Asymmetric Synthesis of (+)-anti- and (-)-syn-Mefloquine Hydrochloride

Article abstract of DOI:10.1021/acs.joc.6b01476

The asymmetric (er > 99:1) total synthesis of (+)-anti- and (-)-syn-mefloquine hydrochloride from a common intermediate is described. The Sharpless asymmetric dihydroxylation is the key asymmetric transformation used in the synthesis of this intermediate. It is carried out on an olefin that is accessed in three steps from commercially available materials, making the overall synthetic sequence very concise. The common diol intermediate derived from the Sharpless asymmetric dihydroxylation is converted into either a trans- or cis-epoxide, and these are subsequently converted to (+)-anti- and (-)-syn-mefloquine, respectively. X-ray crystallographic analysis of derivatives of (+)-anti- and (-)-syn-mefloquine is used to lay to rest a 40 year argument regarding the absolute stereochemistry of the mefloquines. A formal asymmetric (er > 99:1) synthesis of (+)-anti-mefloquine hydrochloride is also presented that uses a Sharpless asymmetric epoxidation as a key step.

Full text of DOI:10.1021/acs.joc.6b01476

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Article
Asymmetric Synthesis of (+)-anti- and (–)-syn-Mefloquine Hydrochloride
Ettore J. Rastelli, and Don M Coltart
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01476 • Publication Date (Web): 22 Sep 2016
Downloaded from http://pubs.acs.org on September 23, 2016
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The Journal of Organic Chemistry
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Asymmetric Synthesis of (+)ꢀantiꢀ and (–)ꢀsynꢀ
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Mefloquine Hydrochloride
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Ettore J. Rastelli and Don M. Coltart*
Department of Chemistry, University of Houston, Houston, TX 77204ꢀ5003
*dcoltart@uh.edu
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RECEIVED DATE
TOC Graphic
ABSTRACT
The asymmetric (er > 99:1) total synthesis of (+)ꢀantiꢀ and (–)ꢀsynꢀmefloquine hydrochloride
from a common intermediate is described. The Sharpless asymmetric dihydroxylation is the key
asymmetric transformation used in the synthesis of this intermediate. It is carried out on an olefin that
is accessed in three steps from commercially available materials, making the overall synthetic sequence
very concise. The common diol intermediate derived from the Sharpless asymmetric dihydroxylation is
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converted into either a transꢀ or cisꢀepoxide, and these are subsequently converted to (+)ꢀantiꢀ and (–)ꢀ
synꢀmefloquine, respectively. Xꢀray crystallographic analysis of derivatives of (+)ꢀantiꢀ and (–)ꢀsyn-
mefloquine is used to lay to rest a 40 year argument regarding the absolute stereochemistry of the
mefloquines. A formal asymmetric (er = 99:1) synthesis of (+)ꢀantiꢀmefloquine hydrochloride is also
presented that uses as a Sharpless asymmetric epoxidation as key step.
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INTRODUCTION
Malaria is the most lethal parasitic disease known. As of 2015, it was reported that 95 countries
and territories have ongoing malaria transmission with approximately 214 million cases of malaria,
leading to 438,000 deaths.1 Antiꢀmefloquine hydrochloride2 (1, Figure 1) is used for both treatment
against malaria and prophylaxis. It is manufactured commercially by HoffmannꢀLaRoche under the
trade name Lariam3 and is administered in racemic form. While extremely effective and widely used,
anti-mefloquine hydrochloride has some limitations.4,5 There are neurotoxic side effects that can be
traced back to the difference in potencies of both enantiomers, with the (+)ꢀenantiomer being at least 1.5
times more potent than the (–)ꢀenantiomer.6 Moreover, although distributed across many different types
of tissue, evidence suggests that the (–)ꢀenantiomer has a shorter in vivo halfꢀlife owing to higher blood
plasma concentrations.7 These issues have led to a growing interest in enantioselective syntheses of
antiꢀmefloquine hydrochloride in order to further understand and potentially benefit from its use as a
single enantiomer drug.
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Figure 1. (+)ꢀ and (–)ꢀ anti-mefloquine hydrochloride and (+)ꢀ and
(–)ꢀsynꢀmefloquine hydrochloride salts.
