Chiral Vicinal Diamines Derived from Mefloquine

Article abstract of DOI:10.1021/acs.joc.1c01316

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.

Full text of DOI:10.1021/acs.joc.1c01316

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Chiral Vicinal Diamines Derived from Mefloquine
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Dawid J. Kucharski, Rafał Kowalczyk, and Przemysław J. Boratynski*
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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.
INTRODUCTION
■
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 organo-
catalysts were formed by replacing the central hydroxyl
group with an amine residue and some further specific
modifications.1,2 The robust structure of the alkaloids,
Figure 1. Comparison of the structures of mefloquine and quinine
and traditional atom numbering.
however, offers rather limited scope for further transformations
and grater tuning of the catalyst. 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. The pharmaceutical
industry produces a close analogue of Cinchona alkaloids
known as mefloquine, a drug against malaria (trade name
Lariam). This compound shares some molecular characteristics
modifications at both reactive positions 11 and 13 could be
of the alkaloids, while the major difference is the replacement
envisaged to arrive at effective organocatalysts or metal ligands.
of the quinuclidine bicyclic system with a piperidine ring and
In this paper, we develop syntheses of all stereoisomers of 11-
consequently a tertiary amine with a secondary one (Figure 1).
Mefloquine derivatives are able to selectively interact with
chiral entities.7 Therefore, these scaffolds could be considered
for asymmetric catalytic purposes. A wide array of
aminomefloquine by the substitution of the central hydroxyl
group with an amino group. Such modification of a similar
Cinchona scaffold was vital to the progress of organocatalysis.
Mefloquine is sold as a racemate of erythro (anti) isomer;
however, there exist a number of reported asymmetric
syntheses3 and procedures for the separation4 or conversion
of enantiomers.5 The dextrorotary compound was proven to be
Received: June 5, 2021
Published: July 27, 2021
more effective against Plasmodium than its levorotary antipode.
The latter is also much more toxic and prone to induce
psychotic behavior.6 Mefloquine could one day become
available as a single enantiomer as this would likely improve
pharmacological properties and reduce side effects. Until now,
these efforts have not been commercially successful.
© 2021 The Authors. Published by
American Chemical Society
https://doi.org/10.1021/acs.joc.1c01316
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Scheme 1. Transformations of Mefloquine (1) to erythro-11-Aminomefloquine (4)
membered ring (Scheme 2). The formation of aziridine occurs
via an SN2 mechanism,9 and the ring-opening also involves SN2
reaction resulting in the net retention of the configuration in
the azidoamine 3.
The hydrogenation of 11-azidomefloquine salt (3·HN3)
delivered quantitatively the corresponding erythro vicinal
primary−secondary diamine 4. The entire sequence from 1
to 4 can be achieved in up to a 75% yield using only paper
filtration as the means of purification. Alternative Staudinger
reduction resulted in the formation of a triphenylphosphine
adduct observed in the MS spectra which could not be
effectively forced to hydrolyze.
In an attempt to produce a diastereomer of diamine 4 along
with primary−tertiary diamine analogues, alkyl substituents
were introduced at the piperidine nitrogen atom (Scheme 1).
The benzyl group was chosen as transient protection since it
could be removed under hydrogenation conditions. Meflo-
quine was benzylated under Schotten−Bauman conditions to
give 5a, while Eschweiler−Clarke methylation provided 5b.
Alkyl mefloquine derivatives 5a,b were then subjected to the
Mitsunobu reaction with an azide source. Good yields were
achieved when triphenylphosphine was first reacted with
azadicarboxylate to produce a zwitterionic adduct prior to the
addition of a mixture of hydrazoic acid and 5a or 5b. An
alternative sequence of the addition of reagents essentially
failed to produce the required products. The 11-amines 7a and
7b were obtained by hydrogenation using palladium on
charcoal in methanol. The benzyl group was removed when
the hydrogenation was performed in a 5% TFA solution.
Surprisingly, it was found that hydrogenation of both 3 and 6a
resulted in the formation of the same product 4. Moreover,
alkylation of azide 3 under acidic or mildly basic conditions
resulted in erythro-products 6a,b identical to those produced
by the alkylation−Mitsunobu sequence (Scheme 1). These
results are indicative of 5a,b reacting with the net retention of
the configuration under the Mitsunobu conditions. This
phenomenon could be explained by transient aziridinium ion
formation followed by ring opening10 (Scheme 3). Lack of
anchimeric assistance impedes formation of 11-azides from 13-
acyl-mefloquine under Mitsunobu conditions.
RESULTS AND DISCUSSION
■
The reactions of Cinchona alkaloids at their central 9 position
are sometimes known to proceed with unpredictable stereo-
chemical outcomes, which could later be explained by various
effects, such as neighboring group participation, chelation, and
formation of hydrophilic cavities. Due to stereocovergence in
the substitution reactions with carbon and oxygen nucleo-
philes, some isomers were more easily obtainable than
others.2,8 The displacement with an azide nucleophile either
in the Mitsunobu reaction or the substitution of alkaloid 9-
methanesulfonates always proceeded according to the
straightforward SN2 mechanism. An attempted exploitation of
the corresponding reactivity of mefloquine at position 11
resulted in a rather surprising stereochemistry (Scheme 1).
erythro-1,2-Diamine. A direct implementation of the
Cinchona alkaloid transformation brought us to the nucleo-
philic displacement in the Mitsunobu reaction with an azide
source followed by Staudinger reduction. The reaction led to
the retention of the configuration rather than the expected
inversion and gave product 4 in low yield (11−15%). We then
turned to producing aziridinie 2 in the Appel reaction
following a reported procedure.9 The aziridine 2 is moderately
stable, though it undergoes gradual decomposition even in the
solid state over the period of months. Efforts to isolate pure
aziridine generally lead to moderate yields. The aziridine ring
was efficiently opened with hydrazoic acid to give azidoamine
3 (Scheme 2). When only partially purified aziridine 2 was
subjected to the same process, the corresponding azide 3 was
formed very efficiently over two steps (81%). Most of the 11-
azide 3 precipitates from the reaction medium in very high
purity as a hydrazoic acid salt (75%), as proven by elemental
analysis. The investigation of the supernatant composition
revealed the formation of 9% of an isomer 3b possessing a 7-
Scheme 2. Nucleophilic Ring Opening of Pure Aziridine 2
threo-1,2-Diamine. The catalytically vital epi-Cinchona
alkaloid series is sterochemically analogous to mefloquine
derivatives of threo configuration, which were not delivered
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Scheme 3. Plausible Course of Retentive Mitsunobu Reaction
Scheme 4. Shortened Method of Inversion of erythro-Mefloquine
Scheme 5. Stereoconvergent Formation of Aziridine 2
Scheme 6. Transformation of threo-Mefloquine (8) to threo-11-Aminomefloquine (12)
through the alkylation−Mitsunobu sequence starting from the
erythro isomer. An attempt was made to repeat the previous
sequence of transformations with threo-mefloquine as a starting
material. We followed partially a method for the inversion of
erythro-mefloquine (1) into the threo-isomer 8 (syn)11
(Scheme 4). Here, rather than resorting to N,O-diacetylation
and subsequent ester hydrolysis, we performed a single-step
selective acetylation of mefloquine (1) at position 13 with
acetic anhydride in 2-propanol in the presence of K2CO3. The
13-acetyl derivative was reacted with thionyl chloride and
hydrolyzed to provide threo-mefloquine (8) hydrochloride in a
94% yield.11
identical to that obtained from erythro-mefloquine could be
isolated by chromatography with mass spectrometry detection
(Scheme 5). The low yield may have resulted from the
instability of the expected diastereomer of aziridine 2. The net
retention of the configuration toward aziridine 2 could be
explained by two sequential SN2 displacements: transient
substitution with a chloride ion followed by ring-closing
reaction.
The reaction of threo-mefloquine with benzyl bromide led to
the corresponding N-alkyl derivative 9. The displacement of
the hydroxyl group under Mitsunobu conditions delivered the
respective azide 10 in good yield. The hydrogenation of 10
under acidic and nonacidic conditions finally provided the
primary−secondary diamine 12 and primary−tertiary diamine
11 (Scheme 6).
The Mitsunobu reaction proved to be ineffective in
converting threo-mefloquine directly into an azide while the
application of Appel conditions to obtain aziridine resulted in a
mixture, from which only a small quantity of aziridine 2
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Scheme 7. Epimerization of erythro-11-Azidomefloquine (3) and Alternative Synthesis of threo-11-Aminomefloquine (12)
Figure 2. Formation of cyclic urea 14 and 15 derived from 11-aminomefloquines 4 and 12, diagnostic interactions observed in NOESY spectra, and
their molecular models at the DFT/B3LYP/cc-pVDZ level of theory (red, strong correlation, magenta, medium intensity correlation, Q = 2,8-
bis(trifluoromethyl)quinolin-4-yl).
