Anovelliquid-phasestrategyfororganicsynthesisusingorganicions

assolublesupports

CongdeHuoaandTakHangChan*b

Received20thNovember2009

FirstpublishedasanAdvanceArticleontheweb17thMay2010

DOI:10.1039/b914497h

Thiscriticalreviewdescribesanewliquid-phasestrategyfororganicsynthesisbyusingorganic

ionsassolublesupports.Catalystsorreagentsorsubstratesareimmobilizedontoorganicions.

Theyaregenerallysolubleinpolarorganicsolvents(e.g.CH3CN)orionicliquidsbutinsolublein

non-polarsolvents(e.g.etherorhexanes).Theirreactionsarecarriedoutinhomogeneous

solutionphasewithapolarorganicsolventorionicliquid.Afterthereaction,theion-supported

speciescanbephaseseparatedthroughprecipitationfromthepolarorganicsolventbythe

additionofalesspolarorganicsolventorextractionwithorganicsolventsfromionicliquids.The

ion-supportedspeciescanthereforebeeasilyrecoveredandpurifiedfromthereactionmixtureby

simplewashingswiththelesspolarsolvent.Theion-taggedspeciescanfunctionintheroleofa

catalyst,orasareagent,orasthesubstrateinthesynthesisofsmallmoleculesorbio-oligomers.

Ion-supportedcatalystsandreagentscanusuallyberecoveredandreusedwithlittlediminutionof

activity.Importantbiooligomerssuchaspeptides,oligosaccharidesandoligonucleotideshave

beensynthesizedwiththismethod(136references).

1.Introduction

1.1Solid-vs.liquid-phaseorganicsynthesis

Organicreactionsareusuallycarriedoutinthesolutionphase.

Aftercompletionofthereaction,phaseseparationbetweentheorganicandaqueousphaseisusuallyperformedtoremove

water-solubleinorganicsintheaqueousphase.Theorganic

producttogetherwiththereagentsandanysideproductsare

thenrecoveredfromtheorganicphaseandpurifiedbyvarious

means.In1963,functionalizedcross-linkedinsolublesolid

polymerresinassupportwasfirstintroducedbyMerrifield

forpeptidesynthesis.1Solid-phaseorganicsynthesishas

developedenormouslysincethen.2,3Solid-phasesynthesis

hasbeenhighlysuccessfulmainlybecausetheproductcan

beeasilyseparatedfromthereagentsbysimplefiltration.The

processisreadilyautomatedforbiopolymersynthesisand

nowaKeyLaboratoryofEco-Environment-RelatedPolymerMaterials,MinistryofEducation,China.GansuKeyLaboratoryofPolymerMaterials,CollegeofChemistryandChemicalEngineering,NorthwestNormalUniversity,Lanzhou,Gansu730070,China.E-mail:huocongde1978@hotmail.combDepartmentofChemistry,McGillUniversity,Montreal,Quebec,CanadaH3A2K6.E-mail:tak-hang.chan@macgill.ca

CongdeHuoDrCongdeHuoobtainedhisBA(2000)andPhD(2005)fromLanzhouUniversity(supervisorZhong-LiLiu)inChina.Hewasthenapost-doctoralfellowattheHongKongPolytechnicUniversity(2005–2007)andMcGillUniversity(2007–2009)underthesupervisionofProf.Tak-HangChan.Inautumn2009,HejoinedNorthwestNormalUniversityasanAssociateProfessorofchemistry.Hisresearchinterestslieingreenchemistry,radicalcationchemistryandmedicinal

chemistry.TakHangChanProf.ChanreceivedhisBSc(Toronto)in1962,MSc(Princeton)in1963andPhD(Princeton)in1965underthesupervisionofR.K.Hill.HewasResearchAssociateinHarvardUniversity,1965–1966,underthesuper-visionofR.B.Woodward.HethenjoinedMcGillUniversityin1966,andiscurrentlyProfessorEmeritus.HeisalsotheDistinguishedChairProfessorofOrganicChemistryintheHongKongPolytechnicUniversity.Hisresearchinter-est.coversthedevelopmentofnovelreactionsinenvironmentallycleansolventssuchaswaterorionicliquids.Thesecondareaofresearchisinmedicinalchemistry.Incollaborationwithbiologicalscientists,compoundswithanticancer,anti-bacterialorantiviralactivitiesaresynthesizedandevaluatedintermsoftheirstructure–activityrelationshipandmechanismofaction.

