Chemoselective late-stage functionalization of peptides have been reported and subsequently used in structure-activity relationship (SAR) studies of therapeutically relevant peptide sequences. While there are examples of peptide backbone modifications, they often require harsh conditions. Specifically, N-aryl glycine derivatives have been shown to oxidize to an α-imino amide intermediate, which allows for coupling to a variety of nucleophiles at the α-carbon. However, examples of such oxidative couplings on longer functionally dense peptide sequences remain scarce. We previously reported that electron-rich N-aryl peptides undergo oxime ligation reactions with aminooxy nucleophiles under mild, catalyst free conditions. Here, we describe the late-stage α-C-H functionalization reaction of resin-bound N-aryl peptides with boronic acid nucleophiles under metal-free conditions. We explore the effect of the electronics of the N-aryl ring on reactivity and present a scope of the optimized reaction where both the peptide sequence and nature of boronic acid derivatives are varied.

Chemoselective functionalization of N-aryl peptides on solid support

ACS Spring 2022

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