The pair of azides 10 and 6a, as well as the pair of vicinal
diamines 4 and 12, display different NMR spectra. Each
mixture of diastereomeric pairs of compounds revealed two
distinct sets of signals that did not converge. Partial
epimerization at position 11 was also achieved by benzylation
of azide 3 under the Schotten−Bauman conditions (dioxane/
aqueous NaOH). The resulting mixture contained 20% of
threo-azide 10 along with the erythro-isomer 6a. Azide 3 could
be epimerized under moderately basic conditions (NaOH in
MeOH) into a new product 13, which was also isolated in 20%
yield. The hydrogenation of 13 quantitatively yielded diamine
12 converging with the threo-mefloquine sequence (Scheme
7). It is noteworthy that NaOH in methanol is insufficient to
induce an observable epimerization of 9S-azidoquinine. Thus,
the electron-withdrawing substituents in the quinoline ring are
needed for epimerization to occur at such moderately basic
conditions.
In yet another approach, we independently treated 13-
benzyl-mefloquine isomers 5a and 9 with thionyl chloride to
obtain intermediate 11-chloro derivatives. Both these trans-
formations converged toward an identical mixture of 11-chloro
derivatives. In the NMR spectra, 11-chloro derivative·HCl
displayed multiple equilibrating species as evidenced by the
NOESY/EXSY experiment (for details, see the Supporting
Information). The subsequent reaction with sodium azide
resulted in azide 6a of erythro configuration. The yield of the
final transformation was low (up to 20%), and the purity of the
product was unsatisfactory. We hypothesize that the net
inversion of threo compound 9 to erythro isomer 6a is a result
of three consecutive SN2 displacements involving the
formation of aziridinium ion.
Assignment of Relative Configuration. The initial
assignment of the relative configuration was based on chemical
correlation and on the published data on the structure of
aziridine 2 and the identification of erythro product obtained
after aziridine ring opening with acetyl anhydride.9 Unequiv-
ocal proof for the relative configuration of both target 11-
aminomefloquines 4 and 12 was based on the NMR
experiments. The diamines were first converted to rigid cyclic
urea derivatives 14 and 15. Only the erythro configuration for
4/14 and threo for 12/15 could explain the observed NOESY
interactions (Figure 2). For the compound of threo
configuration, the H-11 displayed strong correlation with
axial H-17, and weaker correlations with equatorial H-17 and
neighboring H-12. In the molecular model of 15 optimized at
the DFT/B3LYP/cc-pVDZ level of theory, the corresponding
distances from H-11 to H-17(axial), H-17(equatorial), and H-
12, were 2.53, 2.62, and 2.79 Å, respectively. The same order of
proximity was observed in an X-ray structure of a urea derived
from 2-aminomethylpiperidine.12 On the other hand, in the
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erythro isomer H-11 displayed a strong correlation only with
the neighboring H-12. In the molecular model of 14, the
distance for the observed contact is 2.33 Å, while distances
from H-11 to other hydrogen atoms of the piperidine ring are
greater than 3.7 Å. The coupling constants between H-11 and
H-12 were 8.7 Hz for 14 and 5.5 Hz, for 15. This experimental
finding is congruent with the molecular model, where a nearly
perpendicular (dihedral of 100°) arrangement of these
hydrogen atoms is expected for the threo isomer, while
dihedral of −30° was the optimized result for the erythro
isomer. Unscaled spin coupling calculation at the GIAO/
mPW1PW91/6-311+G(2d,p) level predicts 7.5 Hz for erythro
and 0.7 Hz threo isomers.
derivatives by lowering LUMO energy in the expected
intermediate iminium or iminium ion.16 The ancillary
secondary amine unit provides a basic center to activate a
nucleophile (Figure 3).
Figure 3. Features of 11-aminomefloquine catalyst.
Enantiomerically Enriched Products. The initial experi-
ments were performed on commercial racemic mefloquine
samples. Enantiomerically pure products were obtained by
resolution of diastereomeric salts. In one approach, we
crystallized salts of diamine 4 with chiral acids. Separation
was successful when (+)-mandelic acid was used. With ethanol,
the enantiomeric excess reached 98.5% for (+)-4 with a 23%
yield after single crystallization. Lower selectivity was observed
for methanol (77% ee, 43% yield), but it could be improved
with recrystallization. The collected crystals contained
equimolar quantities of 4, mandelic acid, and the respective
alcohol as crystallization solvent. No resolution of enantiomers
was observed for crystals in other solvents (1-propanol, 2-
propanol, 1-butanol, ethyl acetate, acetonitrile, dioxane, and
water−ethanol mixture). For measuring enantiomeric excess,
the diamine 4 or its salt was briefly treated with acetic
anhydride at room temperature to convert it to diacetamide
16, which separates on standard chiral HPLC columns.
Another approach consisted of obtaining (+)-enantiomer of
erythro-mefloquine ((+)-1) with (−)-ditoluyltartaric acid by
reiterating a patented report.13 Crystallization crops from ethyl
acetate removed most of one enantiomer from the supernatant.
Recycling of free (−)-mefloquine base from this enriched
solution followed by crystallization with (+)-ditoluyltartaric
acid led to a sample of enantiomeric purity exceeding 99%.
The overall yield for pure enantiomers was 86% and additional
10% of essentially unresolved material could be recovered. For
the purpose of measuring the enantiomeric purity, erythro-
mefloquine was converted to the N,O-diacetyl compound9
with acetyl anhydride.
To support our hypothesis on the central role of the
secondary amine unit in the catalyst’s structure, we have
chosen the addition of nitromethane to cyclohexenone as a
model transformation. In this type of reaction, the major
challenge is attributed to the anomalous nitroalkane proton
transfer reflecting the pivotal role of the structure and strength
of the applied base. Successful control of chirality transfer in
reactions applying nitroalkanes required multifunctional
catalysts decorated with additional groups such as hydroxyl
group in a set of aminoindanol or aminophenol-based
hydrogen bond donors.17 In our hands, the chiral primary−
secondary diamines gave appreciable level of enantioselection.
The reaction catalyzed by a combination of (+)-erythro-
diamine 4 and achiral carboxylic acid provided up to 93.5% ee
(Table 1).
Table 1. Asymmetric Michael Addition of Nitromethane to
Cyclohexenone
a
entry
catalyst (%), ee of catalyst
yield (%)
% ee (config)
b
1
2
3
4
5
6
7
8
(+)-(11S,12R)-4, >99
(+)-(11S,12R)-4, 98
(+)-(11S,12R)-4, 50
(−)-(11R,12S)-4, 98
(−)-(11R,12R)-12, 98
(−)-(11R,12S)-1, >99
(+)-(11S,12S)-8, 99
(−)-(11R,12S)-7b, >99
(−)-(11R,12S)-7a, >99
(−)-(11R,12R)-11, 98
44
93.5 (S)
92 (S)
54 (S)
91 (R)
77 (R)
37 (R)
20 (S)
rac
46
46
46
30
3
The retention times of the N,O-diacetyl derivative of parent
aminoalcohol and N,N′-diacetyl derivative 16 of the same
configuration are similar. The signs of optical rotation are the
same for amino alcohol 1 and diamine 4 sharing the same
configuration. The 11R,12S stereochemistry of (−)-mefloquine
has been previously established unambiguously.6,14
2
22
6
19
9
10
11
rac
rac
84 (S)
c
(9S,8S)-EAQN, 100
93
a
b
c
Yield was estimated by quantitative NMR. Preparative yield. 9-epi-
The conversion of enantiomerically pure mefloquine into 4
or 12 as shown in Schemes 1 and 6 resulted in essentially the
same yields as with the racemic compound. The reactions
proceeded without erosion of optical purity, as proven by
HPLC chromatography of diacetyl derivatives of the initial
material, intermediate azide 3 and the final product after
derivatization (16). Unlike single site epimerization, race-
mization is rather unlikely because it requires a change of
configuration at two stereogenic centers.
Example of Catalytic Activity. From the perspective of
potential catalytic applications, enantiomerically pure 11-
aminomefloquine 4 and 12 offer two activation sites: the
primary and secondary amine.15 The NH2 group was devised
to form a covalent bond and thus to activate carbonyl
Aminoquinine.
The enantiomeric excess of the formed adduct exhibited a
linear correlation with the enantiomeric composition of the
applied catalyst (Table 1, entries 1−4). The importance of the
primary amine unit was rather undisputable while the parent
mefloquine was both unreactive and unselective in this
reaction. The diamine 4 outperformed in terms of selectivity
even 9-deoxy-epi-aminoquinine (Table 1, entry 11), which
gave only 84% ee but nearly quantitative yield. The threo
isomer 12, which shares the same relative configuration as this
alkaloid derivative, delivered moderate enantioselectivity as
well. The superiority of secondary amine over tertiary amine
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Figure 4. Orientation of hydrogen atoms in protonated catalyst species.
washed with water (8 × 25 mL). The white solid was air-dried and
then vacuum-dried at 85 °C for 6 h. Yield 92−98%.
was proven for 7b, 7a, and 11, which are N-methyl and N-
benzyl derivatives of 11-aminomefloquine of the erythro and
threo configurations. No chirality transfer was observed there
Separation of erythro-Mefloquine Enantiomers. erythro-
Mefloquine free base (1, 21.4 g, 56.5 mmol) was dissolved in
EtOAc (800 mL), and a solution of (+)-O,O-di(p-toluyl)tartaric acid
(22.7 g, 58.9 mmol, 1.04 equiv) in EtOAc (160 mL) was added. The
mixture was stirred for 24 h, and the precipitated wool-like crystals
were separated by filtration and washed with EtOAc (200 mL). The
solid and the filtrate were processed separately: the solid was
triturated with EtOAc (350 mL) for 1 h at reflux (water bath) and 24
h at room temperature, collected by filtration, washed with EtOAc
(100 mL), and air-dried to obtain white crystalline salt of
(−)-mefloquine (20.3 g, 47%). The liberation of the free base
according to the general procedure afforded 9.04 g (42%, >98% ee) of
(−)-(11R,12S)-1.
