Nihon University unveils commercially available boronic acid as a catalyst for peptide synthesis: Advancing next-generation drug synthesis methods

A research group led by Associate Professor Naoyuki Shimada of the Department of Chemistry at the College of Humanities and Sciences at Nihon University, has revealed the successful development of an efficient chemical synthesis method for peptides. The innovative method utilizes inactive esters derived from α-amino acids, with boronic acid acting as a catalyst. This breakthrough is expected to pave the way for advancements in industrial manufacturing technologies for next-generation pharmaceuticals and peptide drugs. The results were published in the December 13 issue of Chemical Communications, the short communications journal affiliated with the Royal Society of Chemistry in the United Kingdom. Peptide drugs with intermediate molecular weights have garnered considerable attention as prospective next-generation drugs, given their capacity to combine the advantages of both small-molecule drugs and antibody drugs.

Conventionally, the solid-phase synthesis of peptides is employed to extend amino acid residues from the C-terminus to the N-terminus of peptides. However, this method poses challenges due to its dependence on large amounts of expensive protective amino acids and condensation reagents, leading to concerns related to efficiency, cost and environmental impact. Therefore, the use of catalysts in chemical synthesis is expected to solve this problem.

In this study, researchers explored novel catalysts capable of extending amino acid residues at the N-terminus. They utilized inactive esters obtained from α-amino acids, specifically methyl esters, as the C-terminus. The results revealed that boronic acid catalysts are effective in facilitating peptide bond formation reactions between methyl esters derived from β-hydroxy-α-amino acids and various α-amino acid esters possessing free amino groups.

Additionally, it was found that the formation of peptide bonds proceeded smoothly in the presence of a 10 mol% boronic acid catalyst. For example, serine and threonine proved to be suitable as β-hydroxy-α-amino acid esters, leading to the successful synthesis of the corresponding dipeptides with high yields. Furthermore, it was confirmed that the boronic acid-catalyzed reaction can be extended to the chemical synthesis of tripeptides and oligopeptides containing three or four amino acid bonds. This was achieved using dipeptides consisting of two amino acid bonds as substrates.

The catalytic reaction, exhibiting high chemoselectivity for β-hydroxy-α-amino acid esters, holds promise for prospective applications in C-terminal amino acid residue-selective peptide ligation. This method involves linking long-chain peptides and could open avenues for future advancements.

Shimada stated, "This research builds upon our expertise in chemoselective amide synthesis reactions using hydroxy groups as an orientation group—a focus area that Shimada's laboratory has been actively exploring independently. However, the discovery that boronic acid, a readily available compound on the market, serves as an effective catalyst for peptide bond formation from α-amino acid esters was surprising. We believe that this research has the potential to evolve into a novel method for peptide synthesis, showcasing a successful demonstration of the newly discovered catalytic function of boronic acid."