Unactivated C-H bonds are ubiquitous in biologically active compounds as well as intermediates in organic synthesis. Development of catalytic methods to functionalize these strong bonds selectively will offer unprecedented and efficient tools for making C-C and C-heteroatom bonds in organic synthesis and medicinal chemistry. A number of promising catalytic reactions have been developed using directed C-H activation as a key strategy. These reactions typically use pre-installed nitrogen-containing auxiliaries as directing groups via binding to metal catalysts. Considering the broad applications of auxiliaries in synthesis, auxiliaries developed for C-H insertion are not yet practical due to multiple steps and harsh conditions involved in their installation and removal. To overcome these drawbacks, we propose to develop catalytic C-H activation reactions of simple and synthetically useful carboxylic acids and amides at the 2-positions. These reactions are also applicable to simple amine derivatives. We will exploit these reactivities to develop an array of C-H activation/C-C coupling reactions using practical coupling partners such as organoboron reagents and olefins. To improve the practicality of C-H activation reactions, we propose to develop mild conditions (50-80?C and pH = 4-12) that allow the use of O2 or air as the stoichiometric oxidant. These advantages will be exploited to site-selectively functionalize biologically active natural products including dehydroabietic acid, podocarpic acid and amino acids. The structurally diversified dehydroabietic acid derivatives will be tested for potentially improved biological activity as BK channel openers. Lastly, we have also discovered an effective ligand to achieve the first Pd(II)-catalyzed enantioselective coupling of sp2 and sp3 C-H bonds with organoboronic acids which will find widespread use in synthesis and medicinal chemistry.

Public Health Relevance

The C-H activation/C-C coupling reactions described in this proposal will expedite the drug discovery process by providing unprecedented routes to access biologically active compounds. The enantioselective alkylation of sp2 and sp3 C-H bonds will provide new methods for the preparation of medicinally relevant chiral molecules. Research plans for applications of these reactions in medicinal chemistry are also outlined. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM084019-01A1
Application #
7533526
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Schwab, John M
Project Start
2008-08-01
Project End
2013-05-31
Budget Start
2008-08-01
Budget End
2009-05-31
Support Year
1
Fiscal Year
2008
Total Cost
$379,000
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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