Asymmetric total synthesis of the antimalarial drug (+)-mefloquine hydrochloride via chiral N-amino cyclic carbamate hydrazones

Article abstract of DOI:10.1021/ol2010193

Mefloquine hydrochloride is an important antimalarial drug. It is currently manufactured and administered in racemic form; however there are indications regarding the biological activity of the two enantiomers that suggest the superiority of the (+)-form. The asymmetric total synthesis of the (+)-enantiomer of mefloquine hydrochloride is described. The key asymmetric transformation utilized is a novel asymmetric Darzens reaction of a chiral α-chloro-N-amino cyclic carbamate hydrazone derived from an N-amino cyclic carbamate (ACC) chiral auxiliary.

Full text of DOI:10.1021/ol2010193

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3118–3121
Asymmetric Total Synthesis of the
Antimalarial Drug (þ)-Mefloquine
Hydrochloride via Chiral N-Amino Cyclic
Carbamate Hydrazones
John D. Knight, Scott J. Sauer, and Don M. Coltart*
Department of Chemistry, Duke University, Durham, North Carolina 27708, United States
don.coltart@duke.edu
Received April 18, 2011
ABSTRACT
Mefloquine hydrochloride is an important antimalarial drug. It is currently manufactured and administered in racemic form; however there are
indications regarding the biological activity of the two enantiomers that suggest the superiority of the (þ)-form. The asymmetric total synthesis of
the (þ)-enantiomer of mefloquine hydrochloride is described. The key asymmetric transformation utilized is a novel asymmetric Darzens reaction
of a chiral R-chloro-N-amino cyclic carbamate hydrazone derived from an N-amino cyclic carbamate (ACC) chiral auxiliary.
Malaria causes more mortality than any other parasitic
disease.1 There are greater than 500 million new cases each
year, worldwide. In the US alone there are approximately
1500 malaria cases per year, with essentially all being
imported from endemic areas. Plasmodium falciparum is
responsible for the most severe cases of malaria, and an
estimated 1.5 to 2.7 million malaria-related deaths each
year result from this organism.1 The majority of these
deaths occur in African children less than five years of age,
in pregnant women, and in nonimmune adults traveling to
endemic areas. Most malaria deaths occur despite treat-
ment with our best drugs.
The drug is manufactured commercially and administered
in racemic form.2 However, the potency of the two en-
antiomers of mefloquine (Figure 1) against malaria appear
to be unequal, with the (þ)-enantiomer [(þ)-1] indicated as
being at least 1.5 times more active than the (ꢀ)-enantio-
mer [(ꢀ)-1].3 Additionally, although distributed across
many different types of tissue, evidence suggests that the
(ꢀ)-enantiomer has a shorter half-life in vivo due to higher
blood plasma concentrations.4
While highly effective and widely used as an antimalarial,
mefloquine causes serious side effects.5,6 These include
nausea, diarrhea, dizziness, weakness, priuritus, mouth
Mefloquine is a highly effective antimalarial drug that
has been used for both malaria treatment and prophylaxis.
(3) Karle, J. M.; Karle, I. L. Antimicrob. Agents Chemother. 2002, 46,
1529–1534.
(4) Dow, G. S.; Koenig, M. L.; Wolf, L.; Gerena, L.; Lopez-Sanchez,
M.; Hudson, T. H.; Bhattacharjee, A. K. Antimicrob. Agents Chemother.
2004, 48, 2624–2632.
(5) Chen, L. H.; Wilson, M. E.; Schlagenhauf, P. J. Am. Med. Assoc.
2007, 297, 2251–2263.
(1) World Health Organization. T. Roy. Soc. Trop. Med. H 2000, 94
Suppl. 1, S1/1ꢀS1/90.
(2) For total syntheses of (()-mefloquine, see: (a) Ohnmacht, C. J.;
Patel, A. R.; Lutz, R. E. J. Med. Chem. 1971, 14, 926–928. (b) Kumar,
M. S.; Nageshwar, Y. V. D.; Meshram, H. M. Synth. Commun. 1996, 26,
1913–1919. (c) Solange, A. Tetrahedron 1989, 45, 1409–1414.
