Biaryl scaffolds are prevalent in a vast array of drug molecules and natural products. These biaryl frameworks are considered privileged motifs in modern drug discovery due to their therapeutic potential for infectious and metabolic diseases, inflammation, oncology, and cardiovascular and central nervous systems. The unique structures and promising bioactivates of axially chiral biaryl natural products make them highly valuable molecules, however this structural feature contributes to their difficulty as synthetic targets.<br/><br/>To overcome the challenges associated with constructing biaryl molecules through traditional synthesis, we propose a chemoenzymatic approach toward this class of molecules. Nature has evolved cytochrome P450 enzymes (P450s) to mediate the oxidative dimerization of these compounds in the biosynthesis of biaryl natural products, with a small subset within this family capable of catalyzing site- and atroposelective reactions. This subset of wild-type P450s are yet to be explored as biocatalysts for unnatural cross-coupling reactions. Moreover, these catalysts exist within a large pool of related enzyme sequences with untapped potential to catalyze oxidative coupling reactions.<br/><br/>This work outlines the development of P450 enzymes into tunable biocatalysts for convergent oxidative cross-coupling reactions with catalyst-controlled reactivity, site-selectivity, and atroposelectivity. In particular, the discovery and characterization of previously unknown P450s form a diverse library of sequences has led to the site-selective generation of biaryl bonds, relevant for the total synthesis of many classes of natural products with known therapeutic potentials. This approach allows for the rapid generation of molecular complexity in natural and novel biaryl compounds, with increased accessibility and structural diversity, thereby accelerating the therapeutic development of these bioactive molecules.

Enzyme enabled synthesis of medicinally relevant biaryl molecules

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.