Fluoro artemisinins: difluoromethylene ketones.
The reactions of the ring-contracted aldehydes, derived from anhydrodihydroartemisinin, with gem-difluoroenoxysilanes in the presence of BF(3).Et(2)O afforded the corresponding difluoromethylene ketol adducts in good yields. Similar Lewis acid catalyzed reactions of dihydroartemisinin acetate with the difluoroenoxysilanes provided the 10-substituted difluoromethylene ketones in good to moderate yields. Interestingly enough, the course and the stereochemistry of these reactions are highly dependent on the nature of the Lewis acids used; the addition reaction was accompanied by epimerization at C-9, and the stereochemistry at C-10 depends on the difluoroenoxysilane used. The best results were obtained using SnCl(4) to give the 9alpha,10beta-stereoisomer in high stereoselectivity. When 0.4 equiv of SnCl(4) was used for the reaction with the alpha-(4-methoxyphenylenoxysilane)-beta,beta-difluoroenoxysilane, however, a rearrangement of the endoperoxide was observed.
Chorki
F
F
BIOCIS, CNRS, Faculté de Pharmacie, Rue J.B. Clément, Châtenay-Malabry F-92296, France.
Grellepois
F
F
Crousse
B
B
Ourévitch
M
M
Bonnet-Delpon
D
D
Bégué
J P
JP
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry; D037621:Artemisinins; D004365:Drugs, Chinese Herbal / Q000138:chemical synthesis / Q000737:chemistry*; D005449:Fluorenes / Q000737:chemistry*; D006838:Hydrocarbons; D007659:Ketones / Q000737:chemistry*; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000187:drug effects; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry*
D000962:Antimalarials; D037621:Artemisinins; D004365:Drugs, Chinese Herbal; D005449:Fluorenes; D006838:Hydrocarbons; D007659:Ketones; D012717:Sesquiterpenes; C030011:carbene; C041509:fluorene; C031327:artemisinin; D008697:Methane