DOC

Advances

By Robin Young,2014-07-23 03:09
18 views 0
AdvancesAdvanc

    Advances

Apr.2008,Volume2,No.4(SerialNo.5)JournalofChemistryandChemicalEngineering,ISS

    N1934?7375,USA

    ;AdvancesinSolid-Phaseheterocyclicchemistry ;CHENWeimitt,HEKeqiang

    ;(DepartmentofPharmaceuticalEngineering,WuhanUniversityofTechnologyHuaxiaC

    o[[ege,Wuhan430223,China)

    ;Abstract:Thispaperisaresultofareviewthrough25paperson ;thesynthesisofthree,four-,five,six,andseven.membered

    ;tingsonsolidsuppoa.Solidphaseorganicsynthesismethods ;thatenabletherapidproductionofarraysofheterocyclesareof ;criticalimportancetothepharmaceuticalindustry.The ;generationofheterocyclicchemistrybysolidphasesynthesis

    ;willdefinitelyacceleratethedevelopmentofpharmaceutical ;research.

    ;Keywords:solidphaseorganicsynthesis;heterocyclic ;chemistry;pharmaceuticalresearch

    ;Thepreparationofdiverselibrariesoforganic ;compoundsisanimportantfacetofmoderndrug ;discoveryprograms.Oneofthemostcommonly

    ;employedmethodsinlibraryproductionissolidphase

    ;organicsynthesis(SPOS)llj.Thefieldofsolidphase

    ;heterocyclicchemistryhasrapidlyexpandedbecause ;experiencehasshownthatcompoundswithbiological ;activityareoftenderivedfromheterocyclicstructures. ;Synthesismethodsthatellabletherapidproductionof ;arraysofheterocycles,usefulfortheidentificationof ;newleadstructures,areofcriticalimportancetothe ;pharmaceuticalindustry[21.Duetocurrentinterestin ;solidphasechemistry,andespeciallyinthe

    ;possibilitiesforthepreparationofheterocyclesona ;solidsupport,Wefounditimportanttoreviewrecent ;papersinthefield.Thispaperi?aresultofareview ;through25papersonthesynthesisofthree,four,

    ;five,six,andsevenmemberedringsonsolidsupport.

    ;1.Three-memberedring

    ;Afewthreesmemberedringswithoutany

    ;heteroatomshavebeensynthesisonsolidsupport.For ;Correspondingauthor:CHENWeimin,male,

    ;researchfield:combinatorialchemistry

;chwm601@163.corn.

    ;42

    ;Master;

    ;Email:

    ;example,cyclopropenederivatives1havebeen ;preparedbyreactionofacetyleneswitharhodium ;carbenoidboundtoapolystyreneresinand

    ;cyclopropanecarboxylates2【】throughthecouplingof

    ;bromoaceticacidwithWangresinfollowedby ;pyridiumylideformationandcondensationoftheylide ;withethylidenemalonatederivatives.The ;cyclopropanenucleusisalsoattractiveinthatitcanbe ;welltoleratedinvivoanddoesnotaprioriconfer ;undesirablepharmacokineticproperties,ascanbeseen ;fromthevarietyofwellestablisheddrugs,availablefor ;bothacuteandchronicindications,thatcontainthe ;group.Alsoafewthreememberedtingswitha

    ;hetcroatomhavebeenpublished.Aziridinesare ;importantheterocyclesinorganicandmedicinal ;chemistry.Thesecompoundscanbepreparedby ;nucleophilicdisplacementreactionsinsolution;for ;example,D-aminohalidesand3-aminosulfatesgive

    ;aziridinesonheatingorontreatmentwithalkali.Inthe ;workbyFiligheddu,etal[5’severalaziridine

    ;2-carboxylates3werepreparedusingasolid-phase ;versionoftheGabrielCromwellreaction(Scheme1).

