芐氧羰基的導(dǎo)入
芐氧羰基（Cbz）是1932年Bergmann發(fā)現(xiàn)的一個(gè)很老的氨基保護(hù)基，但一直到今天還在應(yīng)用。其優(yōu)點(diǎn)在于：試劑的制備和保護(hù)基的導(dǎo)入都比較容易；N-芐氧羰基氨基酸和肽易于結(jié)晶而且比較穩(wěn)定；芐氧羰基氨基酸在活化時(shí)不易消旋；能用多種溫和的方法選擇性地脫去。
芐氧羰基的導(dǎo)入，一般都是用Cbz-Cl。游離氨基在用NaOH 或NaHCO3 控制的堿性條件下可以很容易同Cbz-Cl反應(yīng)得到N-芐氧羰基氨基化合物。α,β-二胺可用該試劑在pH= 3.5-4.5稍有選擇性地被保護(hù)，其選擇性隨碳鏈地增長(zhǎng)而減弱，如H2N(CH2)nNH2, n=2時(shí)71%被單保護(hù);n=7時(shí)29%被單保護(hù)[G.J. Atwell, W. A. Denny., Synthesis, 1984, 1032]。氨基酸酯同Cbz-Cl的反應(yīng)則是在有機(jī)溶劑中進(jìn)行，并用碳酸氫鹽或三乙胺來(lái)中和反應(yīng)所產(chǎn)生的HCl。此外，Cbz-ONB（4-O2NC6H4OCOOBn）等芐氧羰基活化酯也可用來(lái)作為芐氧羰基的導(dǎo)入試劑，該試劑使伯胺比仲胺易被保護(hù)，但苯胺由于親核性不足，與該試劑不反應(yīng)[D.R. Kelly, M. Gingell, Chem. Ind.(London),1991, 888]。
Cbz-Cl很容易用苯甲醇同光氣的反應(yīng)來(lái)制備（見(jiàn)下式），在低溫下可以保存半年以上而不發(fā)生顯著的分解。
除Cbz-Leu為油狀物外，絕大多數(shù)氨基酸的芐氧羰基衍生物都可以得到結(jié)晶。有的N-芐氧羰基氨基酸能同它的鈉鹽按一定比例形成共晶，共晶產(chǎn)物的熔點(diǎn)較高，并難溶于有機(jī)溶劑。例如，苯丙氨酸經(jīng)芐氧羰基化后再加酸析出Cbz-Phe時(shí)往往得到共晶產(chǎn)物（熔點(diǎn)144℃），此共晶產(chǎn)物用乙酸乙酯和1M HCl一道震搖時(shí)可完全轉(zhuǎn)化為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機(jī)溶劑提取的方法來(lái)得到純的N-芐氧羰基氨基酸。
反應(yīng)實(shí)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 acidified 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., Tetrahedrom; 2002, 58(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 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 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.,2000, 65(6), 1623-1628】
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