氨基的保护及脱保护策略

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

药明康德内部保密资料

经典合成反应标准操作—氨基的保护及脱保护 药明康德新药开发有限公司

目 录

1． 2．

氨基的保护及脱保护概要……………………………………………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

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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。

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几种代表性的常用的氨基保护基

结构 OOX缩写 应用 引入条件 脱去条件 H2/Pd-C，供氢体/Pd-C，BBr3/CH2Cl2 or TFA，HBr/HOAc等 3MHCl/EtOAc, HCl/MeOH or diox, TosOH/THF-CH2Cl2, Me3SiI/CHCl3orCH3CN 20%哌啶/DMF，50%哌啶/CH2Cl2等 Ni(CO)4/DMF/H2O; Pd(PPh3)4/Bu3SnH; Cbz 伯胺、仲氨、咪唑、Cbz-Cl/Na2CO3/CHCl3/H2O 吡咯、吲哚等 Boc2O/NaOH/diox/H2伯胺、仲氨、咪唑、O, Boc2O/ /MeOH, Boc2O/Me4NOH/CH3C吡咯、吲哚等 N 伯胺、仲氨等 伯胺、仲氨、咪唑、吡咯、吲哚等 Fmoc-Cl/NaHCO3,/diox/H2O Aloc-Cl/Py OXO Boc XOOFmoc XOO Alloc OClOTMS Teoc 伯胺、仲氨、咪唑、Teoc-Cl/碱/diox/H2O 吡咯、吲哚等 TBAF；TEAF XOOMe( or Et) - 伯胺、仲氨、咪唑、ROCOCl/NaHCO3,/diox/H2O 吡咯、吲哚等 邻苯二甲酸酐/CHCl3/70℃;邻苯二甲酰亚胺-NCO2Et/aq. Na2CO3 Tos-Cl/Et3N TFAA/Py; 苯二甲酰亚胺-NCO2CF3/CH2Cl2 Trt-Cl/Et3N HBr/HOAc; Me3SiI; KOH/H2O/乙二醇 H2NNH2/EtOH，NaBH4/i-PrOH-H2O（6：1） HBr/HOAc, 48%HBr/苯酚（cat） K2CO3/MeOH/H2O; NH3/MeOH; HCl/MeOH HCl/MeOH, H2/Pd/EtOH, TFA/CH2Cl2 HCO2H/Pd-C/MeOH; H2/Pd(OH)2/EtOH; TFA; CAN/ CH3CN HCO2H/Pd-C/MeOH; H2/Pd(OH)2/EtOH; CCl3CH2OCOCl/CH3CN Page 3 of 77

OXNOOXSOPht Tos O伯胺 伯胺、仲氨、咪唑、吡咯、吲哚等 伯胺、仲氨、咪唑、吡咯、吲哚等 伯胺、仲氨、咪唑、吡咯、吲哚等 XCF3 Tfa XTrt MeOOMeX Dmb 伯胺、仲氨、咪唑、ArCHO/NaCNBH3/MeOH 吡咯、吲哚等 PMB-Br/ 伯胺、仲氨、咪唑、K2CO3/CH3CN;PhCH吡咯、吲哚等 O/NaCNBH3/MeOH Bn-Br/Et3N or 伯胺、仲氨、咪唑、K2CO3/CH3CN;PhCH吡咯、吲哚等 O/NaCNBH3/MeOH OMeX PMB X Bn 药明康德内部保密资料

经典合成反应标准操作—氨基的保护及脱保护 药明康德新药开发有限公司

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。

2.1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NaHCO3 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= 3.5-4.5稍有选择性地被保护，其选择性随碳链地增长而减弱，如H2N(CH2)nNH2, 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-O2NC6H4OCOOBn）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]。

R1HNCbz-ClR2BaseR1R2NCbzNH2R2OOCR1Cbz-ClBaseR2OOCNHCbzR1

1．G. J. Atwell, W. A. Denny., Synthesis, 1984, 1032

2．D. R. Kelly, M. Gingell, Chem. Ind.(London), 1991, 888

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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著的分解。

CH2OHCOCl2CH2OCOCl+HCl

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1M HCl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, Chiharu et al., Tetrahedrom; 2002, 58(39), 7851-7865

Cbz-Cl (18.5 μl, 0.155 mmol) in diethyl ether (0.2 ml) was dropped to a solution of (R)-1 (36.4 mg, 0.129 mmol) in 10% aqueous Na2CO3 (1.8 ml) at 0°C, and stirred for 5 h. The reaction mixture was acidified with 10% citric acid, extracted with CHCl3 (10 mlX3). The organic layer was washed with water, dried over Na2SO4, evaporated to give light yellow gels, which were purified by preparative TLC (CHCl3/MeOH=5:1) to afford (R)-6 (25.7 mg, 47.1%) as yellow amorphous solid. Rf = 0.87 (n-BuOH/AcOH/H2O=4:1:5); [a]D23 = -27.270 (c = 0.99, CHCl3);

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2.1.1.2 氨基酸酯的Cbz保护示例

OSONH2.HCl1Cbz-ClK2CO3SOONHCbz2

M. Carrasco, R. J. Jones, S. Kamel et a1., Org. Syn., 70, 29

A 3-L, three-necked, Morton flask equipped with an efficient mechanical stirrer, thermometer, and a dropping funnel is charged with L-methionine methyl ester hydrochloride 1 (117.6 g, 0.56 mol), potassium bicarbonate (282.3 g, 2.82 mol, 5 eq.), water (750 mL), and ether(750 mL), and the solution is cooled to 0°C. Benzyl chloroformate (105 g, 88.6 mL, 0.62 mol, 1.1 eq.) is added dropwise over 1 hr, the cooling bath is removed, and the solution is stirred for 5 hr. Glycine (8.5 g, 0.11 mol, 0.2 eq.) is added (to scavenge excess chloroformate) and the solution is stirred for an additional 18 hr. The organic layer is separated, and the aqueous layer is extracted with ether (2 × 200 mL). The combined organic layers are washed with 0.01 M hydrochloric acid (2 × 500 mL), water (2 × 500 mL), and saturated brine (500 mL), and then dried (Na2SO4), filtered, and evaporated on a rotary evaporator. The resulting oil is further dried in a Kugelrohr oven (50°C, 0.1 mm, 12 hr) to leave product 2 as a clear oil that solidifies upon cooling: 165–166 g (98–99%), mp 42–43°C.

2.1.1.3 氨基醇的Cbz保护示例(1)

H2NOHCbz-ClNa2CO3THF, H2OCbzHNOH

Clariana, Jaume; Santiago, G. G. et al Tetrahedron: Asymmetry, 2000, 11(22), 4549-4558

Benzyl chloroformate (0.95 ml, 6.7 mmol) was added via syringe into a stirred mixture of aminoalcohol 7 (0.9 g, 5.1 mmol) and sodium carbonate (0.683 g, 6.4 mmol) in the solvent system water (10 ml)–THF (3 ml) maintained at 0°C. The mixture was stirred at room temperature for 18 h (TLC monitoring) and then partitioned between dichloromethane and

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water. The organic phase was dried and evaporated to afford a white solid which was passed through a column of silica gel with hexanes–ethyl acetate (v:v 2:1) to afford the desired product (1.198 g, 72%), mp 125–127°C.

2.1.1.4氨基醇的Cbz保护示例(2)

OHCbz-ClH2NOOK2CO3Tol, H2OCbzHNOOOH

Inaba, Takashi; Yamada, Yasuki et al J. Org. Chem., 2000, 65(6), 1623-1628

To a mixture of toluene (3.85 L), water (3.85 L), and K2CO3 (470 g, 3.40 mol) were successively added 1a (770 g, 2.72 mol) and CbzCl (488 g, 2.72 mol) with vigorous stirring at a temperature below 25 °C. After stirring at room temperature for 3 h, triethylamine (27.5 g, 270 mmol) and NaCl (578 g) were successively added, and the mixture was stirred for a further 30 min. The organic layer was separated and concentrated to give the desired product as oil, which was used for the next reaction without purification. The analytical sample was prepared by column chromatography;

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/NH3（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/NH3（液）还原等。

催化氢解如下式所示。催化氢解的供氢体可以是H2、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。

R2R1NCbzH2CH3R2+R1NCOOHCH3+CO2+R1HNR2

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

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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。

1. G. Briefer, T. T. Nesftrick., Chem. Rew., 1974, 74, 567

2. A. E. Jackson, R. A. Johnstone., Synthesis., 1976, 685; G. M. Anantharamaiah, K. M. Sivanandaiah., J. Chem. Soc., Perkin Trans. 1, 1977, 490

3. M. Makowski, B. Rzeszotarska, L. Smelka et al., Liebigs Ann. Chem., 1985, 1457 4. D. R. Coleman, G. P. Royer., J. Org. Chem., 1980, 45, 2268

5. B. Eiamin, G. M. Anantharamaiah, G. P. Royer et al., J. Org. Chem., 1979, 44, 3442 6. M, J. O. Anteunis, C. Becu, F. Becu et al., Bull. Soc. Chim. Belg., 1987, 96, 775

7. D. R. Coleman, G. P. Royer., J. Org. Chem., 1980, 45, 2268 D. R. Coleman, G. P. Royer., J. Org. Chem., 1980, 45, 2268

如果在Boc2O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Boc2O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Boc2O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。 1. M. Sakaitani, K. Hori, Y. Ohfune., Tetrahedron Lett., 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PdCl2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，H2/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]。

1. D. R. Coleman, G. P. Royer., J. Org. Chem., 1980, 45, 2268

2. J. P. Mazaleyrat, J. Xie, M. Wakselman., Tetrahedron Lett., 1992, 33, 4301 3. N. L. Benoiton., Int. J. Pept. Petein Res., 1993, 41, 611

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2.1.2.1 5-10%的钯-碳催化氢解示例

CbzHNOHH215%Pd/CMeOHH2NOH

C. Jaume; G. G. Santiago et al., Tetrahedron: Asymmetry, 2000, 11(22), 4549-4458 A solution of (R)-8 (0.170 g, 0.52 mmol) in absolute methanol (3 ml) was hydrogenated in the

presence of 15% Pd/C (0.026 g) at room temperature for 12 h. The mixture was filtered (Celite) and

washed with methanol. Then, perchloric acid (0.050 ml, 0.83 mmol) was added and the mixture was stirred for 5 min. The solvent was evaporated to afford (R)-7·HClO4, mp 233–235°C; [a]D23=−15.6 (c=0.68, methanol).

2.1.2.2 5-10%的钯-碳催化氢解示例

OHFHNHCbzH220%Pd(OH)2/CMeOHFHOHNH2

B. Pierfrancesco; C. silvia et al., Tetrahedron, 1999, 55(10), 3025

A solution of N-Cbz arylglycinol (17) (1.02 mmol) in MeOH (10 mL) was stirred for 15 min in the presence of an excess of Pd(OH)2/C under a dihydrogen atmosphere. The solution was then filtered on a Celite pad and the solvent removed in vaccuo. Purification of the crude afforded the desired free 2-arylglycinols (S)-21 in 87% yield, white solid; [a]D20=+47.0 (c=0.78, CHCl3); mp 94-96°C (AcOEt)。

2.1.2.3 Pd/C-甲酸铵催化氢解示例

OOHNO1OOHOOHNHCbzO10%Pd-COHCONH4HNO2OOOHOOHNH2O

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

576.6 mg of compound 1 (1 mmol) was dissolved in 20 ml of methanol. Then 150 mg of ammonium formate (3 mmol) and 75 mg of 10% Pd-C was added and the reaction mixture was stirred at room temperature 10 min and then heated to reflux for 45 min. The mixture was

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filtered through celite and the filtrate was evaporate to dryness to give 430 mg of compound 2 (98%). This compound was used without further purification in the subsequent step.

2.1.2.4 Pd/C-甲酸催化氢解示例

OOOO1NHNOOOO10%Pd-CHCOOHO2OOONH2NH2

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

Compound 1 (0.6 g, 0.8 mmol) was dissolved in 1:1 formic acid/methanol (60 mL) and added to a round-bottom flask (100 mL) containing 1 equiv of palladium catalyst (10% Pd/C, 1.0 g, 0.9 mmol). The mixture was continuously stirred under reflux temperature for 24 h. The catalyst was removed by filtration and washed with an additional 10 mL of methanol. The combined solvents were removed by evaporation under reduced pressure to give Compound 2 (0.34 g, 81%, a white solid, mp 96-98 °C). This compound was used without further purification in the subsequent step.

2.1.2.5 Pd/C催化氢解脱Cbz上Boc示例

OOHNO1NHH2/10%Pd-C(Boc)2OBocHNONH2

WO2004092166

10%Pd-C was addede to a solution of compound 1 (596 mg , 1.77 mmol) and (Boc)2O (773 mg, 3.54 mmol) in etnyl acetate (30 ml). The reation vessel was evacuated and back-filled with nitrogen (three times), then back-filled with hydrogen (1 atm). After 2 h, the mixture was filtered and concentrated. Purification by silica gel chromatography (30% ethyl acetate/ hexanes - 50% ethyl acetate/ hexanes) gave compound 2 (2 mg, 54%).

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2.1.2.6 PdCl2催化氢解脱除带卤原子分子上的Cbz示例

HNNClCl1OEt3SiHNOOPdCl2ClCl2NNHNONNH

US20030144297

To a solution o compound 1 (900 mg) in methylene chloride (16.5 ml) was addede PdCl2 (30 mg) and triethylamine (0.229 ml). Triethyl silane was added (2 x 0.395 ml) over 2 h. The reaction mixture stirred 1 h and 2 ml of trifluoroacetic acid was added. After 30 min the reaction was basified with 2 N NaOH, extracted with methylene chloride, dried over MgSO4, filtered and concentrated. Chromatography was run on a biotage 40S column with 3-5% MeOH/CH2Cl2 with 0.5% NH4OH to provide compound 2 as a oil (501 mg, 74%).

2.1.2.7 Pd黑催化氢解，用氨为溶剂,半胱氨酸的Cbz脱除示例

OSOHNHCbz3H2Pd4SNH2OOH

Arthur M. Felix, Manuel H. Jimenz et a1., Org. Syn., 59, 159

A dry 1-L three-necked, round-bottomed flask is equipped with a dry ice reflux condenser, a gas-inlet tube, and a magnetic stirring bar as illustrated in the figure. The reaction vessel is

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immersed in an acetone–dry ice bath, and a total of 300 mL of ammonia is passed through a drying tower containing potassium hydroxide pellets and collected in the flask. The bath is removed to permit the reaction to proceed at the boiling point of ammonia (−33℃), and a gentle stream of dry nitrogen is bubbled into the flask. A solution of 0.708 g (0.80250 mole) of N-benzyloxycarbonyl-L-methionine in 10 ml. of N,N-dimethylacetamide 1.02 g (1.40 ml., 0.0101 mole) of triethylamine and 1.25 g of freshly prepared palladium black are added. The nitrogen stream is discontinued and replaced by a stream of hydrogen that has been passed through a concentrated sulfuric acid scrubber. The mixture is stirred under reflux for 5.5 hours to effect hydrogenolysis. The hydrogen stream is discontinued, a flow of nitrogen is resumed, and the dry ice is removed from the reflux condenser, permitting rapid evaporation of ammonia. The flask is attached to a rotary evaporator, and the mixture is evaporated to dryness under reduced pressure. The residue is dissolved in water and filtered through a sintered funnel of medium porosity to remove the catalyst. The filtrate is evaporated to dryness, and the residue (354 mg, 95%) is crystallized from water–ethanol. The white crystalline product, after drying under reduced pressure at 25°, weighs 272–305 mg. (73–82%), m.p. 280–282° (dec.), [α]25D +23.1° (c = 1, aqueous 5 N hydrochloric acid).

