Preparative Method for Asymmetric Synthesis of (S)-2-Amino-4,4,4-trifluorobutanoic Acid.

Jianlin Han,Takahiro Hiramatsu,Vadim A Soloshonok,Ryosuke Takeda,Xinyi Liu,Hiroki Moriwaki,Hiroyuki Konno,Hidenori Abe

doi:10.3390/molecules24244521

Abstract

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–CH2–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.

Highlights

The modern paradigm in drug discovery is based on two major traits
The data disclosed in this paper demonstrate that alkylation of Ni(II) complex of glycine
Schiff base with CF3 –CH2 –I can be successfully conducted on a scale of over 200 g of the corresponding complex, providing a reliable assess to enantiomerically pure (>99% ee) derivatives of (S)-2-amino-4,4,4-trifluorobutanoic acid

Summary

Introduction

The modern paradigm in drug discovery is based on two major traits. The first includes mimicking the three-dimensional structure of the targeted protein receptor by incorporation of tailor-made amino acids (AAs) [1,2,3,4,5,6,7,8]. The presence of a tailor-made AA’s backbone and fluorinated residues provide an additional host of subtle useful properties, allowing fine-tuning of the desired bio-activity and pharmacokinetics [14,15]. In this line of structural inquiry, fluorinated. AAs, including α- [16,17,18,19,20,21,22,23,24] and β-derivatives [25,26,27], are considered of distinct potential in the modern drug design [28]. Synthesis and biological applications of fluorinated tailor-made AAs reported before

Methods

Results

Conclusion