2.1.1.2 氨基酸酯的Cbz保护示例

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)

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 (0.989 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 dichloromethane and 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)

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。

催化剂主要用5-10%的钯-碳、10-20%的氢氧化钯-碳或钯-聚乙烯亚胺，钯-聚乙烯亚胺/甲酸对于除去Cbz要比前两者要好[7]。当HBr/HOAc脱去Cbz保护基时，产物往往带又一点颜色，而且分解产生的溴化苄会产生一些副反应并难以除尽，而催化氢解多数能得到无色得产物。由于硫能使催化剂中毒，因此，含有胱氨酸、半胱氨酸等含硫的肽等N-苄氧羰基氨基衍生物一般不用催化氢解法脱除。一般溶剂可以用甲醇，乙醇，乙酸乙酯， 四氢呋喃等，在醇类质子溶剂中反应速度要快的多。 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 2.1.2.1 5-10%的钯-碳催化氢解示例

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

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

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 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

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

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/