+
(Table 1, entries 8−10). In protonated form (NH2 ), any of
the two differently oriented hydrogen atoms in 4·H+ may
interact with another species via hydrogen bonds, which
cannot be achieved for analogous Cinchona derivatives (Figure
4). We perceive the presence of the NH proton at the
equatorial position to be pivotal for achieving high
enantioleselectivities. When a proton attached to the tertiary
nitrogen atom of quinuclidine in epi-aminoquinine occupies an
equatorial-like position, chiral discrimination was provided
albeit at a lower level.
The filtrate was concentrated to ca. half of the volume and stored
for 24 h at room temperature. The precipitate was removed by
filtration and the solution concentrated to afford an oily residue
containing acid and enriched (+)-mefloquine (up to 90% ee). The
liberation of free base according to the general procedure and
repeated separation with 1 equv of (−)-O,O-di(p-toluyl)tartaric acid
yielded crystalline salt of (+)-mefloquine. The liberation of free base
according to the general procedure afforded 9.37 g (44%, 99.7% ee)
of (+)-(11S,12R)-1.
Removed washings and precipitate were combined, and after the
liberation of the free base, ( )-mefloquine was recovered in ca. 10%
yield.
The determination of enantiomer composition: a sample of 1 (ca.
1−2 mg) was dissolved in acetic anhydride and stirred at 110 °C for 3
h. The sample was concentrated in vacuo. HPLC (IA-3, 2-
propanol:hexane 1:9, 1 mL/min, λ = 285 nm) tR = 6.5 min for
(+)-(11S,12R)-1 and 10.1 min for (−)-(11R,12S)-1
erythro-11-Azidomefloquine Hydrazoic Acid Salt (3·HN3).
erythro-Mefloquine free base (1, 6.55 g, 17.3 mmol) was suspended in
acetonitrile (50 mL) under argon atmosphere. Next, triphenylphos-
phine (4.77 g, 18.2 mmol, 1.05 equiv) and triethylamine (2.41 mL,
17.3 mmol, 1.0 equiv) were added. After 5 min, CCl4(1.68 mL, 17.3
mmol, 1.0 equiv) was added dropwise. Within 5−10 min the mixture
formed a solution, then gradual precipitation occurred. After 3 days,
the solvent was removed, and the residue was suspended in Et2O (50
mL). The mixture was filtered, and the separated solid was extracted
with Et2O (2 × 25 mL). The combined filtrate was concentrated in
vacuo, providing crude threo-mefloquine aziridine 2 as yellow oil (7.90
g).
Crude threo-mefloquine aziridine (7.90 g) was dissolved in a 1.67
M solution of hydrazoic acid in benzene (35 mL, 58.5 mmol of HN3).
Pure product 3 crystallized from the solution within 24 h as hydrazoic
acid salt. The product was filtered, washed with benzene, and air-dried
to afford 5.79 g of colorless to light yellow crystals (75%).
Chromatography of the mother liquor on silica gel (CH2Cl2/
MeOH 50:1 then 10:1) gave 0.48 g of side product 3b and an
additional portion of 0.45 g of 3 (total 81.5%). The 1H NMR spectra
of 3 hydrazoic acid salt and 3 free base display no differences. Mp =
133−140 °C (dec, MeOH). 1H NMR (400 MHz, CDCl3, TMS) δ =
8.41 (d, J = 8.6 Hz, 1H), 8.22 (d, J = 7.2 Hz, 1H), 7.93 (s, 1H), 7.80
(t, J = 8.0 Hz, 1H), 5.24 (d, J = 6.0 Hz, 1H), 3.03−3.07 (m, 1H),
2.93−2.98 (m, 1H), 2.55 (td, J = 12.2, 2.7 Hz, 1H), 2.27 (br s, 2H),
1.84−1.87 (m, 1H), 1.65−1.68 (m, 1H), 1.57−1.60 (m, 1H), 1.20−
1.43 (m, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3, TMS) δ =
CONCLUSIONS
■
We have demonstrated an efficient method for the preparation
of chiral primary-secondary diamines from mefloquine. No
chromatography was required to obtain high yields of the
erythro-isomer of 11-aminomefloquine (4). Most of the studied
transformations proceeded with a net retention of the
configuration involving aziridine or aziridinium ion partic-
ipation. Product 4 was proven to provide effective chirality
transfer in an asymmetric Michael addition, indicating the
crucial role of the combination of primary and secondary
amine groups. This feature as well as the availability of
enantiomers rather than diastereomers is distinct from the
natural product-based catalysts. We anticipate that 11-amino-
mefloquines and their further derivatives could provide an
interesting alternative to the well-established 9-amino-
Cinchona alkaloid framework, although the starting material
may be up to 10 times more expensive.
EXPERIMENTAL SECTION
■
General Comments. All reagents were obtained from commercial
suppliers and used as received. Racemic mefloquine HCl was sourced
from China by a local chemical distributor. Reported procedures were
used for the preparation of 8 from acetyl mefloquine11 and compound
5b.18 NMR spectra were recorded on 400 and 600 MHz instruments
with TMS as an internal standard for 1H and 13C spectra (δH = 0 and
δC = 0) while 19F NMR spectra were internally referenced to α,α,α-
trifluorotoluene (PhCF3, δF = −63.72 ppm). HRMS spectra were
obtained on a high-resolution TOF mass spectrometer with an
electron spray ionization (ESI) source. Optical rotations were
measured in 10 cm tube on an automatic polarimeter with sodium
lamp. Melting points are uncorrected. HPLC chromatography was
performed on IA-3 and IC-3 4.6 × 250 mm columns at 40 and 22 °C,
respectively with UV detection. Flash chromatography was performed
on standard silica gel 60, 230−400 mesh, Brockman I active neutral,
basic, or acidic aluminum oxide.
General Procedure for Liberation of Mefloquine Free
Base.13 Mefloquine salt (25 mmol) was suspended in methanol
(70 mL) and stirred. Aqueous NaOH (1M, 300 mL, 12 equiv) was
added via a dropping funnel for 0.2 h. Stirring was continued for 18 h
at room temperature. Precipitate was collected by filtration and
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https://doi.org/10.1021/acs.joc.1c01316
J. Org. Chem. 2021, 86, 10654−10664

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
148.4 (q, J = 35.6 Hz), 146.5, 144.3, 129.9 (q, J = 30.4 Hz), 129.4 (q,
J = 5.4 Hz), 127.9, 127.6, 127.2, 123.5 (q, J = 274.0 Hz), 121.2 (q, J =
275.7 Hz), 116.7 (q, J = 2.0 Hz), 67.6, 60.6, 47.2, 28.1, 26.2, 24.2
ppm. 19F NMR (376 MHz, CDCl3, PhCF3) δ = −61.32 (s, 3F),
−68.86 (s, 3F) ppm. HRMS (ESI-TOF) [C17H15F6N5 + H]+ m/z
calcd: 404.1304, found 404.1306. Anal. Calcd for C17H15F6N5·HN3
(446.36): C, 45.74; H, 3.61; N, 25.10. Found: C, 45.93; H, 4.23; N,
24.74. HPLC (IA-3, 2-propanol/hexane 1:9, 1 mL/min, λ = 282 nm)
tR = 4.8 min for (11R,12S)-3 and 5.5 min for (11S,12R)-3.
and racemic 4 (1.5 g, 4.1 mmol, in 5 mL) were mixed and stored at
room temperature, at 4 °C and at −20 °C, sequentially for 24 h
intervals. The white solid was removed by filtration and washed with
cold alcohol. Sample obtained from methanol (1.03 g) was
recrystallized from the same solvent to give 0.73 g of white crystals.
For (+)-(11S,12R)-4 L-mandelic acid salt·MeOH, 95% ee. Mp =
167−169 °C (MeOH).
For (+)-(11S,12R)-4 L-mandelic acid salt EtOH, 98% ee: Mp =
157−166 °C (EtOH).
The L-mandelic acid salt of (11S,12R)-4 methanol solvate (1.15 g,
2.05 mmol) was suspended in a mixture of aqueous NaOH (10%, 7
mL) and CH2Cl2 (20 mL). After 5 min of stirring, the mixture was
separated and the aqueous layer extracted with CH2Cl2 (3 × 15 mL).
Combined organic phases were dried over anhydrous Na2SO4 and
evaporated to give (11S,12R)-4 free base as pale oil (697 mg, 90%).
