氨基的保護及脫保護

經(jīng)典化學合成反響標準操作氨基的保護及脫保護策略編者：彭憲藥明康德藥開發(fā)化學合成部目 錄氨基的保護及脫保護概要… 2烷氧羰基類2-1.芐氧羰〔Cbz〕……………… 42-2.〔Boc〕………………162-3.笏甲氧羰〔Fmoc〕 282-4.烯丙氧羰基〔Alloc〕…………342-5.〔Teoc〕362-6.甲〔或乙〕氧羰基……………40?；?-1.〔Pht〕……………433-2.對甲苯磺酰基〔Tos〕…………493-3.三氟乙?；睺fa〕 …………53烷基類4-1.三苯甲基〔Trt〕………………574-2.2,4-二甲氧基芐基〔Dmb〕……634-3.對甲氧基芐基〔PMB〕 654-4.芐〔Bn〕 70氨基的保護及脫保護概要選擇一個氨基保護基時，必需認真考慮到全部的反響物，反響條件及所設計的反應過程中會涉及的全部官能團。首先，要對全部的反響官能團作出評估，確定哪些在所設定的反響條件下是不穩(wěn)定并需要加以保護的，并在充分考慮保護基的性質(zhì)的根底用一樣的保護基來保護不同的官能團是格外有效〔如芐基可保護羥基為醚，保護羧酸為酯，保護氨基為氨基甲酸酯。要選擇性去除保護基時，就只能承受不同種類的保護基〔如一個CbzBoc。此外，還要從電子和立體的因素去考慮對保護的生成和去除速率的影響〔如羧酸叔醇酯遠比伯醇酯難以生成或除去。最終，假設難以找到適宜的保護基，要么適當調(diào)整反響路線使官能團不再需要保護或使原來在反響中會起反響的保護基成為穩(wěn)定的；要么重設計路線，看是否有可能應用前體官能團〔如硝基，亞胺等；或者設計出的不需要保護基的合成路線。在合成反響中，伯胺、仲氨、咪唑、吡咯、吲哚和其他芳香氮雜環(huán)中的氨基往往N-烷氧羰基保護的氨基酸在接肽時不易發(fā)生消旋化。伯胺、仲氨、咪唑、吡咯、吲哚和其他芳香氮氫都可以選擇適宜的保護基進展保護。下表列舉了幾種代表性的常用的氨基保護基。幾種代表性的常用的氨基保護基構(gòu)造 縮寫 應用 引入條件 脫去條件

H/Pd-C，供氫體2Cbz-Cl/NaCO/CH

2 3CbzCl/HO

3 2 2orTFA，HBr/HOAc3 2等等BocO/NaOH/diox2

3MHCl/EtOAc,/HO,BocO/2 2HCl/MeOHordiox,Boc/MeOH,TosOH/THF-CHCl,2 2等BocO/MeNOH/CH2 43MeSiI/CHClorCH3 3 3CNCNFmoc伯胺、仲氨等

Fmoc-Cl/NaHCO,3

20%哌啶/DMF，50%/diox/HO2

哌啶/CHCl等2 2Allo

唑吡咯吲哚

Ni(CO)/DMF/HO;4 2c Pd(PPh)/BuSnH;34 3等Teoc唑、吡咯、吲哚等-

Teoc-Cl/堿/diox/HO2ROCOCl/NaHCO,/3diox/HO2

TBAF；TEAFHBr/HOAc;MeSiI;3等 KOH/HO/乙二醇2鄰苯二甲酸酐/CHCl/70℃;鄰 HNNH/EtOH，3 2 2Pht 伯胺 苯二甲酰亞胺-NCOEt/aq.2NaCO

NaBH/i-PrOH-HO4 2〔6：1〕2 3Tos等

Tos-Cl/EtN3

HBr/HOAc,〔cat〕伯胺仲氨咪TFAA/Py;苯二甲 KCO/MeOH/HO;2 3 2Tfa等

酰亞胺-NCOCF/CHCl2 3 2

NH/MeOH;3HCl/MeOH伯胺仲氨咪 HCl/MeOH,Trt等

Trt-Cl/EtN3

H/Pd/EtOH,2TFA/CHCl2 2Dmb唑、吡咯、吲哚等

ArCHO/NaCNBH/M3eOHPMB-Br/

HCOH/Pd-C/MeOH;2PMB

KCO/CHCN;PhCH H/Pd(OH)

/EtOH;2 3 3 2 2等 O/NaCNBH3

/MeOH

TFA;CAN/CHCN3Bn-Br/EtNor3HCOH/Pd-C/MeOH;2H/Pd(OH)/EtOH;Bn KCO/CHCN;PhCH222 33CClCHOCOCl/CHC等O/NaCNBH/MeOH33 23N烷氧羰基類保護基烷氧羰基類保護基可用于氨基酸，以在肽合成中削減外消旋化的程度。外消旋化N-?；Ｗo的氨基酸形成的中間體惡唑酮中。要使外消旋化程度減到最小，需使用非極性溶劑、最弱的堿、低的反響溫度，并使用烷氧羰基類保護的氨基酸是有效的。其中常用的有易通過酸性水解去保護的Bocβ-FmocAlloc芐氧羰基〔Cbz〕N-芐氧羰基氨基酸和肽易于結(jié)晶而且比較穩(wěn)定；芐氧羰基氨基酸在活化時不易消旋；能用多種溫存的方法選擇性地脫去。芐氧羰基的導入芐氧羰基的導入，一般都是用Cbz-Cl。游離氨基在用NaOH或NaHCO3

