124. The deoxygenation and isomerization of artemisinin and artemether and their relevance to antimalarial action

Article abstract of DOI:10.1002/hlca.19960790520

The treatment of artemisinin (1) and β-artemether (6) with Zn dissolving in AcOH for a few hours results in mono-deoxygenation giving deoxyartemisinin (5) and deoxy-β-artemether (7), respectively, as the sole product. In contrast, submission of 1 to FeCl₂·4 H₂O in MeCN at room temperature for 15 min causes only isomerization, (3aS,4R,6aS,7R,10S,10aR)-octahydro-4,7-dimethyl-8-oxo-2H,10H-furo[3,2-i] benzopyran-10-yl acetate (8) and (3R)-3-hydroxydeoxyartemismin (9) being produced in 78 and 17% yield, respectively. The action of FeCl₂·4 H₂O in MeCN on 6 is similar. Under the same conditions, 6 gives products analogous to 8 and 9 accompanied by an epimeric mixture of 2-[4-methyl-2-oxo-3-(3-oxobutyl)cyclohexyl]propanaldehyde in yields of 32, 23, and 16%, respectively No epoxide is formed on repeating the last two experiments in the presence of cyclohexene. The deoxygenation of 1 and 6 by Zn is rationalized in terms of its oxophilic nature. The catalyzed isomerization of 1 and 6 by Fe²⁺ is attributed to the redox properties of the Fe²⁺/Fe³⁺ system.