From (−)-(11R,12S)-erythro-mefloquine (11R,12S)-3·HN3 was
24
obtained: [α]D = −41 (c 1, MeOH). From (+)-(11S,12R)-erythro-
20
mefloquine (11S,12R)-3·HN3 was obtained: [α]D = +46 (c 1,
MeOH).
(6S,7S)-7-(2,8-Bis(trifluoromethyl)quinoline-4-yl-1-
azabicyclo[4.1.0]heptane (2). Following the procedure for the
synthesis of 3, starting from (−)-(11R,12S)-mefloquine (1, 9.14 g, 24
mmol), intermediate crude 2 was purified by chromatography on
neutral Al2O3 (hexane/EtOAc 1:0−10:1), and then double
recrystallization from petroleum ether at −20 °C9 gave white wool-
20
[α]D = +44 (c 1.1, MeOH).
erythro-13-Acetyl-11-acetamidomefloquine (16). erythro-11-
Aminomefloquine (4) (22 mg, 0.06 mmol) was dissolved in acetic
anhydride (0.5 mL). After 1 h, the solvent was removed in vacuo, and
the product was obtained as white crystals (27 mg, quantitative yield).
For the purpose of measuring enantiomeric purity, salts of 4 were
25
like crystals 4.82 g (55%). Mp = 78.5−79 °C. [α]D = +136 (c 1,
C6H6). 1H NMR data matched literature data for racemic compound.9
1H NMR (600 MHz, CDCl3, TMS) δ = 8.38 (d, J = 8.4 Hz, 1H), 8.15
1
treated directly with acetic anhydride as described above. H NMR
(600 MHz, CDCl3, TMS) δ = 8.86 (d, J = 8.7 Hz, 1H), 8.19 (d, J =
7.4 Hz, 1H), 8.07 (s, 1H), 7.82 (dd, J = 8.7, 7.4 Hz, 1H), 6.53 (t, J =
9.5 Hz, 1H), 5.51−5.57 (m, 1H), 3.29 (dd, J = 14.3, 3.3 Hz, 1H) 2.50
(td, J = 14.3, 2.5 Hz, 1H), 2.04−2.15 (m, 1H), 2.03 (s, 3H), 1.95−
2.01 (m, 1H), 1.88 (s, 3H), 1.63−1.81 (m, 4H) ppm. 13C{1H} NMR
(151 MHz, CDCl3, TMS) δ = 170.2, 170.1, 148.2 (q, J = 35.3 Hz),
147.8, 144.3, 129.6 (q, J = 29.6 Hz), 129.2 (q, J = 5.4 Hz), 128.4,
128.3, 128.0, 123.7 (q, J = 273.7 Hz), 121.4 (q, J = 275.6 Hz), 116.4,
50.8, 46.7, 43.1, 25.3, 25.1, 23.1, 21.5, 19.4 ppm. 19F NMR (376 MHz,
CDCl3, PhCF3) δ = −61.26 (s, 3F), −68.95 (s, 3F) ppm. HPLC (IA-
3, 2-propanol/hexane 1:9, 1 mL/min, λ = 285 nm) tR = 5.9 min for
(11S,12R)-16 and 10.8 min for (11R,12S)-16. HRMS (ESI-TOF)
[C21H21F6N3O2 + H]+ m/z calcd: 462.1611, found: 462.1659
[C21H21F6N3O2 + Na]+ m/z calcd: 484.1430, found: 484.1428
erythro-13-Benzylmefloquine (5a). erythro-Mefloquine hydro-
chloride (6.01 g, 14.5 mmol) was suspended in a mixture of dioxane
(50 mL) and aqueous NaOH (15%, 20 mL). After 5 min of stirring,
benzyl chloride (1.90 mL, 16.5 mmol, 1.14 equiv) was added
dropwise. The mixture was stirred for 6 days at room temperature.
Subsequently, the phases were separated and the aqueous layer was
extracted with CH2Cl2 (3 × 15 mL). Combined organic phases were
dried over anhydrous Na2SO4, and the solvents were evaporated. The
crystallization from methanol (35 mL) provided 4.65 g (69%) of
(d, J = 7.2 Hz, 1H), 7.86 (s, 1H), 7.73 (t, J = 7.9 Hz, 1H), 3.56−3.62
(m, 1H), 3.22 (d, J = 2.1 Hz, 1H), 3.03 (ddd, J = 13.6, 8.4, 5.4 Hz,
1H), 2.15−2.26 (m, 4H), 1.52−1.66 (m, 4H) ppm. 13C{1H} NMR
(151 MHz, CDCl3, TMS) δ = 150.5, 148.8 (q, J = 35.0 Hz), 143.4,
129.4 (q, J = 30.1 Hz), 128.6 (q, J = 5.5 Hz), 128.3, 127.5, 126.8,
123.6 (q, J = 273.8 Hz), 121.3 (q, J = 275.1 Hz), 114.4 (q, J = 2.1
Hz), 48.5, 42.9, 41.7, 22.1, 21.1, 18.2 ppm.
For racemic compound 2. Mp = 84.5−87 °C (lit.9 mp = 85.5−87
°C).
(2R,3S)-3-Azido-2-(2,8-bis(trifluoromethyl)quinolin-4-yl)-
azepane (3b). The title product was isolated as described in the
preparation of 3 from (+)-(11S,12R)-1 in a 7% yield (0.48 g) as a
yellow crystalline solid. Mp = 93−96 °C. [α]D20 = −29 (c 1, MeOH).
1H NMR (400 MHz, CDCl3, TMS) δ = 8.61(d, J = 8.6 Hz, 1H), 8.19
(d, J = 7.2 Hz, 1H), 7.92 (s, 1H), 7.76 (t, J = 8.0 Hz, 1H), 4.22 (d, J =
9.0 Hz, 1H), 3.89−3.93 (m, 1H), 3.28−3.34 (m, 1H), 2.82−2.89 (m,
1H) 2.31−2.38 (m, 1H), 1.99−2.07 (m, 1H), 1.87−1.93 (m, 2H),
1.78−1.84 (m, 2H), 1.58−1.63 (m, 1H) ppm. 13C{1H} NMR (151
MHz, CDCl3, TMS) δ = 152.3, 148.5 (q, J = 35.4 Hz), 144.4, 129.6
(q, J = 30.1 Hz), 129.2 (q, J = 5.3 Hz), 128.8, 127.5, 127.2, 123.7 (q, J
= 273.5 Hz), 121.3 (q, J = 275.6 Hz), 116.1, 68.2, 66.8, 50.6, 31.9,
30.5, 21.7 ppm. 19F NMR (376 MHz, CDCl3, PhCF3) δ = −61.30 (s,
3F), −68.86 (s, 3F) ppm. HRMS (ESI-TOF) [C17H15F6N5 + H]+ m/
z calcd: 404.1304, found: 404.1308
1
colorless crystals. Mp: 151−152 °C (MeOH). H NMR (400 MHz,
CDCl3, TMS) δ = 8.22 (s 1H), 8.15 (d, J = 7.2 Hz, 1H), 8.08 (d, J =
8.5 Hz, 1H), 7.70 (t, J = 7.9 Hz, 1H), 7.38−7.43 (m, 4H), 7.31−7.36
(m, 1H), 6.01 (d, J = 3.2 Hz, 1H), 4.58 (d, J = 13.2 Hz, 1H), 4.35 (br
s, 1H), 3.44 (d, J = 13.2 Hz, 1H), 3.04−3.07 (m, 1H), 2.85 (dt, J =
11.3, 3.5 Hz, 1H), 2.23 (td, J = 11.9, 2.5 Hz, 1H), 1.53−1.61 (m, 2H),
1.31−1.47 (m, 2H), 0.94−1.04 (m, 1H), 0.60−0.63 (m, 1H) ppm.
13C{1H} NMR(100 MHz, CDCl3, TMS) δ = 150.5, 148.5 (q, J = 35.2
Hz), 143.8, 138.2, 129.8 (q, J = 30.1 Hz), 129.0, 128.8, 128.7 (q, J =
5.5 Hz), 127.7, 127.06, 127.02, 126.6, 123.7 (q, J = 273.7 Hz), 121.5
(q, J = 275.6 Hz), 115.9 (q, J = 2.1 Hz), 67.7, 63.6, 58.7, 53.5, 25.3,
24.9, 23.4 ppm. HRMS (ESI-TOF) [C24H22F6N2O + H]+ m/z calcd:
469.1709, found: 469.1709.
