Selective Bi‐directional Amide Bond Cleavage of N‐Methylcysteinyl Peptide. Issue 20 (6th June 2014)

• Record Type: Journal Article
• Authors: Qiu, Yibo; Hemu, Xinya; Liu, Ding Xiang; Tam, James P.
• Is Part Of: European journal of organic chemistry. Issue 20(2014)
• Page Start: 4370
• Page End: 4380
• Publication Date: 2014-06-06
• Subjects: Peptides -- Amides -- Cleavage reactions -- Cyclization; Chemistry, Organic -- Periodicals; Organic compounds -- Synthesis -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1002/ejoc.201402261
• Languages: English
• ISSNs: 1434-193X

Abstract

Abstract: A selective bi‐directional peptide bond cleavage mediated by N ‐methylcysteine (MeCys) in Xaa‐MeCys‐Yaa peptides (Xaa and Yaa, non‐cysteine residues) leading to thioesters and thiolactones is described. Rate and product analyses showed that an N α ‐amide bond cleavage occurred at the Xaa‐MeCys bond by an N–S acyl shift to generate an Xaa‐S‐(MeCys‐Yaa) thioester at pH 1–5, whereas under strongly acidic conditions of H 0 = –5, the MeCys‐Yaa bond underwent a C α ‐amide bond cleavage via an oxazolone intermediate, which was trapped by thiocresol (TC) as an Xaa‐MeCys‐TC thioester. This thioester was then transformed into an Xaa‐MeCys‐β‐thiolactone at pH 4–5. Replacing MeCys by a Cys residue did not result in significant bi‐directional peptide bond cleavage, which suggests that N ‐methylation in a MeCys residue is important for the N–S acyl shift reaction and formation of oxazolone. The isomerization of amides and thioesters was successfully used to prepare cyclic peptides. Abstract : N ‐Methylcysteine (MeCys) in Xaa‐MeCys‐Yaa peptides undergoes two distinct cleavages under different conditions. N α ‐cleavage of the MeCys residue occurs at the Xaa‐MeCys bond by an N–S acyl shift at pH 1–5 and under strongly acidic conditions at H 0 = –5, the MeCys‐Yaa bond undergoes C α ‐amide bond cleavage via an oxazolone intermediate. Both cleavages afford thioesters for chemical ligation.