Organic Chemistry Seminar

Small molecules make an disproportional impact on human health as drugs that prevent or treat disease, tools for analyzing biological systems, and probes to manipulate whole pathways and individual biomolecules. This limitless potential can be curbed by the practicality and accessibility of target molecules through modern chemical synthesis. The trend away from natural products in drug discovery illustrates this conundrum, as the synthetic challenge associated with accessing these complex structures can guide decision making over their therapeutic potential. Advances in synthetic strategies that allow for control of chemo-, site- or stereoselectivity can facilitate more efficient routes, thus, expanding the pool of practical-to-target molecules. Biocatalytic methods present the opportunity to develop exquisite catalyst-controlled selectivity, enabling highly streamlined synthetic routes. This is exemplified by nature's ability to make intricate secondary metabolites with potent biological activity such as taxol and vancomycin as well as the choice of process chemists to employ biocatalytic strategies in commercial routes. Although biocatalysis has been embraced by select industrial chemists, several factors have prevented the broader adoption and implementation of biocatalysis in mainstream organic synthesis, including limitations in the breadth of well-developed reactions, the unknown substrate scope of functionally characterized enzymes, and the perceived incompatibility with multistep, preparative-scale routes. To address these challenges, my group has embraced high throughput strategies for profiling sequence/function relationships across protein families and reaction discovery. This talk will focus on (1) the development of biocatalytic C–C bond-forming reactions and C–H functionalization chemistries, (2) ancestral sequence reconstruction as a dimension in constructing enzyme libraries for biocatalyst discovery, and (3) platforms for making biocatalysis more accessible to the greater organic chemistry community.