For racemic compound 3b. Mp = 70−74 °C.
erythro-11-Aminomefloquine (4). erythro-11-Azidomefloquine
hydrazoic acid salt (3·HN3) (5.79 g, 13.0 mmol) was dissolved in
methanol (110 mL), and palladium on carbon was added (5%, 103
mg, 0.4mol %). The reaction vessel was loaded with hydrogen (6.0
bar), and the mixture was stirred for 3 h. After that time, the mixture
was filtered, and the solvent was removed. Aminomefloquine 4 (4.89
g) was obtained in a quantitative yield as a white crystalline solid. Mp:
77 °C (MeOH). 1H NMR (400 MHz, CDCl3, TMS) δ = 8.45 (d, J =
8.3 Hz, 1H), 8.17 (d, J = 7.5 Hz, 1H), 8.10 (s, 1H), 7.77 (dd, J = 8.3,
7.5 Hz, 1H), 4.79 (d, J = 5.3 Hz, 1H), 3.03−3.07 (m, 1H), 2.90−2.96
(m, 1H), 2.57−2.62 (m, 1H), 1.78−1.83 (m, 1H), 1.47−1.65 (m,
5H), 1.28−1.41 (m, 2H), 1.17−1.26 (m, 1H) ppm. 13C{1H} NMR
(100 MHz, CDCl3, TMS) δ = 152.8, 148.4 (q, J = 35.3 Hz), 144.0,
129.6 (q, J = 30.2 Hz), 128.9 (q, J = 5.5 Hz), 127.9, 127.8, 127.0,
123.7 (q, J = 274.9 Hz), 121.4 (q, J = 276.9 Hz), 115.8 (q, J = 2.1 Hz)
61.9, 56.0, 47.4, 27.0, 26.2, 24.5 ppm. 19F NMR (376 MHz, CDCl3,
PhCF3) δ = −61.29 (s, 3F), −68.86 (s, 3F) ppm. HRMS (ESI-TOF)
[C17H17F6N3 + H]+ m/z calcd: 378.1399, found: 378.1396.
25
For (11R,12S)-5a. [α]D = −23 (c 1, MeOH).
erythro-11-Azido-13-benzylmefloquine (6a). Method A.
Triphenylphosphine (3.68 g, 14.03 mmol, 2.0 equiv) was dissolved
in a mixture of toluene (40 mL) and THF (22.5 mL). Then
diisopropyl azadicarboxylate (DIAD, 3.04 mL, 15.43 mmol, 2.2 equiv)
was added dropwise at 0 °C, and the suspension was stirred for 10
min. In another flask, erythro-13-benzylmefloquine (5a, 3.29 g, 7.03
mmol) was dissolved in THF (16.5 mL), cooled to 0 °C, mixed with
diphenylphosphoryl azide (DPPA, 3.03 mL dropwise, 14.03 mmol,
2.0 equiv), and stirred for 10 min under argon. Then, this mixture was
added at 0 °C to the previously prepared suspension of Ph3P and
DIAD. The mixture was allowed to slowly attain room temperature
Enantiomerically pure products were pale amorphous solids. For
24
(11S,12R)-4. [α]D25 = +46 (c 1.1, MeOH). For (11R,12S)-4. [α]D
−48 (c 1.3, MeOH).
=
Separation of ( )-4 with L-Mandelic Acid. Alcohol (ethanol or
methanol) solutions of (+)-L-mandelic acid (0.62 g in 5 mL, 1 equiv)
10660
https://doi.org/10.1021/acs.joc.1c01316
J. Org. Chem. 2021, 86, 10654−10664

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
and stirred for 18 h. The solution was concentrated and the crude
product was purified using column chromatography on silica gel
(hexane/EtOAc 9:1), giving 3.54 g of yellowish amorphous solid
containing 17% of triphenylphosphine oxide (86% yield).
chromatography on silica gel (hexane/EtOAc 2:3 to 0:1 gradient) as
yellow oil (25 mg, 48% yield).
1H NMR(400 MHz, CDCl3, TMS) δ = 8.38 (s, 1H), 8.22 (d, J =
8.6 Hz, 1H), 8.15 (d, J = 7.2 Hz, 1H), 7.70 (t, J = 7.9 Hz, 1H), 7.28−
7.45 (m, 5H), 5.48 (d, J = 3.5 Hz, 1H), 4.57 (d, J = 13.4 Hz, 1H),
3.41 (d, J = 13.4 Hz, 1H), 2.97−3.04 (m, 1H), 2.65 (dt, J = 10.8, 3.3
Hz, 1H), 2.11 (td, J = 11.6, 3.0 Hz, 1H), 1.80 (br s, 2H), 1.58−1.71
(m, 2H), 1.36−1.55 (m, 2H), 0.89−1.03 (m, 1H), 0.75−0.84 (m,
1H) ppm. 13C{1H} NMR (100 MHz, CDCl3, TMS) δ = 153.2, 148.4
(q, J = 34.8 Hz), 144.1, 139.4, 129.8 (q, J = 29.9 Hz), 129.3, 128.7,
128.60, 128.56, 127.6, 127.3, 126.9, 123.8 (q, J = 273.8 Hz), 121.6 (q,
J = 275.6 Hz), 117.1 (q, J = 1.9 Hz), 64.7, 58.5, 54.1, 50.5, 25.5, 24.1,
24.0 ppm. 19F NMR (376 MHz, CDCl3, PhCF3) δ = −61.29 (s, 3F),
−68.87 (s, 3F) ppm. HRMS (ESI-TOF) [C24H23F6N3 + H]+ m/z
calcd: 468.1869, found: 468.1867.
Method B. erythro-11-Azidomefloquine hydrazoic acid salt (3·HN3,
0.353 g, 0.791 mmol) and N,N-diisopropylethylamine (0.414 mL,
2.43 mmol, 3.08 equiv) were dissolved in DMF (8 mL). Then benzyl
bromide (0.170 mL, 1.43 mmol, 1.81 equiv) was added. The mixture
was kept for 18 h at room temperature. The mixture was concentrated
in vacuo, diluted with ethyl acetate (25 mL), washed with saturated
aqueous NaHCO3 (25 mL), and brine (3 × 25 mL), and dried over
anhydrous Na2SO4. The crude product was purified on a silica gel
column (hexane/EtOAc 9:1) to give a light yellow amorphous solid
(0.278 g, 71% yield). 1H NMR(400 MHz, CDCl3, TMS) δ = 8.15 (d,
J = 7.2 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.87 (s, 1H), 7.64 (t, J = 7.9
Hz, 1H), 7.16−7.19 (m, 3H), 7.08−7.10 (m, 2H), 5.77 (d, J = 5.5 Hz,
1H), 4.27 (d, J = 13.2 Hz, 1H), 3.54 (d, J = 13.2 Hz, 1H), 3.06−3.11
(m, 1H), 2.86−2.90 (m, 1H), 2.33−2.39 (m, 1H), 1.70−1.85 (m,
2H), 1.57−1.63 (m, 1H), 1.45−1.53 (m, 1H), 1.27−1.41 (m, 2H)
ppm. 13C{1H} NMR (151 MHz, CDCl3, TMS) δ = 148.1 (q, J = 35.5
Hz), 147.6, 144.2, 138.6, 129.8 (q, J = 30.3 Hz), 129.0 (q, J = 5.4 Hz),
128.6, 128.5, 127.40, 127.36, 126.9, 123.6 (q, J = 273.8 Hz), 121.3 (q,
J = 275.7 Hz), 117.1 (q, J = 1.7 Hz), 63.1, 62.2, 58.8, 51.7, 23.1, 22.9,
22.4 ppm (one signal not observed due to overlap). 19F NMR (376
MHz, CDCl3, PhCF3) δ = −61.32 (s, 3F), −68.86 (s, 3F) ppm.
HRMS (ESI-TOF): [C24H21F6N5 + H]+ m/z calcd: 494.1774, found:
494.1774.
22
For (11R,12S)-7a. [α]D = −30 (c 0.7, MeOH).
erythro-11-Amino-13-methylmefloquine (7b). erythro-11-
Azido-13-methylmefloquine (6b, 2.26 g, 5.42 mmol) was dissolved
in methanol (75 mL), and palladium on carbon was added (5%, 170
mg, 1.6 mol %). The reaction vessel was loaded with hydrogen (6.0
bar), and the mixture was stirred overnight. After that time, the
mixture was filtered and the solvent was removed. The crude product
was purified using column chromatography on basic Al2O3 (hexane/
EtOAc 1:0 to 0:1 gradient). The product (1.73 g) was obtained in a
1
82% yield as a light yellow solid. Mp: 128−131 °C. H NMR (400
MHz, CDCl3, TMS) δ = 8.36 (s, 1H), 8.30 (d, J = 8.6 Hz, 1H), 8.14
(d, J = 7.2 Hz, 1H), 7.72 (t, J = 7.9 Hz, 1H), 5.40 (d, J = 3.3 Hz, 1H),
2.95−2.98 (m, 1H), 2.62 (s, 3H), 2.24 (dt, J = 11.1, 3.0 Hz, 1H),
2.12−2.19 (m, 1H), 1.77 (br s, 2H), 1.49−1.62 (m, 4H), 0.83−0.95
(m, 1H), 0.69−0.74 (m, 1H) ppm. 13C{1H} NMR (100 MHz,
CDCl3, TMS) δ = 153.0, 148.3 (q, J = 34.7 Hz), 144.0, 129.6 (q, J =
29.8 Hz), 128.6 (q, J = 5.5 Hz), 127.5, 127.3, 126.9, 123.8 (q, J =
273.7 Hz), 121.6 (q, J = 274.9 Hz), 117.0 (q, J = 2.1 Hz), 66.9, 57.9,
50.4, 43.3, 25.9, 24.1, 23.7 ppm. 19F NMR (376 MHz, CDCl3,
PhCF3) δ = −61.27 (s, 3F), −68.85 (s, 3F) ppm. HRMS (ESI-TOF)
[C18H19F6N3 + H]+ m/z calcd: 392.1556, found: 392.1563.