    ;Aziridineoligopeptideswerepreparedbyadditionof ;Wangresincontainingamiongroupsto

    ;0【一bromoacrylatsanda-acrylamides,orbyadditionof ;differentprimaryaminestobromoacrylatesloadedon ;theresin.Inaddition,anepoxidationreactionhasbeen ;producedonapolymerresin.

    ;Surprisingly,nootherheterocycliccompounds ;withoneortwoheteroatomshavebeenreported ;includingtheformationofoxiranes,thiiranes, ;oxaziridines,diaziridines,anddiazirine,respectively. ;AdvancesinSolid-Phaseheterocycliccherr~stry ;CooH

    ;O

    ;R

    ;2

    ;C0OMe

    ;FmOCP0I/o

    ;ml

;o

    ;1VI

    ;?

    ;n

    ;o

    ;x

    ;?

    ;X\U

    ;Scheme1

    ;2.Four-memberedring

    ;Oneexampleofafourmemberedringsynthesis

    ;onapolymericresinwasdescribedbyRebekand ;GavinaoJwhenthepreparationofacyclobutenering ;wasdemonstrated.Anotherexamplehasrecentlybeen ;publishedbyCHENG,etalfintheutilizationof

    ;allylicsulfonesinsolidphasesynthesis.

    ;Polymerboundallylsulfoneswereutilizedingeminal ;cycloalky1ati0nswithepichlOrOhydrin.Aftercleavage ;fromtheresin,asetofcyclObutylidenes4were ;obtained.What’Smore,13-1actams5and3-sultams6

    ;havebeensynthesized:Ruhland.etalI.utilizedthe

    ;Staudingerreactioninthesynthesisofstructurally ;diverse3-lactamsonsolidsupport.Aconvenient ;approachtowardfourmemberedringscontainingtwo ;heteroatomswasdescribedbyGordeev.etaltinthe

    ;solid-phasesynthesisof13-sultams6.Imine ;intermediatesgeneratedfrompolymerimmobilized

    ;aminoacidsandaldehydeswerereactedwith ;(chlorosulfony1)acetatesinthepresenceofpyridineto ;affordthesolid--phase??tethered13-sultamprouducts ;(Scheme21.

    ;R3

    ;4

    ;OR1

    ;5

    ;R3\

    ;N——S=0

    ;II/——.R’R

    ;6

    ;P.I--c/o

    ;P.’\L/o

    thesisof

    ;benzofurans8wasdescribedbyOuthrie[111. ;Thekeystepoftracelesssynthesisofbenzofurans

;wasconversionofpolymersupportedestersintoenol

    ;ethersusingatitanocenealkylidene,preparedfrom ;thioacetalsandalowvalenttitaniumcomplex,

    ;Cp2Ti[P(OEt)3]2(Scheme3).Aftercleavingthe ;hydroxylprotectinggroup,theintermediatewas ;cleavedfromtheresinbyTFA.whichwasfollowedby ;spontaneouscyclizationtotargetbenzofurans8. ;R1

    ;CD-oR7

    ;carboxylicacid,DIC

    ;DMAP.THF

    ;8

    ;O

    ;,L/,,.

    ;Cp2TiIP(OEI)3]2

    ;,.@

    ;Scheme3

    ;Thepreparationoffive-memberedringswithone ;ortwonitrogenatom,e.g.,pyrroles,pyrrolidines, ;pyrrolinones,andimidazolidineshasbeenreportedin ;severalpublications.Forthepreparationofhighly ;43

    ;AdvancesinSolid-Phaseheterocyclicchemistry ;functionalizedpyrrolidines9,severalpapershave ;recentlyappearedindifferentjournals.In1995, ;Mushy.etalI2preparedpyrrolidinesbya1,3dipolar