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。

R2R1NCbz+R2H+R1NCbzH+Br-HBrCH2Br+CO2+H.HBrNR1R2

1. D. Ben-Ishai, A. Berger., J. Org. Chem., 1952, 17, 15; R. A. Boissonnas, J. Blodinger, A. D. Welcher., J. Am. Chem. Soc., 1952, 74, 5309

2. R. A. Boissonnas, J. Blodinger, A. D. Welcher., J. Am. Chem. Soc., 1952, 74, 5309; J. Meienhofer, E. Schnabel., Z. Naturforsch., 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

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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（CH3SC2H5）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。

1. G. D. Fasman, E. R. Blout., J. Am. Chem. Soc., 1960, 82, 2262

2. S. Fujiwara, S. Moerinaga, K. Narita., Bull. Chem. Soc. Japan., 1962, 35, 438

3. J. Meienhofer, E. Schnabel., Z. Naturforsch., 1965, 20b, 661; 黄惟德等，生物化学与生物物理学报, 1961, 98

4. N. F. Albertson, F. C. Mckay., J. Am. Chem. Soc., 1953, 73, 5323 5. S. Guttmann, R. A. Boissonnas, Helv. Chim. Acta., 1959, 42, 1257

用液体HF在0℃处理10-30分钟即可将Cbz完全脱去[1]。FSO3H[2]、CH3SO3H[2, 3]、CF3SO3H[3, 4]和C6H5SCH3-TFA[5]也是较好的试剂。Me3SiI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BBr3/CH2Cl2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CH2Cl2中大[7]。从肽中脱去Cbz，可在TFA中添加0.5 M 4-（甲硫基）苯酚[8]或使用HF/Me2S/对甲苯酚[9]（25:65:10,v/v）来抑制Bn+对芳香氨基酸的加成。

1. S. Sakakibara et a1., Bull. Chem. Soc. Japan., 1967, 40, 21; S. Matsuura, C. H. Niu, J. S. Cohen., J. Chem. Soc. Chem. Commun., 1976, 451

2. H. Yajima, H. Ogawa, H. Sakurai., J. Chem. Soc. Chem. Commun., 1977, 909 3. H. Yajima et a1., J. Chem. Soc. Chem. Commun., 1974, 107 4. H. Yajima et a1., Chem. Pharm. Bull., 1975, 23, 11

5. Y. Kiso, K. Ukawa, T. Akita., J. Chem. Soc. Chem. Commun., 1980, 101

6. R. S.Lott, V. S. Chauham, C. H. Stammer., J. Chem. Soc. Chem. Commun., 1979, 495 7. J. Pless, W. Bauer., Angew Chem., Int. Ed. Engl., 1973, 12, 147; A. M. Felix., J. Org.

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Chem., 1974, 39, 1427

8. M. Bodanszky, A. Bodanszky., Int. J. Pept. Protein Res., 1984, 23, 287 9. J. P. Tam, W. F. Heath, R. B. Merrifield., J. Am. Chem. Soc., 1983, 105, 42

此外，已经报道过的还有以下的一些不常用的方法。如HCl/CHCl3[1]、HCl/HOAc[2]、HBr/SO2[3]、液体HBr[4]、TosOH[5]、HI/HOAc[6]、碘化磷[7]、Et3SiH[8]、沸腾的TFA[9]、8M HCl的乙醇液或6 M HCl回流1小时[10]或浓盐酸于25-75℃加热处理1-1.5小时[11]等。

1. G. D. Fasman, M. Idelson, E. R. Blout., J. Am. Chem. Soc., 1961, 83, 709 2. R. B. Merrifield., J. Am. Chem. Soc., 1963, 85, 2149 3. M. Idelson, E. R. Blout., J. Am. Chem. Soc., 1958, 80, 4631 4. M. Brenner, H. C. Curtius., Helv. Chim. Acta., 1963, 46, 2126 5. E. Taschner, B. Liberek, Abstr. Int. Cong. Biochemistry, Vienna 1958 6. E. Waldschmidt-Leitz, K. Kuhn., Chem. Ber., 1951, 84, 381

7. E. Brand, B. F. Erlanger, H. Sachs., J. Am. Chem. Soc., 1952, 74, 1849 8. Birkofer et al., Angew. Chem., Int. Ed., 1965, 4, 417 9. F. Weygand, W. Steglich., Z. Naturforsch., 1959, 14b, 472

10. A.E. Barkdoll, W. F. Ross., J. Am. Chem. Soc., 1944, 66, 567; G. Chelucci, M. Falorni, G. Giacomelli., Synthesis., 1990, 1121 11. J. White., J. Biol. Chem., 1934, 106, 141

2.1.2.8 HBr-AcOH脱除Cbz示例

OEtOOCNSNHNONHCbz33% HBrAcOH, 91%EtOOCNSNHONONH2.HBr

B. Anna; P. Gerald., Heterocycles, 2002, 58, 521

A solution of the amine Cbz compund (208 mg, 0.44 mmol) in 33 % hydrobromic acid in acetic acid (1 mL) and glacial acetic acid (0.6 mL) was stirred at rt for 3 h under an atmosphere of nitrogen. The volatiles were removed in vacuo to leave the free amine

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hydrobromide (168 mg, 91 %) as a brown, highly hygroscopic powder; [α]D =-18.0° (c = 0.4, EtOH);

2.1.2.9 TMSI脱除Cbz示例1

OOONH1BrONHCbzMe3SiIEt3N, CH3CNONH2BrONH2OO

US20040204397

Me3SiI (0.73 ml, 0.73 mmol) was added to a soluton of compound 1 (146 mg, 0.33 mmol) in acetonitrile (10 ml) at room temperature, and the resulting mixture was stirred at room temperature for 2 h. Et3N (0.12 ml) was added and the mixture was stirred at room temperature for 15 min. The solvents were removed in vacuo, and the residue was extracted with ethyl acetate. The combined organics were washed with sodium bicarbonate and brine, dried over sodium sulfate and filtered. Solvents were removed and the residue was used directly in the next step.

HNClNNH1NHCbzNNNMe3SiIEt3N, CH3CNClNNH2NH2HNNNN

US20050203078

2.1 g (4.45 mmol) of compound 1 in 30 ml of CH2Cl2 were combined with 1.9 ml (13.4 mmol) Me3SiI and stirred for 16 h at room temperature. Then 20 ml of MeOH were addede, the mixture was stirred for a further 30 min at room temperature and the reaction mixture was evaporated down completely. The residue was purified by chromatography on silica gel (eluding gradient: CH2Cl2/(MeOH/conc. Ammonia 95:5) = 70/30 – 60/40) to yield compound 2 (690 mg, 56%).

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2.2 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NaHCO3 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Boc2O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Boc2O/TEA/MeOH or DMF 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Boc2O/Me4NOH.5H2O/CH3CN是十分有利的。

1. D. S. Tarbell, Y. Yamamoto et al., Proc. Natl. Acad. Sci., USA, 1972, 69, 730 2. E. Ponnusamy, U. Fotadar et al., 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.

Boc2O, DMAPBocArNBoc

ArNH2ArNHBoc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Boc2O生成脲[1]。这个问题可通过该胺NaH或NaHMDS反应，然后再与Boc2O反应来加以避免[2]。

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BrBoc2ODMAP, THFBr+O17%56%OBrNH2BrHNHNHNO

1. H. J. knolker, T. Braxmeier et al., Angew. Chem., Int. Ed. Engl., 1995, 34, 2497; H. J.

knolker, T. Braxmeier et al., Synlett., 1996, 502; Kessier,A.; Coleman, C. M., et al J. Org. Chem.,

2004, 69(23), 7836-7846

2. T. A. Kelly, D. W. McNeil., Tetrahedron Lett., 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。

RNH2Boc2OexcessRNHBoc+Boc2O (excess)H2NNBocHNN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

NH2COOHBoc2ONaOH, t-BuOH, H2ONHBocCOOH Oskar Keller, Walter E. Keller, Gert van Look et al., Org. Syn., 63, 160 A 4-L, four-necked, round-bottomed flask, equipped with an efficient stirrer, a dropping funnel, reflux condenser, and thermometer is charged with a solution of 44 g (1.1 mol) of sodium hydroxide in 1.1 L of water. Stirring is initiated and 165.2 g (1 mol) of L-phenylalanine is added at ambient temperature, and then diluted with 750 mL of tert-butyl alcohol. To the well-stirred, clear solution is added dropwise within 1 hr, 223 g (1 mol) of di-tert-butyl dicarbonate. A white precipitate appears during addition of the di-tert-butyl dicarbonate. After a short induction period, the temperature rises to about 30–35°C. The reaction is brought to completion by further stirring overnight at room temperature. At this 药明康德内部保密资料

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time, the clear solution will have reached a pH of 7.5–8.5. The reaction mixture is extracted two times with 250 mL of pentane, and the organic phase is extracted three times with 100 mL of saturated aqueous sodium bicarbonate solution. The combined aqueous layers are acidified to pH 1–1.5 by careful addition of a solution of 224 g (1.65 mol) of potassium hydrogen sulfate in 1.5 L of water. The acidification is accompanied by copious evolution of carbon dioxide. The turbid reaction mixture is then extracted with four 400-mL portions of ethyl ether. The combined organic layers are washed two times with 200 mL of water, dried over anhydrous sodium sulfate or magnesium sulfate, and filtered. The solvent is removed under reduced pressure using a rotary evaporator at a bath temperature not exceeding 30°C. The yellowish oil that remains is treated with 150 mL of hexane and allowed to stand overnight. Within 1 day the following portions of hexane are added with stirring to the partially crystallized product: 2 × 50 mL, 4 × 100 mL, and 1 × 200 mL. The solution is placed in a refrigerator overnight; the white precipitate is collected on a Büchner funnel and washed with cold pentane. The solid is dried under reduced pressure at ambient temperature to constant weight to give a first crop. The mother liquor is evaporated to dryness leaving a yellowish oil, which is treated in the same manner as described above, giving a second crop. The total yield of pure white N-tert-butoxycarbonyl-L-phenylalanine is 207–230 g (78–87%), mp 86–88°C, [α]D20 + 25.5° (ethanol c 1.0).

2.2.1.2 氨基酸酯Boc保护示例

NH2.HClHOCOOMeBoc2OHOEt3NNHBocCOOMe

Alessandro Dondoni, Daniela Perrone., Org. Syn., 77,

A 500-mL, three-necked, round-bottomed flask, is equipped with a magnetic stirring bar, thermometer, reflux condenser protected from moisture by a calcium chloride-filled drying tube, and a pressure-equalizing dropping funnel that is connected to a nitrogen flow line and is charged with a solution of 97% di-tert-butyl dicarbonate (14.3 g, 63.6 mmol) in tetrahydrofuran (100 mL), Methyl serinate hydrochloride (10.0 g, .3 mmol) is placed in the flask and suspended in tetrahydrofuran (200 mL) and 99% triethylamine (14.0 g, 138 mmol). The resulting white suspension is cooled with an ice-water bath and the solution of

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di-tert-butyl dicarbonate is added dropwise over a period of 1 hr. After 10 min of additional stirring, the ice-water bath is removed and the suspension is stirred overnight (14 hr) at room temperature, then warmed at 50°C for a further 3 hr. The solvent is removed under reduced pressure and the residue is partitioned between diethyl ether (200 mL) and saturated aqueous bicarbonate solution (250 mL). The aqueous phase is extracted with three 150-mL portions of diethyl ether. The combined organic phases are dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 13.4-14.0 g (95-99% crude yield) of N-Boc-L-serine methyl ester as a colorless oil that is used without further purification. [α] D 23 17.0° (MeOH, c 4.41).

2.2.1.3 Boc酸酐在甲醇中与胺直接反应

COOEtBoc2ONH1MeOHNBoc2COOEt Boc2O (262 g, 1.2 mol) in MeOH (250 ml) was added to a soluton of compound 1 (157.2 g, 1.0 mol) in MeOH (350 ml) at 10°C, and the resulting mixture was stirred at room temperature for 2 h. N1, N1-dimethylethane-1,2-diamine (26 g, 0.3 mol) was added and the mixture was stirred at room temperature for 15 min. The solvent was removed in vacuo, and the residue was dissolved with ethyl acetate (750 ml). The combined organics were washed with 1 N HCl (2 x 250 ml) and brine (2 x 250 ml), dried over sodium sulfate and filtered. The solvent was removed to give compound 2 (250 g, 96%), which was used directly in the next step. 2.2.1.4 芳胺的单Boc保护示例

NH2NCOOHBoc2OEt3N, DMFNNHBocCOOH

Luo, Qun-Li; Liu, Zhi-Ying et al., J. Med. Chem., 2003, 46(13), 2631-20

3-Aminopyridine-2-carboxylic acid (5.02 g, 36 mmol) was suspended in 60 mL of dry DMF, and Et3N (15.2 mL, 108 mmol) was added dropwise at room temperature. To the resulting brown solution was added Boc2O (11.80 g, 54 mmol). After being stirred for 10 min, the

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mixture was heated at 40-50 °C overnight. The reaction mixture was poured into water and was then extracted with EtOAc (2 X 50 mL). The aqueous phase was acidified to pH 4-5 with 2 M aqueous HCl and then extracted with CH2Cl2 (3 X 50 mL). The combined organic phases were then processed in the usual way and chromatographed (13:1 CHCl3/MeOH) to yield the desired product (4.2 g, 49%).

2.2.1.5 芳胺的双Boc保护示例

BocNH2SSBoc2ONaHMDS, THFSNBocS Macleod, Calim; Mckieman, Gordon J et al., J. Org. Chem., 2003, 68(2), 387-401 A solution of NaHMDS (22.0 mL, 22.0 mmol, 1 M in THF) was added to a solution of the amine (2.11 g, 10.0 mmol) and (Boc)2O (5.46 g, 25.0 mmol) in THF (50 mL) at 0°C under nitrogen. The reaction was allowed to warm to rt and stirred for 16 h. After this time, the reaction was poured into water, extracted into CH2Cl2 (2 X 25 mL), washed with water (2 X 25 mL), dried over Na2SO4, and concentrated to yield a white-yellow solid. Recrystalization from petroleum ether (40-60 °C) gave the imide as needles (3.21 g, 7.80 mmol, 78%). Rf (hexane/ CH2Cl2 1:9, SiO2): 0.10. Mp: 106-109 °C.

2.2.1.6 酰胺的Boc保护示例

HNBoc2OHNO1NHOBocDMAP, Et3NNO2NBocOBocN

Lars G. J. Hammarström, Yanwen Fu et al., Org. Syn., 81, 213

A 2000-mL, three-necked, round-bottomed flask equipped with an argon inlet adapter, glass stopper, and an overhead mechanical stirrer is charged with a suspension of the hydantoin 1 (26.0 g, 154 mmol) in 1000 mL of 1,2-dimethoxyethane. Triethylamine (15.7 g, 154 mmol) is added in one portion, and the resulting white suspension is stirred for 30 min. Di-tert-butyl

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dicarbonate (168.0 g, 770 mmol) is then added by pipette, followed by 4-dimethylaminopyridine (DMAP) (0.2 g, 1.5 mmol). Six additional 0.2 g-portions of DMAP are added at 12 hr intervals during the course of the reaction. The reaction mixture is stirred vigorously for a total of 72 hr, and the resulting light yellow solid is then collected in a Büchner funnel using suction filtration. The filtrate is concentrated to a volume of 60 mL by rotary evaporation, and the resulting solution is cooled to 15°C. The precipitate which appears is collected using suction filtration, added to the first crop, and the combined solids are dissolved in 500 mL of chloroform. This solution is washed with three 200-mL portions of 1.0N HCl, and the combined aqueous phases are extracted with 100 mL of chloroform. The combined organic layers are washed with 100 mL of saturated aq NaHCO3 solution and 100 mL of brine, dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation. The resulting solid is dried at room temperature at 0.01 mm for 24 hr. The resulting finely ground light yellow solid is suspended in 400 mL of diethyl ether in a 1000-mL, round-bottomed flask equipped with a magnetic stirbar, stirred for 2 hr, and filtered on a Büchner funnel washing with four 50-mL portions of diethyl ether. The product is dried under vacuum (85°C; 0.5 mm) for 24 hr to give 60.0–65.3 g (83-90%) of 2 as a ivory-colored solid.

2.2.1.6 叠氮还原Boc保护示例

OHEtOOCN31COOEtH2/Pd-CBoc2O, EtOAcEtOOCOHCOOEtNHBoc2 Seiki Saito, Kanji Komada, and Toshio Moriwake., Org. Syn., 73, 184 A 500-mL, single-necked, round-bottomed flask, equipped with a Teflon-coated stirring bar, is charged with a suspension of 0.91 g of 10% palladium on carbon catalyst in 100 mL of ethyl acetate. The flask is connected to a normal pressure hydrogenation apparatus and the catalyst is saturated with hydrogen. After removal of the hydrogen, a solution of 18.2 g (0.0785 mol) of 1 and 20.6 g (0.0942 mol) di-tert-butyl dicarbonate in 80 mL of ethyl acetate is added to the suspension of catalyst, a hydrogen atmosphere reestablished, and the suspension is stirred at room temperature under a slight positive pressure of hydrogen for 4–6 hr, The suspension is filtered through a Celite pad, and the pad is rinsed with several portions of ethyl acetate. The combined ethyl acetate solutions are concentrated on a rotary evaporator and finally under high vacuum to give a pale yellow oil that is initially purified by means of a column packed

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with silica gel (100 g) using hexane-ethyl acetate (6:1) as eluent. Fractions containing the product are combined and concentrated on a rotary evaporator to give 23.3 g of crude 2 as a colorless oil. The oily crude 2 is dissolved in 70 mL of hexane-ether (3:1), and the solution is cooled to −30°C, seeded, and kept overnight at that temperature (freezer) to allow crystallization. The mother liquor is siphoned out while the mixture is kept at −30°C (dry ice-acetone bath). The crystals are washed with several portions of hexane-ether (3:1) at −30°C, then dried under high vacuum to provide 12.2–12.7 g of diastereomerically and enantiomerically pure diethyl (2S,3R)-2-(N-tert-butoxycarbonyl)amino-3-hydroxysuccinate (2) as colorless prisms, mp 33–34°C;. The combined mother liquor and the hexane–ether (3:1) washings are concentrated on a rotary evaporator to give a colorless oil, which upon crystallization as above provides an additional 2.7–3.8 g of product 2. The combined yield of crystalline 2 is 15.9–16.5 g (66–73%).

