Methods for asymmetric catalytic fluorination of diazo compounds

描述（由申请人提供）：有机分子中包含氟化物对分子构象、相邻杂原子的酸性和有机分子的反应性具有显著影响。因此，在生物活性分子中添加氟增加了亲脂性、生物利用度和氧化稳定性，使得含氟分子成为有吸引力的药物靶标。用于合成氟化羰基化合物的方法通常通过亲电加成至活化烯醇化物来进行。然而，这些技术遭受苛刻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。另一种获得氟化化合物的方法是亲核氟化，其受益于低成本和丰富的氟化物源，如无水HF或KF。然而，由于氟化物的溶解度低、亲核性差和吸湿性高，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。此外，很少有催化的，更不用说不对称的，方法已经实现了亲核取代。 在本论文中，我们将发展一种温和的双催化方法，通过亲核取代反应与重氮化合物反应，对映选择性地合成了<$-氟羰基衍生物。这种策略将允许高度官能化的羰基底物被容易获得的、廉价的和稳定的氟化物源选择性地氟化。由苯甲酰氟、醇、刘易斯碱催化剂和过渡金属催化剂的组合原位形成HF-胺物质将提供温和的、稳健的、位点特异性的氢化技术。我们建议，与重氮部分存在于分子中，中间体金属稳定的卡宾将优先氟化，无论额外的功能。具体目标1通过双催化方法解决了重氮酯的反应设计和优化，具体目标2探索了使用温和的重氮体系进行PET示踪剂开发的放射性氟化。该方法的发展将为重氮化合物的温和不对称、定点取代反应提供一种新的催化技术。

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.