Transition metal-catalyzed enantioselective sp3 C-H activation reactions can provide new synthetic routes for the expedient construction of bioactive molecules and drug compounds. Despite the great potential of such reactions, the development of enantioselective sp3 C-H functionalizations via an organometallic approach is in its infancy when compared to other more advanced methods of asymmetric catalysis. This proposal is centered on the development of novel enantioselective sp3 C-H activation reactions that would broaden the scope of transition metal-catalyzed asymmetric C-H functionalizations. The key strategy for achieving this goal is via the design and development of ligand scaffold that cooperates with the weak coordination between the substrate and the metal center to promote C-H activation. Additionally, we will relay our efforts through collaborations to biomedical research in identifying new drug candidates for the treatment of human diseases. Furthermore, we will strive to overcome the inherent need for the formation of 5-membered palladacycles in sp3 C-H activation to access remote methyl and methylene C-H bonds. Our key strategy is to design a template that relies on weak coordination to direct the metal towards the desired distal C-H bond. This approach would not only provide unprecedented access to a variety of ?- and ?-substituted aliphatic carboxylic acid derivatives, but also provide a platform for the late-stage diversification of drug molecules via functionalization of previously inaccessible remote C-H bonds.

Public Health Relevance

This proposal centers on utilizing the asymmetric cleavage of carbon-hydrogen bonds to develop new reactions for the enantioselective construction of carbon-carbon bonds. Such reactions will allow for the rapid construction of bioactive chiral compounds and drug molecules from inexpensive and readily available chemicals. In a collaborative effort, we will use our proposed chemistry to discover promising new drug candidates for the treatment of human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM084019-06
Application #
8577984
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2008-08-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
6
Fiscal Year
2013
Total Cost
$530,600
Indirect Cost
$250,600
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Xiao, Kai-Jiong; Chu, Ling; Yu, Jin-Quan (2016) Enantioselective C-H Olefination of α-Hydroxy and α-Amino Phenylacetic Acids by Kinetic Resolution. Angew Chem Int Ed Engl 55:2856-60
Ye, Shengqing; Yang, Weibo; Coon, Timothy et al. (2016) N-Heterocyclic Carbene Ligand-Enabled C(sp(3))-H Arylation of Piperidine and Tetrahydropyran Derivatives. Chemistry 22:4748-52
Zhang, Fang-Lin; Hong, Kai; Li, Tuan-Jie et al. (2016) Organic chemistry. Functionalization of C(sp3)-H bonds using a transient directing group. Science 351:252-6
He, Jian; Jiang, Heng; Takise, Ryosuke et al. (2016) Ligand-Promoted Borylation of C(sp(3))-H Bonds with Palladium(II) Catalysts. Angew Chem Int Ed Engl 55:785-9
Li, Suhua; Zhu, Ru-Yi; Xiao, Kai-Jiong et al. (2016) Ligand-Enabled Arylation of γ-C-H Bonds. Angew Chem Int Ed Engl 55:4317-21
Jiang, Heng; He, Jian; Liu, Tao et al. (2016) Ligand-Enabled γ-C(sp(3))-H Olefination of Amines: En Route to Pyrrolidines. J Am Chem Soc 138:2055-9
Liu, Tao; Mei, Tian-Sheng; Yu, Jin-Quan (2015) γ,δ,ε-C(sp(3))-H Functionalization through Directed Radical H-Abstraction. J Am Chem Soc 137:5871-4
Laforteza, Brian N; Chan, Kelvin S L; Yu, Jin-Quan (2015) Enantioselective ortho-C-H cross-coupling of diarylmethylamines with organoborons. Angew Chem Int Ed Engl 54:11143-6
He, Jian; Takise, Ryosuke; Fu, Haiyan et al. (2015) Ligand-enabled cross-coupling of C(sp(3))-H bonds with arylsilanes. J Am Chem Soc 137:4618-21
Chen, Gang; Shigenari, Toshihiko; Jain, Pankaj et al. (2015) Ligand-enabled β-C-H arylation of α-amino acids using a simple and practical auxiliary. J Am Chem Soc 137:3338-51

Showing the most recent 10 out of 54 publications