Late‐Stage Modification of Halotryptophan‐Containing Peptides Via Negishi Cross‐Coupling

ABSTRACT Late‐stage functionalization of peptides provides powerful opportunities for the rapid diversification of bioactive sequences. Among the available strategies, Negishi cross‐coupling represents a versatile and orthogonal method for the installation of alkyl substituents under mild conditions. We describe the applicability of Negishi cross‐coupling to increasingly complex bromotryptophan‐containing peptides. While conditions effective for bromo‐ l ‐tryptophan proved unsuitable for peptide substrates, leading to incomplete conversion and pronounced debromination, systematic optimization enabled efficient cross‐coupling of the model tripeptide Ac‐Ala‐Trp(6‐Br)‐Gly‐NH 2 . The optimized protocol afforded good to excellent conversions and isolated yields while maintaining operational simplicity. A key limitation arising from peptide solubility was addressed through the yet underexplored use of DMSO and DMSO/DMF solvent systems in Negishi cross‐couplings, which enabled efficient reaction of peptides bearing either 6‐ or 7‐bromo‐ l ‐tryptophan as well as unprotected residues such as aspartic acid and serine. Application to more complex pentapeptides revealed solvent‐dependent reactivity: poor solubility in DMF resulted in reduced conversion and increased debromination, whereas DMSO‐containing solvent systems significantly improved both solubility and catalytic performance. These results demonstrate that Negishi cross‐coupling can be adapted for the late‐stage functionalization of bromotryptophan‐containing peptides with functional group tolerance in structurally complex peptide substrates.