Asymmetric Catalysis with Chiral Brønsted Acids

Asymmetric catalysis with chiral Brønsted acids has emerged as a versatile strategy for the enantioselective synthesis of complex molecules. This approach exploits chiral proton donors—often BINOL-derived phosphoric acids or disulfonimides—to activate substrates through hydrogen bonding or protonation, while simultaneously inducing a chiral environment that directs stereochemical outcome. Recent advances in catalyst design, mechanistic understanding and computational modelling have broadened both substrate scope and practical applicability. Super-strong and spatially confined acid catalysts now enable transformations of traditionally challenging substrates, including purely aliphatic hydrocarbons and unfunctionalised ketones. Concurrently, fundamental studies on noncovalent interactions, such as electrostatic and hydrogen-bonding effects in transition states, have provided predictive models for stereocontrol and guided the development of more efficient catalyst frameworks. Collectively, these advances underscore the global significance of chiral Brønsted acid catalysis in generating enantioenriched building blocks for pharmaceutical, agrochemical and materials applications.

Research from Nature Portfolio

Recent studies have demonstrated that super-strong, confined imidodiphosphorimidate catalysts can mediate asymmetric Wagner–Meerwein rearrangements of purely aliphatic substrates, affording cycloalkene products with exceptional regio- and enantioselectivity. By tailoring the steric and electronic environment of the acid pocket, unbiased hydrocarbons undergo cationic shifts previously accessible only to substrates bearing heteroatoms or aromatic rings. Another milestone is the development of confined organocatalysts for the stereoselective cyanosilylation of both aromatic and aliphatic ketones, achieving enantiomeric ratios comparable to those of engineered enzymes. These catalysts feature tailored pockets that stabilise key silylium intermediates and mimic enzyme-like lock-and-key binding, enabling highly enantioselective transformation of small, unbiased ketones at low catalyst loadings.

Asymmetric Catalysis with Chiral Brønsted Acids publication trend

The graph below shows the total number of articles in asymmetric catalysis with chiral brønsted acids across all publications each year (not limited to Nature Index journals).

Technical terms

Asymmetric catalysis: Catalytic process that converts prochiral or racemic substrates into enantioenriched products by preferential formation of one enantiomer.

Chiral Brønsted acid: Optically active proton donor catalyst that induces stereocontrol through hydrogen bonding or protonation.

Enantioselectivity: Measure of the preferential formation of one enantiomer over the other, often expressed as enantiomeric ratio (e.r.).

Confined acid catalyst: Catalyst bearing a sterically constrained active site that enforces precise substrate orientation in the transition state.

Electrostatic interaction: Noncovalent force between charged or polar groups that can stabilise transition states and influence stereochemical outcome.

Noncovalent interaction: Weak bonding (e.g. hydrogen bonding, dispersion) critical for substrate activation and chiral recognition.

References

1. Catalytic asymmetric cationic shifts of aliphatic hydrocarbons. Nature (2024).
2. Organocatalytic stereoselective cyanosilylation of small ketones. Nature (2022).
3. Electrostatic Interactions in Asymmetric Organocatalysis. Accounts of Chemical Research (2023).
4. Asymmetric Catalytic Friedel–Crafts Reactions of Unactivated Arenes. Journal of the American Chemical Society (2023).
5. Strong and Confined Acids Catalyze Asymmetric Intramolecular Hydroarylations of Unactivated Olefins with Indoles. Journal of the American Chemical Society (2021).