Asymmetric syntheses of enantiomeric 3-p-fluorophenyl 1,2,4-trioxane analogues of the antimalarial artemisinin

Article abstract of DOI:10.1016/S0040-4039(99)01892-4

We have devised an asymmetric synthesis of chiral artemisinin analogues (+)-4a and (-)-4a that retain the tricyclic ring system found in the natural product. The key step in the preparation of (+)-4a involves an asymmetric MgCl₂ promoted Michael addition of the (R)-(-)pyrrolidinemethanol-derived enamine 8 to acrylonitrile. This gives the corresponding ketone 9 in 50% yield (>95% ee). Subsequent elaboration of 9 provides the trioxane target (+)-4a in greater than 85% ee. Enantiomeric trioxane (-)-4a was prepared in a similar manner using (S)-(+)-pyrrolidinemethanol in the first step of the sequence.