1.2.4- Trioxane antimalarials synthesis

Posner, G. H. Oh, C. H. Wang, D. Gerena, L. Milhous, W. K. Meshnick, S. R. Asawamahasadka, W. Mechanism-based design, synthesis, and in vitro antimalarial testing of new 4-methylated trioxanes structurally related to artemisinin The importance of a carbon-centered radical for antimalarial activity. J. Med Chem., 1994, 37(9) 1256-1258. 

In the last few years, variations on the basic stracmre have been launched in combination with other antimalarials (usually variations on the chloroquine structure) such as dihydroartemismin and piperaquine phosphate (Artekin), artemether and lumefantrine (Coartem), artesunate/mefloquine (Artequin) and artesunate, sulfamethoxypyrazine, and pyrimethamine (Co-Arinate). Currently, there is another fixed dose combination with an artemisinin derivative in clinical trials, pyronaridine/artesunate (Pyramax in Phase III). However, the tri-oxo scaffold system in artemisinins has led to the synthesis of not only artemisinin variations but to totally synthetic molecules with the trioxane moiety included, such as arterolane tosylate (81). This compound is in Phase II trials as a single agent under Ranbaxy and is in Phase I trials in combination with piperaquine phosphate, also under Ranbaxy. 

Due to the unabated interest in the antimalarial activity of artemisinin 17 and its derivatives, the synthesis of 1,2,4-trioxanes has been studied intensively a comprehensive overview is given in CHEC-II(1996). Developed methods have been applied continuously and a survey of synthetic paths from 1996 onward is presented below. 

Compared to batch and single-channel microreactors, the results clearly demonstrate that the daily output can considerably be increased by application of the scaled-up dual-channel microreactor. In the next step, the dual-channel reactor was applied for the photosensitized oxidation of aDyUc alcohols 99 (Figure 6.48). The corresponding products, aUyl hydroperoxide alcohols 100, can be employed for the synthesis of artemisinin-derived antimalarial 1,2,4-trioxanes. The... 

Endoperoxides (also 1,2-dioxetanes) are versatile starting materials for further transformations. In view of the weak 0-0 bond, these peroxides are thermally sensitive to homolytic cleavage, a feature that makes most of them ha2aidous. Ring opening opens up attractive opportunities for selective transformations that include reductions (diols), oxidations (dicarbonyl products), rearrangements (hydroxy carbonyl compounds, epoxy carbonyl compounds, fo/s-epoxides, ene diones, etc.) and additions (polycycKc dioxanes or trioxanes, some of which display antimalarial activity). The synthesis and the subsequent reactions of the 2,3-dioxabicyclo[2.2.2]oct-7-en-5-one skeleton have been studied by Adam etak An impressive number of chemical transformations and examples for applications in organic synthesis have been collected in several reviews. 

Recently, extensive efforts have been devoted to the synthesis of cycHc peroxides since the discovery of artemisinin and related antimalarial l,2,4-trioxanes. > As described previously, PET oxygenation is a unique but effective method for the preparion of cycHc peroxides, which is also appHcable to the synthesis of the peroxide structures from arylated cyclopropanes, aziridines, and olefins. - ... 

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