[show abstract][hide abstract] ABSTRACT: The 1,3-dipolar cycloadditions of ethyltrifluorocrotonates to the azomethineylide, generated from 2-(tert-butyl)-3-methyl-imidazolin-4-one and formaldehyde, proceeds with a high degree of stereo- and regioselectivity to give precursors of 4-trifluoromethylpyrrolidine-2,3-dicarboxylic acids in good yields.
[show abstract][hide abstract] ABSTRACT: This report is an overview on the design, preparation, and evaluation of metabolically stable artemisinins, using fluorine substitution. The chemical challenges encountered for the incorporation of fluorine-containing elements and the preparation of a large range of 10-trifluoromethyl artemisinin derivatives are detailed. Impact of the fluorine substitution on the antimalarial activity is also highlighted. Preclinical data of lead compounds, and evidence for their strong and prolonged antimalarial activity are presented.
[show abstract][hide abstract] ABSTRACT: Exo gem-difluoromethylene-artemisinins (8) has been designed to mimic artemisinin. The classical Wittig olefination reaction applied to artemisinin failed. An alternative reaction involving the generation of an α-CF3 carbanion, from the corresponding bromide 6, allowed the access to the target compound 8, and could also be exemplified in sugar series. The replacement of the carbonyl function by a difluoroethylene moiety resulted in a better antimalarial activity.
Journal of Fluorine Chemistry - J FLUORINE CHEM. 01/2006; 127(4):637-642.
[show abstract][hide abstract] ABSTRACT: This present report is devoted to the recent advances, in these last 10 years, in fluorinated analogues of natural products developed as pharmaceuticals, marketed, registered or in clinical development. These mainly concern fluorine-substituted nucleosides, alkaloids, macrolides, steroids, amino acids and prostaglandins.
[show abstract][hide abstract] ABSTRACT: [reaction: see text] New artemisinin-derived dimers, fluorinated or not, have been prepared by a self-cross metathesis reaction in the presence of first- or second-generation ruthenium catalysts without degradation of the endoperoxide bridge and with a good E/Z selectivity (up to 100:0).
[show abstract][hide abstract] ABSTRACT: Trifluoromethylated nitrogen-containing molecules have been shown to have important biological effects and their synthesis is in the focus of the pharmaceutical industry. In the last few years, simple nitrogen derivatives of fluoral, i.e. imines, acetals and oxazolidines, have emerged as powerful building blocks to synthesize these target molecules and relevant precursors. This review summarizes the chemistry of these "N-derivatives of fluoral", with special highlight on the syntheses of peptidomimetic units (amino alcohols, amino acids...) and heterocycles (piperidines, beta-lactams...).
Chemical Society Reviews 08/2005; 34(7):562-72. · 24.89 Impact Factor
[show abstract][hide abstract] ABSTRACT: The synthesis of the title compound is described through original and tailored synthetic protocols. The addition of vinylmagnesium bromide to CF(3)-N-aryl and N-alkyl aldimines was efficient and did not require an activating N-substituent. The resultant CF3-allylamines were converted in an efficient and completely stereoselective route to syn CF3-epoxides 3 via formation of bromhydrins 8. The same sequence performed from the aldimine substituted with the methyl ether of the (R)-phenylglycinol provided the homochiral (R,R)-amino epoxide (de >98%). This study has allowed access to the novel racemic and homochiral trifluoromethyl beta-amino epoxides, analogues of key precursors of various HIV protease inhibitors.
The Journal of Organic Chemistry 01/2005; 70(2):699-702. · 4.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: The synthesis of a series of C-10 trifluoromethyl ethers of artemisinin has been achieved from key bromide 8, itself carried out in two steps from artemisinin. The substitution of 8 with methanol, ethanol, or succinic acid allowed the access of C-10 CF(3) analogues of beta-artemether, beta-arteether, or artesunate, respectively, in good yields (up to 89%). The presence of the CF(3) group at C-10 of artemisinin clearly increased the chemical stability under simulated stomach acid conditions. For example, the CF(3) analogue of arteether was found to be around 45 times more stable than arteether itself. The influence of the CF(3) moiety on biological activity was also highlighted. CF(3) analogues of artemether and arteether exhibited a high in vivo antimalarial activity on mice infected with Plasmodium berghei NK173, with a complete clearance of the parasitemia during the entire observation period (25 days).
Journal of Medicinal Chemistry 06/2004; 47(10):2694-9. · 5.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: New fluoroartemisinin derivatives containing polar or water-soluble functionalities at C-16 (11a-j, 12a-g) were synthesized using the key intermediate 16-bromo-10-trifluoromethyl anhydrodihydroartemisinin 10. The substitution reaction from 10 was more selective than that from the nonfluorinated parent bromide; the allylic bromide 10 underwent no allylic rearrangement and provided only nucleophilic substitution products in high yields with N-, O-, and C-nucleophiles. Among them, amines 11a-c appeared to be highly in vivo efficient antimalarials on mice infected with Plasmodium berghei, more than the reference sodium artesunate 1d. In particular, the most effective piperazinoethanol derivative 11b cured all mice after oral treatment at a dose lower than 10 mg/kg. Further pharmacokinetic studies showed that the bioavailability in rats following oral administration was 25 times greater for 11b than for artemether 1b.
Journal of Medicinal Chemistry 04/2004; 47(6):1423-33. · 5.61 Impact Factor