ISSN:
1434-193X
Keywords:
Antiprotozoals
;
Artemisinin
;
Trioxanes
;
Epoxysilane
;
Vinylsilane
;
Chemistry
;
General Chemistry
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
Notes:
Syntheses of the two artemisinin tricyclic analogs 39 and 40 bearing a methyl group at C-5a have been accomplished. The common starting material in both approaches was enantiomerically pure oxo nitrile (R)-10 which was elaborated through the Michael addition of chiral imine 9 to acrylonitrile. Several strategies for converting 10 into targets 39 and 40 were investigated. The strategy which was ultimately adopted employed the addition of [chloro(trimethylsilyl)methyl]lithium (15) to 10. The resulting epoxysilane 16 was converted into vinylsilane 36 by an original route involving first the regioselective opening of the oxirane ring by means of HBr, followed by zinc reduction. Addition of methyllithium to form 36 furnished pivotal derivative 37 which was finally converted into our targets 39 and 40 by ozonization. These trioxanes were thus synthesized by a linear sequence of seven chemical operations, with an overall yield of ca. 9% and 11%, respectively, from 2-methylcyclohexanone (8). Both compounds proved to be completely devoid of antimalarial activity on the “H” clone of Plasmodium falciparum. In contrast, the two structural analogs 43 and 44 having a hydrogen atom at the C-5a angular position display relatively high antimalarial activities. Thus, the fact that the replacement of the hydrogen atom at C-5a by a methyl group in tricyclic trioxanes 6 was detrimental to biological activity reinforced the hypothesis that tight hemin-trioxane complexes of type 7 are involved in the activation phase of these antimalarial agents.
Additional Material:
3 Ill.
Type of Medium:
Electronic Resource
