The development of novel routes to stereochemically and structurally complex targets of biological interest remains of paramount importance. New strategies, bond disconnections, and catalysts that exploit standard functional groups in innovative ways each contribute to the overall goal of increased scope and efficiency, and decreased time and cost. Catalysis, the use of substoichiometric amounts of reagent, without the need for covalent attachment or pretreatment, carries with it the promise of greener, more efficient, more selective methods for synthesis. This proposal seeks to develop novel methods to use traditional functional groups in non-traditional ways, accessing hitherto unavailable bond disconnection strategies in an effort to greatly expand our toolkit. In the context of this research, we will apply these breakthroughs in order to prepare stermocurtisine and cephalomysin, two members of a family of biologically active agents whose activity spans from anti-fungal to anti-angiogenic and antitumor. We have further developed techniques for the selective and green synthesis of new amide bonds, ubiquitous functional groups in chemistry and biology. The specific goals of this research are as follows: 1) develop the catalytic enantioselective intermolecular Stetter reaction;2) explore cascade catalysis using simple precursors to generate densely functionalized products;3) pursue the rapid total synthesis of a variety of biologically important molecules using this approach;4) investigate the redox chemistry of 1-reducible aldehydes using nucleophilic carbenes. The long-term impact of this science is to enable chemists to rapidly assemble complex structures with high efficiency.

Public Health Relevance

One of the most significant barriers to health-related research involving small molecules is the rapid assembly of therapeutic agents. This proposal seeks to develop new methods to synthesize complex frameworks using easily accessible precursors with high efficiency.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM072586-08S1
Application #
8851917
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2005-09-05
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
8
Fiscal Year
2014
Total Cost
$91,918
Indirect Cost
$28,228
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
Flanigan, Darrin M; Romanov-Michailidis, Fedor; White, Nicholas A et al. (2015) Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes. Chem Rev 115:9307-87
White, Nicholas A; Rovis, Tomislav (2015) Oxidatively Initiated NHC-Catalyzed Enantioselective Synthesis of 3,4-Disubstituted Cyclopentanones from Enals. J Am Chem Soc 137:10112-5
Telitel, Sofia; Vallet, Anne-Laure; Flanigan, Darrin M et al. (2015) Influence of Electronic Effects on the Reactivity of Triazolylidene-Boryl Radicals: Consequences for the use of N-Heterocyclic Carbene Boranes in Organic and Polymer Synthesis. Chemistry 21:13772-7
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
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
Rubush, David M; Rovis, Tomislav (2014) Stereoselective Synthesis of Dioxolanes and Oxazolidines via a Desymmetrization Acetalization/Michael Cascade. Synlett 25:713-717
Ozboya, Kerem E; Rovis, Tomislav (2014) A Late Stage Strategy for the Functionalization of Triazolium-based NHC catalysts. Synlett 25:2665-2668
White, Nicholas A; Rovis, Tomislav (2014) Enantioselective N-heterocyclic carbene-catalyzed β-hydroxylation of enals using nitroarenes: an atom transfer reaction that proceeds via single electron transfer. J Am Chem Soc 136:14674-7
Wheeler, Philip; Vora, Harit U; Rovis, Tomislav (2013) Asymmetric NHC-catalyzed synthesis of α-fluoroamides from readily accessible α-fluoroenals. Chem Sci 4:1674-1679
Zhao, Xiaodan; Glover, Garrett S; Oberg, Kevin M et al. (2013) SNAr-Derived Decomposition By-products Involving Pentafluorophenyl Triazolium Carbenes. Synlett 24:

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