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，廣泛應(yīng)用于藥物分子及復(fù)雜天然產(chǎn)物的合成。其優(yōu)點(diǎn)在于：保護(hù)基的導(dǎo)入比較容易；N-芐氧羰基保護(hù)的胺比較穩(wěn)定，有一定的紫外吸收有利于氨基酸等沒(méi)有紫外吸收的小分子的分離純化；N-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。目前常用的脫保護(hù)條件是氫化脫保護(hù)和強(qiáng)酸脫保護(hù)。但是這兩種條件還是有很多缺點(diǎn)，氫化條件下，當(dāng)分子中含有烯烴或鹵原子(Cl, Br, I)時(shí)，可能會(huì)造成還原或脫鹵副反應(yīng)；強(qiáng)酸脫保護(hù)，最常用的就是HBr/HOAc，此方法強(qiáng)酸大大過(guò)量，對(duì)酸敏感基團(tuán)不友好，且后處理復(fù)雜繁瑣?！尽?/p>

2024年，Vinayagam等人報(bào)道了一種利用AlCl3/HFIP(1,1,1,3,3,3-六氟異丙醇）溫和脫Cbz的方法。該方法具有良好的官能團(tuán)耐受性（包括其他可還原基團(tuán)）、成本效益高、易于操作、安全性好、適合規(guī)模化生產(chǎn)、高收率以及可在常溫下進(jìn)行反應(yīng)等優(yōu)點(diǎn)。可以作為一種優(yōu)秀的替代方案，避免了使用易燃的氫氣和金屬催化劑試劑，從而減少了嚴(yán)重的安全和環(huán)境問(wèn)題。該方法最顯著的特點(diǎn)是在存在O-和N-芐基保護(hù)基的情況下，能夠選擇性脫保護(hù)N-Cbz基團(tuán)，從而擴(kuò)展了設(shè)計(jì)合成路線的范圍，適用于需要多種官能團(tuán)轉(zhuǎn)化的目標(biāo)化合物?！綣. Org. Chem.,2024,89, 5665. DOI: 10.1021/acs.joc.4c00177】

此方法的起主要作用的就是六氟異丙醇（HFIP）這個(gè)神奇溶劑，由于六個(gè)氟原子的拉電子效應(yīng)，使其具有很強(qiáng)的氫鍵給予能力，被廣泛用于底物和試劑的活化，如羰基，環(huán)氧的活化。HFIP廣泛應(yīng)用于各種反應(yīng)，如選擇性上甲基，芳基鹵化， 傅克酰基化等反應(yīng)。

【 Chem. Commun. ,2014, 50, 1836-1838】

【 J. Org. Chem.,2018, 83, 930】

【 Org. Chem. Front.,2024, 11, 3602-3608】

其他還有很多應(yīng)用，小編這里就不多介紹了，否則就跑題了。下面我們看下，HFIP在脫Cbz方面有哪些優(yōu)點(diǎn)。AlCl3/HFIP脫保護(hù)條件對(duì)還原條件敏感的底物的兼容性很高，如氧芐基(化合物3)、N-芐基(化合物4和5)、氰基(化合物4、6和7)、硝基(化合物8)、烯烴(化合物9)、硫醚(化合物10), 芳鹵(如化合物6中的2-氯嘧啶)。

此反應(yīng)條件對(duì)于其他氨基保護(hù)基，叔丁基甲酸酯可在室溫下30分鐘內(nèi)完成脫Boc，而甲基甲酸酯(20)和異丙基甲酸酯(21)在該條件下穩(wěn)定的。Alloc，F(xiàn)moc，Troc在AlCl3/HFIP體系中均未參與反應(yīng)。

反應(yīng)機(jī)理：

反應(yīng)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.

參考文獻(xiàn)：

Vinayagam, V., Sadhukhan, S. K., Botla, D. V., Chittem, R. R., Kasu, S. R., & Hajay Kumar, T. V. Mild Method for Deprotection of the

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