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

## TL;DR

Scientists developed a new method to efficiently create chiral molecules with complex 3D shapes using enzymes, which is important for drug development.

## Contribution

A novel enzymatic method for asymmetric synthesis of chiral 2-cyclohexenones with quaternary stereocenters is introduced.

## Key findings

- Ene-reductases OPR3 and YqjM enable desymmetrizing hydrogenation with high enantioselectivity (>99% ee).
- Mechanistic insights were obtained through experimental and theoretical studies.
- The chiral enones can undergo diversification reactions while preserving stereochemistry.

## 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.