New selective chemical reactions are essential components to advance biology and medicine. The most powerful and efficient chemical reactions commonly use catalysis to control reactivity and selectivity. The discovery of new catalyst concepts with broad utility beyond established reactivity can greatly impact biomedical research by providing unconventional and efficient access to compounds with biological activity. The long-term goal of our catalysis research is to develop new Lewis base-catalyzed transformations with direct application to the syntheses and investigation of bioactive molecules. Our development of N-heterocyclic carbenes (NHCs) as catalysts will continue to uncover new approaches and generate important new concepts of organocatalysis. Our central hypothesis is that new discoveries in the field of carbene catalysis will significantly advance chemical synthesis, bioorganic chemistry and medicine. The specific goals of this proposal are: (1) Develop new cooperative carbene catalysis processes. N-heterocyclic carbenes (Lewis bases) have been discovered to be compatible with Lewis acids to enhance selectivity and reactivity. The combination of Lewis acids, hydrogen bond donors or transition metal complexes with NHCs will provide new opportunities for chemical synthesis; (2) explore azolium-based activation for substitution reactions; (3) investigate carbene catalysis-driven total syntheses. While there has been an explosion of new NHC catalyzed reactions, few target syntheses have employed any of these new reactions as a key step. We will use an NHC-catalyzed intramolecular Michael reaction as the key step in the synthesis of arnamial and related natural products. In addition, a trans-annular NHC-catalyzed lactone formation will be pursued as the main approach to synthesize repin, a potent cytotoxin. Our research in generating new reactivity using organocatalysis will establish new approaches for the efficient synthesis of molecules. This research will also provide important knowledge about nucleophile-catalyzed polarity reversal reactions and cooperative catalysis. These findings will ultimately lead to the development of a powerful collection of stereoselective and related strategies that are useful for medically relevant synthesis and thus further the mission of NIGMS.

Public Health Relevance

New catalytic transformations are critical to advance and produce new molecular probes and therapies. We are involved in the discovery and development of new stereoselective processes that access molecules via unconventional approaches though the combination of unique activation modes. These cooperative catalysis studies will fundamentally advance human health by providing innovative tactics and strategies to access many important classes of health relevant compounds.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Lees, Robert G
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Northwestern University at Chicago
Schools of Arts and Sciences
United States
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Hovey, M Todd; Cohen, Daniel T; Walden, Daniel M et al. (2017) A Carbene Catalysis Strategy for the Synthesis of Protoilludane Natural Products. Angew Chem Int Ed Engl 56:9864-9867
Murauski, Kathleen J R; Walden, Daniel M; Cheong, Paul Ha-Yeon et al. (2017) A Cooperative Ternary Catalysis System for Asymmetric Lactonizations of ?-Ketoesters. Adv Synth Catal 359:3713-3719
Sharma, Hayden A; Todd Hovey, M; Scheidt, Karl A (2016) Azaindole synthesis through dual activation catalysis with N-heterocyclic carbenes. Chem Commun (Camb) 52:9283-6
Wang, Michael H; Cohen, Daniel T; Schwamb, C Benjamin et al. (2015) Enantioselective ?-Protonation by a Cooperative Catalysis Strategy. J Am Chem Soc 137:5891-4
Lee, Anna; Scheidt, Karl A (2015) N-Heterocyclic carbene-catalyzed enantioselective annulations: a dual activation strategy for a formal [4+2] addition for dihydrocoumarins. Chem Commun (Camb) 51:3407-10
Cohen, Daniel T; Johnston, Ryne C; Rosson, Nicholas T et al. (2015) Functionalized cyclopentenes through a tandem NHC-catalyzed dynamic kinetic resolution and ambient temperature decarboxylation: mechanistic insight and synthetic application. Chem Commun (Camb) 51:2690-3
Liu, Kun; Hovey, M Todd; Scheidt, Karl A (2014) A Cooperative N-Heterocyclic Carbene/Palladium Catalysis System. Chem Sci 5:4026-4031
Lee, Anna; Younai, Ashkaan; Price, Christopher K et al. (2014) Enantioselective annulations for dihydroquinolones by in situ generation of azolium enolates. J Am Chem Soc 136:10589-92
Lee, Anna; Scheidt, Karl A (2014) A cooperative N-heterocyclic carbene/chiral phosphate catalysis system for allenolate annulations. Angew Chem Int Ed Engl 53:7594-8
Hovey, M Todd; Check, Christopher T; Sipher, Alexandra F et al. (2014) N-heterocyclic-carbene-catalyzed synthesis of 2-aryl indoles. Angew Chem Int Ed Engl 53:9603-7

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