Biomimetic Nucleophilic Catalysts Based on Neighboring Group Effects

Abstract

Formation and hydrolysis of carboxyl derivatives such as ester, thioester and amide are of great importance in organic chemistry. Efficient and specific formation of the amide bond between peptide/protein fragments is critically important for the synthesis of peptides and proteins, with potential impact in many areas including protein drug discovery and bioconjugation. Native chemical ligation is one of such reaction between thioester and an N-terminal cysteine. Despite its exquisite specificity, this reaction is often very slow and requires high concentration of peptides and proteins. Thus thiol-based nucleophilic catalysts are typically employed. Although the catalyst accelerates the reaction by converting the reactant into a more reactive thioester, the reaction is often still slow for many practical applications. To address this, we propose biomimetic nucleophilic catalysts. Introduction of hydrogen donor and acceptor as neighboring groups to nucleophilic catalysts can stabilize the tetrahedral intermediate of acyl substitution reaction. Alternatively, they can activate the nucleophile or the leaving group. In fact, such a mechanism is well known for many enzymes such as proteases and ligases, which dramatically accelerate acyl substitutions under mild conditions. We report our progress on the development of such biomimetic nucleophilic catalyst. These catalysts can have significant impact in the peptide synthesis, bioconjugation, and the development of artificial enzyme mimics.