Late-stage installation and functionalization of alkyl pyridiniums: a general HTE amenable strategy to access diverse aryl alanine containing macrocyclic peptides†

This manuscript describes a strategy to readily access diverse aryl and homoaryl alanine-containing pharmaceutically relevant macrocyclic peptides. A two-step sequence involving the late-stage installation of the pyridinium functionality on macrocyclic peptides followed by reductive couplings was implemented. These transformations are amenable to microscale high-throughput experimentation (HTE) and enable rapid access to aryl alanine-containing macrocyclic peptides that would otherwise be inaccessible via solid-phase peptide synthesis using commercially available amino acids. Numerous aryl and heteroaryl derivatives can be effectively used in these reactions. In addition, a systematic investigation was undertaken using an “informer” set of macrocyclic peptides which revealed the compatibility of the late-stage diversification with peptides containing diverse side chain functionalities.