Department of Pharmaceutical Chemistry and Small Molecule Discovery Center, University of California, San Francisco , 1700 Fourth Street, San Francisco, California 94158, United States.
Org Lett. 2014 Nov 7;16(21):5776-9. doi: 10.1021/ol5028392. Epub 2014 Oct 21.
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 (67-71% overall yield) synthesis of 1,2,4-trioxolanes possessing the requisite 3″ 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″ substituent and the peroxide bridge, as confirmed by X-ray structural analysis of a 3″-substituted 4-nitrobenzoate analogue.
亚铁离子促进受阻过氧键还原是青蒿素 1,2,4-三噁烷和青蒿琥酯 1,2,4-三噁烷发挥抗疟作用的基础。在经过适当设计的体系中，1,2,4-三噁烷环可以作为一个触发点，实现亚铁离子依赖性和寄生虫选择性药物传递，无论是在体外还是体内。本文报道了一种具有所需 3″取代模式的 1,2,4-三噁烷的立体控制、快速（三步）和高效（总收率为 67-71%）合成方法，该方法能够实现亚铁离子依赖性药物传递。关键的合成步骤涉及非对映选择性的 Griesbaum 共臭氧化反应，主要得到 3″取代基和过氧桥之间具有反式关系的产物，这一点通过对 3″-取代 4-硝基苯甲酸酯类似物的 X 射线结构分析得到了证实。
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