Efficient and Stereocontrolled Synthesis of 1,2,4-Trioxolanes Useful for Ferrous Iron-Dependent Drug Delivery

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• 作者：Shaun D. Fontaine ; Antonio G. DiPasquale ; Adam R. Renslo
• 刊名：Organic Letters
• 出版年：2014
• 出版时间：November 7, 2014
• 年：2014
• 卷：16
• 期：21
• 页码：5776-5779
• 全文大小：294K
• ISSN：1523-7052

文摘

Ferrous iron-promoted reduction of a hindered peroxide bond underlies the antimalarial action of the 1,2,4-trioxane artemisinin and the 1,2,4-trioxolane arterolane. In appropriately designed systems, a 1,2,4-trioxolane ring can serve as a trigger to realize ferrous iron-dependent and parasite-selective drug delivery, both in vitro and in vivo. A stereocontrolled, expeditious (three steps), and efficient (67鈥?1% overall yield) synthesis of 1,2,4-trioxolanes possessing the requisite 3鈥?substitution pattern that enables ferrous iron-dependent drug delivery is reported. The key synthetic step involves a diastereoselective Griesbaum co-ozonolysis reaction to afford primarily products with a trans relationship between the 3鈥?substituent and the peroxide bridge, as confirmed by X-ray structural analysis of a 3鈥?substituted 4-nitrobenzoate analogue.