Edson Barrera, Alberto V. Jerezano, Ulises F. Reyes-González, Daniela Martínez-López, Carlos H. Escalante, Julio López, Eder I. Martínez-Mora, Omar Gómez-García, Dulce Andrade-Pavón, Lourdes Villa-Tanaca, Francisco Delgado, Joaquín Tamariz
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引用次数: 0
摘要
本文介绍了一种简短、高效和立体选择性的方法,用于合成 5-((二甲基氨基)亚甲基)海因并将其转化为氧代芹菜苷元和对位泛酸。在微波辐照下,N-芳基甘氨酸甲酯、异氰酸酯和 DMFDMA 通过高度收敛的一锅两步反应,以单个 E 立体异构体的形式提供了相应的(二甲基氨基)亚甲基海因,总产率高。(S)-1-(1-苯基乙基)手性海因的合成受到了特别关注,它能与乙酸酐、氮杂环和胺发生立体选择性加成反应。与吲哚的反应产生了一系列新型氧代芹菜素。同时,还采用一种新方法制备了对位泛酸,即用 mCPBA 处理(二甲基氨基)亚甲基海因,以产生外环亚甲基的氧化碎片。制备的产品对一系列白色念珠菌属进行了抗真菌评估,发现其具有很强的生长抑制作用。根据之前的对接研究,这种活性可能是由于衍生物与真菌 HMGR 酶的活性位点发生了抑制作用。
(Dimethylamino)methylene hydantoins as building blocks in the synthesis of oxoaplysinopsins and parabanic acids with antifungal activity
A short, efficient, and stereoselective methodology is described for the synthesis of 5-((dimethylamino)methylene)hydantoins and their conversion into oxoaplysinopsins and parabanic acids. A highly convergent one-pot, two-step reaction between methyl N-arylglycinates, isocyanates, and DMFDMA under microwave irradiation provided the corresponding (dimethylamino)methylene hydantoins as a single E-stereoisomer in high overall yields. The synthesis of (S)-1-(1-phenylethyl) chiral hydantoins, which undergo a stereoselective addition of acetic anhydride, aza-heterocycles, and amines, received special attention. The reaction with indole delivered a series of novel oxoaplysinopsins. Meanwhile, parabanic acids were prepared by a new approach, treating (dimethylamino)methylene hydantoins with mCPBA to generate the oxidative fragmentation of the exocyclic methylene. The antifungal evaluation of the prepared products was carried out on a series of Candida spp., finding potent growth inhibition. According to previous docking studies, this activity is probably due to the inhibitory interaction of the derivatives with the active site of the fungal HMGR enzyme.