把握的堿性Cbz-ClNα,β-二胺可用該試劑pH=HN(CH)nNH,n=22 2 271%n=729%被單保護[1]。氨基酸酯同Cbz-ClHClNCHOCOOBn〕2 64但苯胺由于親核性缺乏，與該試劑不反響[2]。1．G.J.Atwell,W.A.Denny.,Synthesis,1984,1032．D.R.Kelly,M.Gingell,Chem.Ind.(London,1991,888Cbz-Cl〔見下式上而不發(fā)生顯著的分解。N-芐氧羰基氨基酸能同它的鈉鹽按確定比例形成共晶，共晶產(chǎn)物的熔點較高，并難溶Cbz-Phe物〔144℃1MHClCbz-GlyN-芐氧羰基氨基酸。游離氨基酸的Cbz保護例如Konda-Yamada,Yaeko;Okada,Chiharuetal.,Tetrahedrom;2023,58(39),7851-7865Cbz-Clμl,mmol)indiethyletherml)wasdroppedtoasolutionof(R)-1mg, mmol)in10%aqueousNaCO ml)at0°C,andstirredfor5h.Thereaction2 3mixturewasacidifiedwith10%citricacid,extractedwithCHCl3

(10mlX3).Theorganiclayerwaswashedwithwater,driedoverNaSO,evaporatedtogivelight2 4yellowgels,whichwerepurifiedbypreparativeTLC(CHCl/MeOH=5:1)toafford3(R)-6mg,%)asyellowamorphoussolid.R= (n-BuOH/AcOH/HO=4:1:5);[a]23f 2 D= (c=,CHCl);3氨基酸酯的Cbz保護例如M.Carrasco,R.J.Jones,S.Kameleta1.,Org.Syn.,70,29Mortonflaskequippedwithanefficientmechanicalstirrer,thermometer,thermometer,andadroppingfunnelischargedwithL-methioninemethylesterhydrochloridehydrochloride1(117.6g, mol),potassiumbicarbonate(282.3g, mol,5eq.),water(750mL),andether(750mL,andthesolutioniscooledto0°CBenzylchloroformatechloroformate(105g, mL, mol, eq.)isaddeddropwiseover1hr,thecoolingbathisremoved,andthesolutionisstirredfor5hr.Glycine(8.5g, bathisremoved,andthesolutionisstirredfor5hr.Glycine(8.5g, eq.)eq.)isadded(toscavengeexcesschloroformate)andthesolutionisstirredforforanadditional18hr.Theorganiclayerisseparated,andtheaqueouslayerwithwith0.01Mhydrochloricacid(2×500mL),water(2×500mL),andsaturatedonarotary2 4evaporator.evaporator.TheresultingoilisfurtherdriedinaKugelrohroven(50°C,0.1mm,mm,12hr)toleaveproduct2asaclearoilthatsolidifiesuponcooling:165–166165–166g(98–99%),mp42–43°C.氨基醇的Cbz保護例如(1)Clariana,Jaume;Santiago,G.G.etalTetrahedron:Asymmetr,y4549-4558

2023,11(22),Benzylchloroformate ml, mmol)wasaddedviasyringeintoastirredmixtureofaminoalcohol7(0.989g, mmol)andsodiumcarbonate(0.683g, mmol)inthesolventsystemwater(10ml)–THF(3ml)maintainedat0°C.Themixturewasstirredatroomtemperaturefor18h(TLCmonitoring)andthenpartitionedbetweendichloromethaneandwater.Theorganicphasewasdriedandevaporatedtoaffordawhitesolidwhichwaspassedthroughacolumnofsilicagelwithacetate(v:v2:1)toaffordthedesiredproduct(1.198g,72%),mp125–127°C.氨基醇的Cbz保護例如(2)Inaba,Takashi;Yamada,YasukietalJ.Org.Chem.,2023,65(6),1623-1628Toamixtureoftoluene(3.85L),water(3.85L),and