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Enantiomerically enriched (+)ꢀantiꢀmefloquine has been synthesized on several occasions
previously, including one instance in which it was generated by resolution of a racemate.8 Asymmetric
hydrogenation (86ꢀ96% ee)9 has been employed to establish the C11 stereocenter in three separate
approaches to enantiomerically enriched anti-mefloquine (Scheme 1). In order to set the C12
stereogenic center in these syntheses, a substrate controlled catalytic hydrogenation was conducted
which gave an 85:15 ratio in favor of the desired diastereomer.10 A different approach11 to (–)ꢀanti
mefloquine relied on the use of an organocatalytic aldol reaction to set the C11 and C12 stereogenic
centers, resulting in 71% ee. The enantiomeric excess was further increased from 71% to 95% as a
result of subsequent synthetic operations. (+)ꢀanti mefloquine has also been synthesized in an
unspecified enantioselectivity12 from (S)ꢀ(–)ꢀ1ꢀNꢀBocꢀ2ꢀpiperidinecarboxylic acid. More recently,
Hall13 and Leonov14 independently reported asymmetric syntheses of both anti- and syn-mefloquine
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hydrochloride, using approaches that led to the production of all four stereoisomers.
An
enantioselective allylboration reaction (99% ee) was used to produce a syn vicinal amino alcohol
precursor in Hall's synthesis of synꢀmefloquine hydrochloride.15 This precursor was subsequently
oxidized to the corresponding vicinal keto amine, which then underwent diastereoselective (10:1 dr)
reduction to give an antiꢀvicinal amino alcohol, that was ultimately converted to antiꢀmefloquine
hydrlochloride. Diastereoselctive (12:1 dr) addition of trimethylsilyl acetylide to an enantiomerically
enriched aldehyde derived from pipecolinic acid served as the basis of Leonov's synthesis of both anti-
and syn- mefloquine hydrochloride. The major diastereomer was used in a domino Sonogashira/6π
electrocyclization to give antiꢀmefloquine as the major product, and synꢀmefloquine as the minor
product. The synꢀmefloquine isomer was formed as a result of epimerization during the domino
reaction. The antiꢀ and synꢀmefloquine products were separated chromatographically and the
enantiomeric ratio was determined to be 93:7 and 96:4, respectively.
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a) Schmid and co-workers
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Rh(L)Cl,
H2
F3C
F3C
N
N
N
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86%
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CF3
L = Cy2P PCy2
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b) Xie and co-workers
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-proline,
OH
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CHO
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F3C
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N
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CF3
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HBpin, Pd(OAc)2, Taniaphos,
PhNMe2, dioxane; then 5,
PhMe, mW, 130 °C
OTf
OH
F3C
N
BocN
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Boc
CF3
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OBz
I
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Et3N, 75 °C
F3C
N
F3C
CF3
+
N
BocN
86%
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OBz
CF3
11
96:4 er
BocN
10
Scheme 1. Previous asymmetric syntheses of anti and syn-mefloquine.
In 2012, our lab reported an asymmetric total synthesis of (–)ꢀantiꢀmefloquine hydrochloride16
(>99:1 er) (Scheme 2). The synthesis was built around a cascading azide reduction/regioselective and
stereospecific epoxide ringꢀopening reaction beginning with 13 that, following trapping of the 3,4ꢀ
dehydropiperidine intermediate with Boc2O, ultimately led to 3,4ꢀdehydroꢀNꢀBocꢀmefloquine (14) in a
oneꢀpot reaction. Reduction of the olefin, removal of the Boc protecting group, and HCl formation led
to (–)ꢀantiꢀmefloquine hydrochloride in excellent yield. A key intermediate in this synthesis was trans-
epoxide 12, which we had cause to prepare in enantiomerically enriched form via an asymmetric Nꢀ
amino cyclic carbamate (ACC)ꢀbased17 Darzens reaction.16
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Scheme 2. Prior synthesis of (–)ꢀantiꢀmefloquine hydrochloride.
