Enhanced Reactivity and Selectivity in Organocatalysis via In-Situ Proline-Boronic Acid Complex Modification

The aldol reaction is a pivotal carbon-carbon bond-forming process integral to the biosynthesis of natural compounds. Yet, its application remains limited due to the challenges of selectivity, stereochemistry, and reaction efficiency. Herein, we report a boronic acid (BA)-modified proline catalyst system that significantly enhances both reactivity and selectivity in asymmetric aldol reactions, particularly for unbranched linear aliphatic aldehydes, a long-standing challenge in synthetic chemistry. Employing dynamic covalent and non-covalent interactions, BA acts as a secondary-sphere modifier, forming a catalytic pocket that emulates enzymatic processes. This system enables high diastereo- and enantioselectivity under mild conditions across a broad substrate scope, including challenging aldehydes and ketones, and demonstrates gram-scale applicability in synthesizing (+)-Disparlure, a bioactive natural product. Mechanistic investigations, including NMR and crystallographic studies, reveal the critical role of BA in modulating the catalyst microenvironment, achieving unprecedented selectivity and efficiency.