthespectroscopicdataofsynthetic(()-1andthepublisheddata,andX-raycrystallographicdetailsfor6,10,andE-13.ThismaterialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.

’AUTHORINFORMATION

CorrespondingAuthor

*E-mail:[email protected].

’ACKNOWLEDGMENT

WethanktheEPSRCandGSKforaDTA-CASEaward(toA.M.)’REFERENCES

E.;(1)Mangoni,Aknin,A.M.;TetrahedronSamb,A.;Mirailles,J.;Constantino,V.;Fattorusso,(b)(2)deReviews:(a)Gribble,Lett.G.W.1992Chem.,33,Soc.555Rev.–558.

1999,28,335–346.Q.-A.;(3)Carvalho,Zhang,ForrecentL.T.;Sun,representativeR.;Roque,N.L.-X.;Wang,examplesF.Quim.NovaM.-S.J.Mol.see:Struct.(a)2000Liu,,232009Q.-W.;,757–764.,

929Qiao,,1–5.

D

dx.doi.org/10.1021/np200596q|J.Nat.Prod.XXXX,XXX,000–000

(b)(c)Li,10Li,K.;K.;Li,Li,X.-M.;X.-M.;Ji,Ji,N.-Y.;Wang,B.-G.J.Nat.Prod.2008,71,28–30.Fan,,1429–1432.(d)Ma,N.-Y.;M.;Zhao,Gloer,J.;J.Wang,B.;Wang,S.;Li,B.-G.S.;Yang,Org.Lett.Y.;Shi,2008J.;,N.-Y.;X.;Q.-W.;Wang,He,L.B.-G.J.Nat.Bioorg.Prod.Med.2007,Chem.70,3372007–341.,15(e),Li,K.;Li,X.-M.;Ji,J.Li,AsianTan,Nat.C.-H.;Prod.Res.Zhang,2006T.;,8Zhang,,379–383.S.-J.;Han,L.-J.;6627Fan,–6631.X.;Zhu,(f)D.-Y.Liu,(h)S.;N.;Zhao,Yang,Y.;Shi,J.;Fan,X.;He,L.J.(g)Nat.Ma,Prod.M.;2006Zhao,,69J.;,Wang,206–210.S.;Wang,Fan,X.;J.;He,Ma,L.M.;J.Wang,Nat.Prod.S.;Li,2005S.;,Cao,P.;Yang,Y.;L€u,Y.;Shi,J.;Xu,67S.;Li,S.;Yang,Y.;Xu,N.;L68€u,,691Y.;–Shi,694.J.(i)J.Nat.Zhao,Prod.J.;Fan,2004X.;66,14,4551032––458.1035.(k)(j)Fan,Fan,X.;X.;Xu,Xu,N.J.;N.-J.;Shi,Shi,J.-G.J.Nat.Prod.2003,,Lett.,1045Lett.2003–1047.,14,807(l)–Xu,809.N.(m)J.;Fan,Fan,X.;X.;Yang,J.Xu,N.Y.G.C.;Chin.J.;Shi,Shi,Chem.J.J.G.G.Chin.Lett.Chem.2003,also.(4)2003Assorted,14,939–941,andreferencestherein.

Chin.Chem.50Yang,,6814See:–(a)6817.Popplewell,bromophenols(b)Xu,X.;W.Song,L.;Northcote,havebeenP.isolatedT.TetrahedronfrombrownLett.2009algae,(c)Chem.Xu,Y.;X.Shang,L.;Fan,S.;X.;Yang,Song,L.;F.Shi,F.;H.;J.Zhao,J.Wang,Nat.J.L.;Prod.S.;Li,Han,2004S.;Xiao,L.J.;,67Shi,,F.;1661Zhao,J.–1666.J.;K.(5)Lett.2004,15,661–663,andreferencestherein.

G.Chin.(b)A.;refsCytotoxicity:Kurihara,Forexample:H.;refsKim,(a)α-glucosidaseinhibitors:Kim,K.Y.;Nam,4bandS.M.Phytochemistry2008,69,2820–2825.Lee,3b,J.Agric.J.-H.;3c,andChae,3e.C.-S.;(d)Isocitrate3g.Chung,S.-C.;lyase(c)DPPH-radicalinhibitor:scavengingability:Shin,D.-S.;Lee,Shin,H.-S.;J.;Lee,Oh,T.-H.;A.;(6)Vasas,ForFoodA.;aChem.review2007,55,6923–6928.

K.-B.Hohmann,ofnaturallyJ.occurringphenanthrenessee:Kov acs,Fleming,(7)Whiting,referencesI.,Eds.;D.PergamonA.InComprehensivePhytochemistry2008,69,1084–1110.

