An alkyl-swap platform for late-stage modification of secondary N-methylamines

Abstract

The selective functionalization of unprotected amines with simple, unactivated alkenes and alkynes remains a challenge in contemporary synthesis. Here we present a strategy for the peripheral modification of secondary N-methylamines that complements state-of-the-art approaches and tolerates a wide range of functional groups and native amine substrates. This method is primed for application in late-stage functionalization contexts, including the direct bioconjugation of fully functionalized, unprotected building blocks and complex peptides. The retrosynthetic flexibility unlocked by this method also enables the preparation of several commercial, high-grossing pharmaceuticals in a single synthetic step. The selective functionalization of unprotected amines with alkenes remains a challenge in contemporary synthesis. Now a strategy has been developed for an alkyl swap of N-methylamines, enabling late-stage bioconjugation and peptide modification. The resulting retrosynthetic disconnection also streamlines the preparation of several pharmaceuticals and medicinally relevant compounds.