Structure-Guided Directed Evolution of a Carbonyl Reductase Enables the Stereoselective Synthesis of (2S,3S)-2,2-Disubstituted-3-hydroxycyclopentanones via Desymmetric Reduction

In this study, an engineered carbonyl reductase (M4) was obtained through structure-guided directed evolution of a carbonyl reductase (SSCR) from Sporobolomyces salmonicolor AKU4429. Mutant M4 showed 23.9-fold enhancement of enzyme activity toward the model substrate 2-methyl-2-benzyl-1,3-cyclo-pentanedione, affording the (2S,3S)-stereoisomer in >98% ratio. This variant also showed excellent stereoselectivity toward most of the tested substrates, offering a valuable biocatalyst for the stereoselective reduction of these cyclic diketones to access the corresponding (2S,3S)-2,2-disubstituted-3-hydroxyketones.