(470g, mol)were2 3successivelyadded1a(770g, mol)andCbzCl(488g, mol)withvigorousstirringatatemperaturebelow25°C.Afterstirringatroomtemperaturefor3h,triethylamine(27.5g,270mmol)andNaCl(578g)weresuccessivelyadded,andthemixturewasstirredforafurther30min.Theorganiclayerwasseparatedandconcentratedtogivethedesiredproductasoil,whichwasusedforthenextreactionwithoutpurification.Theanalyticalsamplewaspreparedbycolumnchromatography;芐氧羰基的脫去芐氧羰基的脫除主要有以下幾種方法：1).催化氫解；2).酸解裂解；3).Na/NH3〔液〕復原。一般而言目前試驗室常用簡潔的方法就是催化氫解，但當分子中存在對催化氫解敏感或鈍化的基團時，我們就必需承受化學方法如酸解裂解或Na/NH〔液〕3復原等。2[2][3]和甲酸[4-6]氫化反響更快速。/Cbz[7]HBr/HOAcCbz帶又一點顏色，而且分解產(chǎn)生的溴化芐會產(chǎn)生一些副反響并難以除盡，而催化氫解多數(shù)能得到無色得產(chǎn)物。由于硫能使催化劑中毒，因此，含有胱氨酸、半胱氨酸等含硫G.Briefer,T.T.Nesftrick.,Chem.Rew.,1974,74,567Johnstone.,Synthesis.,1976,685;G.M.Anantharamaiah,K.M.Sivanandaiah.,J.Chem.Soc.,PerkinTrans.1,1977,490M.Makowski,B.Rzeszotarska,L.Smelkaetal.,LiebigsAnn.Chem.,1985,1457D.R.Coleman,G.P.Royer.,J.Org.Chem.,1980,45,2268B.Eiamin,G.M.Anantharamaiah,G.P.Royeretal.,J.Org.Chem.,1979,44,3442M,J.O.Anteunis,C.Becu,F.Becuetal.,Bull.Soc.Chim.Belg.,1987,96,775D.R.Coleman,G.P.Royer.,J.Org.Chem.,1980,45,2268D.R.Coleman,G.P.Royer.,J.Org.Chem.,1980,45,2268假設在BocO存在下用Pd/CBoc衍生物[1]2且這類反響往往要比不加BocO2BocO反響為酰胺后則去除了這一效果。另外有時2在氫解時參與適當?shù)乃岽龠M反響也是一樣的道理，避開了生成的胺降低反響的活性。1.M.Sakaitani,K.Hori,Y.Ohfune.,TetrahedronLett.,1988,29,2983另外當分子中有鹵原子(Cl,Br,I)存在時，一般直接用Pd/C會造成脫鹵的發(fā)生，一般這種狀況下，使用PdCl2

鹵的發(fā)生。N-甲基化的賴氨2化劑毒化，此外，氨還會阻擋BnO醚的復原，所以對Cbz可得到一些選擇性[2-3]。D.R.Coleman,G.P.Royer.,J.Org.Chem.,1980,45,2268N.L.Benoiton.,Int.J.Pept.PeteinRes.,1993,41,6115-10%的鈀-碳催化氫解例如C.Jaume;G.G.Santiagoetal.,Tetrahedron:Asymmetry,2023,11(22),4549-4458Asolutionof(R)-8(0.170g, mmol)inabsolutemethanol(3ml)washydrogenatedinthepresenceof15%Pd/C(0.026g)atroomtemperaturefor12h.Themixturewasfiltered(Celite)andwashedwithmethanol.Then,perchloricacid ml, mmol)wasaddedandthemixturewasstirredfor5min.toafford(R)-7·HClO,mp233–235°C;[a]23=?(c=,4 Dmethanol).5-10%的鈀-碳催化氫解例如B.Pierfrancesco;C.silviaetal.,Tetrahedron,1999,55(10),3025AsolutionofN-Cbzarylglycinol(17)mmol)inMeOH(10mL)wasstirredfor15mininthepresenceofanexcessofPd(OH)/Cunderadihydrogenatmosphere.2ThesolutionwasthenfilteredonaCelitepadandthesolventremovedinvaccuo.ofthecrudeaffordedthedesiredfree2-arylglycinols(S)-21insolid;[a]20=+(c=,CHClmp94-96°C(AcOEt)。D 3Pd/C-甲酸銨催化氫解例如Alargov,D.K;Naydenova,Z;Monatsh.Chem.,1997,128(6-7),725-732mgofcompound1(1mmol)wasdissolvedin20mlofmethanol.Then150mgofammoniumformate(3mmol)and75mgof10%Pd-Cwasaddedandthereactionmixturewasstirredatroomtemperature10minandthenheatedtorefluxfor45min.Themixturewasfilteredthroughceliteandthefiltratewasevaporatetodrynesstogive430mgofcompound2(98%).Thiscompoundwasusedwithoutfurtherpurificationinthesubsequentstep.Pd/C-甲酸催化氫解例如Fyles,T.M.;Zeng,B.;J.Org.Chem.,1998,63(23),8337-8345Compound1(0.6g, mmol)wasdissolvedin1:1formicacid/methanol(60mL)andaddedtoaround-bottomflask(100mL)containing1equivofpalladiumcatalyst(10%Pd/C,1.0g, wascontinuouslystirredunderrefluxtemperaturefor24h.Thecatalystwasremovedbyfiltrationandwashedwithanadditional10mLofmethanol.ThecombinedsolventswereremovedbyevaporationunderreducedpressuretogiveCompound2(0.34g,81%,awhitesolid,mp96-98°C).Thiscompoundwasusedwithoutfurtherpurificationinthesubsequentstep.Pd/CCbzBoc10%Pd-Cwasaddedetoasolutionofcompound1(596mg, mmol)and(Boc)O(7732mg, mmol)inetnylacetate(30ml).Thereationvesselwasevacuatedandback-filledwithnitrogen(threetimes),thenback-filledwithhydrogen(1atm).After2h,themixturewasfilteredandconcentrated.Purificationbysilicagelchromatography(30%ethylacetate/hexanes-50%ethylacetate/hexanes)gavecompound2(289mg,54%).PdCl2

