College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, Jiangsu, China.
Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka 533-0024, Japan.
Molecules. 2019 Dec 10;24(24):4521. doi: 10.3390/molecules24244521.
Enantiomerically pure derivatives of 2-amino-4,4,4-trifluorobutanoic acid are in great demand as bioisostere of leucine moiety in the drug design. Here, we disclose a method specifically developed for large-scale (>150 g) preparation of the target ()--Fmoc-2-amino-4,4,4-trifluorobutanoic acid. The method employs a recyclable chiral auxiliary to form the corresponding Ni(II) complex with glycine Schiff base, which is alkylated with CF-CH-I under basic conditions. The resultant alkylated Ni(II) complex is disassembled to reclaim the chiral auxiliary and 2-amino-4,4,4-trifluorobutanoic acid, which is in situ converted to the N-Fmoc derivative. The whole procedure was reproduced several times for consecutive preparation of over 300 g of the target ()--Fmoc-2-amino-4,4,4-trifluorobutanoic acid.
作为药物设计中亮氨酸部分的生物等排体，2-氨基-4,4,4-三氟丁酸的对映体纯衍生物的需求量很大。在这里，我们公开了一种专门为大规模（>150g）制备目标物（）--Fmoc-2-氨基-4,4,4-三氟丁酸而开发的方法。该方法采用可回收的手性助剂与甘氨酸席夫碱形成相应的 Ni(II)配合物，在碱性条件下用 CF3-CH2-I 进行烷基化。所得烷基化 Ni(II)配合物被拆开以回收手性助剂和 2-氨基-4,4,4-三氟丁酸，然后将其原位转化为 N-Fmoc 衍生物。整个过程被重复多次，用于连续制备超过 300g 的目标物（）--Fmoc-2-氨基-4,4,4-三氟丁酸。
