Todd Hyster

Scholar: 2017

Awarded Institution
Assistant Professor
Princeton University
Department of Chemistry


Research Interests

Photon Induced Enzyme Promiscuity

Structurally complex small organic molecules constitute the majority of medicines used in treatment today. These molecules are prepared from feedstock chemicals, frequently using catalysts to build the molecular scaffold. As the stereochemical nature of medicines is integral to their function, the catalysts used to build them need to be highly selective. While many catalysts have been developed for selective synthesis, there remain swaths of reactivity where small molecule catalysts are ineffective. In particular, radical mediated reactions have proven exceptionally challenging to control using small molecule catalysts. As radical reactions offer new and more efficient methods for building molecules, the challenge of selectivity hampers their application in synthesis.

Enzymes are attractive catalysts in organic synthesis because they can be engineered to provide levels of selectivity and efficiency that exceed traditional small molecule catalysts. Unfortunately, enzymes are not currently capable of the breadth the reactions accessible to small molecule catalysts. Our goal is to discover novel methods for changing enzyme function such that existing biocatalysts can be used to address the challenge of selectivity in radical mediated reactions.

Our approach for obtaining new enzyme function is to utilize the photoexcitated states of cofactors. Biological coenzymes, such as flavin and nicotinamide, effect biocatalytic reaction using their ground state reactivity. However, upon photoexcitation their reactivity changes, making them potent single electron oxidants and reductants. While this reactivity is well known in the small molecule literature, it has not been utilized as a means for obtaining new function in biological systems. In our seminal report, we demonstrated the viability of this approach using NADPH in ketoreductase active sites to effect a highly enantioselective radical dehalogenation. In future studies we will explore the potential of this general approach with different enzyme/cofactor combinations for a range of synthetically valuable radical transformations.