氨基酸的合成

药明康德内部保密资料StereoselectiveSynthesisofAminoacidanditsderivant经典合成反应标准操作—Mitsunobu反应药明康德新药开发有限公司药明康德内部保密资料Page1of46目录1.前言…………………………………………………………………22．U.Schollkopf法---从氨基酸模块开始的合成2.1U.Schollkopf法---从氨基酸模块开始的合成示例2.2SynthesisofthekeyintermediateofthenovelrennininhibitorAliskiren2.3EfficientsynthesesofbiologicallyimportantaminoacidSynthesisofα-aminoacidanditsderivantfromaziridine3．synthesisoftheaminoacidsfrom2-isopropyl-3,6-dimethoxy(or:diethoxy)-2,5-dihydro-pyrazine4．4.Synthesisofα-aminoacidfromEvansReagent经典合成反应标准操作—Mitsunobu反应药明康德新药开发有限公司药明康德内部保密资料Page2of461．前言不对称合成a-氨基酸的工作自1970年代后期系统地开展起来，在其后的十余年中，发现了几十种不对称合成方法。已经报道的a-氨基酸不对称合成方法可以分为五类，即酶合成法、αβ-脱氢氨基酸氢化或环加成法、Strecker型反应、亲电或亲核氨基化法以及亲电或亲核烷基化法，上述反应都涉及α-碳的手性控制.就立体选择性的控制方法而言，手性辅基(chiralauxiliary)方法仍占多数。用于不对称合成a-氨基酸的手性辅基种类较多，常见的环系模板(cyclictemplates)(也叫环系手性辅基)和非环系模板(acyclictemplates)（也叫非环系手性辅基）应用手性辅基的a-氨基酸不对称合成方法甘氨酸或丙氨酸衍生烯醇盐(enolates)的亲电烷基化是最早发展的a-氨基酸合成方法，该法变化形式丰富，研究和应用广泛，其中有几种已成为当前制备手性氨基酸的常规方法.U.Schollkopf法—从氨基酸模块开始的合成,D.Seebach法---手性中心自我再生”原理的成功应用,Y.N.Belokon法—含甘氨酸席夫碱的金属配位化合物,W.Oppolzer法---方便回收的天然手性源辅基,D.A.Evans法---一种广泛应用的手性辅基,M.J.O'Donnell法---基于金鸡纳碱的手性相转移催化。2.制备手性氨基酸的常用方法2．1U.Schollkopf法---从氨基酸模块开始的合成U.Schollkopf用L-Val和Gly缩合制得环二肽7,7与Meerwein盐(Me30+BF4-)作用得甲基醚1，经丁基锂脱质子得甘氨酸负离子8，烷基化生成9，酸水解，得手性a-氨基酸10.此法所得氨基酸的ee值可达95%以上.制备反应如Scheme1所示。Scheme1NH2OOHtriphosgeneTHF,40℃HNOOOCHCl3,THF,Et3N,-70℃NH2ONHCOOEtNH2EtOOC.HCltoluenerefluxHNNHOO3Et3O+BF4-CH2Cl2,72hNNOEtEtOBuLiNNOEtEtORCH2XCH2RH0.25NHClNH2OOHRNH2OO经典合成反应标准操作—Mitsunobu反应药明康德新药开发有限公司药明康德内部保密资料Page3of46Example:2.1.1U.Schollkopf法---从氨基酸模块开始的合成示例NH2OOHtriphosgeneTHF,40℃HNOOOCHCl3,THF,Et3N,-70℃NH2ONHCOOEtNH2EtOOC.HCltoluenerefluxHNNHOO3Et3O+BF4-CH2Cl2,72hNNOEtEtO1.0.25NHCl2.0.25NLiOHSPhBrPhPhNNOMeMeOSPhPhPh(89%)SH2NCOOMePhPhPhNa/NH3LiOHSH2NCOOHPhPhPhSNaH2NCOOHAcidicconditionSH2NCOOHSNH2COOHSHH2NCOOHHI52%40%n-BuLi1234578910111213146References:TetrahedranAsymmetry,10(1999),4151~4156.NH2OOHtriphosgeneTHF,40℃HNOOO12ToastirredsuspensionofD-valine1(117.15g,1.0mol)inTHF(1200mL)wasaddedphosgene(148.5g,0.5mol),thetemperaturewasmaintainedat40℃withaheatingmantle.Afterthesolidinsolutiondisappeared,thesolutionwhichresultedwaspurgedwithN2for2h,thesolventwasremovedinvacuoandtheresiduewasflashedwithTHFtwice,theN-carboxyanhydridewhichformedwasdriedinthevacuumtoprovidearudeproduct2(206.37g,100%),duetotheunstablenatureofthisanhydrideitwasusedimmediatelyinthenextstepwithoutfurtherpurification.CHCl3,THF,Et3N,-70℃NH2ONHCOOEtNH2EtOOC.HCltoluenereflux34HNNHOO5HNOOO2经典合成反应标准操作—Mitsunobu反应药明康德新药开发有限公司