Dispiro-1,2,4,5-tetraoxanes via ozonolysis of cycloalkanone O-methyl oximes:: A comparison with the peroxidation of cycloalkanones in acetonitrile-sulfuric acid media
Dispiro-1,2,4,5-tetraoxanes via ozonolysis of cycloalkanone O-methyl oximes:: A comparison with the peroxidation of cycloalkanones in acetonitrile-sulfuric acid media
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DOI：
10.1021/jo981261i
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发表时间：
1998-11-13
影响因子：
3.6
通讯作者：
Vennerstrom, JL
中科院分区：
文献类型：
--
作者：
Dong, YX;Vennerstrom, JL
二环-1，2，4，5-四氧六环，也称为酮二过氧化物、二聚过氧化物或羰基氧化物二聚体，可能是最广为人知的热分解大环烃和内酯的前体。1我们最近发现，某些二-1，2，4，5-四氧六环具有与青蒿素(青蒿素)相当的抗疟疾活性，青蒿素是一种临床上有用的内源性过氧化倍半萜内酯。为了优化这类新型抗疟疾过氧物的活性并阐明其作用机理，需要合成结构不同的二螺-1，2，4，5-四氧杂环化合物。合成二-1，2，4，5-四氧六环的最直接方法3是用过氧化氢水溶液酸催化环烷酮的过氧化反应，该反应由Sanderson等人优化。4和McCullough等人，5或在该反应的无水变体中，在三甲基硅基三氟甲磺酸存在下使用双(三甲基硅基)过氧化氢。6不幸的是，在某些情况下，会形成一种复杂的过氧化产物混合物，包括三环-1，2，4，5，7，8-六氧烷和各种过氧化氢中间体以及所需的二环-1，2，4，5-四氧烷。4A，7或者，二环-1，2，4，5-四氧六环可以通过环烷基环烷8或环烷酮烯醇醚9的臭氧化反应得到，也可以通过环烷酮O-甲基肟的臭氧化反应得到。事实上，伊藤等人对苯乙酮及其类似物的O-甲基肟的臭氧化反应。10得到相应的1，2，4，5-四氧六环产物，由于偏爱BaeyerrVilliger反应，这些产物不容易通过酸催化的过氧化反应获得。最近，Griesbaum11开发了O-甲基肟和酮的冷臭氧分解作为一种制备各种臭氧(1，2，4-三氧杂环己烷)的简便方法，这表明O-甲基肟的臭氧分解生成了羰基氧化物。在这项工作中，我们证明了环烷酮O-甲基肟的臭氧分解是一条合成二-1，2，4，5-四氧烷的有效的替代路线，其中一些是不能通过相应的环烷酮的酸催化过氧化得到的。
Dispiro-1, 2, 4, 5-tetraoxanes, also known as ketone diperoxides, dimeric peroxides, or carbonyl oxide dimers, are probably best known as precusors to macrocyclic hydrocarbons and lactones via thermal decomposition. 1 We recently found2 that certain dispiro-1, 2, 4, 5-tetraoxanes possess potent antimalarial activity comparable to artemisinin (qinghaosu), a clinically useful endoperoxide sesquiterpene lactone. To optimize activity and elucidate the mechanism of action for this novel class of antimalarial peroxides, the synthesis of structurally diverse dispiro-1, 2, 4, 5-tetraoxanes was required. The most direct method for dispiro-1, 2, 4, 5-tetraoxane synthesis3 is by acid-catalyzed peroxidation of cycloalkanones using aqueous hydrogen peroxide, a reaction optimized by Sanderson et al. 4 and by McCullough et al., 5 or by the use of bis (trimethylsilyl) peroxide in the presence of trimethylsilyl trifluoromethanesulfonate in an anhydrous variant on this reaction. 6 Unfortunately, in some cases, a complex mixture of peroxidic products is formed including trispiro-1, 2, 4, 5, 7, 8-hexaoxonanes and various hydroperoxide intermediates along with the desired dispiro-1, 2, 4, 5-tetraoxanes. 4a, 7 Alternatively, dispiro-1, 2, 4, 5-tetraoxanes can be obtained by ozonolysis of cycloalkylidenecycloalkanes8 or cycloalkanone enol ethers9 and conceivably by ozonolysis of cycloalkanone O-methyl oximes. Indeed, ozonolysis of the O-methyl oximes of acetophenone and several of its analogues by Ito et al. 10 afforded the corresponding 1, 2, 4, 5-tetraoxane products, which were not readily available via the acid-catalyzed peroxidation route due to a preference for the BaeyerrVilliger reaction. More recently, Griesbaum11 has developed the coozonolysis of O-methyl oximes and ketones as a convienent route to prepare a variety of ozonides (1, 2, 4-trioxolanes), suggesting carbonyl oxides are formed upon ozonolysis of O-methyl oximes. In this work, we show that ozonolysis of cycloalkanone O-methyl oximes is a useful alternative synthetic route to dispiro-1, 2, 4, 5-tetraoxanes, some of which could not be obtained via acid-catalyzed peroxidation of the corresponding cycloalkanones.