Extending the toolbox: The title reaction was identified as a chemoselective means to modify azides in peptides and proteins in high yields at room temperature in various solvents including aqueous buffers at physiological pH. In combination with nonnatural protein translation the Staudinger‐phosphite reaction allows the site‐specific incorporation of phosphorylated Tyr analogues in proteins.

The Staudinger reaction of unprotected azido-peptides with silylated phosphinic acids and esters on the solid support offers a straightforward acid-free entry to different phosphonamidate peptide esters or acids under mild conditions in high purity and yield.

Site-specific functionalization of proteins by bioorthogonal modification offers a convenient pathway to create, modify, and study biologically active biopolymers. In this paper the Staudinger reaction of aryl-phosphonites for the chemoselective functionalization of azido-peptides and proteins was probed. Different water-soluble phosphonites with oligoethylene substituents were synthesized and reacted with unprotected azido-containing peptides in aqueous systems at room temperature in high conversions. Finally, the Staudinger-phosphonite reaction was successfully applied to the site-specific modification of the protein calmodulin.

Head-to-tail peptide macrocyclisations are significantly improved, as measured by isolated yields, reaction rates and product distribution, by substitution of one of the backbone amide CO bonds with an oxetane ring.