While the annulative epoxide ring opening sequence used in the above synthesis was appealing
to us, the route leading to 12 left room for improvement. After some effort, we were able to develop a
new, concise, highly enantioselective (er > 99:1) synthesis of (–)ꢀantiꢀmefloquine hydrochloride that
maintained the annulative epoxide ring opening strategy.18 The key asymmetric transformation in this
case was a Sharpless asymmetric dihydroxylation of a structurally advanced olefin. As part of this
work, we were also able to gain access to (–)ꢀsynꢀmefloquine hydrochloride in an equally concise
manner from the same Sharplessꢀderived diol. In what follows, we provide a full account of that work.
In addition, we describe a new, more practically useful approach to the synthesis of the advanced olefin
used for the Sharpless asymmetric dihydroxylation. We also present a formal asymmetric (er = 99:1)
synthesis of (+)ꢀantiꢀmefloquine hydrochloride that employs a Sharpless asymmetric epoxidation as key
transformation.
RESULTS AND DISCUSSION
In our initial efforts to improve the efficiency of our first synthesis of (–)ꢀantiꢀmefloquine
hydrochloride (Scheme 2), we planned to pursue a different route to epoxide 12 that would take
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advantage of the Sharpless asymmetric epoxidation.19 In the event, as a matter of convenience and
economy, we prepared epoxide 18 (Scheme 3), the enantiomer of 12, instead. The allylic alcohol (17)
required for the epoxidation would be obtained from a Heck coupling between aryl bromide 16 and
ethyl acrylate, followed by ester reduction. The synthesis of epoxide 18 began with the preparation of
aryl bromide 16 from commercially available quinolinol 15, according to a literature procedure20
(Scheme 3). With the aryl bromide in hand, we were pleased to find that the proposed Heck coupling
with ethyl acrylate proceeded in good yield under standard conditions. The resulting ester was then
subjected to a DIBALꢀmediated reduction to afford allylic alcohol 17. As hoped, Sharpless asymmetric
epoxidation of 17 furnished the desired epoxy alcohol (18) in good yield (77%) and with excellent
enantioselectivity (er = 98:2). The enantiomeric purity of 18 was established by comparing it with a
corresponding racemic sample21 by HPLC analysis on a chiral, nonracemic stationary phase.22 The
enantiomeric purity of 18 was increased to >99:1 in a single and reasonably efficient (70% recovery)
recrystallization using a mixture of Et2O and hexanes. By analogy to what we have previously
described for its enantiomer (12), epoxy alcohol 18 can be converted to (+)ꢀantiꢀmefloquine
hydrochloride in six steps, which constitutes a formal second generation synthesis that is considerably
improved over our first effort. 16
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Scheme 3. Formal second generation synthesis of (+)ꢀantiꢀmefloquine hydrochloride.
Having developed an effective synthesis of (+)ꢀantiꢀmefloquine hydrochloride, we turned our
attention to the synthesis of the synꢀisomer. As was recently reported by Hall,Error! Bookmark not defined. (+)ꢀ
synꢀmefloquine hydrochloride also exhibits strong potency towards Plasmodium falciparum. In theory,
access to (+)ꢀsynꢀmefloquine hydrochloride could be gained using a similar strategy to that shown for
the synthesis of (+)ꢀ1 in Scheme 3, but by substituting cisꢀepoxide 21 in place of transꢀepoxide 18. Our
attempt at preparing 21 began with a Sonogashira coupling between aryl bromide 16 and propargyl
alcohol, which led to alkyne 19 in very good yield (Scheme 4). This was followed by careful reduction
of the alkyne using Lindlar’s catalyst to generate cisꢀallylic alcohol 20. Unfortunately, all attempts at
the Sharpless asymmetric epoxidation of 20 were unsuccessful, and showed no indication of epoxide
formation. In each case, the starting material was recovered intact. We next attempted the epoxidation
of 20 using the Shi conditions,23 but once again the desired epoxide was not formed, and only 20 was
recovered. Out of curiosity, we also tried to form a racemic epoxide from 20 by treatment with mꢀ
CPBA, but this also resulted in only recovered starting material. A similar result was obtained when
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either DMDO or Vo(acac)2 was used. Interestingly, the cisꢀform of the allylic alcohol (20) appears to
be unreactive towards various modes of epoxidation, which is in contrast to the transꢀisomer (17).