25
For (11R,12S)-6a. [α]D = −13 (c 0.9, MeOH).
erythro-11-Azido-13-methylmefloquine (6b). Method A.
Triphenylphosphine (1.47 g, 5.60 mmol, 1.1 equiv) was dissolved
in CH2Cl2 (25 mL), the solution was cooled to 0 °C, and diisopropyl
azadicarboxylate (DIAD, 1.00 mL, 5.08 mmol, 1.0 equiv) was added
dropwise with stirring. Stirring was continued for 10 min at 0 °C.
In another flask, erythro-13-methylmefloquine18 (5b, 2.00 g, 5.10
mmol) was dissolved in CH2Cl2 (45 mL), and a solution of hydrazoic
acid in benzene (1.67 M, 6.1 mL, 10.2 mmol, 2.0 equiv) was added.
After 10 min, the previously prepared mixture of phosphine and
DIAD was added. The reaction mixture was allowed to slowly attain
room temperature and stirred for 5 days. Then the mixture was
concentrated and the crude product was purified using column
chromatography on silica gel (CH2Cl2/EtOAc 9:1), giving 1.45 g of
yellowish amorphous solid (68%).
25
For (11R,12S)-7b. [α]D = −75 (c 1.1, MeOH).
erythro-13-Acetylmefloquine. erythro-Mefloquine hydrochlor-
ide (1·HCl, 27.3 g, 65.9 mmol) was suspended in isopropyl alcohol
(300 mL), and solid K2CO3 (30.5 g, 221 mmol, 3.4 equiv) was added.
The suspension was heated under reflux for 10 min in a heating
mantle. After the mixture had reached room temperature, acetic
anhydride (8.5 mL, 89.9 mmol, 1.37 equiv) was added dropwise, and
the suspension was stirred overnight. Then, the mixture was
concentrated, and the residue was suspended in distilled water (130
mL) for 1 h. The white crystalline solid was separated by filtration,
washed with water, and air-dried. Residual inorganic material was
removed by dissolving most of the sample in CHCl3 (300 mL)
followed by filtration and evaporation to give 27.7 g of product, a
quantitative yield as a white crystalline solid. Mp: 197−199 °C (lit.11
mp 202 °C).
Method B. erythro-11-Azidomefloquine hydrazoic acid salt (3·HN3,
522 mg, 1.17 mmol) was suspended in formic acid (0.6 mL) and
formaldehyde solution (36−38% aqueous, 0.60 mL). The mixture was
heated in an oil bath at 80 °C overnight. Then the suspension was
evaporated to dryness and dissolved in CH2Cl2(30 mL). The organic
phase was washed with a saturated solution of NaHCO3. The aqueous
layer was extracted with CH2Cl2. The combined organic phases were
dried over anhydrous Na2SO4. The solvent was evaporated giving
pure product (450 mg, 92%) as pale crystalline solid. Mp = 114.5−
threo-13-Benzylmefloquine (9). threo-Mefloquine hydrochlor-
ide11 (8·HCl, 2.75 g, 6.63 mmol) was suspended in dioxane (20 mL)
and aqueous NaOH (10%, 7 mL) and stirred for 5 min. Benzyl
bromide (0.89 mL, 7.49 mmol, 1.13 equiv) was added dropwise. The
mixture was stirred for 8 days at room temperature. Next, the phases
were separated, and the organic phase was washed with a saturated
NaHCO3 solution. The aqueous layer was extracted with CH2Cl2 (3
× 10 mL). Organic phases were combined, dried over anhydrous
Na2SO4, and evaporated. Crystallization from methanol (15 mL) gave
a pure product (three crops, 2.68 g, 86%) as light yellow crystals. Mp
1
117 °C dec. H NMR (400 MHz, CDCl3, TMS) δ = 8.20−8.23 (m,
2H), 7.98 (s, 1H), 7.81 (t, J = 7.9 Hz, 1H), 6.00 (d, J = 2.6 Hz, 1H),
3.03−3.06 (m, 1H), 2.72 (s, 3H), 2.34 (dt, J = 10.9, 2.6 Hz, 1H),
2.12−2.19 (m, 1H), 1.55−1.70 (m, 4H), 0.89−1.00 (m, 2H) ppm.
13C{1H} NMR (100 MHz, CDCl3, TMS) δ = 148.3 (q, J = 35.5 Hz),
146.9, 144.2, 130.0 (q, J = 30.5 Hz), 129.1 (q, J = 5.5 Hz), 127.8,
126.9, 126.5, 123.5 (q, J = 273.8 Hz), 121.2 (q, J = 275.8 Hz), 116.9
(q, J = 2.1 Hz), 67.2, 61.0, 57.7, 43.5, 25.4, 24.4, 23.8 ppm. 19F NMR
(376 MHz, CDCl3, PhCF3) δ = −61.33 (s, 3F), −68.88 (s, 3F) ppm.
HRMS (ESI-TOF) [C18H17F6N5 + H]+ m/z calcd: 418.1461, found:
418.1461.
1
= 121−123 °C. H NMR (400 MHz, CDCl3, TMS) δ = 8.05−8.08
(m, 2H), 7.71 (s, 1H), 7.36−7.45 (m, 6H), 5.46 (br s, 1H), 5.38 (d, J
= 10.0 Hz, 1H), 3.96 (s, 2H), 3.10−3.17 (m, 1H), 2.86−2.95 (m,
2H), 1.60−1.84 (m, 4H), 1.46−1.49 (m, 1H), 0.99−1.03 (m, 1H)
ppm. 13C{1H} NMR (100 MHz, CDCl3, TMS) δ = 152.0, 148.0 (q, J
= 35.1 Hz), 144.3, 138.6, 129.47, 128.9, 128.8 (q, J = 5.5 Hz), 128.6,
127.92, 127.91, 126.7, 123.7 (q, J = 273.5 Hz), 121.3 (q, J = 275.3
Hz), 117.2 (q, J = 2.0 Hz), 68.5, 60.7, 57.2, 47.1, 20.8, 19.34, 19.31
ppm (one signal not observed due to overlap). 19F NMR (376 MHz,
24
For (11R,12S)-6b. [α]D = −96 (c 1.1, MeOH).
erythro-11-Amino-13-benzylmefloquine (7a). erythro-11-
Azido-13-benzyl-mefloquine (6a, 55.0 mg, 0.112 mmol) was dissolved
in methanol (2.5 mL) and palladium on carbon was added (5%, 5.0
mg, 2 mol %). The reaction vessel was loaded with hydrogen (6.0 bar)
and the mixture was stirred for 24 h. Then, the mixture was filtered
and the solvent was evaporated. The product was obtained by flash
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CDCl3, PhCF3) δ = −61.37 (s, 3F), −68.96 (s, 3F) ppm. HRMS
(ESI-TOF) [C24H22F6N2O + H]+ m/z calcd: 469.1709, found:
469.1711.
For (11R,12R)-9. Mp = 132−133.4 °C. [α]D = −83 (c 1,
MeOH).
= 153.9, 148.4 (q, J = 35.0 Hz), 144.1, 129.7 (q, J = 30.1 Hz), 129.0
(q, J = 5.5 Hz), 127.8, 127.7, 127.2, 123.7 (q, J = 273.7 Hz), 121.4 (q,
J = 275.5 Hz), 115.4 (q, J = 1.8 Hz), 62.2, 55.8, 47.0, 30.3, 26.2, 24.7
ppm. 19F NMR (376 MHz, CDCl3, PhCF3) δ = −61.31 (s, 3F),
−68.85 (s, 3F) ppm. HRMS (ESI-TOF) [C17H17F6N3 + H]+ m/z
calcd: 378.1399, found: 378.1398.
