Bifunctional boron/phosphorus organocatalysts for amide bond formation

Abstract: The construction of amide bonds, ubiquitous in biological molecules and pharmaceutical targets, is typically conducted with peptide coupling reagents or other stoichiometric activators that generate significant waste on process scale and are often associated with safety concerns. Boronic acid catalysts have shown promise as alternatives but are usually limited to elevated temperatures and/or have restricted substrate scopes on account of the energetic cost to eliminating water in the rate-limiting step. We have designed a new bifunctional organocatalyst that incorporates a boronic acid functionality in combination with a P(V) center as the second binding site to facilitate catalysis at room temperature with a scope of substrates that includes acyclic secondary amines and heterocycles of interest in the pharmaceutical industry. In addition to its synthetic utility, we identified novel mechanistic features that showcase how the combination of the boronic acid and phosphine oxide enable catalysis through a different monomeric mechanism to previously reported arylboronic acid catalysts, which form an activated bicyclic intermediate. In this presentation, the optimization and scope of the catalytic conditions will be discussed, applications in peptide synthesis presented, and mechanistic studies that show differences from previously published arylboronic acid catalysts will be presented.