Synthetic Approaches to Mono- and Bicyclic Perortho-Esters with a Central 1,2,4-Trioxane Ring as the Privileged Lead Structure in Antimalarial and Antitumor-Active Peroxides and Clarification of the Peroxide Relevance.

The synthesis of 4-styryl-substituted 2,3,8-trioxabicyclo[3.3.1]nonanes, peroxides with the core structure of the bioactive 1,2,4-trioxane ring, was conducted by a multistep route starting from the aryl methyl ketones 1a - 1c . Condensation and reduction/oxidation delivered enals 4a - 4c that were coupled with ethyl acetate and reduced to the 1,3-diol substrates 6a - 6c . Highly diastereoselective photooxygenation delivered the hydroperoxides 7a - 7c and subsequent PPTS (pyridinium- p -toluenesulfonic acid)-catalyzed peroxyacetalization with alkyl triorthoacetates gave the cyclic peroxides 8a - 8e . These compounds in general show only moderate antimalarial activities. In order to extend the repertoire of cyclic peroxide structure, we aimed for the synthesis of spiro-perorthocarbonates from orthoester condensation of β-hydroxy hydroperoxide 9 but could only realize the monocyclic perorthocarbonate 10 . That the central peroxide moiety is the key structural motif in anticancer active GST (glutathione S-transferase)-inhibitors was elucidated by the synthesis of a 1,3-dioxane 15 -with a similar substitution pattern as the pharmacologically active peroxide 11 -via a singlet oxygen ene route from the homoallylic alcohol 12 .