    ;cycloadditionreactionofresinboundazomethine

    ;ylideswitholefinsoracetylenedipolarophiles.By ;screeningthislibraryagainstangiotensinconverting ;enzyme(ACE),theauthorshaveidentifiedan ;unusuallypotentinhibitorofthistherapeutically ;significantmetalloprotease.LIandWilson[13] ;describedanovelcyclativecleavageprotocolforthe ;preparationofhydantoin10(Scheme4).Themethod ;takesadvantageoftheintramolecularcyclizationto ;affordthedesiredproductsingoodqualitywithno ;needforfurtherpurificationinmanycasesandthe ;methodcouldbeeasilyappliedtothecombinatorial ;synthesisoflargentlm~gersoftrisubstituted ;2aminoinidaxolonecompoundsandlibraries. ;R2

    ;PoI

    ;/\

    ;I

;R1

    ;9

    ;Bocaminoacid

    ;HPoI八料

    ;R2

    ;o

    ;o

    ;OR

    ;T

    ;

    ;FA.DCM

    ;..

    ;

    ;———oI/\N/\/

    ;10

    ;R1

    ;HH

    ;s0

    ;\\/

    ;}{,

    R,\, ;.

    ;Scheme4

    ;R310

    ;R

    ;Thepreparationofsubstitutedimidazoles11, ;thiazoles12,andoxazoles13usingtraceless ;solidphasesulfonelinkerstrategywasdescribedbyLI ;l

    ;.Keystepsinvolvedweresulfinateacidification. ;sulnnicacidcondensationwithaldehydeamine.and ;tracelessproductreleasebyaone-pot

    ;elimination--cyclizationreaction(Scheme5,.The ;eliminationreactionwascarriedoutinthepresenceof ;athiazoliumcatalystthatfacilitatedtheinsitu ;formationofthea-ketoamide,whichwassubsequently ;convertedtothecorrespondingimidazoles,and ;thiazolesbytreatmentwithamines,ecentlybeenpublished.Gordeev,

    ;etalilS].

    ;reactedN.immobilizedesterswith

    ;2-arylideneBketoestersandaldehydestoafford,upon ;cleavage,1,4dihydropyridinederivatives.

    ;2,4,6Trisubstitutedpyridineshave,inaddition,been ;synthesizedthroughaClaisenSchmid/Michael

    ;reactiononWangresinandcyclization[16.An

;efficientmethodforthepreparationof

    ;2,3--dihydro-4--pyridones16onsolidsupportthrougha ;LewisacidcatalyzedtandemMannichMichaels

    ;reactionofDanishefsky’Sdienewithpolymer-bound

    ;aldimineshasbeenreportedbyWangandWilsonU71. ;a3R,

    ;141516

    ;Severalpapershavereportedthesolidphase

    ;synthesisofheterocycleswithtwonitrogenatoms ;(piperzinesdiones17,18)andwithoneoxygenandone ;nitrogenatom(diketomorpholines19)inthering.Inan ;earlypaperbyGavina,etal[18thepreparationofa

    ;AdvancesinSolid-Phaseheterocyclicchemistry ;cyclicdiimineonsolidsupportwasdiscussed.Not ;untilrecentlyhadotherheterocycleswithtwo ;nitrogensintheringbeenreported.Afewyearslater, ;GordonandStee1?9describedanewandefficient

    ;routetowardsynthesisofdiketOpiperazines17on ;WangresinesterifiedwithFmocaminoacids.After

    ;Fmoccleavagewithpiperidine,theliberatedamino ;groupswerereductivelyalkylatedandtheresinbound

    ;secondaryaminogroupswereacylatedby

    ;Bocprotectedaminoacids.Scott.etal2obuiltWang

    ;resinboundsecondaryaminoacidestersfrom ;dbromocarhoxylicacidstopreparaalibraryof22000 ;tetrasubstitutedpiperazine2,5diones(Scheme5).The

    ;resinboundN(0【一bromoacy1)aminoacidesterwas ;alsouseh.etal2ldevelopedasolidphasesynthesis ;offusedpolycycliccompound20onchloroformate ;resin.Anthranilicacidswerelinkedtoresinthroughthe ;nitrogen,thecarboxylicacidwasactivatedwithamines ;toformalinearprecursoroftargetcompounds. ;Exposuretoelevatedtemperaturereleased ;quinazolinediones2Ofromtheresin(Scheme6). ;CI

