Expansion of current reactivity umpolung of aldehydes catalyzed by chiral nucleophilic carbenes promises to reveal new reactivity and lead to novel bond disconnections relevant to the synthesis of a number of biologically significant targets. Reaction with a nucleophilic carbene transforms an electrophilic aldehyde into a nuclephile acyl anion equivalent which can be intercepted with a variety of electrophiles, providing a novel means of forming carbon-carbon bonds. If conducted using a chiral nucleophilic carbene as catalyst, we expect to induce asymmetry into the subsequent bond-forming event. These reactions will be applied to the synthesis of challenging, biologically active natural products. The specific goals of this research are as follows: 1) apply the asymmetric Stetter reaction to alkaloidal substrates to generate novel architectures and develop domino processes using these approaches; 2) develop the diastereoselective asymmetric Stetter reaction, which will be able to effect the formation of multiple contiguous stereocenters in a single operation; 3) use the asymmetric Stetter reaction in the synthesis of the angiogenesis inhibitor azaspirene; 4) design and execute a rapid approach to the stereochemically complex alkaloid asparagamine using the diastereoselective asymmetric Stetter reaction; 5) apply the asymmetric Stetter reaction to the synthesis of crinamine 1 and viridin using orthoquinones and dienones as electrophiles; 6) explore aldehyde umpolung redox chemistry by exploiting the large negative oxidation potential of the nucleophilic alkene and internal redox systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM072586-04
Application #
7488917
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Schwab, John M
Project Start
2005-09-05
Project End
2010-04-30
Budget Start
2008-09-01
Budget End
2010-04-30
Support Year
4
Fiscal Year
2008
Total Cost
$209,968
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Chen, Dian-Feng; Rovis, Tomislav (2017) N-Heterocyclic Carbene and Chiral Brønsted Acid Cooperative Catalysis for a Highly Enantioselective [4+2] Annulation. Synthesis (Stuttg) 49:293-298
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White, Nicholas A; Ozboya, Kerem E; Flanigan, Darrin M et al. (2014) Rapid Construction of (-)-Paroxetine and (-)-Femoxetine via N-Heterocyclic Carbene Catalyzed Homoenolate Addition to Nitroalkenes. Asian J Org Chem 3:442-444
White, Nicholas A; Rovis, Tomislav (2014) Enantioselective N-heterocyclic carbene-catalyzed ?-hydroxylation of enals using nitroarenes: an atom transfer reaction that proceeds via single electron transfer. J Am Chem Soc 136:14674-7
Hsieh, Sheng-Ying; Wanner, Benedikt; Wheeler, Philip et al. (2014) Stereoelectronic basis for the kinetic resolution of N-heterocycles with chiral acylating reagents. Chemistry 20:7228-31
Rubush, David M; Rovis, Tomislav (2014) Stereoselective Synthesis of Dioxolanes and Oxazolidines via a Desymmetrization Acetalization/Michael Cascade. Synlett 25:713-717

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