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 #
5R01GM084019-05
Application #
8266389
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2008-08-01
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$371,458
Indirect Cost
$175,438
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Xiao, Kai-Jiong; Lin, David W; Miura, Motofumi et al. (2014) Palladium(II)-catalyzed enantioselective C(sp³)-H activation using a chiral hydroxamic acid ligand. J Am Chem Soc 136:8138-42
Li, Suhua; Chen, Gang; Feng, Chen-Guo et al. (2014) Ligand-enabled ?-C-H olefination and carbonylation: construction of ?-quaternary carbon centers. J Am Chem Soc 136:5267-70
He, Jian; Li, Suhua; Deng, Youqian et al. (2014) Ligand-controlled C(sp³)-H arylation and olefination in synthesis of unnatural chiral ?-amino acids. Science 343:1216-20
Chan, Kelvin S L; Wasa, Masayuki; Chu, Ling et al. (2014) Ligand-enabled cross-coupling of C(sp3)-H bonds with arylboron reagents via Pd(II)/Pd(0) catalysis. Nat Chem 6:146-50
Zhu, Ru-Yi; He, Jian; Wang, Xiao-Chen et al. (2014) Ligand-promoted alkylation of C(sp3)-H and C(sp2)-H bonds. J Am Chem Soc 136:13194-7
Deng, Youqian; Gong, Wei; He, Jian et al. (2014) Ligand-enabled triple C-H activation reactions: one-pot synthesis of diverse 4-aryl-2-quinolinones from propionamides. Angew Chem Int Ed Engl 53:6692-5
Chu, Ling; Xiao, Kai-Jiong; Yu, Jin-Quan (2014) Room-temperature enantioselective C-H iodination via kinetic resolution. Science 346:451-5
Li, Gang; Leow, Dasheng; Wan, Li et al. (2013) Ether-directed ortho-C-H olefination with a palladium(II)/monoprotected amino acid catalyst. Angew Chem Int Ed Engl 52:1245-7
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
Cheng, Xiu-Fen; Li, Yan; Su, Yi-Ming et al. (2013) Pd(II)-catalyzed enantioselective C-H activation/C-O bond formation: synthesis of chiral benzofuranones. J Am Chem Soc 135:1236-9

Showing the most recent 10 out of 29 publications