On‐Resin Preparation of Allenamidyl Peptides: A Versatile Chemoselective Conjugation and Intramolecular Cyclisation Tool

• Published in: Angewandte Chemie International Edition 2020-10, Vol.59 (41), p.18054-18061
• Main Authors: Cameron, Alan J., Harris, Paul W. R., Brimble, Margaret A.
• Format: Article
• Language: English
• Subjects: allenamides; allenes; Amides - chemistry; Aqueous solutions; Aromatic compounds; Biocompatibility; Catalysts; Chemical reactions; Chromatography, High Pressure Liquid - methods; click chemistry; Conjugation; Cyclization; Cysteine - chemistry; Disulfide bonds; Disulfides - chemistry; Michael addition; Oxytocin; Peptides; Peptides - chemical synthesis; Peptides - chemistry; Peptides - isolation & purification; Proton Magnetic Resonance Spectroscopy; Resins; Sulfhydryl Compounds - chemistry; Sulfides; Thiols
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202004656

The ability to modify peptides and proteins chemoselectively is of continued interest in medicinal chemistry, with peptide conjugation, lipidation, stapling, and disulfide engineering at the forefront of modern peptide chemistry. Herein we report a robust method for the on‐resin preparation of allenamide‐modified peptides, an unexplored functionality for peptides that provides a versatile chemical tool for chemoselective inter‐ or intramolecular bridging reactions with thiols. The bridging reaction is biocompatible, occurring spontaneously at pH 7.4 in catalyst‐free aqueous media. By this “click” approach, a model peptide was successfully modified with a diverse range of alkyl and aryl thiols. Furthermore, this technique was demonstrated as a valuable tool to induce spontaneous intramolecular cyclisation by preparation of an oxytocin analogue, in which the native disulfide bridge was replaced with a vinyl sulfide moiety formed by thia‐Michael addition of a cysteine thiol to the allenamide handle. A method has been developed for the on‐resin preparation of allenamide‐modified peptides, which can subsequently undergo chemoselective thia‐Michael addition with thiols. The approach was shown to be a versatile tool to modify peptides with thiols and to prepare cyclic peptides with excellent conversion (see scheme).