Ene-Reductase-Catalyzed Reduction for Kinetic Resolution of Morita-Baylis-Hillman Adducts and Asymmetric Synthesis of Roche Ester Derivatives.

Morita-Baylis-Hillman (MBH) adducts and their double-bond-reduced products are critical intermediates in the synthesis of herbicides, fragrance components, antibiotics, and vitamins. However, the preparation of optically pure compounds remains challenging. Asymmetric reduction catalyzed by ene reductase (ERED) offers a potential strategy for preparing optically pure MBH adducts and their reduced products. Herein, we synthesized two types of MBH adducts, those with cyclic enones and those with ethyl acrylate, via MBH reactions. Through structure-guided engineering of ERED XenA, chiral MBH adducts with cyclic enones were obtained by kinetic resolution. For example, several recovered (R)-isomers of MBH adducts with cyclic enones were obtained with >99% enantiomeric excess values by XenA variant-catalyzed kinetic resolution. Additionally, asymmetric reduction of the C═C double bond of MBH adducts with ethyl acrylate afforded optically pure Roche ester derivatives. The (R,R)- or (S,R)-stereoisomers of Roche ester derivatives with diastereomeric ratios (dr) up to 98:2 were obtained by XenA-catalyzed asymmetric reduction of MBH adducts with ethyl acrylate. This study provides an efficient strategy for the preparation of optically pure MBH adducts and their double-bond-reduced products.