(6) AlKadi, H. O. Chemotherapy 2007, 53, 385–391.
r
10.1021/ol2010193
Published on Web 05/26/2011
2011 American Chemical Society

(92% ee),12 while in another approach an organocatalytic
aldol addition was used (71% ee).13 In each instance,
further synthetic operations conducted on the products
of these asymmetric transformations are reported to have
led to an increase in the enantiomeric purity of the (þ)-
mefloquine produced (99% ee and 95% ee, respectively).
Ourplanfor the asymmetricsynthesisof(þ)-mefloquine
is shown in Scheme 1. Compound (þ)-1 would be obtained
via hydrogenation of olefin 2. To establish the 1,2-anti-
amino alcohol function of 2, we would take advantage of
the stereospecific, regioselective opening of trans-epoxide
3. Regiocontrol would be expected on the basis of both the
Figure 1. Mefloquine hydrochloride.
ulcers, severe depression, anxiety, paranoia, aggression,
nightmares, insomnia, and other central nervous system
problems.7 The more mild central nervous system events
have been reported to occur in up to a quarter of all
patients taking mefloquine while the severe events occur
in 1/6000 to 1/13000.4 To date, there has been no definitive
biochemical basis for the neurotoxicity of this drug.
Research has suggested that mefloquine may interfere with
calcium homeostasis in the endoplasmic reticulum within
neuron cells.8 This type of disruption leads to problems in
protein synthesis and folding in eukaryotic cells. There has
alsobeen someresearchsuggesting a link between themore
severe psychotropic side effects and the (ꢀ)-enantiomer,
which, unlike the (þ)-enantiomer, may be able to bind
specifically to adenosine receptors in neuron cells.9
Scheme 1. Synthetic Plan
The side effects severely restrict the usefulness of me-
floquine, nearly eliminating use of this otherwise effective
drug. Clearly, it is important to understand the toxicities of
thisdrug and how to avoid themsothatit can beusedmore
safely. To initiate our studies along these lines, we required
access to significant quantities of each of the enantiomers
of mefloquine in pure form for cell-based and animal
studies, a goal most reasonably achieved via asymmetric
total synthesis. Herein, we describe the asymmetric total
synthesis of (þ)-mefloquine hydrochloride utilizing, as a
key step, a novel asymmetric Darzens reaction of a chiral
R-chloro-N-amino cyclic carbamate hydrazone (8) de-
rived from an N-amino cyclic carbamate (ACC) chiral
auxiliary10 (18).
stereoelectronic factors favoring formation of the 6- over
the 7-membered ring, as well as the electronic factors
favoring ring opening at the more electron-rich allylic
carbon of the epoxide. The benzylic carbon in this case
would be made relatively electron deficient by the
(bis)trifluoromethyl quinoline system. Access to com-
pound 3 would be gained from R,β-epoxy aldehyde 4
by Wittig olefination with ylide 5, followed by azide
reduction. In turn, 4 would be prepared by regioselective
BaeyerꢀVilliger oxidation of R,β-epoxyketone6, followed
by oxidation state adjustment of the resulting phenylester.
In order to prepare key intermediate 6 in single enantiomer
form, we would make use of the asymmetric Darzens
reaction of ACC hydrazone 8 and aldehyde 9 to prepare
7, the hydrolysis of which would provide 6.
(þ)-Mefloquine has been prepared previously via reso-
lution of the racemate.11 It has also been obtained via
asymmetric total synthesis. In one instance asymmetric
hydrogenation was utilized for asymmetric induction
(7) (a) Barrett, P.; Emmins, P.; Clarke, P. D.; Bradley, D. J. Brit.
Med. J. 1996, 313, 525–528. (b) Corbett, E. L.; Doherty, J. F.; Behrens,
R. H. Brit. Med. J. 1996, 313, 1552. (c) Steffen, R.; Fuchs, E.; Schildkneckht,
J.; Naef, U.; Funk, M.; Schlgenhauf, P.; Phillips-Howard, P.; Nevill, C.;
€
Stuurchler, D. Lancet 1993, 341, 1299–1302. (d) Schlagenhauf, P.; Tschopp,
A.; Johnson, R.; Nothdurft, H. D.; Beck, B.; Schwartz, E.; Herold, M.;
Krebs, B.; Veit, O.; Allwinn, R.; Steffen, R. Brit. Med. J. 2003, 3327, 1078–
1084.