    ;P0l/\ooR

    ;PyBOP

    ;DlEA

    ;0

    ;oH

    ;,Rz

    ;R1DCM

    ;o

    ;OH

;R1

    ;z30Pol~O0

    ;Pol~O

    ;,

    ;Scheme6

    ;5.Seven-memberedring

    ;Sevenmemberdenngscontainingoneheteroatom ;playanimportantroleinthedevelopmentofnewdrugs. ;Mediumringlactamsdisplayabiologicactivityand ;importantsyntheticintermediates.Onsolidsupport ;severalapproachtowardthesynthesisoflactams21 ;havebeenreported.Veerman[22]describedthe ;applicationofringclosingmetathesisfortraceless ;solidphasesynthesisofunsaturatedlactams21ona ;solidphase.Inasubsequentfullpaper,theauthors ;optimizedconditionsforthecyclationcleavageand ;isolatedtheproductin89%yield.Thebeneficialeffect ;ofolefinadditionandcyclizationofdifferentringsizes ;werealsostudied.ThesynthesisofFreidingerlactams ;waslatermodifiedbyPiscopio[23].Theresinbound

    ;sulfonamide21waspreparedandthenitrogenwas ;alkylatedunderMitsunobuconditions.Thesecondary ;resinboundaminewasliberatedandacylatedbythe ;substitutedpent-4enoicacid.Metathesiscatalyzedwith ;rutheniumeffectedcyclativecleavageofthetarget ;laetam.Preparingpeptidosulfonamides,aclassof ;peptidomimeticshavingapeptidebondreplacedbya ;sulfonamidemoiety,deBont.etal[Jdescribedthe ;synthesisof22.HydroxyTentaGelwasesterifiedwith ;anFmocaminoacid,theFmocgroupwasesterified ;withanFmocaminoacid,theFmocgroupwasremoved, ;andliberatedaminewasreactedwithsubstituted ;Bocaminoethanesulfinylchloride.Theformed ;sulfonamidewasoxidizedtosulfonamide,theBoc ;groupwascleaved,andtheproductwasreleasedfrom ;45

    ;H,z?

    ;AdvancesinSolid-Phaseheterocyclicchemistry ;theresinbycyclativecleavage.Fusedsevenmembered

    ;heterocycleshavealsoshownbiologicalactivitywith ;interestingprope~iesinseveralstudies.Thesynthesisof ;1,4-benzodiazepine2,5dionesbyMayer,etalj

    ;illustratedcyclativecleavageyieldingafused ;sevenmemberedring(Scheme71.Wangresinesterified

    ;withFmoc-protectedaminoacidswastreatedwith ;piperidine,andtheliberatedaminogroupwasacylated ;eitherbyFmocprotectedanthranilicacidsor

    ;onitrobenzoicacids.AtiereitherFmocremovaIOrnitro ;groupreduction,thecycllzationwaspromotedby ;NaOtBuinTHF.Thesynthesisprovidedtarget

    ;compounds23withhighpurity(8199%).

    ;21

    ;R1

    ;tures,allowingthe

    ;discoveryofnovelcompoundswithinterestingand ;varyingactivity.Thedevelopmentofsolidphase

    ;synthesistowardnewheterocyclesisbecomingmore ;andmoredemanding,asbeingdemonstratedviarecent ;observationsreviewedinthiscurrentwork.The ;generationofheterocyclicchemistrybysolid-phase ;synthesiswilldefinitelyacceleratethedevelopmentof ;pharmaceuticalresearch.

    ;References:

    ;flGuilliierF,OrainD,BradleyM.Linkersandcleavage ;strategiesinsolidphaseorganicsyntheisand

    ;combinatorialchemistry.Chem.Rev,2000,100 ;20912157.

    ;2FranzenRG.Recentadvancesinthepreparationof ;heterocyclesonsolidsupport:Areviewoftheliterature..,. ;Comb.Chem..2oo0.2:1952l4.

