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（申请人提供）：有机分子中氟的加入对所检测的有机分子的分子构象、邻近杂原子的酸性和反应性具有显着影响，生物活性分子中氟的添加增加了亲脂性、生物利用度。和氧化稳定性，使含氟分子成为有吸引力的药物靶标的合成方法。然而，氟化羰基化合物通常通过亲电加成到活化的烯醇化物上进行，但这些技术会发生剧烈的反应和非选择性氟化，这限制了该方法的总体范围和实用性。获得氟化化合物的另一种方法是亲核氟化。然而，亲核氟化反应因需要苛刻且操作上具有挑战性的反应条件而臭名昭著。由于氟化物溶解度低、亲核性差和吸水性高，目前实现亲核氟化的催化方法非常少，更不用说不对称方法了。 在本提案中，我们将开发一种温和的双催化方法来对映选择性合成 ¿ -氟代羰基衍生物，通过与重氮化合物的亲核氟化，可以用现成的、廉价且稳定的氟化物源选择性地氟化高度官能化的羰基底物，并通过组合物原位形成 HF-胺。我们建议，苯甲酰氟、醇、路易斯碱催化剂和过渡金属催化剂将提供一种温和、稳健、位点特异性的氟化技术，其中存在重氮部分。在分子中，无论附加功能如何，中间体金属稳定的卡宾将优先被氟化，具体目标 1 解决了通过双催化方法重氮酯氟化的反应设计和优化，具体目标 2 探讨了重氮酯氟化的使用。温和氟化系统用于PET示踪剂开发的放射性氟化该方法的发展将为温和不对称、位点特异性氟化提供一种新的催化技术。重氮化合物。