An Unusual Acid-catalyzed Rearrangement of 1,2,4-Trioxanes

A new Lewis acid-catalyzed rearrangement of the peroxide group in two 1,2,4-uioxanes, deoxoartemisinin and 12P-allyldeoxoa1temisinin, yielding ring enlarged oxide, is described.The discovery in 1979 that artemisinin (I), the active principle of the medicinal herb Artemisia annua, was an effective antimalarial drug against chloroquine-resistant strains of Plasmodium faciparum prompted several groups to synthesize artemisinin, its derivatives,' and other 1,2,4-trioxanes.3A variety of esters, ethers, carbonates and other derivatives of dihydroartemisinin (2) were prepared.A study of the metabolites of the ethyl ether of dihydroartemisinin, arteether, with rat liver microsomes revealed that the ethyl group was rapidly lost to form dihydroartemisinin.4 Hydrolysis of esters of dihydroartemisinin probably also occurred to yield dihydroanemisinin.Several group$ prepared 12a-and 12P-alkyldeoxoartemisinin derivatives from artemisinic acid in an effort to obtain compounds that would not he degraded enzymatically to dihydroartemisinin (2).We prepared 12P-allyldeoxoartemisinin (3) from dihydroartemisinin6 and found it was accompanied by small quantities of an isomeric product (4).which was found to have arisen from the action of boron trifluoride etherate on 3. The 'H-nmr spectrum of 4 was similar to that of 3 except for a new resonance at 6 = 4.10 (1H).The presence of overlapping resonances between the allyl group and another proton in its 'H nmr spectrum made a structural assignment difficult.To circumvent this difficulty we tteated a sample of deoxoartemisinin (5),7 with boron trifluoride etherate.A less polar isomeric product (6) was formed in satisfactory yield (57%). with a new