Cycloadditions between Carbonyl Oxides Generated by the Ozonolyses of Cycloalkenes and Carbonyl Compounds: Novel Method for the Synthesis of Bicyclic 1,2,4,6-Tetroxepanes

Mono-and polycyclic peroxides have attracted consider-able attention as models or analogues of an increasing num-ber of peroxidic natural products, some of which posses attractive pharmacological properties.1,2 [3+2] cycloaddition reactions between carbonyl oxides generated in situ by ozo-nolysis of olefins, and carbonyl oxides are well established. Ozonolyses of certain cycloolefins 1 in methanol, however, revealed a partially anomalous behavior as compared to acy-clic olefins. A priori, one would have expected that the pri-mary intermediates of type 2 are trapped by methanol to give compounds of type 4. But in addition to 4, variable amounts of the isomeric product of type 5 were obtained.4,5 This was explained by an intramolecular reaction between the carbo-nyl oxide moiety and the aldehyde group of 2 to give inter-mediate 3, which is subsequently trapped by methanol to give 5 (Scheme 1). In the present work, we are interested to find out whether the carbonyl oxide moieties in intermediates of type 3 can be trapped by added aldehydes 6 to give tetroxepanes 9 in addi-tion to cross ozonides of type 8.6-9 We now report the first examples of bicyclic peroxides 9, containing the compara-tively rare 1,2,4,6-tetroxepane system, derived from cyclo-additions between carbonyl oxide 3 generated by the ozonol-ysis of cycloolefins 1 and aldehydes 6. We have ozonized the cyclic olefins 1a-e in dichlo-romethane at-78 oC in the presence of two molar equiva-lents of a formaldehyde 6a. Ozonolyses of cylopentene 1a, cyclohexene 1b, cycloheptene 1c, cyclooctene 1d and cyclododecene 1e in the presence of formaldehyde 6a as a good dipolarophile10,11 afforded in each case the peroxidic products and the corresponding cross ozonides 8. Peroxidic products were ozonide 7a in the ozonolysis of cyclopentene 1a and the tetroxepanes 9b-9e in the ozonolyses of 1b, 1c, 1d and 1e, respectively. These results show that trapping of the carbonyl oxide moiety of intermediates 2 and 3 with formaldehyde can be effectively performed as outlined i