cbz

经典化学合成反应标准操作

氨基的保护及脱保护策略

编者：彭宪

药明康德新药开发有限公司化学合成部

目录

1．氨基的保护及脱保护概要……………………………………………2

2．烷氧羰基类

2-1.苄氧羰基（Cbz）………………………………………………4

2-2.叔丁氧羰基（Boc）………………………………………………

16

2-3.笏甲氧羰基（Fmoc）…………………………………………28

2-4.烯丙氧羰基（Alloc）…………………………………………

34

2-5.三甲基硅乙氧羰基（Teoc）……………………………………

36

2-6.甲（或乙）氧羰基……………………………………………

40

3．酰基类

3-1.邻苯二甲酰基（Pht）……………………………………………

43

3-2.对甲苯磺酰基（Tos）…………………………………………

49

3-3.三氟乙酰基（Tfa）…………………………………………

53

4．烷基类

4-1.三苯甲基（Trt）………………………………………………

57

4-2.2,4-二甲氧基苄基（Dmb）……………………………………

63

4-3.对甲氧基苄基（PMB）………………………………………65

4-4.苄基（Bn）……………………………………………………70

1．氨基的保护及脱保护概要

选择一个氨基保护基时，必须仔细考虑到所有的反应物，反应条件及所设计的反

应过程中会涉及的所有官能团。首先，要对所有的反应官能团作出评估，确定哪些在

所设定的反应条件下是不稳定并需要加以保护的，并在充分考虑保护基的性质的基础

上，选择能和反应条件相匹配的氨基保护基。其次，当几个保护基需要同时被除去时，

用相同的保护基来保护不同的官能团是非常有效（如苄基可保护羟基为醚，保护羧酸

为酯，保护氨基为氨基甲酸酯）。要选择性去除保护基时，就只能采用不同种类的保护

基（如一个Cbz保护的氨基可氢解除去，但对另一个Boc保护的氨基则是稳定的）。此

外，还要从电子和立体的因素去考虑对保护的生成和去除速率的影响（如羧酸叔醇酯

远比伯醇酯难以生成或除去）。最后，如果难以找到合适的保护基，要么适当调整反应

路线使官能团不再需要保护或使原来在反应中会起反应的保护基成为稳定的；要么重

新设计路线，看是否有可能应用前体官能团（如硝基，亚胺等）；或者设计出新的不需

要保护基的合成路线。

在合成反应中，伯胺、仲氨、咪唑、吡咯、吲哚和其他芳香氮杂环中的氨基往往

是需要进行保护的。已经使用过的氨基保护基很多，但归纳起来，可以分为烷氧羰基、

酰基和烷基三大类。烷氧羰基使用最多，因为N-烷氧羰基保护的氨基酸在接肽时不易

发生消旋化。伯胺、仲氨、咪唑、吡咯、吲哚和其他芳香氮氢都可以选择合适的保护

基进行保护。下表列举了几种代表性的常用的氨基保护基。

几种代表性的常用的氨基保护基

结构缩写应用引入条件脱去条件

Cbz

伯胺、仲氨、咪

唑、吡咯、吲哚

等

Cbz-Cl/Na

2

CO

3

/CH

Cl

3

/H

2

O

H

2

/Pd-C，供氢体

/Pd-C，BBr

3

/CH

2

Cl

2

orTFA，HBr/HOAc

等

Boc

伯胺、仲氨、咪

唑、吡咯、吲哚

等

Boc

2

O/NaOH/diox

/H

2

O,Boc

2

O/

/MeOH,

Boc

2

O/Me

4

NOH/CH

3

CN

3MHCl/EtOAc,

HCl/MeOHordiox,

TosOH/THF-CH

2

Cl

2

,

Me

3

SiI/CHCl

3

orCH

3

CN

Fmoc伯胺、仲氨等

Fmoc-Cl/NaHCO

3

,

/diox/H

2

O

20%哌啶/DMF，50%

哌啶/CH

2

Cl

2

等

Allo

c

伯胺、仲氨、咪

唑、吡咯、吲哚

等

Aloc-Cl/Py

Ni(CO)

4

/DMF/H

2

O;

Pd(PPh

3

)

4

/Bu

3

SnH;

Teoc

伯胺、仲氨、咪

唑、吡咯、吲哚

等

Teoc-Cl/碱

/diox/H

2

O

TBAF；TEAF

-

伯胺、仲氨、咪

唑、吡咯、吲哚

等

ROCOCl/NaHCO

3

,/

diox/H

2

O

HBr/HOAc;

Me

3

SiI;

KOH/H

2

O/乙二醇

Pht伯胺

邻苯二甲酸酐

/CHCl

3

/70℃;邻

苯二甲酰亚胺

-NCO

2

Et/aq.

Na

2

CO

3

H

2

NNH

2

/EtOH，

NaBH

4

/i-PrOH-H

2

O

（6：1）

Tos

伯胺、仲氨、咪

唑、吡咯、吲哚

等

Tos-Cl/Et

3

N

HBr/HOAc,

48%HBr/苯酚（cat）

Tfa

伯胺、仲氨、咪

唑、吡咯、吲哚

等

TFAA/Py;苯二甲

酰亚胺

-NCO

2

CF

3

/CH

2

Cl

2

K

2

CO

3

/MeOH/H

2

O;

NH

3

/MeOH;

HCl/MeOH

Trt

伯胺、仲氨、咪

唑、吡咯、吲哚

等

Trt-Cl/Et

3

N

HCl/MeOH,

H

2

/Pd/EtOH,

TFA/CH

2

Cl

2

Dmb

伯胺、仲氨、咪

唑、吡咯、吲哚

等

ArCHO/NaCNBH

3

/M

eOH

PMB

伯胺、仲氨、咪

唑、吡咯、吲哚

等

PMB-Br/

K

2

CO

3

/CH

3

CN;PhCH

O/NaCNBH

3

/MeOH

HCO

2

H/Pd-C/MeOH;

H

2

/Pd(OH)

2

/EtOH;

TFA;CAN/CH

3

CN

Bn

伯胺、仲氨、咪

唑、吡咯、吲哚

等

Bn-Br/Et

3

Nor

K

2

CO

3

/CH

3

CN;PhCH

O/NaCNBH

3

/MeOH

HCO

2

H/Pd-C/MeOH;

H

2

/Pd(OH)

2

/EtOH;

CCl

3

CH

2

OCOCl/CH

3

C

N

2．烷氧羰基类保护基

烷氧羰基类保护基可用于氨基酸，以在肽合成中减少外消旋化的程度。外消旋化

发生在碱催化的N-保护的羧基活化的氨基酸的偶联反应中，也发生在易由N-酰基保护

的氨基酸形成的中间体恶唑酮中。

要使外消旋化程度减到最小，需使用非极性溶剂、最弱的碱、低的反应温度，并

使用烷氧羰基类保护的氨基酸是有效的。其中常用的有易通过酸性水解去保护的Boc

基、由催化氢解去保护的Cbz基、用碱经β-消除去保护的Fmoc基和易由钯催化异构

化去保护的Alloc基。

苄氧羰基（Cbz）

苄氧羰基（Cbz）是1932年Bergmann发现的一个很老的氨基保护基，但一直到今

天还在应用。其优点在于：试剂的制备和保护基的导入都比较容易；N-苄氧羰基氨基

酸和肽易于结晶而且比较稳定；苄氧羰基氨基酸在活化时不易消旋；能用多种温和的

方法选择性地脱去。

2.1.1苄氧羰基的导入

苄氧羰基的导入，一般都是用Cbz-Cl。游离氨基在用NaOH或NaHCO

3

控制的碱性

条件下可以很容易同Cbz-Cl反应得到N-苄氧羰基氨基化合物。α,β-二胺可用该试剂

在pH=稍有选择性地被保护，其选择性随碳链地增长而减弱，如H

2

N(CH

2

)nNH

2

,n=2时

71%被单保护;n=7时29%被单保护[1]。氨基酸酯同Cbz-Cl的反应则是在有机溶剂中进

行，并用碳酸氢盐或三乙胺来中和反应所产生的HCl。此外，Cbz-ONB（4-O

2

NC

6

H

4

OCOOBn）

等苄氧羰基活化酯也可用来作为苄氧羰基的导入试剂，该试剂使伯胺比仲胺易被保护，

但苯胺由于亲核性不足，与该试剂不反应[2]。

1．,.,Synthesis,1984,1032

2．,l,.(London),1991,888

Cbz-Cl很容易用苯甲醇同光气的反应来制备（见下式），在低温下可以保存半年以

上而不发生显着的分解。

除Cbz-Leu为油状物外，绝大多数氨基酸的苄氧羰基衍生物都可以得到结晶。有的

N-苄氧羰基氨基酸能同它的钠盐按一定比例形成共晶，共晶产物的熔点较高，并难溶

于有机溶剂。例如，苯丙氨酸经苄氧羰基化后再加酸析出Cbz-Phe时往往得到共晶产

物（熔点144℃），此共晶产物用乙酸乙酯和1MHCl一道震摇时可完全转化为Cbz-Phe

而溶于乙酸乙酯中。因此。除Cbz-Gly以外，一般都是采用酸化后用有机溶剂提取的

方法来得到纯的N-苄氧羰基氨基酸。

2.1.1.1游离氨基酸的Cbz保护示例

Konda-Yamada,Yaeko;Okada,Chiharuetal.,Tetrahedrom;2002,58(39),

7851-7865

Cbz-Clμl,mmol)indiethyletherml)wasdroppedtoasolutionof(R)-1

mg,mmol)in10%aqueousNa

2

CO

3

ml)at0°C,ction

mixturewasacidifiedwith10%citricacid,extractedwithCHCl

3

(10mlX3).The

organiclayerwaswashedwithwater,driedoverNa

2

SO

4

,evaporatedtogivelight

yellowgels,whichwerepurifiedbypreparativeTLC(CHCl

3

/MeOH=5:1)toafford

(R)-6mg,%)asyellowamorphoussolid.R

f

=(n-BuOH/AcOH/H

2

O=4:1:5);[a]

D

23

=(c=,CHCl

3

);

2.1.1.2氨基酸酯的Cbz保护示例

co,,ta1.,.,70,29

A3-L,three-necked,Mortonflaskequippedwithanefficientmechanicalstirrer,

thermometer,andadroppingfunnelischargedwithL-methioninemethylester

hydrochloride1(117.6g,mol),potassiumbicarbonate(282.3g,mol,5eq.),

water(750mL),andether(750mL),andthesolutioniscooledto0°

chloroformate(105g,mL,mol,eq.)isaddeddropwiseover1hr,thecooling

bathisremoved,e(8.5g,mol,

eq.)isadded(toscavengeexcesschloroformate)andthesolutionisstirred

aniclayerisseparated,andtheaqueouslayer

isextractedwithether(2×200mL).Thecombinedorganiclayersarewashed

with0.01Mhydrochloricacid(2×500mL),water(2×500mL),andsaturated

brine(500mL),andthendried(Na

2

SO

4

),filtered,andevaporatedonarotary

ultingoilisfurtherdriedinaKugelrohroven(50°C,0.1

mm,12hr)toleaveproduct2asaclearoilthatsolidifiesuponcooling:

165–166g(98–99%),mp42–43°C.

2.1.1.3氨基醇的Cbz保护示例(1)

Clariana,Jaume;Santiago,trahedron:Asymmetry,2000,11(22),

4549-4558

Benzylchloroformateml,mmol)wasaddedviasyringeintoastirredmixture

ofaminoalcohol7(0.989g,mmol)andsodiumcarbonate(0.683g,mmol)in

thesolventsystemwater(10ml)–THF(3ml)maintainedat0°ture

wasstirredatroomtemperaturefor18h(TLCmonitoring)andthenpartitioned

anicphasewasdriedandevaporated

toaffordawhitesolidwhichwaspassedthroughacolumnofsilicagelwith

hexanes–ethylacetate(v:v2:1)toaffordthedesiredproduct(1.198g,72%),

mp125–127°C.

2.1.1.4氨基醇的Cbz保护示例(2)

Inaba,Takashi;Yamada,.,2000,65(6),1623-1628

Toamixtureoftoluene(3.85L),water(3.85L),andK

2

CO

3

(470g,mol)were

successivelyadded1a(770g,mol)andCbzCl(488g,mol)withvigorous

stirringatatemperaturebelow25°tirringatroomtemperaturefor

3h,triethylamine(27.5g,270mmol)andNaCl(578g)weresuccessivelyadded,

aniclayerwasseparated

andconcentratedtogivethedesiredproductasoil,whichwasusedforthe

lyticalsamplewaspreparedby

columnchromatography;

2.1.2苄氧羰基的脱去

苄氧羰基的脱除主要有以下几种方法：1).催化氢解；2).酸解裂解；3).Na/NH

3

（液）还原。一般而言目前实验室常用简洁的方法就是催化氢解，但当分子中存在

对催化氢解敏感或钝化的基团时，我们就必须采用化学方法如酸解裂解或Na/NH

3

（液）

还原等。

催化氢解如下式所示。催化氢解的供氢体可以是H

2

、环己二烯[1,2]、1，4-环己二烯

[2]、甲酸铵[3]和甲酸[4-6]等，以后四个为供氢体的反应又叫催化转氢反应，通常这比催化

氢化反应更迅速。

催化剂主要用5-10%的钯-碳、10-20%的氢氧化钯-碳或钯-聚乙烯亚胺，钯-聚乙烯

亚胺/甲酸对于除去Cbz要比前两者要好[7]。当HBr/HOAc脱去Cbz保护基时，产物往往

带又一点颜色，而且分解产生的溴化苄会产生一些副反应并难以除尽，而催化氢解多

数能得到无色得产物。由于硫能使催化剂中毒，因此，含有胱氨酸、半胱氨酸等含硫

的肽等N-苄氧羰基氨基衍生物一般不用催化氢解法脱除。一般溶剂可以用甲醇，乙醇，

乙酸乙酯，四氢呋喃等，在醇类质子溶剂中反应速度要快的多。

r,ick.,.,1974,74,567

n,one.,Synthesis.,1976,685;aramaiah,

ndaiah.,.,PerkinTrans.1,1977,490

ki,tarska,etal.,.,1985,

1457

n,.,.,1980,45,2268

,aramaiah,tal.,.,1979,

44,3442

6.M,is,,al.,.,1987,

96,775

n,.,.,1980,45,n,

.,.,1980,45,2268

如果在Boc

2

O存在下用Pd/C进行氢化，则释放出的胺直接转变成Boc衍生物[1]。而

且这类反应往往要比不加Boc

2

O来的快，其主要由于氢解出来的胺往往会与贵金属有一

定的络合，使催化剂的活性降低，和Boc

2

O反应为酰胺后则去除了这一效果。另外有时

在氢解时加入适当的酸促进反应也是一样的道理，避免了生成的胺降低反应的活性。

ani,,.,TetrahedronLett.,1988,29,2983

另外当分子中有卤原子(Cl,Br,I)存在时，一般直接用Pd/C会造成脱卤的发生，

一般这种情况下，使用PdCl

2

为催化剂，以乙酸乙酯或二氯甲烷为溶剂可较好的避免脱

卤的发生。

用MeOH/DMF为溶剂时，在Cbz-赖氨酸衍生物氢化的过程中会生成N-甲基化的赖氨

酸[1]。使用氨为溶剂时，H

2

/Pd-C在-33℃下氢化，肽中的半胱氨酸或蛋氨酸单元不使催

化剂毒化，此外，氨还会阻止BnO醚的还原，所以对Cbz可得到一些选择性[2-3]。

n,.,.,1980,45,2268

yrat,,man.,TetrahedronLett.,1992,33,4301

on.,Res.,1993,41,611

2.1.2.15-10%的钯-碳催化氢解示例

;goetal.,Tetrahedron:Asymmetry,2000,11(22),4549-4458

Asolutionof(R)-8(0.170g,mmol)inabsolutemethanol(3ml)was

hydrogenatedinthepresenceof15%Pd/C(0.026g)atroomtemperaturefor

turewasfiltered(Celite),

perchloricacidml,mmol)wasaddedandthemixturewasstirredfor5min.

Thesolventwasevaporatedtoafford(R)-7·HClO

4

,mp233–235°C;[a]

D

23=?(c=,

methanol).

2.1.2.25-10%的钯-碳催化氢解示例

ancesco;etal.,Tetrahedron,1999,55(10),3025

AsolutionofN-Cbzarylglycinol(17)mmol)inMeOH(10mL)wasstirredfor

15mininthepresenceofanexcessofPd(OH)

2

/Cunderadihydrogenatmosphere.

ThesolutionwasthenfilteredonaCelitepadandthesolventremovedinvaccuo.