2.2.1.7 吡咯Boc保护示例

Boc2ONHBrDMAPNBocBr Wha Chen, E. Kyle Stephenson et al., Org. Syn., 70, 151 The solution of 2-bromo-1H-pyrrole (9.8 g, 67.2 mmol) in 40 mL of THF is cooled to −78°C in a dry ice-acetone bath. The flask is equipped with a magnetic stirring bar and a three-way stopcock attached to a balloon filled with nitrogen. To the stirred dark-green solution is added 2.71 g (26.9 mmol) of triethylamine followed immediately by addition of 20.4 g (93.9 mmol) of di-tert-butyl dicarbonate and a catalytic amount (ca. 0.1 g) of 4-dimethylaminopyridine. The flask is evacuated and purged with nitrogen. The mixture is stirred for 8 hr while it is allowed to warm to room temperature. The solvent is removed under reduced pressure at room temperature and 100 mL of hexane is added to the crude product, which is washed with deionized water (3 × 100 mL), dried over sodium sulfate, and concentrated under reduced pressure at room temperature. The crude product is purified by chromatography on amine-treated neutral silica (270 g) using hexane as the eluent. The fractions containing the product are identified by TLC, combined, and concentrated under reduced pressure at room temperature to yield N-tert-Butoxycarbonyl-2-bromopyrrole as a colorless oil (13.5–14.7 g, 82–%). 药明康德内部保密资料

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2.2.1.8 吲哚Boc保护示例

Boc2OMeONHDMAP, CH3CNMeONBoc G. Tong; P. Ruiyan et al., J. Org. Chem., 1997, 26, 9298 To a solution of 6-methoxy-3-methylindole (5.0 g, 31 mmol) in distilled acetonitrile (150 mL) were added di-tertbutyl dicarbonate (7.44 g, 34.1 mmol) and DMAP (0.195 g, 1.6 mmol). The reaction mixture was stirred at rt for 12 h. The solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2 (100 mL) and washed with an aqueous solution of 1 N HCl (2 x 50 mL). The aqueous layer was extracted with CH2Cl2 (3 x 30 mL). The combined organic ayers were dried (K2CO3). After removal of solvent under reduced pressure, the residue was solidified to afford the product (8.12 g, 99%) as a yellow solid: mp 45-46 °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CO2（见下式）。在液相肽的合成中，Boc的脱除一般可用TFA或50%TFA（TFA:CH2Cl2 = 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1-2M HCl/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Me3SiI在CHCl3或CH3CN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

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醚[6]。在Boc脱去过程中TBDPS[7]和TBDMS[8]基对CF3COOH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，ZnBr2/CH2Cl2可以选择性的脱除仲胺上的Boc[9]。

1. F. Cavelier, C. Enjabal., Tetrahedron Lett., 1996, 37, 5131

2. F. S. Gibson, S. C. Bergmeier, H. Rapoport., J. Org. Chem., 1994, 59, 3216 3. A.Nudelman, Y. Bechor et al., Synth. Commun., 1998, 28, 471

4. R. S. Lott, V. S. Chauhan et al., J. Chem. Soc. Chem. Commun., 1979, 495; G. A. Olah, S. C. Narang., Tetrahedron., 1982, 38, 2225

5. R. A. T. M. van Benthem, H. Hiemstra et al., J. Org. Chem., 1992, 57, 6083

6. M. Bodanszky, A. Bodanszky., Int. J. Pept. Protein Res., 1984, 23, 565; Y. Masui, N. Chino et al., Bull. Chem. Soc. Jpn., 1980, 53, 4

7. P. A. Jacobi, S. Murphree et al., J. Org. Chem., 1996, 61, 2413 8. J. Deng, Y. Hamada et al., J. Am. Chem. Soc., 1995, 117, 7824 9. S. C. Nigam, A. Mann et al., Synth. Commun., 19, 19, 3139

2.2.2.1.1 TMSOTf中性条件下脱Boc示例

ONBocHNOHOTBDMSOTfCH2Cl2H2NOTBDMSN

Gilbertson, Scott R; Chang, Cheng-Wei et al., J. Org. Chem., 1998, 63(23), 8424-8431 To a solution containing 2 (1.0 g, 3.9 mmol) in 30 mL of dry CH2Cl2 was slowly added TBDMSOTf (0.9 mL, 4.1 mmol). After stirring the reaction mixture for 6 h, the solvent was evaporated, and the crude product (0.8 g, 75%) was obtaineded, which was used directly in the next step.

2.2.2.1.2 TMSOTf-2,6-lutidine中性条件下脱Boc示例1

BocHNOOOSOOOOSOTBDMSOTf2,6-LutidineCH2Cl2H2N Kemp, Scott J; Bao, Jiaming et al J. Org. Chem., 1996, 61(20), 7162-7167

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To a stirring solution of compound 1 (800 mg, 2.0 mmol) and 2,6-lutidine (0.4463 ml, 4.0 mmol) in CH2Cl2 (6 mL) was added tert-butyldimethylsilyl triflate (0.690 ml, 3.0 mmol) dropwise over 5 min. After 20 min, saturated NH4Cl (10 mL) was added. The mixture was stirred and separated, and the aqueous layer was extracted with Et2O (3 x 15 mL). The combined organic layers were washed with water (2 x 10 mL) and saturated NaCl (10 mL), dried (MgSO4), and concentrated to give the crude silyl carbamate, which was dissolved in THF (10 mL) and cooled to 0°C. A 1.0 M solution of TBAF in THF (2 mL, 2 mmol) was added over 5 min, and then the solution was stirred at 0°C for 1 h. The solution was concentrated and chromatographed (95:5 CH2Cl2-methanol) through a small plug of silica to give compound 2 (882 mg, 75%) as a clear oil.

2.2.2.1.3 TMSOTf-2,6-lutidine 条件下脱Boc示例2

OHNOO1OOTBDMSOTfO2,6-LutidineCH2Cl2OOHNH2N2OOBocHN

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

To a stirred solution of compound l (500 mg, 1.52 mmol) and 2,6-lutidine (0.353 ml, 3.04 mmol) in dry CH2C12 (3.0 mL) at 0 \"C was added dropwise t-BuMe2SiOTf (0.523 ml, 2.28 mmol). The reaction mixture was stirred at 0°C for 15 min, quenched with saturated aqueous ammonium chloride solution, and extracted with ether several times. The combined organic phase was washed with H2O and then brine, dried (MgSO4), and concentrated in vacuo to give an oily residue, which upon purification by column chromatography on silica gel (elution with 50% ether in hexane) gave O-silyl ester compound 2 (652 mg, 97%): colorless needles; mp .0-65.0°C (hexane).

2.2.2.2 TFA脱Boc示例

TBSONHBocCOOMeTFACH2Cl2TBSONH2COOMeCbzNCbzN

M. Alberto; A. Eduardo et al., J. Org. Chem., 2004, 21, 7004

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To a solution of the β-aminoester (0.2 mmol) in CH2Cl2 (3 mL), cooled to 0°C was added TFA (1mL). After the consumption of the starting material (45 min, monitored by TLC), the mixture was evaporated and then saturated aqueous NaHCO3 was added. The aqueous layer was extracted twice with CH2Cl2 (15 mL), and the organic layer washed with brine and dried over anhydrous Na2SO4. The solvent was removered under vacuum, to afford the amine, which were employed without further purification to prepare the Mosher’s diastereoisomeric amides.

2.2.2.3 HCl-Et2O脱Boc示例

ONHBocOOHClEt2OHOOCClH.HNO

C. Mühlemann, P. Hartmann, J. P. Obrecht., Org. Syn., 71, 200

tert-Butyl [1-(tert-butoxycarbonyl)-3-oxo-4-pentenyl]carbamate, 8.73 g (0.0308 mol), is dissolved in 280 mL of an ice-cooled, saturated solution of hydrogen chloride in ether. The solution is kept without stirring at room temperature overnight. The resulting suspension is filtered and the filter cake is immediately washed with dry ether. The washing with ether is repeated four times and, after drying under reduced pressure, 5.48 g (99%) of 4-ketopipecolic acid hydrochloride is obtained as a colorless powder, mp 139–142°C dec.

2.2.2.4 HCl-THF脱Boc示例

OHNHCOOt-BuBocHNH2N HClTHFH2NOHNHCOOHH

J. Wehbe et al., Tetrahedron: Asymmetry, 2004, 15, 851

To the Boc protected amine (0.06 g, 0.17 mmol) dissolved in THF (1mL) was added 2M HCl (1mL, 2 mmol) and the mixture stirred 2 h at room temperature. After evaporation of the solvent, the product was extracted into EtOAc (3. 5mL). The organic layer was dried and evaporated under vacuum to afford 17b in 95% yield as a white solid.

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2.2.2.5.1 叔丁酯存在下的脱Boc示例1

OO1Me3SiICHCl3ONH2OOONBoc

US5610144

1.77 ml of Me3SiI are added dropwise at room temperature in the vicinity of 25°C to a soution of 3.8 g of compound 1 in 50 ml of CHCl3. Stirring is contiuned for 30 min, then 20 ml f water are addede. The aqueous phase is separated, then extracted with CHCl3(2 x 20 ml). The organic phases are combined, washed successively with a saturated aqueous Na2CO3(30 ml) and water(2 x 30 ml), then dried over MgSO4 and concentrated to dryness under reduced pressure at 40°C. The mixture of the two diastereoisomers obtained is separated by chromatography on silica (eluent: ethyl acetate/cyclohexane = 1/4). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40°C to give compound 2 (0.5 g), as a yellow-orange oil, used as it is in subsequent syntheses.

2.2.2.5.2 叔丁酯存在下的脱Boc示例1

ONOO1Boc1.1 M HClEtOAcNHOO2O

US2002045623

To asolution of compound 1 (6.3 g, 21.0 mmol) in ethyl acetate (50 ml) was added 1.1 M HCl in ethyl acetate (28.7 ml, 31.5 mmol). The reaction was stirred at room temperature for 1 h, then washed with water, saturated aq. NaHCO3 and brine. The organic phase was dried (MgSO4), filtered and evaporated to afford compound 2 (3.11 g, 74%) as a yellow oil which crystallized upon standing.

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2.2.2.5.3 叔丁酯存在下的脱Boc示例3

NHBocOOOOOTFACH2Cl2OOOONH2O12

WO20040106286

To a solution of compound 1 (149 mg, 0.33 mmol) in CH2Cl2 (2 ml), TFA (1 ml) as added at 0°C and the mixture was stirred for 1 h at 0°C. Saturated aqueous Na2CO3 was added and the mixture was etracted with CHCl3. The etract was purified by silica gel column chromatography to obtained compound 2 (92 mg, 79%).

2.2.2.6 吲哚环上Boc直接加热脱除示例

NHOEtOOCH(neat)MeONBoc1MeO2NHNHHOEtOOCHNHNHH

G. Tong; P. Ruiyan et al., J. Org. Chem., 1997, 26, 9298

Compound 1 (62 mg)was heated (neat) at 160-180 °C for 45 min. The residue was purified by flash chromatography (silica gel, CHCl3/MeOH 95/5) to afford Compound 2 (25 mg) as a solid in 50% yield. 11: [R]27D= - 65.9 (c = 0.97, in CHCl3).

2.3 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H2/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]。

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1. L. A. Carpino., Acc. Chem. Res. 1987, 20 401; L. A. Carpino, D. Sadat-Aalaee et al., J. Org. Chem., 1990, 55, 1673

2. E. Atherton, C. Bury et al., Tetrahedron Lett., 1979, 3041

3. C. A. Bodanszky rt al., J. Org. Chem., 1980, 45, 72; J. Meienhofer et al., J. Pept. Prot. Res., 1978, 11, 246; J. Martinez, J. C. Tolle et al., J. Org. Chem., 1979, 44, 5396; R. B. Merrifield, A. E. Bach., J. Org. Chem., 1978, 43, 4808

2.3.1笏甲氧羰基的导入

笏甲醇在无水CH2Cl2中与过量的COCl2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/Na2CO3或NaHCO3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。

1. L. A. Carpino, G. Y. Han., J. Org. Chem., 1972, 37, 3404 2. F. M. F. Chen, N. L. Benoiton., Can. J. Chem., 1987, 65, 1224

2.3.1.1.1 氨基酸的笏甲氧羰基的导入示例1

OHONH2Fmoc-Claq. Na2CO312HOONHFmoc

R. J. Malene; A. O. Christian et al., J. Med. Chem., 2005, 1, 56

A solution of Fmoc-Cl (31 g, 0.12 mol) in dioxane (150 ml) was added to a suspension of compound 1 (24.1 g, 0.1 mol)in dioxane (100 ml) and 10% aqueous Na2CO3 (150 ml) at 0°C. The mixture was stirred for 1 h at 0°C and then for 1 h at room temperature. The reaction mixture was poured into water and washed with Et2O. The aqueous phase was acidified with concentrated aqueous HCl, and the precipitated product was isolated by filtration and dried in vacuo to give compound 2 (45 g g, 98%).

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2.3.1.1.2 氨基酸的笏甲氧羰基的导入示例2

OOONOOOH2NOHO1OFmocHNOHO2BocNBocNNaHCO3, DMF(Fmoc-OSu)

Carrasco, Michael R; Brown, Ryan T et al., J. Org. Chem., 2005, 68(1), 195-197 Compound 1 (1.25 mmol), were dissolved in DMF (30 mL) and H2O (30 mL), treated with NaHCO3 (210 mg, 2.5 mmol) and Fmoc-OSu (4 mg, 1.37 mmol), and stirred for 24 h. The solvents were removed, and the residue was dissolved in EtOAc (150 mL) and washed with 0.1 M KHSO4 (4 x 50 mL), H2O (4 x 50 mL), and brine (100 mL). After drying and removal of the solvent, the residue was chromatographed (acetone:CH2Cl2:AcOH, 5:95: 0.5 to 10:90:0.5) and then purified by size exclusion chromatography (LH-20, CH2Cl2) to yield compound 2 (456 mg, 0.969 mmol, 78%) as a glassy solid.

2.3.1.2.3 氨基酸酯的笏甲氧羰基的导入示例

OFmoc-Cl10%Na2CO3CH3CNFmoc2OHNCOOMe1NCOOH

R. J. Malene; A. O. Christian et al., J. Med. Chem., 2005, 1, 56

Compound 1 (197 mg, 0.726 mmol) was suspended in a mixture of MeCN (10 mL) and 10% aqueous Na2CO3 (15 mL), and the mixture was stirred overnight at room temperature, followed by stirring for 16 h at 40 °C. MeCN was removed in vacuo, and dioxane (20 mL) and Fmoc-Cl (188 mg, 0.726 mmol) in dioxane (3 mL) were added successively at 0 °C. The mixture was stirred at 0 °C for 1 h and was then poured into water (100 mL). The resulting mixture was washed with hexane (50 mL), and the aqueous phase was acidified with 4 M aqueous HCl and extracted with EtOAc (4 x 50 mL). The combined EtOAc phases were dried (Na2SO4), filtered, and concentrated. Purification by TLC (hexanes-EtOAc 2:1 to hexanes-EtOAc-HOAc 1000:1000:1) afforded compound 2 (237 mg, 68%) as a syrup. TLC: Rf 0.20 (hexanes-EtOAc-HOAc 1000:1000:1).