Thisjournalis󰀂cTheRoyalSocietyofChemistry2010Chem.Soc.Rev.,2010,39,2977–3006|

2977CRITICALREVIEWwww.rsc.org/csr|ChemicalSocietyReviewsroutinelyusedforthesynthesisofpeptidesandoligonucleotides.

Ontheotherhand,solid-phasesynthesisisnotwithout

problems,particularlythoseduetotheheterogeneousreaction

conditionsandthelowloadingorhighcostofsomesolid

supports.Inordertorestorehomogeneousreactionconditions,

solublepolymerssuchaspolyethyleneglycols(PEGs)have

beenemployedassupports.Afterthereaction,theproduct

anchoredonthe‘‘soluble’’polymerisseparatedfrom

thereactionmixturebyprecipitation.This‘‘liquidphase’’

alternativemethodcombinesconventionalsolution-phase

reactionconditionswiththeadvantagesofthesolid-phase

foreasyseparation.4Recently,theuseof‘‘fluorousphase’’

synthesishasbeenadvocatedbasedonthefactthatfluorinated

compoundspreferentiallydissolveinafluoroussolvent.A

‘‘fluorous’’-taggedspeciescanbeseparatedfromother

reagentsorproductsbyextractionwithafluoroussolvent

andthusfacilitatepurification.5,6Thisreviewfocusesonthe

quiterecent(since1999)strategyofusingion-taggedspecies

forsolution-phasesynthesis.Thehomogeneousreactionis

usuallycarriedoutinarelativelypolarsolventorinanionic

liquid(IL).Afterthereaction,theion-taggedspeciesareeasily

separatedfromtheotherreagentsbyprecipitationwithaless

polarsolventwhenpolarorganicsolventsareusedasthe

reactionmedia;orbyextractionwithorganicsolventswhen

ionicliquidsareused.Theion-taggedspeciescanfunctionin

theroleofacatalyst,orasareagent,orasthesubstrateinthe

synthesisofsmallmoleculesorbio-oligomers.Thesubjectwas

firstreviewedin20067andmanydiverseexampleshave

appearedsincethen.Indeed,arecentreviewoncatalystswith

ionictagsasthesubjectmatterhasappearedin2008.8Inthis

review,wewillgivemoreemphasisonrecentdevelopment.

1.2Organicionsassupportstocontrolsolubility

Organiccationsareusuallyemployedasthephasetags,

thoughinsomecases,anionshavebeenusedastagsaswell.

Theorganicionisfirstfunctionalizedsothatitcanbetagged

onthroughcovalentbondwiththedesiredcatalystorreagent

orsubstrate.Thecovalentbondattachmentmustberobust

enoughtosurviveallthechemicaltransformationsthatwillbe

carriedoutintheintendedsynthesis,butcanbecleaved

readilywithoutaffectingthedesiredproduct.Thecommon

organiccationsusefulasionictagsaretheammoniumand

phosphoniumcations.Heterocyclicammoniumcations,such

astheimidazoliumorthepyridiniumcationsareverycommonly

usedastheyarestableinmanychemicaltransformations.For

anionictags,organicsulfonateanionshavebeenused.