Purificationofthecrudeaffordedthedesiredfree2-arylglycinols(S)-21in

87%yield,whitesolid;[a]

D

20=+(c=,CHCl

3

);mp94-96°C(AcOEt)。

2.1.2.3Pd/C-甲酸铵催化氢解示例

Alargov,D.K;Naydenova,Z;.,1997,128(6-7),725-732

mgofcompound1(1mmol)150mgof

ammoniumformate(3mmol)and75mgof10%Pd-Cwasaddedandthereactionmixture

wasstirredatroomtemperature10minandthenheatedtorefluxfor45min.

Themixturewasfilteredthroughceliteandthefiltratewasevaporateto

drynesstogive430mgofcompound2(98%).Thiscompoundwasusedwithout

furtherpurificationinthesubsequentstep.

2.1.2.4Pd/C-甲酸催化氢解示例

Fyles,T.M.;Zeng,B.;.,1998,63(23),8337-8345

Compound1(0.6g,mmol)wasdissolvedin1:1formicacid/methanol(60mL)

andaddedtoaround-bottomflask(100mL)containing1equivofpalladium

catalyst(10%Pd/C,1.0g,mmol).Themixturewascontinuouslystirredunder

alystwasremovedbyfiltrationandwashed

binedsolventswereremovedby

evaporationunderreducedpressuretogiveCompound2(0.34g,81%,awhite

solid,mp96-98°C).Thiscompoundwasusedwithoutfurtherpurificationin

thesubsequentstep.

2.1.2.5Pd/C催化氢解脱Cbz上Boc示例

10%Pd-Cwasaddedetoasolutionofcompound1(596mg,mmol)and(Boc)

2

O(773

mg,mmol)inetnylacetate(30ml).Thereationvesselwasevacuatedand

back-filledwithnitrogen(threetimes),thenback-filledwithhydrogen(1atm).

After2h,cationbysilica

gelchromatography(30%ethylacetate/hexanes-50%ethylacetate/hexanes)

gavecompound2(289mg,54%).

2.1.2.6PdCl

2

催化氢解脱除带卤原子分子上的Cbz示例

Toasolutionocompound1(900mg)inmethylenechlorideml)wasaddedePdCl

2

(30mg)andtriethylamineml).Triethylsilanewasadded(2xml)over2h.

Thereactionmixturestirred1hand2mloftrifluoroaceticacidwasadded.

After30minthereactionwasbasifiedwith2NNaOH,extractedwithmethylene

chloride,driedoverMgSO4,tographywasrun

onabiotage40Scolumnwith3-5%MeOH/CH

2

Cl

2

with%NH4OHtoprovidecompound

2asaoil(501mg,74%).

2.1.2.7Pd黑催化氢解，用氨为溶剂,半胱氨酸的Cbz脱除示例

,eta1.,.,59,159

Adry1-Lthree-necked,round-bottomedflaskisequippedwithadryicereflux

condenser,agas-inlettube,andamagneticstirringbarasillustratedinthe

ctionvesselisimmersedinanacetone–dryicebath,andatotal

of300mLofammoniaispassedthroughadryingtowercontainingpotassium

hisremovedtopermit

thereactiontoproceedattheboilingpointofammonia(?33℃),andagentle

ionof0.708gmole)

,N-dimethylacetamide1.02

gml.,mole)oftriethylamineand1.25goffreshlypreparedpalladiumblack

rogenstreamisdiscontinuedandreplacedbyastreamof

hydrogenthathasbeenpassedthroughaconcentratedsulfuricacidscrubber.

hydrogenstreamisdiscontinued,aflowofnitrogenisresumed,andthedry

iceisremovedfromtherefluxcondenser,permittingrapidevaporationof

skisattachedtoarotaryevaporator,andthemixtureis

idueisdissolvedinwater

andfilteredthroughasinteredfunnelofmediumporositytoremovethecatalyst.

Thefiltrateisevaporatedtodryness,andtheresidue(354mg,95%)is

crystallizedfromwater–tecrystallineproduct,afterdrying

underreducedpressureat25°,weighs272–305mg.(73–82%),.280–282°

(dec.),[α]25D+°(c=1,aqueous5Nhydrochloricacid).

酸解脱除氨基甲酸苄酯在强酸性条件下容易去保护。HBr/HOAc是酸解脱除苄氧

羰基的最常用的试剂[1]。脱除反应主要按下式进行[2]。反应需要消耗2分子的HBr，Cbz

的脱除速度随HBr浓度的增大而增大，因此实际上都是采用高浓度的过量HBr/HOAc溶

液（1.2M-3.3M）以保证反应的完全。

-Ishai,.,.,1952,17,1564;nnas,

ger,r.,.,1952,74,5309

nnas,ger,r.,.,1952,

74,5309;ofer,el.,orsch.,1965,20b,661

含有丝氨酸[1]和苏氨酸[2]的肽或其它含羟基的氨基衍生物用HBr/HOAc脱除Cbz时

会发生羟基的O-乙酰化反应。虽然O-乙酰基能用碱皂化或氨解脱去，但为了避免这个

副反应，可以改用HBr/二氧六环或HBr/三氟乙酸来代替HBr/HOAc[3]。由于HBr在三氟

乙酸中的溶解度较小，因此不能预先制成HBr/三氟乙酸溶液，而只能将保护的肽或氨

基衍生物溶于无水三氟乙酸中，先于0℃下通入干燥的HBr，待Cbz大部分脱除后，再

室温通短时间以求完全脱除变化基。Cbz被HBr分解产生的溴化苄能同肽中的某种氨基

酸反应，也是需要加以注意的。如，甲硫氨酸的硫原子能同溴化苄反应生成S-苄基甲

硫氨酸[4]，防止的办法是加入硫醚（CH

3

SC

2

H

5

）为捕捉剂[5]。色氨酸被HBr/HOAc分解产

生有色物质，防止的办法是加入亚磷酸二乙酯。硝基精氨酸会发生硝基的部分脱落，

改用液体HBr于-67℃处理可以避免。

,.,.,1960,82,2262

ra,aga,.,.,1962,35,

438

ofer,el.,orsch.,1965,20b,661;黄惟德等，

生物化学与生物物理学报,1961,98

son,.,.,1953,73,5323

nn,nnas,.,1959,42,1257

用液体HF在0℃处理10-30分钟即可将Cbz完全脱去[1]。FSO

3

H[2]、CH

3

SO

3

H[2,3]、

CF

3

SO

3

H[3,4]和C

6

H

5

SCH

3

-TFA[5]也是较好的试剂。Me

3

SiI在氯仿、乙腈中能于几分钟内选择

性脱去Cbz和Boc保护基[6]。对于BBr

3

/CH

2

Cl

2

而言，较大分子的肽的Cbz衍生物可在

TFA中去除，因为肽在酸中的溶解度比在CH

2

Cl

2

中大[7]。从肽中脱去Cbz，可在TFA中

添加0.5M4-（甲硫基）苯酚[8]或使用HF/Me

2

S/对甲苯酚[9]（25:65:10,v/v）来抑制

Bn+对芳香氨基酸的加成。

baraeta1.,.,1967,40,2164;ra,

,.,.,1976,451

,,i.,.,1977,909

eta1.,.,1974,107

eta1.,.,1975,23,1164

,,.,.,1980,101

6.R.,m,r.,.,1979,495

,.,AngewChem.,.,1973,12,147;.,

.,1974,39,1427

zky,zky.,nRes.,1984,23,287

,,ield.,.,1983,105,

6442

此外，已经报道过的还有以下的一些不常用的方法。如HCl/CHCl

3

[1]、HCl/HOAc[2]、

HBr/SO

2

[3]、液体HBr[4]、TosOH[5]、HI/HOAc[6]、碘化磷[7]、Et

3

SiH[8]、沸腾的TFA[9]、8MHCl

的乙醇液或6MHCl回流1小时[10]或浓盐酸于25-75℃加热处理小时[11]等。

,n,.,.,1961,83,709

ield.,.,1963,85,2149

n,.,.,1958,80,4631

r,s.,.,1963,46,2126

er,k,mistry,Vienna1958

hmidt-Leitz,.,.,1951,84,381

,er,.,.,1952,74,1849

eretal.,.,.,1965,4,417

d,ch.,orsch.,1959,14b,472

10..Barkdoll,.,.,1944,66,567;ci,M.

Falorni,elli.,Synthesis.,1990,1121

.,.,1934,106,141

2.1.2.8HBr-AcOH脱除Cbz示例

;.,Heterocycles,2002,58,521

AsolutionoftheamineCbzcompund(208mg,mmol)in33%hydrobromicacid

inaceticacid(1mL)andglacialaceticacidmL)wasstirredatrtfor3h

atileswereremovedinvacuotoleave

thefreeaminehydrobromide(168mg,91%)asabrown,highlyhygroscopicpowder;

[α]

D

=°(c=,EtOH);

2.1.2.9TMSI脱除Cbz示例1

Me

3

SiIml,mmol)wasaddedtoasolutonofcompound1(146mg,mmol)in

acetonitrile(10ml)atroomtemperature,andtheresultingmixturewasstirred

3

Nml)wasaddedandthemixturewasstirred

ventswereremovedinvacuo,andthe

binedorganicswerewashed

withsodiumbicarbonateandbrine,driedoversodiumsulfateandfiltered.

Solventswereremovedandtheresiduewasuseddirectlyinthenextstep.

2.1gmmol)ofcompound1in30mlofCH

2

Cl

2

werecombinedwithmlmmol)Me

3

SiI

20mlofMeOHwereaddede,the

mixturewasstirredforafurther30minatroomtemperatureandthereaction

iduewaspurifiedby

chromatographyonsilicagel(eludinggradient:CH

2

Cl

2

/(MeOH/a95:5)

=70/30–60/40)toyieldcompound2(690mg,56%).

叔丁氧羰基（Boc）

除Cbz保护基外，叔丁氧羰基（Boc）也是目前多肽合成中广为采用的氨基保护基，

特别是在固相合成中，氨基的保护用Boc而多不用Cbz。Boc具有以下的于的优点：Boc-

氨基酸除个别外都能得到结晶；易于酸解除去，但有具有一定的稳定性，Boc-氨基酸

能较长期的保存而不分解；酸解时产生的是叔丁基阳离子再分解为异丁烯，它一般不

会带来副反应；对碱水解、肼解和许多亲核试剂稳定；Boc对催化氢解稳定，但比Cbz

对酸要敏感得多。当Boc和Cbz同时存在时，可以用催化氢解脱去Cbz，Boc保持不变，

或用酸解脱去Boc而Cbz不受影响，因而两者能很好地搭配。

2.1.1叔丁氧羰基的导入

游离氨基在用NaOH或NaHCO

3

控制的碱性条件下用二氧六环和水的混合溶剂中很

容易同Boc

2

O反应得到N-叔丁氧羰基氨基化合物[1]。这是引入Boc常用方法之一，它的

优点是其副产物无多大干扰并容易除去。有时对一些亲核性较大的胺，一般可在甲醇

中和Boc酸酐直接反应即可，无须其他的碱，其处理也方便。

对水较为敏感的氨基衍生物，采用Boc

2

O/TEA/MeOHorDMF在40-50℃下进行较好，

因为这些无水条件下用于保护O17标记的氨基酸而不会由于与水交换使O17丢失[2]。有空

间位阻的氨基酸而言，用Boc

2

O/CH

3

CN是十分有利的。

l,toetal.,.,USA,1972,69,

730

amy,retal.,Synthesis.,1986,48

芳香胺由于其亲核性较弱，一般反应需要加入催化剂，另外对于伯胺，通过DMAP

的使用可以上两个Boc.

对于有酚羟基存在的胺，酚羟基上接Boc的速度也是相当快的，因而一般没太大

的选择性。对于有醇羟基存在的，若用DMAP做催化剂，时间长了以后醇羟基也能上

Boc，因此反应尽量不要过夜。

由于氰酸酯的生成，有位阻的胺往往会与Boc

2

O生成脲[1]。这个问题可通过该胺NaH

或NaHMDS反应，然后再与Boc

2

O反应来加以避免[2]。

r,ieretal.,.,.,1995,34,

2497;r,ieretal.,Synlett.,1996,502;Kessier,A.;

Coleman,C.M.,.,2004,69(23),7836-7846

,.,TetrahedronLett.,1994,35,9003

有时在反应中有可能多加了Boc酸酐，当分子中无游离酸碱时很难出去，若一定

要除去，一般在体系中加入一些N,N-二甲基乙二胺或N,N-二甲基丙二胺，而后将上了

Boc的N,N-二甲基乙二胺或N,N-二甲基丙二胺用稀酸除去。

由于Boc对酸敏感，因此在合成过程中用到酸洗或酸溶解等操作时，为了保险起

见，尽量不用盐酸而用10%柠檬酸（0.5M）或在低温条件进行。

2.2.1.1氨基酸Boc保护示例

OskarKeller,,GertvanLooketal.,.,63,160

A4-L,four-necked,round-bottomedflask,equippedwithanefficientstirrer,

adroppingfunnel,refluxcondenser,andthermometerischargedwithasolution

of44gmol)ngisinitiatedand

165.2g(1mol)ofL-phenylalanineisaddedatambienttemperature,andthen

ell-stirred,clearsolution

isaddeddropwisewithin1hr,223g(1mol)ofdi-tert-butyldicarbonate.A

whiteprecipitateappearsduringadditionofthedi-tert-butyldicarbonate.

Afterashortinductionperiod,thetemperaturerisestoabout30–35°

reactionisbroughttocompletionbyfurtherstirringovernightatroom

time,theclearsolutionwillhavereachedapHof–.

Thereactionmixtureisextractedtwotimeswith250mLofpentane,andthe

organicphaseisextractedthreetimeswith100mLofsaturatedaqueoussodium

binedaqueouslayersareacidifiedtopH1–by

carefuladditionofasolutionof224gmol)ofpotassiumhydrogensulfate

dificationisaccompaniedbycopiousevolutionof

bidreactionmixtureisthenextractedwithfour400-mL

binedorganiclayersarewashedtwotimeswith

200mLofwater,driedoveranhydroussodiumsulfateormagnesiumsulfate,and

ventisremovedunderreducedpressureusingarotary

evaporatoratabathtemperaturenotexceeding30°lowishoilthat

1daythefollowingportionsofhexaneareaddedwithstirringtothepartially

crystallizedproduct:2×50mL,4×100mL,and1×ution

isplacedinarefrigeratorovernight;thewhiteprecipitateiscollectedon

aBüidisdriedunderreduced

motherliquorisevaporatedtodrynessleavingayellowishoil,whichistreated

inthesamemannerasdescribedabove,alyield

ofpurewhiteN-tert-butoxycarbonyl-L-phenylalanineis207–230g(78–87%),

mp86–88°C,[α]

D

20+°(ethanolc.

2.2.1.2氨基酸酯Boc保护示例

AlessandroDondoni,DanielaPerrone.,.,77,64

A500-mL,three-necked,round-bottomedflask,isequippedwithamagnetic

stirringbar,thermometer,refluxcondenserprotectedfrommoisturebya

calciumchloride-filleddryingtube,andapressure-equalizingdroppingfunnel

thatisconnectedtoanitrogenflowlineandischargedwithasolutionof

97%di-tert-butyldicarbonate(14.3g,mmol)intetrahydrofuran(100mL),

Methylserinatehydrochloride(10.0g,mmol)isplacedintheflaskand

suspendedintetrahydrofuran(200mL)and99%triethylamine(14.0g,138mmol).

Theresultingwhitesuspensioniscooledwithanice-waterbathandthesolution

10minofadditionalstirring,theice-waterbathisremovedandthesuspension

isstirredovernight(14hr)atroomtemperature,thenwarmedat50°Cfora

ventisremovedunderreducedpressureandtheresidue

ispartitionedbetweendiethylether(200mL)andsaturatedaqueousbicarbonate

solution(250mL).Theaqueousphaseisextractedwiththree150-mLportions

binedorganicphasesaredriedwithanhydroussodium

sulfateandconcentratedunderreducedpressuretogive-14.0g(95-99%crude

yield)ofN-Boc-L-serinemethylesterasacolorlessoilthatisusedwithout

furtherpurification.[α]

D

23°(MeOH,c.

2.2.1.3Boc酸酐在甲醇中与胺直接反应

Boc

2

O(262g,mol)inMeOH(250ml)wasaddedtoasolutonofcompound1(157.2

g,mol)inMeOH(350ml)at10°C,andtheresultingmixturewasstirredat

roomtemperaturefor2h.N1,N1-dimethylethane-1,2-diamine(26g,mol)was

vent

wasremovedinvacuo,andtheresiduewasdissolvedwithethylacetate(750

ml).Thecombinedorganicswerewashedwith1NHCl(2x250ml)andbrine(2

x250ml),ventwasremovedto

givecompound2(250g,96%),whichwasuseddirectlyinthenextstep.

