New chemical transformations enable the efficient construction of important molecules that are essential for biomedical research. The most powerful and efficient chemical reactions use catalysis to control reactivity and selectivity. The developments in catalytic methodology over the last quarter century have focused primarily on established reactivity patterns, such as carbonyl additions, cycloadditions, oxidations, and reductions. Many of these reactions follow principles predicted by electronegativity concepts. Umpolung reactions invert the normal reactivity of functional groups, thereby facilitating unconventional synthetic strategies. This transformation of an electron-poor species (electrophile) into an electron-rich reactant (nucleophile) is typically accomplished using stoichiometric reagents. Even though Umpolung reactions are important in organic synthesis, there are limited catalytic polarity reversal transformations with broad scope. Our central hypothesis is new approaches to catalysis using N-heterocyclic carbenes (NHCs) can significantly advance the field of chemical methodology and health relevant chemical synthesis. The specific goals of this proposal are: (1) Explore new carbene-catalyzed homoenolate equivalent reactions. The development of innovative formal cycloadditions, silylations, and alkylations will provide direct access to a large array of bioactive structures. (2) Develop new cooperative carbene catalysis processes. We have discovered that carbenes (Lewis bases) are compatible with Lewis acids to enhance selectivity and reactivity. The combination of Lewis acid or transition metal complexes with NHCs should provide new opportunities for chemical synthesis. (3) Investigate carbene catalysis-driven total syntheses. While there has been an explosion of NHC catalyzed reactions, few target syntheses have employed any of these new reactions as a key step. We will use an NHC-catalyzed desymmetrization as the key step in the synthesis of secologanin, a key secoiridoid natural product. Additionally, we will pursue a synthesis of arnamial using our NHC-catalyzed intramolecular Michael reaction. 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. These findings will ultimately lead to the development of a powerful collection of stereoselective and related strategies that are useful for synthesis.

Public Health Relevance

New chemical transformations are critical to advance and produce new molecular therapies. We are involved in the discovery and development of new catalytic chemical processes that access molecules via unconventional approaches. Our studies will fundamentally advance human health by providing innovative tactics and strategies to access many important classes of health relevant compounds.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM073072-08
Application #
8545179
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2006-09-20
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
8
Fiscal Year
2013
Total Cost
$271,882
Indirect Cost
$83,707
Name
Northwestern University at Chicago
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
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
Johnston, Ryne C; Cohen, Daniel T; Eichman, Chad C et al. (2014) Catalytic Kinetic Resolution of a Dynamic Racemate: Highly Stereoselective ?-Lactone Formation by N-Heterocyclic Carbene Catalysis. Chem Sci 5:1974-1982
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
Jang, Ki Po; Hutson, Gerri E; Johnston, Ryne C et al. (2014) Asymmetric homoenolate additions to acyl phosphonates through rational design of a tailored N-heterocyclic carbene catalyst. J Am Chem Soc 136:76-9
McCusker, Elizabeth O'Bryan; Scheidt, Karl A (2013) Enantioselective N-heterocyclic carbene catalyzed annulation reactions with imidazolidinones. Angew Chem Int Ed Engl 52:13616-20
Izquierdo, Javier; Orue, Ane; Scheidt, Karl A (2013) A dual Lewis base activation strategy for enantioselective carbene-catalyzed annulations. J Am Chem Soc 135:10634-7
Cohen, Daniel T; Cardinal-David, Benoit; Roberts, John M et al. (2011) NHC-catalyzed/titanium(IV)-mediated highly diastereo- and enantioselective dimerization of enals. Org Lett 13:1068-71
Cohen, Daniel T; Cardinal-David, Benoit; Scheidt, Karl A (2011) Lewis acid activated synthesis of highly substituted cyclopentanes by the N-heterocyclic carbene catalyzed addition of homoenolate equivalents to unsaturated ketoesters. Angew Chem Int Ed Engl 50:1678-82

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