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propargyl alcohol,
PdCl2(PPh3)2, CuI,
Et3N, reflux
F3C
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N
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80%
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CF3
19
Lindlar catalyst, quinoline,
MeOH, H2
F3C
N
N
OH
OH
82%
CF3
20
O
asymmetric epoxidation
F3C
X
CF3
21
Scheme 4. Attempted formation of cisꢀepoxy alcohol 21.
Frustrated by our inability to generate the desired cisꢀepoxide (21), we decided to modify our
synthetic plan. Rather than rely on the asymmetric epoxidation of an allylic alcohol as a means of
inducing asymmetry, we would generate a more structurally advanced olefin (25, Scheme 5) and
attempt to conduct a Sharpless asymmetric dihydroxylation24 on it. In principle, the required
dihydroxylation substrate could still be accessed using a Heck reaction, but this time using an Nꢀ
protected 1ꢀaminohexene species of some type (26). Such an approach could potentially lead to an even
more convergent and streamlined approach to the synthesis of the mefloquines than the formal synthesis
shown above in Scheme 3. Significantly, the diol (24) obtained from the asymmetric dihydroxylation
reaction would be leveraged to gain access to either antiꢀ or synꢀmefloquine. In one instance it would
be converted to transꢀepoxide 22 using the known Sharpless procedure.25 Nitrogen deprotection
followed by intramolecular epoxide ring opening would then give rise to antiꢀmefloquine (1). In the
second instance, the stereospecific formation of cisꢀepoxide 23 would require the regioselective
conversion of one of the hydroxyl groups of diol 24 into a leaving group, with the other acting as a
nucleophile in a SN2 reaction. We reasoned that the C11 hydroxyl group should be considerably more
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acidic than the C12 hydroxyl, due to the strongly electronꢀwithdrawing nature of the aryl ring, and that
this would allow for selective baseꢀmediated functionalization of the C11 hydroxyl, ultimately leading
to the required cisꢀepoxide.
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OH
OH
HN
F3C
F3C
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N
HN
N
HCl
HCl
CF3
(+)-1
CF3
(–)-2
O
O
NPG
F3C
F3C
N
PGN
N
CF3
CF3
22
23
Regioselective Hydroxyl
Activation/SN2 Displacement
Sharpless Protocol
OH
12
F3C
N
11
OH
CF3
24
NPG
Sharpless Asymmetric
Dihydroxylation
Heck
Coupling
Br
F3C
N
F3C
+
N
CF3
NPG
CF3
16
NPG
25
26
Scheme 5. Retrosynthetic analysis towards both antiꢀ and synꢀmefloquine
hydrochloride from a common diol intermediate.
Work on the new synthetic strategy began with the preparation of the Nꢀprotected 1ꢀ
aminohexene. We chose to mask the amine as something other than an azide, which we had done
previously (see scheme 2), due to expected complications related to the use of phosphine ligands in the
Heck coupling. In the event, we elected to protect the amine with a Boc group and, thus, prepared
compound 27 (Scheme 6) according to a literature procedure.26 Heck coupling between aryl bromide 16
and 27 did produce the desired product (28), however, in only a very low yield, with the major product
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being 29, the product of protodehalogenation of 16. The use of a variety of different Pd sources and
phosphine ligands did not led to any significant improvement in the outcome of the reaction. Moreover,
the purification of 28 from the reaction mixture by column chromatography over silica gel was
extremely difficult, and it could not be obtained in a highly pure form.
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Pd(OAc)2 (10 mol%), P(t-Bu)3
(20 mol%), Et3N, DMF, 110 °C
16 +
BocHN
27
F3C
F3C
+
N
N
CF3
CF3
NHBoc
28
29
Scheme 6. Heck coupling of 16 and 27.
Despite the fact the Heck coupling was low yielding and the product obtained was difficult to
purify, we were able to generate enough of it in semiꢀpure form to test the asymmetric Sharpless
dihydroxylation.24 We were pleased to find that the dihydroxylation proceeded smoothly (Scheme 7)
and, conveniently, purification of the resulting diol (30) was very straightforward. A yield was not
determined for the dihydroxylation reaction given the impure nature of olefin 28. Transformation of 30
into transꢀepoxide 31 proceeded smoothly using the Sharpless procedure,25 but was also low yielding.