(8) Dow, G. S.; Hudson, T. H.; Vahey, M.; Koenig, M. L. Malaria J.
2003, 2, 1–14.
(9) Fletcher, E. A. Uses of (þ)-Mefloquine for the Treatment of
Malaria. International PCT patent application PCT/GB98/00675, 1998.
(10) (a) Lim, D.; Coltart, D. M. Angew. Chem., Int. Ed. 2008, 47,
5207–5210. (b) Krenske, E. H.; Houk, K. N.; Lim, D.; Wengryniuk,
S. E.; Coltart, D. M. J. Org. Chem. 2010, 75, 8578–8584.
(11) (a) Carroll, F. I.; Blackwell, J. T. J. Med. Chem. 1974, 17, 210–
219. (b) Baxter, A. D.; Harris, M. J.; Brown, S. International PCT patent
application PCT/GB2003/005286, 2003.
(12) Schmid, R.; Broger, E. A.; Cereghetti, M.; Crameri, Y.; Foricher,
€
J.; Lalonde, M.; Muller, R. K.; Scalone, M.; Schoettel, G.; Zutter, U.
Pure Appl. Chem. 1996, 68, 131–138.
(13) Xie, Z.-X.; Zhang, L.-Z.; Ren, X.-J.; Tang, S.-Y.; Li, Y. Chin. J.
Chem. 2008, 26, 1272–1276.
Org. Lett., Vol. 13, No. 12, 2011
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A short time ago, we described a new method for the
asymmetric R-alkylation of ketones using chiral N-amino
cyclic carbamate (ACC) auxiliaries (Scheme 2a). Given the
practical simplicity of this method, along with the high
levels of asymmetric induction produced, we initiated a
study of the use of ACC auxiliaries in the context of the
aldol addition and related transformations. One such
reaction of interest to us in the present context was the
asymmetric addition of R-halo ACC hydrazones to alde-
hydes (Scheme 2b). Providing the addition step was anti-
selective,14 this could provide a convenient means of
accessing trans-R,β-epoxy ketones (16), either directly
from Darzens15 intermediate 15 or via the corresponding
X-ray crystal structure of the major product was obtained
(Scheme 3), establishing it as trans-diastereomer 7. We
subsequently found that the conversion of 8 to 7 could be
carried out on a multigram scale without compromising
the outcome of the reaction.
Scheme 3. Asymmetric ACC Darzens Reaction
Scheme 2. Asymmetric ACC Transformations
Having established an effective route to compound 7, we
embarked on the remainder of our synthesis, which began
with the removal of the chiral auxiliary (Scheme 4). This
was achieved using our previously reported10a conditions
(p-TsOH•H2O in acetone), giving 6 and the corresponding
acetone hydrazone (20), with quantitative conversion.
Unfortunately, attempted separation of 6 and 20 via silica
gel chromatography or crystallization proved extremely
difficult. This problem was easily solved by conducting the
auxiliary cleavage reaction in 3-pentanone instead of
acetone, which gave readily separable hydrazone 21 as
the byproduct. Next, we needed to effect the regioselective
BaeyerꢀVilliger oxidation of 6 to phenyl ester 22. In
studies on chalcone-derived epoxides, it has been shown
that the migratory aptitude of the phenyl substituent is
greater than that of the epoxide function and that the
corresponding phenyl esters could be obtained in high
yield.16 This proved to be the case for R,β-epoxy ketone
6 as well, which gave the desired phenyl ester (22) after
R-halo-β-hydroxy hydrazones (14). Application of this
method in the context of aldehyde 9 could then provide
access to key intermediate 6 for the synthesis of (þ)-
mefloquine.
