苄氧羰基(Cbz)保护氨基

  • A+

苄氧羰基的导入


苄氧羰基(Cbz)是1932Bergmann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:{attr}3121{/attr}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

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{attr}3119{/attr}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[G.J. Atwell, W. A. Denny., Synthesis1984, 1032]。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[D.R. Kelly, M. Gingell, Chem. Ind.(London),1991, 888]。

Cbz-Cl很容易用苯甲醇同光气的反应来制备(见下式),在低温下可以保存半年以上而不发生显著的分解。

除Cbz-Leu为油状物外,绝大多数氨基酸的苄氧羰基衍生物都可以得到结晶。有的N-苄氧羰基氨基酸能同它的钠盐按一定比例形成共晶,共晶产物的熔点较高,并难溶于有机溶剂。例如,苯丙氨酸经苄氧羰基化后再加酸析出Cbz-Phe时往往得到共晶产物(熔点144℃),此共晶产物用乙酸乙酯和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。


反应实例

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 {attr}3227{/attr}ified with 10% citric acid,extracted with CHCl3(10mlX3). The organic layer was washed with water, driedover Na2SO4, evaporated to give light yellow gels, which werepurified by preparative TLC (CHCl3/MeOH=5:1) to afford (R)-6 (25.7 mg, 47.1%) as yellowamorphous solid.

Konda-Yamada,Yaeko; Okada, Chiharu et al., Tetrahedrom200258(39),7851-7865



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 (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 to0°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 with0.01 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.

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




To a mixture oftoluene (3.85 L),water (3.85 L), andK2CO3(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 atemperature below 25 °C. After stirringat room temperature for 3 h, triethylamine (27.5 g, 270 mmol) and NaCl (578 g) were successively added, and the mixture wasstirred for a further 30 min. The organic layer was separated and concentratedto give the desired product as oil, which was used for the next reactionwithout purification. The analytical sample was prepared by columnchromatography。

Inaba, Takashi; Yamada, Yasuki et al J. Org. Chem.,200065(6), 1623-1628



未完待续


本文非原创内容,版权归原作者所有。



weinxin
我的微信
关注我了解更多内容

发表评论

目前评论:0