Compound 31 was treated with TFA to remove the Boc protecting group. The resulting amine was
combined with freshly ground K2CO3 in MeOH at 50 ºC, followed by HCl, which gave (+)ꢀantiꢀ
mefloquine hydrochloride [(+)ꢀ1] in 88% yield for the one pot, three step reaction sequence. The
enantiomeric purity of this material was not determined.
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OH
ADmix α, H2NSO2Me,
1
t-BuOH, H2O
F3C
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N
N
N
OH
NHBoc
CF3
30
MeC(OMe3)3, PPTS,
CH2Cl2; MeCOBr, CH2Cl2;
K2CO3, MeOH
O
F3C
27%
CF3
NHBoc
31
TFA, CH2Cl2, 0 °C;
K2CO3, MeOH, 50 °C;
Et2O, HCl
OH
F3C
HN
HCl
88%
CF3
[(+)-1]
Scheme 7. Completion of synthesis of (+)ꢀantiꢀmefloquine hydrochloride [(+)ꢀ1]
With the basis of our new strategy established as viable, we set out to improve on it. We began
by trying the use of a different nitrogen protecting group for the 1ꢀaminohexeneꢀderived Heck coupling
partner. Specifically, we chose the phthalimide protecting group. In this case, we would initiate the
cascading deprotection/cyclization sequence (cf. 22 → 1, Scheme 5) by treatment with hydrazine. The
phthalimide protected amino alkene 32 was prepared according to a literature procedure,27 and tried in
the Heck coupling reaction with aryl bromide 16. Upon screening different coupling conditions (Table
1), we found that the coupling of 32 and 16 could be carried out to a synthetically useful level using
NHC ligand 34 (Table 1, entry 3). While protodehalogenation product 29 (see Scheme 6) was still
observed, it was produced in a considerably reduced amount relative to the desired product. Once
again, purification of the Heck product (33) proved difficult, so the yields shown in Table 1 correspond
to material of approximately 95% purity, as judged by 1H NMR.28
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Table 1. Ligand screen for the Heck coupling of 16 and 32.[a]
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F3C
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CF3
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O
i-Pr
i-Pr
i-Pr
i-Pr
N
N
N
N
i-Pr i-Pr
i-Pr i-Pr
34
35
entry
Ligand
P(tꢀBu)3
XPhos
34
Yield (%)
1
2
3
4
ꢀꢀ
48
68
65
35
[a]Reaction conditions: Pd(OAc)2 (5 mol%), ligand (10 mol%), Et3N, DMF, 110 °C.
Asymmetric dihydroxylation of semiꢀpurified olefin 33 produced the desired diol (36), which
was then easily purified by silica gel chromatography (Scheme 8). The enantiomeric purity of 36 was
determined by converting it into its corresponding acetonide, and comparing that with a racemic
acetonide sample by HPLC analysis on a chiral, nonracemic stationary phase.28 The er of the acetonide
was established as 96:4, which is a likely a reasonable indication of the enantiomeric purity of the diol.
The enantiomeric purity of the diol was easily increased to >99:1 by a single and efficient (92%
recovery) recrystallization from acetonitrile.
With access to the diol secured, we converted it to trans epoxide 37 in very good yield via the
Sharpless oneꢀpot protocol (36 → 37).25 To ensure that there was no loss of stereochemical integrity
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The Journal of Organic Chemistry
during epoxide formation, it was compared to a corresponding racemic sample, by HPLC analysis on a
chiral, nonracemic stationary phase.28 The er of epoxide 37 was found to be >99:1. To complete the
synthesis of anti-mefloquine hydrochloride, 37 was treated with hydrazine hydrate under reflux
conditions, which served to remove the phthalimide protecting group and enable epoxide ringꢀopening.
Subsequent acidification with HCl provided (+)ꢀantiꢀmefloquine hydrochloride [(+)ꢀ1] in excellent
yield. The enantiomeric purity of our synthetic material was established by HPLC analysis on a chiral,
nonracemic stationary phase of the corresponding NꢀBoc derivative,16 and was found to be >99:1 er. In
addition, the optical rotation of the synthetic material was determined to be [∝]ꢁꢀꢂ = +26.0 (c = 0.45,
MeOH), which corresponds to the reported value of [∝]ꢁꢀꢂ = +29.8 (c = 0.45, MeOH).Error!