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2.3.1.2 一般胺的氨基酸酯的笏甲氧羰基的导入示例

OTBSOH2NOTBSFmoc-Clsat. NaHCO3CH2Cl2OHNFmoc

R. A. Tromp; M. V. D. Michael et al., Tetrahedron: Asymmetry, 2003, 12, 15

To a vigorously stirred mixture of 3 mL of dichloromethane and 6 mL of saturated NaHCO3 (aq.) and 1mmol of 4 was added 1.4 equiv. of Fmoc-Cl. After the reaction had come to completion (TLC), 6 mL of dichloromethane and 3 mL of water were added, and the layers separated. The organic phase was washed once with brine, dried (MgSO4), and the solvent evaporated. The crude compound was purified by column chromatography (pet. ether 40–60/EtOAc 95/5, v/v) to yield 5e in 79% yield as a white solid, mp 88°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。

NH2+R1R2OOHNR1R2HN

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/4M NaOH(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%CH2Cl2的溶液脱去。另外，Bu4N+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]。

1. For a review of the use of Fmoc protection in peptide synthesis, see E. Atherton and R. C. Sheppard, ‘The Fluorenylmethoxycarbonyl Amino Protecting Group’, in The Peptides, S. Udenfriend and J. Meienhofer, Eds., Academic Press, New York, 1987, 9, 1 2. M. Ueki, M. Amemiya., Tetrahedron Lett., 1987, 28, 6617

3. L. A. Carpino, G. Y. Han., J. Am. Chem. Soc., 1970, 92, 5748; C. D. Cheang et al., Int. Pept. Prot. Res., 1980, 15, 59

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2.3.2.1 三乙胺用于脱除笏甲氧羰基示例

STrFmocHNO1OAllylDEACH3CNH2NO2STrOAllyl

Shu-Li You and Jeffery W. Kelly., J. Org. Chem. 2003, 68, 9506

Diethylamine (30 mL) was added to a solution of 5 (5.63 g, 9 mmol) in CH3CN (30 mL), and the resulting mixture was stirred at 25 °C for 30 min to ensure complete removal of the Fmoc protecting group. After concentration in vacuo, the reaction mixture was azeotroped to dryness with CH3CN (2 x 30 mL) to give compound 2 (3.4 g, %).

2.3.2.2 20%的哌啶用于脱除笏甲氧羰基示例1

NNNONHFmocPiperidineNHNONH2MeOHNH12

US63293

Piperidine (0.66 ml) was addede to a solution of compound 1 (0.797 g) in MeOH (10 ml) at room temperature. The reaction mixture was stirred at room temperature for 18 h, then concentrated and the residue was purified by alumina column chromatography (rthyl acetate/methanol = 10/1) to obtain compound 2 (0.382 g, 76%).

HNClOHNOHNOOHNHFmocHNOClHNOHNOOHNH2PiperidineDMF12

US63310

Piperidine (0.88 ml, 0. mmol) was addede to a solution of compound 1 (116 mg, 0.18 mmol) in DMF (5 ml) at room temperature. The solution was stirred at room temperature for 30 min, and then solvent was evaporated. The resulting white solid was triturated with ether five times and dried in vacuo to give compound 2 (59 mg, 81%) as an off-white solid.

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2.4. 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/Na2CO3、NaHCO3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]。

1. E. J. Corey, J. W. Suggs., J. Org. Chem., 1973, 38, 3223

2.4.1.1氨基酸的烯丙氧羰基（Alloc）的引入示例

OHONH2OOOAlloc-Claq. NaHCO3, THFOOOHNHAlloc

Micale, Nicola; Vairagounder, Rajendran et al J. Med. Chem., 2004, 47(26), 55-58 To a stirred solution of compound 1 (3.0 g, 15.86 mmol) in a mixture of aq. NaHCO3 and THF (8/2, 20 mL) was added allylchloro formate (2.54 mL, 23.81 mmol), dropwise and at 0 °C. The mixture was stirred at room temperature for 12 h and then diluted with ethyl acetate and washed 3 N HCl, dried and the solvent removed in vacuo to give compound 2 as a pale yellow oil, which was used without further purification (3.55 g, 82%).

2.4.1.2一般氨基的烯丙氧羰基（Alloc）的引入示例

1. HCl/EtOAcNBocCONH2HNBoc2. Alloc-Cl, Et3NNAllocCONH2HNAlloc12

H. Imamura; A. Shimizu et al., Tetrahedron, 2000, 56(39), 7705

To a solution of 17 (1.0 g, 1.97 mmol) in EtOAc (10 ml) was added 4 M HCl/EtOAc (20 mL), and the mixture was stirred for 6 h at room temperature. After evaporation, to the suspension of the residue in CH2Cl2 (40 mL) were added triethylamine (2.75 mL, 19.7 mmol) and allyl chloroformate (0.627 mL, 5.91 mmol) at -10°C. The reaction mixture was poured into H2O

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and the whole was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/acetone = 8:1) to give 18 (863 mg, 92.1%) as a foam. [ a]D25=19.6 (c =1.0, CHCl3).

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(PPh3)4或Pd(PPh3)2Cl2存在的条件去保护。例如，Alloc衍生物用Pd(PPh3)4/Me2NTMS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(PPh3)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(PPh3)2Cl2/Bu3SnH/p-NO2C6H4OH/CH2Cl2[3]。在异戊烯酯或肉桂酸酯存在下，可用Pd(OAc)2/TPPT/CH3CN/Et3N/H2O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Boc2O、AcCl、TsCl、或丁二酸酐时，Pd(PPh3)2Cl2/Bu3SnH可将Alloc基转变为其它的胺衍生物。另外，Alloc也可在Pd(PPh3)4/HCOOH/TEA[5]或AcOH/NMO催化脱去[6]。

1. A. Merzouk, F. Guibe., Tetrahedron Lett., 1992, 33, 477

2. H. Kunz, C. Unverzagt., Angew. Chem. Int. Ed. Engl., 1984, 23, 436

3. O. Dangles, F. Guibe et al., J. Org. Chem., 1987, 52, 4984; P. Four, F. Guibe., Tetrahedron Lett., 1982, 23, 1825

4. S. Lemaire-Audoire, M. Savignac et al., Tetrahedron Lett., 1994, 35, 8783; E. Blart, J. M. Bernard et al., Tetrahedron Lett., 1997, 38, 2955; J. P. Genet, E. Blart et al., Tetrahedron Lett., 1993, 34, 41

5. Y. Kanda, H. Arai et al., J. Med. Chem., 1992, 35, 2781 6. J. Lee, J. H. Griffin, T. I. Nicas., J. Org. Chem., 1996, 61, 3983

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2.4.2.1 Pd(PPh3)4-THF体系脱除烯丙氧羰基（Alloc）示例

EEOOOTMSNHAllocEEOPd(PPh3)4THFOOTMSNH2

Y. Matsushima; H. Itoh etal., J. Chem. Soc. Perkin Trans. 1., 2004, 7, 949

To a solution of the Alloc protected ester (140.7 mg, 0.2.23 mmol) and 1,3-dimethylbarbituric acid (228 mg, 1.46 mmol) in THF (15 mL) was added tetrakis(triphenylphosphine)palladium (43.9 mg, 0.0379 mmol, 17 mol%), and the resulting mixture was stirred at rt for 27 h. The mixture was then poured into saturated aq. NaHCO3 and extracted four times with Et2O. The combined extract was dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (CHCl3/MeOH, 20 : 1 to 2 : 1) to give the corresponding free amino ester as a colorless oil (79.5 mg, 65%).

2.4.2.2 Pd(PPh3)4/Me2NTMS体系脱除烯丙氧羰基（Alloc）示例

ONSiOSHNMeOOONSPd(PPh3)4, TMS-DMATMS-TFA, CH2Cl2MeOONHAllocONSiOSHNONSNH2

P. Angehrm; S. Buchmann et al., J. Med. Chem., 1992, 47(6), 1487

To a solution of 112 (0.97 g, 1.4 mmol) in CH2Cl2 (19 mL) were added dimethylamino- trimethylsilane (1.32 mL, 8.4 mol) and trimethylsilyl trifluoroacetate (1.45 mL, 8.4 mmol). The solution was stirred at 20 °C for 10 min, and then Pd(PPh3)4 (97 mg, 0.084 mmol) was added and stirring was continued for 2.5 h. The mixture was evaporated and the residual oil was dissolved in EtOAc (50 mL). The solution was washed with 10% aq NaHCO3 and brine, dried, and evaporated. The residue was chromatographed (SiO2; EtOAc/hexane 1:2) to give 113 (0.67 g, 78%): foam; TLC Rf ) 0.27 (EtOAc).

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2.5 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]。

1. Seth, Punit P; Ray, Robinson, Dale E et al Bioorg. Med. Chem. Lett., 2004, 14(22), 5569-5572; Olsen, Christian A; Joergensen, Malene R et al Eur. J. Org. Chem., 2003, 17, 3288-3299; Boger, Dale L; Kim, Seong Heon et al J. Am. Chem. Soc., 2001, 123(9), 1862-1871

2. Tius, Marcus A; Thurkauf, Andrew; Tetrahedron Lett., 1986, 27(38), 4541-4544 3. Park, Haengsoon; Cao, Bin et al J. Org. Chem., 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。

RNH2+ClOOTeoc ClTMSORNHOTMSBu4N.FRNH2RNHTeoc

1. Zubert, Sheena; Glen, Angela et al Tetrahedron Lett. 1998, 39(41), 7567-7570; Trost, Barry M; Cossy, Janine; J. Am. Chem. Soc., 1982, 104(24), 6881-6882; Sulline, David W; Bobik, Thomas A et al J. Am. Chem. Soc., 1993, 115(15), 66-6651 2. Shute, Richard; Rich, Daniel H; Synthesis, 1987, 4, 346-349

3. Boger, Dale L; Kim, Seng Heon et al., J. Am. Chem. Soc., 2001, 123(9), 1862-1871; Boger, Dale L;

Kim, Seng Heon et al., J. Am. Chem. Soc., 2000, 122(30), 7416-7417

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2.5.1.1 Teoc-Cl引入三甲基硅乙氧羰基(Teoc)示例

SiOOClOH2N1OHOTeocHN2OHaq. NaHCO3, dioxane

Shute, Richard; Rich, Daniel H; Synthesis, 1987, 4, 346-349

NaHCO3(3.78 g, 45 mmol) and compound 1(15 mmol) are added to water (15 ml) and the mixture is stirred at room temperature for 30 min or until the majority of the solids dissolve. To this suspension is added a solution of Teoc-Cl in dioxane (30 ml). The resultant mixture is stirred vigorously at room temperature overnight, poured into water (50 ml) and extracted with ether (3 x 50 ml), the organic extracts being discarded. The aqueous layer is acidified to Ph = 2 with saturated potassium hydrogen sulfate solution and extracted with ether (3 x 50 ml). The combined organic extracts are washed with water (3 x 75 ml), dried with MgSO4, and evaporated to give compound 2 ().

2.5.1.2 Teoc-OSu引入三甲基硅乙氧羰基(Teoc)示例1

OSiOHONH2O1OHOOONOOHOOHOEt3N, dioxane, H2OTeocNH2

Shute, Richard; Rich, Daniel H; Synthesis, 1987, 4, 346-349

To a stirred suspension of compound 1 (0.13 g, 1 mmol) in water (1 ml) is added a solution of triethylamine (0.26 g, 2.6 mmol) in dioxane (1 ml). To the resultant solution is added solid Teoc-OSu (0.29 g, 1.1 mmol). The mixture is stirred at room temperature overnight, then diluted with water (5 ml), acidified with saturated potassium hydrogen sulfate solution, and extracted with ether (3 x 15 ml). The combined organic layers are washed with water (4 x 20 ml), dried with MgSO4, and evaporated to afford compound 2 (0.23 g, 84%) as an oily residue.

Teoc-OSu引入三甲基硅乙氧羰基(Teoc)示例2

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OSiOHONH2O1OHOOONOOHOOHOEt3N, dioxane, H2OTeocNH2

Shute, Richard; Rich, Daniel H; Synthesis, 1987, 4, 346-349

To a stirred suspension of compound 1 (0.13 g, 1 mmol) in water (1 ml) is added a solution of triethylamine (0.26 g, 2.6 mmol) in dioxane (1 ml). To the resultant solution is added solid Teoc-OSu (0.29 g, 1.1 mmol). The mixture is stirred at room temperature overnight, then diluted with water (5 ml), acidified with saturated potassium hydrogen sulfate solution, and extracted with ether (3 x 15 ml). The combined organic layers are washed with water (4 x 20 ml), dried with MgSO4, and evaporated to afford compound 2 (0.23 g, 84%) as an oily residue.

3.5.1.3 Teoc-OBt引入三甲基硅乙氧羰基(Teoc)示例

OO2NF1NH2OMeSiOOONNNOO2NF2OMeNHTeocEt3N, dioxane, H2O

Boger, Dale L; Kim, Seng Heon et al., J. Am. Chem. Soc., 2001, 123(9), 1862-1871; Boger, Dale L; Kim, Seng Heon et al., J. Am. Chem. Soc., 2000, 122(30), 7416-7417

To a stirred suspension of compound 1 (0.24 g, 1 mmol) in water (1 ml) is added a solution of triethylamine (0.26 g, 2.6 mmol) in dioxane (1 ml) followed by solid Teoc-Bt (0.31 g, 1.1 mmol). The mixture is stirred at room temperature overnight, then diluted with water (5 ml), acidified with saturated potassium hydrogen sulfate solution, and extracted with ether (3 x 15 ml). The combined organic layers are washed with water (4 x 20 ml), dried with MgSO4, and evaporated to afford compound 2 (0.36 g, 92%).

2.5.1.4一般氨基的三甲基硅乙氧羰基（Teoc）的引入示例

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SiOOClNH21NHTeoc2DIPEA, DMAPCH2Cl2

Mueller, Paul; Imogai, Hassan; Tetrahedron: Asymmetry, 1998, 9(24), 4419-4428 To compound 1 (486 mg, 8.5 mmol) in CH2Cl2 (15 mL) was added, at −10°C, diisopropylethylamine (1.72 g, 17 mmol) followed by Teoc-Cl (3.06 g, 17 mmol) in CH2Cl2, and finally, dimethylaminopyridine (DMAP, 30 mg). The mixture was stirred overnight, then hydrolyzed with satd NaHCO3, and extracted with CH2Cl2 (3 x 30 mL) at 0°C and satd Na2CO3. After drying and evaporation of the solvent, the crude product was purified by chromatography (SiO2; hexane:AcOEt = 85:5) and afforded compound 2 (1.49 g, 88%) as a colorless liquid.

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

OOOMeMeO1OOOOHOOPO2NHTeocTBAFTHFMeOOMeOOOOOHOPONH2

Gugiu, Bogdan G; Salomon, Robert G; Org. Lett., 2003, 5(16), 2797-2800

Compound 1 (33 mg, 0.042 mmol) was dissolved in THF and TBAF (0.070 mL 1M in THF containing 18.4 mg, 0.070 mmol) was added, and the solution stirred at room temperature for 48 h under argon following the disappearance of compound 1 by TLC (36 h). After the removal of solvent by rotary evaporation under low pressure the product was purified by flash chromatography using CHCl3/MeOH/H2O (60:38:2) to give compound 2 (20 mg, 72%) with Rf = 0.53 in CHCl3/MeOH/H2O (60:38:2).

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2.6 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/Na2CO3、NaHCO3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]。

1. E. J. Corey, M. G. Bock et al., Tetrahedron Lett. 1978, 1051

2.6.1.1 甲（或乙）氧羰基的引入示例

SNHCOOHSClCOOEtNEt3NCOOHCOOEt

E. F. B. Mara; S. B. Hugo et al., Synthesis, 1999, 6, 943

To a suspension of 2b (5 mmol, 1.05 g) in acetone (10 mL) cooled to 0 °C (ice-salt bath) was added TEA (9.56 mmol, 1.74 mL). The mixture was stirred at r.t. for 15 min. To this mixture at 0 °C was added dropwise ethyl chloroformate (12.9 mmol, 1.16 mL). The solution was stirred at r.t. for 2 h and the solvent was removed in vacuo. The residue was treated with H2O (25mL) and then with HCl 10% until pH 3 and extracted with EtOAc. The organic layer was washed with H2O, dried (Na2SO4) and the solvent was removed in vacuo yielded 4b (76%) as thick oil.

2.6.1.2 甲（或乙）氧羰基的引入示例

NH2COOHO1ClCOOMeNaHCO3O2NHCOOMeCOOH

M. Dawei; D. Ke et al., Tetrahedron: Asymmetry, 2002, 13, 961

A suspension of compound 1 (20 g, 77.8 mmol), NaHCO3 (13.0 g, 155.6 mmol) in water (120 mL) and chloroform (20 mL) was treated with methyl chloroformate (12.0 mL, 155.6 mmol) in a dropwise manner. The solution was stirred for 24 h and 1N aq. HCl was added to adjust

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the pH to 4. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over MgSO4, and concentrated to yield compound 2 (23.3 g, 94%) as a crude solid.

