Cascade reactions occupy an important place in organic synthesis due to their power, versatility, and efficiency. In particular, the control of radical formation using biocatalytic methods enables our group to tackle challenging chemical transformations, such as the efficacious synthesis of asymmetric products from both racemic mixtures and achiral substrates.

The field of asymmetric synthesis remains one of the most important in modern organic chemistry. Countless small-molecule products only have one useful enantiomer, as the other may be either useless or actively harmful. One method of rendering a racemic mixture enantiopure is through a process called dynamic kinetic resolution (DKR). DKRs rely on the identification of critical stereocenters in a given compound, which are then epimerized by a catalyst which selectively lowers the energy of the transition state corresponding to one of the enantiomers. Biocatalysis is uniquely poised to facilitate DKRs, as numerous enzymes are natively used to epimerize organic motifs which are beyond the reach of traditional catalysts. In 2020, in a collaboration with the MacMillan Group, DeHovitz (Hyster group, PhD 2021) et al. developed a system by which racemic unactivated beta-ketostereocenters could be resolved to a single enantiomer. The generation of a prochiral radical at the desired stereocenter was accomplished by an iridium photocatalyst, which in turn enabled the ketone to interconvert between its two enantiomers.

Upon generation, the active enantiomer was then enantioselectively reduced by a ketoreductase (wild-type Lactobacillus kefir alcohol dehydrogenase, LK-ADH), which was in turn regenerated by a glucose dehydrogenase and either glucose or excess alcohol cosolvent. The reduced ketone, no longer able to be epimerized by the iridium photocatalyst, was trapped as the desired enantiomer, thereby resolving the epimerization and concluding the resolution with high yield and >99:1 er. This catalytic system serves as an excellent example of how our group was able to merge traditional photocatalysis with biocatalysis, resulting in a highly efficient dynamic kinetic resolution facilitated by a selective cascade reaction. In addition, the reaction works with a wide range of substrates, and the enantioselectivity of the ketoreductase steps (both the selection of the active enantiomer and the enantioselective reduction) can be tuned, allowing access to all possible stereoisomers from a single substrate. Biocatalytic strategies for such challenges are rarely constrained by a lack of substrate promiscuity as even in situations where such challenges exist, they may be overcome through the use of techniques such as directed evolution, resulting in a highly flexible approach to even the most challenging cascade reactions facing modern chemistry.