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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM043214-10
Application #
6138419
Study Section
Special Emphasis Panel (ZRG3-BMT (03))
Program Officer
Schwab, John M
Project Start
1991-01-01
Project End
2001-12-31
Budget Start
2000-01-01
Budget End
2000-12-31
Support Year
10
Fiscal Year
2000
Total Cost
$381,669
Indirect Cost
Name
Harvard University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
071723621
City
Cambridge
State
MA
Country
United States
Zip Code
02138
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
Park, Yongho; Schindler, Corinna S; Jacobsen, Eric N (2016) Enantioselective Aza-Sakurai Cyclizations: Dual Role of Thiourea as H-Bond Donor and Lewis Base. J Am Chem Soc 138:14848-14851

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