Non-enzymatic methylcyclization of alkenes.

Abstract

Methyltransferases are a broad class of enzymes that catalyse the transfer of methyl groups onto a wide variety of substrates and functionalities. In their most striking variant, bifunctional methyltransferase-cyclases both transfer a methyl group onto alkenes and induce cyclization (methylcyclization). Although recent years have seen substantial advances in the methylation of alkenes, especially hydromethylation, the reactivity demonstrated by bifunctional methyltransferase-cyclases in nature has yet to be developed into a synthetically viable method. Here we report a silver(I)-mediated electrophilic methylcyclization that rivals selectivities found in enzymes while not being limited by their inherent substrate specificity. Our method benefits from the use of commercial reagents, is applicable to a wide range of substrates, including heterocycles, and affords unique structures that are difficult to access via conventional synthetic methods. Furthermore, computational studies have been utilized to unravel the underlying mechanism and ultimately support a stepwise cationic reaction pathway with a rate-limiting methyltransfer.