"Electrophilic Fluorination Strategies using Fischer Carbenes"

 描述（由申请人提供）：许多药物和生物活性天然产物含有环丙烷或β-内酰胺部分;然而，这些官能团难以合成获得。Fischer卡宾配合物是构建复杂分子结构的重要试剂。它们表现出广泛的反应性和优异的官能团相容性，易于制备，并且可以在环境条件下处理。亲电FCC是特别有吸引力的，因为它们经历[2+1]和[2+2]环加成以提供手性的应变碳环或杂环。氟稳定的FCC是有前途的，虽然难以捉摸的，亲电配合物与潜在的应用在催化剂的战略。在此，将探索FCC的脱氧核苷作为获得氟代卡宾的方法。由于FCC表现出与羧酸衍生物类似的反应性，因此预期酰氟的氟卡宾电子等排体来自脱氧氟化剂（例如，氨基硫烷）对FCC的影响。 所提出的方法是一种发散的，温和的合成氟亚甲基和氟烯酮模拟物，可用于制备上述环状基序。氟FCC与烯烃反应将得到氟化环丙烷，而与亚胺反应将得到氟化β-内酰胺。由于药物支架的修饰通常会改善其理化性质，因此所提出的策略将能够快速访问具有潜在治疗价值的定制手性支架库。 最初，将筛选商业脱氧氟化试剂和合成FCC以实现目标转化。替代氟化策略（例如，用Olah试剂处理酰化的FCC）将被同时探索。这些新的复合物将使用标准光谱和计算来评估其结构和固有的反应性。然后努力将集中在与各种烯烃的[2+1]环加成（例如，电子中性、终端、内部等）以制备氟代环丙烷。还将探索与亚胺的光化学[2+2]环加成以提供氟化的β-内酰胺。机制评价（例如，19 F NMR和Hammett的研究），这两个反应，提出了促进设计的配合物具有最佳的活性。

 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.