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、6 N HCl 和TMSI等。

1. M. C. Wani, H. F. Campbell et al., J. Am. Chem. Soc., 1972, 94, 3631; P. Magnus, J. Rodrigues-Lopez et al., J. Am. Chem. Soc., 1992, 114, 382; J. Patjens; G. T. Ramin et al., Helv. Chim. Acta. 1986, 69(4), 905-607

2.6.2.1 HBr-AcOH脱除甲（或乙）氧羰基示例

COOEtN33% HBr-AcOHNN2 HBrH2HNHNN1

J. Patjens; G. T. Ramin et al., Helv. Chim. Acta. 1986, 69(4), 905-607

Compound 1 (18.1 g, 0.1 mol) was added to 33 % HBr (in AcOH, 100 mL, 0.52 mol) at room temperature. The mixture was stirred and heated to 70℃for 12 h. The excess HBr and AcOH were removed in vacuo. The residue was washed with dry ether (3 x 50 ml) to give compound 2 (23 g, 85 %) as a orange solid

2.6.2.2 KOH-MeOH脱除甲（或乙）氧羰基示例

AcOHO5 N KOHNHCOOMe1MeOHH2NH2H

A. R. Hergueta; C. Lopez et al., Tetrahedron: Asymmetry, 2003, 23, 3773

A mixture of compound 1(3.60 g, 14.0 mmol) and 5N KOH (25 mL) in MeOH (50 mL) was refluxed for 18 h and brought to pH 3 with 2N H2SO4. Removal of the solvents at low pressure afforded a white solid (10 g) that was extracted with MeOH, the extract was passed

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through basic ion exchange resin (Amberlite IRA-400(OH), 100 mL), and the eluate was concentrated under reduced pressure to a brown oil (2.81 g) that upon flash chromatography (1:1 EtOAc/MeOH) afforded a colourless oil that 1H NMR spectroscopy showed to be virtually pure compound 2 (1.87 g, 85%). [α]D25 = +22.6 (c=0.52, MeOH).

2.6.2.3 6NHCl脱除甲（或乙）氧羰基示例

COOMeNHMeO1COOMe6 N HClrefluxHHO2NH.HClCOOH

F. Liu; Z. Huiyan et al., J. Org. Chem., 2003, 17, 6679

Compound 1 (44 mg, 0.14 mmol) was refluxed with HCl (6 N, 10 mL) for 4 days. The mixture was concentrated in vacuo to give compound 2 as a white solid (38 mg, 100%). [α] D

20

= +33.2 (c =1.20, H2O).

2.6.2.3 TMSI脱除甲（或乙）氧羰基示例

CF3CF3ONHTMSINHCOOMeCH3CNONHNH2

G. M. Ksander; J. Reynalda de et al., J. Med. Chem., 2001, 26, 4677

A mixture of 8aR (1.53 g, 3.27 mmol), 75 mL of acetonitrile, and trimethylsilyliodide (1.86 mL, 13 mmol) was stirred overnight at room temperature. Methanol was added, and the mixture was concentrated, cold 1 N NaOH added, and the mixture was extracted with EtOAc. The organic layer was washed with aqueous Na2S2O3 and brine, dried, filtered, concentrated and recrystallized from ether to give 1.19 g (%) of 9aR as a white solid melting at 109-112 °C.

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3．酰基类

3.1 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/NH3（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/CHCl3/70℃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Na2CO3水溶液仲于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]。

OEtOCOClNKONOOOOEtRCOOHNH2CONHCOOEtCONHCHRCOONaNa2CO3ORNCOONaO+H2NCOOEt+NaHCO3HClORNCOOHO

1. S. J. Leach, H. Lindley., Australian, J. Chem., 1954, 7, 173 2. T. Sasaki, K. Minamoto et al., J. Org. Chem., 1978, 43, 2320

3. G. H. I. Nefkens, G. I. Tesser et al., Rec. Trav. Chim., 1960, 79, 688; Soai, Kenso; Ookawa,

Atsuhiro et al., Bull. Chem. Soc. Jpn., 1982, 55(5), 1671-1672; N. Aguilar; A. Moyano et al., J. Org. Chem., 1998, 11, 3560; Santaniello, Enzo; Ponti, Fedegco et al., Synth. Commun., 1980, 10(8), 611-614; Siedlecka, Renata; Skarzewski, Jacek et al., Synth. Commun., 1997, 27(12), 281-2086

4. C. R. McArthur, P. M. Worster et al., Synth. Commun., 1983, 13, 311 5. G. Sosnovsky, J. Lukszo., Z. Naturforsch. B., 1986, 41B, 122

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3.1.1.1 邻苯二甲酸酐引入邻苯二甲酰基示例

OOSCOOMeNH2.HClOSCOOMeNPhtEt3N, Toluene

P. Meffre, P. Durand., Org. Syn., 76, 123

Into a 2-L, round-bottomed flask fitted with a Dean-Stark apparatus, reflux condenser, and drying tube containing calcium chloride are placed L-methionine methyl ester hydrochloride (50.0 g, 0.25 mol), phthalic anhydride (37.1 g, 0.25 mol), triethylamine (100 mL, 0.72 mol), and toluene (1 L). The mixture is magnetically stirred and heated under reflux for 4.5 hr at which point approximately 4.5 mL of water has separated. The reaction mixture is allowed to cool to room temperature and the precipitated triethylamine hydrochloride (34 g) is collected by suction filtration. The filtrate is washed with four 300-mL portions of 1 N aqueous hydrochloric acid followed by three 300-mL portions of water. The organic layer is dried over magnesium sulfate , filtered, and the filtrate is concentrated under reduced pressure using a rotary evaporator. The residual oil is placed under reduced pressure for 12 hr at 0.1-0.5 mm, followed by trituration with 200 mL of pentane to give 59 g (80%) of product as a white solid after collection and drying at room temperature under reduced pressure (mp 37-40°C). mp 37-40°C,; [α]20 D −41.6° (CHCl3, c 1.49).

3.1.1.2 邻苯二甲酸单乙酯引入邻苯二甲酰基示例

COOHNH2OHOH7COOEtNPhtOHOH8PyBOP, i-Pr2NEt

N. Aguilar; A. Moyano et al., J. Org. Chem., 1998, 11, 3560

To a suspension of PyBOP (2.84 g, 5.46 mmol, 1.1 equiv) in dry THF (10 mL) was added a solution of 2-ethoxycarbonylbenzoic acid (1.08 g, 5.46 mmol, 1.1 equiv) in THF (10 mL) and i-Pr2NEt (1.27 mL, 7.44 mmol, 1.5 equiv), and the resulting mixture was stirred for 30-40 min at rt. Afterwards, this solution was added to a suspension of 7 (0.8 g) in THF (10 mL) at 0 °C, and the mixture was stirred at rt for 3 h. The solvent was eliminated in vacuo, and the residue was heated at 85 °C overnight. The reaction mixture was then dissolved in 250 mL of

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dichloromethane and washed with saturated NaHCO3 solution (2 x 100 mL) and with brine (100 mL). The organic layer was dried (Na2SO4) and evaporated to give a crude product which

was

purified

by

column

chromatography

to

yield

1.28

g

of

(2S,3S)-4-phenyl-3-phthalimidobutane-1,2- diol (8) (83%) as a white solid: mp 91-93 °C.

3.1.1.3 N-乙氧羰基邻苯二甲酰胺引入邻苯二甲酰基示例:

ONHOEtOCOClEt3N, DMFNCOOEtOO

Worster, Paul M; Leznoff, Clifford C et al., J. Org. Chem., 1980, 45(1), 174-175 Ethyl chloroformate (115 mL, 1.29 mol) was added dropwise over a period of 90 min to a stirred solution of phthalimide (149.9 g, 1.02 mol) and triethylamine (160 mL, 1.15 mol) in dimethylformamide (500 mL) at 0-5°C under argon. The reaction mixture was allowed to warm to room temperature and stand for 4 h. It then was slowly added to an agitated mixture of ice and water (3 L). The solid product was collected and extracted with two portions of chloroform (450 mL and then 50 mL). The extract was dried (Na2SO4), cooled overnight in the refrigerator, and filtered to remove phthalimide (mp 238°C). The chloroform solution was concentrated to about 350 mL, diluted with petroleum ether (bp 60-80 °C; 350 mL) and allowed to stand at room temperature to give N-(ethoxycarbony1)phthalimide (179 g, followed by two additional crops for a total of 212 g, 95% yield): mp 83°C.

ONCOOEtOONH21OOONPht2NaHCO3

W. Shijun; Y. Zhujun et al., Org. Lett., 2004, 16, 2721

The solution of compound 1 (150.2 mg, 1.05 mmol) in THF (4 mL) was treated with N-(ethoxycarbonyl)-phthalimide (230 mg, 1.05 mmol), and NaHCO3 (88 mg, 1.05 mmol) at 0°C. The reaction was stirred for 7 h at rt, and separated. The aqueous layer was extracted with EtOAc (4 x 5 mL). The combined organic extracts were washed with saturated aqueous NH4Cl (3 x 3 mL) and brine (3 mL), dried (Na2SO4), and concentrated in vacuo. Chromatography (hexane/EtOAc = 5/1) provided 9 as an oil (215 mg, 75%).

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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，NaBH4/i-PrOH-H2O(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]。

ONaBH4NRONROHNROO+RNH2OHOHO

1. J. C. Sheehan, D. W. Chapman et al., J. Am. Chem. Soc., 1952, 74, 3822; F. E. King et al., J. Chem. Soc., 1951, 243, 2976

2. F. Dasgupta, P. J. Garegg., J. Carbohydr. Chem., 1988, 7, 701 3. J. O. Osby; M. G. Martin et al., Tetrahedron Lett., 1984, 25, 2093-2096 4. Lee, Chang-Hee; Lee, Jin-Suk et al., J. Org. Chem., 2005, 6, 2067-2074

3.1.2.1 NH2NH2/MeOH脱除邻苯二甲酰胺示例

OONPht12NH2

N2H4/MeOHOOW. Shijun; Y. Zhujun et al., Org. Lett., 2004, 16, 2721

To a solution of compound 1 (313 mg, 1.04 mmol) in MeOH (6 mL) was added hydrazine monohydrate (0.1 mL, 1.67 mmol) at 0 °C. After being stirred at same temperature for 3h, the solvents were removed in vacuo and the residue was re-dissolved into water (10 mL). The pH of solution was then adjusted to 1-2 by adding 1N HCl at 0 °C. The whole mixture was stirred for 1 h at rt, and then filtered. The filtrate was treated with solid Na2CO3 until the pH reached 9-10. The mixture was extracted with CH2Cl2 (10 mL x 4). The combined extracts were dried (Na2SO4), concentrated and dried in vacuo to provide compound 2 (209 mg, quantitatively) as a yellowish oil.

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3.1.2.2 NH2NH2/EtOH脱除邻苯二甲酰胺示例

HNHNNPhtNH2NH2EtOH1HNHNNH22

Lee, Chang-Hee; Lee, Jin-Suk et al., J. Org. Chem., 2005, 6, 2067-2074

Compound 1 (1.66 g, 4.77 mmol) was dissolved in ethanol (50 mL), and then hydrazine monohydrate (0.93 mL, 19 mmol) was added. The resulting mixture was heated at reflux for 24 h and then cooled to room temperature. The mixture then was combined with aqueous NaOH (50 mL) and extracted with CH2Cl2. The solvent was removed in vacuo to afford compound 2 (0.79 g, 76%), which was used directly in the next step without further purification.

3.1.2.3 HCl脱除邻苯二甲酰胺示例

ONPht1conc. HClONH2.HCl2

Lee, Chang-Hee; Lee, Jin-Suk et al., J. Org. Chem., 2005, 6, 2067-2074

Compound 1 (1.0 g, 3.86 mmol) and concentrated HCl (3 mL) was heated for 60 h at 100 °C. After the mixture was allowed to cool to room temperature, water (20 mL) was added. The solid precipitate that formed was removed by filtration and discarded, and the aqueous layer was washed with diethyl ether twice, with these washings also being discarded. The water was removed in vacuo, and the remaining solid was dried to give compound 2 (0.61 g, 95%), which was then used to the next step without further purification due to its instability.

3.1.2.4 NaBH4/i-PrOH-H2O(6:1)和AcOH脱除示例

OHNPhtNH1OHNaBH4, AcOHi-PrOH, H2ONH2HNH2OOH

J. O. Osby; M. G. Martin et al., Tetrahedron Lett., 1984, 25, 2093-2096

To a stirred solution of compound 1 (0.36 g, 1 mmol) in 2-propanol (7.7 ml) and H2O (1.3 ml) was added NaBH4 (0.19 g, 5 mmol). After stirring 24 h, TLC indicated complete consumption

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of starting material. AcOH (1 ml) was added carefully and when the foaming subsided, the flask was stoppered and heated to 80°C for 2 h. The crude reaction mixture was then eluted onto a Dowex 50 (H+) column (2.7 x 10 cm), washed with H2O (150 ml), then eluted with 1 M NH4OH (200 ml). Ninhydrin-active fractions were collected and pooled for freeze drying, and thus afforded compound 2 (0.2 g, %) as an ammonium salt.

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3.2 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-NH2、醛和CO（见下式）[1]

RClOCH2ONHTosNaOHClOCRN-TosNa++H2ORNTos+CO+NaClTos-NH2+RCHO+CO+NaCl

1. A. F. Beecham., Chem. Ind., (London)., 1955, 1120; J. Am. Chem. Soc., 1957, 79, 3257

3.2.1 对甲苯磺酰基的引入

对甲苯磺酰氯在NaOH、NaHCO3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]

1. S. Sakakibara, T. Fujii., Bull. Chem. Soc. Jpn., 1969, 42, 1466

3.2.1.1对甲苯磺酰基的引入示例

ONHNH21Et3N, THFHCOOMeOTsClNNHTs2COOMe

Arthur G. Schultz and Carlos W. Alva., Org. Syn., 73, 174

22.9 g (90 mmol) of compound 1 , 13.66 g (135 mmol) of triethylamine, and 100 mL of dry THF are

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placed in a 300-mL, round-bottomed flask, equipped with a pressure-equalizing dropping funnel, a magnetic stirring bar, and a nitrogen inlet. The dropping funnel is charged with a solution of

18.9 g (99.1 mmol) of p-toluenesulfonyl chloride in 50 mL dry THF. The reaction mixture is cooled

to 0°C with magnetic stirring, and the solution of p-toluenesulfonyl chloride is delivered dropwise over a 30-min period. The resulting cloudy solution is stirred for 60 hr at ambient temperature. After this time period, the reaction mixture is diluted with 50 mL of saturated

sodium chloride solution and 50 mL of ethyl acetate, transferred to a 500-mL separatory funnel,

mixed thoroughly, and the organic phase separated. The aqueous phase is extracted twice with

50 mL of ethyl acetate. The combined organic layers are dried (Na2SO4), filtered, concentrated

under reduced pressure, and the resulting residue purified by chromatography to give 22.43 g (61%) of compound 2 (Rf = 0.34, CHCl3/EtOAc, 1:1) as a colorless solid, mp 144–146°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/NH3(液) [2] 和 Li/NH3(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/NH3(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]

。

1. Masuda, Yui; Mori, Kenji et al., Biosci. Biotechnol. Biochem., 2002, 66(7), 1531-1537; Kaiser, Alexander; Balbi, Miriam et al., Tetrahedron: Asymmetry, 1999, 10(5), 1001-1014; Takikawa, Hirosato; Muto, Shiu-etsu et al., Tetrahedron, 1998, 54(13), 3141-3150; Sugimura, Hideyuki; Miura, Masayuki et al., Tetrahedron: Asymmetry, 1997, 8(24), 40-4100

2. J. Kovacs, U. R. Ghatak., Chem. Ind. (London)., 1963, 913; Dolence, E. Kurt; Roylance, Jason B et al., Tetrahedron: Asymmetry, 2004, 15(20), 3307-3322; Amat, Mercedes; Seffar, Fatima et al., Synthesis, 2001, 2, 267-275; Hoye, Thomas R; Chen, Minzhang et al., Tetrahedron Lett., 1996, 37(18), 3099-3100; Hoye, Thomas R; Chen, Minzhang et al., J. Org. Chem., 1999, (19), 7184-7201

3. Burgess, Kevin; Liu, Lee T et al., J. Org. Chem., 1993, 58(17), 4758-4763

4. Kotek, Jan; Lebduskova, Petra et al., Chem. Europ. J., 2003, 9(23), 59-5915; Calvisi,

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Giuseppina; Dell-Uomo, Natalina et al., Eur. J. Org. Chem., 2003, 23, 4501-4506; Currie, Gordon S; Drew, Micheal G. B et al., J. Chem. Soc. Perkin Trans. 1, 2000, 17, 2982-2990; Davis, Franklin A; Srirajan, Vaidyanathan et al., J. Org. Chem., 2000, 65(10), 3248-3251; Davis, Franklin A; Liu, Hu et al., J. Org. Chem., 1999, (20), 7559-7567; Drury, William J; Ferraris, Dana et al., J. Am. Chem. Soc., 1998, 120(42), 11006-11007

5. Y. Yokoyama, T. Matsumoto et al., J. Org. Chem., 1995, 60, 1486; B. Nyasse, L. Grehn et al., J. Chem. Soc. Chem. Commun., 1997, 1017; Nenajdenko, Valentine G; Karpov, Alexei S et al., Tetrahedron: Asymmetry, 2001, 12(18), 2517-2528

6. Takikawa, Hirosato; Maseda, Takeshi et al., Tetrahedron Lett., 1995, 36(42), 76-7692

3.1.2.1 Na/NH3脱除对甲苯磺酰基示例

TosHNH1 Na/NH3OHOHH2NH2OHOH

A. Schrey; F. Osterkamp et al., Eur. J. Org. Chem., 1999, 11, 2977

To a two necked flask equipped with a dry ice condenser was added compound 1 (3.20 g, 10.1 mmol) in THF (15 ml) and ammonia gas to condense about 25 ml of liquid. Small pieces of sodium (552 mg, 24.2 mmol) were added to the stirred solution until a blue color color persisted for 5 min. After stirring for 10 min, the reaction was quenched by adding dropwise glacial acetic acid (2 ml). The NH3 was allowed to evaporate. The crude product was dried in vacuo for 1 h to give compound 2 (1.3 g, %) as a colorless oil.

