Heterocyclic rings are ubiquitous motifs in drug molecules, and their functionalization primarily relies on ring formation from acyclic precursors or transition metal-catalyzed cross-coupling strategies. We propose to develop site-selective C-H functionalizations of readily available and simple heterocycles, such as pyridine, to access complex heterocycles for the preparation of pharmacologically important molecules. Despite recent developments, transition metal-catalyzed C-H functionalization reactions currently rely on chelating functional groups to direct selective metalation and subsequent functionalization. This directing group strategy is not suitable for pyridine-like heterocyclic substrates due to both the poor-electron nature of the aromatic ring and the strong ?-coordination of the nitrogen lone pair with the metal, which sequesters the catalyst away from target C-H bonds. We therefore propose to develop new and broadly applicable catalysts to answer these widely recognized challenges in the synthetic and medicinal chemical communities. Based on our recently discovered ligand scaffold for Pd-catalyzed C-3-selective C-H olefination of pyridine, we propose to develop more effective Pd- and Cu-based catalysts using two strategies to access a number of novel chemical transformations available for the selective functionalization of nitrogen heterocycles. At the onset of the research program, we will design ligands based on the phenanthroline scaffold to further weaken the ?-coordination of the pyridine nitrogen atom with the metal catalyst and promote the beneficial ?-coordination with the metal that is necessary for selective C-3 functionalization. Additionally, we propose to construct ligand scaffolds that contain a second binding site to recruit the pyridine substrate, thereby increasing the effective molarity of pyridine in the vicinity of the metal and allowing for use of the heterocycle as the limiting reagent. These methods will be applied to prepare diverse analogs of important heterocyclic pharmaceuticals, such as the cancer drug Gleevec, for extensive biological screening in order to develop new anti-cancer agents.

Public Health Relevance

Catalyst-controlled, C-3 selective C-H functionalizations of pyridines and other heterocycles described in this proposal will provide broadly useful tools for the rapid synthesis of drug molecules. The expedient syntheses of diverse heterocyclic pharmaceuticals, including analogs of the cancer drug Gleevec, are outlined. Furthermore, the biological activities of these Gleevec analogs will be screened in a collaborative effort to identiy new anti-cancer drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM102265-03
Application #
8704957
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2012-09-05
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Yang, Weibo; Ye, Shengqing; Schmidt, Yvonne et al. (2016) Ligand-Promoted C(sp(3) )-H Olefination en Route to Multi-functionalized Pyrazoles. Chemistry 22:7059-62
Shen, Peng-Xiang; Wang, Xiao-Chen; Wang, Peng et al. (2015) Ligand-Enabled Meta-C-H Alkylation and Arylation Using a Modified Norbornene. J Am Chem Soc 137:11574-7
Yang, Weibo; Ye, Shengqing; Fanning, Dewey et al. (2015) Orchestrated triple C-H activation reactions using two directing groups: rapid assembly of complex pyrazoles. Angew Chem Int Ed Engl 54:2501-4
Chu, Ling; Shang, Ming; Tanaka, Keita et al. (2015) Remote Meta-C-H Activation Using a Pyridine-Based Template: Achieving Site-Selectivity via the Recognition of Distance and Geometry. ACS Cent Sci 1:394-9
Wang, Xiao-Chen; Gong, Wei; Fang, Li-Zhen et al. (2015) Ligand-enabled meta-C-H activation using a transient mediator. Nature 519:334-8
Tang, Ri-Yuan; Li, Gang; Yu, Jin-Quan (2014) Conformation-induced remote meta-C-H activation of amines. Nature 507:215-20
Liu, Yue-Jin; Xu, Hui; Kong, Wei-Jun et al. (2014) Overcoming the limitations of directed C-H functionalizations of heterocycles. Nature 515:389-93
Engle, Keary M; Yu, Jin-Quan (2013) Developing ligands for palladium(II)-catalyzed C-H functionalization: intimate dialogue between ligand and substrate. J Org Chem 78:8927-55
Wang, Xiao-Chen; Hu, Yi; Bonacorsi, Samuel et al. (2013) Pd(II)-catalyzed C-H iodination using molecular I2 as the sole oxidant. J Am Chem Soc 135:10326-9

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