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1、DirectedMolecularEvolutionofProteins:orHowtoImproveEnzymesforBiocatalysis.EditedbySusanneBrakmannandKaiJohnssonCopyrightã2002Wiley-VCHVerlagGmbH&Co.KGaAISBNs:3-527-30423-1(Hardback);3-527-60064-7(Electronic)11DirectedEvolutionasaMeanstoCreateEnantioselectiveEnzymesforUse
2、inOrganicChemistryManfredT.ReetzandKarl-ErichJaeger11.1IntroductionThestereoselectivesynthesisofchiralorganiccompoundsisofconsiderableacademicandindustrialinterest[1±3].Forexample,theso-calledªchiralmarketºofenantio-mericallypureorenrichedorganiccompoundsisexpandingrapid
3、ly,thetotalsalesofchiralpharmaceuticalsaloneexceeding100billionUSin2000[1e].Manyofthesecompoundsarepreparedinthelaboratoriesoforganicchemists.Presently,classicalantipodeseparationisthemethodmostoftenusedinindustry[1d].However,thisrequiresstoichiometricamountsofanappropri
4、ateopticallyactivereagentaswellaslargeamountsoforganicsolvents.Forecologicalandeconomicreasons,asym-metriccatalysiscanbeexpectedtobemoreefficient,providedthatactiveandhighlyenantioselectivecatalystscanbefound.Catalyticasymmetrictransformationscanbecarriedouteitherinthefo
5、rmofkineticresolutionofracematesorinreactionsinvol-vingprochiralsubstrates.Twooptionsareavailable,namelytransitionmetalcatalysis[2]andbiocatalysis[3].Successintheareaofasymmetrictransitionmetalcatalysisrequiresefficientligandtuning(Fig.11.1a),whichisadifficultgoal[2].Exp
6、eri-ence,intuition,knowledgeofthereactionmechanismandapplicationofmolecularmodelingaswellastime-consumingtrialanderrorarerequired.Manysuccessfulexampleshavebeenreportedintheacademicliterature,andsomeofthesehavebeencommercialized[1].Inthecaseofbiocatalysis,enzymes[3]andca
7、talyticantibodies[4]haveattractedmostattention.Sinceenzymesareinherentlythemoreactivecatalysts,theyhavebeenusedmostoften.Indeed,manyindustrialprocessesfortheenantioselectiveproductionofcertainchiralintermediatesarebasedontheapplicationofenzymes,asinthelipase-catalyzedkin
8、eticresolutionofanepoxy-esterusedintheproductionoftheanti-hypertensivetherapeuticDiltiazem[5].Recently,
