The overarching goal of this proposal is the development of new reactions, and the reagents that control them, to generate enantioenriched organic compounds. These products are valuable precursors to more elaborate small molecules that are medicinal agents and/or more complex biologically active natural products. The proposed methods specifically target the concise synthesis of secondary amines, tertiary amines, and vicinal diamines as single stereoisomers. These methods are based on the development of bis (amidine) reagents that form chiral proton complexes (a polar ionic hydrogen bond) when a strong acid is added, or when used with acidic substrates. Exploration of a new variant is also described, which contains a single amidine in close proximity to a hydrogen bond donor (polar covalent hydrogen bond) when projected from the same chiral scaffold. These studies continue the successful application of bifunctional organocatalysts to the stereocontrolled creation of structural and functional motifs that, while common, are otherwise difficult to prepare using conventional alternatives. These studies also explore an entirely new mode of activation that involves chiral Bronsted acid mediated halogen- alkene reactions. A range of innovative multicomponent coupling reactions will be developed using chiral proton catalysis as the means to control enantioselection. These studies have the potential to impact small molecule synthesis, and ultimately the development of therapeutic agents. Moreover, the methods enable the metal-free production of functionally dense, single enantiomer (and diastereomer) organic compounds.

Public Health Relevance

The development of small molecule organocatalysts based on Bronsted acid catalysis, particularly those that enable the streamlined synthesis of complex small molecule therapeutics is an activity that ultimately promises low-cost medicines.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01GM084333-05
Application #
8697731
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Toda, Yasunori; Pink, Maren; Johnston, Jeffrey N (2014) Brønsted acid catalyzed phosphoramidic acid additions to alkenes: diastereo- and enantioselective halogenative cyclizations for the synthesis of C- and P-chiral phosphoramidates. J Am Chem Soc 136:14734-7
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Davis, Tyler A; Danneman, Michael W; Johnston, Jeffrey N (2012) Chiral proton catalysis of secondary nitroalkane additions to azomethine: synthesis of a potent GlyT1 inhibitor. Chem Commun (Camb) 48:5578-80
Shackleford, Jessica P; Shen, Bo; Johnston, Jeffrey N (2012) Discovery of competing anaerobic and aerobic pathways in umpolung amide synthesis allows for site-selective amide 18O-labeling. Proc Natl Acad Sci U S A 109:44-6
Johnston, Jeffrey N (2011) A chiral N-phosphinyl phosphoramide: another offspring for the sage phosphoric acid progenitor. Angew Chem Int Ed Engl 50:2890-1
Tomasiak, Thomas M; Archuleta, Tara L; Andrell, Juni et al. (2011) Geometric restraint drives on- and off-pathway catalysis by the Escherichia coli menaquinol:fumarate reductase. J Biol Chem 286:3047-56

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