Biocatalytic Alkylation of Ambident Nucleophiles Enables Selective <i>N</i> ‐Functionalization of Heterocycles and Late‐Stage Modifications
Abstract
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.
Article Details
Authors (11)
Felipe Ospina
Research Group for Organic Chemistry and Biocatalysis Faculty of Chemistry Bielefeld University Universitätsstraße 25 33615 Bielefeld Germany
Kai H. Schülke
Research Group for Organic Chemistry and Biocatalysis Faculty of Chemistry Bielefeld University Universitätsstraße 25 33615 Bielefeld Germany
Marius Schnutenhaus
Research Group for Organic Chemistry and Biocatalysis Faculty of Chemistry Bielefeld University Universitätsstraße 25 33615 Bielefeld Germany
Alina Klein
Research Group for Organic Chemistry and Biocatalysis Faculty of Chemistry Bielefeld University Universitätsstraße 25 33615 Bielefeld Germany
Om Desai
Research Group for Organic Chemistry and Biocatalysis Faculty of Chemistry Bielefeld University Universitätsstraße 25 33615 Bielefeld Germany
Shubhanshu Jain
Research Group for Organic Chemistry and Biocatalysis Faculty of Chemistry Bielefeld University Universitätsstraße 25 33615 Bielefeld Germany
Christine Krofta
Research Group for Organic Chemistry and Biocatalysis Faculty of Chemistry Bielefeld University Universitätsstraße 25 33615 Bielefeld Germany
Lukas Stratmann
Research Group for Organic Chemistry and Biocatalysis Faculty of Chemistry Bielefeld University Universitätsstraße 25 33615 Bielefeld Germany
Jianing Yang
Chair of Industrial Organic Chemistry and Biotechnology Faculty of Chemistry Bielefeld University Universitätsstraße 25 33615 Bielefeld Germany
Harald Gröger
Chair of Industrial Organic Chemistry and Biotechnology Faculty of Chemistry Bielefeld University Universitätsstraße 25 33615 Bielefeld Germany
Stephan C. Hammer
Research Group for Organic Chemistry and Biocatalysis Faculty of Chemistry Bielefeld University Universitätsstraße 25 33615 Bielefeld Germany