Bookmark not defined.
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OH
12
11
ADmix α, MeSO2NH2
THF, H2O, 0 ˚C
F3C
33
N
OH
NPhth
47% (over two
steps from 15)
CF3
36 (er = > 99:1)
MeC(OMe)3,
1) TsCl, t-BuOK,
THF, –78 ˚C to rt
2) K2CO3, THF,
MeOH
76%
(over two
steps, based
on recoved 36)
PPTS, CH2Cl2;
MeCOBr, CH2Cl2;
K2CO3, MeOH
75%
O
O
F3C
F3C
N
N
CF3
NPhth
CF3
NPhth
37 (er > 99:1)
38 (er >99:1)
H2NNH2〈H2O
EtOH, reflux; HCl
H2NNH2〈H2O
EtOH, reflux; HCl
92%
91%
OH
OH
F3C
F3C
N
•HN
HCl
N
•HN
HCl
CF3
CF3
(+)-anti-mefloquine
hydrochloride [(+)-1] (er > 99:1)
(–)-syn-mefloquine
hydrochloride [(–)-2] (er > 99:1)
Scheme 8. Synthesis of (+)ꢀ1 and (–)ꢀ2.
Having completed the synthesis of (+)ꢀantiꢀmefloquine hydrochloride [(+)ꢀ1], we turned our
attention to preparing synꢀmefloquine hydrochloride [(–)ꢀ2]. As indicated above, in order to access this
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compound from diol 36 we intended to take advantage of the predicted enhanced acidity of the C11
hydroxyl in order to regioselectively activate it, and then have it undergo a SN2 displacement by the C12
hydroxyl group. After considerable experimentation, we found that this transformation was best
executed as a oneꢀpot procedure using 0.8 equiv. of t-BuOK and 1.0 equiv. of TsCl. This led to the
conversion of the C11 hydroxyl into its corresponding tosylate, which then underwent baseꢀmediated
SN2 displacement by the C12 hydroxyl group, giving the desired cis-epoxide in 76% yield (based on
recovered starting material). The enantiomeric purity of 38 was established by comparison to the
corresponding racemate by HPLC analysis on a chiral, nonracemic stationary phase, and was
determined to be >99:1.28
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To conclude the synthesis of synꢀmefloquine hydrochloride, all that remained was removal of the
phthalimide protecting group, intramolecular epoxide ring opening, and HCl salt formation. To achieve
this, epoxide 38 was treated with hydrazine and the resulting mixture was acidified with HCl to afford
(–)ꢀ2 in excellent yield. Once again, the enantiomeric purity of our synthetic material was established
by HPLC analysis on a chiral, nonracemic stationary phase on the corresponding NꢀBoc derivative,16
and was found to be >99:1. The optical rotation of (–)ꢀ2 was found to be [∝]ꢁꢀꢂ = –41.4 (c = 0.91,
MeOH), which is in agreement with the reported value of [∝]ꢁꢀꢂ = –49.9 (c = 0.45, MeOH).Error!
Bookmark not defined.
Although we had developed a concise synthesis of both (+)ꢀantiꢀ and (–)ꢀsynꢀmefloquine from
an advanced common intermediate (36), we were curious about the possibility of improving on the Heck
coupling strategy that was used to access olefin 33. As indicated above, when using the phthalimide
alkene coupling partner, our best result gave a 68% yield (see Table 1, entry 3) of material having a
purity of approximately 95%. In an effort to improve on this result, we investigated a modified
synthetic strategy involving a Suzuki coupling between aryl bromide 16 and phthalimido containing
boronic ester 40. Compound 40 was easily prepared from commercially available acetylene 39 (Scheme
9).29 After screening multiple Pd/ligand combinations, we found that Pd(OAc)2/XPhos gave an
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excellent outcome in the coupling of 40 and 16, producing pure 33 in 77% yield, following silica gel
chromatography. Notably, no protoꢀdehalogenation occurred in this instance and the purification of the
product was straightforward.
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Scheme 9. Suzuki coupling approach to olefin 33.
