Direct Asymmetric α-Alkylation of NH2-Unprotected Amino Acid Esters Enabled by Biomimetic Chiral Pyridoxals

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 NH2 and α-C-H, two nucleophilic sites. Direct asymmetric α-C-alkylation of NH2-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 NH2 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.