2.2.1.4芳胺的单Boc保护示例

Luo,Qun-Li;Liu,Zhi-Yingetal.,.,2003,46(13),2631-2640

3-Aminopyridine-2-carboxylicacid(5.02g,36mmol)wassuspendedin60mLof

dryDMF,andEt

3

NmL,108mmol)

resultingbrownsolutionwasaddedBoc

2

O(11.80g,54mmol).Afterbeingstirred

for10min,themixturewasheatedat40-50°ctionmixture

waspouredintowaterandwasthenextractedwithEtOAc(2X50mL).Theaqueous

phasewasacidifiedtopH4-5with2MaqueousHClandthenextractedwithCH

2

Cl

2

(3X50mL).Thecombinedorganicphaseswerethenprocessedintheusualway

andchromatographed(13:1CHCl

3

/MeOH)toyieldthedesiredproduct(4.2g,49%).

2.2.1.5芳胺的双Boc保护示例

Macleod,Calim;Mckieman,GordonJetal.,.,2003,68(2),387-401

AsolutionofNaHMDSmL,mmol,1MinTHF)wasaddedtoasolutionofthe

amine(2.11g,mmol)and(Boc)2O(5.46g,mmol)inTHF(50mL)at0°Cunder

thistime,thereactionwaspouredintowater,extractedintoCH

2

Cl

2

(2X25

mL),washedwithwater(2X25mL),driedoverNa2SO4,andconcentratedtoyield

talizationfrompetroleumether(40-60°C)gave

theimideasneedles(3.21g,mmol,78%).Rf(hexane/CH

2

Cl

2

1:9,SiO

2

):.Mp:

106-109°C.

2.2.1.6酰胺的Boc保护示例

str?m,YanwenFuetal.,.,81,213

A2000-mL,three-necked,round-bottomedflaskequippedwithanargoninlet

adapter,glassstopper,andanoverheadmechanicalstirrerischargedwitha

suspensionofthehydantoin1(26.0g,154mmol)in1000mLof

1,ylamine(15.7g,154mmol)isaddedinoneportion,

-tert-butyl

dicarbonate(168.0g,770mmol)isthenaddedbypipette,followedby

4-dimethylaminopyridine(DMAP)(0.2g,mmol).Sixadditional0.2g-portions

reactionmixtureisstirredvigorouslyforatotalof72hr,andtheresulting

lightyellowsolidisthencollectedinaBüchnerfunnelusingsuction

trateisconcentratedtoavolumeof60mLbyrotary

evaporation,andtheresultingsolutioniscooledto15°cipitate

whichappearsiscollectedusingsuctionfiltration,addedtothefirstcrop,

lution

iswashedwiththree200-mLportionsofHCl,andthecombinedaqueousphases

binedorganiclayersarewashed

with100mLofsaturatedaqNaHCO

3

solutionand100mLofbrine,driedover

anhydrousMgSO

4

,filtered,

ulting

finelygroundlightyellowsolidissuspendedin400mLofdiethyletherin

a1000-mL,round-bottomedflaskequippedwithamagneticstirbar,stirredfor

2hr,andfilteredonaBüchnerfunnelwashingwithfour50-mLportionsof

ductisdriedundervacuum(85°C;0.5mm)for24hrto

give–65.3g(83-90%)of2asaivory-coloredsolid.

2.2.1.6叠氮还原Boc保护示例

SeikiSaito,KanjiKomada,andToshioMoriwake.,.,73,184

A500-mL,single-necked,round-bottomedflask,equippedwithaTeflon-coated

stirringbar,ischargedwithasuspensionof0.91gof10%palladiumoncarbon

skisconnectedtoanormalpressure

removalofthehydrogen,asolutionof18.2gmol)of1and20.6gmol)

di-tert-butyldicarbonatein80mLofethylacetateisaddedtothesuspension

ofcatalyst,ahydrogenatmospherereestablished,andthesuspensionisstirred

atroomtemperatureunderaslightpositivepressureofhydrogenfor4–6hr,

ThesuspensionisfilteredthroughaCelitepad,andthepadisrinsedwith

binedethylacetatesolutionsare

concentratedonarotaryevaporatorandfinallyunderhighvacuumtogivea

paleyellowoilthatisinitiallypurifiedbymeansofacolumnpackedwith

silicagel(100g)usinghexane-ethylacetate(6:1)ons

containingtheproductarecombinedandconcentratedonarotaryevaporator

ycrude2isdissolved

in70mLofhexane-ether(3:1),andthesolutioniscooledto?30°C,seeded,

andkeptovernightatthattemperature(freezer)

motherliquorissiphonedoutwhilethemixtureiskeptat?30°C(dry

ice-acetonebath).Thecrystalsarewashedwithseveralportionsof

hexane-ether(3:1)at?30°C,thendriedunderhighvacuumtoprovide–12.7

gofdiastereomericallyandenantiomericallypurediethyl

(2S,3R)-2-(N-tert-butoxycarbonyl)amino-3-hydroxysuccinate(2)ascolorless

prisms,mp33–34°C;.Thecombinedmotherliquorandthehexane–ether(3:1)

washingsareconcentratedonarotaryevaporatortogiveacolorlessoil,which

uponcrystallizationasaboveprovidesanadditional–

combinedyieldofcrystalline2is–16.5g(66–73%).

2.2.1.7吡咯Boc保护示例

WhaChen,ephensonetal.,.,70,151

Thesolutionof2-bromo-1H-pyrrole(9.8g,mmol)in40mLofTHFiscooled

to?78°skisequippedwithamagnetic

stirringbarandathree-waystopcockattachedtoaballoonfilledwithnitrogen.

Tothestirreddark-greensolutionisadded2.71gmmol)oftriethylamine

followedimmediatelybyadditionof20.4gmmol)ofdi-tert-butyldicarbonate

andacatalyticamount(ca.0.1g)skis

tureisstirredfor8hrwhileit

ventisremovedunderreduced

pressureatroomtemperatureand100mLofhexaneisaddedtothecrudeproduct,

whichiswashedwithdeionizedwater(3×100mL),driedoversodiumsulfate,

deproduct

ispurifiedbychromatographyonamine-treatedneutralsilica(270g)using

ctionscontainingtheproductareidentifiedby

TLC,combined,andconcentratedunderreducedpressureatroomtemperatureto

yieldN-tert-Butoxycarbonyl-2-bromopyrroleasacolorlessoil–14.7g,

82–89%).

2.2.1.8吲哚Boc保护示例

;etal.,.,1997,26,9298

Toasolutionof6-methoxy-3-methylindole(5.0g,31mmol)indistilled

acetonitrile(150mL)wereaddeddi-tertbutyldicarbonate(7.44g,mmol)and

DMAP(0.195g,mmol).

iduewasdissolvedinCH

2

Cl

2

(100mL)andwashedwithanaqueoussolutionof1NHCl(2x50mL).Theaqueous

layerwasextractedwithCH

2

Cl

2

(3x30mL).Thecombinedorganicayerswere

dried(K

2

CO

3

).Afterremovalofsolventunderreducedpressure,theresiduewas

solidifiedtoaffordtheproduct(8.12g,99%)asayellowsolid:mp45-46°C.

2.2.2叔丁氧羰基的脱去

Boc比Cbz对酸敏感，酸解产物为异丁烯和CO

2

（见下式）。在液相肽的合成中，Boc

的脱除一般可用TFA或50%TFA（TFA:CH

2

Cl

2

=1:1,v/v）。而在固相肽合成中，由于TFA

会带来一些副反应（如在得到的胺上上一个三氟乙酰基等），因此多采用1-2MHCl/有

机溶剂。一般而言用HCl/二氧六环，比较多见。

用甲醇作溶剂，HCl/EtOAc的组合使TBDMS和TBDPS酯[1]以及叔丁酯和非酚类酯在

Boc脱除时不被断裂，而S-Boc除外[2]。但当同时脱除分子中Boc和叔丁酯,或分子中

有游离羧酸基，千万记住不能用HCl/MeOH,其可将羧酸变为甲酯。同时AcCl/MeOH，则

是一个在甲醇中产生无水HCl的便利方法。这些条件也可用来从羧酸制备酯以及形成

胺的盐酸盐[3]。

在中性的无水条件下Me

3

SiI在CHCl

3

或CH

3

CN中除了能脱除Boc外，也能断裂氨基

甲酸酯、酯、醚和缩酮。通过控制条件可以得到一定的选择性[4]。

当分子中存在一些官能团其可与副产物叔丁基碳正离子在酸性下反应时，需要添

加硫酚(如苯硫酚)来清除叔丁基碳正离子，如此举可防止蛋氨酸和色氨酸的脱Boc时

的烷基化[5]。也可使用其它的清除剂，如苯甲醚、苯硫基甲醚、甲苯硫酚、甲苯酚及二

甲硫醚[6]。在Boc脱去过程中TBDPS[7]和TBDMS[8]基对CF

3

COOH是稳定的（在TBS存在，

用相对稀一些的10－20％TFA）。伯胺衍生物存在下，ZnBr

2

/CH

2

Cl

2

可以选择性的脱除

仲胺上的Boc[9]。

er,l.,TetrahedronLett.,1996,37,5131

,ier,rt.,.,1994,59,3216

3.,etal.,.,1998,28,471

,netal.,.,1979,495;

,.,Tetrahedron.,1982,38,2225

them,raetal.,.,1992,57,6083

zky,zky.,nRes.,1984,23,565;Y.

Masui,tal.,.,1980,53,464

,eeetal.,.,1996,61,2413

,etal.,.,1995,117,7824

,al.,.,1989,19,3139

中性条件下脱Boc示例

Gilbertson,ScottR;Chang,Cheng-Weietal.,.,1998,63(23),

8424-8431

Toasolutioncontaining2(1.0g,mmol)in30mLofdryCH

2

Cl

2

wasslowlyadded

TBDMSOTfmL,mmol).Afterstirringthereactionmixturefor6h,thesolvent

wasevaporated,andthecrudeproduct(0.8g,75%)wasobtaineded,whichwas

useddirectlyinthenextstep.

-2,6-lutidine中性条件下脱Boc示例1

Kemp,ScottJ;Bao,.,1996,61(20),7162-7167

Toastirringsolutionofcompound1(800mg,mmol)and2,6-lutidineml,

mmol)inCH

2

Cl

2

(6mL)wasaddedtert-butyldimethylsilyltriflateml,mmol)

20min,saturatedNH

4

Cl(10mL)ture

wasstirredandseparated,andtheaqueouslayerwasextractedwithEt

2

O(3x

15mL).Thecombinedorganiclayerswerewashedwithwater(2x10mL)and

saturatedNaCl(10mL),dried(MgSO

4

),andconcentratedtogivethecrudesilyl

carbamate,whichwasdissolvedinTHF(10mL)andcooledto0°C.A1.0Msolution

ofTBAFinTHF(2mL,2mmol)wasaddedover5min,andthenthesolutionwas

stirredat0°utionwasconcentratedandchromatographed(95:5

CH

2

Cl

2

-methanol)throughasmallplugofsilicatogivecompound2(882mg,75%)

asaclearoil.

-2,6-lutidine条件下脱Boc示例2

Sakaitani,Masahiro;Ohfune,Yasufumi;.,1990,55(3),870-876

Toastirredsolutionofcompoundl(500mg,mmol)and2,6-lutidineml,mmol)

indryCH

2

C1

2

mL)at0"Cwasaddeddropwiset-BuMe

2

SiOTfml,mmol).The

reactionmixturewasstirredat0°Cfor15min,quenchedwithsaturatedaqueous

ammoniumchloridesolution,

combinedorganicphasewaswashedwithH

2

Oandthenbrine,dried(MgSO

4

),and

concentratedinvacuotogiveanoilyresidue,whichuponpurificationbycolumn

chromatographyonsilicagel(elutionwith50%etherinhexane)gaveO-silyl

estercompound2(652mg,97%):colorlessneedles;mp-65.0°C(hexane).

2.2.2.2TFA脱Boc示例

o;oetal.,.,2004,21,7004

Toasolutionoftheβ-aminoestermmol)inCH

2

Cl

2

(3mL),cooledto0°Cwas

addedTFA(1mL).Aftertheconsumptionofthestartingmaterial(45min,

monitoredbyTLC),themixturewasevaporatedandthensaturatedaqueousNaHCO

3

eouslayerwasextractedtwicewithCH

2

Cl

2

(15mL),andthe

organiclayerwashedwithbrineanddriedoveranhydrousNa

2

SO

4

.Thesolvent

wasremoveredundervacuum,toaffordtheamine,whichwereemployedwithout

furtherpurificationtopreparetheMosher’sdiastereoisomericamides.

2.2.2.3HCl-Et

2

O脱Boc示例

C.Mühlemann,nn,t.,.,71,200

tert-Butyl[1-(tert-butoxycarbonyl)-3-oxo-4-pentenyl]carbamate,8.73gmol),

isdissolvedin280mLofanice-cooled,saturatedsolutionofhydrogenchloride

utioniskeptwithoutstirringatroomtemperatureovernight.

Theresultingsuspensionisfilteredandthefiltercakeisimmediatelywashed

hingwithetherisrepeatedfourtimesand,afterdrying

underreducedpressure,5.48g(99%)of4-ketopipecolicacidhydrochlorideis

obtainedasacolorlesspowder,mp139–142°Cdec.

2.2.2.4HCl-THF脱Boc示例

tal.,Tetrahedron:Asymmetry,2004,15,851

TotheBocprotectedamine(0.06g,mmol)dissolvedinTHF(1mL)wasadded

2MHCl(1mL,2mmol)

evaporationofthesolvent,theproductwasextractedintoEtOAc(3.5mL).The

organiclayerwasdriedandevaporatedundervacuumtoafford17bin95%yield

asawhitesolid.

2.2.2.叔丁酯存在下的脱Boc示例1

US5610144

mlofMe

3

SiIareaddeddropwiseatroomtemperatureinthevicinityof25°C

toasoutionof3.8gofcompound1in50mlofCHCl

3

.Stirringiscontiuned

for30min,eousphaseisseparated,then

extractedwithCHCl

3

(2x20ml).Theorganicphasesarecombined,washed

successivelywithasaturatedaqueousNa

2

CO

3

(30ml)andwater(2x30ml),then

driedoverMgSO

4

andconcentratedtodrynessunderreducedpressureat40°C.

Themixtureofthetwodiastereoisomersobtainedisseparatedbychromatography

onsilica(eluent:ethylacetate/cyclohexane=1/4).Thefractionscontaining

theexpectedproductarecombinedandconcentratedtodrynessunderreduced

pressureat40°Ctogivecompound2(0.5g),asayellow-orangeoil,usedas

itisinsubsequentsyntheses.

2.2.2.叔丁酯存在下的脱Boc示例1

Toasolutionofcompound1(6.3g,mmol)inethylacetate(50ml)wasadded

1.1MHClinethylacetateml,mmol).Thereactionwasstirredatroom

temperaturefor1h,thenwashedwithwater,

3

andbrine.

Theorganicphasewasdried(MgSO

4

),filteredandevaporatedtoaffordcompound

2(3.11g,74%)asayellowoilwhichcrystallizeduponstanding.

2.2.2.叔丁酯存在下的脱Boc示例3

Toasolutionofcompound1(149mg,mmol)inCH

2

Cl

2

(2ml),TFA(1ml)asadded

at0°Candthemixturewasstirredfor1hat0°tedaqueousNa

2

CO

3

wasaddedandthemixturewasetractedwithCHCl

3

.Theetractwaspurifiedby

silicagelcolumnchromatographytoobtainedcompound2(92mg,79%).

2.2.2.6吲哚环上Boc直接加热脱除示例

;etal.,.,1997,26,9298

Compound1(62mg)washeated(neat)at160-180°iduewas

purifiedbyflashchromatography(silicagel,CHCl

3

/MeOH95/5)toafford

Compound2(25mg)asasolidin50%yield.11:[R]

27

D=-(c=,inCHCl

3

).

笏甲氧羰基（Fmoc）

Fmoc保护基的一个主要的优点是它对酸极其稳定，在它的存在下，Boc和苄基可

去保护。Fmoc的其他优点是它较易由简单的胺不通过水解来去保护，被保护的胺以游

离碱释出[1]。一般而言Fmoc对氢化稳定，但某些情况下，它可用H

2

/Pd-C在AcOH和MeOH

仲脱去[2]。Fmoc保护基可与酸脱去的保护基搭配而用于液相和固相的肽合成[3]。

o.,.1987,20401;o,-Aalaee

etal.,.,1990,55,1673

on,al.,TetrahedronLett.,1979,3041

zkyrtal.,.,1980,45,72;oferetal.,

.,1978,11,246;ez,tal.,.

