Chiral Vicinal Diamines Derived from Mefloquine

Abstract

Novel 1,2-diamines based on the mefloquine scaffold prepared in enantiomerically pure forms resemble 9-amino- Cinchona alkaloids. Most effectively, 11-aminomefloquine with an erythro configuration was obtained by conversion of 11-alcohol into azide and hydrogenation. Alkylation of a secondary amine unit was needed to arrive at diastereomeric threo -11-aminomefloquine and to introduce diversity. Most of the substitution reactions of the hydroxyl group to azido group proceeded with net retention of the configuration and involved actual aziridine or plausible aziridinium ion intermediates. Enantiomerically pure products were obtained by the resolution of either the initial mefloquine or one of the final products. The evaluation of the efficacy of the obtained vicinal diamines in enantioselective transformations proved that erythro -11-aminomefloquine is an effective catalyst in the asymmetric Michael addition of nitromethane to cyclohexanone (up to 96.5:3.5 er) surpassing epi -aminoquinine in terms of selectivity.

A Review of Modifications of Quinoline Antimalarials: Mefloquine and (hydroxy)Chloroquine

“…The resolution of the racemic mixture was also conducted with O,O ′-di- p -toluoyl-tartaric acid [ 20 ]. The recycling of the material and the use of either enantiomer of the resolving agent provided both enantiomers in a very high yield (86%) and enantiomeric excess (ee above 99%) [ 21 ].…”

“…Mefloquine acetamide MQ-1 was produced by either one-step mono-acetylation by acetic anhydride in isopropanol at room temperature or via selective hydrolysis of diacetyl derivative MQ-2 with LiOH in methanol [ 19 , 21 ].…”

“…Retention of configuration is consistent with the aziridinium ion participation. The azides MQ-54 – 55 were hydrogenated to obtain the corresponding amines MQ-56 – 57 [ 21 ].…”

“…The formed derivative was hydrogenated to afford the primary-tertiary amine MQ-60, which is reminiscent of epi -9-aminocinchona alkaloids. Removal of the benzyl group was performed by hydrogenation in acidic solutions [ 21 ].…”

“…Since the replacement of the hydroxy group for a primary amino group in quinine afforded a potent asymmetric organocatalyst, the aminomefloquine derivatives were assayed for the catalytic activity. Indeed, (+)- erythro -11-aminomefloquine MQ-53 was proven as a better catalyst than 9- epi -aminoquinine in the asymmetric Michael Addition of nitromethane to cyclohexanone in terms of enantioselectivity, delivering the catalytic product with a very good ee (93%) and a moderate yield [ 21 ].…”