We began our study by testing the validity of the
proposed aldol/Darzens addition of R-halo ACC hydra-
zones (Scheme 3). To do so, hydrazone 8 was prepared
from 2-chloroacetophenone (17) and ACC auxiliary 18
and was then treated with LDA at ꢀ78 °C, followed by
aldehyde 9. Interestingly, no R-chloro-β-hydroxy hydra-
zone products (cf. 14) were observed. Instead, two diaster-
eomeric Darzens products were formed in a 92:8 ratio.
Based on 1H NMR analysis, the minor product appeared
to contain a cis-configured epoxide, whereas the major
product appeared to be a trans-epoxide. The diastereomers
were easily separable using silica gel chromatography. An
(14) Other studies conducted by us on the aldol addition using, for
example, the 3-pentanone-derived ACC hydrazone (13, R1 = Et; X =
Me) showed the reaction to be highly anti-selective for the diastereomer
corresponding to 14 (R1 = Et; X = Me). Unpublished results.
(15) Rosen, T. Darzens Glycidic Ester Condensation. In Comprehen-
sive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
New York, 1991; Vol. 2, pp 409ꢀ439.
(16) Baures, P. W.; Eggleston, D. S.; Flisak, J. R.; Gombatz, K.;
Lantos, I.; Mendelson, W.; Remich, J. J. Tetrahedron Lett. 1990, 31,
6501–6504.
3120
Org. Lett., Vol. 13, No. 12, 2011

refluxing in the presence of m-CPBA. Treatment of the
crude material with lithium aluminum hydride gave 2,
3-epoxy alcohol 23 in very good yield over the two steps.
Oxidation of 23 by DessꢀMartin periodinane then gave
aldehyde 4, cleanly.
was then analyzed by chiral HPLC to establish conditions
that gave baseline resolution of the enantiomers. The
synthetic 27 we had prepared was then analyzed under the
same conditions and found to exist as a single enantiomer.
Scheme 5. Synthesis of (þ)-Mefloquine Hydrochloride
Scheme 4. Synthesis of Aldehyde 4
In conclusion, we have developed an effective asym-
metric total synthesis of (þ)-mefloquine hydrochloride.
Establishment of the stereochemistry is achieved early in
the synthesis via a novel ACC-mediated Darzens reaction.
With aldehyde 4 in hand, we undertook the final stages
of the synthesis of (þ)-mefloquine (Scheme 5). Thus,
compound 4 was allowed to react with the ylide obtained
from 24 upon deprotonation with KHMDS,17 which gave
olefins 25 as a 5:1 (Z/E) mixture. This set the stage for a
cascading azide reductionꢀepoxide opening sequence,
which was effected by treatment with Ph3P in wet THF.
In order to facilitate purification, the resulting amino
alcohol was not isolated but was instead converted directly
tothe N-Boc protectedcompound 26by addition of Boc2O
to the reaction mixture. Olefin hydrogenation was then
carried out to give 27. Finally, the Boc protecting group
was removed, and the resulting TFA salt was converted to
(þ)-mefloquine hydrochloride [(þ)-1].
Acknowledgment. We thank Dr. Wayne Beyer (Duke
University), Dr. Timothy Haystead (Duke University),
Dr. Brandy Salmon (Duke University), and Dr. Brice
Weinberg (Duke University) for their assistance in the
development of this project. S.J.S. is grateful for support
from the Pharmacological Sciences Training Program ꢀ
Duke University. We thank Nicholas J. Amato, Stacey D.
Gates, and Dr. Kristin Kirschbaum (University of Toledo)
for X-ray crystal structure determination. This work was
supported by Duke University’s CTSA Grant 1 UL1
RR024128-01 from NCRR/NIH, and NCBC (2008-
IDG-1010).
The enantiomeric purity of our synthetic material was
established as follows. A racemic sample of 27 was pre-
pared from commercially available (()-mefloquine. This
Supporting Information Available. Experimental pro-
cedures and analytical data for all new compounds, as
well as CIF files. This material is available free of charge
via the Internet at http://pubs.acs.org.
ꢀ
(17) Chhen, A.; Vaultier, M.; Carrie, R Tetrahedron Lett. 1989, 30,
4953–4956.
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