Chem.,1979,44,5396;ield,.,.,1978,

43,4808

2.3.1笏甲氧羰基的导入

笏甲醇在无水CH

2

Cl

2

中与过量的COCl

2

反应可以得到很好产率的Fmoc-Cl（熔点61。

5-63℃），所得Fmoc-Cl在二氧六环/Na

2

CO

3

或NaHCO

3

溶液同氨基酸反应则可得到Fmoc

保护的氨基酸[1]。在用Fmoc-Cl引入Fmoc的过程中二异丙基乙胺可抑制二肽的生成[2]。

或用Fmoc-OSu(Su=丁二酰亚胺基)在乙腈/水中导入，该方法在制备氨基酸衍生物时

很少低聚肽生成。

o,.,.,1972,37,3404

,on.,.,1987,65,1224

2.3.1.氨基酸的笏甲氧羰基的导入示例1

;ianetal.,.,2005,1,56

AsolutionofFmoc-Cl(31g,mol)indioxane(150ml)wasaddedtoasuspension

ofcompound1(24.1g,mol)indioxane(100ml)and10%aqueousNa

2

CO

3

(150ml)

at0°turewasstirredfor1hat0°Candthenfor1hatroom

ctionmixturewaspouredintowaterandwashedwithEt

2

O.

TheaqueousphasewasacidifiedwithconcentratedaqueousHCl,andthe

precipitatedproductwasisolatedbyfiltrationanddriedinvacuotogive

compound2(45gg,98%).

2.3.1.氨基酸的笏甲氧羰基的导入示例2

Carrasco,MichaelR;Brown,RyanTetal.,.,2005,68(1),195-197

Compound1mmol),weredissolvedinDMF(30mL)andH

2

O(30mL),treatedwith

NaHCO

3

(210mg,mmol)andFmoc-OSu(464mg,mmol),

solventswereremoved,andtheresiduewasdissolvedinEtOAc(150mL)andwashed

with0.1MKHSO

4

(4x50mL),H

2

O(4x50mL),andbrine(100mL).Afterdrying

andremovalofthesolvent,theresiduewaschromatographed(acetone:CH

2

Cl

2

:AcOH,

5:95:to10:90:andthenpurifiedbysizeexclusionchromatography(LH-20,

CH

2

Cl

2

)toyieldcompound2(456mg,mmol,78%)asaglassysolid.

2.3.1.氨基酸酯的笏甲氧羰基的导入示例

;ianetal.,.,2005,1,56

Compound1(197mg,mmol)wassuspendedinamixtureofMeCN(10mL)and10%

aqueousNa

2

CO

3

(15mL),andthemixturewasstirredovernightatroomtemperature,

followedbystirringfor16hat40°sremovedinvacuo,anddioxane

(20mL)andFmoc-Cl(188mg,mmol)indioxane(3mL)wereaddedsuccessively

at0°turewasstirredat0°Cfor1handwasthenpouredinto

water(100mL).Theresultingmixturewaswashedwithhexane(50mL),andthe

aqueousphasewasacidifiedwith4MaqueousHClandextractedwithEtOAc(4

x50mL).ThecombinedEtOAcphasesweredried(Na2SO4),filtered,and

cationbyTLC(hexanes-EtOAc2:1tohexanes-EtOAc-HOAc

1000:1000:1)affordedcompound2(237mg,68%):R

f

(hexanes-EtOAc-HOAc1000:1000:1).

2.3.1.2一般胺的氨基酸酯的笏甲氧羰基的导入示例

;letal.,Tetrahedron:Asymmetry,2003,12,1645

Toavigorouslystirredmixtureof3mLofdichloromethaneand6mLofsaturated

NaHCO

3

(aq.)hereaction

hadcometocompletion(TLC),6mLofdichloromethaneand3mLofwaterwere

added,anicphasewaswashedoncewithbrine,

dried(MgSO

4

),decompoundwaspurifiedby

columnchromatography(40–60/EtOAc95/5,v/v)toyield5ein79%

yieldasawhitesolid,mp88°C.

2.3.2笏甲氧羰基的脱去

Fmoc同前面提到的Cbz和Boc不同，它对酸稳定，较易由简单的胺不通过水解来

去保护，被保护的胺以游离碱释出。

Fmoc-ValOH在DMF中用不同的胺碱去保护的快慢有较大的差异，20%的哌啶较快[1]。

Fmoc保护基一般也能用浓氨水、二氧六环/4MNaOH(30:9:1)以及用哌啶、乙醇胺、环

己胺、吗啡啉、吡咯烷酮、DBU等胺类的50%CH

2

Cl

2

的溶液脱去。另外，Bu

4

N+F-/DMF在

室温的脱去效果也很好[2]。叔胺（如三乙胺）的脱去效果较差，具有空间位阻的胺的脱

除效果最差[3]。

viewoftheuseofFmocprotectioninpeptidesynthesis,seeE.

rd,‘TheFluorenylmethoxycarbonylAmino

ProtectingGroup’,inThePeptides,ofer,Eds.,

AcademicPress,NewYork,1987,9,1

,a.,TetrahedronLett.,1987,28,6617

o,.,.,1970,92,5748;

etal.,.,1980,15,59

2.3.2.1三乙胺用于脱除笏甲氧羰基示例

.,.2003,68,9506

Diethylamine(30mL)wasaddedtoasolutionof5(5.63g,9mmol)inCH

3

CN(30

mL),andtheresultingmixturewasstirredat25°Cfor30mintoensurecomplete

oncentrationinvacuo,thereaction

mixturewasazeotropedtodrynesswithCH

3

CN(2x30mL)togivecompound2(3.4

g,89%).

2.3.2.220%的哌啶用于脱除笏甲氧羰基示例1

US6329389

Piperidineml)wasaddedetoasolutionofcompound1(0.797g)inMeOH(10

ml)ctionmixturewasstirredatroomtemperature

for18h,thenconcentratedandtheresiduewaspurifiedbyaluminacolumn

chromatography(rthylacetate/methanol=10/1)toobtaincompound2(0.382g,

76%).

US6331640

Piperidineml,mmol)wasaddedetoasolutionofcompound1(116mg,mmol)

inDMF(5ml)utionwasstirredatroomtemperature

for30min,ultingwhitesolidwas

trituratedwithetherfivetimesanddriedinvacuotogivecompound2(59mg,

81%)asanoff-whitesolid.

.烯丙氧羰基（Alloc）

烯丙氧羰基（Alloc）同前面提到的Cbz、Boc和Fmoc不同，它对酸、碱等都很稳

定，在它的存在下，Cbz、Boc和Fmoc等可选择性去保护，而它的脱去则通常在Pd(0)

的存在下进行。

2.4.1烯丙氧羰基（Alloc）的引入

Alloc-Cl在有机溶剂/Na

2

CO

3

、NaHCO

3

溶液或吡啶中同氨基化合物反应则可得到

Aloc保护的氨基衍生物[1]。

,.,.,1973,38,3223

2.4.1.1氨基酸的烯丙氧羰基（Alloc）的引入示例

Micale,Nicola;Vairagounder,.,2004,47(26),

6455-6458

Toastirredsolutionofcompound1(3.0g,mmol)

3

andTHF(8/2,20mL)wasaddedallylchloroformatemL,mmol),dropwiseand

at0°turewasstirredatroomtemperaturefor12handthendiluted

withethylacetateandwashed3NHCl,driedandthesolventremovedinvacuo

togivecompound2asapaleyellowoil,whichwasusedwithoutfurther

purification(3.55g,82%).

2.4.1.2一般氨基的烯丙氧羰基（Alloc）的引入示例

a;uetal.,Tetrahedron,2000,56(39),7705

Toasolutionof17(1.0g,mmol)inEtOAc(10ml)wasadded4MHCl/EtOAc

(20mL),

evaporation,tothesuspensionoftheresidueinCH

2

Cl

2

(40mL)wereadded

triethylaminemL,mmol)andallylchloroformatemL,mmol)at-10°

reactionmixturewaspouredintoH

2

OandthewholewasextractedwithEtOAc.

Theorganiclayerwaswashedwithbrine,driedoverMgSO

4

,andevaporatedunder

iduewaspurifiedbysilicagelcolumnchromatography

(EtOAc/acetone=8:1)togive18(863mg,%)asafoam.[a]

D

25=(c=,CHCl

3

).

2.4.2烯丙氧羰基（Alloc）的脱去

Alloc保护基对酸、碱等较强的稳定性，它们通常只用Pd(0)，如Pd(PPh

3

)

4

或

Pd(PPh

3

)

2

Cl

2

存在的条件去保护。例如，Alloc衍生物用Pd(PPh

3

)

4

/Me

2

NTMS处理，可以

得到易水解的氨基甲酸TMS酯[1]。脱去含硫衍生物中的Alloc时，如蛋氨酸，Pd(PPh

3

)

4

/

二甲基环己二酮/TH则不会被毒化[2]。如果在酸性条件下脱除Alloc，则最好采用

Pd(PPh

3

)

2

Cl

2

/Bu

3

SnH/p-NO

2

C

6

H

4

OH/CH

2

Cl

2

[3]。在异戊烯酯或肉桂酸酯存在下，可用

Pd(OAc)

2

/TPPT/CH

3

CN/Et

3

N/H

2

O去保护，但随时间的增加，这些酯也会反应，并且氨基

甲酸异戊烯酯和烯丙基碳酸酯同样被断裂[4]。当加入Boc

2

O、AcCl、TsCl、或丁二酸酐

时，Pd(PPh

3

)

2

Cl

2

/Bu

3

SnH可将Alloc基转变为其它的胺衍生物。另外，Alloc也可在

Pd(PPh

3

)

4

/HCOOH/TEA[5]或AcOH/NMO催化脱去[6]。

k,.,TetrahedronLett.,1992,33,477

,agt.,.,1984,23,436

s,tal.,.,1987,52,4984;,.,

TetrahedronLett.,1982,23,1825

e-Audoire,acetal.,TetrahedronLett.,1994,35,8783;

,detal.,TetrahedronLett.,1997,38,2955;J.P.

Genet,tal.,TetrahedronLett.,1993,34,4189

,al.,.,1992,35,2781

,n,.,.,1996,61,3983

2.4.2.1Pd(PPh

3

)

4

-THF体系脱除烯丙氧羰基（Alloc）示例

hima;al.,Trans.1.,2004,7,949

ToasolutionoftheAllocprotectedestermg,0.2.23mmol)and

1,3-dimethylbarbituricacid(228mg,mmol)inTHF(15mL)wasadded

tetrakis(triphenylphosphine)palladiummg,mmol,17mol%),andtheresulting

turewasthenpouredintosaturated

3

andextractedfourtimeswithEt

2

binedextractwasdried

(MgSO

4

)iduewaspurifiedbychromatography

(CHCl

3

/MeOH,20:1to2:1)togivethecorrespondingfreeaminoesterasa

colorlessoilmg,65%).

2.4.2.2Pd(PPh

3

)

4

/Me

2

NTMS体系脱除烯丙氧羰基（Alloc）示例

m;nnetal.,.,1992,47(6),1487

Toasolutionof112(0.97g,mmol)inCH

2

Cl

2

(19mL)wereaddeddimethylamino-

trimethylsilanemL,mol)andtrimethylsilyltrifluoroacetatemL,mmol).

Thesolutionwasstirredat20°Cfor10min,andthenPd(PPh

3

)

4

(97mg,mmol)

turewasevaporatedand

theresidualoilwasdissolvedinEtOAc(50mL).Thesolutionwaswashedwith

10%aqNaHCO

3

andbrine,dried,iduewaschromatographed

(SiO

2

;EtOAc/hexane1:2)togive113(0.67g,78%):foam;TLCR

f

)(EtOAc).

三甲基硅乙氧羰基（Teoc）

三甲基硅乙氧羰基(Teoc)同前面提到的Cbz、Boc,Fmoc和Alloc不同，它对酸、

大部分碱，及贵金属催化等都很稳定，在它的存在下，Cbz、Boc，Fmoc和Alloc等可

选择性去保护，而它的脱去则通常在氟负离子进行。如TBAF[1]、TEAF和HF[2]等。另外，

TFA也可选择性去保护三甲基硅乙氧羰基[3]。

,PunitP;Ray,Robinson,.,2004,

14(22),5569-5572;Olsen,ChristianA;Joergensen,MaleneRetalEur.J.

.,2003,17,3288-3299;Boger,DaleL;Kim,SeongHeonetalJ.

.,2001,123(9),1862-1871

,MarcusA;Thurkauf,Andrew;TetrahedronLett.,1986,27(38),4541-4544

,Haengsoon;Cao,.,2001,66(21),7223-7226

2.5.1三甲基硅乙氧羰基（Teoc）的引入

Teoc-Cl[1,2]、Teoc-OSu[2]或Teoc-OBt[3]在有机溶剂，碱的存在下同氨基化合物反应

则可得到Teoc保护的氨基衍生物。

,Sheena;Glen,AngelaetalTetrahedronLett.1998,39(41),7567-7570;

Trost,BarryM;Cossy,Janine;.,1982,104(24),6881-6882;

Sulline,DavidW;Bobik,.,1993,115(15),

6646-6651

,Richard;Rich,DanielH;Synthesis,1987,4,346-349

,DaleL;Kim,SengHeonetal.,.,2001,123(9),

1862-1871;Boger,DaleL;Kim,SengHeonetal.,.,

2000,122(30),7416-7417

2.5.1.1Teoc-Cl引入三甲基硅乙氧羰基(Teoc)示例

Shute,Richard;Rich,DanielH;Synthesis,1987,4,346-349

NaHCO

3

(3.78g,45mmol)andcompound1(15mmol)areaddedtowater(15ml)and

themixtureisstirredatroomtemperaturefor30minoruntilthemajority

suspensionisaddedasolutionofTeoc-Clin

dioxane(30ml).Theresultantmixtureisstirredvigorouslyatroomtemperature

overnight,pouredintowater(50ml)andextractedwithether(3x50ml),the

eouslayerisacidifiedtoPh=2with

saturatedpotassiumhydrogensulfatesolutionandextractedwithether(3x

50ml).Thecombinedorganicextractsarewashedwithwater(3x75ml),dried

withMgSO

4

,andevaporatedtogivecompound2().

2.5.1.2Teoc-OSu引入三甲基硅乙氧羰基(Teoc)示例1

Shute,Richard;Rich,DanielH;Synthesis,1987,4,346-349

Toastirredsuspensionofcompound1(0.13g,1mmol)inwater(1ml)isadded

asolutionoftriethylamine(0.26g,mmol)indioxane(1ml).Totheresultant

solutionisaddedsolidTeoc-OSu(0.29g,mmol).Themixtureisstirredat

roomtemperatureovernight,thendilutedwithwater(5ml),acidifiedwith

saturatedpotassiumhydrogensulfatesolution,andextractedwithether(3x

15ml).Thecombinedorganiclayersarewashedwithwater(4x20ml),dried

withMgSO

4

,andevaporatedtoaffordcompound2(0.23g,84%)asanoilyresidue.

Teoc-OSu引入三甲基硅乙氧羰基(Teoc)示例2

Shute,Richard;Rich,DanielH;Synthesis,1987,4,346-349

Toastirredsuspensionofcompound1(0.13g,1mmol)inwater(1ml)isadded

asolutionoftriethylamine(0.26g,mmol)indioxane(1ml).Totheresultant

solutionisaddedsolidTeoc-OSu(0.29g,mmol).Themixtureisstirredat

roomtemperatureovernight,thendilutedwithwater(5ml),acidifiedwith

saturatedpotassiumhydrogensulfatesolution,andextractedwithether(3x

15ml).Thecombinedorganiclayersarewashedwithwater(4x20ml),dried

withMgSO

4

,andevaporatedtoaffordcompound2(0.23g,84%)asanoilyresidue.

3.5.1.3Teoc-OBt引入三甲基硅乙氧羰基(Teoc)示例

Boger,DaleL;Kim,SengHeonetal.,.,2001,123(9),

1862-1871;Boger,DaleL;Kim,SengHeonetal.,.,2000,

122(30),7416-7417

Toastirredsuspensionofcompound1(0.24g,1mmol)inwater(1ml)isadded

asolutionoftriethylamine(0.26g,mmol)indioxane(1ml)followedbysolid

Teoc-Bt(0.31g,mmol).Themixtureisstirredatroomtemperatureovernight,

thendilutedwithwater(5ml),acidifiedwithsaturatedpotassiumhydrogen

sulfatesolution,andextractedwithether(3x15ml).Thecombinedorganic

layersarewashedwithwater(4x20ml),driedwithMgSO

4

,andevaporatedto

affordcompound2(0.36g,92%).