Becauseoftheirioniccharacter,ion-taggedspeciesare

usuallynotsolubleinnon-polarorganicsolventssuchas

hexaneorlesspolarsolventssuchasdiethylether.Theyare

usuallysolubleinpolarorganicsolventssuchasacetonitrileor

dimethylformamide.Theirsolubilityinorganicsolventsof

intermediatepolarity,suchaschloroformordichloromethane,

dependsonthestructureoftheion-taggedspeciesaswellas

thecounterion.Anotherimportantconsiderationiswhether

theion-taggedspeciesissolubleinwater.Ifaqueouswashing

ofinorganicsideproductsisemployedinthesynthesis,one

willneedtouseiontagswhicharenotsolubleinwater.This

canbeachievedusuallybyusingiontagswhicharelesshydrophilicbyhavinglongeralkylchainsinthestructure,or

byusinganionssuchasPF6ÀorNTf2ÀinsteadofBF4Àor

halides.

1.3Ion-supportedsynthesis

Inthisreview,wewilldiscusstheuseofiontagsassupports

forcatalyst,assupported-reagentsandassupportsforthe

synthesisofsmallmoleculesandbiopolymers.Inthepartof

ion-taggedcatalysts,ion-taggedligandsformetalcomplexes

andion-taggedorganocatalystsarebothdiscussed.For

ion-taggedmetalcomplexes,thereactionsdiscussedinclude

Ru-andRh-catalyzedolefinmetatheses,hydrogenationsand

hydroformylations,aswellasPd-catalyzedcrosscoupling

reaction,especiallyHeckreactionandSuzukireaction.

Ion-taggedligandsforothermetalssuchasCu,Ni,V,Mn,

FeandTiarealsointroducedbriefly.Thesemetal-catalyzed

reactionsaremainlyperformedinionicliquidsorbiphasic

aqueousenvironment.

Underthetopicsofusingion-taggedreagents,Wittig-type

reactionsandStille-typereactionsleadingtotheformation

ofcarbon–carbonbondarediscussed.Thisisfollowed

byadiscussionofusingion-taggedreagentsforeffecting

functionalgrouptransformationssuchasoxidation,reduction,

carbodiimide-mediatedreactionsandMitsunobureaction.

Therelativemeritsofion-taggedreagentsarecomparedwith

soluble-polymersupportedandfluorous-taggedreagents.

Forthetopicsofusingionicsupportsforthesynthesisof

smallmolecules,thedifferenttypesofionicsupportsare

discussedandevaluated.Theapplicationsofthisapproach

forthesynthesisofheterocycliccompounds,substituted

biphenylsusingtheSuzukicoupling,anantithrombotictirofiban

analog,cis-b-lactamlibraryand1,4-benzodiazepine-2,5-

dionesaredescribed.Thisisfollowedbyexamplesintheuse

ofion-supportedsubstratestoundergoasymmetricsynthesis

orfreeradicalreactions.

Intheuseofionicsupportfortheliquid-phasesynthesisof

bio-oligomers,applicationsforthesynthesisofoligopeptides,

oligonucleotidesandoligosaccharidesaregiven.Thecurrent

limitationsofthisapproachforthesynthesisofhigher

molecularweightoligomersarediscussedandpossiblesolutions

examined.Comparisonofthisapproachtothesolid-phase

synthesisofbio-oligomersismadewithparticularreferenceto

theopportunityofusingthisapproachforthelarge-scale

synthesisoftherapeuticoligopeptidesorsiRNAs.

2.Ion-taggedcatalysts

Thedevelopmentofrecoverableandrecyclablecatalystsisan

importantresearchthemeincontemporarysyntheticchemistry

duetoenvironmentalconcernsandeconomicaldemands,

especiallyfortheexpensivenobletransitionmetalcatalyst

systems.Ion-taggedcatalysts,bypossessingtheionictag,can

beeasilyseparatedfromthesubstrateandproduct,recovered

andreused(Scheme1).

2.1Metalcatalysts

2.1.1Ion-taggedligandsforRuandRh.Becauseofthe

versatilityofRuandRhincatalyzingorganicreactionsand

theirhighcost,considerablestudiesoniontaggedligandsfor

2978|Chem.Soc.Rev.,2010,39,2977–3006Thisjournalis󰀂cTheRoyalSocietyofChemistry

2010