氨基的保护及脱保护

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1、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1. 氨基的保护及脱保护概要 22. 烷氧玻基类2-1.节氧玻基（Cbz） 42-2,叔丁氧玻基（Boc） 162-3.笏甲氧玻基（Fmoc） 282-4.烯丙氧玻基（Alloc） 342-5,三甲基硅乙氧玻基（Teoc） 362-6,甲（或乙）氧玻基 403. 酰基类3-1,邻苯二甲酰基（Pht） 433-2,对甲苯磺酰基（Tos） 493-3.三氟乙酰基（Tfa） 534. 烷基类4-1.三苯甲基（Trt） 574-2. 2,4-二甲氧基节基（Dmb） 634-3,对甲氧基节基（PMB） 654-4.

2、节基（Bn） 701 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）。止匕外，还要从电子和立体的因素去

3、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。烷氧染基使用最多，因为N-烷氧染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

4、保护。下表列举了几种代表性的常用的氨基保护基。几种代表性的常用的氨基保护基结构缩写应用引入条件脱去条件0AopXCbz伯胺、仲氨、咪陛、 口比咯、口引喋等Cbz-Cl/Na 2CO3/CHCl 3 /H2OH2/Pd-C,供氢体 /Pd-C, BBr3/CH2cl2 or TFA, HBr/HOAc 等xZXBoc伯胺、仲氨、咪陛、 口比咯、口引喋等Boc2O/NaOH/diox/H 2 0, Boc 20/ /MeOH,Boc2O/Me4NOH/CH 3c N3MHCl/EtOAc, HCl/MeOH or diox, TosOH/THF-CH 2cl2, Me 3SiI/CHCl 3orC

5、H 3CNoX弋Fmoc伯胺、仲氨等Fmoc-Cl/NaHCO 3,/dio x/H 2O20% 哌咤/DMF , 50% 哌 咤/CH 2cl2 等XAlloc伯胺、仲氨、咪陛、 口比咯、口引喋等Aloc-Cl/PyNi(CO) 4/DMF/H 2O;Pd(PPh3)4/Bu3SnH;0JL 八JMSCl0Teoc伯胺、仲氨、咪陛、 口比咯、口引喋等Teoc-Cl/碱/diox/H 2OTBAF ; TEAFX,Me( or Et) oz-伯胺、仲氨、咪陛、 口比咯、口引喋等ROCOCl/NaHCO 3,/dio x/H 2OHBr/HOAc;Me3SiI;KOH/H 2O/乙二醇0 xR0

6、Pht伯胺邻苯一甲酸酎/CHCl 3/70 C ;邻苯一甲 酰亚胺-NC02Et/aq.Na2CO3H2NNH 2/EtOH , NaBH 4/i-PrOH-H 2O (6:1)XiQTos伯胺、仲氨、咪陛、 口比咯、口引喋等Tos-Cl/Et 3NHBr/HOAc, 48%HBr/ 苯 酚(cat)X 人CF3Tfa伯胺、仲氨、咪陛、 口比咯、口引喋等TFAA/Py;苯一甲酰 亚胺-NCO2CF3/CH 2cl2K2CO3/MeOH/H 2O;NH 3/MeOH;HCl/MeOHo大二Trt伯胺、仲氨、咪陛、 口比咯、口引喋等Trt-Cl/Et 3NHCl/MeOH, H2/Pd/EtOH,

7、 TFA/CH 2cl2Me0 .O0Mex弋vDmb伯胺、仲氨、咪陛、 口比咯、口引喋等ArCHO/NaCNBH 3/Me OHxL-0MlePMB伯胺、仲氨、咪陛、 口比咯、口引喋等PMB-Br/K2CO3/CH3CN;PhCHO/NaCNBH 3/MeOHHCO2H/Pd-C/MeOH;H2/Pd(OH)2/EtOH; TFA;CAN/ CH 3CNXBn伯胺、仲氨、咪陛、 口比咯、口引喋等Bn-Br/Et 3N or K2CO3/CH3CN;PhCH O/NaCNBH 3/MeOHHCO2H/Pd-C/MeOH;H2/Pd(0H) 2/EtOH;CCl3CH2OCOCl/CH 3CN2