2.5.1.4一般氨基的三甲基硅乙氧羰基（Teoc）的引入示例

Mueller,Paul;Imogai,Hassan;Tetrahedron:Asymmetry,1998,9(24),4419-4428

Tocompound1(486mg,mmol)inCH

2

Cl

2

(15mL)wasadded,at?10°C,

diisopropylethylamine(1.72g,17mmol)followedbyTeoc-Cl(3.06g,17mmol)

inCH

2

Cl

2

,andfinally,dimethylaminopyridine(DMAP,30mg).Themixturewas

stirredovernight,thenhydrolyzedwithsatdNaHCO

3

,andextractedwithCH

2

Cl

2

(3x30mL)at0°CandsatdNa

2

CO

3

.Afterdryingandevaporationofthesolvent,

thecrudeproductwaspurifiedbychromatography(SiO

2

;hexane:AcOEt=85:5)

andaffordedcompound2(1.49g,88%)asacolorlessliquid.

2.5.2三甲基硅乙氧羰基（Teoc）的脱去

一般三甲基硅乙氧羰基(Teoc)脱除主要通过TBAF(四丁基氟化胺)，TEAF(四乙基

氟化胺)或TMAF(四甲基氟化胺)来脱除，在脱除过程中，TBAF将产生四丁基胺盐的副

产物，常常不易除去，而且它的质谱丰度高，往往影响产品的交货，此时可用TMAF或

TEAF来代替。

2.5.2.1三甲基硅乙氧羰基（Teoc）的脱去示例

Gugiu,BogdanG;Salomon,RobertG;.,2003,5(16),2797-2800

Compound1(33mg,mmol)wasdissolvedinTHFandTBAFmL1MinTHFcontaining

mg,mmol)wasadded,andthesolutionstirredatroomtemperaturefor48h

underargonfollowingthedisappearanceofcompound1byTLC(36h).Afterthe

removalofsolventbyrotaryevaporationunderlowpressuretheproductwas

purifiedbyflashchromatographyusingCHCl

3

/MeOH/H

2

O(60:38:2)togivecompound

2(20mg,72%)withR

f

=0.53inCHCl

3

/MeOH/H

2

O(60:38:2).

甲（或乙）氧羰基

甲（或乙）氧羰基同前面提到的各种烷氧羰基不同，它对一般的酸、碱和氢解等

都很稳定，在它的存在下，Cbz、Boc和苄基等可选择性去保护。

2.6.1甲（或乙）氧羰基的引入

同Cbz、Fmoc和Alloc的引入方法类似，用甲（或乙）氧羰酰氯在有机溶剂/Na

2

CO

3

、

NaHCO

3

或有机碱同氨基化合物反应则可得到甲（或乙）氧羰基保护的氨基衍生物[1]。

,al.,TetrahedronLett.1978,1051

2.6.1.1甲（或乙）氧羰基的引入示例

;al.,Synthesis,1999,6,943

Toasuspensionof2b(5mmol,1.05g)inacetone(10mL)cooledto0°C(ice-salt

bath)wasaddedTEAmmol,mL).

thismixtureat0°Cwasaddeddropwiseethylchloroformatemmol,mL).The

residuewastreatedwithH

2

O(25mL)andthenwithHCl10%untilpH3andextracted

aniclayerwaswashedwithH

2

O,dried(Na

2

SO

4

)andthesolvent

wasremovedinvacuoyielded4b(76%)asthickoil.

2.6.1.2甲（或乙）氧羰基的引入示例

;.,Tetrahedron:Asymmetry,2002,13,961

Asuspensionofcompound1(20g,mmol),NaHCO

3

(13.0g,mmol)inwater(120

mL)andchloroform(20mL)wastreatedwithmethylchloroformatemL,mmol)

added

turewasextractedwithethylacetateandthe

organiclayerwaswashedwithbrine,driedoverMgSO

4

,andconcentratedtoyield

compound2(23.3g,94%)asacrudesolid.

2.5.2甲（或乙）氧羰基的脱去

因为甲（或乙）氧羰基较强的稳定性，它们通常只用较剧烈的条件去保护，如

HBr/HOAc处理[1]、KOH/MeOH、6NHCl和TMSI等。

,lletal.,.,1972,94,3631;P.

Magnus,ues-Lopezetal.,.,1992,114,382;J.

Patjens;tal.,.1986,69(4),905-607

2.6.2.1HBr-AcOH脱除甲（或乙）氧羰基示例

s;tal.,.1986,69(4),905-607

Compound1(18.1g,mol)wasaddedto33%HBr(inAcOH,100mL,mol)atroom

turewasstirredandheatedto70℃essHBr

iduewaswashedwithdryether(3x50

ml)togivecompound2(23g,85%)asaorangesolid

2.6.2.2KOH-MeOH脱除甲（或乙）氧羰基示例

ta;tal.,Tetrahedron:Asymmetry,2003,23,3773

Amixtureofcompound1(3.60g,mmol)and5NKOH(25mL)inMeOH(50mL)was

refluxedfor18handbroughttopH3with2NH

2

SO

4

.Removalofthesolvents

atlowpressureaffordedawhitesolid(10g)thatwasextractedwithMeOH,

theextractwaspassedthroughbasicionexchangeresin(AmberliteIRA-400(OH),

100mL),andtheeluatewasconcentratedunderreducedpressuretoabrownoil

(2.81g)thatuponflashchromatography(1:1EtOAc/MeOH)affordedacolourless

oilthat1HNMRspectroscopyshowedtobevirtuallypurecompound2(1.87g,

85%).[α]

D

25=+(c=,MeOH).

2.6.2.36NHCl脱除甲（或乙）氧羰基示例

;etal.,.,2003,17,6679

Compound1(44mg,mmol)wasrefluxedwithHCl(6N,10mL)

mixturewasconcentratedinvacuotogivecompound2asawhitesolid(38mg,

100%).[α]

D

20=+(c=,H

2

O).

2.6.2.3TMSI脱除甲（或乙）氧羰基示例

r;dadeetal.,.,2001,26,4677

Amixtureof8aR(1.53g,mmol),75mLofacetonitrile,and

trimethylsilyliodidemL,13mmol)wasstirredovernightatroomtemperature.

Methanolwasadded,andthemixturewasconcentrated,cold1NNaOHadded,and

aniclayerwaswashedwithaqueous

Na

2

S

2

O

3

andbrine,dried,filtered,concentratedandrecrystallizedfromether

togive1.19g(89%)of9aRasawhitesolidmeltingat109-112°C.

3．酰基类

邻苯二甲酰基（Pht）

同一般的酰基氨基酸比较，Pht-氨基酸在接肽时不易消旋，但它对碱不稳定，在

碱皂化的条件下发生邻苯二甲酰亚胺环的开环生成邻羧基苯甲酰基衍生物[1]。因此，当

选用Pht作氨基保护基时，肽链的羧基末端则不能用甲酯（或乙酯）保护，而只能用

苄酯或叔丁酯保护，以避免将来用皂化去酯的步骤。Pht对催化氢解、HBr/HOAc处理

以及Na/NH

3

（液）还原（后处理的碱性条件需要避免）等均稳定，但很容易用肼处理

脱去。

3.1.1邻苯二甲酰基的引入

最先导入Pht基的方法是将邻苯二甲酸酐同氨基酸在145-150℃进行熔融反应，但

这个方法对有的氨基酸会引起部分消旋作用，因而后来又进行了一些改进，如邻苯二

甲酸酐/CHCl

3

/70℃下反应[2]。然而最成功的是Nefkens提出的用N-乙氧羰基邻苯二甲

酰亚胺为试剂的方法（见下式）[3]，即N-乙氧羰基邻苯二甲酰亚胺与氨基酸在Na

2

CO

3

水溶液中于25℃反应10-15分钟，就可以得到85-95%的Pht-氨基衍生物[4]。这个试剂

可在仲胺的存在的情况下选择性地保护伯胺[5]。

,y.,Australian,.,1954,7,173

,toetal.,.,1978,43,2320

s,etal.,.,1960,79,688;Soai,

Kenso;Ookawa,Atsuhiroetal.,.,1982,55(5),1671-1672;

r;etal.,.,1998,11,3560;Santaniello,

Enzo;Ponti,Fedegcoetal.,.,1980,10(8),611-614;Siedlecka,

Renata;Skarzewski,Jaceketal.,.,1997,27(12),281-2086

ur,retal.,.,1983,13,311

sky,.,orsch.B.,1986,41B,122

3.1.1.1邻苯二甲酸酐引入邻苯二甲酰基示例

,.,.,76,123

Intoa2-L,round-bottomedflaskfittedwithaDean-Starkapparatus,reflux

condenser,anddryingtubecontainingcalciumchlorideareplacedL-methionine

methylesterhydrochloride(50.0g,mol),phthalicanhydride(37.1g,mol),

triethylamine(100mL,mol),andtoluene(1L).Themixtureismagnetically

stirredandheatedunderrefluxforhratwhichpointapproximatelymLof

ctionmixtureisallowedtocooltoroomtemperature

andtheprecipitatedtriethylaminehydrochloride(34g)iscollectedbysuction

trateiswashedwithfour300-mLportionsof1Naqueous

aniclayer

isdriedovermagnesiumsulfate,filtered,andthefiltrateisconcentrated

idualoilisplaced

underreducedpressurefor12hrat-0.5mm,followedbytriturationwith200

mLofpentanetogive59g(80%)ofproductasawhitesolidaftercollection

anddryingatroomtemperatureunderreducedpressure(mp37-40°C).mp

37-40°C,;[α]20

D

?°(CHCl

3

,c.

3.1.1.2邻苯二甲酸单乙酯引入邻苯二甲酰基示例

r;etal.,.,1998,11,3560

ToasuspensionofPyBOP(2.84g,mmol,equiv)indryTHF(10mL)wasadded

asolutionof2-ethoxycarbonylbenzoicacid(1.08g,mmol,equiv)inTHF(10

mL)andi-Pr

2

NEtmL,mmol,equiv),andtheresultingmixturewasstirredfor

ards,thissolutionwasaddedtoasuspensionof7(0.898

g)inTHF(10mL)at0°C,vent

waseliminatedinvacuo,andtheresiduewasheatedat85°

reactionmixturewasthendissolvedin250mLofdichloromethaneandwashed

withsaturatedNaHCO

3

solution(2x100mL)andwithbrine(100mL).Theorganic

layerwasdried(Na

2

SO

4

)andevaporatedtogiveacrudeproductwhichwaspurified

bycolumnchromatographytoyield1.28gof

(2S,3S)-4-phenyl-3-phthalimidobutane-1,2-diol(8)(83%)asawhitesolid:mp

91-93°C.

3.1.1.3N-乙氧羰基邻苯二甲酰胺引入邻苯二甲酰基示例:

Worster,PaulM;Leznoff,CliffordCetal.,.,1980,45(1),174-175

Ethylchloroformate(115mL,mol)wasaddeddropwiseoveraperiodof90min

toastirredsolutionofphthalimide(149.9g,mol)andtriethylamine(160

mL,mol)indimethylformamide(500mL)at0-5°ction

was

slowlyaddedtoanagitatedmixtureoficeandwater(3L).Thesolidproduct

wascollectedandextractedwithtwoportionsofchloroform(450mLandthen

50mL).Theextractwasdried(Na

2

SO

4

),cooledovernightintherefrigerator,

andfilteredtoremovephthalimide(mp238°C).Thechloroformsolutionwas

concentratedtoabout350mL,dilutedwithpetroleumether(bp60-80°C;350

mL)andallowedtostandatroomtemperaturetogive

N-(ethoxycarbony1)phthalimide(179g,followedbytwoadditionalcropsfora

totalof212g,95%yield):mp83°C.

;etal.,.,2004,16,2721

Thesolutionofcompound1mg,mmol)inTHF(4mL)wastreatedwith

N-(ethoxycarbonyl)-phthalimide(230mg,mmol),andNaHCO

3

(88mg,mmol)at

0°ctionwasstirredfor7hatrt,eouslayer

wasextractedwithEtOAc(4x5mL).Thecombinedorganicextractswerewashed

withsaturatedaqueousNH

4

Cl(3x3mL)andbrine(3mL),dried(Na

2

SO

4

),and

tography(hexane/EtOAc=5/1)provided9asan

oil(215mg,75%).

3.1.2邻苯二甲酰基的脱去

Pht-氨基衍生物很容易用肼处理脱去。一般用水合肼的醇溶液回流2小时[1,4]或用

肼的水或醇溶液室温放置1-2天都可完全脱去Pht保护基[2]。在此条件下Cbz、Boc、

甲酰基、Trt、Tos等均可不受影响。在肼效果差的情况下，NaBH

4

/i-PrOH-H

2

O(6:1)和

AcOH在80℃反应5-8小时，这个方法是很有效的(见下式)[3]。另外，浓HCl回流也容

易脱去Pht保护基[4]。

n,netal.,.,1952,74,3822;F.

al.,.,1951,243,2976

ta,.,.,1988,7,701

;etal.,TetrahedronLett.,1984,25,2093-2096

,Chang-Hee;Lee,Jin-Suketal.,.,2005,6,2067-2074

3.1.2.1NH

2

NH

2

/MeOH脱除邻苯二甲酰胺示例

;etal.,.,2004,16,2721

Toasolutionofcompound1(313mg,mmol)inMeOH(6mL)wasaddedhydrazine

monohydratemL,mmol)at0°eingstirredatsametemperaturefor

3h,thesolventswereremovedinvacuoandtheresiduewasre-dissolvedinto

water(10mL).ThepHofsolutionwasthenadjustedto1-2byadding1NHCl

at0°lemixturewasstirredfor1hatrt,

filtratewastreatedwithsolidNa

2

CO

3

ture

wasextractedwithCH

2

Cl

2

(10mLx4).Thecombinedextractsweredried(Na

2

SO

4

),

concentratedanddriedinvacuotoprovidecompound2(209mg,quantitatively)

asayellowishoil.

3.1.2.2NH

2

NH

2

/EtOH脱除邻苯二甲酰胺示例

Lee,Chang-Hee;Lee,Jin-Suketal.,.,2005,6,2067-2074

Compound1(1.66g,mmol)wasdissolvedinethanol(50mL),andthenhydrazine

monohydratemL,19mmol)ultingmixturewasheatedatreflux

turethenwascombined

withaqueousNaOH(50mL)andextractedwithCH

2

Cl

2

.Thesolventwasremoved

invacuotoaffordcompound2(0.79g,76%),whichwasuseddirectlyinthe

nextstepwithoutfurtherpurification.

3.1.2.3HCl脱除邻苯二甲酰胺示例

Lee,Chang-Hee;Lee,Jin-Suketal.,.,2005,6,2067-2074

Compound1(1.0g,mmol)andconcentratedHCl(3mL)washeatedfor60hat

100°hemixturewasallowedtocooltoroomtemperature,water(20

mL)idprecipitatethatformedwasremovedbyfiltrationand

discarded,andtheaqueouslayerwaswashedwithdiethylethertwice,withthese

erwasremovedinvacuo,andtheremaining

solidwasdriedtogivecompound2(0.61g,95%),whichwasthenusedtothe

nextstepwithoutfurtherpurificationduetoitsinstability.

3.1.2.4NaBH

4

/i-PrOH-H

2

O(6:1)和AcOH脱除示例

;etal.,TetrahedronLett.,1984,25,2093-2096

Toastirredsolutionofcompound1(0.36g,1mmol)in2-propanolml)and

H

2

Oml)wasaddedNaBH

4

(0.19g,5mmol).Afterstirring24h,TLCindicated

(1ml)wasaddedcarefullyand

whenthefoamingsubsided,theflaskwasstopperedandheatedto80°Cfor2

dereactionmixturewasthenelutedontoaDowex50(H+)columnx

10cm),washedwithH

2

O(150ml),thenelutedwith1MNH

4

OH(200ml).

Ninhydrin-activefractionswerecollectedandpooledforfreezedrying,and

thusaffordedcompound2(0.2g,89%)asanammoniumsalt.