    ;3CanoM,CampsF,JoglarJ,eta1.Solidphasesynthesisof

    ;cycl0propenes.TetrahedronLett.,1998,39:9819.9822. ;4VoNH,EyermannCJ,HodgeCN.Transformationof ;resinboundpyridiumylides:Astereoselectivesynthesis ;0f2,2,3trisubstituedcyclopropanecarboxylates. ;Tetrahedron,1997.38:79517954.

    ;5FilighedduSN,MasalaS,TaddeiM,Solid-phase ;synthesisofazifidine2-carboxylates.TetrahedronLeff_ ;1999.40:65036506.

    ;{61RebekJ,GavinaF.Thethreephasetestforreactive

    ;intermediatescyclobutadiene.Am.Chem.Soc.,1974,96: ;7l12.7114.

    ;[71CHENGW.C.,HalmC,EvartsjB,eta1.Allicsulrunesin ;solidphasesynthesis:preparationofcyclobutylidenes.J ;OrgCllem,1999,64:85578562.

    ;8RuhlandB,BhandafiA,GordonEM.eta1.Solid ;supportedcombinatorialsynthesisofstructurallydiverse ;Blactams.Am.Chem.Soc.,996,118:253254

    ;9GordeevMF,GordonEM,PatelDV.Solid.phase ;synthesisof3-sultams..,.0rg.Chem.,1997,62, ;817788.

    ;10BeebeX,SchoreNE,KurthMJ.Polymersupposed

    ;synthesisofcyclicethers:Electrophiliccyclizationof ;isoxazolines.D.c1em.,l995,60:4196.42O3.

    ;11GuthrieEJ,MacritchieJ,HartleyRC.Alkylidenationof ;estersonsolidsupportandtracelesssynthesisof ;2substitutedbenzofurans.Tetrahedronrf..20o0.41:

    ;4987.4990.

    ;fl2MurphyMM,SchullekJR,GordonEM,eta1.

    ;Combinatorialorganicsynthesisofhighlyfunctionalized ;pyrrolidines:Identificationofapotentangiotensin ;conveningenzymeinhibitorfromamereaptoaeylpraline ;library.j.Am.Chem.Soc..,995.1l7:70297030,

    ;13LIM,WilsonLJ.Afacileandpracticalsolid.phase ;synthesisoftrisubstituted2.aminoimidazolones. ;TetrahedronLP.20o1.42:1455.1458.

    ;141LIW.W.,LamY.L..Afacilesolidphasesynthesisof

    ;1.2,4,5tetrasubstitutedimidazolesusingsodium ;benzenesulfinateasatracelegglinder.J_Comb.Chem.. ;20o5.7644647.

    ;l5GordeevMF,PatelDV,GordonEM.Approachesto ;combinatorialsynthesisofheterocycles:Asolid-phase ;synthesisof1,4?dihydr0pyridines.Org.Chem.,1996,61: ;924928.

    ;ft0becontinuedonPageS6)

    ;Experimentalstudyofrefiningsolanesolfromcrudesolanesoibysaponification

    ;2J

    ;[31

    ;4

    ;5

    ;f6

    ;SeparationandPurificationTechnology,20o7.6: ;29295.

    ;ZH0UHHayingandLIUChunzhao.

    ;Microwaveassistedextractionofsolanesolfromtobacco ;leaves.JournalofChromatographyA.2006.29:l35l39.

    ;RaghunathRaoJonnalagadda(IN).MethodofIsolating ;SolanesolExtractFromTobaccoUtilizingSuperCritical ;CD,FluidExtractionProcessing.W0200702926. ;B.H.Lipshutz,P.Mollard.S.S.Pfeiffr,eta1.Ashort. ;highlyefficientsynthesisofcoenzymeQll1.Am.Chem. ;Soc,2002.124:1428214283.

null

Report this document

For any questions or suggestions please email
cust-service@docsford.com