Molecular Diversity Generation via Selective Enzymatic C–CN Bond Scission

Abstract

Selective removal of functional groups offers a powerful route to streamline molecular design and generate structural diversity. The use of such deletion strategies has surged in organic synthesis, yet achieving these transformations with high selectivity remains a formidable challenge. Here, we present a photoenzymatic platform for stereocontrolled C–CN bond cleavage of malononitriles, enabling access to diverse chiral nitriles. Directed evolution of the flavin-dependent enzyme OYE1 yielded a variant that efficiently converted a wide range of geminal dinitriles, affording products in high yields (up to >99%) and enantioselectivities (up to 3:97 e.r.). The platform was further extended to a one-pot cascade combining Michael addition with enzymatic decyanation. Mechanistic studies revealed a pathway involving a benzyl radical intermediate (Int1), followed by a carbanion species (Int2). This work establishes the first photobiocatalytic cyano group deletion strategy and provides a modular approach for sustainable synthesis of valuable chiral nitrile scaffolds.