PUB - Publikationen an der Universität Bielefeld

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.