Angewandte
Chemie
DOI: 10.1002/anie.201303931
Drug Synthesis
Concise Synthesis and Antimalarial Activity of All Four Mefloquine
Stereoisomers Using a Highly Enantioselective Catalytic Borylative
Alkene Isomerization**
Jinyue Ding and Dennis G. Hall*
Dedicated to Professor Pierre Deslongchamps on the occasion of his 75th birthday
Malaria is a mortal disease caused by Plasmodium parasites,
which are spread to humans by infected mosquitoes. Accord-
[
1]
ing to the latest estimates, almost half of the worldꢀs
population—over three billion inhabitants—are in danger of
contracting malaria. In 2010, malaria caused about 216 million
[
1]
clinical cases and approximately 655000 deaths. Currently,
a number of effective antimalarial drugs and treatments are
available, but drug resistance remains a problem because of
the rapid evolution and adaptation of the malaria parasites.
Moreover, current antimalarial drugs are still unaffordable
for underdeveloped countries where people are most vulner-
able. Therefore, novel and economical alternatives are
Figure 1. Stereoisomers of mefloquine.
stereoisomers (Figure 1). These stereoisomers have been
demonstrated to possess various biological activities.
[
2]
[7,8a]
needed.
One of the leading antimalarial drugs, mefloquine, was
formulated in the 1970s and was soon developed and
marketed under the name Lariam, the Roche branded
formulation. Mefloquine remains effective against all
human malaria parasites, including the recently identified
Studies have shown that (+)-erythro and threo mefloquine
((+)-1a and (+)-1b) have similar IC50 values against Plasmo-
dium parasites, and that they are 1.7–2.0 times more active
[
8a]
than their respective enantiomers ((ꢀ)-1a and (ꢀ)-1b). On
the other hand, (ꢀ)-1a was found to bind to the adenosine
receptor in the central nervous system, which can cause
[
3]
fifth species, Plasmodium knowlesi. Additionally, meflo-
quine has a longer half-life compared to other antimalarial
drugs, and thus allows for less frequent administration making
[8]
severe psychotropic effects. Furthermore, owing to its
higher plasma concentrations, the half-life of (ꢀ)-1a is 2.5
[
4]
[9]
patient compliance less problematic. However, its clinical
use as a prophylactic antimalarial drug comes with the risk for
times longer than that of the (+)-1a. Lariam consists of
racemic (ꢁ)-erythro mefloquine (Figure 1), and thus contains
both the active and harmful forms of the drug. To the best of
our knowledge, use of the threo enantiomers 1b has never
been explored for treating malaria, which may be due to
a more difficult synthesis. Thus far, they have only been
[
5]
severe neurotoxic side effects. As a result, the U.S. military
withdrew mefloquine as their primary antimalarial drug in
[
5]
2
009. Regardless, it is still widely prescribed in other
countries. Recent reports allege that upon returning from
foreign missions, many Canadian soldiers were suffering from
[8a]
obtained by chiral HPLC separation. An enantioselective
synthesis for all four mefloquine isomers is an unmet need,
and its realization could be beneficial in the global fight
[
6]
adverse side effects from taking mefloquine. Structually,
mefloquine is an a-hydroxyalkyl piperidine with two con-
tiguous stereogenic centers, and thus may exist as four
[10]
against malaria parasites. Herein, we describe a concise and
scalable synthesis of six mefloquine analogues, including all
four stereoisomers, using a carefully optimized Pd-catalyzed
asymmetric borylative alkene isomerization in tandem with
stereoselective aldehyde allylboration.
[*] J. Ding, Prof. Dr. D. G. Hall
Department of Chemistry, University of Alberta, Gunning-Lemieux
Chemistry Centre
4
-010 Centennial Centre for Interdisciplinary Science, Edmonton,
Even though the threo enantiomers display promising
[8a]
Alberta, T6G 2G2 (Canada)
E-mail: dennis.hall@ualberta.ca
Homepage: http://www.chem.ualberta.ca/~dhall/
antimalarial properties,
several research groups focused
instead on developing selective syntheses of (+)-erythro-
[11]
mefloquine.
The first enantioselective synthesis of
[
**] This research was generously funded by the Natural Sciences and
Engineering Research Council (NSERC) of Canada, and the
University of Alberta. The authors thank Stꢀphanie Lessard for
advice and discussions. We also thank the Medicines for Malaria
Venture (Dr. Xavier Ding) for their support in providing and
coordinating the biological tests.
(
+)-erythro-mefloquine was completed in 1993 by Roche
[11a]
et al.
using Rh-catalyzed enantioselective hydrogenation.
[
11b]
In 2008, Xie et al.
addition for the asymmetric total synthesis of (+)-erythro-
mefloquine. Recently, using an asymmetric Darzens reac-
tion
applied an organocatalytic aldol
[11c]
as the key step, another enantioselective total syn-
thesis of (+)-erythro-mefloquine was completed by Coltart
Angew. Chem. Int. Ed. 2013, 52, 8069 –8073
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8069