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. 2026 Jan 14;148(1):1306-1315.
doi: 10.1021/jacs.5c17872. Epub 2025 Dec 27.

Attractive Noncovalent Interactions versus Steric Confinement in Asymmetric Supramolecular Catalysis

Cristina V Craescu  1   2 , Colton D David  1   2 , Elizabeth D Heafner  1   2 , Kenneth N Raymond  1   2 , Robert G Bergman  1   2 , F Dean Toste  1   2
Affiliations

Attractive Noncovalent Interactions versus Steric Confinement in Asymmetric Supramolecular Catalysis

Cristina V Craescu et al. J Am Chem Soc. .

Abstract

The remarkable catalytic performance of enzymes stems from their ability to engage in precise noncovalent interactions (NCIs) within a sterically confined space. Supramolecular catalysis seeks to emulate and understand these strategies through the rational design of simple and controlled catalyst microenvironments. While both steric confinement and attractive interactions have been invoked as key to host activity, their relative contribution to rate enhancement and selectivity, as well as potential trade-offs, remains an outstanding question. Here, we address this question by systematically comparing two metal-organic supramolecular catalysts, which differ in the strength of their attractive noncovalent interactions and in their cavity volume. Our findings reveal that the catalyst with the larger cavity, and with stronger available NCIs, exhibits both significant rate acceleration (100-fold) and enhanced enantioselectivity (84% vs 14% ee) in a model ketone reduction compared to its smaller analogue. Mechanistic analysis, binding competition experiments, and computational modeling indicate that these differences predominantly stem from stabilizing noncovalent interactions in the larger catalyst, a result that challenges existing steric-based models of supramolecular stereoinduction. Understanding the governing factors of asymmetric induction and rate acceleration in supramolecular hosts will undoubtedly inform future catalyst design.

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Figures

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Modes of enantioinduction for small-molecule catalysts and enzymes. (A) Minimizing steric repulsion. (B) Maximizing attractive NCIs. (C) Hybrid model of A and B. This figure was created with BioRender.com. (D) The goals of this work: investigating the trade-off between confinement effects and attractive NCIs for asymmetric supramolecular host catalysis.
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(A) Ga4L6 12– supramolecular hosts 1 and 2. (B) Control experiments and reaction screening.
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Yield and % ee achieved in the reduction of ketones a–i with both host catalysts (*reaction stopped after 24 h).
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(A) Rate acceleration and KIE experiments. (B) Proposed mechanism for host-catalyzed reductions. (C) Eyring analysis on reaction rates with 1 and 2. (D) Binding competition experiments.
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(A) Reaction conditions and selected substrates for Eyring analysis on selectivity. (B) Extracted differential activation parameters for host 1. (C) Extracted differential activation parameters using host 2. (D) Correlation between |ΔΔH ⧧| and calculated interaction enthalpy.
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