Synfacts 2019; 15(04): 0429
DOI: 10.1055/s-0037-1612399
Chemistry in Medicine and Biology
© Georg Thieme Verlag Stuttgart · New York

A Chemoselective Conjugation of Peptides with Electron-Rich (Hetero)Arenes

Dirk Trauner
Bryan S. Matsuura
Cohen DT. * Zhang C, Fadzen CM, Mijalis AJ, Hie L, Johnson KD, Shriver Z, Plante O, Miller SJ, Buchwald SL, Pentelute BL. * Massachusetts Institute of Technology, Cambridge, Yale University, New Haven, and Visterra Inc., Cambridge, USA
A Chemoselective Strategy for Late-Stage Functionalization of Complex Small Molecules with Polypeptides and Proteins.

Nat. Chem. 2019;
11: 78-85
Further Information

Publication History

Publication Date:
19 March 2019 (online)



The site-selective functionalization of peptides with small molecules is a formidable challenge in organic synthesis. Cohen, Pentelute, and co-workers have described a new high-yielding conjugation reaction between electron-rich aromatics and of 2-thiol-5-nitropyridine (TNP)-protected selenocysteine. This methodology is an ­important advance in the production of homo­genously functionalized proteins such as antibody–drug conjugates.



A range of unprotected pharmaceutical agents and natural products are competent substrates, as demonstrated by the syntheses of vancomycin–peptide conjugates and a homogenous genistein–trastuzumab conjugate, generated by a two-step selenocysteine ligation–sortagging sequence. In general, electron-rich arenes with acidic N–H or O–H bonds are the most efficient substrates. CuSO4 and a bipy ligand can be used to promote the reaction with less reactive arenes.