苄氧羰基（Cbz）是1932年Bergmann发现的一个很老的氨基保护基，广泛应用于药物分子及复杂天然产物的合成。其优点在于：保护基的导入比较容易；N-苄氧羰基保护的胺比较稳定，有一定的紫外吸收有利于氨基酸等没有紫外吸收的小分子的分离纯化；N-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。目前常用的脱保护条件是氢化脱保护和强酸脱保护。但是这两种条件还是有很多缺点，氢化条件下，当分子中含有烯烃或卤原子(Cl, Br, I)时，可能会造成还原或脱卤副反应；强酸脱保护，最常用的就是HBr/HOAc，此方法强酸大大过量，对酸敏感基团不友好，且后处理复杂繁琐。【苄氧羰基(Cbz)保护氨基及脱保护方法】
近期，Vinayagam等人报道了一种利用AlCl3/HFIP(1,1,1,3,3,3-六氟异丙醇）温和脱Cbz的方法。该方法具有良好的官能团耐受性（包括其他可还原基团）、成本效益高、易于操作、安全性好、适合规模化生产、高收率以及可在常温下进行反应等优点。可以作为一种优秀的替代方案，避免了使用易燃的氢气和金属催化剂试剂，从而减少了严重的安全和环境问题。该方法最显著的特点是在存在O-和N-苄基保护基的情况下，能够选择性脱保护N-Cbz基团，从而扩展了设计合成路线的范围，适用于需要多种官能团转化的目标化合物。
【 J. Org. Chem., 2018, 83, 930】
【 Org. Chem. Front., 2024, 11, 3602-3608】
其他还有很多应用，小编这里就不多介绍了，否则就跑题了。下面我们看下，HFIP在脱Cbz方面有哪些优点。AlCl3/HFIP脱保护条件对还原条件敏感的底物的兼容性很高，如氧苄基(化合物3)、N-苄基(化合物4和5)、氰基(化合物4、6和7)、硝基(化合物8)、烯烃(化合物9)、硫醚(化合物10), 芳卤(如化合物6中的2-氯嘧啶)。
此反应条件对于其他氨基保护基，叔丁基甲酸酯可在室温下30分钟内完成脱Boc，而甲基甲酸酯(20)和异丙基甲酸酯(21)在该条件下稳定的。Alloc，Fmoc，Troc在AlCl3/HFIP体系中均未参与反应。
反应机理：
反应操作：
To a solution of N-Cbz-protected amines (1.0 equiv) in HFIP (4.0 mL) was added AlCl3 (3.0 equiv) at room temperature (Note: AlCl3 was not soluble completely in HFIP in the reaction dilution, and the reaction mass was in the suspension form). The reaction mixture was stirred at the same temperature for 2 to 16 h. After the completion of the reaction, as observed by thin-layer chromatography (TLC) and (UPLC−MS) analysis, the reaction mixture was diluted with CH2Cl2 (20 mL) (now the reaction mass became a clear homogeneous solution). The reaction mixture was quenched with aqueous NaHCO3 (20 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous Na2SO4, filtered, and evaporated. The crude residue was purified by CombiFlash column chromatography using a mixture of hexanes/EtOAc or CH2Cl2/MeOH as an eluent to yield the corresponding amines in the free form.
Of note: After completion of the reaction, the pH was on the acidic side. To the reaction mixture was added water (10 mL) and extracted with EtOAc (2 × 10 mL) to remove the impurities. Later, aq NaHCO3 was added to bring its pH to the basic side and extracted with EtOAc (3× 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and evaporated to provide the amines in their pure form. Using this acid−base workup method, compounds 2h, 2l, 2m, 2s, 2t, 2v, and 2y were obtained without column chromatography in the pure form.
参考文献：
Vinayagam, V., Sadhukhan, S. K., Botla, D. V., Chittem, R. R., Kasu, S. R., & Hajay Kumar, T. V. Mild Method for Deprotection of the N-Benzyloxycarbonyl (N-Cbz) Group by the Combination of AlCl3 and HFIP. J. Org. Chem., 2024, 89, 5665. DOI: 10.1021/acs.joc.4c00177.
