The Arthur C. Cope Award-winning research that bridges enzymatic and small-molecule catalysis
In the world of organic chemistry, few honors carry the prestige of the Arthur C. Cope Award, a prize that recognizes outstanding achievement in the field. When Eric N. Jacobsen, the Sheldon Emery Professor of Chemistry at Harvard University, received this award in 2016, it celebrated a body of work that has fundamentally reshaped how chemists think about building molecules. The official citation honored his "contributions, both fundamental and practical, to the fields of asymmetric catalysis and organic synthesis"—a formal description for truly transformative science that has bridged academic discovery and practical application 1 .
What makes Jacobsen's work particularly compelling is his driving scientific goal: "I am very excited about connecting the worlds of small-molecule and enzymatic catalysis in meaningful ways." This quest to harness the powerful strategies of nature's own catalysts—enzymes—and translate them into accessible chemical tools has been the hallmark of his career 1 . His colleague Stephen L. Buchwald of MIT summarized the impact well: "Jacobsen's catalyst systems have been used widely in industry and academia, and the underlying concepts he has elucidated now serve to guide research throughout the world" 1 . This article explores the key concepts, innovative methodologies, and future directions of Jacobsen's award-winning research.
Recognized in 2016 for transformative contributions to asymmetric catalysis
Sheldon Emery Professor of Chemistry leading innovative research
For decades, the prevailing strategy in creating chiral catalysts—molecules that can bias chemical reactions toward producing one mirror-image form of a product over another—relied heavily on steric effects. Think of this as the "bully" approach: designers created catalysts with bulky groups that physically blocked approaching molecules from certain directions, effectively slowing down or preventing the formation of undesired products. While this approach produced effective catalysts, it had limitations, particularly in achieving the exquisite selectivity that natural enzymes routinely accomplish.
In contrast to the synthetic "bully" approach, enzymes—nature's master catalysts—operate on a different principle. They achieve phenomenal rate acceleration and perfect selectivity not by blocking unwanted pathways, but by actively stabilizing the preferred transition state through networks of attractive, noncovalent interactions (NCIs) 8 . These interactions—including hydrogen bonding, Coulombic attraction, aromatic interactions, and hydrophobic effects—are individually weak (typically <5 kcal/mol), but when operating cooperatively in an enzymatic active site, they can induce dramatic rate accelerations and perfect selectivity 8 .
| Strategy | Mechanism | Primary Approach | Inspiration |
|---|---|---|---|
| Traditional Steric Control | Destabilizes unwanted pathways | Physical blocking of approaching molecules | Synthetic design principles |
| Noncovalent Catalysis | Stabilizes desired pathway | Attractive interactions with transition state | Enzyme mechanisms |
| Enzyme Catalysis | Stabilizes desired pathway | Cooperative networks of noncovalent interactions | Biological evolution |
A compelling example of Jacobsen's NCC approach can be found in his group's study of thiourea-catalyzed ring opening of episulfonium ions with indoles 8 . This reaction presented an ideal system for investigating cation-π interactions—attractive forces between electron-rich aromatic systems and positively charged ions.
The researchers designed a series of chiral thiourea catalysts featuring an arylpyrrolidine–tert-leucine motif with systematically varied aromatic substituents. The experimental design was elegant in its logic: if cation-π interactions between the catalyst's aromatic group and the positively charged sulfonium ion in the substrate were important for transition state stabilization, then increasing the strength of this interaction should lead to both higher reaction rates and improved enantioselectivity 8 .
Synthesized catalysts with different aromatic substituents (phenyl, naphthyl, phenanthryl) known to have varying abilities to participate in cation-π interactions 8 .
For each catalyst, they carefully measured both the reaction rate and the enantioselectivity (the ratio of mirror-image products) 8 .
To directly probe the proposed cation-π interaction, they used NMR to observe whether the thiourea catalysts caused characteristic shifts in the proton resonances of a model sulfonium ion compound 8 .
| Catalyst | Aromatic Group | Enantioselectivity (e.r.) | Relative Rate (kcat,maj) |
|---|---|---|---|
| 1.1a | None (control) | Baseline | Baseline |
| 1.1b | Phenyl | Moderate improvement | Moderate increase |
| 1.1c | Naphthyl | Significant improvement | Significant increase |
| 1.1e | Phenanthryl | Highest improvement | Highest increase |
Catalysts with expanded aromatic systems showed simultaneously higher enantioselectivity and faster reaction rates 8 .
Improved selectivity correlated with selective increases in the rate of the major pathway while the minor pathway remained largely unaffected 8 .
The strength of cation-π interaction correlated linearly with the rate constant for the major pathway 8 .
The importance of these findings extends far beyond this specific reaction. They provide experimental validation for a catalytic strategy that mimics nature's approach: using attractive interactions to achieve both rate acceleration and selectivity simultaneously. This represents a paradigm shift from the traditional view that selectivity must come at the cost of reactivity.
Jacobsen's work has helped establish several key concepts and tools that now form the essential toolkit for researchers in asymmetric catalysis.
Function: Act as chiral controllers through directional noncovalent interactions
Enable catalysis of reactions without traditional functional groups
Function: Provide stabilizing attraction between electron-rich aromatics and positively charged species
Exemplify how subtle attractive forces can dictate reaction pathways
Function: Recognize and activate anionic species through complementary hydrogen bonding
Opens pathways to catalyze traditionally challenging transformations
Function: Uses statistical analysis and computational modeling to refine catalyst structures
Accelerates catalyst design beyond traditional intuition-based approaches
Function: Combines multiple catalytic entities for enhanced function
Mimics the multicomponent active sites of enzymes
Function: Creates cooperative interaction networks for enhanced selectivity
Mimics the cooperative interactions found in enzyme active sites
Eric Jacobsen's Arthur C. Cope Award-winning research represents more than just a collection of new chemical reactions—it embodies a fundamental shift in how chemists design molecular transformations. By demonstrating that attractive noncovalent interactions can provide powerful control over chemical reactivity and selectivity, his work has helped bridge the historical divide between synthetic chemistry and enzymatic catalysis.
This ambition—to create chemical tools that combine the broad scope of synthetic systems with the precision and efficiency of enzymes—continues to inspire a new generation of chemists. As research in this area progresses, we move closer to a future where chemical synthesis is not only more efficient and selective, but more sustainable and biomimetic, truly representing the best of what chemistry can achieve when it learns from nature's billions of years of research and development.