Rapid Additive-Free Selenocystine–Selenoester Peptide Ligation

• DOI: 10.1021/jacs.5b07237
• Publication Date: 2015-10-21T08:08:13Z
• Authors: Nicholas J. Mitchell; Lara R. Malins; Xuyu Liu; Robert E. Thompson; Bun Chan; Leo Radom; Richard J. Payne
• Keywords: :030599 - Organic Chemistry not elsewhere classified [FoR]; FoR::030599 - Organic Chemistry not elsewhere classified; Antigens, Bacterial; Monomers; Molecular Conformation; Esters; Peptides and proteins; Mycobacterium tuberculosis; 01 natural sciences; 0104 chemical sciences; Bacterial Proteins; Oligomers; Organoselenium Compounds; Cystine; Peptides; Selenium Compounds; Ligation Acyls; Chorismate Mutase

We describe an unprecedented reaction between peptide selenoesters and peptide dimers bearing N-terminal selenocystine that proceeds in aqueous buffer to afford native amide bonds without the use of additives. The selenocystine-selenoester ligations are complete in minutes, even at sterically hindered junctions, and can be used in concert with one-pot deselenization chemistry. Various pathways for the transformation are proposed and probed through a combination of experimental and computational studies. Our new reaction manifold is also showcased in the total synthesis of two proteins.