Epoxy ester-orthoester rearrangement as a key step in the method of indirect dihydroxylation of monoterpenoid homoallyl alcohols.

Polyhydroxy containing compounds, in particular those derived from monoterpenoids, have attracted attention as biologically active compounds, but a key limitation in their synthesis is the need for regio- and stereoselective hydroxylation. Here, the synthesis of two dihydroxy derivatives and potential metabolites of the antiparkinsonian agent Prottremine, which is a monoterpenoid diol with a para-menthene scaffold, was carried out using an epoxy ester-orthoester rearrangement as the key step. The isomerization of epoxyacetate derivative of Prottremine to corresponding orthoester proceeded stereoselectively, as a result, two new stereoisomeric tetraols were obtained in yields of 22% and 3%. Using a similar approach directly and in combination with the Mitsunobu reaction, three stereoisomeric triols based on (-)-isopulegol and (+)-neoisopulegol were synthesized in yields ranging from 13% to 36%, thus demonstrating the potential to expand the approach to other compounds. Isomerization of the epoxyacetate derivative in the presence of superacids was accompanied by aromatization of cyclohexene ring with the formation of the dioxolane cation, which then, upon longer storage at room temperature, was completely converted into a mixture of protonated ketones, one of which was a dimeric form (dication).