对甲苯磺酰基（Tos）

对甲苯磺酰胺由胺和对甲苯磺酰氯在吡啶或水溶性碱存在下制得的，它是最稳定的

氨基保护基之一，对碱性水解和催化还原稳定。碱性较弱的胺如吡咯和吲哚形成的对

甲苯磺酰胺比碱性更强的烷基胺所形成的对甲苯磺酰胺更易去保护，可以通过碱性水

解去保护，而后者通过碱性水解去保护是不可能的。对甲苯磺酰胺一个很有吸引力的

性质是这些衍生物的酰胺或氨基甲酸酯更容易形成结晶。除在早期作过α-氨基的保护

基外，一般都是用作碱性氨基酸的侧链保护基。

Tos-氨基酸能够通过酰氯、叠氮、DCC和四乙基焦亚磷酸等方法进行接肽，但混合

酸酐法一般不能采用。这是因为Tos基得强烈吸电子效应使得被酰化的氨基上的氢原

子容易离去，而在用混合酸酐法接肽时会产生N，N-双取代等副反应使产率很低。同样，

Tos-氨基酸的酰氯在NaOH等强碱作用下很不稳定，会发生分解生成Tos-NH

2

、醛和CO

（见下式）[1]

m.,.,(London).,1955,1120;.,1957,

79,3257

3.2.1对甲苯磺酰基的引入

对甲苯磺酰氯在NaOH、NaHCO

3

或其他有机碱存在下同氨基酸、吡咯和吲哚等反应

很容易得到良好产率的Tos-衍生物[1]

bara,.,.,1969,42,1466

3.2.1.1对甲苯磺酰基的引入示例

.,.,73,174

22.9g(90mmol)ofcompound1,13.66g(135mmol)oftriethylamine,and

100mLofdryTHFareplacedina300-mL,round-bottomedflask,equipped

withapressure-equalizingdroppingfunnel,amagneticstirringbar,and

ppingfunnelischargedwithasolutionof18.9g

mmol)ctionmixture

iscooledto0°Cwithmagneticstirring,andthesolutionof

thistimeperiod,thereactionmixtureisdilutedwith50mLofsaturated

sodiumchloridesolutionand50mLofethylacetate,transferredtoa500-mL

separatoryfunnel,mixedthoroughly,

bined

organiclayersaredried(Na

2

SO

4

),filtered,concentratedunderreducedpressure,

andtheresultingresiduepurifiedbychromatographytogive22.43g(61%)

ofcompound2(R

f

=,CHCl

3

/EtOAc,1:1)asacolorlesssolid,mp144–146°C.

3.2.2对甲苯磺酰基的脱去

Tos非常稳定，它经得起一般酸解(TFA和HCl等）、皂化、催化氢解等多种条件得

处理比受影响，常用萘钠[1]、Na/NH

3

(液)[2]和Li/NH

3

(液)[3]处理脱去。HBr/苯酚[4]和

Mg/MeOH也是比较好的去保护方法[5]。值得注意的是，Na/NH

3

(液)的操作比较麻烦，并

且会引起一些肽键的断裂和肽链的破坏。另外，有时HF/MeCN回流也能脱去Tos基[6]。

,Yui;Mori,Kenjietal.,m.,2002,66(7),

1531-1537;Kaiser,Alexander;Balbi,Miriametal.,Tetrahedron:Asymmetry,

1999,10(5),1001-1014;Takikawa,Hirosato;Muto,Shiu-etsuetal.,

Tetrahedron,1998,54(13),3141-3150;Sugimura,Hideyuki;Miura,Masayuki

etal.,Tetrahedron:Asymmetry,1997,8(24),4089-4100

,.,.(London).,1963,913;Dolence,;

Roylance,JasonBetal.,Tetrahedron:Asymmetry,2004,15(20),3307-3322;

Amat,Mercedes;Seffar,Fatimaetal.,Synthesis,2001,2,267-275;Hoye,

ThomasR;Chen,Minzhangetal.,TetrahedronLett.,1996,37(18),3099-3100;

Hoye,ThomasR;Chen,Minzhangetal.,.,1999,64(19),7184-7201

s,Kevin;Liu,LeeTetal.,.,1993,58(17),4758-4763

,Jan;Lebduskova,Petraetal.,.J.,2003,9(23),5899-5915;

Calvisi,Giuseppina;Dell-Uomo,Natalinaetal.,.,2003,

23,4501-4506;Currie,GordonS;Drew,.,.

PerkinTrans.1,2000,17,2982-2990;Davis,FranklinA;Srirajan,

Vaidyanathanetal.,.,2000,65(10),3248-3251;Davis,Franklin

A;Liu,Huetal.,.,1999,64(20),7559-7567;Drury,William

J;Ferraris,Danaetal.,.,1998,120(42),

ma,otoetal.,.,1995,60,1486;,

tal.,.,1997,1017;Nenajdenko,

ValentineG;Karpov,AlexeiSetal.,Tetrahedron:Asymmetry,2001,12(18),

2517-2528

wa,Hirosato;Maseda,Takeshietal.,TetrahedronLett.,1995,36(42),

7689-7692

3.1.2.1Na/NH

3

脱除对甲苯磺酰基示例

;ampetal.,.,1999,11,2977

Toatwoneckedflaskequippedwithadryicecondenserwasaddedcompound1

(3.20g,mmol)inTHF(15ml)andammoniagastocondenseabout25mlofliquid.

Smallpiecesofsodium(552mg,mmol)wereaddedtothestirredsolutionuntil

tirringfor10min,thereaction

wasquenchedbyaddingdropwiseglacialaceticacid(2ml).TheNH

3

wasallowed

deproductwasdriedinvacuofor1htogivecompound

2(1.3g,89%)asacolorlessoil.

3.1.2.2Li/NH

3

脱除对甲苯磺酰基示例

Burgess,Kevin;Liu,LeeTetal.,.,1993,58(17),4758-4763

Lithiummetalwasaddedtoasolutionofcompound1(1.5g,mmol)in5mlof

THFand200mlofliquidNH

3

.Theresultingdarkbluesolutionwasstirredfor

oniawasevaporated.

TheresiduewasdilutedwithsaturatedaqueousNaCl(30ml),andextractedwith

CH

2

Cl

2

(4x20ml).Thecombinedlayerswasdriedandthesolventevaporated

togivecompound2(0.4g,55%)asoil.

3.1.2.3Na/萘脱除对甲苯磺酰基示例

Kaiser,Alexander;Balbi,Miriametal.,Tetrahedron:Asymmetry,1999,10(5),

1001-1014

Toasolutionofcompound1(0.78g,mmol)indryTHF(20ml)asolutionof

sodiumnaphthalenide[31ml;preparedbystirringnaphthalene(3.96g,mmol)

andsmallpiecesofsodium(1.92g,mmol)indryTHF(120ml)for3hatroom

temperatureundernitrogen]wasaddedover10minat-78°at-78°C,

water(5ml)wasadded,ture

wasdilutedwithwater(10ml)andextractedwithEtOAc(3x30ml).Thecombined

EtOAclayerswerewashedwithbrine(2x20ml),

chromatography(CH

2

Cl

2

:MeOH,9:1)affordedcompound2(0.17g,39%)asa

colorlessoil.

3.1.2.4HBr/苯酚脱除对甲苯磺酰基示例

Calvisi,Giuseppina;Dell-Uomo,Natalinaetal.,.,2003,23,

4501-4506

Around-bottomflaskcontainingamixtureofcompound1(600mg,mmol),phenol

(547mg,mmol)andHBrmL,48%)wasplacedinanoilbathpreviouslyheated

to130°ctionmixturewasthenallowed

tocooltoroomtemperature,dilutedwithwaterandextractedtwicewithEtOAc.

Theaqueouslayerwasevaporatedundervacuum,theresiduewastakenupseveral

timeswithCH

3

CN(evaporatingundervacuumeverytime)untilasolidresidue,

insolubleinCH

3

CN,idwasfilteredanddriedtogive

compound2(230mg,95%)asthedihydrobromidesalt.

3.1.2.5Mg/MeOH脱除对甲苯磺酰基示例

Nenajdenko,ValentineG;Karpov,AlexeiSetal.,Tetrahedron:Asymmetry,2001,

12(18),2517-2528

ToasuspensionofMg(0.45g,20mmol)inMeOH(5mL)wasaddedasolution

ofcompound1(0.74g,2mmol)inMeOH(10mL).Theresultingsuspensionwas

reactionmixturewasthendilutedwithaqueousNH4Clandextractedwithether

(3x5mL).TheorganiclayerwasdriedoverMgSO

4

lting

oilethanolicsolutionHCl(2M,mL)hloridewasprecipitated,

filteredandwashedwithethertoaffordcompound2HClsalt(0.46g,90%)as

awhitesolid.

三氟乙酰基（Tfa）

三氟乙酰基（Tfa）是Weygand最先引入到多肽合成中的[1]。三氟乙酰基（Tfa）可

用三氟醋酐导入，在稀碱液中很容易脱去。Tfa保护的氨基酸或多肽在高真空下易于气

化，因而能用于气相层析以检测消旋的程度[2]和测定天然肽的排列顺序[3]，而且由于含

有F，也可用19FNMR来检测合成肽的纯度、消旋程度以及类似物的鉴定等[4]。由于N-Tfa-

氨基酸在接肽时易于消旋，也是采用此保护基时应该注意的地方。

d,s.,.,1952,64,136

d,,.,orsch.,1968,23b,279

a.,m.,1963,54,279

tal.,.,1972,94,265

3.3.1三氟乙酰基的引入

由于三氟醋酐同氨基酸反应时易生成恶唑烷酮而发生消旋[1]，因此，同甲酰基的引

入一样，在低温下于三氟醋酸溶液中用三氟醋酐酰化为好[2]。一般而言，

CF

3

COOEt/Et

3

N/MeOH是较好的方法[3]，可在仲胺存在下，选择性地保护伯胺[4]。并且该

方法地聚合物方法也已得到发展[5]。在TFAA/18-crown-6/Et

3

N中，伯胺与18-crown-6

形成络合物，可选择性地酰化仲胺[6]。而在仲胺存在下，CF3COO-邻苯二甲酰亚胺也可

选择性地将TFA基团引入到伯胺[7]。

d,g.,.,1954,87,248

d,.,.,1956,89,647

y.,.,1979,44,2805

,,pleetal.,TetrahedronLett.,1995,36,7357;

M.C.O’Sullivan,ple.,TetrahedronLett.,1995,36,3451

aya,f,an.,.,1987,52,1362

t,.,.,1978,471

on,s.,.,1988,53,3108

3.3.1.1TFAA引入三氟乙酰基示例

Chambers,JamesJ;Parrish,JeasenCetal.,.,2003,46(16),

3526-3535

Toastirredsuspensionofthehydrobromidesaltofcompound1(1.3g,mmol)

and4-N,N-(dimethylamino)pyridine(0.04g,mmol)inCH

2

Cl

2

(40mL)wasadded

Et

3

NmL,mmol),andthemixturewascooledto0°oroaceticanhydride

mL,17mmol)turewasallowed

turewasthendiluted

withCH

2

Cl

2

(50mL)andwashedwith2NHCl(50mL),saturatedNaHCO

3

(50mL),

andbrine(50mL).Theorganicphasewasthendried(MgSO

4

),filtered,and

evaporatedtoleavecompound2asawhitesolidthatwasrecrystallizedfrom

Et

2

O(1.2g,92%):mp197-198°C.

3.3.1.2三氟乙酸乙酯引入三氟乙酰基示例

Knoops,Niele;Derioover,Geertretal.,Tetrahedron,1997,53(37),

Ethyltrifluoroacetatemmol)wasdissolvedin10mldrydiethyletherand

stirredat0°nd1mmol)wasaddedandthereaction

emovalofthe

solvent,theresidueswerepurifiedbyfastcolumnchromatography(SiO

2

;CHCl

3

)

togivecompound2(yield98%)asayellowcrystalline.:68-69°C

(CH

2

Cl

2

/hexanes).

4.3.1.3三氟乙酸乙酯选择性保护伯胺示例

Whitlock,GavinA;Carreira,ErickMetal.,.,2000,83(8),

2007-2022

Compound1mmol)wasdissolvedinTHF(10mL),cooledto0°C,andCF

3

COOEt

mL,mmol)turewasstirredat0°Cfor1handthenat23°C

ventwasthenevaporatedunderreducedpressuretogiveapale

cationbyFC(silicagel;MeOH)afforded2(119mg,85%)as

(MeOH):R

f

=.[α]=+(c=,CHCl

3

).

3.3.2三氟乙酰基的脱去

三氟乙酰胺也是较易去保护地酰胺之一。Tfa基可以在水或乙醇水溶液中用N

NaOH处理或者用1M哌啶溶液处理很容易地脱去。由于脱去地条件温和，也适用于一

些长链肽中的Tfa基的脱去，例如，Anfisen用上述条件于8M尿素中5℃处理8小时

脱去42肽中的Lys侧链的Tfa基[1]，不过考虑到溶解度以及断链副反应等不利因素，

长链肽的碱水解脱除保护基时要综合考虑各种因素。在K

2

CO

3

或Na

2

CO

3

/MeOH/H

2

O条件下，

Tfa可在甲基酯存在下于室温去保护[2]。也可在NH

3

/MeOH[3]，HCl/MeOH[4]或通过相转移

水解(KOH/Et

3

Bn+Br-/H

2

O/CH

2

Cl

2

或乙醚)脱去[5]。

,en.,.,1969,244,6314

on,s.,.,1988,53,3108;.,

.,1965,30,1287;,.,.,1979,44,

573;tz,al.,.,1973,95,612;

,es.,.,1989,54,2498

a,in.,.,1979,44,2039

,.,.,1994,116,562

se,la,ietal.,Trans.

I,1997,247

3.3.2.1KOH脱去三氟乙酰基示例

Chambers,JamesJ;Parrish,JasonCetal.,.,2003,46(16),

3526-3535

Asolutionofcompound1(1.7g,mmol)inMeOH(250mL)wascooledto0°C,

andthen5NKOHsolution(30mL)ctionmixturewas

allowedtowarmtoroomtemperatureandstirredovernight,andthentheMeOH

iduewasdilutedwithH

2

O(25mL)and

extractedwithEt

2

O(4x100mL),dried(Na

2

SO

4

),filtered,andevaporatedto

lwasdissolvedinEt

2

O(100mL),filteredthrougha

plugofglasswool,andneutralizedbytheslowadditionofoxalicacid(54

mL,0.1MinMeOH).Thesolventswereremoved,andtheresultingwhiteresidue

wasrecrystallizedfromMeOHtoaffordcompound2(0.9g,59%)asthehemioxalate

salt,243°C.

3.3.2.2K

2

CO

3

脱去三氟乙酰基示例

Whitlock,GavinA;Carreira,ErickMetal.,.,2000,83(8),

2007-2022

Compound1(45mg,mmol)wasdissolvedin5%K

2

CO

3

inMeOH/H

2

O(15mL),andthe

rredat23°Cfor4h.H

2

O(3mL)wasadded,urated

withNaCl,andthenextractedwithCH

2

Cl

2

(5×15mL).ts

weredried(Na

2

SO

4

)andconcentratedunderreducedpressuretoaffordcompound

2mg,85%).

4．烷基类

三苯甲基（Trt）

三苯甲基（Trt）是50年代开始用于多肽合成的，现在体积大的Trt被用于保护

各种氨基，如氨基酸、青霉素、头孢霉素等。N-Trt-α-氨基酸的酯不能发生水解，需

要较强的去保护条件，α-质子同样不易被脱去，这意味着，在分子中其他地方的酯可

以选择性的水解。

Trt的立体位阻的影响还表现在接肽反应中，Trt-氨基酸（除Trt-Gly和Trt-Ala

以外）一般不能采用混合酸酐法接肽[1]，Trt-氨基酸的酯不能水解，也就不能用叠氮法

接肽，而只能采用DCC这类方法来接肽。但Trt的立体位阻只表现在对Trt-氨基酸的

反应影响上，Trt-肽则不存在这个问题，因此对长链肽的末端氨基的保护来说，Trt

还是可用的，特别是对于带有含硫氨基酸的肽来说，由于不能采用催化氢解来实现Cbz

和Boc之间的选择性脱去，采用Trt则将有其有利之处。

,ropoulos.,.,1956,78,1359

4.1.1三苯甲基的引入

由于Trt有很大的立体位阻，除氨基酸侧链很小的Trt-甘氨酸酯以外，一般的Trt-

氨基酸酯都难以皂化，而用很强烈的条件（如高温）则有引起消旋的危险。因此Trt

的引入一般是采用以下反应来实现的。

尽管可采用先制得Trt-氨基酸苄酯，然后控制吸收当量的氢选择性氢解的方法，

但由于总有部分Trt被氢化，因此需要除去所生成的自由氨基酸副产物。玉置等人曾

经提出[1]，将氨基酸悬浮与CHCl

3

中，加入当量的Trt-Cl和当量的Et

3

N，搅拌反应5-10

小时先生成Trt-氨基酸三苯甲酯，然后用HCl/HOAc处理5-20分钟脱去三苯甲酯而得

到Trt-氨基酸。另一个办法是用肽的酯同Trt-Cl反应得到Trt-肽酯，后者容易皂化

而不存在Trt的立体位阻作用。吡咯、吡唑和咪唑等也可用类似反应容易地得到良好

产率的Trt-衍生物。另外，利用Trt-Cl/Me

3

SiCl/Et

3

N[2]和Trt-Cl/TMSCl/Et

3

N[3]也容易

得到Trt-氨基酸。

1.玉置健太郎，工藤士郎.,有机合成协会志.,1971,29,599

n,RobertV;Maslouh,Najibetal.,.,2002,67(4),

1045-1056;Sim,TaeBo;Rapoport,Henryetal.,.,1999,64(7),

2532-2536

n,RobertV;TaoJunhua,.,1998,63(12),3979-3985

4.1.1.1氨基酸的三苯甲基的引入示例

Hoffman,RobertV;Maslouh,Najibetal.,.,2002,67(4),1045-1056

ChlorotrimethylsilanemL,mmol)wasaddedatroomtemperaturetoastirred

suspensionofancompound1(1.61g,mmol)in18mLofCHCl

3

/MeCN(5:1).The

reactionmixturewasrefluxedfor2handthencooledto0°seaddition

oftriethylaminemL,mmol)wasfollowedbyasolutionoftritylchloride

(2.79g,mmol)inchloroform(10mL).Theresultingmixturewasstirredfor

1h,andthenmethanol(2mL)oncentration,thepaleyellow

eouslayerwas

extractedtwicewithdiethylether(20mL).Thecombinedorganiclayerswere

dried(MgSO

4

)andconcentratedtogivecompound2(2.14g,53%),whichwasused

forthenextstepwithoutfurtherpurification.