To complete our studies, we set out to confirm the absolute stereochemistry of antiꢀ and synꢀ
mefloquine hydrochloride. Over the past 40 years there has been disagreement on the absolute
stereochemistry of antiꢀmefloquine. The initial absolute stereochemical assignment by Carroll and
Blackwell8a was completed on the basis of circular dichroism (CD) experiments, and (+)ꢀantiꢀ and (–)ꢀ
antiꢀ mefloquine were assigned the structures opposite to those shown in Figure 1. 28 years later, Karle
and Karle contradicted the original assignment by using Xꢀray diffraction studies on anti-mefloquine
hydrochloride and claimed the absolute stereochemistry of anti-mefloquine to be what is shown in
Figure 1.6 An argument against the revised assignment was then made by Xie and coꢀworkers during
their total synthesis of (–)ꢀantiꢀmefloquine hydrochloride.Error! Bookmark not defined. They
employed a Mosher analysis that supported the absolute stereochemistry that Carroll and Blackwell
originally assigned (i.e., the opposite of that depicted in Figure 1). Recently, another argument
regarding the absolute configuration of (+)ꢀ and (–)ꢀantiꢀmefloquine was put forth.2 This analysis was
based upon residual dipolar coupling (RDC) enhanced NMR spectroscopy in combination with optical
rotatory dispersion (ORD) and CD spectroscopy. The result of this study recognized the absolute
configuration given by Karle and Karle6 to be correct [i.e., (+)ꢀ1 and (–)ꢀ1, Figure 1]. In 2013, support
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for the revised assignment was reported by Hall and Ding as part of a synthetic study.Error!
1
2
3
Bookmark not defined.
4
5
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7
8
While the above contributions towards the determination of the absolute stereochemistry of antiꢀ
mefloquine are important, we were surprised to find there were no studies reporting the derivatization of
mefloquine with a known chiral, nonracemic compound, followed by Xꢀray crystallographic analysis.
Thus, we set out to do this.
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We initially attempted to achieve this by forming salt between (+)ꢀantiꢀmefloquine (41) (Scheme
10) and a chiral, nonracemic acid. Compound 41 was prepared according to Scheme 8, but without the
final HCl salt formation step that was used to prepare (+)ꢀ1.
LꢀTartaric acid, (+)ꢀcamphorsulfonic acid,
and (+)ꢀmandelic acid were each used attempts to make a crystalline salt of 41, but with no success.
Given that we were unable to form a suitable salt for Xꢀray analysis, we attempted to make a covalent
derivative of 41 and obtain a crystal of that. To do so, compound 41 was coupled to (S)ꢀ(+)ꢀmandelic
acid tertꢀbutyldimethylsilyl ether (42)30 under nonꢀepimerizing conditions to give 43 (Scheme 10). The
optical rotation of the (S)ꢀ(+)ꢀmandelic acid used to prepare 42 was measured as [∝]ꢁꢀꢂ = +153.52 (c =
2.5, H2O), which is consistent with the literature value [∝]ꢁꢀꢂ = +149.0 (c = 2.5, H2O).31 By reference to
the known Sꢀconfiguration of the mandelic acidꢀderived stereogenic center, Xꢀray crystallography
determined the absolute stereochemistry of Cꢀ11 and Cꢀ12 of 43 to be S, and R, respectively. This
analysis confirms the absolute stereochemistry of (+)ꢀantiꢀmefloquine to be that shown in Figure 1 [(+)ꢀ
1], thus verifying the assignment by Karle and Karle.6
In an analogous manner, we carried out Xꢀray crystallographic analysis on our synthetic synꢀ
melfoquine. Compound 44, synthesized according to Scheme 8 but without the final HCl salt
formation, was coupled to (S)ꢀ(+)ꢀmandelic acid tertꢀbutyldimethylsilyl ether (42) under nonꢀ
epimerizing conditions to give 45 (Scheme 11). Again, using the known Sꢀconfiguration of the
mandelic acidꢀderived stereogenic center as a reference, Xꢀray crystallographic analysis established the
absolute stereochemistry of Cꢀ11 and Cꢀ12 of 45 to be R, and R, respectively. On this basis we were
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able to establish unambiguously, and for the first time, that the absolute stereochemistry of (–)ꢀsynꢀ
mefloquine hydrochloride is that shown in Figure 1 [(–)ꢀ2].