催化氫解脫除帶鹵原子分子上的Cbz例如Toasolutionocompound1(900mg)inmethylenechloride ml)wasaddedePdCl2(30mg)andtriethylamine ml).Triethylsilanewasadded(2x ml)over2h.Thereactionmixturestirred1hand2mloftrifluoroaceticacidwasadded.After30minthereactionwasbasifiedwith2NNaOH,extractedwithmethylenechloride,driedoverMgSO4,filteredandconcentrated.Chromatographywasrunonabiotage40Scolumnwith3-5%MeOH/CHClwith%NH4OHtoprovidecompound2 22asaoil(501mg,74%).Pd黑催化氫解，用氨為溶劑,半胱氨酸的Cbz例如ArthurM.Felix,ManuelH.Jimenzeta1.,Org.Syn.,59,159Adry1-Lthree-necked,round-bottomedflaskisequippedwithadryicerefluxcondenser,agas-inlettube,andamagneticstirringbarasillustratedinthefigure.Thereactionvesselisimmersedinanacetone–dryicebath,andatotalof300mLofammoniaispassedthroughadryingtowercontainingpotassiumhydroxidepelletsandcollectedintheflask.Thebathisremovedtopermitthereactiontoproceedattheboilingpointofammonia(?3),andagentlestreamofdrynitrogenisbubbledintotheflask.Asolutionof0.708g mole)in10ml.ofN,N-dimethylacetamide1.02g ml., mole)oftriethylamineand1.25goffreshlypreparedpalladiumblackareadded.Thenitrogenstreamisdiscontinuedandreplacedbyastreamofhydrogenthathasbeenpassedthroughaconcentratedsulfuricacidscrubber.Themixtureisstirredunderrefluxfor hourstoeffecthydrogenolysis.Thehydrogenstreamisdiscontinued,aflowofnitrogenisresumed,andthedryiceisremovedfromtherefluxcondenser,permittingrapidevaporationofammonia.Theflaskisattachedtoarotaryevaporator,andthemixtureisevaporatedtodrynessunderreducedpressure.Theresidueisdissolvedinwaterandfilteredthroughasinteredfunnelofmediumporositytoremovethecatalyst.Thefiltrateisevaporatedtodryness,andtheresidue(354mg,95%)isfromwater–ethanol.Thewhitecrystallineproduct,afterdryingunderreducedpressureat25°,weighs272–305mg.(73–82%),.280–282°(dec.),[α]25D+°(c=1,aqueous5Nhydrochloricacid).酸解脫除氨基甲酸芐酯在強酸性條件下簡潔去保護。HBr/HOAcHBr/HOAc液〔1.2M-3.3M〕以保證反響的完全。D.Ben-Ishai,A.Berger.,J.Org.Chem.,1952,17,1564;R.A.Boissonnas,J.Blodinger,A.D.Welcher.,J.Am.Chem.Soc.,1952,74,5309R.A.Boissonnas,J.Blodinger,A.D.Welcher.,J.Am.Chem.Soc.,1952,7,5309;J.Meienhofer,E.Schnabel.,Z.Naturforsch,1965,20,661含有絲氨酸[1]和蘇氨酸[2]的肽或其它含羥基的氨基衍生物用HBr/HOAc脫除Cbz時O-乙?；错?。雖然O-乙?；苡脡A皂化或氨解脫去，但為了避開這個副反響，可以改用HBr/HBr/HBr/HOAc[3]。由于HBrHBr/三氟乙酸溶液，而只能將保護的肽或氨基衍生物溶于無水三氟乙酸中，先于0℃下通入枯燥的HBr，待Cbz大局部脫除后，再CbzHBr酸反響，也是需要加以留意的。如，甲硫氨酸的硫原子能同溴化芐反響生成S-芐基甲硫氨酸[4]，防止的方法是參與硫醚〔CHSCH〕為捕獲劑[5]。色氨酸被HBr/HOAc分解產(chǎn)3 25HBr-67℃處理可以避開。G.D.Fasman,E.R.Blout.,J.Am.Chem.Soc.,1960,82,2262S.Fujiwara,S.Moerinaga,K.Narita.,Bull.Chem.Soc.Japan.1962,438J.Meienhofer,E.Schnabel.,Z.Naturforsch,1965,20,661;生物化學與生物物理學196198N.F.Albertson,F.C.Mckay.,J.Am.Chem.Soc.,1953,73,5323S.Guttmann,R.A.Boissonnas,Helv.Chim.Acta.,1959,42,1257HF0℃10-30Cbz[1]。FSOH[2]、CHSOH[2,3]、3 3 3CFSOH[3,4]CHSCH-TFA[5]MeSiI3 3 65 3 3性脫去Cbz和Boc保護基[6]。對于BBr/CHCl而言，較大分子的肽的Cbz衍生物可在3 2 2TFA中去除，由于肽在酸中的溶解度比在CHCl2 2

