Antimalarials, peroxidic, synthesis

A short synthesis of the antimalarial peroxide yingzhaosu C, which allowed the relative stereochemistry of the natural product to be assigned as cis, has been achieved by means of tandem peroxyl radical cyclization-oxygen entrapment... 

SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIPS OF PEROXIDIC ANTIMALARIALS BASED ON ARTEMISININ... 

However, in this section, the total synthesis of yingzhaosu A, the lead compound of a particular class of antimalarial 1,2-dioxocins, is reported. The synthesis involves eight steps and a 7.3% overall yield starting from (A)-limonene (Scheme 64). Besides the TOCO procedure that allowed the formation of five bonds in one step, the most intriguing steps involved the selective hydrogenation of a C-C double bond in the presence of a peroxide and an aldehyde functionalities (step vi) and the stereoselective reduction of the side-chain carbonyl with (R)-CBS catalyst (step viii). Last but not least, the old classical fractional recrystallization allowed the separation of yingzhaosu A from its C-14 epimer and saved two synthetic steps <2005JOC3618>. 

Avery, M. A. Alvimgaston, M. Woolfrey, J. R. Synthesis and structure-activity -relationships of peroxidic antimalarials based on artemisinin. Advanc. Medicinal Chem.,... 

Synthesis and reactions of antimalarial bicyclic peroxides 00JHC639. 

General methods for the preparation of 1,2,4,5-tetraoxanes Key structures for the development of peroxidic antimalarial agents 12KGS60. Reactions oftetrazines with dienophiles 12KGS1237. 1,2,4,5-Tetrazines and azolo[l,2,4,5]tetrazines Synthesis and reactions with nucleophiles 13KGS75. 

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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