Department of Chemistry, Brooklyn College, The City University of New York , Brooklyn, New York 11210, United States.
PhD Program in Chemistry, The Graduate Center of The City University of New York , New York, New York 10016, United States.
J Org Chem. 2018 Feb 2;83(3):1478-1485. doi: 10.1021/acs.joc.7b03032. Epub 2018 Jan 22.
α-Hydroxytropolones (αHTs) are troponoids that demonstrate inhibition against an array of therapeutically significant targets, making them potential drug leads for several human diseases. We have utilized a recently discovered one-pot three-component oxidopyrylium cycloaddition in a solid-supported synthesis of αHTs. Though the procedure is time efficient and generates assay-ready molecules, the system suffers from low yields and an inability to perform reaction modifications on resin-bound intermediates. In order to combat these issues with the solid-phase platform, we incorporated fluorous tags into our synthetic route. Through the implementation of fluorous phase chemistry, we demonstrate a substantial increase in the overall yield of αHTs, as well as an ability to execute metal-catalyzed cross coupling and amide coupling on fluorous tagged intermediates. We also show that tagged molecules can be separated from nonfluorous impurities, and vice versa, by utilizing fluorous liquid-liquid and solid-phase extractions. Hence, these proof-of-principle investigations describe the viability of a fluorous phase approach to αHT synthesis and its potential to serve as a combinatorial technique to produce structurally diverse substrates.
α-羟基三酮（αHTs）是一种肌钙蛋白类似物，对一系列具有治疗意义的靶标具有抑制作用，使它们成为几种人类疾病的潜在药物先导物。我们利用最近发现的一锅三组分氧化吡喃鎓环加成反应在固相合成αHTs。虽然该方法具有时间效率，并且可以生成适合检测的分子，但该系统的产率较低，并且无法对树脂结合的中间体进行反应修饰。为了解决固相平台上的这些问题，我们将氟标签纳入我们的合成路线中。通过实施氟相化学，我们证明了αHTs 的总产率有了显著提高，并且能够在氟标记的中间体上进行金属催化的交叉偶联和酰胺偶联。我们还表明，标记的分子可以通过氟液相-液相和固相等萃取与非氟杂质分离，反之亦然。因此，这些原理验证研究描述了氟相方法在αHT 合成中的可行性及其作为产生结构多样的底物的组合技术的潜力。