8、 .烷氧玻基类保护基烷氧染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-保护的竣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口坐酮中。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 用烷氧染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B -消除去保护的Fmoc基和易由钳催化异构化去保 护的Alloc基。2.1 节氧玻基(Cbz)甲氧城基(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。具优点在于：试剂的

9、制备和保护基的导入都比较容易；N-甲氧染基氨基酸和肽易于结晶而且比较稳定；甲氧染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 甲氧跋基的导入苇氧跋基的导入，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-甲氧城基氨基化合物。a, B-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 2。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HC

10、l。止匕外，Cbz-ONB(4-O2NC6H4OCOOBn)等甲氧染基活化酯也可用来作为甲氧跋基的导入试剂，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。H.NxR1 R2Cbz-ClBaseR2I/N.R1 CbzNH2R200c. R1Cbz-ClBaseNHCbzR200cR1Cbz-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。CH20HCOC12CH20C0C1+ HC1除Cbz-Leu为油状物外，绝大多数氨基酸的甲氧染基衍生物都可以得到结晶。有的 N-羰氧染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

11、高，并难溶于 有机溶剂。例如，苯丙氨酸经甲氧跋基化后再加酸析出Cbz-Phe时往往得到共晶产物（熔点144C）,此共晶产物用乙酸乙酯和1M HC1 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-甲氧染基氨基酸。2.1.1.1 游离氨基酸的Cbz保护示例Konda-Yamada, Yaeko; Okada, Chiharu et alTetrahedrom 2002, 58(39), 7851-7865Cbz-Cl (18.5 1i l, 0.155 mmol) in diethyl ether (0.

12、2 ml) Waspped to a solution of(R)-1 (36.4 mg, 0.129 mmol) in 10% aqueous NaCO3 (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 NaSO4, evaporated to give light yellow gel

13、s, which were purified by preparative TLC (CHCl3/MeOH=5:1) to afford (R)-6 (25.7 mg, 47.1%) as yellow amorphous solid. R = 0.87 (n-BuOH/AcOH/H 20=4:1:5); ad23 = -27.270 (c =0.99, CHCl3);2.1.1.2 氨基酸酯的Cbz保护示例1Cbz-ClK2CO3M. Carrasco, R. J. Jones, S. Kamel et alOrg. Syn.,70, 29A 3-L, three-necked, Morto

14、n 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 chlo

15、roformate (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 scavengeexcess chloroformate) and the solution is stirred for an additional 18 hr. The organic layer is separa

16、ted, and the aqueous layer is extracted with ether (2200 mThe combined organic layers are washed with 0.01 Mhydrochloric acid (2 500 mL), water (2 500mL), and saturated brine (500 mL), and then dried (Na2SO4), filtered, and evaporated on a rotary evaporator. The resulting oil is further dried in a K

17、ugelrohr oven (50 C, 0.1 mm, 12 hr) to leave product 2 as a clear oil that solidifies upon cooling: 165 T66 g (98 -99%), mp 42 伺3 C.2.1.1.3 氨基醇的Cbz保护示例（1）Cbz-ClNa2CO3THF, H2OClariana, Jaume; Santiago, G. G. et aT etrahedron: Asymmetry 2000, 11(22), 4549-4558Benzyl chloroformate (0.95 ml, 6.7 mmol) w

18、as added via syringe into a stirred mixture of aminoalcohol 7 (0.989 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 dichloromet

19、hane andwater. 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 T27 c2.1.1.4 氨基酉1的Cbz保护示例（2）Cbz-ClK2CO3Tol, H2OCbzHNInaba, Takashi; Yamada, Yasu

