First enantioselective synthesis of 4-aminoalcohol quinoline derivatives through a regioselective SN2 epoxide opening mechanism

Mefloquine derivatives, contrary to chloroquine derivatives have not been widely studied to date. Consequently, mefloquine and its derivatives still remain very attractive synthetic targets. Although mefloquine is usually used clinically as a racemic mixture, some studies have shown that its (+)-enantiomer is more potent than the (−)-enantiomer. Moreover, the (−)-enantiomer is responsible for side effects due to reaction with the central nervous system adenosine receptors, while the (+)-enantiomer does no bind at this binding site. Recently, different libraries of racemic 4-aminoalcohol quinolines showed interesting antimalarial activities. Herein, we describe an enantiopure synthetic and straightforward route to prepare pure enantiomer 4-aminoalcohol quinoline derivatives through a 4-oxirane key-intermediate. A regioselective SN2 ring opening of this epoxide, by diverse amines, allows us to obtain the corresponding (R) or (S) 4-aminoquinolines with good yields and enantiomeric excesses generally superior to 92%. The reported methodology appears suitable for the synthesis of a large number of pure enantiomer 4-aminoalcohol quinoline derivatives.

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(R)-1-[2,8-Bis(trifluoromethyl)quinolin-4yl]ethane-1,2-diolC13H9F6NO298% Ee[α]D20=-52 (c 0.25, DCM)Source of chirality: asymmetric dihydroxylation of Sharpless

(R)-1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-((tert-butyldimethylsilyl)oxy)ethanolC19H23F6NO2Si99% Ee[α]D21=-41.1 (c 0.25, DCM)Source of chirality: (R)-1-[2,8-bis(trifluoromethyl)quinolin-4yl]ethane-1,2-diol

(R)-(R)-1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl-3,3,3-trifluoro-2-methoxy-2-phenylpropanoateC29H30F9NO4Si95% Ee[α]D24=-19.2 (c 0.25, DCM)Source of chirality: (R)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-((tert-butyldimethylsilyl)oxy)ethanol

(R)-4-(Oxiran-2-yl)-2,8-bis(trifluoromethyl)quinolineC13H7F6NO92% Ee[α]D20=-52 (c 0.25, DCM)Source of chirality: (R)-1-[2,8-bis(trifluoromethyl)quinolin-4yl]ethane-1,2-diol

(R)-4-(Oxiran-2-yl)-2,8-bis(trifluoromethyl)quinolineC13H7F6NO95% Ee[α]D20=-34.5 (c 0.25, DMSO)Source of chirality: (R)-4-[oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline

(R)-Ethyl-4-(4-(2-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(hydroxyethyl)piperazin-1-yl)butanoateC23H27F6N3O389% Ee[α]D24=-70.7 (c 0.25, DCM)Source of chirality: (R)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline

(R)-1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-(pentylamino)ethanolC18H20F6N2O94% Ee[α]D26=-50.3 (c 0.25, MeOH)Source of chirality: (R)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline

(R)-1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)-2-(hexylamino)ethanolC19H22F6N2O94% Ee[α]D26=-47.5 (c 0.25, MeOH)Source of chirality: (R)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline

(R)-tert-Butyl-(3-(4-(3((2-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(hydroxyethyl)amino)propyl)piperazin-1-yl)propyl)carbamateC28H39F6N5O393% Ee[α]D24=-49.6 (c 0.25, DCM)Source of chirality: (R)-4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline