As global and political awareness about sustainable practices sharpens in the face of dramatic climate change and environmentally harmful practices, one appealing strategy is to harness the catalytic potential of enzymes. Apart from the outstanding synthetic power of enzymes in the asymmetric synthesis of complex molecules, biocatalytic approaches reduce the environmental impact compared with organic synthetic pathways, as enzymes are renewable resources and often perform more efficiently than the analogous organic chemistry route. Our efforts are focused on engineering a novel deoxyribose phosphate aldolase (DERA) enzyme variant and employing it in the chemosynthesis of widely-prescribed cholesterol-lowering statin drugs, especially rosuvastatin (Crestor). Engineered DERA biocatalysts will utilize simple achiral feedstocks to construct a novel chiral synthon (containing the syn-3,5-dihydroxy acid pharmacophore that is universal to all statins), which can be incorporated into the statin core through atom-economical transition-metal catalysis. DERA, a ubiquitous bacterial enzyme, has been extensively studied owing to its ability to catalyze enantioselective tandem aldol reactions and its tolerance towards a broad range of polar substrates. Yet, its application is hindered by poor tolerance towards high concentrations of aldehydes and even acetaldehyde, its natural substrate. In this work, we engineered a DERA variant to accept novel nonpolar substrates that, along with acetaldehyde, can generate functionalized intermediates to be deployed in valuable synthetic processes. Based on DERA crystal structures, rationally designed active-site variants have been produced by mutagenesis. Several of our mutants displayed elevated tolerance towards electrophilic aldehydes, including acetaldehyde, and showed successful incorporation of functionalized acceptor aldehydes into the targeted aldol product. Transition-metal catalyzed cross-coupling reaction strategies are being evaluated for efficient installation of the biocatalytically-prepared chiral side chain onto the heterocyclic core structure. Preliminary efforts towards immobilization of our engineered DERA enzyme to create an integrated flow-based system for the continuous synthesis of statins will also be discussed.

Harnessing the power of biocatalysis and integrating cross-coupling chemistry to realize a novel greener synthetic routes for statins

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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