One-Pot Deracemization of Secondary Alcohols via Synergistic Photoredox Catalysis and Biocatalysis

Abstract

Chiral alcohols are ubiquitous in the production and structure of pharmaceuticals and other chemicals. For cost-saving and/or synthesis reasons, it is often more practical to resolve a racemic compound to the desired enantiomer than to produce it enantioselectively. Conventional methods of resolving racemic compounds, including classical and kinetic resolutions, have maximum yields of 50%. In comparison, deracemizations can produce the desired enantiomer with a theoretical maximum yield of 100%. Current methods of deracemizing secondary alcohols often utilize redox chemistry and/or biocatalysis. One- pot, one-step deracemizations of secondary alcohols are rare in literature as it is challenging to prevent individual redox steps from interfering with the other. By synergistic merging of photoredox and biocatalysis, novel ketone reductase activity has been enabled in the ‘ene’-reductase family of flavoproteins through a radical mechanism. This work couples the non-natural radical reactivity in ‘ene’-reductases with the natural two-electron oxidation reaction of alcohol dehydrogenases to construct a one-pot deracemization of secondary alcohols. After rounds of optimization, this deracemization achieved enantiomeric ratios of >99:1 of (S)-1-phenyl ethanol at 87% yield. This deracemization reaction produced moderate to great yields and enantiomeric ratios on substituted derivatives, and a promising deracemization to the (R)-enantiomer was developed.