The structure and antimalarial activity of some cis-fused bicyclic 1,2,4-trioxane derivatives

(4aRS,7aRS)-4a,7a-Dihydro-3,3-dimethyl-6,7a-diphenyl-7H-cyclopenta[1,2-e][1,2,4]trioxine (1) was converted into its exo-5,6-epoxide (7) and dichloromethylene (8) derivatives. The reaction of (4'aRS,7'aRS)-6',7'a-bis(4-fluorophenyl)-4'a,7'a-dihydrospiro[cyclopentane-1,3'-7' H-cyclopenta[1,2-e]-[1,2,4]trioxine] (3) with Pb(OAc)(4) and N-aminophthalimide gave the exo-5,6-N-phthalimidoimine (9). Acid catalysis of 9 afforded the cyclopentenylamino derivative (10). Treatment of 3 with Me3SiN3 and C6H5IO gave mainly the exo-5-azidobenzyl dimer (12) of C-2 symmetry. A minor isomer was assigned as the meso-dimer (14). The structure of 12 was determined by X-Ray. The in vitro activity of 7, 8, 9, 10 and 11 against Plasmodium falciparum was determined and found, with the exception of 8, to be similar to that of 1 and 3.