Shah, Aneela; (1994) The synthesis and reactions of some potentially antimalarial 1,2,4-trioxanes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

A series of potentially antimalarial 1,2,4-trioxanes were prepared by the electrophile-mediated cyclisation of allylic hemiperoxyacetals. The starting allylic hemiperoxyacetals were obtained by the addition of allylic hydroperoxides to aldehydes and ketones. Studies were carried out on the effects upon 1,2,4-trioxane yields of varying the starting aldehydes, ketones, hydroperoxides and electrophiles. Generally 1,2,4-trioxanes derived from aldehydes (CHO) were isolated in higher yields than those derived from ketones (R1COR2). In addition aliphatic aldehydes gave higher yields than aromatic aldehydes. Ketone-derived 1,2,4-trioxanes in which R1=R2 were not conformationally locked. The ring inversion barriers for these compounds were determined from dynamic nmr studies of their conformational mobility. Different electrophiles were used to effect the cyclisation step. Mercury(II) acetate, mercury(II) trifluoroacetate, N-iodosuccinimide and N-bromosuccinimide were all used. In general the intramolecular oxymercuriations proved to be much more versatile and gave higher yields than the halogenocyclisations. The starting allylic hydroperoxides were obtained by singlet oxygenation of the appropriate alkene. The two allylic hydroperoxide systems studied were 2,3-dimethylbutyl-1-en-3-yl hydroperoxide and cyclohex-2-enyl hydroperoxide. The 2,3-dimethylbutyl-1-en-3-yl hydroperoxide system was the more versatile of the two and gave the highest 1,2,4-trioxane yields via both the intramolecular oxymercuriation and halogenocyclisation routes. The cyclohex-2-enyl hydroperoxide-derived hemiperoxyacetal only yielded bicyclic 1,2,4-trioxanes via mercury(II) trifluoroacetate-mediated ring closure. A silver-salt-assisted substitution method for the synthesis of 1,2,4-trioxanes was also attempted. Halogen-containing hemiperoxyacetals derived from the reaction of β-halohydroperoxides and aldehydes, were treated with silver(I) salts with limited success. The 1,2,4-trioxanes were subjected to photolysis and to treatment with iron(II) sulfate. In both cases preference for rearrangement via 1,5-transfer of a hydrogen from C-3 to an oxygen centred radical was observed. Some 1,2,4-trioxane compounds were tested for antimalarial activity in vitro and were found to be significantly active.

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