24
threo-11-Azido-13-benzylmefloquine (10). threo-13-Benzyl-
mefloquine (9, 1.40 g, 3.00 mmol) was dissolved in dry THF (5
mL) and a solution of hydrazoic acid in benzene (1.50 M, 3.10 mL,
4.65 mmol, 1.55 equiv) was added. In another flask, triphenylphos-
phine (1.33 g, 5.08 mmol, 1.7 equiv) was dissolved in dry THF (10
mL) and the solution was cooled to 0 °C. Then, diisopropyl
azadicarboxylate (DIAD, 1.00 mL, 5.08 mmol, 1.7 equiv) was added
dropwise and soon a precipitate was formed. This suspension was
added to the previously prepared solution of the substrate and
hydrazoic acid, and stirred for 18 h at room temperature. Then, the
mixture was concentrated and the crude product was purified using
column chromatography on acidic aluminum oxide (CH2Cl2/EtOAc
2:3) giving 1.34 g of yellow crystalline solid (82%). Mp: 109.6−111.8
°C (EtOAc). 1H NMR (400 MHz, CDCl3, TMS) δ = 8.23 (d, J = 8.6
Hz, 1H), 8.15 (d, J = 7.2 Hz, 1H), 7.75 (s, 1H), 7.61 (t, J = 8.0 Hz,
1H), 7.27−7.42 (m, 5H), 5.53 (d, J = 9.4 Hz, 1H), 4.05 (d, J = 13.3
Hz, 1H), 4.00 (d, J = 13.3 Hz, 1H), 3.30−3.33 (m, 1H), 3.10−3.15
(m, 1H), 2.77−2.80 (m, 1H), 1.48−1.66 (m, 5H), 0.88−0.91 (m,
1H) ppm. 13C{1H} NMR (151 MHz, CDCl3, TMS) δ = 148.2 (q, J =
35.5 Hz), 147.5, 144.5, 139.5, 129.8 (q, J = 30.3 Hz), 129.2 (q, J = 5.3
Hz), 128.9, 128.55, 128.45 127.4, 127.3, 127.2, 123.6 (q, J = 273.7
Hz), 121.2 (q, J = 275.6 Hz), 117.3, 63.6, 61.5, 58.0, 47.3, 23.1, 21.2,
21.1 ppm. 19F NMR (376 MHz, CDCl3, PhCF3) δ = −61.34 (s, 3F),
−68.90 (s, 3F) ppm. HRMS (ESI-TOF) [C24H21F6N5 + H]+ m/z
calcd: 494.1774, found: 494.1773
20
For (11R,12R)-12. [α]D = −22 (c 1, MeOH).
threo-11-Azidomefloquine (13). erythro-11-Azidomefloquine
hydrazoic acid salt (3·HN3 65 mg, 0.15 mmol) was dissolved in
methanol (1.6 mL) and sodium hydroxide (25 mg, 0.56 mmol, 3.7
equiv) was added. The mixture was briefly stirred until dissolution
and stored at room temperature for 72 h. The solution was diluted
with saturated aqueous NaHCO3 (25 mL) and CH2Cl2 (25 mL),
washed with saturated NaCl (15 mL), dried over K2CO3, and
evaporated. Chromatography on silica gel (CH2Cl2/MeOH 20:1)
gave 12 mg of white solid (20% yield, dr 95:5). 1H NMR (600 MHz,
CDCl3, TMS) δ = 8.42 (d, J = 8.9 Hz, 1H) 8.23 (d, J = 7.1 Hz, 1H),
7.88 (s, 1H), 7.80 (dd, J = 8.9, 7.1 Hz, 1H), 5.14 (d, J = 8.2 Hz, 1H),
3.13−3.18 (m, 1H), 2.89 (ddd, J = 10.6, 8.9, 2.7 Hz, 1H), 2.63 (td, J =
12.1, 2.9 Hz, 1H), 2.0 (br., 1H), 1.68−1.73 (m, 1H), 1.58−1.63 (m,
1H), 1.39−1.47 (m, 1H), 1.13−1.26 (m, 2H), 1.06−1.10 (m, 1H)
ppm. 13C{1H} NMR (151 MHz, CDCl3, TMS) δ = 148.5 (q, J = 35.7
Hz), 146.6, 144.4, 129.8 (q, J = 30.8 Hz), 129.4 (q, J = 5.3 Hz), 127.8,
127.7, 127.5, 123.5 (q, J = 273.6 Hz), 121.2 (q, J = 275.5 Hz), 117.0,
68.1, 60.8, 46.8, 29.7, 25.8, 24.3 ppm. HRMS (ESI-TOF)
[C17H15F6N5 + H]+ m/z calcd: 404.1299, found:404.1306
erythro-Hexahydro-1-(2,8-Bis(trifluoromethyl)-4-quinolin-
yl)-imidazo-[1,5-a]pyridin-3(2H)-one (14). erythro-11-Aminome-
floquine (4, 50 mg, 0.14 mmol) was dissolved in CH2Cl2 (4 mL), and
N,N-diisopropylethylamine (50 μL, 0.29 mmol, 2 equiv) and
phosgene solution (20% in toluene, 15 μL, ca. 1.1 equiv) were
added. The mixture was stirred for 18 h, evaporated, and filtered
through a plug of silica gel with EtOAc. The mixture was evaporated
and the residue triturated with chloroform (1.5 mL). Obtained 31 mg
26
For (11R,12R)-10. Yellow amorphous solid, [α]D = −67 (c 0.9,
MeOH).
threo-11-Amino-13-benzylmefloquine (11). threo-11-Azido-
13-benzylmefloquine (10, 48.5 mg, 0.0984 mmol) was dissolved in
methanol (2.5 mL). Next, palladium on carbon was added (5%, 5.0
mg, 2.5 mol %) was added. The reaction vessel was loaded with
hydrogen (6.0 bar), and the mixture was stirred for 24 h. Then, the
mixture was filtered and the solvent was removed. The product was
obtained by flash chromatography on silica gel (hexane/EtOAc 1:0 to
2:3 gradient) as a pale amorphous solid (30 mg, 65% yield). 1H NMR
(400 MHz, CDCl3, TMS) δ = 8.53 (d, J = 8.6 Hz, 1H), 8.13 (d, J =
7.2 Hz, 1H), 7.97 (s, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.30−7.44 (m,
5H), 5.05 (d, J = 9.9 Hz, 1H), 3.95 (s, 2H), 2.99−3.08 (m, 2H),
2.74−2.78 (m, 1H), 2.14 (br s, 2H), 1.36−1.73 (m, 5H), 0.93−0.99
(m, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3, TMS) δ = 154.5,
148.3 (q, J = 35.0 Hz), 144.3, 139.8, 129.5 (q, J = 30.0 Hz), 129.0,
128.8 (q, J = 5.5 Hz), 128.62, 128.56, 127.4, 126.6, 123.8 (q, J = 273.6
Hz), 121.4 (q, J = 275.5 Hz), 117.2 (q, J = 2.0 Hz), 63.6, 55.6, 52.1,
47.0, 22.1, 21.0, 19.2 ppm (one signal not observed due to overlap).
19F NMR (376 MHz, CDCl3, PhCF3) δ = −61.32 (s, 3F), −68.88 (s,
3F) ppm. HRMS (ESI-TOF) [C24H23F6N3 + H]+ m/z calcd:
468.1869, found: 468.1869.
1
of white crystalline product (58%). H NMR (600 MHz, DMSO-d6,
TMS) δ = 8.65 (d, J = 8.5 Hz, 1H), 8.40 (d, J = 7.3 Hz, 1H), 8.01 (s,
1H), 7.97 (dd, J = 8.5, 7.3 Hz, 1H), 7.16 (d, J = 1.2 Hz, 1H), 5.80
(dd, J = 8.5, 1.2 Hz, 1H), 4.20 (ddd, J = 12.0, 8.8, 3.4 Hz, 1H), 3.75−
3.79 (m, 1H), 2.72 (td, J = 12.9, 3.4 Hz, 1H), 1.52−1.56 (m, 1H),
1.41−1.46 (m, 1H), 1.19−1.27 (m, 1H), 1.03−1.14 (m, 1H), 0.62
(qd, J = 12.5, 3.5 Hz, 1H), 0.50−0.54 (m, 1H) ppm. 13C{1H} NMR
(151 MHz, DMSO-d6, TMS) δ = 160.2, 150.1, 147.3 (q, J = 34.5 Hz),
143.0, 130.5 (q, J = 5.3 Hz), 129.4, 129.0, 127.8, 127.6 (q, J = 29.7
Hz), 124.1 (q, J = 273.6 Hz), 121.7 (q, J = 275.4 Hz), 115.6, 57.6,
53.7, 41.0, 26.3, 24.5, 23.2 ppm. 19F NMR (400 MHz, DMSO-d6,
PhCF3) δ = −61.40 (s, 3F), −69.22 (s, 3F) ppm. HRMS (ESI-TOF)
[C18H15F6N3O + H]+ m/z calcd: 404.1201, found: 404.1191.
threo-Hexahydro-1-(2,8-Bis(trifluoromethyl)-4-quinolinyl)-
imidazo-[1,5-a]pyridin-3(2H)-one (15). threo-11-Aminomeflo-
quine (12, 42.5 mg, 0.113 mmol) was dissolved in acetonitrile (3.5
mL). Next, 1,1′-carbonyldiimidazole (CDI, 20.3 mg, 0.125 mmol, 1.1
equiv) was added. After 14 days, the mixture was purified on a silica
gel column with ethyl acetate. The product was isolated as a white,
25
For (11R,12R)-11. [α]D = −57 (c 1, MeOH).
1
threo-11-Aminomefloquine (12). threo-11-Azido-13-benzyl-me-
floquine (10, 103 mg, 0.209 mmol) was dissolved in a mixture of
methanol (17 mL) and TFA (0.80 mL). Palladium on carbon (5%, 8
mg, 2 mol %) was added, the reaction vessel was loaded with
hydrogen (6.0 bar), and the mixture was stirred for 18 h. Then the
catalyst was filtered off, and the solution was concentrated in vacuo.
The crude product was diluted with ethyl acetate (25 mL) and
washed with saturated aqueous NaHCO3 (10 mL). The organic phase
was dried over anhydrous Na2SO4, and the solvent was evaporated.
