药物合成反应 第四章 缩合反应

Chapter4CondenationReaction第四章缩合反应第一节a-羟烷基、卤烷基、氨烷基化反应一、a-羟烷基化反应1.醇醛缩合反应(Aldol缩合)(1)含有a-活泼氢的醛或酮的自身缩合碱催化机理:R'+R'R'+BHCHCRCH2OBCROCHCROR'δδδδ+R'R'R'R'R'CRCH2OCHCROCRCH2CORCHOBHHOHCRCH2CCORBR'△R'+OHRCRCH2CCOBH(62%)-OHCCHO(CH2)3C3H7CHOH1150CC3H7CHO(90%)OCH2COCH3KOHO甲醛与含有a-活泼氢的醛、酮之间的缩合NaOH(稀)40-420C+(45%)-HCHOCH3COCH3H2CCHCOCH3H2O14-200C,3h+(90%)CH2CH2K2CO3OH2HCHOCH3CH2CHOCH2CH3CCHOCH2OH(1)[H](2)HCHO+NaOHCH3CH2COHCH2OHCH2OHCH2三羟甲基丙烷•催化剂的影响•以碱催化剂为主，酸催化剂应用较少•④应用特点•定向醇、醛缩合•(a)烯醇盐法•(b)烯醇硅醚法•（2）芳醛与a-活性氢的醛、酮的缩合•应用特点•制备反式芳丙醛有机小分子脯氨酸催化直接Aldol反应List,B.etal,J.Am.Chem.Soc.2000,122,2395NHCOOHR=Ar,78%ee;R=Alkyl,99%ee,R=4-NO2Ph,78%eeROHOR'+ROR'OHCatalystDMSO,RT•制备手性b-羟基醛•（3）分子内的羟醛缩合•Robinson环化•2.不饱和烃的a羟烷基化（Prins反应）Mechanism•3.安息香缩合•影响因素•①芳醛结构的影响•强吸电子、强供电子对反应都不利；•自身缩合、交叉缩合•②催化剂的影响•NaCN剧毒，可用噻唑鎓盐、咪唑鎓盐等代替Example4.有机金属化合物的a-羟烷基化(1)Reformatsky反应:醛或酮与a-卤代酸酯在金属锌粉存在下缩合而得b-羟基酸酯或脱水得a、b-不饱和羧酸酯的反应：metal:Zn,Mg,Cd,Ba,In,Ge,Co,Ni,Ce;metalsalt:SmI2,CrCl2,TiCl2,CeX3,Na2Te,R3SnLi,R3Sb/I2,Et2AlCl•mostoftenethersolventsareusedsuchasdiethylether,tetrahydrofuran,1,4-dioxaneanddimethoxyethane,butmixturesofthesesolventswitharomatichydrocarbonsandmorepolarsolventssuchasacetonitrile,dimethylformamide,dimethylsulphoxide,andhexamethylphosphorictriamidearealsoused;催化剂•锌粉必须活化，常用20%盐酸处理，再用丙酮、乙醚洗涤，真空干燥。•亦可用K、Na、Li等还原无水氯化锌，此法活性较高。•Mg,Cd,Ba,In,Ge,Co,Ni,Ce等。例如:+Zn/(CH3O)3B/THFr.t.(95%)CHOCH3BrCH2COOC2H5CH2COOC2H5CH3CHOH加入(CH3O)3B/THF可提高收率(如上)+(50%)CHOOBrZnCH2COOC2H5OCH2COOC2H5CHOH00CTHF•（2）Grignard反应机理:+乙醚(干)RXMgRMgXOMgX+RCH2+δδ+-+CHOH3OMg(OH)XCHRMgXRHHOH•③影响因素•1)thereagentsarepredominantlypreparedbyreactingalkyl,aryl,orvinylhalideswithmagnesiummetalinaproticnucleophilicsolvents(e.g.,ethers,tertiaryamines);•2)thereagentsareusuallythermodynamicallystablebutairandmoisturesensitiveandincompatiblewithacidicfunctionalgroups(e.g.,alcohols,thiols,phenols,carboxylicacids,1°,2°amines,terminalalkynes);•二、a-卤烷基化反应(Blanc反应)3.影响因素•也可用ZnCl2(干)等Lewis酸。苯环上供电子基,有利于反应进行。吸电子基不利于反应进行。(87%)•引入-CH2Cl后，可进一步转化成其他官能团并增长碳链。三、a-氨烷基化反应Mannich反应：有活泼氢的化合物(醛、酮等)与甲醛、胺进行缩合，H原子被a-氨甲基取代称为a-氨甲基化反应(Mannich反应)反应机理如：(90%)抗胆碱药阿托品的中间体IntroductionSiliconEnolatesKetonesAldehydesMannichProductsAldehydes+AminesIminesandImineSurrogatesElectrophilesNucleophiles+One-PotPreformedIminesOrganicSol.AqueousMedia•1.MetalCatalysis•2.ProlineCatalysis•3.BrønstedAcid-Catalysis•4.ProtonatedChiralCatalysis•5.ACDC•6.H-BondCatalysis•7.PTCTrost,B.M.J.Am.Chem.Soc.2006,128,2778-2779.ProlinecatalysisBrønstedacid-catalysis(1)磷原子的四齿结构(2)磷酸的酸性足以诱捕亚胺(3)双功能手性催化剂4.ProtonatedChiralCatalysisJ.Am.Chem.Soc.2004,126,3418-3419Ishihara,K.J.Am.Chem.Soc2008,130,16858–16860.H-BondCatalysisJacobsen,E.N.Angew.Chem.Int.Ed.2005,44,466–468.