Trifluoromethyl artemisinin

Extensive research has been carried out in efforts to increase the duration of action of artemisinin derivatives. An approach to design more metabolically stable artemisinins has been developed by introducing a trifluoromethyl group at C-10 43 5 electron-withdrawing character, this substituent was expected to... 

Finally, gem-difluoromethylene analogs, e.g., 315 and 316, designed to mimic artemisinin, have been prepared by the treatment of the trifluoromethyl derivatives 169 and 173 with 2 equiv of MeLi in THF at —78 °C, and their anti-malarial activity investigated (Scheme 53) <2006JFC637>. 

The hemiketal 12 was easily prepared in high yield (80%) from artemisinin by treatment with trifluoromethyl trimethylsilane (TMSCF3) in the presence of tetrabutylammonium fluoride trihydrate (TBAF, 3H20). Complete desilylation occurred after addition of water (see Scheme 6.5). The reaction was stereoselective, and the a configuration of the CF3 group was unambiguously determined (P-12) [40,44], However, this configuration at C-10 is not the result of an a approach of the CF3 but of a thermodynamic equilibrium of the... 

Aryl difluoroenoxysilanes 20 were prepared by Mg-promoted defluorination of trifluoromethyl ketones, according to Uneyama s procedure [60], Their reaction with DHA acetate appeared to be much more critical than any other Lewis acid-catalyzed reaction and the setup was very troublesome. Each difluoroenoxysilane required specific reaction conditions (e.g., Lewis acid and rate of addition) (see Scheme 6.11 and Table 6.4) [61]. For instance, the best conditions found for the preparation of the difluoroketone 21a (SnCh, 0.4 equivalents) provided a completely rearranged artemisinin skeleton when applied to the enoxysilane 20b. Furthermore, the stereochemical outcome of reactions was unusual difluoroketones 21a-c all possess the epf-artemisinin configuration at C-9 (9a-Me). The mechanism of this epimerization at C-9 is not fully understood, but probably... 

Grellepois, F., Chorki, F., Crousse, B. and Ourevitch, M. (2002) Anhydrodihydroartemisinin and its 10-trifluoromethyl analogue access to novel D-ring-contracted artemisinin trifluoromethyl ketones. J. Org. Chem., 67, 1253-1260. 

Another recent application of the reagent, in the pharmaceutical chemistry, is the trifluoromethylation of the antimalarial compound artemisinin, with the aim of improving the pharmacological profile of the natural compound [76] (Scheme 2.130). 

Scheme 2.130 Nucleophilic trifluoromethylation of artemisinin to the -trimethylsilyl ether as the kinetic primary product and the a-trifluoromethyl hemiketal as the thermodynamic final product after desilylation [76].

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