Desulfurative Borylation of Small Molecules, Peptides, and Proteins

Abstract

We introduce a direct conversion of alkyl thiols into boronic acids, facilitated by a water-soluble phosphine, 1,3,5-triaza-7-phosphaadamantane (PTA), in conjunction with tetrahydroxydiboron (B₂(OH)₄), acting as both a radical initiator and a boron source. This desulfurative borylation reaction has been successfully applied to various substrates, including cysteine residues in oligopeptides and small proteins, primary alkyl thiols found in pharmaceutical compounds, disulfides, and selenocysteine. Optimization of reaction conditions was undertaken to reduce the formation of unwanted reactions, such as the reduction of alanyl or other primary radicals, and to prevent deleterious reactions between the phosphine and N-terminal amine that lead to methylene adducts by utilizing a buffer containing glycine-glycine (GG) dipeptide. The developed method is characterized by its operational simplicity and robustness. Moreover, its compatibility with various functional groups present in peptides and proteins makes it a promising tool for late-stage functionalization, extending its potential application across a broad spectrum of chemical and biological targets.

Scheme 1.. Bioactive Boronic Acids and Their Synthesis

Scheme 2.. Scope of Desulfurative Borylation^a

^aReagents and conditions: peptide substrate (2 mM), B₂(OH)₄ (2 M), PTA (0.2 M), KF (2 M), GG (0.75 M), pH 7.0, white light (LED), 12 h. Yields based on LC-MS analysis of the reaction mixture by integrating UV absorptions (214 nm); isolated yields after HPLC purification in parentheses. Abbreviations: Acm = S-acetamidomethyl.

Scheme 3.. Reaction Scope with Complex Substrates^a

^aOptimized conditions from Table 1, entry 11. Yields based on LC-MS analysis of the reaction mixture by integrating UV absorptions (214 nm); isolated yields after HPLC purification in parentheses.

Scheme 4.. Proposed Reaction Mechanism

Scheme 5.. Summary of Computational Investigations: Calculated Free Energies of the Proposed PTA-Promoted and PTA-Free Desulfurative Borylation of 2-Acetamido-3-mercaptopropanamide^a

^aOptimization and frequency calculations were performed at the UB3LYP/6-311+G(d,p)-SMD(water) level of theory and depict ΔG (kcal/mol) at 1 atm, 298 K.