Hyster (Rivas-Souchet) Diversity Supplement

Asymmetric Photoenzymatic Csp3—Csp3 Decyanative Couplings Nitriles are present in a range of different biologically active molecules and can also serve as a synthetic handle to other functional groups, making their facile and stereoselective assembly crucial for modern drug development. The current methods to synthesize nitrile stereocenters are limited to Csp2–Csp3 precursors. Biocatalysis offers a unique approach to establish nitrile stereocenters with the added benefit of directed evolution for catalyst development. We propose a novel asymmetric Csp3–Csp3 coupling to forge tertiary nitrile stereocenter via photoenzymatic biocatalysis of malononitriles and readily available 𝛼𝛼-chloroamides. Preliminary work shows moderate to good yields and enantioselectivities of cross- coupled product accelerated by flavin-dependent ene-reductase (ERED). The current strategy for the continued advancement of this project is to: identify ideal conditions for the decyanative transformation, conduct a directed evolution campaign on the most selective ERED candidate, and investigate the underlying mechanism of this novel reactivity. This approach will allow the exploration of an enzyme- mediated reactive intermediates that can be directed into new stereoselective assemblies.