中大[7]CbzTFA添加0.5M4-〔甲硫基〕苯酚[8]或使用HF/MeS/對甲苯酚[9]〔25:65:10,v/v〕來抑制2Bn+對芳香氨基酸的加成。S.Sakakibaraeta1.,Bull.Chem.Soc.Japan.,1967,40,2164;S.Matsuura,C.H.Niu,J.S.Cohen.,J.Chem.Soc.Chem.Commun.,1976,451Chem.Commun.,1977,909H.Yajimaeta1.,J.Chem.Soc.Chem.Commun.,1974,107H.Yajimaeta1.,Chem.Pharm.Bull.,1975,23,1164Y.Kiso,K.Ukawa,T.Akita.,J.Chem.Soc.Chem.Commun.,1980,101R.,V.S.Chauham,C.H.Stammer.,J.Chem.Soc.Chem.Commun.1,979,495J.Pless,W.Bauer.,AngewChem.,Int.Ed.Engl.,1973,12,147;A.M.Felix.,J.Org.Chem.,1974,39,1427M.Bodanszky,A.Bodanszky.,Int.J.Pept.ProteinRes.,1984,23,287R.B.Merrifield.,J.Am.Chem.Soc.,1983,105,6442此外，已經(jīng)報道過的還有以下的一些不常用的方法。如HCl/CHCl[1]、HCl/HOAc[2]、3HBr/SO[3]HBr[4]TosOH[5]HI/HOAc[6][7]EtSiH[8]TFA[9]8MHCl2 36MHCl1[10]25-75℃加熱處理小時[11]等。G.D.Fasman,M.Idelson,E.R.Blout.,J.Am.Chem.Soc.,1961,83,709R.B.Merrifield.,J.Am.Chem.Soc.,1963,85,2149M.Idelson,E.R.Blout.,J.Am.Chem.Soc.,1958,80,4631M.Brenner,H.C.Curtius.,Helv.Chim.Acta.,1963,46,2126E.Taschner,B.Liberek,Abstr.Int.Cong.Biochemistr,yVienna1958E.Waldschmidt-Leitz,K.Kuhn.,Chem.Ber.,1951,84,381E.Brand,B.F.Erlanger,H.Sachs.,J.Am.Chem.Soc.,1952,74,1849Birkoferetal.,Angew.Chem.,Int.Ed.,1965,4,417F.Weygand,W.Steglich.,Z.Naturforsch.,1959,14b,472.Barkdoll,W.F.Ross.J.Am.Chem.Soc.1944,6,567;G.Chelucci,Falorni,G.Giacomelli.,Synthesis.,1990,112111.J.White.,J.Biol.Chem.,1934,106,141HBr-AcOHCbzB.Anna;P.Gerald.,Heterocycles,2023,58,521AsolutionoftheamineCbzcompund(208mg, mmol)in33%hydrobromicacidinaceticacid(1mL)andglacialaceticacid mL)wasstirredatrtfor3hunderanatmosphereofnitrogen.Thevolatileswereremovedinvacuotoleavethefreeaminehydrobromide(168mg,91%)asabrown,highlyhygroscopicpowder;[α]D

=°(c=,EtOH);TMSICbz1MeSiI ml, mmol)wasaddedtoasolutonofcompound1(146mg, mmol)in3acetonitrile(10ml)atroomtemperature,andtheresultingmixturewasstirredatroomtemperaturefor2h.EtN ml)wasaddedandthemixturewasstirred3atroomtemperaturefor15min.Thesolventswereremovedinvacuo,andtheresiduewasextractedwithethylacetate.Thecombinedorganicswerewashedwithsodiumbicarbonateandbrine,driedoversodiumsulfateandfiltered.Solventswereremovedandtheresiduewasuseddirectlyinthenextstep.g mmol)ofcompound1in30mlofCHClwerecombinedwith ml mmol)MeSiI2 2 3andstirredfor16hatroomtemperature.Then20mlofMeOHwereaddede,themixturewasstirredforafurther30minatroomtemperatureandthereactionmixturewasevaporateddowncompletely.Theresiduewaspurifiedbychromatographyonsilicagel(eludinggradient:CHCl/(MeOH/conc.Ammonia95:5)2 2=70/30–60/40)toyieldcompound2(690mg,56%).叔丁氧羰基〔Boc〕BocBocBoc-氨基酸能較長期的保存而不分解；酸解時產(chǎn)生的是叔丁基陽離子再分解為異丁烯，它一般不會帶來副反響；對堿水解、肼解和很多親核試劑穩(wěn)定；BocCbzBocCbz叔丁氧羰基的導入NaOH或NaHCO3

