Desymmetric Reductive Amination of 1,3-Cyclopentadiones to Single Stereoisomer of β-Amino Ketones with an All-Carbon Quaternary Stereocenter by Engineered Amine Dehydrogenases

Regio- and stereoselective reductive amination of diketones offers an attractive method to access chiral β-amino ketones with multiple stereocenters which are unique scaffolds and building blocks for bioactive molecules, but it is still a great challenge in organic chemistry. In this study, mutant amine dehydrogenases (LsAmDHs) were created by directed evolution of a l-phenylalanine dehydrogenase from Lysinibacillus sphaericus to catalyze the desymmetric reductive amination of 2,2-disubstituted-1,3-cyclopentadiones. Using these beneficial LsAmDHs, the corresponding (2R, 3R)-β-amino ketones with an all-carbon quaternary stereocenter were prepared with up to 99% de and ee and up to 84% isolated yields. A cyclopenta[b]hydroquinoline derivative was obtained from 2-methyl-2-(2′-bromobenzyl)-1,3-cyclopentadione or 2-methyl-2-(2′-chlorobenzyl)-1,3-cyclopentadione via sequential enzymatic desymmetric reductive amination and an intramolecular Buchwald–Hartwig cross coupling reaction. Molecular docking and dynamics simulations provided some insights into the roles of key mutations on the improved activity and excellent stereoselectivity toward these un-native substrates. This study not only developed biocatalysts to realize the unprecedented desymmetric reductive amination of 2,2-disubstituted-1,3-cyclopentadiones to the single stereoisomer of the corresponding β-amino ketones but also suggested that engineering of amine dehydrogenase provides a useful tool to address the challenges in asymmetric reductive amination of diketones.