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Chemo-andChemo,and,chemo

    Chemo-and

AvailableonlineatWWW.sciencedirect.com

    ;‘:j,ScienceDirect

    ;ChineseChemicalLetters19(2008)1391-1394

    ;CHINESE

    ;CHEMlCAL

    ;LETTER5

    ;WWW.elsevier.com/locate/cclet

    ;Chemo—andregioselectivehydroborationofA4’5incertain

    ;cephalostatinanalogue

    ;MansourNawasreh

    ;BasicSciencesDepartmen~FacultyofEngineeringTechnolog~AlBalqaAppliedUniv

    ersity,P.B.15008,Marka,11134Amman,Jordan

    ;Received16April2008

    ;Abstract

    ;ThesymmetricaldiketoneII.whichcanbesynthesizedingramscaleusingawellestablishedmethod,wasusedasastarting

    ;materialtOpreparethel1.methoxyketomethyleneVI.ThisiSincontinuationofourstudyaimingatthesynthesisofmulti

    ;hydroxylatedcephalostatinanalogues,asforexamplecephalostatinlI,apotentantitumo

    rnaturalproduct.CompoundVI

    ;underwentchemoandregioselectivehydroborationreactionatonlyoneofA’doublebon

    dsfumishingcompoundIXasamajor

    ;productinafairyield.

    ;2008MansourNawasreh.PublishedbyElsevierB.VonbehalfofChineseChemicalSociety.A1lrightsreserved.

    ;Keywords:Cephalostatin1:Diketone;HydroborationofA…doublebond;Anti—cancer

    activity

    ;Cephalostatin

    I,apotenttumor.ce1linhibitorymarinenaturalproduct(GI50values<lnmol/L),wasisolatedby

    ;Pettit’SGroupatArizonaStateUniversityin1988[1.CompoundIbelongstothecephalo

    statinfamilythatconsisting

    ;of19bissteroidalpyrazinealkaloids,whichhavebeenisolatedfromthemarinewormCephalodiscusgilchristi2].

    ;FuchsandCO.workershavereportedthetotalsynthesisofcephalostatin1I3.ThiscompoundhasseveralOHgroups.

    ;Theauthorconcentratedonthesynthesisofbiologicallyactiveanaloguesbyintroducingseveralhydroxylgroupson

    ;thesymmetdcaldiketoneII.whichcanbeeasilypreparedinagramscalestartingfromtheco

mmerciallyavailable

    ;naturalproducthecogineneacetateusingastraightforwardprocedure[4.

    ;27

    ;,

    ;25

    ;Sincecephalostatin1Iisrelativelyhighlypolarcompound,thepurposewastopreparepolaranalogues.Oneofthe

    ;selectedrouteswastoopenthespiroketalmoiety[5].Somepositiveresultswereachievedinenhancingthebiological

    ;E-mailaddresses:MNawasra@fet.edu.jo,mansreh@yahoo.com.

    ;1001.8417/$seefrontmatter?

    2008MansourNawasmh.PublishedbyElsevierB.VonbehalfofChineseChemic’,dSociety.

    Allrightsreserved

    ;doi:10.1Ol6/j.cclet.2008.09.055

    ;

    ;1392

    ;?

    ;Nawasreh/ChineseChemicalLetters19(200S)13911394

    ;Scheme1.ChemoselectivereactionsofcompoundHIandVI.

    ;acfivities.Otherselectedroutewastointroduceseveralhydroxylgroupsatdifferentpositionsthroughthe

    ;hydroborationeitherofA,Jdoublebondsoroftheexocyclicdoublebond[6,7.Startingfr

    omdiketone?,11.

