The diastereoselective synthesis of 1,2-dioxanes and 1,2,4-trioxanes through electrophilic cyclizations of unsaturated hydroperoxyacetals and -ketals

Malaria, a debilitating and sometimes a lethal disease, has historically been treated with alkaloid based antimalarials. Some of the most virulent malarial strains have developed resistance to these traditional pharmaceuticals. However, potent antimalarial activity has recently been exhibited by the peroxide containing natural products, yingzhaosu A and artemisinin. The discovery of a novel class of antimalarials, in which activity is dependent upon the presence of peroxide linkage, has led to increased interest in development of methods for producing 1,2,4-trioxanes and 1,2-dioxanes. The synthesis of peroxide compounds is often limited by inability to directly introduce the peroxide functionality. We have discovered a general and facile method to unsaturated hydroperoxyacetals and -ketals, precursors of 1,2-dioxanes and 1,2,4-trioxanes, through selective ozonolysis.* The synthesis of 1,2,4-trioxanes and 1,2-dioxanes through electrophilic cyclization of unsaturated hydroperoxyacetals and -ketals has also led to some interesting mechanistic studies. Cyclization was originally postulated to proceed through a pseudo chair transition state, established by the substituents therein. Synthesis of 1,2,4-trioxanes provided high selectivity for the trans-3,6-dialkyl diastereomer. Synthesis of 1,2-dioxanes proceeded with moderate selectivity for the cis-3,6-dialkyl diastereomer (B), which can be linked to bias in the transition state. Equilibration of a mixture of diastereomers (A and B) with acidic methanol afforded a 3:1 mixture enriched in the trans-3,6-dialkyl-1,2-dioxane diastereomer, in which both alkyl groups occupy equatorial positions.* The stereoselectivity of the cyclizations was explained by the nucleophilic involvement of the anomeric peroxidic oxygen. Initial cyclization through a more rapid 5-exo cyclization of this ketal oxygen on the developing carbenium ion furnishes a 5-membered peroxonium ion intermediate which can rearrange to 1,2-dioxane product. The unexpected selectivity within this cyclization can be explained by comparison of 1,2-steric interactions of substituents in this newly proposed intermediate. In the synthesis of 1,2,4-trioxanes, a similar 5-membered peroxonium ion intermediate is also initially formed. However, preferential equilibration back to hydroperoxide substrate leads to effective cyclization through the pseudo chair transition state. ftn*Please refer to dissertation for diagrams