A series of C-9 beta-substituted artemisinin analogs (2-21) were synthesized via dianion alkylation of the total synthetic intermediate 57 followed by subsequent ozonolysis/acidification, or by alkylation of the enolate derived from (+)-9-desmethylartemisinin, 2. Inactive acyclic analogs 22 and 23 were synthesized by nucleophilic epoxide opening and the ring contracted analog 24 was prepared by an alternate route. 10-Deoxo-9-alkyl derivatives 68 and 70 were synthesized convergently from intermediates in the preparation of 9-alkyl derivatives. In vitro bioassay was conducted in W-2 and D-6 clones of drug resistant Plasmodium falciparum. Comparative molecular field analysis (CoMFA) of the 9-alkyl lactone derivatives provided a model with a cross-validated r2 = 0.793. Inclusion of inactive 1-deoxyartemisinin analogs 26-42 provided a model with a value of 0.857. The activities of a number of other analogs of divergent structure (43-56) were predicted with good accuracy using the CoMFA model.

Novel 3- and 9-substituted analogs (4-19) of 10-deoxoartemisinin, 3, were prepared from the corresponding known lactones by one-pot reduction with sodium borohydride and boron trifluoride etherate. Reproducibility problems associated with this heterogeneous reaction were encountered on small reaction scales, and thus alternative methodology was sought for this reduction. Conversion of the lactones to tetrahydropyrans via the corresponding intermediate lactols was made more reproducible using a two-step sequence involving low-temperature reduction with diisobutylaluminum hydride followed by deoxygenation with boron trifluoride etherate in the presence of triethylsilane. In this manner, 10-deoxoartemisinin (3) could be obtained from artemisinin (1) in greater than 95% overall yield. All analogs were tested in vitro against W-2 and D-6 strains of Plasmodium falciparum. Several of the analogs were much more active than the natural product (+)-artemisinin (1) or 10-deoxoartemisinin (3). Conventional structure-activity relationships are discussed in relation to the bioassay data.

Novel antimalarial artemisinin analogs, 3-alkylartemisinins as well as 3-(arylalkyl)- and 3-(carboxyalkyl)artemisinins, were prepared via the synthetic intermediate 2. Formation of the N,N-dimethylhydrazones 5 and 24 and then regio- and chemoselective deprotonation followed by alkylation provided initially alkylated hydrazones that upon chromatography gave ketones 6-13 and 25-30. Direct ozonolysis of the ketones followed by in situ acidification lead directly to the formation of title compounds 14-21 and 31-36. The analogs were tested in vitro against W-2 and D-6 strains of Plasmodium falciparum and found to be in some cases much more active than the natural product (+)-artemisinin. The results were included in structure-activity relationship (CoMFA) studies for further analog design.