Crude product was purified using column chromatography on basic
aluminum oxide (EtOAc/MeOH 1:0 to 0:1 gradient). The product
(54 mg, 64% yield) was obtained as a light orange amorphous solid.
1H NMR (400 MHz, CDCl3, TMS) δ = 8.42 (d, J = 8.6 Hz, 1H), 8.19
(d, J = 7.2 Hz, 1H), 7.97 (s, 1H), 7.75 (t, J = 7.9 Hz, 1H), 4.68 (d, J =
6.5 Hz, 1H), 3.12−3.15 (m, 1H), 2.78−2.83 (m, 1H), 2.58 (td, J =
11.9, 2.8 Hz, 1H), 2.03 (br s, 3H), 1.74−1.77 (m, 1H), 1.59−1.62 (m,
1H), 1.25−1.47 (m, 4H) ppm. 13C NMR (151 MHz, CDCl3, TMS) δ
amorphous solid (31.0 mg, 66% yield). H NMR (600 MHz, CDCl3,
TMS) δ = 8.24 (d, J = 8.6 Hz, 1H), 8.21 (d, J = 7.3 Hz, 1H), 8.08 (s,
1H), 7.80 (t, J = 8.0 Hz, 1H), 6.54 (s, 1H), 5.21 (d, J = 5.4 Hz, 1H),
3.88 (dd, J = 13.3, 4.5 Hz, 1H), 3.34−3.37 (m, 1H), 2.65 (td, J = 12.9,
3.2 Hz, 1H), 2.00−2.02 (m, 1H), 1.94−1.96 (m, 1H), 1.72−1.79 (m,
1H), 1.62−1.64 (m, 1H), 1.41−1.49 (m, 1H), 1.31−1.39 (m, 1H)
ppm. 13C{1H} NMR (151 MHz, CDCl3, TMS) δ = 160.7, 150.1,
148.8 (q, J = 35.4 Hz), 144.1, 130.0 (q, J = 30.3 Hz), 129.1 (q, J = 5.3
Hz), 127.7, 127.1, 126.6, 123.5 (q, J = 273.7 Hz), 121.2 (q, J = 275.5
Hz), 114.9, 63.5, 56.7, 41.0, 30.9, 24.5, 23.4 ppm. 19F NMR (376
MHz, CDCl3, PhCF3) δ = −61.37 (s, 3F), −68.88 (s, 3F) ppm.
HRMS (ESI-TOF) [C18H15F6N3O + H]+ m/z calcd: 404.1192,
found: 404.1191.
13-Benyzl-11-chloromefloquine Hydrochloride. erythro-13-
Benzyl mefloquine (5a, 1.39 g, 2.96 mmol) was dissolved in thionyl
chloride (6 mL) and heated in an oil bath at 65 °C for 18 h. Then the
mixture was evaporated to give 1.47 g of light pink crystalline solid
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(95%). Mp: 151−159 °C. HRMS (ESI-TOF) [C24H21ClF6N2 + H]+
m/z calcd: 487.1370, found: 487.1382.
Squaramide Derivatives are Excellent Hydrogen Bond Donor
Catalysts. J. Am. Chem. Soc. 2008, 130, 14416−14417.
Identical results were obtained starting from threo-13-benzylme-
floquine (9, 109 mg, 0.23 mmol) and 2 mL of thionyl chloride.
Asymmetric Michael Reaction.19 Catalyst (15.1 mg for 4, 0.040
mmol, 10 mol %) was dissolved in nitromethane (1 mL). Next,
benzoic acid (4.88 mg, 0.040 mmol, 10 mol %) was added, and the
mixture was stirred until dissolution. Finally, 2-cyclohexen-1-one
(38.7 μL, 0.40 mmol) was slowly added via syringe. The mixture was
stirred in an oil bath at 40 °C for 4 days and filtered through a silica
gel plug (4 g) with ethyl acetate. The solvent was evaporated, and the
HPLC analysis of the crude product was performed (IC-3 column, 4.6
× 250 mm, hexane/2-propanol, 6/4, flow rate: 0.8 mL/min, λ = 220
nm); tR = 24 min (S enantiomer) and 31 min (R enantiomer).
́
́
(2) For a review, see: (a) Boratynski, P. J.; Zielinska-Błajet, M.;
Skarzewski, J. Cinchona Alkaloids-Derivatives and Applications.
̇
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Arceo, E.; Bravo, F.; Melchiorre, P. Synthesis of 9-Amino(9-Deoxy)
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01316.
■
sı
Plots of NMR spectra, assignment of NMR signals for
compounds 3b, 14, and 15, chiral HPLC chromato-
grams of mefloquine derivatives and catalytic products,
and computational data for compounds 14 and 15
(PDF)
FAIR data, including the primary NMR FID files, for
compounds 2−7b and 9−16 (ZIP)
chloride. Adv. Synth. Catal. 2013, 355, 3575−3580. (f) Schu
̈
tzenmeis-
ter, N.; Muller, M.; Reinscheid, U. M.; Griesinger, C.; Leonov, A.
̈
Trapped in Misbelief for Almost 40 Years: Selective Synthesis of the
Four Stereoisomers of Mefloquine. Chem. - Eur. J. 2013, 19, 17584−
17588. (g) Ding, J.; Hall, D. G. Concise Synthesis and Antimalarial
Activity of All Four Mefloquine Stereoisomers Using a Highly
Enantioselective Catalytic Borylative Alkene Isomerization. Angew.
Chem., Int. Ed. 2013, 52, 8069−8073. (h) Rastelli, E. J.; Coltart, D. M.
A Concise and Highly Enantioselective Total Synthesis of (+)-anti-
and (−)-syn-Mefloquine Hydrochloride: Definitive Absolute Stereo-
chemical Assignment of the Mefloquines. Angew. Chem., Int. Ed. 2015,
54, 14070−14074. (i) Rastelli, E. J.; Coltart, D. M. Asymmetric
Synthesis of (+)-anti- and (−)-syn-Mefloquine Hydrochloride. J. Org.
Chem. 2016, 81, 9567−9575.
AUTHOR INFORMATION
Corresponding Author
■
́
Przemysław J. Boratynski − Department of Organic and
Medicinal Chemistry, Wrocław University of Technology,
Wrocław 50370, Poland; orcid.org/0000-0002-7139-
8568; Email: przemyslaw.boratynski@pwr.edu.pl
Authors
(4) (a) Kreituss, I.; Chen, K.-Y.; Eitel, S. H.; Adam, J.-M.; Wuitschik,
G.; Fettes, A.; Bode, J. W. A Robust, Recyclable Resin for Decagram
Scale Resolution of ( )-Mefloquine and Other Chiral N-Hetero-
cycles. Angew. Chem., Int. Ed. 2016, 55, 1553−1556. (b) Kreituss, I.;
Bode, J. Flow Chemistry and Polymer-Supported Pseudoenantiomeric
Acylating Agents Enable Parallel Kinetic Resolution of Chiral
Saturated N-Heterocycles. Nat. Chem. 2017, 9, 446−452.
(5) Engwerda, A. H. J.; Maassen, R.; Tinnemans, P.; Meekes, H.;
Rutjes, F. P. J. T.; Vlieg, E. Attrition-Enhanced Deracemization of the
Antimalaria Drug Mefloquine. Angew. Chem., Int. Ed. 2019, 58, 1670−
1673.
(6) Karle, J. M.; Karle, I. L. Crystal Structure of (−)-Mefloquine
Hydrochloride Reveals Consistency of Configuration with Biological
Activity. Antimicrob. Agents Chemother. 2002, 46, 1529−1534.
(7) Kohout, M.; Kählig, H.; Wolrab, D.; Roller, A.; Lindner, W.
Novel Chiral Selector Based on Mefloquine - A Comparative NMR
Study to Elucidate Intermolecular Interactions with Acidic Chiral
Selectands. Chirality 2012, 24, 936−943.
Dawid J. Kucharski − Department of Organic and Medicinal
Chemistry, Wrocław University of Technology, Wrocław
50370, Poland; orcid.org/0000-0001-5074-4719
Rafał Kowalczyk − Department of Bioorganic chemistry,
Wrocław University of Technology, Wrocław 50370, Poland;
orcid.org/0000-0001-5228-9131
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01316
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
̇
We thank Dawid Zuchora for separation of mefloquine
enantiomers and Maciej Dajek for developing HPLC
separations. We acknowledge the Wrocław Center for
Networking and Supercomputing for the allotment of
computer time (No. 362). We thank the National Science
Center for support (No. 2018/30/E/ST5/00242).
(8) (a) Braje, W. M.; Holzgrefe, J.; Wartchow, R.; Hoffmann, H. M.
R. Structure and Mechanism in Cinchona Alkaloid Chemistry:
Aqueous Hydrolysis Proceeds with Complete Inversion or Complete
Retention of Configuration. Angew. Chem., Int. Ed. 2000, 39, 2085−
́
2087. (b) Boratynski, P. J.; Turowska-Tyrk, I.; Skarzewski, J.
̇
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