Use of homoserinyl γ-aldehyde–containing peptides in solid-phase reductive amination

Abstract

Reduced peptide bonds of the methyleneamino Ψ[CH₂–NH] type are widely recognized as peptide bond isosteres with significant value in drug discovery and development. Solid-Phase Synthesis (SPS) enables Solid-Phase Fragment Condensation (SPFC), a key strategy for the construction of complex peptides. In this study, we report the SPS of peptides containing selectively side-chain deprotected homoserine (Hse) residues, followed by solution-phase oxidation of the liberated Hse side-chain hydroxyl group to the corresponding γ-aldehydes. The intrinsic instability of these intermediates, primarily due to intramolecular cyclization to γ-hydroxy lactam or lactone products, is systematically examined, and stabilization strategies to overcome these limitations are developed. The resulting stabilized homoserinyl γ-aldehyde peptides were subsequently employed, as proof of concept, in solid-phase reductive amination with the N-terminus of resin-bound peptides. Overall, this approach enables the efficient formation of Hse-β-Ψ[CH₂–NH] reduced peptide bonds and establishes a versatile platform for broader peptide ligation and modification strategies.