Mesoporous Confinement Enables Activity Boost in Cooperative Asymmetric Catalysis in Analogy to Enzymes

Abstract

Enzymes achieve substantial rate accelerations by combining cooperative functional group activation with confinement inside organized active sites, which reduce entropic costs and enforce productive orientations of activated substrates. Here, we translate these principles into artificial cooperative asymmetric catalysis using mesoporous confinement. Embedding a chiral bifunctional catalyst into ordered mesoporous silica creates a synthetic analogue of enzymatic pockets, in which cooperative activation and nanoscale confinement act synergistically. By such confinement, reaction half-lives could be reduced by up to 97% in asymmetric 1,4-additions. Kinetic analyses attribute this enhancement to entropic advantages of confinement, while molecular dynamics simulations reveal narrowing of the catalyst’s conformational space closely paralleling the enzymatic preorganization as a molecular origin. Unlike enzymes, however, the mesoporous framework remains tunable, allowing linker length and pore size to systematically adjust reactivity. This work establishes confinement engineering as a modular strategy to design “unnatural active sites” that merge enzymatic efficiency with synthetic catalyst flexibility. It could thus bridge the gap between nature’s precision and the versatility of synthetic chemistry.