Methods for asymmetric catalytic fluorination of diazo compounds

描述（由申请人提供）：有机分子中氟化物的包含对分子构象、相邻杂原子的酸度和有机分子的反应性有显著影响。因此，在生物活性分子中加入氟增加了亲脂性、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点。合成氟化羰基化合物的方法通常是通过在活化的烯酸酯上进行亲电加成。然而，这些技术受到剧烈反应和非选择性氟化的影响，这限制了这些方法的总体范围和效用。获得氟化化合物的另一种方法是亲核氟化，这种方法受益于低成本和丰富的氟化物来源，如无水氟化氢或KF。然而，由于氟化物的溶解度低、亲核性差和高吸水性，亲核氟化反应以要求苛刻和操作困难的反应条件而臭名昭著。此外，很少有催化，更不用说不对称的方法已经实现亲核氟化。

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.