Chiral Vicinal Diamines Derived from Mefloquine.

Dawid J Kucharski,Rafał Kowalczyk,Przemysław J Boratyński

doi:10.1021/acs.joc.1c01316

Dawid J Kucharski, Rafał Kowalczyk + Show 1 more

Open Access

https://doi.org/10.1021/acs.joc.1c01316

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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.

Highlights

Progress in organocatalytic approaches relies on the availability of effective chiral scaffolds and the means for their modification
A spectacular example is the application of Cinchona alkaloid derivatives: the most effective organocatalysts were formed by replacing the central hydroxyl group with an amine residue and some further specific modifications.[1,2]
We develop syntheses of all stereoisomers of 11aminomefloquine by the substitution of the central hydroxyl group with an amino group

Summary

Introduction

Progress in organocatalytic approaches relies on the availability of effective chiral scaffolds and the means for their modification. The available natural products, i.e., quinine and quinidine, are diastereomers, so different planned enantiomers of the target catalytic product require a separate method development. This compound shares some molecular characteristics of the alkaloids, while the major difference is the replacement of the quinuclidine bicyclic system with a piperidine ring and a tertiary amine with a secondary one (Figure 1). Mefloquine is sold as a racemate of erythro (anti) isomer; there exist a number of reported asymmetric syntheses[3] and procedures for the separation[4] or conversion of enantiomers.[5] The dextrorotary compound was proven to be more effective against Plasmodium than its levorotary antipode

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