    ;methoxydiketoneH1waspreparedbyoxidationoftheenolateof?

    withdiacetoxyiodosobenzene61.Itwasfound

    ;t11atonlyoneofthecarbonylgroupsincompoundHIunderwentselectivereductionuponthetreatmentwithsodium

    ;boroh~rdrideNaBH4leadingto12B.hydroxy.11.methoxyketoneIVInthiscompound,thereducedcarbonylis

    ;situatedinthepartwithout.themethoxygroup(southernpart)(Scheme1). ;Thisshowsthatthemethoxygroupprotectstheadjacentcarbonylfromtheborohydrideionattackingfromthe

    ;backside.TllisresultisveryimportantinthedesymmetrizationofdiketoneII.Thiswasappliedinoximeformation

    ;andWittigreaction.TreatingcompoundmwithhydroxylamineNHEOHinbasicmediumgavetheexpected1lot.

    ;methoxymonoximeVasasingleproductin81%yield.Thesameresultwasobtainedwhencompound?wastreated

    ;witl1methylenediphenylohosphiniumylide(preparedfromCH3PI)b

    andn.BuLi)togivethemethoxyketomethylene

    ;derivativeVIin86%yield(Schemel1.Inbothcases.thecarbonylgroupadiacenttothemethoxygroupwas

    ;completelyprotectedandaregioselectivereactiontookplaceonlyonthesouthernpartofthe?.Because.both

;derivativesIV6and?[7

    showedrelativelygoodbiologicalactivities,thetargetwasthepreparationofdenvatve ;?

    usingdirecthydroborafionofcompoundVI.UponthetreatmentofcompoundV1withthreeequivalents

    ;BH1.THEcompound?

    insteadofVmwassurprisinglyfurnishedasamajorproductalongwithtwootherside ;products(Scheme1)inafairyield.ThemassspectrumofIXshowsanincreaseof36units,whichindicatesthe

    ;additionoftwomolesofwaterbythehvdrOborationprocess.FromtheHNMRspectrum.thedisappearanceof

    ;themethyleneprotonsandtheaDpearanceofoneofH.15protonsandnewhigh.frequencysignalsshowthatnotonly

    ;theexocyclicdoublebondunderwenthydroboration,butalsooneoftheA’doublebonds.Thefirstquestionwas.

    ;whichoftheA’Jdoublebondshasreactedandwhy(chemoselectivity,?However,thesecon

    dquestionwas”whatis

    ;theconfigurationofthenewhydroxylgroupandwhy(regioselectivity17Toanswerthesequestions.allextensive

    ;structuralstudyofcompoundIXwascarriedout.ByusingspectroscopictechniquesespeciallyHMOC,}C,

    ;

    ;Nawasreh/ChineseChemicalLetters19(2008)1391-1394

    ;H

    ;Fig.1.The2D?NMRresultsofcompoundIX.

    ;1393

    ;27

    ;Y

    ;T0CSYandR0ESYThestructureofcompoundIXwasapprovedbycombiningallinformationcolletedfromNMR

    ;andMS(especiallyESIandHRMS).FromtheHSQcexperiment,itwasfoundthatthene

    wprotonH15at4.05

    ;correlatedwimC15at71.84andH16at4-30withC16at

    84.57.ImportantinformationgatheredfromHSQc

    ;andR0ESYspectraenabledustodifferentiatebetweenH.17andH.17.ItwasfoundthattheprotonH.17at2.21

    ;correlatedwimC.17at54.92inHSQCexperiment.H.17correlatedwithH

    15andH.16inbothTOCSYandR0ESY

    ;spectra.Ontheotherhand,theH.17.whichresonatesalongwithomersevenprotonsintherange62.46to2.90,

    ;correlateswitl1H.16at64.87,whichinturn,correlateswithH.15at65_37inbotllDQFC

    OSYandIESY(Fig.1).

    ;TheeasyhydroborationoftheA’doublebondinnorthernpartcomparedtoitscorrespondinginthesouthern

    ;partmayberationalizedonthebasisofthepresenceoftheelectronrichll.methoxygroupwhichenhancestlle

    ;electrondensityinthedoublebondthrough盯一

    donation.Acompleteanswerofthechemoselectivityquestionneeds

    ;furtherkineticandthermodynamicstudies.