Press,1991;OrganicVol.Synthesis3,;Trost,B.M.;(as(8)Anintramoleculartherein.

pp659À703,andfree-radicaldimerizationoftwocarbonopposed(9)Àtooxidativecoupling)hasbeenproposedphenylastheradicalskey(a)(10)Kurata,carbonForK.;bondAmiya,formingT.Bull.stepinChem.thebiogenesisSoc.Jpn.1980ofurceolatin,53,2020(ref–2022.3c).ActaAkbaba,Chung,2010,93K.;the,1127Balaydin,synthesis–1135.H.of(b)T.;halogenatedOh,Goksu,S.;bis(hydroxyphenyl)methanesSahin,E.;Menzek,A.Helv.Chim.see:19Lett.,945–S.-C.;948.(c)Jeon,Li,H.J.;B.;Guo,Shin,S.J.;J.;Su,Lee,K.-B.;H.;H.-S.Lee,Han,Bioorg.J.H.;Lee,L.J.;Med.J.Shi,D.Chem.W.;Yoon,Y.Chin.Lett.K.-M.;2009,aromatize(11)2008Biveratryl,19,1290–Chem.(compound1292.

6inthisSlater,74L.M.;duringGiessert,oxidativeR.E.;couplingSakwa,S.usingwork)A.;Herr,PIFA:isR.J.(a)knownJ.Org.Rossiter,toreadilyL.M.;73,Eur.,60459554J.Org.––6047.9557.Chem.(c)(b)2002Moreno,Zeng,W.;,2126I.;–Tellitu,Chemler,2135,andI.;Dominguez,S.R.J.Org.Chem.Chem.20092008,,referencesE.;SanMartin,R.J.withChem.(12)computationalthis1983Forsolutionstudiessee:(a)Schaefer,T.;Laatikainen,therein.

R.Can.motif,see:(b)61,224Caillet,–229.ForJ.ActaadiscussionCrystallogr.of198232X-ray,B38,crystal1786–1791.structures12Blockhuys,,132–135.F.(d)studiesInt.Vandesee:(c)J.Quant.Velde,Chem.C.;Chein,2007Bultinck,R.-J.;,107,E.;Corey,670Tersago,E.–679,andK.;J.Org.referencesVanAlsenoy,Lett.2010ForC.;,their(13)forparentCCDCaromatic831106.ring,ThetheArtwoÀOMemethoxytwistgroupsanglesbeingarecoplanartherein.ca.3°andwith8°conformationalthe3-and4-methoxyestablishedpreferencegroups,of1,2-dimethoxybenzenerespectively.Giventhathasthecoplanarconformationinlographicdepositeddataobservedsolutionforthehere(ref12a),weconsiderthatthealsosolid-statebeenstructuresshouldreportedtranslateintothissolutionpaperalso.Crystal-ofCCDC,thedatawith336033or12cantheCambridgeCrystallographicDataCentre.haveCopiesbeene-mail:Unionbeobtained,Road,[email protected]).

Cambridgefreeofcharge,CB2on1EZ,applicationUK(fax:to+44-(0)1223-theDirector,to(14)phenanthreneOnereferee7isnotedafour-electronthattheoveralloxidation,conversiontheoreticallyofdihydrostilbenerequiring62

ARTICLE

equivalentsrefalllikelihood11)onlyof1.2PIFAaerialequivalentstoeffect.Inourworkandotherpreviouswork(seeoxidationofisPIFAinvolvedareused.intheThefinalrefereearomatization.

suggestedthatin6255(15)–6258.

Nishimura,N.;Kobayashi,K.Angew.Chem.,Int.Ed.2008,47,1210(16)Duan,X.-J.;Li,X.-M.;Wang,B.-G.J.Nat.Prod.2007,70the(17)–1213.

,20072-position3,4-DimethoxytolueneusingNBSinDMF:isregioselectivelyFukuda,T.;monobrominatedat(18),74,701–720.

Iwao,M.Heterocycleswith(19)Erdtman,andtheirCCDCH.Ann.Chem.1933,195–202.

parent789908.aromaticThering,twothemethoxyArÀOMeunitstwistareessentiallyanglesbeingcoplanarca.2(20)8°for(21)Srikrishna,the4-andA.;5-methoxySatyanarayana,groups,G.Tetrahedronrespectively.

°2006,62,2892substituent)(22)Ueda,CCDCS.831197.YakugakuTheZasshi4-methoxy1962,groups82,714–2900.(adjacent–718.

tothebeingca.88°are(thetwistedtwistoutofthearylringplane,theArÀOMetwistbromineangle1985(23)Iyoda,M.;Sakaitani,anglesforM.;theOtsuka,5-methoxyHi.;groupsOda,M.areca.Chem.5°).Lett.data(24),127The–130.

spectroscopicdataofsynthetic1in(25)inref1(seeSupportingInformation).

matchedthepublishedCHAttemptedPIFAcyclizationof2into1usingPIFA/BF33OEt2Yang,(26)2ClOh,2failed.

K.-B.;Jeon,20,D.;Kwon,M.;Shin,H.J.;B.;Lee,Han,H.-S.Y.-R.;Bioorg.Lee,T.-J.;Med.Park,Chem.J.;Lett.Lee,S.-H.;on(27)6644–2010,The6648.

moderateisolatedyieldof18isareflectionofitsinstability(28)silicageloriginal(29)Phelan,onpuriN.fiF.cation.

J.Chem.Educ.1968,45,633–637.

isolationAmeltingpaperpoint(reffor1).

polysiphenolwasnotreportedintheE

dx.doi.org/10.1021/np200596q|J.Nat.Prod.XXXX,XXX,000–000