Center for Bioinformatics and Molecular Medicine, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo, Nagasaki, 852-8521, Japan.
Laboratory of Emerging Viral Diseases, International Research Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
Org Biomol Chem. 2024 Nov 21;22(45):8847-8856. doi: 10.1039/d4ob01247j.
Biological molecules incorporating trifluoromethyl ketones (TFMKs) have emerged as reversible covalent inhibitors, aiding in the management and treatment of inflammatory diseases, cancer, and respiratory conditions. TFMKs, renowned for their versatile binding properties and adaptability, are pivotal in the rational design of novel drugs for diverse diseases. The photocatalytic insertion of alkenes, abundant feedstocks, into the α-carbon of trifluoromethylacetone represents a highly effective and atom-economical method for synthesizing valuable TFMKs. However, these processes typically necessitate high-energy photoirradiation ( > 300 nm, Hg lamp) and stoichiometric oxidants to generate the acetonyl radical from acetone. In our study, we demonstrate the visible-light photocatalytic radical addition into olefins using bromotrifluoroacetone as the trifluoroacetonyl radical precursor under mild conditions. Aliphatic trifluoromethyl ketones or the corresponding bromo-substituted products can be obtained by selecting an appropriate photocatalyst and solvent. Comprehensive experimental investigations, including cyclic voltammetry, Stern-Volmer quenching studies, and kinetic isotope effects, corroborate the synthesis of trifluoroacetonyl radical species from bromotrifluoroacetone under photoredox conditions. Further, we demonstrate the efficient synthesis of an oseltamivir derivative bearing a trifluoromethylketone moiety, which shows promising biological activity. Hence, this methodology will streamline the direct introduction of trifluoromethyl ketone into biological target molecules during drug discovery.
含三氟甲基酮（TFMKs）的生物分子已成为可逆的共价抑制剂，有助于管理和治疗炎症性疾病、癌症和呼吸道疾病。TFMKs 以其多功能的结合特性和适应性而闻名，是合理设计用于治疗各种疾病的新型药物的关键。烯烃的光催化插入，即丰富的原料，进入三氟甲基丙酮的α-碳，是合成有价值的 TFMKs 的一种非常有效和原子经济的方法。然而，这些过程通常需要高能光照射（>300nm，汞灯）和化学计量的氧化剂，以从丙酮中生成乙酰基自由基。在我们的研究中，我们展示了使用溴代三氟乙酮作为三氟乙酰基自由基前体，在温和条件下通过可见光光催化自由基加成到烯烃中的反应。通过选择适当的光催化剂和溶剂，可以得到脂肪族三氟甲基酮或相应的溴取代产物。包括循环伏安法、Stern-Volmer 猝灭研究和动力学同位素效应在内的综合实验研究证实了在光还原条件下从溴代三氟乙酮合成三氟乙酰基自由基物种的过程。此外，我们还展示了含有三氟甲基酮部分的奥司他韦衍生物的有效合成，该衍生物表现出有希望的生物活性。因此，该方法将简化在药物发现过程中直接将三氟甲基酮引入生物靶分子。
