Unnatural Thiamine Radical Enzymes for PhotobiocatalyticAsymmetric Alkylation of Benzaldehydes and a-Ketoacids

Despite substantial progress made toward elucidating the elegant natural radical enzymology with thiamine pyrophosphate (TPP)-dependent pyruvate:ferredoxin oxidoreductases (PFORs) and pyruvate oxidases (POXs), repurposing naturally occurring two electron TPP-dependent enzymes to catalyze single-electron transformations with significant synthetic value remains a daunting task. Enabled by the synergistic use of visible-light photocatalyst fluorescein and a set of engineered TPP-dependent enzymes derived from benzoylformate decarboxylase (BFD) and benzaldehyde lyase (BAL), we developed an asymmetric photobiocatalytic decarboxylative alkylation of benzaldehydes and a-keto acids to produce highly enantioenriched a-branched ketones. Mechanistically, this dual catalytic radical alkylation involves single-electron oxidation of the enzyme-bound Breslow intermediate and subsequent interception of the photoredox-generated transient alkyl radical. In conjunction with visible light photoredox catalysis, thiamine radical biocatalysis represents a new platform to discover and optimize new asymmetric radical transformations which are unknown to biological systems and not amenable to small-molecule catalysis.