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 researc, we will apply these strategies to the formation of lactams, common structural features across many families of biologically active molecules. The specific goals of this research are as follows: 1) Develop asymmetric intermolecular Stetter reactions involving less activated Michael acceptors;2) Control stereochemistry at the beta position via the homoenolate reactivity pathway;3) Investigate oxidative pathways of enal activation;4) Control oxidatively initiated [3+2]-type annulation of enals leading to cyclopentanone products. 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 #
2R01GM072586-09
Application #
8731604
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2005-09-05
Project End
2018-05-31
Budget Start
2014-09-05
Budget End
2015-05-31
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Fort Collins
State
CO
Country
United States
Zip Code
80521
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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