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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
Farmer, Marcus E; Wang, Peng; Shi, Hang et al. (2018) Palladium Catalyzed meta-C-H Functionalization of Masked Aromatic Aldehydes. ACS Catal 8:7362-7367
Saint-Denis, Tyler G; Zhu, Ru-Yi; Chen, Gang et al. (2018) Enantioselective C(sp3)?H bond activation by chiral transition metal catalysts. Science 359:
Shen, Peng-Xiang; Hu, Liang; Shao, Qian et al. (2018) Pd(II)-Catalyzed Enantioselective C(sp3)-H Arylation of Free Carboxylic Acids. J Am Chem Soc 140:6545-6549
Zhu, Ru-Yi; Li, Zi-Qi; Park, Han Seul et al. (2018) Ligand-Enabled ?-C(sp3)-H Activation of Ketones. J Am Chem Soc 140:3564-3568
Wu, Qing-Feng; Wang, Xiao-Bing; Shen, Peng-Xiang et al. (2018) Enantioselective C-H Arylation and Vinylation of Cyclobutyl Carboxylic Amides. ACS Catal 8:2577-2584
Park, Hojoon; Verma, Pritha; Hong, Kai et al. (2018) Controlling Pd(IV) reductive elimination pathways enables Pd(II)-catalysed enantioselective C(sp3)-H fluorination. Nat Chem :
Shao, Qian; Wu, Qing-Feng; He, Jian et al. (2018) Enantioselective ?-C(sp3)-H Activation of Alkyl Amines via Pd(II)/Pd(0) Catalysis. J Am Chem Soc 140:5322-5325
Hong, Kai; Park, Hojoon; Yu, Jin-Quan (2017) Methylene C(sp3)-H Arylation of Aliphatic Ketones Using a Transient Directing Group. ACS Catal 7:6938-6941
Zhu, Ru-Yi; Saint-Denis, Tyler G; Shao, Ying et al. (2017) Ligand-Enabled Pd(II)-Catalyzed Bromination and Iodination of C(sp3)-H Bonds. J Am Chem Soc 139:5724-5727
Zhu, Ru-Yi; Liu, Luo-Yan; Park, Han Seul et al. (2017) Versatile Alkylation of (Hetero)Aryl Iodides with Ketones via ?-C(sp3)-H Activation. J Am Chem Soc 139:16080-16083

Showing the most recent 10 out of 78 publications