This program has as its objectives the discovery, development, application, and mechanistic elucidation of selective catalytic reactions of use in organic synthesis. In particular, the focus of this research is on catalytic reactions that generate optically active products from achiral or racemic starting materials. The critical importance of absolute stereochemistry in drug function provides the major driving force behind this effort. The principal approach we take to the development of chiral catalysts involves the design of synthetically accessible chiral coordination compounds. A variety of sterically and electronically tunable chiral Schiff base ligands serve as templates for complexes of catalytically-active first- and second-row transition metals and main group metals. One important class of these complexes, the so-called salen complexes, has already proven effective for highly-enantioselective catalytic epoxidation of conjugated olefins and ring-opening of epoxides. Through a combination of aggressive screening of different types of chiral coordination complexes and mechanistically-driven design of specific bimetallic systems, this proposal outlines an approach to the discovery of clean, practical, and enantioselective catalysts for an extremely wide range of reactions between nucleophiles and electrophiles. In a critical facet of this research, we also propose to apply these new methods to a broad assortment of synthetic targets. We outline strategies for the practical generation of valuable chiral building blocks such as epoxides and aziridines; the efficient synthesis of the pharmaceutically-relevant compounds VX-478 and biotin; the total synthesis of muconin, a natural product of moderate complexity; and the solid phase synthesis of structurally and functionally diverse and pharmacologically-revelant libraries. By such effort, our goal is to heighten the relevance and utility of the synthetic methods we discover to bioorganic and biomedical research.
| Wendlandt, Alison E; Vangal, Prithvi; Jacobsen, Eric N (2018) Quaternary stereocentres via an enantioconvergent catalytic SN1 reaction. Nature 556:447-451 |
| Zhou, Biying; Haj, Moriana K; Jacobsen, Eric N et al. (2018) Mechanism and Origins of Chemo- and Stereoselectivities of Aryl Iodide-Catalyzed Asymmetric Difluorinations of ?-Substituted Styrenes. J Am Chem Soc 140:15206-15218 |
| Kwan, Eugene E; Zeng, Yuwen; Besser, Harrison A et al. (2018) Concerted nucleophilic aromatic substitutions. Nat Chem 10:917-923 |
| Mennie, Katrina M; Banik, Steven M; Reichert, Elaine C et al. (2018) Catalytic Diastereo- and Enantioselective Fluoroamination of Alkenes. J Am Chem Soc 140:4797-4802 |
| Banik, Steven M; Levina, Anna; Hyde, Alan M et al. (2017) Lewis acid enhancement by hydrogen-bond donors for asymmetric catalysis. Science 358:761-764 |
| Klausen, Rebekka S; Kennedy, C Rose; Hyde, Alan M et al. (2017) Chiral Thioureas Promote Enantioselective Pictet-Spengler Cyclization by Stabilizing Every Intermediate and Transition State in the Carboxylic Acid-Catalyzed Reaction. J Am Chem Soc 139:12299-12309 |
| Banik, Steven M; Mennie, Katrina M; Jacobsen, Eric N (2017) Catalytic 1,3-Difunctionalization via Oxidative C-C Bond Activation. J Am Chem Soc 139:9152-9155 |
| Park, Yongho; Harper, Kaid C; Kuhl, Nadine et al. (2017) Macrocyclic bis-thioureas catalyze stereospecific glycosylation reactions. Science 355:162-166 |
| Kwan, Eugene E; Park, Yongho; Besser, Harrison A et al. (2017) Sensitive and Accurate 13C Kinetic Isotope Effect Measurements Enabled by Polarization Transfer. J Am Chem Soc 139:43-46 |
| Ford, David D; Lehnherr, Dan; Kennedy, C Rose et al. (2016) On- and Off-Cycle Catalyst Cooperativity in Anion-Binding Catalysis. J Am Chem Soc 138:7860-7863 |
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