Desymmetric Reductive Amination of 1,3-Cyclopentadiones to Single Stereoisomer of fl-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 fi-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)-fi-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-1,3cyclopentadiones to the single stereoisomer of the corresponding fi-amino ketones but also suggested that engineering of amine dehydrogenase provides a useful tool to address the challenges in asymmetric reductive amination of diketones.

Automated summary

Mutant amine dehydrogenases (LsAmDHs) were developed through directed evolution from L-phenylalanine dehydrogenase, enabling the asymmetric reductive amination of 2,2-disubstituted-1,3-cyclopentadiones with high yield. This study not only synthesized the corresponding stereoisomeric fi-amino ketones, but also provided a useful tool for addressing the challenges in asymmetric reductive amination of diketones.