The development of general and efficient chemical reactions provides the necessary tools for the design and synthesis of biologically and pharmaceutically important molecules. There has been a growing emphasis on developing practical methodologies for the synthesis of enantiomerically pure compounds, since enantiomeric isomers often exhibit different biological activities. Compared to a racemic mixture, the use of an enantiomerically pure compound improves the desired activity and reduces toxicity in addition to other clinical benefits. Consequently, the Food and Drug Administration requires the evaluation of both enantiomers of new chiral drugs before they can be submitted for approval. Among different approaches for preparing chiral non-racemic molecules, transition metal-based asymmetric catalysis offers promise for the development of cost-effective and environmentally benign methods. In today's pharmaceutical industry, where the market share of single enantiomer chiral drugs continues to rise, there are growing demands for new powerful stereoselective catalytic processes. Catalytic C-H amination via nitrene insertion represents one of the most important classes of chemical transformations. This type of catalytic nitrene transfer process provides a direct and general approach for the functionalization of C-H bonds in abundant hydrocarbons through stereoselective C-N bond formation. It serves as a valuable tool for the design and synthesis of biologically and pharmaceutically important chiral amine molecules. This research project is directed toward the development of new catalytic systems for stereoselective C-H amination reactions. For this particular proposal, we will focus on the utilization of cobalt(II) chiral porphyrin complexes [Co(II)(Por*)] as a class of new chiral catalyts to advance the enantioselective C-H amination reactions for stereoselective synthesis of valuable diamines and amino alcohols. These new catalytic methods will be applied to the stereoselective synthesis of biologically and pharmaceutically interesting nitrogen-containing molecules, including optically active amino acid-, diamino acid-, and fluoridated amino acid-based compounds that are antibiotics or tumor imaging agents. We hope these studies will ultimately lead to the development of practical Co(II)-based catalytic systems for general C-H amination reactions that can be successfully applied toward the stereoselective synthesis of biologically important natural products and pharmaceutically interesting small molecules.

Public Health Relevance

This proposed research is directed toward the development of general and efficient chemical reactions that will provide the necessary tools for the design and synthesis of biologically and pharmaceutically important molecules. There has been a growing emphasis to develop practical methodologies for the synthesis of enantiomerically pure compounds, since enantiomeric isomers often exhibit different biological activities. Compared to a racemic mixture, the use of an enantiomerically pure compound improves the desired activity and reduces toxicity, in addition to other clinical benefits. Consequently, the Food and Drug Administration requires the evaluation of both enantiomers of new chiral drugs before they can be submitted for approval.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM098777-01A1
Application #
8297064
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2012-04-01
Project End
2017-02-28
Budget Start
2012-04-01
Budget End
2013-02-28
Support Year
1
Fiscal Year
2012
Total Cost
$255,145
Indirect Cost
$65,145
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
Paul, Nanda D; Mandal, Sutanuva; Otte, Matthias et al. (2014) Metalloradical approach to 2H-chromenes. J Am Chem Soc 136:1090-6
Jin, Chunyang; Decker, Ann M; Huang, Xi-Ping et al. (2014) Synthesis, pharmacological characterization, and structure-activity relationship studies of small molecular agonists for the orphan GPR88 receptor. ACS Chem Neurosci 5:576-87
Jin, Li-Mei; Lu, Hongjian; Cui, Yuan et al. (2014) Selective Radical Amination of Aldehydic C(sp(2))-H Bonds with Fluoroaryl Azides via Co(II)-Based Metalloradical Catalysis: Synthesis of N-Fluoroaryl Amides from Aldehydes under Neutral and Nonoxidative Conditions. Chem Sci 5:2422-2427
Lu, Hongjian; Li, Chaoqun; Jiang, Huiling et al. (2014) Chemoselective amination of propargylic C(spĀ³)-H bonds by cobalt(II)-based metalloradical catalysis. Angew Chem Int Ed Engl 53:7028-32
Ruppel, Joshua V; Cui, Xin; Xu, Xue et al. (2014) Stereoselective Intramolecular Cyclopropanation of ?-Diazoacetates via Co(II)-Based Metalloradical Catalysis. Org Chem Front 1:515-520
Xu, Xue; Zhu, Shifa; Cui, Xin et al. (2013) Cobalt(II)-catalyzed asymmetric olefin cyclopropanation with *-ketodiazoacetates. Angew Chem Int Ed Engl 52:11857-61
Paul, Nanda D; Chirila, Andrei; Lu, Hongjian et al. (2013) Carbene radicals in cobalt(II)-porphyrin-catalysed carbene carbonylation reactions; a catalytic approach to ketenes. Chemistry 19:12953-8
Jin, Li-Mei; Xu, Xue; Lu, Hongjian et al. (2013) Effective synthesis of chiral N-fluoroaryl aziridines through enantioselective aziridination of alkenes with fluoroaryl azides. Angew Chem Int Ed Engl 52:5309-13