20、ki et al J. Org. Chem., 2000, 65(6), 1623-1628To a mixture of toluene (3.85 L), water (3.85 L), and K2CO3 (470 g, 3.40 mol) were successively added1a (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, triethyl

21、amine (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 c

22、olumn chromatography;2.1.2 甲氧跋基的脱去甲氧跋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、甲酸俊 N. L. Benoiton., Int. J. Pept. Petein Res.,1993, 41, 611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

23、反应更迅速。R2.N .R1CbzH2CH3+ CO2+RrHN”催化剂主要用5-10%的钳-碳、10-20%的氢氧化钳-碳或钳-聚乙烯亚胺，钳-聚乙烯亚胺/甲酸对于除去Cbz要比前两者要好7。当HBr/HOAc脱去Cbz保护基时，产物往往 带又一点颜色，而且分解产生的溴化苄会产生一些副反应并难以除尽，而催化氢解多数能得到无色得产物。由于硫能使催化剂中毒，因此，含有胱氨酸、半胱氨酸等含硫的肽等 N- 苄氧羰基氨基衍生物一般不用催化氢解法脱除。一般溶剂可以用甲醇，乙醇，乙酸乙酯， 四氢呋喃等，在醇类质子溶剂中反应速度要快的多。1. G. Briefer, T. T. Nesftrick., Ch

24、em. Rew.,1974, 74, 5672. A. E. Jackson, R. A. Johnstone., Synthesis.,1976, 685; G. M. Anantharamaiah, K. M.Sivanandaiah.,J. Chem. Soc., Perkin Trans. 11, 977, 4903. M. Makowski, B. Rzeszotarska, L. Smelka et al.,Liebigs Ann. Chem.,1985, 14574. D. R. Coleman, G. P. Royer.,J. Org. Chem.,1980, 45, 2268

25、5. B. Eiamin, G. M. Anantharamaiah, G. P. Royer et al.,J. Org. Chem.,1979, 44, 34426. M, J. O. Anteunis, C. Becu, F. Becu et al.B, ull. Soc. Chim. Belg.,1987, 96, 7757. 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

26、 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

27、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 C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 。 D. R. Coleman, G. P. Royer.,J. Org. Chem.,1980, 45, 2268 J. P. Mazaleyrat, J. Xie, M. Wakselman.,Tetrahedron Lett.,1992, 33, 4301 32.1.2.1 5-10%的钳-碳催化氢解示例15%Pd/

28、C MeOHC. Jaume; G G. Santiago et al.,Tetrahedron: Asymmetry2。，11(22), 4549-4458A 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, p

29、erchloric 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 7235c aD23=- 15.6 (c=0.68, methanol).2.1.2.25-10%的钳-碳催化氢解示例20%Pd(OH) 2/C MeOHH21nh2HOHB. Pierfrancesco; C. silvia et al.,Tetrahedron,1999, 55(10), 3025A solu

30、tion 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/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-arylglycin

31、ols (S)-21 in 87% yield, white solid; aD20=+47.0 (c=0.78, CHCl3); mp 94-96 C (AcOEt)。2.1.2.3 Pd/C-甲酸俊催化氢解示例10%Pd-CHCONH 4Alargov, D. K; Naydenova, Z; Monatsh. Chem., 1997, 128(6-7), 725-732576.6 mg of compound 1 (1 mmol) was dissolved in 20 ml of methanol. Then 150 mg of ammonium formate (3 mmol) an

32、d 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 wasfiltered through celite and the filtrate was evaporate to dryness to give 430 mg of compound 2 (98%). This compound was used without further purification

33、 in the subsequent step.2.1.2.4 Pd/C-甲酸催化氢解示例Fyles, T. M.; Zeng, B.; J. Org. Chem, 1998, 63(23), 8337-8345Compound 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). Th

34、e 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 Compou2d (0.34 g, 81%, a white solid, mp 96-98 C). This compo

35、und 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HWO200409216610%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

