General Asymmetric Synthesis of Noncanonical Amino Acids

Abstract Noncanonical amino acids (ncAAs) are valuable building blocks with applications spanning biology, material science, and pharmaceutical development. The concise asymmetric syntheses of diverse ncAAs from fundamental building blocks would be highly enabling, yet methods to achieve this goal are limited. Herein, we present a general strategy for the asymmetric synthesis of ncAAs from ubiquitous carboxylic acids involving transformation to α-ketoesters followed by a biocatalytic lipase hydrolysis-transamination cascade. The process features a broad scope, delivering ncAAs from carboxylic acids with diverse cyclic frameworks, multiple stereogenic centers, and even oligopeptides. Either ncAA enantiomer with various chain lengths is easily accessed upon simple modification of the sequence, which may also be performed in a telescoped, one-pot fashion. This approach combines the power of organic synthesis and biocatalysis to enable the general asymmetric synthesis of ncAAs.