    ;Withrespecttotheregioselectivity.itcouldberationalizedthatoneequivalentofborane.THFisexpectedtobe

    ;complexedbythemethoxygroupfromthebackside(.face)leavingtheBfacefreetobe

    attackedfromanother

    ;boraneequivalent.Tllisled,afteroxidationwithH202,toaBconfiguratedhydroxygrou

    patC.15.

    ;Biologicalstudy:Thesynthesizedcompoundsweretestedagainstthethreecancercelllines;HMO2.HEPG2and

    ;MCF7intheProfessorWBeilLaboratoryattheMedicalSchoolofHannoyer~VIHH)8.Itwasfoundthat,

    ;compoundIVshownrelativelygoodactivityagainstthethreecancercelllines.ThemostaffectedcelllinewasHEP

    ;G2withaGIsnvalueof0.015~mol/LandaTGIvalueof9.8I~mol/L.Moreover,compoundV?,whichhasbeen

    ;testedagainstthe60cancercelllinesintheNCI,shownrelativelygoodactivity

    7.TIlehighlyaffectedcelllineswere

    ;RXF393fromtherenalcancerandRPMI.8226fromLeukemia.However,compoundIXhaveveryweakactivity

    ;againstthethreecelllines.T11isshowstheimportantroleinbiologicalactivityplayedbyA,ldoublebondespecially

    ;inthemethoxyregion.ThepreviousstudiesshowedalsotheimportanceoftheA,ldoublebond.Forexample.

    ;dihydrocephalostatin1ismuchlessactivethancephalostatin1I.whichmaybeduetobothgeometryandsolubility

    ;reasonsthatdirectlyaffectedbytheAIJdoublebondinsteroids91.

    ;1.Experimental

    ;PreparationofmethoxyketodiolIX:AsampleofVI(0.190g.0.2176mmol,1.0eq)wasdissolvedin5mLofabs.

    ;THFinadry1o0mL2.neckflaskflushedwithargon.Thesolutionwascooleddownto0.Cpriortheadditionof

    ;0.66mL(0.66mmol.3.0eq)ofBH.THFcomplex(1mol/LsolutioninTHF).Thereactionmixturewasstirredfor2h

    ;beforewarmingitto+7.C.atwhichitwasconductedforfurther15hwithoutstirring.Thereactionwasquenchedat

    ;O.Cwiththeslowadditionof2mLofNaOH(6mol/L)solutionandafter20min,itwasstirredatAfterwards,

    ;2mLofeachEtOHandDEEwasadded,followedbytheadditionof2mLofH2O,(35%solution),whichwasthen

    ;vigorouslystirredfor2h.ThereactionmixturewaspartitionedtwicebetweenDCMandbri

neandthecombined

    ;organicphasewasdriedoverNa2SO4.Afterthesolventremovalunderreducedpressure,a1ightyellowishcrude

    ;substancewasyielded.Chromatographicpurificationofthecrudematerial(silicagelstationaryphase,ethylacetate

    ;andpetroleumetherasmobilephase)provided0.093gofIXasawhitesolidf47%yield). ;LCS(ESI)(909.5352,basepeak,MH)

    ;M.Nawasreh/ChineseChemicalLetters19I2OO8)1391-1394

    (CHCl3/v;

    ax(cm-1)):3612br(O-H),3567br(O-H),2931s(C-H),1726s(c---o),1647w(c---c),1459m(C

    ;H),1399s(pyrazine),1242(Co).

    ;UV(CHC1.(cm)):310(sh),293s.

