| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 1345795 | Tetrahedron: Asymmetry | 2016 | 11 Pages |
Recently, the asymmetric synthesis and biological activity of (R)- and (S)-4-aminoquinolinemethanols 1 as mefloquine analogues were reported. Several compounds showed very promising antimalarial activity, in the nanomolar range, against Plasmodium falciparum 3D7 and W2. Enantiomers with an (S)-absolute configuration were more active than their (R)-counterparts by a factor ranging from 2 to 15-fold, according to the compound and the plasmodial strain considered. In continuation of our work, three novel series of enantiopure aminoquinolines 2a, 2b, and 3 were synthesized via an asymmetric aminohydroxylation reaction. These compounds were obtained in 2 or 4 steps from a common amidoalcohol key-intermediate 4. They displayed IC50 values close to the micromolar against the two P. falciparum strains 3D7 and W2. The study of the structure–activity relationships allows us to better understand the importance of the substitution and of the stereochemistry at C11 and C12 position of the quinoline and gives tracks for the design of new compounds more active against the plasmodial strains.
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(S)-Benzyl (1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-hydroxyethyl)carbamateC21H16F6N2O380% ee[α]D20 = −28.9 (c 0.1, MeOH)Source of chirality: Asymmetric Sharpless aminohydroxylationAbsolute configuration: (S)
(S)-Benzyl(1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)carbamateC27H30F6N2O3Si76% ee[α]D20 = −7.8 (c 0.1, MeOH)Source of chirality: (S)-Benzyl (1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-hydroxyethyl)carbamateAbsolute configuration: (S)
(S)-1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-((tert-butyldimethylsilyl)oxy)ethan-amineC19H24F6N2OSi74% ee[α]D20 = +37.8 (c 0.1, MeOH)Source of chirality: (S)-Benzyl(1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)carbamateAbsolute configuration: (S)
(R)-N-((S)-1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)-3,3,3-trifluoro-2-methoxy-2-phenylpropanamideC29H31F9N2O3Si[α]D20 = +39.9 (c 0.1, MeOH)Source of chirality: (S)-1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-((tert-butyldimethylsilyl)oxy)ethan-amineAbsolute configuration: (R),(S)
(S)-N-(1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)pentan-1-amineC24H34F6N2OSi78% ee[α]D20 = +30.7 (c 0.1, MeOH)Source of chirality: (S)-1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-((tert-butyldimethylsilyl)oxy)ethan-amineAbsolute configuration: (S)
(S)-N-(1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)heptan-1-amineC26H38F6N2OSi74% ee[α]D20 = +18.0 (c 0.1, MeOH)Source of chirality: (S)-1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-((tert-butyldimethylsilyl)oxy)ethan-amineAbsolute configuration: (S)
(S)-2-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-(pentylamino)ethanolC18H20F6N2O86% ee[α]D20 = +22.0 (c 0.1, MeOH)Source of chirality: (S)-N-(1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)pentan-1-amineAbsolute configuration: (S)
(S)-2-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-(heptylamino)ethanolC20H24F6N2O74% ee[α]D20 = +25.6 (c 0.1, MeOH)Source of chirality: (S)-N-(1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)pentan-1-amineAbsolute configuration: (S)
(S)-2-((1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-(pentyloxy)ethyl)imino)-1-phenylethanoneC26H26F6N2O364% ee[α]D20 = −12.6 (c 0.1, MeOH)Source of chirality: (S)-Benzyl (1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-hydroxyethyl)carbamateAbsolute configuration: (S)
(S)-1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-(pentyloxy)ethanamineC18H20F6N2O58% ee[α]D20 = +28.1 (c 0.1, MeOH)Source of chirality: (S)-2-((1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-(pentyloxy)ethyl)imino)-1-phenylethanoneAbsolute configuration: (S)