4.1.1.2氨基醇的三苯甲基的引入示例

Gros,Christel;Boulegue,Cyriletal.,Tetrahedron,2002,58(13),2673-2680

Aminoalcohol1(2.15g,mmol)andEt

3

NweredissolvedindryCH

2

Cl

2

(60mL).

Totheice-bathcooledprecedingsolution,tritylchloride(3.43g,mmol)

dissolvedinCH

2

Cl

2

(20mL)tirring1

hatrt,iduedissolvedinAcOEt(100mL)

andfollowedbyaflashcolumnchromatographypurification(AcOEt/cyclohexane

80:20)toaffordalcohol2asanoilin:83%yield.

4.1.2三苯甲基的脱去

Trt容易用酸脱去，如用HOAc或50%（或75%）HOAc的水溶液在30℃或回流数分

钟顺利除去。这时N-Boc和O-But可以稳定不动[1]。其他如HCl/MeOH[2]、HCl/CHCl

3

、

HBr/HOAc和TFA[3]都能很方便的脱去Trt，用HCl/MeOH处理Trt-Lys(Trt)OCH

3

可以得

到Lys(Trt)OCH

3

，说明侧链上的Trt比α-Trt对酸更稳定一些[4]。Cys(Trt)、His(Trt)

和Try(Trt)等的侧链上的N-Trt比Nα-Trt对酸稳定，因此可以采用适当的酸解条件

选择性脱去Nα-Trt而保留侧链上的N-Trt。

Trt对酸的敏感程度还随所用的酸的不同而异，例如Trt对醋酸比较敏感，在80%

的醋酸中，Trt的脱除速度大约比Bpoc快7倍，比Boc快21，000倍，因而可以在Boc

或Moz存在下选择性地脱去Trt。但如用0.1MHBr/HOAc为试剂，Trt脱去速度反而慢

于Boc和Moz[1]。

Trt也能被催化氢解脱去[5]，但脱去速度比O-苄基和N-Cbz要慢得多。根据所用试

剂和脱去方法得不同，Trt被分解所形成的产物也不同（见下式）。

,ropoulos.,.,1956,78,1359;F.

,on.,.,1957,79,4686;er,

.,.,1961,44,159

-Suk,-Juetal.,.,2004,10,2499;

,ietal.,.,2002,10,3829

,-Sangetal.,TetrahedronLett.,2003,8,1537

,.,.,1961,83,719;,B.

t.,.,1956,698

asekhar,S.,Babu,raetal.,TetrahedronLett.,2003,10,

2057;,yetal.,Tetrahedront.,2002,44,8921

4.1.2.1TFA脱去三苯甲基示例

MohdMustapa,RichardHarris,NivesBulic-Subanovicetal.,.

Chem.,2003,21,8185;,tal.,Tetrahedron,2002,44,9101

Compound1(3.5g,mmol)wastreatedwitha5%solutionoftrifluoroacetic

acidmL,18mmol,4equiv)inCHCl

3

(27mL)underinertconditionsfor4h.

TheresultingsolutionwasdilutedwithCHCl

3

(200mL)andwashedwithsodium

hydrogencarbonate(5%aqw/v,2×75mL)andwater(2×50mL).Thesolvent

erialwasthenredissolvedinCHCl

3

(20mL)and

MeOH(20mL),andthesolventswereagainremovedinvacuotoyieldcompound

2(2.1g,87%)asapaleyellowliquid.

4.1.2.2TFA-TIS脱去三苯甲基示例

Swall,Vinay;Matteuccletal.,Tetrahedron,2002,58(44),9101-9110

Compound1(2.0g,mmol)wasstirredwithTFA,CH

2

Cl

2

andTISmL)for1h.

Solventwasremovedinvacuoandtheresiduepurifiedbycolumnchromatography

(SiO

2

,MeOH/CHCl

3

,1:9v:v)toaffordcompound2(1.16g,91%)asawhitesolid.

4.1.2.3TFA-Et

3

SiH脱去三苯甲基示例

Pickersgill,;Rapoport,Henry;.,2000,65(13),4048-4057

Toastirredsolutionofcompound1(3.34g,mmol)andtriethylsilanemL,

mmol)inCH

2

Cl

2

(16mL)cooledto0°CwasaddeddropwiseTFA(16mL).The

resultantcolorlesssolutionwasallowedtowarmtort,withstirringcontinued

ventswereevaporated,theresiduewastrituratedwithhexanes

(5x50mL),thehexaneextractswerediscarded,andtheoilyresiduewas

partitionedbetweenCHCl

3

/IPA(250mL,3/1)and1MNaOH(precooledto0°C,

100mL).TheaqueousphasewasextractedwithfurtherportionsofCHCl

3

/IPA(2

x200mL,3/1),andthecombinedorganicphasewasdried,filtered,and

evaporatedtogivecompound2(2.04g,100%crudeyield)asapaleyellowoil.

4.1.2.4HOAc脱去三苯甲基示例

Vago,Istvan;Kalaus,Groergyetal.,Heterocycles,2001,55(5),873-880

0.85g(2mmol)ofcompound1wasdissolvedinthemixtureof20mLofacetic

utionwasheatedunderargonat60oCfor1h,

ulteddarksolutionwasdilutedwith

200mLofwater;thetriphenylmethanolwasremovedbyextractionwithether.

ThepHofthewateryphasewasadjustedtoavalueof8withsodiumcarbonate

solution,extractedwithdichloromethane;theextractwasdriedwithmagnesium

sulfate,evaporatedtodrynessinvacuumtogive,compound2(0.24g,64%)as

unstablebrownoil.

4.1.2.5TBS和Boc官能团存在下用BF

3

-HOAc脱去三苯甲基示例

Pickersgill,I,Fraser;Rapoport,Henry;.,2000,65(14),4048-4057

Toasolutionof32(2.67g,mmol)inCH

2

Cl

2

(27mL)cooledto0°Cwereadded

glacialaceticacidmL)andmL,mmol)dropwise,andthemixturewasstirred

at0°(0°C)1MNaOH(160mL)wasaddedandthemixturepartioned

betweenCHCl

3

/IPA(320mL,3/1)andcold(0°C)1MNaOH(66mL),followedby

extractionwithfurtherportionsofCHCl

3

/IPA(2x160mL,3/1).Thecombined

organicphasewasdried,filtered,andevaporatedtoaresiduewhichwas

chromatographed(CH

2

Cl

2

/MeOH,19/1to9/1)togive33(1.50g,88%)asacolorless

oil:[α]22

D

=+(c=,CHCl

3

).

2,4-二甲氧基苄基（DMB）

2,4-二甲氧基苄基（DMB）是较稳定的氨基保护基之一,对催化氢解较Cbz、PMB

和Bn稳定，故用H

2

/8%Pd-C/EtOH处理，则可除去Bn，而保留N-DMB[1]。同样，用

Pd(PPh3)4/HOAc/THF处理，则可保留N-DMB,而除去Alloc[2]。酰胺的苄基，常规加氢

方法不易脱除，但DMB和PMB容易脱除。在设计合成路线时，2,4-二甲氧基苄胺常被

用为氨的等价物加以使用。

1．Simig,Gyula;Doleschall,Gaboretal.,Tetrahedron,1985,41(2),479-484

2．Boeckman,RobertK;Weidner,CharlesHetal.,.,1989,111(20),

8036-8037

4.2.12,4-二甲氧基苄基（DMB）引入

2,4-二甲氧基苄基（DMB）一般由ArCHO/NaBH

3

CN或NaBH(OAc)

3

[1]还原胺化类引入。

,;Cox,RussellJetal.,Tetrahedron,1998,54(31),9195-9206

4.2.1.12,4-二甲氧基苄基（DMB）引入示例

Moore,;Cox,RussellJetal.,Tetrahedron,1998,54(31),9195-9206

MethanolicHClwasaddedtoastirredsolutionofL-phenylalaninemethylester

(4.33g，mmol)inmethanol(100mL)toadjusttopH6.

2,4-Dimethoxybenzaldehyde,mmol)wasthenadded,thesolutionstirredat

20°Cfor30minandthenNaBH

3

CN(2.20g，wasaddedandthereactionstirred

ventwasremovedinvucuo,water(50mL)addedand

thesolutionextractedwithdiethylether(3x100mL).Theorganicextracts

werecombined:washedwithanaqueoussolutionofFeSO

4

,dried(MgSO

4

),filtered

andreducedinvucuo,ties

of2,4-dimethoxybenzylalcoholwereremovedbydistillationunderreduced

presure(furnacetemparature110°C,mmHg).Theproductcouldbefurther

purifiedbychromatography(hexane:ethylacetate,50:50)togivecompound

1(3.71g,mmo1,%)[α]21

D

=-(c=,EtOH).

4.2.22,4-二甲氧基苄基（DMB）脱去

DMB容易用酸脱去，如用TFA[1,2,3,4],TosOH[5]或HCl[1]的有机溶液在0℃或室温即可

顺利除去。采用TFA/i-Pr

3

SiH/CH

2

Cl

2

时,N-Fmoc可以稳定不动[6]。其他如DDQ/CH

2

Cl

2

[7]

也能很方便的脱去DMB，而叔丁酯和N-Boc可以不受影响。

1．Hill,Bryan;Liu,Yongetal.,.,2004,6(23),4285-4288

2．Gardiner,JohnM;Goss,AndrewDetal.,TetrahedronLett.,2002,43(43),

7707-7710

3．Davidson,JamesP;Martin,StephenFetal.,TetrahedronLett.,2000,41(49),

9459-9464

4．Floyd,ChristopherD;Harmett,LauraAetal.,.,1998,6,637-639

5．Horiguchi,Yoshie;Saitch,Toshiwakietal.,Heterocycles,2002,57(6),

1063-1078

6．Goronovsky,Sofia;Meir,Simchaetal.,.,2003,10,1411-1414

7．Dagoneau,Christelle;Denis,Jean-Noeeletal.,.,1999,5,602-604

4.2.2.12,4-二甲氧基苄基（DMB）酸脱去示例

Hill,Bryan;Liu,Yongetal.,.,2004,6(23),4285-4288

RouteA:Toacooled0°CsolutionofSulfonamide3mg,mmole)andCH

2

Cl

2

mL)

wasaddedTFAmL).ction

wasstirredat0°Cforhrsthenthesolventwasremovedinvacoutoyield

idwassuspendedinacetoneandfilteredthruaplugof

cotton(acetonerinse).Thefiltratewasevaporatedandtheresiduepurified

byflashchromatography(15:85EtOAc:Hexanes)yieldedsulfonamide2mg,90%)

asaclearcolorlessoil.

RouteB:Asolutionofsulfonamide1mg,mmole),1NHClmL)andTHFmL)

turewasdilutedwithEt

2

O,washedwithaq.

NaHCO

3

,brine,driedoverMgSO

4

,hromatography

(15:85EtOAc:Hexanes)yieldedsulfonamide2mg,87%).

4.2.2.2DDQ脱去2,4-二甲氧基苄基（DMB）示例

Dagoneau,Christelle;Denis,Jean-Noeeletal.,.,1999,5,602-604

Asolutionofester1andDDQinCH

2

Cl

2

/H

2

O(19/1,6mL)wasstirredfor1day

turewasthendilutedwithCH

2

Cl

2

andtreatedbyasaturatedaqueous

solutionofNaHCO

3

.Classicalwork-up,followedbycolumnchromatography

(silicagel,AcOEt/pentane:1/9)affordedtheN-Bocamine2asacolorlessoil.

对甲氧基苄基（PMB）

对甲氧基苄基（PMB）是也最稳定的氨基保护基之一。它对大多数反应都是稳定的，

在Bn存在下，可用CAN[1,2]或DDQ[3,4,5]氧化选择脱PMB；同样，在Boc和叔丁酯存在下，

可用CAN氧化选择脱PMB[6]；也可用H

2

/Pd(OH)

2

去掉Bn，而保留PMB[7,8]。

i;tal.,TetrahedronLett.,2004,45(11),2381

i;tal.,.,2004,346(11),1355

;etal.,Trans.1,2000,22(1),

3765

;etal.,,2000,5,337

hoff;aetal.,.,2000,1,77

;netal.,.,2004,14(12),3103

;eretal.,Tetrahedron,2003,59(26),4911

;eretal.,TetrahedronAsymmetry,2002,13(3),227

4.3.1对甲氧基苄基（PMB）的引入

PMB一般采用MeOC

6

H

4

CH

2

Br或MeOC

6

H

4

CH

2

Cl和碱（K

2

CO

3

[1]、i-Pr

2

NEt[2]、NaH[3]和DBU[4]

等）在有机溶剂(如DMF、二氯甲烷和乙腈等)中反应来引入，或MeC

6

H

4

CHO/NaBH

3

CN[5]

或NaBH(OAc)

3

[6]还原胺化等。

;tal.,.,2001,15,2841;;

tal.,.,2000,1,122

a;uchietal.,Tetrahedron,2004,60(35),7743;T.

Shibuguchi;etal.,TetrahedronLett,2002,43(52),9539;T.

Ohshima;esikanetal.,.,2003,125(37),11206;

;doetal.,.,2002,17,3050

s;netal.,.,1997,62,4418

;netal.,TetrahedronLett,2001,42(20),3411

;setal.,.,2001,66(9),3133

one;gh.,.,1999,9(14),

1991

4.3.1.1烷基化引入对甲氧基苄基（PMB）示例1

;tal.,.,2001,15,2841

AnhydrousK

2

CO

3

(780mg,mmol,equiv.),n-Bu

4

NI(100mg,mmol,equiv.),and

p-methoxybenzylbromide(630mg,mmol,equiv.)wereaddedsuccessivelyto

asolutionofcompound1(700mg,mmol)inCH

3

CN(6mL).After1hat40°C

andovernightatroomtemperature,thereactionmixturewasdilutedwithether,

filtered,dematerialwas

purifiedbyflashchromatography(cyclohexane-AcOEt,95:5to90:10)togive

0.68g(65%)ofcompound2ascolorlessoil.[α]

D

20=+(c=,CHCl

3

).

4.3.1.2烷基化引入对甲氧基苄基（PMB）示例2

;doetal.,.,2002,17,3050

Amagneticallystirredsuspensionofcompound1(0.39g;mmol)and

diisopropylethylamine(DIPEA,25mL;mmol)intoluene(10mL)wasgently

warmeduntilaclearsolutionwasobtained.4-MethoxybenzylchloridemL;17

mmol)wasthenaddedinoneportion,andtheresultingsolutionwasheatedunder

reflux,andalsotheintermediateN-monosubstitutedderivativewerecompletely

consumed(ca.5h,TLCmonitoring).Thereactionmixturewasthencooledin

anicebath,dilutedwithethylacetate(0.2L),andextractedwith10%aq.

aniclayerwaswashedwithbrineanddried(Na

2

SO

4

),andthe

solventswereevaporatedunderreducedpressuretoaffordacrudereaction

product,chromatographyofwhichonsilicagel(petroleumether/Et

2

O,8:2)gave

thepure,oilytitlecompound2(0.37g;85%).

