New Catalytic Systems for Stereoselective C?H Amination Nitrogen-containing compounds are of central importance in biology and medicine. The development of synthetic methodologies that allow for selective conversion of omnipresent C?H bonds into valuable amine functional groups promises to transform the art and practice of organic synthesis and should lead to many new applications. Among different approaches, 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 organic compounds through stereoselective C?N bond formation. It serves as a useful tool for the design and synthesis of biologically and pharmaceutically important chiral amine molecules. While considerable progress has been made for C?H amination by existing catalytic systems with the widely-used reagent PhI=NTs and related iminoiodane derivatives as nitrene sources, important challenges remain in the field that validate the need to identify more effective nitrene sources in conjunction with the development of fundamentally new metal catalysts for C?H amination. Guided by the concept of metalloradical catalysis (MRC), this research project is directed toward the development of new catalytic systems for stereoselective C?H amination reactions. As stable metalloradicals, cobalt(II) complexes of porphyrins [Co(Por)] have been shown to function as a unique class of catalysts for C?H amination through stepwise radical mechanism. Supported by porphyrin ligands bearing amide functionalities, the Co(II)-based MRC has been shown to be particularly effective in activating various azides for radical amination of different types of C?H bonds, leading to formation of amine derivative with effective control of reactivity and selectivity. In this new proposal, we will focus on the utilization of cobalt(II) complexes of chiral porphyrins [Co(II)(Por*)] as chiral metalloradical catalysts to advance the enantioselective C?H amination reactions for stereoselective synthesis of optically active amine derivatives, including amino acids, diamines, amino alcohols and N-heterocycles. We hope these studies will ultimately lead to the development of Co(II)-based new catalytic systems for stereoselective C?H amination reactions that can be generally applied toward practical synthesis of biologically important nitrogen-containing natural products and pharmaceutically interesting compounds.

Public Health Relevance

New Catalytic Systems for Stereoselective C?H Amination 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. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM098777-08
Application #
9677645
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Yang, Jiong
Project Start
2012-04-01
Project End
2020-02-29
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Boston College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
045896339
City
Chestnut Hill
State
MA
Country
United States
Zip Code
02467
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Lu, Hongjian; Lang, Kai; Jiang, Huiling et al. (2016) Intramolecular 1,5-C(sp3)-H Radical Amination via Co(II)-Based Metalloradical Catalysis for Five-Membered Cyclic Sulfamides. Chem Sci 7:6934-6939
Cui, Xin; Xu, Xue; Jin, Li-Mei et al. (2015) Stereoselective Radical C-H Alkylation with Acceptor/Acceptor-Substituted Diazo Reagents via Co(II)-Based Metalloradical Catalysis. Chem Sci 6:1219-1224
Subbarayan, Velusamy; Jin, Li-Mei; Xin, Cui et al. (2015) Room Temperature Activation of Aryloxysulfonyl Azides by [Co(II)(TPP)] for Selective Radical Aziridination of Alkenes via Metalloradical Catalysis. Tetrahedron Lett 56:3431-3434
Goswami, Monalisa; Lyaskovskyy, Volodymyr; Domingos, Sérgio R et al. (2015) Characterization of Porphyrin-Co(III)-'Nitrene Radical' Species Relevant in Catalytic Nitrene Transfer Reactions. J Am Chem Soc 137:5468-79
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Lu, Hongjian; Li, Chaoqun; Jiang, Huiling et al. (2014) Chemoselective amination of propargylic C(sp³)-H bonds by cobalt(II)-based metalloradical catalysis. Angew Chem Int Ed Engl 53:7028-32
Paul, Nanda D; Mandal, Sutanuva; Otte, Matthias et al. (2014) Metalloradical approach to 2H-chromenes. J Am Chem Soc 136:1090-6
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
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

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