Expanding amide bond formation with CaLB-BOP: from sterically hindered substrates to aqueous and micellar media

TL;DR

A new method called CaLB-BOP efficiently forms amide bonds from non-activated esters and amines, especially in challenging conditions like water and with bulky substrates.

Contribution

The CaLB-BOP method improves amide bond formation for sterically hindered substrates and aqueous media using a combination of enzyme and phosphonium-based chemistry.

Findings

The CaLB-BOP method outperforms classical enzymatic aminolysis for sterically hindered substrates.

Amide synthesis proceeds cleanly in aqueous and micellar media with minimal purification.

Increased stirring and surfactant concentration enhance yields in aqueous conditions.

Abstract

Amide bond formation remains a cornerstone transformation in the synthesis of biologically active molecules, yet efficient methods for converting non-activated ethyl esters into amides under mild conditions remain limited. This work investigates the applicability of a one-pot protocol that combines Candida antarctica lipase B (CaLB)-mediated ester hydrolysis with phosphonium-based amidation (CaLB-BOP method) for amide synthesis. A set of esters and amines are examined via the CaLB-BOP method and benchmarked against classical base-catalyzed and CaLB-catalyzed aminolysis. Molecular docking is employed to probe substrate orientation within the CaLB active site, enabling correlation with experimental ester hydrolyzability and aminolysis reactivity. The CaLB-BOP method demonstrates markedly enhanced efficiency for sterically hindered and less reactive substrate combinations, overcoming limitations of classical enzymatic aminolysis that requires simultaneous binding of ester and amine. The method is also evaluated in aqueous and micellar media, where reactions proceed cleanly, require minimal purification, and display enhanced yields at increased stirring rates and surfactant concentrations. Overall, the CaLB-BOP method provides a practical and mild approach to amide bond formation, especially valuable for sterically demanding substrates and aqueous-phase synthesis.

CaLB-BOP method enables efficient amide bond formation from non-activated esters and amines under mild conditions. It outperforms classical enzymatic aminolysis for sterically hindered substrates and operates effectively in water and micellar media.

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