36、 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 (289 mg, 54%).2.1.2.6 PdCl2催化氢解脱除带卤原子分子上的Cbz示例2US20030144297To a solution o compo

37、und 1 (900 mg) in methylene chloride (16.5 ml) was addede PdC2 (30 mg) and triethylamine (0.229 ml). Triethyl silane was added (2 x 0.395 ml) over 2 h. Thereaction 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 met

38、hylene chloride, dried over MgSO4, filtered and concentrated. Chromatography was run on a biotage 40S column with 3-5% MeOH/CH 2cl2 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Arthur M. Felix, Manuel H. Jimenz et a1., Org. Syn.,59, 159A dry 1-L thre

39、e-necked, round-bottomed flask is equipped with a dry ice reflux condenser, a gas-inlet tube, and a magnetic stirring bar as 川ustrated in the figure. The reaction vessel isimmersed in an acetone -dry ice bath, and a total of 300 mL of ammonia is passed through a drying tower containing potassium hyd

40、roxide pellets and collected in the flask. The bath is removed to permit the reaction to proceed at the boiling point of ammonia (-33 C), 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-dimethyla

41、cetamide 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

42、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 pres

43、sure. 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

44、, weighs 272 W05 mg. (73 -82%), m.p. 280282 (dec.),商D +23.1 (c = 1, aqueous 5N hydrochloric acid).酸解脱除 氨基甲酸苇酯在强酸性条件下容易去保护。HBr/HOAc是酸解脱除甲氧跋基的最常用的试剂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/HOAcN2Rf Cbz溶液(1.2M-3.3M)以保证反应的完全。R2R1&Cbz+ H +1. D. Ben-Ishai, A. Berger., J. Org.

45、 Chem.,1952, 17, 1564; R. A. Boissonnas, J. Blodinger, A.D. Welcher., J. Am. Chem. Soc.1952, 74, 53092. 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

46、。-乙酰基能用碱皂化或氨解脱去，但为了避免这个副反应，可以改用 HBr/二氧六环或HBr/三氟乙酸来代替 HBr/HOAc S. Sakakibara et a1.,Bull. Chem. Soc. Japan.,1967, 40, 2164; S. Matsuura, C. H. Niu, J. S. Cohen., J. Chem. Soc. Chem. Commun.1,976, 451 H. Yajima, H. Ogawa, H. Sakurai.,J. Chem. Soc. Chem. Commun.1,977, 909 H. Yajima et a1.,J. Chem. Soc.

47、 Chem. Commun.1,974, 107 H. Yajima et a1.,Chem. Pharm. Bull., 1975, 23, 1164。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分解产生的澳化苇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澳化苇反应生成 S-苇基甲硫 氨酸4,防止的办法是加入硫醴（CH3SC2H5）为捕捉剂5。色氨酸被HBr/HOAc分解产 生有

48、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, 22622. S. Fujiwara, S. Moerinaga, K. Narita.,Bull. Chem. Soc. Japan.,1962, 35, 4383. 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, 984. N. F. Alber

49、tson, F. C. Mckay.,J. Am. Chem. Soc.,1953, 73, 53235. S. Guttmann, R. A. Boissonnas,Helv. Chim. Acta., 1959, 42, 1257用液体HF在0c处理10-30分钟即可将Cbz完全脱去1。FSO3H2、CH3SO3H2, 3、 CF3SO3H3, 4和C6H5SCH3-TFA Y. Kiso, K. Ukawa, T. Akita., J. Chem. Soc. Chem. Commun.1,980, 101也是较好的试剂。Me3SiI在氯仿、乙月青中能于几分钟内 选择性脱去Cbz和Boc保

50、护基 R. S.Lott, V. S. Chauham, C. H. Stammer.J, . Chem. Soc. Chem. Commun.1,979, 495 J. Pless, W. Bauer., Angew Chem., Int. Ed. Engl., 1973, 12, 147; A. M. Felix., J. Org.。对于BBr3/CH2c12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)苯酚网或使用HF/Me2S/M甲苯酚9 (25:65:10,v/v)来抑 制B