4.3.1.3还原胺化引入对甲氧基苄基（PMB）示例

;setal.,.,2001,66(9),3133

Toasolutionof5.031gmmol)ofamine1in13mLofMeOHwasaddedat0°C

mgmmol)ofNaBH

3

CNfollowedbymL(1.68g,mmol)ofp-anisaldehydeandmL

ctionmixturewaswarmedtoroomtemperature,stirredovernight,

andquenchedwithH

2

OandsolidNa

2

CO

3

.Theviscoussuspensionwastransferred

toaseparatoryfunnelandextractedwithCH

2

Cl

2

.Thecombinedorganicextracts

weredried(Na

2

SO

4

)andconcentratedinvacuotogiveabrightyellowoilthat

waspurifiedbychromatographyonSiO

2

(hexanes/EtOAc;9:1)toafford5.324g

mmol,84%)ofamine2asalightyellowoil:[α]

D

=(c=,CHCl

3

).

4.3.2对甲氧基苄基（PMB）的脱去

对甲氧基苄基（PMB）的脱去较多，除了常规的催化氢解外，CAN[1]、DDQ[2]或

SmI

2

[3]氧化去保护和在TFA[4]中加热脱去也经常应用。

i;tal.,TetrahedronLett.,2004,45(11),2381;A.

Dondoni;tal.,.,2004,346(11),1355;;

netal.,.,2004,14(12),3103;;

doetal.,.,2002,17,3050;h;Synth.

Commun.,2000,30(10),1779;;tal.,.,2000,

9,1336

;etal.,Trans.1,2000,22(1),

3765;;etal.,,2000,5,337;B.

Hungerhoff;aetal.,.,2000,1,77

;onetal.,.,1998,63(26),9932

hi;shietal.,Heterocycles,1998,48(9),1813;S.F.

Martin;etal.,.,1998,41(10),1581

4.3.2.1DDQ脱去对甲氧基苄基（PMB）示例

;etal.,Trans.1,2000,22(1),

3765-3774

DDQ(1.15g,mmol)wasaddedportionwisetoastirredsolutionofcompound

1(400mg,mmol)inMeCN-H

2

O(5:1,6mL)ctionwas

quenchedbytheadditionofsaturatedaqueoussodiumbicarbonatesolutionand

stirredvigorouslyfortenminutesbeforeextractingwithEt

2

bined

organicextractsweredried(MgSO

4

),filteredandconcentratedinvacuoefore

purificationbycolumnchromatographyonsilicagel(hexane-Et

2

O2:1)togive

compound2(246mg,79%)asacolourlessoil.

4.3.2.2CAN脱去对甲氧基苄基（PMB）示例

;tal.,.,2000,9,1336

Amixtureofcompound1(104mg,mmol)andCAN(350mg,mmol)ina1:1solution

ofMeCN-watermL)wasstirredat0°(5mL)wasaddedand

themixtureextractedwithEtOAc(3x10mL).Thecombinedorganicextractswere

dried(MgSO

4

)cationby

chromatographyonsilicawithpetrol-EtOAc(6:1)aseluentgaveamine2(65

mg,87%)asayellowoil.

4.3.3.3TFA脱去酰胺对甲氧基苄基（PMB）示例

;etal.,.,1998,41(10),1581

Compound1(200mg,mmol)wasdissolvedintrifluoroaceticacid(TFA)(10mL),

ctionmixture

wasconcentratedunderreducedpressure,andtheresiduewasdissolvedinCH

2

Cl

2

(50mL).Theorganiclayer

waswashedwithwater(2x25mL),dried(MgSO

4

),andconcentratedunderreduced

pressuretoleaveawhitesolidthatwaspurifiedbyflashchromatography

elutingwithhexanes/EtOAc(1:1)containing2%AcOHtogivecompound2(180

mg,77%)ofasawhitesolid:mp150-152°C.

苄基（Bn）

苄基（Bn）是也最稳定的氨基保护基之一，同PMB一样，对大多数反应都是稳定

的，但比PMB更加稳定，因而也更难脱除。酰胺的苄基，常规加氢方法不易脱除，可

以通过Na/NH

3

脱除。

4.4.1苄基（Bn）的引入

一般和PMB一样也采用C

6

H

4

CH

2

Br或C

6

H

4

CH

2

Cl和K

2

CO

3

[1]、DIPEA[2]、NaH[3]、Et

3

N[4]和

n-BuLi[5]在有机溶剂(如DMF、二氯甲烷和乙腈等)中反应来引入[6]，或C

6

H

4

CHO/NaBH

4

[7]、

NaBH

3

CN[8]或NaBH(OAc)

3

[9]还原胺化。

z,Mario;Cruz-Cordero,Ricardodeetal.,.,2004,6,

672-673;Gibson,SusanE;Mainolfi,Nelloetal.,.,2003,13,

1568-1569;Yamanaka,Masamichi;Nishida,Atsushietal.,.,2003,

68(8),3112-3120;Gutierrez-Garrica,VictorManueletal.,Tetrahedron,

2001,57(30),6487-6496;Cossy,Janine;Pevet,Isabelleetal.,.,

2001,15,2841-2850;Cossy,Janine;Pevet,Isabelleetal.,.,2000,

1,122-124

tas,Enver;Smith-Jones,PeterMetal.,.,2004,19,

3979-3984

wa,Yasushi;Ito,Hisanakaetal.,Tetrahedron,2004,60(6),1385-1392;

Cappelli,Andrea;Mohr,GallaPericotetal.,.,2003,46(17),

3568-3571

,Sujiu;Kang,Yonghan;Heterocycles,2002,57(12),2393-2400

n,Jonathan;Pink,JenniferHetal.,Trans.1,

2002,7,901-917

,etal.,.,1954,1012;N.

Yamazaki,shi.,.,1989,111,1397;,

.,.,1987,1329

,ti.,.,1992,22,853;ni,

oetal.,.,1996,61,3221;Berkom,LeonW.A.

Van;Gelder,RaneDeetal.,.,2005,5,907-917

,setal.,Tetrahedron.,1990,46,523;Kawasaki,

Temomi;Kouko,Takashietal.,TetrahedronLett.,2003,44(44),8849-8852;

Page,Daniel;Naismith,Angelaetal.,.,2001,44(15),2387-2390

y,KarolienVan;Eynde,etal.,Tetrahedron,2003,59(24),4421-4432

4.4.1.1烷基化引入苄基(Bn)示例

;tal.,.,2001,15,2841

AnhydrousK

2

CO

3

(500mg,mmol,equiv.),n-Bu

4

NI(66mg,mmol,equiv.),and

benzylbromidemL,mmol,equiv.)wereaddedsuccessivelytoasolutionof

compound1(500mg,mmol)inCH

3

CN(5mL).After2hat35-40°Candovernight

atroomtemperature,thereactionmixturewasdilutedwithether,filtered,

dematerialwaspurifiedby

flashchromatography(cyclohexane-AcOEt,95:5to90:10)togivecompound2

(0.54g,81%)asacolorlessoil.[α]

D

20=+(c=,CHCl

3

).

4.4.1.2还原胺化引入苄基（Bn）示例

Rompaey,KarolienVan;Eynde,IsabelleVandenetal.,Tetrahedron,2003,59(24),

4421-4432

Compound1(0.5g,mmol)wasdissolvedin1,2-dichloroethane(50mL)andthe

aldehyde(0.122g,mmol),Et

3

N(0.172g,mmol),NaBH(OAc)

3

(0.505g,mmol)

andMgSO

4

(30wt%)ctionwasstirredatroomtemperature.

turewasquenched

withsaturatedNaHCO

3

(50mL)andextractedwithEtOAc(3x70mL).Theorganic

layerwasdried(MgSO

4

),filteredandevaporatedtogivecompound2,whichwere

usedwithoutfurtherpurification.

4.4.2苄基（Bn）的脱去

Bn常用催化氢解脱去，如H

2

/20%Pd(OH)

2

-C[1]、H

2

/Pd-C[2]、H

2

/PdCl

2

[3]、Pd/HCOOH[4]

或Pd-C/HCOOH[5]、Pd-C/HCOONH

4

[6]、Pd-C/NH

2

NH

2

[7]或Pd-C/环已烯[8]作氢源转移氢化，而

用H

2

/Pd-C去保护通常很慢[9]，除非添加Boc

2

O促进Bn的离去。另外

CCl

3

CH

2

COCl/CH

3

CN[10]、Li/MH

3

[11]、Na/NH

3

[12]、CAN[13]和CH

3

CHClOCOCl[14]也经常应用。酰氨

上的苄基一般较难用氢解脱除，此时可以用AlCl

3

进行脱除。

as,.,.,1990,20,1209;Ueda,Shigeo;

Terauchi,Hideoetal.,.,2004,12(15),4101-4116;

Gathergood,Nicholas;Scammells,PaterJetal.,.,2003,5(6),

921-924

,Chantal;Couchet,Jean-Marcetal.,.,2005,6,2274-2284;

Wolin,Ronald;Santillan,Alejandroetal.,.,2004,12(16),

4511-4532;Tseng,Shi-Liang;Teng-Kuei;Tetrahedron:Asymmetry,2004,

15(21),3375-3380;Tseng,Shi-Liang;Teng-Kuei;Tetrahedron:Asymmetry,

2005,16(4),773-782;Dhavale,DilipD;Matin,MohammedMetal.,Bioorg.

.,2003,11(15),3295-3306;Mewshaw,RichardE;Zhou,Dahuietal.,

.,2004,47(15),3823-3842;Evans,OaryB;Furneaux,Richard

Hetal.,.,2003,46(15),3412-3423

a,Xavier;Pericas,MiquelAetal.,.,2005,35(2),

289-298

man,AlexanderL;Houghton,PeterJetal.,.,2005,3,

792-804;Basso,Andrea;Banfi,Lucaetal.,.,2005,70(2),

575-579

,.,.,1987,1329;,

aramaiahetal.,.,1979,44,3442

,.,TetrahedronLett.,1987,28,515;idem,.,

1987,17,415;Dullin,Anja;Dufrasne;Francoisetal.,.

(WeinheimGer.),2004,337(12),654-667;Grener,Elisabeth;FOLK,JohnE

etal.,.,2004,12(1),233-238;Dhavale,DilipD;Chaudhari,

VinodDetal.,TetrahedronLett.,2003,44(39),7321-7324;Chianelli,Dona;

Kim,Yong-Chuletal.,.,2003,11(23),5059-5068;Tilekar,

JayantN;Patil,NitinTetal.,Tetrahedron,2003,59(11),1873-1876

,C.O’Farrelletal.,Synthesis,1987,53

,l.,.,1995,117,10597

g,ff.,.,1953,7,263

,tal.,.,1987,52,19

,Ke-Gang;Yan,Shietal.,.,2004,6(13),2269-2272;Liu,

Ke-Gang;Zhou,Hai-Binetal.,.,2003,68(24),9528-9531

,XiaodongJ;Hart,ScottAetal.,.,2003,68(6),2343-2349

,StevenD;Davies,StephenGetal.,Trans.1,

2001,23,3106-3111

ori,Hideo;Ohno,Takeshietal.,.,2000,65(25),

8747-8757

4.4.2.1H

2

/Pd-C氢化脱苄基(Bn)示例

Basso,Andrea;Banfi,Lucaetal.,.,2005,70(2),575-579

Amixtureofcompound1(1.5g,mmol)and10%Pd/C(300mg)inmethanol(40

mL)wasstirredovernightunderH

2

(3bar).Thereactionmixturewasfiltered

overCelite,nd2(1.07g)

wasobtainedasapaleyellowoilinquantitativeyield.

4.4.2.2HCOONH

4

/Pd-C氢化脱苄基(Bn)示例

Tilekar,JayantN;Patil,NitinTetal.,Tetrahedron,2003,59(11),1873-1876

Asolutionofcompound1(1.1g,mmol),ammoniumformate(0.92g,mmol)and

10%Pd–C(0.2g)inmethanol(10mL)alyst

wasfilteredthroughceliteandwashedwithmethanol(5mLx2).Tothefiltrate,

cooledto0°Cwasaddedsodiumbicarbonate(0.725g,mmol)and

benzyloxycarbonylchloride(0.47g,mmol)andthestirredreactionmixture

2h,methanolwasremovedunderreduced

pressureandtheresiduewasextractedwithethylacetate(5mLx3).Combined

extractwaswashedwithbrine,driedoveranhydroussodiumsulphateand

concentratedonrotovaportoaffordaresiduewhichwaspurifiedbycolumn

chromatography(chloroform/methanol,9/1)togivecompound2(0.81g,84%)as

athickliquid;R

f

(20%methanol/chloroform);[α]

D

=+(c=,CHCl

3

).

4.4.2.3ClCOOCH

2

CCl

3

脱苄基(Bn)示例

,tal.,.,1987,52,19

Tocompound1(2.30g,mmol)inacetonitrile(25mL)wasaddedtrichloroethyl

chloroformatemL,mmol).Themixturewasstirredfor30minandconcentrated.

Thecrudeproductwaschromatographed(hexanes:methylenechloride=1:l)to

yieldcompound2(2.68g,93%)asawhiteneedles,whichcrystallizedfrom

absoluteethanol:mp162.5°C.

Toasolutionofcompound2(1.40g,mmol)inaceticacid(30mL)wasadded

powderedzinc(0.5g)ctionwasfiltered,

trate

aniclayerwasneutralized

withsaturatedsodiumbicarbonatesolutionanddried(Na

2

SO

4

).Thecrudeproduct

wasconcentratedandchromatographed(methylenechloride:ether=10:1)toyield

compound3(0.72g,88%)asayellowoil,whichgraduallycrystallized:mp

103-104°C.

4.4.2.4Na/NH

3

脱苄基(Bn)示例

Wang,XiaodongJ;Hart,ScottAetal.,.,2003,68(6),2343-2349

NH

3

(ca.160mL)wasdistilledinto40mLofTHFat-78°Candallowedtowarm

toreflux(-33°C).Na(ca.2.0g,87mmol)wasaddeduntiladeepbluesolution

ionofacid1(2.0g,mmol)inTHF(10mL)wasadded

directlytotheNa/NH

3

eing

stirredfor45minatreflux,thereactionwasquenchedwithNH

4

Cl(10mL)and

thenallowedtowarmtortwithconcentrationtoca.30mL(caution!NH

3

evolved).

ThemixturewasdilutedwithNH

4

Cl(50mL),acidifiedwith1NHCltopH7,and

extractedwithCHCl

3

(10x50mL),driedonMgSO

4

,andconcentratedtogive810

mg(66%)ofthealcohol2asapaleyellowoil(furtherpurificationcanbe

achievedbychromatographyonsilicawith3%MeOHinCHCl

3

ifdesired).

4.4.2.5CAN脱苄基(Bn)示例

Bull,StevenD;Davies,StephenGetal.,Trans.1,2001,

23,3106-3111

CAN(3.9g,mmol)wasaddedportionwisetoastirredsolutionof24(1.0g,

mmol)inMeCN-H

2

O(30mL,5:1)ixteenhours,the

reactionwasquenchedbytheadditionofsaturatedaqueoussodiumbicarbonate

solutionandstirredvigorouslyfortenminutesbeforeextractionwithEt

2

O.

Thecombinedorganicextractsweredried(MgSO

4

),filteredandconcentratedin

vacuobeforepurificationbycolumnchromatographyonsilicagel(hexane-Et

2

O

=5:1and1%Et

3

N)gave25(562mg,73%)asacolourlessoil;[α]24

D

=-(c=,

CHCl

3

).

CAN选择脱苄基(Bn)示例

.

Bull,StevenD;Davies,StephenGetal.,Trans.1,2000,

22,3765-3774

CAN(190mg,mmol)wasaddedportionwisetoastirredsolutionofcompound

1(90mg,mmol)inMeCN-H

2

O(5:1,5mL)ctionwas

quenchedbytheadditionofsaturatedaqueoussodiumbicarbonatesolutionand

stirredvigorouslyfortenminutesbeforeextractingwithEt

2

bined

organicextractsweredried(MgSO

4

),filteredandconcentratedinvacuoefore

purificationbycolumnchromatographyonsilicagel(gradientelution,30-40

petrol-Et

2

O7:3to1:1)togivecompound2(68mg,91%)asagum.[α]

D

24=

-(c=,CHCl

3

).

4.4.2.6CH

3

CHClOCOCl脱苄基(Bn)示例

US6410592：该方法也可用于脱甲基

Toasolutionofcompound1(727mg)indichloromethane(75ml)whichwasbeing

maintainedat0°Cundernitrogenwasadded1-chloroethylchloroformateml)

turewasthenallowedtowarmtoroomtemperature,beforebeing

pproximately2hanalysisofthereactionmixture

hloromethane

wasevaporatedandtheresiduewasthentakenupintomethylalcoholandheated

ventwasevaporatedtoaffordthecompound2(481

mg,85%),whichwasusedinthenextreactionwithoutfurtherpurification.

TheEnd