Exploration of the Scope of Suzuki-Miyaura Cross-Coupling in Peptide Ligation

摘要

Suzuki-Miyaura cross-coupling reaction is one of the most powerful methods for the construction of carbon-carbon bonds. In a typical Suzuki-Miyaura reaction, an aryl boronic acid is cross-coupled with an aryl or vinyl halide or pseudo-halide in the presence of a palladium catalyst and a base in organic solvent at elevated temperature [1,2]. Whereas the Suzuki-Miyaura reaction has a high potential in peptide ligation and conjugation due to advantages like bio-orthogonality and tolerance toward a broad range of functional groups, it has been rarely used in peptide chemistry presumably because of relatively incompatible reaction conditions to peptides, such as high temperature and use of organic solvents [3-6]. In this study, we examined the scope and limitations of the Suzuki-Miyaura cross-coupling as a tool for peptide ligation. The reaction conditions were optimized by surveying various catalysts, bases, temperature, solvents, and additives. We also determined the effects of amino acid side chains on the ligation reactions of peptides. Following the optimized conditions, we then demonstrated the feasibility of ligations between two long peptides.