Site‐Selective Modification of Proteins with Oxetanes

Oxetanes are four‐membered ring oxygen heterocycles that are advantageously used in medicinal chemistry as modulators of physicochemical properties of small molecules. Herein, we present a simple method for the incorporation of oxetanes into proteins through chemoselective alkylation of cysteine. We demonstrate a broad substrate scope by reacting proteins used as apoptotic markers and in drug formulation, and a therapeutic antibody with a series of 3‐oxetane bromides, enabling the identification of novel handles (S‐to‐S/N rigid, non‐aromatic, and soluble linker) and reactivity modes (temporary cysteine protecting group), while maintaining their intrinsic activity. The possibility to conjugate oxetane motifs into full‐length proteins has potential to identify novel drug candidates as the next‐generation of peptide/protein therapeutics with improved physicochemical and biological properties.