Johnson, Karen Amanda; (1996) Synthesis of 1,2,4-trioxanes with antimalarial activity. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

A series of 1,2,4-trioxanes has been synthesised by the mercury(II)- mediated cyclisation of allylic hemiperoxyacetals obtained by the addition of allylic hydroperoxides to aldehydes and ketones. The methodology has been extended by variation of the carbonyl compound, the allylic hydroperoxide and the mercury(II) salt. Allylic hydroperoxides CH2:C(Ph)CH(OOH)CH2OX (X=H, CONHPh and Ac), obtained from the regiospecific photooxygenation of the corresponding allylic alcohol and derivatives CH3C(Ph):CHCH2OX, gave hemiperoxyacetals with aldehydes and ketones which upon cyclisation with mercury(II) trifluoroacetate then reduction with sodium borohydride diastereoselectively afforded 1,2,4-trioxanes with XOCH2 substituents at C-6. β-Mercuriated allylic hydroperoxides from the hydroperoxymercuriation of conjugated dienes reacted with propanal to form hemiperoxyacetals and subsequent reaction with mercury(II) acetate followed by anion exchange gave bis-mercuriated 1,2,4-trioxanes. The synthesis of 1,2,4-trioxanes from 2,3-dimethylbut-1-en-3-yl hydroperoxide was extended to the use of dicarbonyl compounds. This afforded peroxides with a 3,3-spirocycloalkyl substituent and a 3-phenyl substituent, each with additional functionality in the form of the second carbonyl group. These 1,2,4-trioxanes were modified by carrying out reduction and condensation reactions at the remaining carbonyl group. The 3,3-spirocycloalkyl-1,2,4-trioxanes were not conformationally locked but peroxide ring inversion was frozen out at -59 °C. Carbohydrate molecules were fused directly onto the 1,2,4-trioxane structure by using the mercury(II)-mediated cyclisation of hemiperoxyacetals derived from carbohydrate-aldehydes with 2,3-dimethylbut-1-en-3-yl hydroperoxide. An attempt was made to combine two antimalarial components (the 1,2,4-trioxane structure and cinchonine) to see if the resultant compounds would exhibit synergistic effects on activity. Our approach was to oxidise the 3-vinyl group of cinchonine to the aldehyde level. However, the cinchonine- aldehyde failed to afford 1,2,4-trioxanes under our cyclooxymercuriation conditions. Many of the 1,2,4-trioxanes were tested in vitro against the human malaria parasite P. falciparum and displayed significant and wide-ranging activity.

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