Copper-Mediated Deprotection of Thiazolidine and Selenazolidine Derivatives Applied to Native Chemical Ligation

Abstract

Cupric sulfate efficiently opens thiazolidine and selenazolidine rings, producing a protected N-terminal cysteine or selenocysteine derivative without the use of inert gas or solvent. This is a clear advantage over methods that use water-soluble palladium salts, which fail to react with the selenazolidine ring. This copper-mediated reaction proceeds with monovalent or divalent copper ions, and disulfide bond formation followed by ring-opening promotes the process. This copper-mediated reaction, which is compatible with the standard native chemical ligation conditions, was applied to the synthesis of the 77-mer CXCL14 protein.

Cysteine protecting groups: applications in peptide and protein science

“…239 Aside from Pd, Cu complexes can also be used to deprotect Thz. 139,240 Thz is removed by CuSO 4 in the presence of sodium ascorbate (critical for avoiding oxidation by-products), in 5 M GdnÁHCl in HEPPS buffer (pH 7.0, 1 h, 37 1C). This was demonstrated in the synthesis of CXCL14 (Fig.…”

“…30d). 139 As discussed previously, the reaction can then be quenched with DTT or EDTA. 73 No epimerisation or side products are observed using this method of deprotection, and the reaction can be performed under standard NCL conditions.…”

Chemoselective Copper-Mediated Radical Modification of Selenocysteines in Peptides and Proteins

“…Recently, we reported on the use of Cu(II) ions for the deprotection of selenazolidine (Sez) and thiazolidine (Thz) during chemical protein synthesis, [48][49][50] and proposed that Cu(II) acts as a Lewis acid that binds the selenium of Sec. In addition, Arsenyan's group reported the use of Cu(II) in binding the Se atom of Ph2Se2, which was followed by oxidation to electrophilic PhSe + , which in turn reacted with triple-bond-containing molecules.…”

Thiazolidine Deprotection by 2-Aminobenzamide-Based Aldehyde Scavenger for One-Pot Multiple Peptide Ligation

“…Thus, in this method, an excess amount of the third N-terminal segment needs to be added to reach a full conversion in three peptide segments ligation. Palladium or copper-mediated Thz ring-opening was reported by the Brik group [31][32][33] and by the Otaka group [34] respectively (Scheme 1b.). These metals can promote the hydrolysis of Thz as a Lewis acid to the sulfur atom to produce Cys and formaldehyde.…”