Preparative Method for Asymmetric Synthesis of (S)-2-Amino-4,4,4-trifluorobutanoic Acid
2019
Jianlin Han | Ryosuke Takeda | Xinyi Liu | Hiroyuki Konno | Hidenori Abe | Takahiro Hiramatsu | Hiroki Moriwaki | Vadim A. Soloshonok
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 (S)-N-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 CF3&ndash:CH2&ndash: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 (S)-N-Fmoc-2-amino-4,4,4-trifluorobutanoic acid.
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