New Methods for Site-Selective Trifluoromethylation of Aromatic Heterocycles

描述(申请人提供)：含有三氟甲基官能团的杂环分子支架在制药工业的目标生物活性化合物中变得越来越常见。从抗抑郁剂到抗癌剂的各种化疗药物都成功地利用了三氟甲基的掺入，因为它们的存在引起了独特的性质。出于这个原因，化学界一直在推动开发化学方法，将三氟甲基安装到与药物相关的杂环支架中。这项研究旨在通过高通量筛选和机理分析相结合的方法，开发和改进芳香族杂环的位置选择性三氟甲基化的新化学策略。高通量筛查将有效地测试和突破最近报道的但不发达的三氟甲基化方案的极限，该方案已被证明比以前的方法具有显著的优势。DFT计算将与反应筛选一起进行，以开发基于基态底物属性的反应性和位置选择性的预测模型。包括动力学分析和动力学同位素效应研究在内的机理研究将有助于更好地了解这一重要的反应类别，从而进一步发展和发现相关过程。最后，拟议研究的长期目标是开发一套通用的实验方法，用于各种杂环类的高产率和高位置选择性的三氟甲基化。健壮的发展 在与药物相关的支架中选择性安装三氟甲基的化学策略将对医学界产生重大和直接的影响，因为药物化学家和制药行业可能会更有效和更多地针对含三氟甲基的化疗药物。 与公共卫生相关：拟议的研究描述了将三氟甲基选择性地结合到与药物相关的结构支架中的新方法的开发。有机氟化合物因其在代谢稳定性和生物利用度方面的优势，成为药物化学家开发化疗药物的常用靶点。因此，制定强有力的化学战略，在与药物相关的支架中选择性地安装三氟甲基基团，将对医学界产生重大和直接的影响，因为含有三氟甲基的化疗药物可能会更有效和更多地成为靶点。

DESCRIPTION (provided by applicant): Heterocyclic molecular scaffolds containing the trifluoromethyl functional group have become increasingly common in biologically active compounds targeted by the pharmaceutical industry. Chemotherapeutics ranging from antidepressants to anticancer agents have successfully utilized the incorporation of trifluoromethyl groups due to the unique properties their presence elicits. For this reason, there has been a consistent drive within the chemical community towards the development of chemical methods for the installation of the trifluoromethyl group into pharmaceutically relevant heterocyclic scaffolds. The proposed research aims to develop and refine novel chemical strategies for site-selective trifluoromethylations of aromatic heterocycles through a combination of high-throughput screening and mechanistic analysis. High-throughput screening will efficiently test and push the limits of a recently reported, but underdeveloped trifluoromethylatio protocol that has been show to have significant advantages over previous methods. DFT calculations will be performed in tandem with reaction screens to develop a predictive model of reactivity and site-selectivity based on ground-state substrate properties. Mechanistic investigation involving kinetic analysis and kinetic isotope effect studies will lead to better understanding of this important reaction class, allowing for further development and the discovery of related processes. Finally, the long term goal of the proposed research is the development of a suite of general experimental procedures for the trifluoromethylation of a variety of heterocyclic classes in high yield with high site-selectivity. The development of robust chemical strategies for the selective installation of trifluoromethyl groups into pharmaceutically relevant scaffolds would have a significant and immediate impact on the medical community as trifluoromethyl- containing chemotherapeutics may be targeted more efficiently and in greater numbers by medicinal chemists and pharmaceutical industries. PUBLIC HEALTH RELEVANCE: The proposed research describes the development of novel methods for the site-selective incorporation of trifluoromethyl groups into pharmaceutically relevant structural scaffolds. Organofluorine compounds are routinely targeted by medicinal chemists in the development of chemotherapeutics because of advantages in metabolic stability and bioavailability. Therefore, the development of robust chemical strategies for the selective installation of trifluoromethyl groups into pharmaceutically relevant scaffolds would have a significant and immediate impact on the medical community as trifluoromethyl-containing chemotherapeutics may be targeted more efficiently and in greater numbers.