    ;HNMR(400

    Iz,CDC13,6ppm):5.37(brs,1H,15-H),4.87(brd,1H,J16’-17,=8.3Hz,16-H),4.30(1H,

    ;J16-17=J16-15=7.2Hz,16H),4.05(dd,1H,J1516=7.2Hz,J1514=0.8Hz,15

    H),3.77(brd,1H,/28,a_

    ;28,b=17.7Hz,28a.H),3.75(s,3H,28

    H),3-353.55(m,5H,26a/26a,26b,26b,28b—H),2.96(d,1H,Jl’a-

    ;Vb=16.8Hz,l’a.H),2.46.2.90(m,8H,la/lb/1b/4a/4a/4b/4b/17.H),2.43(m,1H,l1-H),2.21

    (m,1H,17?H),1.24

    ;(s,3H,18.H),1.04(d,3H,J21,2o,=6.8Hz,2l-H),0.96(d,3H,1-20=6.7Hz,21

    H),0.9O(s,3H,19-H),0.85(s,

    ;3H,18.H),0.81(d,6H,J=5.6Hz,27/27’-H),O.79(s,3H,19.H).CNMR(100MHz,CDC13,

    ppm):175.25(C,12

    ;C),160.33(C.14),148.39,148.38,148.36,148.34(a11C,pyrazine.C),117.40(CH,15

    C),107.26(C,22-C),106.85

    ;(C,22.C),84.57(CH,l6.C),81.61(CH,16.C),77-31(CH,l1

    C),71.84(CH,15-C),67-3l(CH2,26-C),67.10(CH2,

    ;26.C),64.85(CH2,28.C),61.18(CH,14.C),56.69(CH,17-C),55.80(CH),55.75(CH3,28C),54.92(CH,17-C),

    ;54.09(CH),53.42(C),51.93(CH),51.90(CH),48.54(C),46.34(CH),45.85,45.80(bothCH2,1/1-C),44.27(CH),

    ;41.51(CH),38.77(CH),36.11,36.05(bothCH2,4/4’-C),35-42(C),35.11(C),34.59(CH),

    31.O8(CH2),30.36(CH),

    ;30.27(CH),29.71(CH2),29.30(CH2),29.10(CH2),28.72(CH2),28.68(CH2),28.07(CH2),27.95(CH2),25.67

    ;(CH3,18

    C),24.92(CH2),17.14,17.09(bothCH3,27,27.C),15.52(CH3,18-C),14.15,14.00(bothCH3,21,21-C),

    ;l1.83(CH,19.C),11.58(CH3,19C).

    ;TheauthorwouldliketoacknowledgetheDeutscheForschungsgemeinschaftDFGforfundingthiswork,which

    ;carriedoutinthelaboratoriesofProfessorH.Duddeck,LeibnizUniversityofHannover,to

whomtheauthorisvery

    ;gratefu1.TheauthoralsoacknowledgesProfessorWBellforbiologicalevaluation. ;f1(a)G.R.Pe

    t,z.A.Cichacz,FGao,C.L.Herald,M.R.Boyd,J.M.Schmidt,J.N.A.Hooper,J.Org.Chem.58(1993)1302

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    ;(c)G.R.Pemt,C.L.Heraid,Z.A.Cichacz,FGao,M.R.Boyd,N.D.Christie,J.M.Schmidt,Nat.Prod.LeU.3(1993)239.

    ;f2

    G.R.Pettit,J.EXu,YIchihara,M.D.Williams,M.R.Boyd,Can.J.Chem.72(1994)2260,referencestherein.

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    tG.LaCtour,C.Guo,S.Bhandaru,M.R.Boyd,EL.Fuchs,J.Am.Chem.Soc.120(1998)692. ;f41A.Kramer,U.Ullmann,E.Winterfeldt,J.Chem.Soc.PerkinTraas.1(1993)2865. ;f51M.Nawasreh,Bioorg.Med.Chem.16(1)(2008)255-265,doi:10.1016~.bmc.20o7.O9.043.

    ;6]M.Nawasreh,E.Winterfeldt,CUlT.Org.Chem.7(7)(2003)649.

    ;f71M.Nawasreh,Nat.Prod.Res.21(2)(20o7)91.

    ;f81FordetailsconcerningthestandardtestingmethodinMHH,pleaseseetheexperimentalpartofreference[5].

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