Epimerization in acid degradation products of artemisinin

Abstract

Treatment of artemisinin 1 with acid leads to either a cyclohexane dione degradation product 10, which is a useful intermediate for biosynthetic studies of artemisinin, or to a decalin system which has undergone epimerization 8. It is shown by NMR spectroscopy, chemical reactions and molecular modelling that the bulky 7-substituent in the epimerized decalin series (8, 17, 14) adopts an axial solution conformation and that this is thermodynamically favoured over the natural configuration for which this substituent is equatorial (11, 15, 13). Conversely, for the cyclohexane dione series, the natural configuration in which the 7-substituent is equatorial is more favoured. Reasons for the differing conformational preferences in the two series, which are ultimately responsible for promoting epimerization, are discussed and a simple spectroscopic procedure for identification of epimerized products is presented.