Radical Relay Methods for Selective C-H Oxidation

选择性 C-H 氧化的自由基接力方法

• 批准号: 9767243
• 负责人: Shannon S Stahl
• 金额: $ 29.76万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767243
• 关键词: Acids; Alkylating Agents; Architecture; Biological; Boronic Acids; Carbon; Chemicals; Collaborations; Complement; Complex; Coupled; Coupling; Development; Dimensions; Electron Transport; Electrons; Esters; Exhibits; Generations; Hybrids; Hydrogen; Hydrogen Bonding; Mediating; Mediator of activation protein; Metabolic; Methodology; Methods; Modification; Natural Products; Nitrogen; Oxidants; Oxygen; Pathway interactions; Peroxides; Pharmaceutical Preparations; Pharmacologic Substance; Protons; Reaction; Reagent; Research; Site; Structure; Targeted Research; Therapeutic Agents; base; c new; comparative; drug candidate; drug discovery; drug efficacy; method development; novel therapeutics; oxidation

Project Summary Oxidation reactions exhibit significant value in the synthesis of pharmaceuticals, natural products and other bioactive compounds. The proposed studies will develop powerful new synthetic methods for selective oxidative functionalization of C(sp3)–H bonds. Benzylic C–H bonds represent a strategic target: such bonds are ubiquitous in pharmaceuticals and they are comparatively weak relative to most other C–H bonds. The latter feature provides the basis for selective functionalization of these sites via radical intermediates. In addition, benzylic sites often contribute to the metabolic instability of pharmaceuticals, and their selective modification will confer enhanced biological potency. Our efforts target the development of synthetic methods that may be readily adapted to pharmaceutical discovery and facilitate access to drug candidates with more-complex three dimensional architectures. The project will employ two complementary experimental strategies. One will make use of chemical oxidants that initiate selective hydrogen-atom abstraction from benzylic sites, while the second will exploit electrochemical methods that utilize catalytic electron-, electron/proton-, or hydrogen-atom-abstraction mediators to generate radical intermediates. Both the chemical and electrochemical methods will target benzylic C–H coupling reactions that generate diversely functionalized products. The electrochemical methodology will also target the generation of radicals that undergo addition reactions with (hetero)aromatic rings to produce medicinally relevant aromatic molecules. Several of the benzylic C–H oxidative coupling reactions show effective reactivity with the benzylic coupling partner as the limiting reaction, thereby making them highly appealing for late-stage functionalization of complex molecules. Opportunities toward this end will be explored in collaboration with Merck. Overall, the complementary chemical and electrochemical C–H oxidation methods are poised to greatly impact drug discovery efforts.

项目总结

项目成果

Copper-Catalyzed Benzylic C-H Cross-Coupling Enabled by Redox Buffers: Expanding Synthetic Access to Three-Dimensional Chemical Space.

• DOI: 10.1021/acs.accounts.3c00580
• 发表时间: 2023-12
• 期刊: Accounts of chemical research
• 影响因子: 18.3
• 作者: Si-Jie Chen;S. Krska;S. Stahl