3.1.2.2 Li/NH3脱除对甲苯磺酰基示例

NHTosOH12Li/NH3NH2OH

Burgess, Kevin; Liu, Lee T et al., J. Org. Chem., 1993, 58(17), 4758-4763

Lithium metal was added to a solution of compound 1 (1.5 g, 5.01 mmol) in 5 ml of THF and 200 ml of liquid NH3. The resulting dark blue solution was stirred for 1 h and then quenched with 1 ml of absolute ethanol. The ammonia was evaporated. The residue was diluted with saturated aqueous NaCl (30 ml), and extracted with CH2Cl2 (4 x 20 ml). The combined layers was dried and the solvent evaporated to give compound 2 (0.4 g, 55%) as oil.

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3.1.2.3 Na/萘脱除对甲苯磺酰基示例

NH2NHTosNaNaphthalenide12NH2NH2

Kaiser, Alexander; Balbi, Miriam et al., Tetrahedron: Asymmetry, 1999, 10(5), 1001-1014 To a solution of compound 1 (0.78 g, 1.83 mmol) in dry THF (20 ml) a solution of sodium naphthalenide [31 ml; prepared by stirring naphthalene (3.96 g, 31.2 mmol) and small pieces of sodium (1.92 g, 83.8 mmol) in dry THF (120 ml) for 3 h at room temperature under nitrogen] was added over 10 min at -78°C. After 6.5 h at -78°C, water (5 ml) was added, and THF was removed under reduced pressure. The mixture was diluted with water (10 ml) and extracted with EtOAc (3 x 30 ml). The combined EtOAc layers were washed with brine (2 x 20 ml), dried and evaporated. Column chromatography (CH2Cl2: MeOH, 9:1) afforded compound 2 (0.17 g, 39%) as a colorless oil.

3.1.2.4 HBr/苯酚脱除对甲苯磺酰基示例

OHO1HBr/PhOHHBr.H2NHBr.H2N2OOHH2NTosNH

Calvisi, Giuseppina; Dell-Uomo, Natalina et al., Eur. J. Org. Chem., 2003, 23, 4501-4506

A round-bottom flask containing a mixture of compound 1 (600 mg, 1.94 mmol), phenol (547 mg, 5.82 mmol) and HBr (7.5 mL, 48%) was placed in an oil bath previously heated to 130 °C and refluxed for 18 hours. The reaction mixture was then allowed to cool to room temperature, diluted with water and extracted twice with EtOAc. The aqueous layer was evaporated under vacuum, the residue was taken up several times with CH3CN (evaporating under vacuum every time) until a solid residue, insoluble in CH3CN, was obtained. The solid was filtered and dried to give compound 2 (230 mg, 95%) as the dihydrobromide salt.

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3.1.2.5 Mg/MeOH脱除对甲苯磺酰基示例

TosHNS1Mg/MeOHSH2N2

Nenajdenko, Valentine G; Karpov, Alexei S et al., Tetrahedron: Asymmetry, 2001, 12(18), 2517-2528

To a suspension of Mg (0.45 g, 20 mmol) in MeOH (5 mL) was added a solution of compound 1 (0.74 g, 2 mmol) in MeOH (10 mL). The resulting suspension was sonicated for 1 h until consumption of the starting material was complete. The reaction mixture was then diluted with aqueous NH4Cl and extracted with ether (3 x 5 mL). The organic layer was dried over MgSO4 and evaporated. To resulting oil ethanolic solution HCl (2 M, 0.5 mL) was added. Hydrochloride was precipitated, filtered and washed with ether to afford compound 2 HCl salt (0.46 g, 90%) as a white solid.

3.3 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

19

F NMR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。

1. F. Weygand, E. Csendes., Angew. Chem., 1952, , 136

2. F. Weygand, D.Hoffmann, A. Prox., Z. Naturforsch., 1968, 23b, 279 3. N. Ikekawa., J. Biochem., 1963, 54, 279 4. E. Bayer et al., J. Am. Chem. Soc., 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，

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CF3COOEt/Et3N/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/Et3N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]。

1. F. Weygand, E. Leising., Chem. Ber., 1954, 87, 248 2. F. Weygand, R. Geiger., Chem. Ber., 1956, , 7 3. T. J. Curphey., J. Org. Chem., 1979, 44, 2805

4. D. Xu, K. Prasad, D. M. Dalrymple et al., Tetrahedron Lett., 1995, 36, 7357; M. C. O’Sullivan, D. M. Dalrymple., Tetrahedron Lett., 1995, 36, 3451

5. P. I. Svirskaya, C. C. Leznoff, M. Steinman., J. Org. Chem., 1987, 52, 1362 6. A. G. M. Barrett, J. C. Lana., J. Chem. Soc. Chem. Commun., 1978, 471 7. R. J. Bergeron, J. J. McManis., J. Org. Chem., 1988, 53, 3108

3.3.1.1 TFAA引入三氟乙酰基示例

OHNH2TFAABrO1HEt3N, DMAPBrO2HOHNHCOCF3

Chambers, James J; Parrish, Jeasen C et al., J. Med. Chem., 2003, 46(16), 3526-3535 To a stirred suspension of the hydrobromide salt of compound 1 (1.3 g, 3.6 mmol) and 4-N,N- (dimethylamino) pyridine (0.04 g, 0.3 mmol) in CH2Cl2 (40 mL) was added Et3N (16.0 mL, 12.0 mmol), and the mixture was cooled to 0 °C. Trifluoroacetic anhydride (2.5 mL, 17 mmol) was then added to the reaction dropwise. The mixture was allowed to warm to room temperature and stirred for 8 h. The mixture was then diluted with CH2Cl2 (50 mL) and washed with 2 N HCl (50 mL), saturated NaHCO3 (50 mL), and brine (50 mL). The organic phase was then dried (MgSO4), filtered, and evaporated to leave compound 2 as a white solid that was recrystallized from Et2O (1.2 g, 92%): mp 197-198 °C.

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3.3.1.2 三氟乙酸乙酯引入三氟乙酰基示例

ONH2OMe1CF3COOEtEt2O2NHOMeCF3

Knoops, Niele; Derioover, Geert ret al., Tetrahedron, 1997, 53(37), 12699-12716

Ethyl trifluoroacetate (9.2 mmol) was dissolved in 10 ml dry diethylether and stirred at 0 °C for 10 minutes. Compound 1 (8.8 mmol) was added and the reaction mixture was stirred at the same temperature for one hour. After removal of the solvent, the residues were purified by fast column chromatography (SiO2; CHCl3) to give compound 2(yield 98 %) as a yellow crystalline m.p.: 68-69 °C (CH2Cl2/hexanes).

4.3.1.3 三氟乙酸乙酯选择性保护伯胺示例

HNH1OBnNH2CF3COOEtHNH2OBnNHCOCF3

Whitlock, Gavin A; Carreira, Erick M et al., Helv. Chim. Acta., 2000, 83(8), 2007-2022 Compound 1 (0.39 mmol) was dissolved in THF (10 mL), cooled to 0°C, and CF3COOEt (0.01 mL, 0.39 mmol) was added. The mixture was stirred at 0°C for 1 h and then at 23°C for 1 h. The solvent was then evaporated under reduced pressure to give a pale yellow oil. Purification by FC (silica gel; MeOH) afforded 2 (119 mg, 85%) as colorless oil. TLC (MeOH): Rf = 0.29. [α]24D = +4.8 (c =0.48, CHCl3).

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0.1-0.2 N NaOH处理或者用1 M 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8 M 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K2CO3或Na2CO3/MeOH/H2O条件下，Tfa可在甲基酯存在下于室温去保护[2]。也可在NH3/MeOH[3]，HCl/MeOH[4]或通过相转移水解(KOH/Et3Bn+Br-/H2O/CH2Cl2或乙醚)脱去[5]。

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1. D. A. Ontjes, C. B. Anfinsen., J. Biol. Chem., 1969, 244, 6314

2. R. J. Bergeron, J. J. McManis., J. Org. Chem., 1988, 53, 3108; H. Newman., J. Org. Chem., 1965, 30, 1287; J. Quik, C. Meltz., J. Org. Chem., 1979, 44, 573; M. A. Schwartz, B. F. Rose et al., J. Am. Chem. Soc., 1973, 95, 612; D. L. Boger, D. Yohannes., J. Org. Chem., 19, 54, 2498

3. M. Imazawa, F. Eckstein., J. Org. Chem., 1979, 44, 2039 4. S. B. King, B. Ganem., J. Am. Chem. Soc., 1994, 116, 562

5. D. Albanese, F. Corcella, D. Landini et al., J. Chem. Soc. Perkin Trans. I, 1997, 247

3.3.2.1 KOH脱去三氟乙酰基示例

OHNHCOCF3KOHMeOH, H2OO1O2OHNH2

Chambers, James J; Parrish, Jason C et al., J. Med. Chem., 2003, 46(16), 3526-3535

A solution of compound 1 (1.7 g, 5.4 mmol) in MeOH (250 mL) was cooled to 0°C, and then 5 N KOH solution (30 mL) was added slowly. The reaction mixture was allowed to warm to room temperature and stirred overnight, and then the MeOH was removed by rotary evaporation. The residue was diluted with H2O (25 mL) and extracted with Et2O (4 x 100 mL), dried (Na2SO4), filtered, and evaporated to afford clear oil. This oil was dissolved in Et2O (100 mL), filtered through a plug of glass wool, and neutralized by the slow addition of oxalic acid (54 mL, 0.1 M in MeOH). The solvents were removed, and the resulting white residue was recrystallized from MeOH to afford compound 2 (0.9 g, 59%) as the hemioxalate salt, m.p 243 °C.

3.3.2.2 K2CO3脱去三氟乙酰基示例

HN1NHCOCF35% K2CO3MeOH, H2OHN2NH2

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Whitlock, Gavin A; Carreira, Erick M et al., Helv. Chim. Acta., 2000, 83(8), 2007-2022 Compound 1 (45 mg, 0.18 mmol) was dissolved in 5% K2CO3 in MeOH/H2O (15 mL), and the soln. was stirred at 23°C for 4 h. H2O (3 mL) was added, the soln. was saturated with NaCl, and then extracted with CH2Cl2 (5×15 mL). The combined org. extracts were dried (Na2SO4) and concentrated under reduced pressure to afford compound 2 (23.5 mg, 85%).

4．烷基类

4.1 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。

1. L. Zervas, D. M. Theodoropoulos., J. Am. Chem. Soc., 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。

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RCl+HOOCNH2Et3NNHRCOOHRCl+BnOOCNH21. Et3NNH2. H2/Pd-CRCOOH

尽管可采用先制得Trt-氨基酸苄酯，然后控制吸收1.1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CHCl3中，加入2.2当量的Trt-Cl和2.2当量的Et3N，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/Me3SiCl/Et3N[2]和Trt-Cl/TMSCl/Et3N[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

2. Hoffman, Robert V; Maslouh, Najib et al., J. Org. Chem., 2002, 67(4), 1045-1056; Sim, Tae Bo; Rapoport, Henry et al., J. Org. Chem., 1999, (7), 2532-2536 3. Hoffman, Robert V; Tao Junhua, J. Org. Chem., 1998, 63(12), 3979-3985

4.1.1.1 氨基酸的三苯甲基的引入示例

OONH21OOHTrt-ClMe3SiCl, Et3NONHTrt2OOOH

Hoffman, Robert V; Maslouh, Najib et al., J. Org. Chem., 2002, 67(4), 1045-1056 Chlorotrimethylsilane (1.27 mL, 10.0 mmol) was added at room temperature to a stirred suspension of an compound 1 (1.61 g, 10.0 mmol) in 18 mL of CHCl3/MeCN (5:1). The reaction mixture was refluxed for 2 h and then cooled to 0 °C. Dropwise addition of triethylamine (2.79 mL, 20.0 mmol) was followed by a solution of trityl chloride (2.79 g, 10.0 mmol) in chloroform (10 mL). The resulting mixture was stirred for 1 h, and then methanol (2 mL) was added. After concentration, the pale yellow residue was partitioned between diethyl

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ether and water. The aqueous layer was extracted twice with diethyl ether (20 mL). The combined organic layers were dried (MgSO4) and concentrated to give compound 2 (2.14 g, 53%), which was used for the next step without further purification.

4.1.1.2 氨基醇的三苯甲基的引入示例

OOH2N1OHEt3N, CH2Cl2Ph3C-ClPh3CHN2OOOH

Gros, Christel; Boulegue, Cyril et al., Tetrahedron, 2002, 58(13), 2673-2680

Amino alcohol 1 (2.15 g, 12.3 mmol) and Et3N were dissolved in dry CH2Cl2 (60 mL). To the ice-bath cooled preceding solution, trityl chloride (3.43 g, 12.3 mmol) dissolved in CH2Cl2 (20 mL) was added dropwise over 15 min. After stirring 1 h at rt, the solvent was evaporated. The residue dissolved in AcOEt (100 mL) and followed by a flash column chromatography purification (AcOEt/cyclohexane 80:20) to afford alcohol 2 as an oil in: 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/CHCl3、HBr/HOAc和TFA[3]都能很方便的脱去Trt，用HCl/MeOH处理Trt-Lys(Trt)OCH3可以得到Lys(Trt)OCH3，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0.1M HBr/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）。

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H2/Pd-CPh3C-HHCl/CHCl3R1NHR2OHCl/MeOHHCl/H2OPh3C-ClPh3C-OHPh3C-OMeHOAcPh3C-OAc

1. 1. L. Zervas, D. M. Theodoropoulos., J. Am. Chem. Soc., 1956, 78, 1359; F. C. McKay, N. F.

Abertson., J. Am. Chem. Soc., 1957, 79, 4686; R. Schwyzer, W. Rittel., Helv. Chim. Acta., 1961, 44, 159

2. L. Hyun-Suk, P. Jeong-Ju et al., Bioorg. Med. Chem. Lett., 2004, 10, 2499; K. Yuji, T.

Ryuichi et al., Bioorg. Med. Chem., 2002, 10, 3829

3. S. Rita, K. Yeong-Sang et al., Tetrahedron Lett., 2003, 8, 1537

4. B. Bezas, L. Zervas., J. Am. Chem. Soc., 1961, 83, 719; G. Amiard, B. G. Offinet., Bull. Soc. Chim.

France., 1956, 698

5. Chandrasekhar, S., Babu, B. Nagendra et al., Tetrahedron Lett., 2003, 10, 2057; E. Janos,

K. Gyoergy et al., Tetrahedront., 2002, 44, 21

4.1.2.1 TFA脱去三苯甲基示例

HFmocHNHTrtHNO1SOOHOTFACHCl3FmocHNHH2NO2SOOO

M. Firouz Mohd Mustapa, Richard Harris, Nives Bulic-Subanovic et al., J. Org. Chem., 2003, 21, 8185; S. Vinay, M. Mizio et al., Tetrahedron, 2002, 44, 9101

Compound 1 (3.5 g, 4.6 mmol) was treated with a 5% solution of trifluoroacetic acid (1.4 mL, 18 mmol, 4 equiv) in CHCl3 (27 mL) under inert conditions for 4 h. The resulting solution was diluted with CHCl3 (200 mL) and washed with sodium hydrogen carbonate (5% aq w/v, 2

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× 75 mL) and water (2 × 50 mL). The solvent was removed in vacuo. The material was then redissolved in CHCl3 (20 mL) and MeOH (20 mL), and the solvents were again removed in vacuo to yield compound 2 (2.1 g, 87%) as a pale yellow liquid.

4.1.2.2 TFA-TIS脱去三苯甲基示例

OTrtHNOO1ONHFmocTFATIS, CH2Cl2H2NOO2OOHNHFmoc

Swall, Vinay; Matteuccl et al., Tetrahedron, 2002, 58(44), 9101-9110

Compound 1 (2.0 g, 2.71 mmol) was stirred with TFA (4.9mL), CH2Cl2 (4.9mL) and TIS (0.2 mL) for 1 h. Solvent was removed in vacuo and the residue purified by column chromatography (SiO2, MeOH/CHCl3, 1:9 v:v) to afford compound 2 (1.16 g, 91%) as a white solid.

4.1.2.3 TFA-Et3SiH脱去三苯甲基示例

TBSOTrtHN1NBocOTFAOBnEt3SiH, CH2Cl2H2N2NHOBnTBSOO

Pickersgill, I. Fraser; Rapoport, Henry; J. Org. Chem., 2000, 65(13), 4048-4057

To a stirred solution of compound 1 (3.34 g, 3.82 mmol) and triethylsilane (0. mL, 4.01 mmol) in CH2Cl2 (16 mL) cooled to 0 °C was added dropwise TFA (16 mL). The resultant colorless solution was allowed to warm to rt, with stirring continued for 1 h. The solvents were evaporated, the residue was triturated with hexanes (5 x 50 mL), the hexane extracts were discarded, and the oily residue was partitioned between CHCl3/IPA (250 mL, 3/1) and 1 M NaOH (precooled to 0 °C, 100 mL). The aqueous phase was extracted with further portions of CHCl3/IPA (2 x 200 mL, 3/1), and the combined organic phase was dried, filtered, and evaporated to give compound 2 (2.04 g, 100% crude yield) as a pale yellow oil.

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4.1.2.4 HOAc脱去三苯甲基示例

NHTrtNH1HOAcH2ONH2NH2

Vago, Istvan; Kalaus, Groergy et al., Heterocycles, 2001, 55(5), 873-880

0.85 g (2 mmol) of compound 1 was dissolved in the mixture of 20 mL of acetic acid and 0.5 mL of water. The solution was heated under argon at 60 ºC for 1 h, and then allowed to cool to rt. The resulted dark solution was diluted with 200 mL of water; the triphenylmethanol was removed by extraction with ether. The pH of the watery phase was adjusted to a value of 8 with sodium carbonate solution, extracted with dichloromethane; the extract was dried with magnesium sulfate, evaporated to dryness in vacuumto give, compound 2 (0.24 g , %) as unstable brown oil.

4.1.2.5 TBS和Boc官能团存在下用BF3-HOAc脱去三苯甲基示例

OTBSTrtHN1NHBocBF3.Et2OAcOHH2N2OTBSNHBoc

Pickersgill, I, Fraser; Rapoport, Henry; J. Org. Chem., 2000, 65(14), 4048-4057 To a solution of 32 (2.67 g, 3.98 mmol) in CH2Cl2 (27 mL) cooled to 0 °C were added glacial acetic acid (6.7 mL) and BF3.Et2O (0.529 mL, 4.17 mmol) dropwise, and the mixture was stirred at 0 °C for 2 h. Cold (0 °C) 1 M NaOH (160 mL) was added and the mixture partioned between CHCl3/IPA (320 mL, 3/1) and cold (0 °C) 1 M NaOH (66 mL), followed by extraction with further portions of CHCl3/IPA (2 x 160 mL, 3/1). The combined organic phase was dried, filtered, and evaporated to a residue which was chromatographed (CH2Cl2/MeOH, 19/1 to 9/1) to give 33 (1.50 g, 88%) as a colorless oil: [α]22D = +3.1 (c = 1.0, CHCl3).

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4.2 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H2/8%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, Gabor et al., Tetrahedron, 1985, 41(2), 479-484

2．Boeckman, Robert K; Weidner, Charles H et al., J. Am. Chem. Soc., 19, 111(20), 8036-8037

4.2.1 2,4-二甲氧基苄基（DMB）引入

2,4-二甲氧基苄基（DMB）一般由ArCHO/NaBH3CN或NaBH(OAc)3[1]还原胺化类引入。

1. Moore, M. Caragh; Cox, Russell J et al., Tetrahedron, 1998, 54(31), 9195-9206

4.2.1.1 2,4-二甲氧基苄基（DMB）引入示例

MeOOMeCOOMeNHOMeCOOMeNH2OHCNaBH3CN/MeOH1OMe

Moore, M. Caragh; Cox, Russell J et al., Tetrahedron, 1998, 54(31), 9195-9206 Methanolic HCl was added to a stirred solution of L-phenylalanine methyl ester (4.33 g，24.16 mmol) in methanol (100 mL) to adjust to pH 6. 2,4-Dimethoxybenzaldehyde (4.82, 29.00 mmol) was then added, the solution stirred at 20°C for 30 min and then NaBH3CN (2.20 g，35.01mmol) was added and the reaction stirred for a further 16h. The solvent was removed in vucuo, water (50 mL) added and the solution extracted with diethyl ether (3x 100 mL). The organic extracts were combined: washed with an aqueous solution of FeSO4, dried (MgSO4), filtered and reduced in vucuo, to afford a crude pruduct as a pale yellow oil. Impurities of 2,4-dimethoxybenzylalcohol were removed by distillation under reduced presure

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(furnace temparature 110°C, 0.1 mmHg). The product could be further purified by chromatography (hexane: ethylacetate, 50 : 50) to give compound 1 (3.71 g, 11.26 mmo1, 46.6%) [α]21D = - 65.22 (c = 0.01, EtOH).

4.2.2 2,4-二甲氧基苄基（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-Pr3SiH/CH2Cl2时,N-Fmoc可以稳定不动[6]。其他如DDQ/CH2Cl2[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, Yong et al., Org. Lett., 2004, 6(23), 4285-4288

2．Gardiner, John M; Goss, Andrew Det al., Tetrahedron Lett., 2002, 43(43), 7707-7710 3．Davidson, James P; Martin, Stephen F et al., Tetrahedron Lett., 2000, 41(49), 9459-94 4．Floyd, Christopher D; Harmett, Laura A et al., Syn. Lett., 1998, 6, 637-639 5．Horiguchi, Yoshie; Saitch, Toshiwaki et al., Heterocycles, 2002, 57(6), 1063-1078 6．Goronovsky, Sofia; Meir, Simcha et al., Syn. Lett., 2003, 10, 1411-1414 7．Dagoneau, Christelle; Denis, Jean-Noeel et al., Syn. Lett., 1999, 5, 602-604

4.2.2.1 2,4-二甲氧基苄基（DMB）酸脱去示例

FFSNO2DMBF30%TFA/CH2Cl2or 1N HCl/THFOFSNHOO1

Hill, Bryan; Liu, Yong et al., Org. Lett., 2004, 6(23), 4285-4288

Route A: To a cooled 0°C solution of Sulfonamide 3 (43.5 mg, 0.117 mmole) and CH2Cl2 (2.6 mL) was added TFA (1.1 mL). The reaction mixture immediately turned pink. The reaction was stirred at 0°C for 4.5 hrs then the solvent was removed in vacou to yield a pink solid. The solid was suspended in acetone and filtered thru a plug of cotton (acetone rinse). The filtrate was evaporated and the residue purified by flash chromatography (15:85 EtOAc:Hexanes) yielded sulfonamide 2 (23.4 mg, 90%) as a clear colorless oil.

Route B: A solution of sulfonamide 1 (96.2 mg, 0.286 mmole), 1N HCl (3.8 mL) and THF (3.8 mL) was stirred at rt overnight. The mixture was diluted with Et2O, washed with aq. NaHCO3, brine, dried over MgSO4, filtered and concentrated. Flash chromatography (15:85 EtOAc:Hexanes) yielded sulfonamide 2 (55.2 mg, 87%).

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4.2.2.2 DDQ脱去2,4-二甲氧基苄基（DMB）示例

ODMBNODDQCH2Cl2, H2O1HNBoc2OOBoc

Dagoneau, Christelle; Denis, Jean-Noeel et al., Syn. Lett., 1999, 5, 602-604

A solution of ester 1 (0.08mmol) and DDQ (0.28mmol) in CH2Cl2/H2O (19/1, 6mL) was stirred for 1 day at r.t. The mixture was then diluted with CH2Cl2 and treated by a saturated aqueous solution of NaHCO3. Classical work-up, followed by column chromatography (silica gel, AcOEt/pentane:1/9) afforded the N-Boc amine 2 as a colorless oil.

4.3 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H2/Pd(OH)2去掉Bn，而保留PMB[7,8]。

1. A. Dondoni; A. Massi et al., Tetrahedron Lett., 2004, 45(11), 2381 2. A. Dondoni; A. Massi et al., Adv. Synth. Catal., 2004, 346(11), 1355

3. S. D. Bull; S. G. Davies et al., J. Chem. Soc. Perkin Trans. 1, 2000, 22(1), 3765 4. S. D. Bull; S. G. Davies et al., Chem. Commun, 2000, 5, 337 5. B. Hungerhoff; S. S. Samanta et al., Syn. Lett., 2000, 1, 77

6. B. Raju; S. Anandan et al., Bioorg. Med. Chem. Lett., 2004, 14(12), 3103 7. J. L. Vasse; V. Levacher et al., Tetrahedron, 2003, 59(26), 4911 8. J. L. Vasse; V. Levacher et al., Tetrahedron Asymmetry, 2002, 13(3), 227

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4.3.1 对甲氧基苄基（PMB）的引入

PMB一般采用MeOC6H4CH2Br或MeOC6H4CH2Cl和碱（K2CO3[1]、i-Pr2NEt[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MeC6H4CHO/NaBH3CN[5]或NaBH(OAc)3[6]还原胺化等。

1. J. Cossy; I. Pevet et al., Eur. J. Org. Chem., 2001, 15, 2841; J. Cossy; I. Pevet et al., Syn. Lett., 2000, 1, 122

2. T. Ohshima; T. Shibuguchi et al., Tetrahedron, 2004, 60(35), 7743; T. Shibuguchi; Y. Fukuta et al., Tetrahedron Lett, 2002, 43(52), 9539; T. Ohshima; V. Gnanadesikan et al., J. Am. Chem. Soc., 2003, 125(37), 11206; R. Caputo; C. Romualdo et al., Eur. J. Org. Chem., 2002, 17, 3050

3. M. Lautens; E. Fillion et al., J. Org. Chem., 1997, 62, 4418 4. R. A. Bragg; J. Clayden et al., Tetrahedron Lett, 2001, 42(20), 3411 5. P. Wipf; C. R. Hopkins et al., J. Org. Chem., 2001, 66(9), 3133

6. T. M. Ciccarone; S. C. MacTough., Bioorg. Med. Chem. Lett., 1999, 9(14), 1991

4.3.1.1 烷基化引入对甲氧基苄基（PMB）示例1

BnPMBBr, K2CO3On-Bu4NI, CH3CNBnNHHO1NHPMBO2O

J. Cossy; I. Pevet et al., Eur. J. Org. Chem., 2001, 15, 2841

Anhydrous K2CO3 (780 mg, 5.66 mmol, 2.0 equiv.), n-Bu4NI (100 mg, 0.28 mmol, 0.1 equiv.), and p-methoxybenzyl bromide (630 mg, 3.11 mmol, 1.1 equiv.) were added successively to a solution of compound 1 (700 mg, 2.83 mmol) in CH3CN (6 mL). After 1 h at 40°C and overnight at room temperature, the reaction mixture was diluted with ether, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (cyclohexane-AcOEt, 95:5 to 90:10) to give 0.68 g (65%) of compound 2 as colorless oil. [α]D20 = +12.5 (c = 2.02, CHCl3).

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4.3.1.2 烷基化引入对甲氧基苄基（PMB）示例2

O1NH2HClCO2MePMBClDIPEATolueneON(MPM)2CO2Me2

R. Caputo; C. Romualdo et al., Eur. J. Org. Chem., 2002, 17, 3050

A magnetically stirred suspension of compound 1 (0.39 g; 2.84 mmol) and diisopropylethylamine (DIPEA, 25 mL; 0.14 mmol) in toluene (10 mL) was gently warmed until a clear solution was obtained. 4-Methoxybenzyl chloride (2.3 mL; 17 mmol) was then added in one portion, and the resulting solution was heated under reflux, and also the intermediate N-monosubstituted derivative were completely consumed (ca. 5 h, TLC monitoring). The reaction mixture was then cooled in an ice bath, diluted with ethyl acetate (0.2 L), and extracted with 10% aq. NH4Cl. The organic layer was washed with brine and dried (Na2SO4), and the solvents were evaporated under reduced pressure to afford a crude reaction product, chromatography of which on silica gel (petroleum ether/Et2O, 8:2) gave the pure, oily title compound 2 (0.37 g; 85%).

4.3.1.3 还原胺化引入对甲氧基苄基（PMB）示例

OMeO2NOTBDPSNH21MeOCHOOMeO2NOTBDPSNHPMBNaCNBH3, MeOH2

P. Wipf; C. R. Hopkins et al., J. Org. Chem., 2001, 66(9), 3133

To a solution of 5.031 g (11.17 mmol) of amine 1 in 13 mL of MeOH was added at 0 °C 712.7 mg (11.34 mmol) of NaBH3CN followed by 1.50 mL (1.68 g, 12.3 mmol) of p-anisaldehyde and 0.5 mL of AcOH. The reaction mixture was warmed to room temperature, stirred overnight, and quenched with H2O and solid Na2CO3. The viscous suspension was transferred to a separatory funnel and extracted with CH2Cl2. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give a bright yellow oil that was purified by chromatography on SiO2 (hexanes/EtOAc; 9:1) to afford 5.324 g (9.336 mmol, 84%) of amine 2 as a light yellow oil: [α]D = -37.3 (c = 0.74, CHCl3).

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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SmI2[3]氧化去保护和在TFA[4]中加热脱去也经常应用。

1. A. Dondoni; A. Massi et al., Tetrahedron Lett., 2004, 45(11), 2381; A. Dondoni; A. Massi et al., Adv. Synth. Catal., 2004, 346(11), 1355; B. Raju; S. Anandan et al., Bioorg. Med. Chem. Lett., 2004, 14(12), 3103; R. Caputo; C. Romualdo et al., Eur. J. Org. Chem., 2002, 17, 3050; J. Podlech; Synth. Commun., 2000, 30(10), 1779; P. P. Obrien; W. David et al., Syn. Lett., 2000, 9, 1336

2. S. D. Bull; S. G. Davies et al., J. Chem. Soc. Perkin Trans. 1, 2000, 22(1), 3765; S. D. Bull; S. G. Davies et al., Chem. Commun, 2000, 5, 337; B. Hungerhoff; S. S. Samanta et al., Syn. Lett., 2000, 1, 77

3. H. Adams; J. C. Anderson et al., J. Org. Chem., 1998, 63(26), 9932

4. T. Yamauchi; H. Takahashi et al., Heterocycles, 1998, 48(9), 1813; S. F. Martin; G. O. Dorsey et al., J. Med. Chem., 1998, 41(10), 1581

4.3.2.1 DDQ脱去对甲氧基苄基（PMB）示例

OMeDDQPhPhNOOCH2Cl2, H2OPhPhNHOO2

S. D. Bull; S. G. Davies et al., J. Chem. Soc. Perkin Trans. 1, 2000, 22(1), 3765-3774

1DDQ (1.15 g, 2.1 mmol) was added portionwise to a stirred solution of compound 1 (400 mg, 1.0 mmol) in MeCN-H2O (5 : 1, 6 mL) and stirred at RT. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution and stirred vigorously for ten minutes before extracting with Et2O. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo efore purification by column chromatography on silica gel (hexane-Et2O 2: 1) to give compound 2 (246 mg, 79%) as a colourless oil.