把握的堿性條件下用二氧六環(huán)和水的混合溶劑中很簡潔同BocO反響得到N-叔丁氧羰基氨基化合物[1]Boc2BocBocO/TEA/MeOHorDMF40-50℃下進展較好，2由于這些無水條件下用于保護O17標記的氨基酸而不會由于與水交換使O17喪失[2]間位阻的氨基酸而言，用BocO/CHCN是格外有利的。2 3D.S.Tarbell,Y.Yamamotoetal.,Proc.Natl.Acad.Sci.,UA1972,730E.Ponnusamy,U.Fotadaretal.,Synthesis.,1986,48DMAPBoc.BocDMAPBoc，BocO生成脲[1]NaH2NaHMDSBocO[2]。2H.J.knolker,T.Braxmeieretal.,Angew.Chem.,Int.Ed.Engl.,1995,34,2497;H.J.knolker,T.Braxmeieretal.,Synlett.,1996,502;Kessier,A.;Coleman,C.M.,etalJ.Org.Chem.,2023,69(23),7836-7846T.A.Kelly,D.W.McNeil.,TetrahedronLett.,1994,35,9003Boc要除去，一般在體系中參與一些N,N-N,N-二甲基丙二胺，而后將上了BocN,N-N,N-二甲基丙二胺用稀酸除去。Boc10%檸檬酸〔0.5M〕或在低溫條件進展。BocOskarKeller,WalterE.Keller,GertvanLooketal.,Org.Syn.,63,160A4-L,four-necked,round-bottomedflask,equippedwithanefficientstirrer,adroppingfunnel,refluxcondenser,andthermometerischargedwithasolutiongmol)ofsodiumhydroxidein1.1Lofwater.Stirringisinitiatedand165.2g(1mol)ofL-phenylalanineisaddedatambienttemperature,andthendilutedwith750mLoftert-butylalcohol.Tothewell-stirred,clearsolutionisaddeddropwisewithin1hr,223g(1mol)ofder-butyldicarbonate.Awhiteprecipitateappearsduringadditionofthedi-tert-butyldicarbonate.Afterashortinductionperiod,thetemperaturerisestoabout335°C.Thereactionisbroughttocompletionbyfurtherstirringovernightatroomtemperature.AtthistheclearsolutionwillhavereachedapHof–.Thereactionmixtureisextractedtwotimeswith250mLofpentane,andtheorganicphaseisextractedthreetimeswith100mLofsaturatedaqueoussodiumbicarbonatesolution.ThecombinedaqueouslayersareacidifiedtopH1bycarefuladditionofasolutionof224gmol)ofpotassiumhydrogensulfatein1.5Lofwater.Theacidificationisaccompaniedbycopiousevolutionofcarbondioxide.Theturbidreactionmixtureisthenextractedwithfour400-mLportionsofethylether.Thecombinedorganiclayersarewashedtwotimeswith200mLofwater,driedoveranhydroussodiumsulfateormagnesiumsulfate,andfiltered.Thesolventisremovedunderreducedpressureusingarotaryevaporatoratabathtemperaturenotexceeding30°C.Theyellowishoilthatremainsevaporatoratabathtemperaturenotexceeding30°C.Theyellowishoilthatremainsistreatedwith150mLofhexaneandallowedtostandovernight.Within1daythefollowingportionsofhexaneareaddedwithstirringtothepartiallycrystallizedproduct:2×50mL,4×100mL,and1×200LThesolutionisplacedinarefrigeratorovernight;thewhiteprecipitateiscollectedonaBüchnerfunnelandwashedwithcoldpentane.Thesolidisdriedunderreducedpressureatambienttemperaturetoconstantweighttogiveafirstcrop.Themotherliquorisevaporatedtodrynessleavingayellowishoil,whichistreatedinthesamemannerasdescribedabove,givingasecondcrop.Thetotalyield86–88°C,[α]20+°(ethanolc.D氨基酸酯Boc保護例如AlessandroDondoni,DanielaPerrone.,Org.Syn.,77,64A500-mL,three-necked,round-bottomedflask,isequippedwithamagneticA500-mL,three-necked,round-bottomedflask,isequippedwithamagneticstirringstirringbar,thermometer,refluxcondenserprotectedfrommoisturebyacalciumcalciumchloride-filleddryingtube,andapressure-equalizingdroppingfunnelthatisconnectedtoanitrogenflowlineandischargedwithasolutionof97%di-tert-butyldicarbonate(14.3g, mmol)intetrahydrofuran(100mL),Methylserinatehydrochloride(10.0g, mmol)isplacedintheflaskandsuspendedsuspendedintetrahydrofuran(200mL)and99%triethylamine(14.0g,138mmol).TheTheresultingwhitesuspensioniscooledwithanice-waterbathandthesolutionofdi-tert-butyldicarbonateisaddeddropwiseoveraperiodof1hr.After1010minofadditionalstirring,theice-waterbathisremovedandthesuspensionisisstirredovernight(14hr)atroomtemperature,thenwarmedat50°Cforafurtherfurther3hr.Thesolventisremovedunderreducedpressureandtheresidueisispartitionedbetweendiethylether(200mL)andsaturatedaqueousbicarbonatesolutionsolution(250mL).Theaqueousphaseisextractedwiththree150-mLportionsofofdiethylether.Thecombinedorganicphasesaredriedwithanhydroussodiumsulfatesulfateandconcentratedunderreducedpressuretogive-14.0g(95-99%crudeyield)yield)ofN-Boc-L-serinemethylesterasacolorlessoilthatisusedwithoutfurtherfurtherpurification.[α]23°(MeOH,c.DBocBocBocO(262g, mol)inMeOH(250ml)wasaddedtoasolutonofcompound1(157.22g, mol)inMeOH(350ml)at10°C,andtheresultingmixturewasstirredatroomtemperaturefor2h.N1,N1-dimethylethane-1,2-diamine(26g, mol)wasaddedandthemixturewasstirredatroomtemperaturefor15min.Thesolventwasremovedinvacuo,andtheresiduewasdissolvedwithethylacetate(750ml).Thecombinedorganicswerewashedwith1NHCl(2x250ml)andbrine(2x250ml),driedoversodiumsulfateandfiltered.Thesolventwasremovedtogivecompound2(250g,96%),whichwasuseddirectlyinthenextstep.芳胺的單Boc保護例如Luo,Qun-Li;Liu,Zhi-Yingetal.,J.Med.Chem.,2023,46(13),2631-26403-Aminopyridine-2-carboxylicacid(5.02g,36mmol)wassuspendedin60mLofdryDMF,andEtN mL,108mmol)wasaddeddropwiseatroomtemperature.Tothe3resultingbrownsolutionwasaddedBocO(11.80g,54mmol).Afterbeingstirred2for10min,themixturewasheatedat40-50°Covernight.ThereactionmixtureandwasthenextractedwithEtOAc(2X50mL).TheaqueousphasewasacidifiedtopH4-5with2MaqueousHClandthenextractedwithCHCl2 2(3X50mL).Thecombinedorganicphaseswerethenprocessedintheusualwayandchromatographed(13:1CHCl/MeOH)toyieldthedesiredproduct(4.2g,49%).3芳胺的雙Boc保護例如Macleod,Macleod,Calim;Mckieman,GordonJetal.,J.Org.Chem.,2023,68(2),387-401AsolutionofNaHMDS mL, mmol,1MinTHF)wasaddedtoasolutionoftheamine(2.11g, mmol)and(Boc)2O(5.46g, mmol)inTHF(50mL)at0°Cundernitrogen.Thereactionwasallowedtowarmtortandstirredfor16h.Afterthistime,thereactionwaspouredintowater,extractedintoCHCl(2X252 2mL),washedwithwater(2X25mL),driedoverNa2SO4,andconcentratedtoyieldawhite-yellowsolid.Recrystalizationfrompetroleumether(40°C)theimideasneedles(3.21g, mmol,78%).Rf(hexane/CHCl1:9,SiO):.Mp:2 2 2106-109°C.BocLarsG.J.Hammarstr?m,YanwenFuetal.,Org.Syn.,81,213A2023-mL,three-necked,round-bottomedflaskequippedwithanargoninletadapter,glassstopper,andanoverheadmechanicalstirrerischargedwithasuspensionofthehydantoin1(26.0g,154mmol)in1000mLof1,2-dimethoxyethane.Triethylamine(15.7g,154mmol)isaddedinoneportion,andtheresultingwhitesuspensionisstirredfor30min.Di-tert-butyldicarbonate(168.0g,770mmol)isthenaddedbypipette,followedby4-dimethylaminopyridine(DMAP)(0.2g, mmol).Sixadditional0.2g-portionsofDMAPareaddedat12hrintervalsduringthecourseofthereaction.Thereactionmixtureisstirredvigorouslyforatotalof72hr,andtheresultinglightyellowsolidisthencollectedinaBüchnerfunnelusingsuctionfiltration.Thefiltrateisconcentratedtoavolumeof60mLbyrotaryevaporation,andtheresultingsolutioniscooledto15°C.Theprecipitatewhichappearsiscollectedusingsuctionfiltration,addedtothefirstcrop,andthecombinedsolidsaredissolvedin500mLofchloroform.Thissolutioniswashedwiththree200-mLportionsof HCl,andthecombinedaqueousphasesareextractedwith100mLofchloroform.Thecombinedorganiclayersarewashedwith100mLofsaturatedaqNaHCO3

