Significant portions of important molecules involved in the biochemistry of life have "handedness," i.e. they are primarily found in one nonsuperimposible mirror image form. Additionally, the majority of drugs and drug candidates also have handedness (chirality) and all stereoisomers of these compounds are normally synthesized and evaluated for biological activity. Due to the chirality of nature, the mirror image forms of drug candidates can have vastly differing biological effects. One approach to the synthesis of chiral molecules that is growing steadily in usage is the application of versatile, stereoselective catalytic methodology in key steps where stereocontrol is required. Organocatalysis, the use of small organic (non-metal based) molecules as catalysts is an attractive alternative to traditional metal-based catalysis. This approach has found a number of recent successes and the continued evaluation of organocatalytic-based chemistry is clearly a worthwhile endeavor. Since 2004 the use of chiral phosphoric acid-based organocatalysis has been shown to provide for excellent stereoselectivity in a growing number of reactions. Our efforts have been involved in the development of new methodology where chiral phosphoric acids can be applied stereoselectively.
The specific aims of this proposal are divided into the design, analysis, and refinement of a number of new reactions whereby chiral phosphoric acids can be efficient, stereoselective catalysts. The potential health-related utility of the newly created chiral products are also described in each new reaction study.

Public Health Relevance

The chemistry described in this proposal addresses a fundamental, important aspect of modern synthesis -- the control of three-dimensional (3-D) chemical structure. The vast majority of the "molecules of life" and most pharmaceutical drugs have specific 3-D structure that must be controlled for efficient, low cost synthesis. Therefore methods that allow for this control are very important for public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM082935-05
Application #
8299496
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2008-09-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$254,277
Indirect Cost
$77,859
Name
University of South Florida
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33612
Ingle, Gajendrasingh; Mormino, Michael G; Antilla, Jon C (2014) Lithium BINOL phosphate catalyzed desymmetrization of meso-epoxides with aromatic thiols. Org Lett 16:5548-51
Nimmagadda, Sri Krishna; Zhang, Zuhui; Antilla, Jon C (2014) Asymmetric one-pot synthesis of 1,3-oxazolidines and 1,3-oxazinanes via hemiaminal intermediates. Org Lett 16:4098-101
Li, Guilong; Liang, Tao; Wojtas, Lukasz et al. (2013) An asymmetric Diels-Alder reaction catalyzed by chiral phosphate magnesium complexes: highly enantioselective synthesis of chiral spirooxindoles. Angew Chem Int Ed Engl 52:4628-32
Jain, Pankaj; Wang, Hao; Houk, Kendall N et al. (2012) Bronsted acid catalyzed asymmetric propargylation of aldehydes. Angew Chem Int Ed Engl 51:1391-4
Zheng, Wenhua; Zhang, Zuhui; Kaplan, Matthew J et al. (2011) Chiral calcium VAPOL phosphate mediated asymmetric chlorination and Michael reactions of 3-substituted oxindoles. J Am Chem Soc 133:3339-41
Larson, Shawn E; Li, Guilong; Rowland, Gerald B et al. (2011) Catalytic asymmetric aza-Darzens reaction with a vaulted biphenanthrol magnesium phosphate salt. Org Lett 13:2188-91
Ingle, Gajendrasingh K; Mormino, Michael G; Wojtas, Lukasz et al. (2011) Chiral phosphoric acid-catalyzed addition of thiols to N-acyl imines: access to chiral N,S-acetals. Org Lett 13:4822-5
Zhang, Zuhui; Zheng, Wenhua; Antilla, Jon C (2011) Highly enantioselective catalytic benzoyloxylation of 3-aryloxindoles using chiral VAPOL calcium phosphate. Angew Chem Int Ed Engl 50:1135-8
Ingle, Gajendrasingh K; Liang, Yuxue; Mormino, Michael G et al. (2011) Chiral magnesium BINOL phosphate-catalyzed phosphination of imines: access to enantioenriched ýý-amino phosphine oxides. Org Lett 13:2054-7
Zhang, Zuhui; Jain, Pankaj; Antilla, Jon C (2011) Asymmetric reduction of ketones by phosphoric acid derived catalysts. Angew Chem Int Ed Engl 50:10961-4

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