"Electrophilic Fluorination Strategies using Fischer Carbenes"

 说明(申请人提供)：许多药物和生物活性天然产品含有环丙烷或内酰胺部分；然而，这些功能很难综合获得。Fischer卡宾络合物(FCC)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良好的官能团相容性，易于制备，并且可以在环境条件下处理。亲电性催化裂化催化剂特别有吸引力，因为它们通过[2+1]和[2+2]环加成得到手性、张力碳环或杂环。氟稳定的催化裂化化合物是很有前途的，尽管难以捉摸，但在氟化策略中具有潜在的应用前景。在这里，将探索催化裂化碳化合物的脱氧氟化反应作为一种获得氟化碳的方法。由于催化裂化化合物表现出与羧酸衍生物类似的反应性，因此脱氧氟化剂(如氨基磺酸呋喃)对催化裂化化合物的作用可能会导致酰基氟化物的氟卡宾异构体。 所提出的方法是一种发散的、温和的氟亚甲基和氟酮酮类化合物的合成方法，可用于制备上述环状基序。含氟催化裂化产物与烯烃反应生成含氟环丙烷，而与亚胺反应生成含氟伯内酰胺。由于药物支架的氟化通常会改善它们的物理化学性质，建议的策略将使人们能够快速访问具有潜在治疗价值的定制手性支架的库。 首先，将筛选商用脱氧氟试剂和合成催化裂化催化剂，以实现目标转化。将同时探索替代的氟化策略(例如，用Olah试剂处理酰化催化裂化碳化合物)。这些新的配合物将使用标准光谱和计算来研究，以评估它们的结构和固有的反应性。然后将重点放在与各种烯烃(例如，电子中性、末端、内部等)的[2+1]环加成反应上。制备含氟环丙烷。还将探索与亚胺的光化学[2+2]环加成反应，以获得氟化的伯内酰胺。建议对这两个反应进行机理评估(例如，19F核磁共振和Hammett研究)，以便于设计具有最佳活性的配合物。

 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.