Methods for asymmetric catalytic fluorination of diazo compounds

重氮化合物的不对称催化氟化方法

• 批准号: 8712705
• 负责人: Kimberly Choquette
• 金额: $ 5.15万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8712705
• 关键词: Acidity; Address; Alcohols; Amines; Biological Availability; Development; Drug Targeting; Fluorides; Fluorine; In Situ; Laboratory Procedures; Metals; Methods; Molecular Conformation; Pharmaceutical Preparations; Positron-Emission Tomography; Radio; Reaction; Site; Solubility; Source; System; Techniques; Tracer; Transition Elements; base; carbene; carbonyl compound; catalyst; cost; design; diazo compound; enolate; innovation; lipophilicity; method development; public health relevance

DESCRIPTION (provided by applicant): The inclusion of fluoride in organic molecules has a significant impact on the molecular conformation, acidity of neighboring heteroatoms, and reactivity of the organic molecule. Consequently, the addition of fluorine in biologically active molecules increases the lipophilicity, bioavailability, and oxidative stability, making fluorine-bearing molecules attractive drug targets. Methods for synthesizing ¿-fluorinated carbonyl compounds generally proceed through electrophilic addition to an activated enolate. These techniques, however, suffer from harsh reactions and unselective fluorinations, which restrict the overall scope and utility of the methods. Another approach to obtaining fluorinated compounds is nucleophilic fluorination, which benefits from the low cost and abundance of fluoride sources such as anhydrous HF or KF. Nevertheless, nucleophilic fluorination reactions are notorious for requiring harsh and operationally challenging reaction conditions due to the low solubility, poor nucleophilicity, and high hydroscopicity of fluoride. Furthermore, very few catalytic, let alone asymmetric, methods have been realized for nucleophilic fluorination. In this proposal we will develop a mild, dual-catalytic approach to the enantioselective synthesis of ¿-fluoro carbonyl derivatives by nucleophilic fluorination with diazo compounds. This strategy will allow for highly functionalized carbonyl substrates to be selectively fluorinated with a readiy available, inexpensive, and stable fluoride source. The in situ formation of an HF-amine species from the combination of benzoyl fluoride, an alcohol, Lewis base catalyst and transition metal catalyst will afford a mild, robust, site-specific fluorination technique. We propose that with a diazo moiety present in the molecule, the intermediate metal-stabilized carbene will be preferentially fluorinated, regardless of the additional functionalities. Specific aim 1 addresses reaction design and optimization of the fluorination of diazoesters through a dual-catalytic approach, and specific aim 2 explores the use of the mild fluorination system to carry out radiofluoriations for the development of PET tracers. The development of this method will provide a new catalytic technique for the mild asymmetric, site-specific fluorination of diazo compounds.

描述（由适用提供）：在有机分子中包含氟化物对分子构象，相邻杂原子的酸度和有机分子的反应性具有重大影响。因此，在生物活性分子中添加氟会增加亲脂性，生物利用度和氧化稳定性，从而使含氟的分子有吸引力的药物靶标。合成�-氟化羰基化合物的方法通常是通过激活的烯醇酸化而进行的。但是，这些技术遭受有害反应和非选择性荧光的影响，这限制了方法的总体范围和效用。获得氟化化合物的另一种方法是核氟化，这受益于氟化物源（如无水HF或KF）的低成本和抽象。然而，由于溶解度较低，核穿法较差和氟化物的高水位效率，核氟化反应臭名昭著，并在操作中挑战反应条件臭名昭著。此外，很少有催化性，更不用说不对称的方法已实现用于核系统性氟化的方法。 在此提案中，我们将通过用重氮化合物进行核氟化来开发一种温和的双催化方法，以对对映选择性合成 - 氟羰基衍生物。该策略将允许高度功能化的羰基底物通过可用的，便宜且稳定的氟化物来源地氟化。苯甲酰氟，酒精，刘易斯碱催化剂和过渡金属催化剂的组合，将HF胺物种的原位形成将提供一种轻度，健壮，特定于现场的氟化技术。我们建议，对于分子中存在的重氮部分，中间金属稳定的碳纤维将更受欢迎，无论其他功能如何。特定的目标1通过双催化方法解决了重氮植物氟化的反应设计和优化，并且特定的目标2探讨了轻度氟化系统的使用来执行放射性荧光以开发宠物示踪剂。该方法的开发将为重氮化合物的轻度不对称，特异性氟化提供一种新的催化技术。