"Electrophilic Fluorination Strategies using Fischer Carbenes"

“使用费歇尔卡宾的亲电氟化策略”

• 批准号: 9407615
• 负责人: Johnathan Brantley
• 金额: $ 0.06万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9407615
• 关键词: Address; Alkenes; Architecture; Biological; Carboxylic Acids; Chemicals; Combinatorial Synthesis; Complex; Computer Simulation; Coupling; Electrons; Elements; Evaluation; Exhibits; Family; Fluorides; Fluorine; Imines; Investigation; Libraries; Methodology; Methods; Molecular; Monitor; NMR Spectroscopy; Nature; Pathway interactions; Periodicity; Pharmaceutical Preparations; Pharmacologic Substance; Positioning Attribute; Property; Reaction; Reagent; Spectrometry; Spectrum Analysis; Structure; Therapeutic; Transition Elements; Work; base; beta-Lactams; bioactive natural products; carbene; cycloaddition; cyclopropane; design; drug discovery; functional group; improved; novel; public health relevance; scaffold; tool

 DESCRIPTION (provided by applicant): Numerous pharmaceuticals and bioactive natural products contain cyclopropane or ß-lactam moieties; however, these functionalities are difficult to access synthetically. Fischer carbene complexes (FCCs) are valuable reagents for constructing complex molecular architectures. They exhibit broad reactivity and excellent functional group compatibility, are easily prepared, and can be handled under ambient conditions. Electrophilic FCCs are particularly attractive, as they undergo [2+1] and [2+2] cycloadditions to afford chiral, strained carbocycles or heterocycles. Fluorine stabilized FCCs are promising, albeit elusive, electrophilic complexes with potential applications in fluorination strategies. Here, deoxyfluorination of FCCs will be explored as a method to access fluorocarbenes. As FCCs exhibit analogous reactivity to carboxylic acid derivatives, fluorocarbene isosteres of acyl fluorides are expected from the action of deoxyfluorinating agents (e.g., aminosulfuranes) on FCCs. The proposed methodology is a divergent, mild synthesis of fluoromethylene and fluoroketene mimics that can be used to prepare the aforementioned cyclic motifs. Reaction of fluoro-FCCs with olefins will afford fluorinated cyclopropanes, while reaction with imines will afford fluorinaed ß-lactams. As fluorination of drug scaffolds typically improves their physiochemical properties, the proposed strategy will enable rapid access to libraries of tailored, chiral scaffolds with potential therapeutic value. Initially, commercial deoxyfluorinating reagents and synthetic FCCs will be screened to effect the target transformation. Alternative fluorinating strategies (e.g., treating acylated FCCs with Olah's reagent) will be explored in tandem. These novel complexes will be investigated using standard spectroscopies and computation to evaluate their structure and innate reactivity. Efforts will then focus on [2+1] cycloadditions with various olefins (e.g., electron neutral, terminal, internal, etc.) to prepare fluorocyclopropanes. Photochemical [2+2] cycloadditions with imines will also be explored to afford fluorinated ß-lactams. Mechanistic evaluations (e.g., 19F NMR and Hammett studies) of both reactions are proposed to facilitate the design of complexes with optimal activity.



项目成果

Isolation and Reactivity of Trifluoromethyl Iodonium Salts.

三氟甲基碘盐盐的分离和反应性。

• DOI: 10.1021/acscentsci.6b00119
• 发表时间: 2016-05-25
• 期刊: ACS central science
• 影响因子: 18.2
• 作者: Brantley JN;Samant AV;Toste FD
• 通讯作者: Toste FD