Late-Stage Serine Modification Enables Noncanonical Peptide Synthesis

Noncanonical amino acids play a critical role in enhancing drug efficacy, specificity, pharmacokinetics, and other key therapeutic properties. However, their incorporation into peptides or small molecules often presents significant synthetic challenges. Late-stage modification of natural residues, after the primary structural framework of a molecule is established, offers an efficient strategy for generating analogue libraries. Serine, one of the most abundant natural amino acids, remains underutilized due to the incompatibility of existing deoxygenative methods with complex peptides. Currently, no method is available for the late-stage modification of serine residues in peptides through carbon-carbon bond formation. Here, we address this gap by developing a site-selective, late-stage deoxygenative functionalization of serine residues. Inspired by automated DNA synthesis, we employ a phosphoramidite reagent in combination with a photocatalytic system to achieve efficient serine deoxygenative activation and radical addition to diverse acceptors, enabling the transformation of serine into various noncanonical residues such as homoglutamine, homoglutamic acid, 5-hydroxynorvaline, phosphonates, and alanine-3-<i>d</i>₁. The method proved compatible with complex peptides such as enkephalin, bradykinin, and α-MSH both on solid support and in solution. The broad substrate scope, operational robustness, and high chemoselectivity of this approach position it as a versatile platform for peptide diversification and the advancement of medicinal chemistry.