•2.Pictet-Spenglerreaction•Baldwin环化规则•Baldwin环化规则•SP3=tet；SP2=trig；SP=dig•SP3:5-6-endo禁阻•SP2:3-5-endo禁阻•SP:3-4-exo禁阻•其他允许•（3）影响因素•①onlyβ-arylethylamineswithelectron-donatingsubstituentsaffordhighyields;•②thereactionisusuallycarriedoutwithaslightexcessofthecarbonylcompound(toensurethecompleteconsumptionoftheamine)ineitherproticoraproticmedium;•3.Strecker反应•（1）反应通式•（2）反应机理•（3）应用-Corey，1999第三节b-羟烷基、b-羰烷基化反应一b-羟烷基化反应1.反应通式-F-C反应•2.反应机理CH3CHCH2CH2OHCH3CHCH2CH2OH苯环连在取代基多的C上SnCl2/CS2-100C+(40%)C6H5CH3CHCH2OCH3CHCH2CH2OHCH23.应用特点•（1）区域选择性•（2）立体选择性•构型反转•（3）制备环内酯二、b-羰烷基化反应Michael加成反应反应机理:+δδδδ+OHCH3OOCH3HHOOCH3OOCH3COCH2CH+CH2OHCH3OOCH3COCH2CHHCH3OOCH2CH3CO△CH3-H2OOOδδ+OOCH3OOCH3OCH2CH3OOCH2COCH2HOHH（3）影响因素•1)thenucleophile(Michaeldonor)canbederivedbythedeprotonationofCH-activatedcompoundssuchasaldehydes,ketones,nitriles,β-dicarbonylcompounds,etc.aswellasbythedeprotonationofheteroatoms;•2)dependingonthetypeandstrengthoftheelectron-withdrawinggroup(negativechargestabilizinggroup),theuseofevenrelativelyweakbasesispossible(e.g.,NEt3);•（4）应用第四节亚甲基化反应一羰基烯化反应（1）反应通式及机理+n-C4H8Li/EtON2,250C(C6H5)3CH3PBrC6H6250C(C6H5)3PCH3BrR'+CH2CH2R(C6H5)3P(C6H5)3PCOR'R'R'+OCH2HOHC(C6H5)3PCRHOHC(C6H5)3PCRRC(C6H5)3P•（2）影响因素•theylidesarewateraswellasoxygen-sensitive；•thephosphorousylideschemoselectivelyreactwithaldehydes(fast)andketones(slow),othercarbonylgroups(e.g.,esters,amides)remainintactduringthereaction;•thestereoselectivity,E-orZ-selectivity,isinfluencedbymanyfactors:typeofylide,typeofcarbonylcompound,natureofsolvent；•TheWittigreactionhasseveralimportantvariants:HWEReaction•①thephosphonatecarbanionsaremorenucleophilicthanthecorrespondingphosphorousylides,sotheyreadilyreactwithpracticallyallaldehydesandketonesundermilderreactionconditions；•②theby-productdialkylphosphatesarewater-soluble,soitismucheasiertoseparatethemfromthealkeneproductsthanfromthewater-insolubletriphenylphosphineoxide.•③high(E)-selectivityfordisubstitutedalkenesundermuchmilderconditionsthannormallyusedinWittigreactions；•④the(E)-selectivityismaximizedbyincreasingthesizeofthealkylgroupoftheR1orR2substituents•⑤ThereareanimportantmodificationsoftheHWEolefination:•intheStill-GennarimodificationR1=OCH2CF3andthereactionaffords(Z)-olefinsexclusively；•forbase-sensitivesubstrates,theuseofametalsalt(LiClorNaI)andaweakaminebase(e.g.,DBU)hasproveneffectivetoavoidepimerization.•（4）应用