Direct Asymmetric α-Alkylation of NH<sub>2</sub>-Unprotected Amino Acid Esters Enabled by Biomimetic Chiral Pyridoxals
Pengwei Ji, Jianyu Li, Yuhang Tao, Mingzhe Li, Weibo Ling, Jianfeng Chen, Baoguo Zhao
Abstract
Biosynthesis utilizes kinetic strategies to regulate the chemoselectivity for the transformations of molecules containing multiple active reaction sites. But it is a grand challenge to realize the transformations without protecting group manipulations for chemosynthesis. α-Amino acid esters contain NH 2 and α-C-H, two nucleophilic sites. Direct asymmetric α-C-alkylation of NH 2 -unprotected amino acid esters with alkyl halides represents one of the most straightforward strategies to access chiral quaternary α-amino acids, which are widely present in many pharmaceuticals. However, the transformation is challenging due to the high reactivity of intrinsic N-alkylation. Here, by using chiral pyridoxal 6 having a benzene-pyridine biaryl skeleton as a carbonyl catalyst, we successfully unlock the nucleophilic reactivity of the α-amino C–H bonds of α-amino acid esters toward alkyl halides without protection of the NH 2 group, forming a wide range of chiral quaternary α-amino acid esters in up to 99% yield and 99% ee. Like transformations in biological systems, this protocol is featured with no protecting group manipulations and high atom and step efficiencies enabled by a biomimetic organocatalyst.