Biocatalytic Alkylation of Ambident Nucleophiles Enables Selective N-Functionalization of Heterocycles and Late-Stage Modifications

Abstract

The alkylation with electrophilic haloalkanes is a key methodology in chemical synthesis to build desired molecules. Although alkylation of compounds bearing a single nucleophilic site is routine, the selective alkylation of polyfunctional molecules with multiple competing nucleophilic positions of comparable reactivity is often very challenging. In this work, we report a generalizable solution for selective alkylation chemistry that combines the selectivity of enzyme catalysis with the reactivity of off-the-shelf alkylation reagents. We employ engineered transferases in a modular cyclic cascade and use functionalized N-heteroarenes as challenging proof-of-concept substrates. This catalytic alkylation approach is mild, highly chemo- and regioselective, proceeds on gram-scale, provides rapid access to important N-alkylated heterocyclic building blocks and enables challenging late-stage alkylations. This study demonstrates a generalizable strategy to streamline synthetic routes to many pharmaceutically important compounds by selective biocatalytic alkylation of polyfunctional molecules and ambident nucleophiles.