51、n+对芳香氨基酸的加成。Chem.,1974, 39, 14278. M. Bodanszky, A. Bodanszky., Int. J. Pept. Protein Res., 1984, 23, 2879. J. P. Tam, W. F. Heath, R. B. Merrifield.J. Am. Chem. Soc. 1983, 105, 6442止匕外，已经报道过的还有以下的一些不常用的方法。如HCl/CHCl31、HCl/HOAc2、HBr/SO23、液体 HBr4、TosOH5、HI/HOAc 6 碘化磷7、Et3SiH网、沸腾的 TFA Anna; P. Gerald.,

52、Heterocycles 2002, 58, 521 A solution of the amine Cbz compund (208 mg, 0.44 mmol) in 33 % hydrobromic acid in、 8M HCl的乙醇液或6 M HCl回流1小时acetic acid (1 mL) and glacial acetic acid (0.6 mL) was stirred at rt for 3 h under an或浓盐酸于25-75C力口热处理1-1.5小时atmosphere of nitrogen. The volatiles were removed in va

53、cuo to leave the free amine 等。1. G. D. Fasman, M. Idelson, E. R. Blout.,J. Am. Chem. Soc.1961, 83, 7092. R. B. Merrifield., J. Am. Chem. Soc. 1963, 85, 21493. M. Idelson, E. R. Blout., J. Am. Chem. Soc.,1958, 80, 46314. M. Brenner, H. C. Curtius., Helv. Chim. Acta.,1963, 46, 21265. E. Taschner, B. L

54、iberek,Abstr. Int. Cong. Biochemistry, Vienna 19586. E. Waldschmidt-Leitz, K. Kuhn., Chem. Ber.,1951, 84, 3817. E. Brand, B. F. Erlanger, H. Sachs.J . Am. Chem. Soc. 1952, 74, 18498. Birkofer et al., Angew. Chem., Int. Ed.,1965, 4, 4179. F. Weygand, W. Steglich.Z. Naturforsch., 1959, 14b, 47210. A.E

55、. Barkdoll, W. F. Ross., J. Am. Chem. Soc.,1944, 66, 567; G Chelucci, M. Falorni, G.Giacomelli., Synthesis.,1990, 112111. J. White., J. Biol. Chem., 1934, 106, 1412.1.2.8 HBr-AcOH脱除Cbz示例33% HBrAcOH, 91%hydrobromide (168 mg, 91 %) as a brown, highly hygroscopic powder; d = -18.0 (c = 0.4, EtOH);2.1.2

56、.9 TMSI 脱除 Cbz 示例 11US20040204397Me3SiI (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 temperatu

57、re 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 useddirectly in the next step.1Me 3siI _ EtaN, C

58、H 3CNUS200502030782.1 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 co

59、mpletely. 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%).2.2叔丁氧碟基（Boc）除Cbz保护基外，叔丁氧染基（Boc）也是目前多肽合成中广为采用的氨基保护基， 特别是在周相合成中，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，Bo

60、c-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、肌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 叔丁氧染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-叔丁氧族基氨基化合物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酸酊

61、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40-50C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, 7302. E. Ponnusamy, U. Fotadar et al.Synthesis.,1986, 48芳香胺由于其亲核性较弱

62、，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, DMAP,BocAr-NH2 Ar-NHBoc Ar NBoc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。由于氟酸酯的生成，有位阻的胺往往会与Boc2O生成月尿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。Brnh2Boc2ODMAP, THF17%BrBrN N1. H. J. knolker, T. Braxmeier e

63、t 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), 7836-78462. T. A. Kelly, D. W. McNeil., Tetrahedron Lett.,1994, 35, 9003有时在反应中有可能多加了 Boc酸酊，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。Boc 2OR-NH2 R-NHBoc+ Boc2O (excess)H2NexcessBocHN