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4.3.2.2 CAN脱去对甲氧基苄基（PMB）示例

MePhCl1NArHCO2EtCAN(3 eq.)MeCN, H2OCl2PhMeNHHCO2Et

P. P. Obrien; W. David et al., Syn. Lett., 2000, 9, 1336

A mixture of compound 1 (104 mg, 0.2 mmol) and CAN (350 mg, 0.6 mmol) in a 1:1 solution of MeCN-water (0.86 mL) was stirred at 0 °C for 30 min. Brine (5 mL) was added and the mixture extracted with EtOAc (3 x10 mL). The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure. Purification by chromatography on silica with petrol-EtOAc (6:1) as eluent gave amine 2 (65 mg, 87%) as a yellow oil.

4.3.3.3 TFA脱去酰胺对甲氧基苄基（PMB）示例

HOHO1HOHN(PMB)BnCF3CO2HOHOHO2HHNHBn

S. F. Martin; G. O. Dorsey et al., J. Med. Chem., 1998, 41(10), 1581

Compound 1 (200 mg, 0.810 mmol) was dissolved in trifluoroacetic acid (TFA) (10 mL), and the solution was stirred for 24 h at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in CH2Cl2 (50 mL). The organic layer was washed with water (2 x 25 mL), dried (MgSO4), and concentrated under reduced pressure to leave a white solid that was purified by flash chromatography eluting with hexanes/EtOAc (1:1) containing 2% AcOH to give compound 2 (180 mg, 77%) of as a white solid: mp 150-152 °C.

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4.4 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/NH3脱除。

4.4.1 苄基（Bn）的引入

一般和PMB 一样也采用C6H4CH2Br或C6H4CH2Cl和K2CO3[1]、DIPEA[2]、NaH[3]、Et3N[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C6H4CHO/ NaBH4[7]、NaBH3CN[8]或NaBH(OAc)3[9]还原胺化。

1. Ordonez, Mario; Cruz-Cordero, Ricardo de et al., Chem. Commun., 2004, 6, 672-673; Gibson, Susan E; Mainolfi, Nello et al., Chem. Commun., 2003, 13, 1568-1569; Yamanaka, Masamichi; Nishida, Atsushi et al., J. Org. Chem., 2003, 68(8), 3112-3120; Gutierrez-Garrica, Victor Manuel et al., Tetrahedron, 2001, 57(30), 87-96; Cossy, Janine; Pevet, Isabelle et al., J. Org. Chem., 2001, 15, 2841-2850; Cossy, Janine; Pevet, Isabelle et al., Syn. Lett., 2000, 1, 122-124

2. Arslautas, Enver; Smith-Jones, Peter M et al., J. Org. Chem., 2004, 19, 3979-3984 3. Takigawa, Yasushi; Ito, Hisanaka et al., Tetrahedron, 2004, 60(6), 1385-1392; Cappelli, Andrea; Mohr, Galla Pericot et al., J. Med. Chem., 2003, 46(17), 3568-3571

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

5. Clayden, Jonathan; Pink, Jennifer H et al., J. Chem. Soc. Perkin Trans. 1, 2002, 7,

901-917

6. L. Velluz, G. Amiard et al., Bull. Soc. Chim. Fr., 1954, 1012; N. Yamazaki, C. Kibayashi., J. Am. Chem.

Soc., 19, 111, 1397; B. D. Gray, P. W. Jeffs., J. Chem. Soc. Chem. Commun., 1987, 1329

7. A. Guy, J. F. Barbetti., Synth. Commun., 1992, 22, 853; J. A. Sclafani, M. T. Maranto et al., J. Org. Chem., 1996, 61, 3221; Berkom, Leon W. A. Van; Gelder, Rane De et al., Eur. J. Org. Chem., 2005, 5, 907-917

8. C. M. Cain, R. P. C. Cousins etal., Tetrahedron., 1990, 46, 523; Kawasaki, Temomi; Kouko, Takashi et al., Tetrahedron Lett., 2003, 44(44), 8849-8852; Page, Daniel; Naismith, Angela et al., J. Med. Chem., 2001, 44(15), 2387-2390

9. Rompaey, Karolien Van; Eynde,et al., Tetrahedron, 2003, 59(24), 4421-4432

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4.4.1.1 烷基化引入苄基(Bn)示例

HNBnBr, K2CO3OBnHPMBONn-Bu4NI, CH3CNHPMBOO12 J. Cossy; I. Pevet et al., Eur. J. Org. Chem., 2001, 15, 2841

Anhydrous K2CO3 (500 mg, 3.62 mmol, 2.0 equiv.), n-Bu4NI (66 mg, 0.18 mmol, 0.1 equiv.), and benzyl bromide (0.24 mL, 1.98 mmol, 1.1 equiv.) were added successively to a solution of compound 1 (500 mg, 1.81 mmol) in CH3CN (5 mL). After 2 h at 35 - 40 °C and overnight at room temperature, the reaction mixture was diluted with ether, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (cyclohexane - AcOEt, 95:5 to 90:10) to give compound 2 (0.54 g, 81%) as a colorless oil. [α]D20 = +12.9 (c = 1.99, CHCl3).

4.4.1.2 还原胺化引入苄基（Bn）示例

BocNHH2NCOOHNa(OAc)3BH1HNBoc2CHOHOOCNH

Rompaey, Karolien Van; Eynde, Isabelle Van den et al., Tetrahedron, 2003, 59(24), 4421-4432 Compound 1 (0.5 g, 1.70 mmol) was dissolved in 1,2-dichloroethane (50 mL) and the aldehyde (0.122 g, 1.70 mmol), Et3N (0.172 g, 1.70 mmol), NaBH(OAc)3 (0.505 g, 2.38 mmol) and MgSO4 (30 wt%) were added. The reaction was stirred at room temperature. RP-HPLC indicated reaction times between 2 and 4 h. The mixture was quenched with saturated NaHCO3 (50 mL) and extracted with EtOAc (3 x 70 mL). The organic layer was dried (MgSO4), filtered and evaporated to give compound 2, which were used without further purification.

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4.4.2 苄基（Bn）的脱去

Bn常用催化氢解脱去，如H2/20%Pd(OH)2-C [1 ]、H2/Pd-C [2 ]、H2/PdCl2 [3]、Pd/HCOOH[4]或Pd-C/HCOOH[5]、Pd-C/HCOONH4[6]、Pd-C/NH2NH2[7]或Pd-C/环已烯[8]作氢源转移氢化，而用H2/Pd-C去保护通常很慢[9]，除非添加Boc2O促进Bn的离去。另外CCl3CH2COCl/CH3CN[10]、Li/MH3[11]、Na/NH3[12]、CAN[13]和CH3CHClOCOCl[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AlCl3进行脱除。

1. R. C. Bernotas, R. V. Cube., Synth. Commun., 1990, 20, 1209; Ueda, Shigeo; Terauchi, Hideo et al., Bioorg. Med. Chem., 2004, 12(15), 4101-4116; Gathergood, Nicholas; Scammells, Pater J et al., Org. Lett., 2003, 5(6), 921-924

2. Galaup, Chantal; Couchet, Jean-Marc et al., J. Org. Chem., 2005, 6, 2274-2284; Wolin, Ronald; Santillan, Alejandro et al., Bioorg. Med. Chem., 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, Dilip D; Matin, Mohammed M et al., Bioorg. Med. Chem., 2003, 11(15), 3295-3306; Mewshaw, Richard E; Zhou, Dahui et al., J. Med. Chem., 2004, 47(15), 3823-3842; Evans, Oary B; Furneaux, Richard H et al., J. Med. Chem., 2003, 46(15), 3412-3423

3. Ginesta, Xavier; Pericas, Miquel A et al., Synth. Commun., 2005, 35(2), 2-298

4. Ruchelman, Alexander L; Houghton, Peter J et al., J. Med. Chem., 2005, 3, 792-804; Basso, Andrea; Banfi, Luca et al., J. Org. Chem., 2005, 70(2), 575-579

5. B. D. Gray, P. W. Jeffs., J. Chem. Soc. Chem. Commun., 1987, 1329; B. ElAmin, G. M. Anantharamaiah et al., J. Org. Chem., 1979, 44, 3442

6. S. Ram, L. D. Spicer., Tetrahedron Lett., 1987, 28, 515; idem, Synth. Commun., 1987, 17, 415; Dullin, Anja; Dufrasne; Francois et al., Arch. Pharm. (Weinheim Ger.), 2004, 337(12), 654-667; Grener, Elisabeth; FOLK, John E et al., Bioorg. Med. Chem., 2004, 12(1), 233-238; Dhavale, Dilip D; Chaudhari, Vinod D et al., Tetrahedron Lett., 2003, 44(39), 7321-7324; Chianelli, Dona; Kim, Yong-Chul et al., Bioorg. Med. Chem., 2003, 11(23), 5059-5068; Tilekar, Jayant N; Patil, Nitin T et al., Tetrahedron, 2003, 59(11), 1873-1876 7. B. M. Adger, C. O’Farrell et al., Synthesis, 1987, 53

8. A. S. Kende, K. Liu etal., J. Am. Chem. Soc., 1995, 117, 10597

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9. W. H. Hartung, R. Simonoff., Org. React., 1953, 7, 263 10. V. H. Rawal, R. J. Jones et al., J. Org. Chem., 1987, 52, 19

11. Liu, Ke-Gang; Yan, Shi et al., Org. Lett., 2004, 6(13), 2269-2272; Liu, Ke-Gang; Zhou, Hai-Bin et al., J. Org. Chem., 2003, 68(24), 9528-9531

12. Wang, Xiaodong J; Hart, Scott A et al., J. Org. Chem., 2003, 68(6), 2343-2349

13. Bull, Steven D; Davies, Stephen G et al., J. Chem. Soc. Perkin Trans. 1, 2001, 23, 3106-3111

14. Shiratori, Hideo; Ohno, Takeshi et al., J. Org. Chem., 2000, 65(25), 8747-8757

4.4.2.1 H2/Pd-C氢化脱苄基(Bn)示例

t-BuOOCt-BuOOCNC6H5t-BuOOCNBn1NBnH210%Pd/C,MeOHHNt-BuOOCHNCOOBu-t2N

Basso, Andrea; Banfi, Luca et al., J. Org. Chem., 2005, 70(2), 575-579

A mixture of compound 1 (1.5 g, 2.4 mmol) and 10% Pd/C (300 mg) in methanol (40 mL) was stirred overnight under H2 (3 bar). The reaction mixture was filtered over Celite, and the filtrate was concentrated in vacuo. Compound 2 (1.07 g) was obtained as a pale yellow oil in quantitative yield.

4.4.2.2 HCOONH4/Pd-C氢化脱苄基(Bn)示例

HOBnHNHOOBnOHOHCOONH4O10% Pd-CO2H2NHOHOO1 Tilekar, Jayant N; Patil, Nitin T et al., Tetrahedron, 2003, 59(11), 1873-1876

A solution of compound 1 (1.1 g, 2.75 mmol), ammonium formate (0.92 g, 15.1 mmol) and 10% Pd–C (0.2 g) in methanol (10 mL) was refluxed for 40 min. The catalyst was filtered through celite and washed with methanol (5 mL x 2). To the filtrate, cooled to 0°C was added sodium bicarbonate (0.725 g, 8.61 mmol) and benzyloxycarbonyl chloride (0.47 g, 2.70 mmol) and the stirred reaction mixture warmed to room temperature. After 2 h, methanol was

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removed under reduced pressure and the residue was extracted with ethyl acetate (5 mL x 3). Combined extract was washed with brine, dried over anhydrous sodium sulphate and concentrated on rotovapor to afford a residue which was purified by column chromatography (chloroform/methanol, 9/1) to give compound 2 (0.81 g, 84%) as a thick liquid; Rf (20% methanol/chloroform) 0.6; [α]D = +18.02 (c = 0.20, CHCl3).

4.4.2.3 ClCOOCH2CCl3脱苄基(Bn)示例

EtO2CS1NCH2PhClCO2CH2CCl3EtO2CS2NCO2CH2CCl3Zn/HOAcEtO2CS3NR

V. H. Rawal, R. J. Jones et al., J. Org. Chem., 1987, 52, 19

To compound 1 (2.30 g, 6.8 mmol) in acetonitrile (25 mL) was added trichloroethyl chloroformate (0.100 mL, 6.8 mmol). The mixture was stirred for 30 min and concentrated. The crude product was chromatographed (hexanes:methylene chloride = 1:l) to yield compound 2 (2.68 g, 93%) as a white needles, which crystallized from absolute ethanol: mp 162.5 °C.

To a solution of compound 2 (1.40 g, 3.3 mmol) in acetic acid (30 mL) was added powdered zinc (0.5 g) in portions over a period of 2 h. The reaction was filtered, and the precipitate was washed thoroughly with methylene chloride. The filtrate was concentrated and extracted with ether. The organic layer was neutralized with saturated sodium bicarbonate solution and dried (Na2SO4). The crude product was concentrated and chromatographed (methylene chloride:ether = 10:1) to yield compound 3 (0.72 g, 88%) as a yellow oil, which gradually crystallized: mp 103-104 °C.

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4.4.2.4 Na/NH3脱苄基(Bn)示例

OBnNa/NH3BnO1OHTHF, -33°CNHBocHO2OOHBocN

Wang, Xiaodong J; Hart, Scott A et al., J. Org. Chem., 2003, 68(6), 2343-2349

NH3 (ca. 160 mL) was distilled into 40 mL of THF at -78 °C and allowed to warm to reflux (-33 °C). Na (ca. 2.0 g, 87 mmol) was added until a deep blue solution was sustained. A solution of acid 1 (2.0 g, 4.3 mmol) in THF (10 mL) was added directly to the Na/NH3 solution slowly via cannula over ca. 5 min. After being stirred for 45 min at reflux, the reaction was quenched with NH4Cl (10 mL) and then allowed to warm to rt with concentration to ca. 30 mL (caution! NH3 evolved). The mixture was diluted with NH4Cl (50 mL), acidified with 1 N HCl to pH 7, and extracted with CHCl3 (10 x 50 mL), dried on MgSO4, and concentrated to give 810 mg (66%) of the alcohol 2 as a pale yellow oil (further purification can be achieved by chromatography on silica with 3% MeOH in CHCl3 if desired).

4.4.2.5 CAN脱苄基(Bn)示例

PhNMeO1CAN (2.1 eq)OOMeCN, H2OMeO2NHOO

Bull, Steven D; Davies, Stephen G et al., J. Chem. Soc. Perkin Trans. 1, 2001, 23, 3106-3111 CAN (3.9 g, 7.1 mmol) was added portionwise to a stirred solution of 24 (1.0 g, 2.54 mmol) in MeCN-H2O (30 mL, 5:1) and stirred at RT. After sixteen hours, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution and stirred vigorously for ten minutes before extraction with Et2O. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo before purification by column chromatography on silica gel (hexane-Et2O = 5 : 1 and 1% Et3N) gave 25 (562 mg, 73%) as a colourless oil; [α]24D= - 58.6 ( c= 1.05, CHCl3).

CAN选择脱苄基(Bn)示例

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OPhONPhPhO1PhCAN (2.1 eq.)MeCN, H2OPhO2PhOOHNPh.

Bull, Steven D; Davies, Stephen G et al., J. Chem. Soc. Perkin Trans. 1, 2000, 22, 3765-3774 CAN (190 mg, 0.35 mmol) was added portionwise to a stirred solution of compound 1 (90 mg, 0.17 mmol) in MeCN-H2O (5 : 1, 5 mL) and stirred at RT. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution and stirred vigorously for ten minutes before extracting with Et2O. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo efore purification by column chromatography on silica gel (gradient elution, 30-40 petrol-Et2O 7: 3 to 1 : 1) to give compound 2 (68 mg, 91%) as a gum. [α]D24 = - 8.3 (c = 1.2, CHCl3).

4.4.2.6 CH3CHClOCOCl脱苄基(Bn)示例

NClOOClNHS1S2

US10592：该方法也可用于脱甲基

To a solution of compound 1 (727 mg) in dichloromethane (75 ml) which was being maintained at 0 °C under nitrogen was added 1-chloroethylchloroformate (0.208 ml) dropwise. The mixture was then allowed to warm to room temperature, before being heated to reflux. After approximately 2 h analysis of the reaction mixture indicated complete consumption of the starting material. The dichloromethane was evaporated and the residue was then taken up into methyl alcohol and heated to reflux for 1 h. The solvent was evaporated to afford the compound 2 (481 mg, 85%), which was used in the next reaction with out further purification.

The End

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