药明康德内部保密资料Page4of46AsolutionoftheN-carboxyanhydride2(206.37g,1.44mol)inTHF(1600mL)wasaddeddropwisetoavigorouslystirredmixtureofglycineethylesterhydrochloride3(201.32g,1.44mol),triethylamine(461mL,3.31mol),andchloroform(2000mL)at–70℃.After3hofstirringat–70℃and2hatroomtemperature,thereactionsolutionwasfilteredtoremovethetriethylaminehydrochloride,thefiltratewasconcentrateinvacuotogivetheresidue4.Theresidue4wasaddedtoluene,thesuspensionwhichresultedwasheatedatrefluxfor12handthencooledto0℃,thebis-lactimwhichresultedwasrecoveredbyvacuumfiltration,washedwithetheranddriedundervacuumat100℃toprovidethepurecompound5.HNNHOO3Et3O+BF4-CH2Cl2,72hNNOEtEtO576Toastirredsolutionoftriethyloxoniumtetrafluoroborate6(1063.19g,5.60mol)inCH2Cl2wasaddedthebislactim5(291g,1.86mol)inportions,afterseveralhoursthereactionmixturebecamehomogeneous,thereactionwasstirredatroomtemperatureunderN2for3days,afterwhichasolutionofNaH2PO4andNa2HPO4inwaterwasaddedtothesolutionwithstirring,theorganicphasewasseparatedandtheaqueousphasewasre-extractedwithCH2Cl2twice.ThecombinedorganiclayersweredriedoverMgSO4,evaporatedtoremovethesolvent,theresiduewasvacuumdistilledtoprovidethepurebis-ethoxylactimether7.NNOEtEtOSPhBrPhPhNNOMeMeOSPhPhPhn-BuLi789n-BuLi(1.6Minhexanes,9.6mL,15.4mmol)wasaddedtoa−78°Csolutionof(R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine7(3,2.5mL,14mmol)and1,3-dimethyl-2-imidazolidinone(DMEU,3.1mL,28mmol)indryTHF(140mL).After45min,asolutionof2-bromoethyltriphenylmethylsulfide8(6.32g,16.5mmol,1.2equiv.)indryTHF(30mL)wasaddedover25min.After20hat−78°C,thecherrycoloredreactionmixturewasquenchedwith5mLof100mmol,pH7.2phosphatebufferandwarmedtoambienttemperature.Theyellowsolutionwasconcentratedinvacuoandtheresultingresidue经典合成反应标准操作—Mitsunobu反应药明康德新药开发有限公司药明康德内部保密资料Page5of46waspartitionedbetweenethylacetate(EtOAc,100mL)andwater(100mL).TheaqueouslayerwasseparatedandextractedwithEtOAc(50mL).CombinedorganicextractsweredriedoverNa2SO4,decantedandconcentratedinvacuotogiveanoil.Purificationbyflashchromatography(5%EtOAc/hexanes)gave1.60g(47%basedonrecoveredstartingmaterial)of(2R,5S)-2-isopropyl-3,6-dimethoxy-5-[2-(tritylsulfanyl)ethyl]-2,5-dihydropyrazine9.Compound9:1HNMR(CDCl3)_7.42–7.38(m,5H),7.29–7.12(m,10H),3.96(ddd,J=7.2,3.6,3.6Hz,1H),3.81(dd,J=3.6,3.6Hz,1H),3.61(s,3H),3.55(s,3H),2.27–2.07(m,2H),1.99–1.88(m,1H),1.78–1.66(m,1H),1.00(d,J=6.6Hz,3H),0.65(d,J=6.9Hz,3H);13CNMR(CDCl3)_163.67,163.22,144.98,129.60,127.75,126.47,66.51,60.73,54.52,52.36,33.19,31.78,27.75,18.99,16.64;ESMS(M+2H)2+243.2.Ana