solutionand100mLofbrine,driedoveranhydrousMgSO,filtered,andconcentratedbyrotaryevaporation.The4resultingsolidisdriedatroomtemperatureat0.01mmfor24hr.Theresultingfinelygroundlightyellowsolidissuspendedin400mLofdiethyletherina1000-mL,round-bottomedflaskequippedwithamagneticstirbar,stirredfor2hr,andfilteredonaBüchnerfunnelwashingwithfour50-mLportionsofdiethylether.Theproductisdriedundervacuum(85°C;0.5mm)for24hrtogive–65.3g(83-90%)of2asaivory-coloredsolid.疊氮復原Boc保護例如SeikiSeikiSaito,KanjiKomada,andToshioMoriwake.,Org.Syn.,73,184A500-mL,single-necked,round-bottomedflask,equippedwithaTeflon-coatedstirringbar,ischargedwithasuspensionof0.91gof10%palladiumoncarboncatalystin100mLofethylacetate.Theflaskisconnectedtoanormalpressurehydrogenationapparatusandthecatalystissaturatedwithhydrogen.Afterremovalofthehydrogen,asolutionof18.2g mol)of1and20.6g mol)di-tert-butyldicarbonatein80mLofethylacetateisaddedtothesuspensionofcatalyst,ahydrogenatmospherereestablished,andthesuspensionisstirredatroomtemperatureunderaslightpositivepressureofhydrogenfo6hr,ThesuspensionisfilteredthroughaCelitepad,andthepadisrinsedwithseveralportionsofethylacetate.Thecombinedethylacetatesolutionsareconcentratedonarotaryevaporatorandfinallyunderhighvacuumtogiveapaleyellowoilthatisinitiallypurifiedbymeansofacolumnpackedwithsilicagel(100g)usinghexane-ethylacetate(6:1)aseluent.Fractionscontainingtheproductarecombinedandconcentratedonarotaryevaporatortogive23.3gofcrude2asacolorlessoil.Theoilycrude2isdissolvedin70mLofhexane-ether(3:1),andthesolutioniscooledto?30°C,seeded,andkeptovernightatthattemperature(freezer)toallowcrystallization.Themotherliquorissiphonedoutwhilethemixtureiskeptat?30°C(dryice-acetonebath).Thecrystalsarewashedwithseveralportionsofhexane-ether(3:1)at?30°C,thendriedunderhighvacuumtoprovide12.7g of diastereomerically and enantiomerically pure diethyl(2S,3R)-2-(N-tert-butoxycarbonyl)amino-3-hydroxysuccinate(2)ascolorlessprisms,mp3–34°C;.Thecombinedmotherliquorandthehexaeether(3:1)onarotaryevaporatortogiveacolorlessoil,whichuponcrystallizationasaboveprovidesanadditional–3.8gofproduct2.Thecombinedyieldofcrystalline2is–16.5g(66–73%).BocWhaWhaChen,E.KyleStephensonetal.,Org.Syn.,70,151Thesolutionof2-bromo-1H-pyrrole(9.8g, mmol)in40mLofTHFiscooledto?78°Cinadryice-acetonebath.Theflaskisequippedwithamagneticandathree-waystopcockattachedtoaballoonfilledwithnitrogen.Tothestirreddark-greensolutionisadded2.71g mmol)oftriethylaminefollowedfollowedimmediatelybyadditionof20.4g mmol)ofdi-tert-butyldicarbonateandacatalyticamount(ca.0.1g)of4-dimethylaminopyridine.Theflaskisevacuatedandpurgedwithnitrogen.Themixtureisstirredfor8hrwhileitisallowedtowarmtoroomtemperature.Thesolventisremovedunderreducedpressureatroomtemperatureand100mLofhexaneisaddedtothecrudeproduct,whichiswashedwithdeionizedwater(3×100mL),driedoversodiumsulfate,andconcentratedunderreducedpressureatroomtemperature.Thecrudeproductispurifiedbychromatographyonamine-treatedneutralsilica(270g)usinghexaneastheeluent.ThefractionscontainingtheproductareidentifiedbyTLC,combined,andconcentratedunderreducedpressureatroomtemperaturetoyieldN-tert-Butoxycarbonyl-2-bromopyrroleasacolorlessoil–14.7g,82–89%).BocG.G.Tong;P.Ruiyanetal.,J.Org.Chem.,1997,26,9298Toasolutionof6-methoxy-3-methylindole(5.0g,31mmol)indistilled(7.44g,mmol)andDMAP(0.195g,mmol).Thereactionmixturewasstirredatrtfor12h.Thesolventwasremovedunderreducedpressure.TheresiduewasdissolvedinCHCl2 2(100mL)andwashedwithanaqueoussolutionof1NHCl(2x50mL).TheaqueouslayerwasextractedwithCHCl(3x30mL).Thecombinedorganicayerswere2 2dried(KCO).Afterremovalofsolventunderreducedpressure,theresiduewas2 3solidifiedtoaffordtheproduct(8.12g,99%)asayellowsolid:mp45-46°C.2.2.2叔丁氧羰基的脫去2TFA50%TF〔TFA:CHCl1:1,v/v。而在固相肽合成中，由于TFA2 2會帶來一些副反響〔如在得到的胺上上一個三氟乙?；?-2MHCl/HCl/二氧六環(huán)，比較多見。BocS-Boc[2]。但當同時脫除分子中Boc有游離羧酸基，千萬記住不能用HCl/MeOH,其可將羧酸變?yōu)榧柞?。同時AcCl/MeOH，則HCl胺的鹽酸鹽[3]。MeSiICHCl或CHCNBoc3 3 3甲酸酯、酯、醚和縮酮。通過把握條件可以得到確定的選擇性[4]。當分子中存在一些官能團其可與副產(chǎn)物叔丁基碳正離子在酸性下反響時，需要添Boc甲硫醚[6]BocTBDPS[7]TBDMS[8]CFCOOH〔TBS310－20％TFA。伯胺衍生物存在下，ZnBr/CHCl仲胺上的Boc[9]。

2 2 2F.Cavelier,C.Enjabal.,TetrahedronLett.,1996,37,5131,Y.Bechoretal.,Synth.Commun.,1998,28,471R.S.Lott,V.S.Chauhanetal.,J.Chem.Soc.Chem.Commun.1979,495;G.A.Olah,S.C.Narang.,Tetrahedron.,1982,38,2225H.Hiemstraetal.,J.Org.Chem.,1992,57,6083M.Bodanszky,A.Bodanszky.,Int.J.Pept.ProteinRs1984,2,565;Masui,N.Chinoetal.,Bull.Chem.Soc.Jpn.,1980,53,464P.A.Jacobi,S.Murphreeetal.,J.Org.Chem.,1996,61,2413J.Deng,Y.Hamadaetal.,J.Am.Chem.Soc.,1995,117,7824S.C.Nigam,A.Mannetal.,Synth.Commun.,1989,19,31392.2.2.TMSOTfBocGilbertson,ScottR;Chang,Cheng-Weietal.,J.Org.Chem.,1998,63(23),8424-8431ToToasolutioncontaining2(1.0g, mmol)in30mLofdryCHClwasslowlyadded2 2TBDMSOTf mL, mmol).Afterstirringthere