"Electrophilic Fluorination Strategies using Fischer Carbenes"

“使用费歇尔卡宾的亲电氟化策略”

基本信息

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
项目类别：
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

项目摘要

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.

描述（由适用提供）：许多药物和生物活性天然产物包含环丙烷或β-内酰胺部分；但是，这些功能难以合成。 Fischer Carbene复合物（FCC）是用于构建复杂分子体系结构的宝贵试剂。他们暴露了广泛的反应性和出色的功能组兼容性，很容易准备，并且可以在环境条件下进行处理。亲电的FCC特别有吸引力，因为它们经历了[2+1]和[2+2]的环加成，以提供手性，紧张的碳循环或异环。氟稳定的FCC是有希望的，尽管具有弹性的电力复合物，并具有潜在的氟化策略中的应用。在这里，将探索FCC的脱氧荧光，以获取氟化碳的方法。由于FCC对羧酸衍生物暴露了类似的反应性，因此预计乙酰氟的氟苯甲酸等当异类药物可以通过脱氧氟化剂（例如氨基磺酰氟烷）对FCC的作用。所提出的方法是荧光甲基和荧光素模拟物的不同，轻度合成，可用于制备近似环状基序。 Fluoro-FCC与烯烃的反应将提供氟化的环丙烷，而与亚胺的反应将提供氟β-内酰胺。随着药物脚手架的氟化通常会提高其生理化学特性，该策略将能够快速访问具有潜在治疗价值的量身定制的手性支架的库。最初，将筛选商业脱氧试剂和合成FCC以实现目标转换。将在同时探索替代性荧光策略（例如，用OLAH试剂处理酰化的FCC）。这些新型复合物将使用标准光谱和计算来评估其结构和先天反应性。然后，努力将集中在[2+1]的环加成上，以各种烯烃（例如电子中性，末端，内部等）制备荧光丙核植物。还将探索具有氟化β-内酰胺的光化学[2+2]环加成。提出了两种反应的机械评估（例如19F NMR和Hammett研究），以促进具有最佳活性的复合物的设计。