Peptide and Protein Desulfurization with Diboron Reagents

Abstract

In this Letter, we report a direct and robust desulfurization method employing water-soluble phosphine, specifically tris(2-carboxyethyl)phosphine hydrochloride (TCEP), and tetrahydroxydiboron (B₂(OH)₄), which serves as a radical initiator. This innovative reaction exhibits compatibility with a diverse array of substrates, including cysteine residues in chemically synthesized oligopeptides and cyclic peptides, alkyl thiols in bioactive molecules, disulfides in commercial proteins, and selenocysteine. We optimized the reaction conditions to minimize the formation of undesired oxidized and borylated byproducts. Furthermore, the refined desulfurization process is executed after native chemical ligation (NCL) in a single pot, streamlining the existing synthetic approaches. This demonstrates its potential applications in the synthesis of complex peptides and proteins, showcasing a significant advancement in the field.

Scheme 1.. Overview of Key Protein Synthesis Technologies

Scheme 2.. Reaction Scope with Linear Oligopeptides^a

^a Reaction conditions adopted from Table 1, entry 1. LC yields based on LC-MS analysis of the reaction mixture by integrating UV absorptions (214 nm); isolated yields after HPLC purification shown in parentheses.

Scheme 3.. Reaction Scope with Complex Substrates^a

^a Reaction conditions were adopted from Table 1, entry 1. LC yields based on LC-MS analysis of the reaction mixture by integrating UV absorptions (214 nm); isolated yields after HPLC purification shown in parentheses.

Scheme 4.. Reaction Scope with Protein Substrates^a

^aThe reaction conditions were adopted from Table 1, entry 1. Isolated yields after HPLC purification.