Asymmetric Synthesis of Chiral 2-Cyclohexenones with Quaternary Stereocenters via Ene-Reductase Catalyzed Desymmetrization of 2,5-Cyclohexadienones

Michael Friess; Amit Singh Sahrawat; Bianca Kerschbaumer; Silvia Wallner; Ana Torvisco; Roland Fischer; Karl Gruber; Peter Macheroux; Rolf Breinbauer

doi:10.1021/acscatal.4c00276

Asymmetric Synthesis of Chiral 2-Cyclohexenones with Quaternary Stereocenters via Ene-Reductase Catalyzed Desymmetrization of 2,5-Cyclohexadienones

ACS Catal. 2024 Apr 24;14(9):7256-7266. doi: 10.1021/acscatal.4c00276. eCollection 2024 May 3.

Authors

Affiliations

¹ Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria.
² Institute of Molecular Biosciences, University of Graz, Humboldtstraße 50, 8010 Graz, Austria.
³ Institute of Biochemistry, Graz University of Technology, Petersgasse 10-12, 8010 Graz, Austria.
⁴ Institute of Inorganic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria.
⁵ BIOTECHMED Graz, 8010 Graz, Austria.

Abstract

Stereoselective synthesis of quaternary stereocenters represents a significant challenge in organic chemistry. Herein, we describe the use of ene-reductases OPR3 and YqjM for the efficient asymmetric synthesis of chiral 4,4-disubstituted 2-cyclohexenones via desymmetrizing hydrogenation of prochiral 4,4-disubstituted 2,5-cyclohexadienones. This transformation breaks the symmetry of the cyclohexadienone substrates, generating valuable quaternary stereocenters with high enantioselectivities (ee, up to >99%). The mechanistic causes for the observed high enantioselectivities were investigated both experimentally (stopped-flow kinetics) as well as theoretically (quantum mechanics/molecular mechanics calculations). The synthetic potential of the resulting chiral enones was demonstrated in several diversification reactions in which the stereochemical integrity of the quaternary stereocenter could be preserved.