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OH
OTBS
CO2H
7
8
F3C
+
N
HN
Ph
9
42
CF3
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OH
S
12
11
F3C
R
O
N
N
HATU, i-Pr2NEt, CH2Cl2
18
CF3
65%
O
Ph
TBS
43
X-ray crystal structure of 43
Scheme 10. Synthesis and Xꢀray crystal structure of 43.
OH
OTBS
F3C
+
N
HN
Ph
CO2H
42
CF3
44
OH
R
12
11
F3C
R
O
N
HATU, i-Pr2NEt, CH2Cl2
N
18
CF3
66%
O
Ph
TBS
45
X-ray crystal structure of 45
Scheme 11. Synthesis and Xꢀray crystal structure of 45.
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CONCLUSION
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In conclusion, we have developed a concise and highly enantioselective (er > 99:1) synthesis of
both (+)ꢀantiꢀ and (–)ꢀsynꢀmefloquine hydrochloride [(+)ꢀ1 and (–)ꢀ2, respectively]. A key step in the
synthesis of each compound is the enantioselective conversion of olefin 33 to diol 36, the latter being
converted into either a transꢀ or cisꢀepoxide, and ultimately to (+)ꢀantiꢀmefloquine hydrochloride [(+)ꢀ
1] and (–)ꢀsynꢀmefloquine hydrochloride [(–)ꢀ2], respectively. Access to olefin 33 is achieved either via
a Heck coupling or a Suzuki coupling, with the latter approach offering certain practical advantages. As
a result of Xꢀray crystallographic and optical rotation studies on our synthetic material, the absolute
stereochemistry for (+)ꢀantiꢀmefloquine hydrochloride has been definitively confirmed as that reported
by Karle and Karle [(+)ꢀ1, Figure 1].6 In addition, a similar analysis has established unambiguously,
and for the first time, the absolute stereochemistry of (–)ꢀsynꢀmefloquine hydrochloride [(–)ꢀ2, Figure
1]. Finally, we have also developed a formal synthesis of (+)ꢀantiꢀmefloquine hydrochloride [(+)ꢀ1]
that uses, as a key step, a Sharpless asymmetric epoxidation.
Experimental Section
General Considerations. Unless stated to the contrary, where applicable, the following considerations
apply: reactions were carried out using dried solvents (see below) and under a slight static pressure of
Ar (preꢀpurified quality) that had been passed through a column (5 x 20 cm) of Drierite. Glassware was
dried in an oven at 120 °C for at least 12 h prior to use and then either cooled in a desiccator cabinet
over Drierite or assembled quickly while hot, sealed with rubber septa, and allowed to cool under a
stream of Ar. Reactions were stirred magnetically using Teflonꢀcoated magnetic stirring bars. Teflonꢀ
coated magnetic stirring bars and syringe needles were dried in an oven at 120 °C for at least 12 h prior
to use then cooled in a desiccator cabinet over Drierite. Hamilton microsyringes were dried in an oven at
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60 °C for at least 24 h prior to use and cooled in the same manner. Dry PhMe, CH2Cl2, and THF were
obtained using asolvent purification system. All other dry solvents were of anhydrous quality purchased.
Commercial grade solvents were used for routine purposes without further purification. Et3N was
distilled from CaH2 under a N2 atmosphere prior to use. Flash column chromatography was performed
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1
13
on silica gel 60 (230ꢀ400 mesh). H and C NMR spectra were recorded on a 600 MHz, 500, MHz or
400 MHz spectrometer at ambient temperature. All 1H chemical shifts are reported in ppm (δ) relative to
TMS (7.26), 13C shifts are reported in ppm (δ) relative to CDCl3 (77.16). HRMS analyses were
performed using a QꢀToF ꢀMS instrument. HPLC analysis was performed using a 4.6 x 250 mm
Chiralcel ODꢀH column. (+)ꢀ1 has been previously characterized.16 (–)ꢀ2 has been previously
characterized.Error! Bookmark not defined. The synthesis of 33, 36, 37, 38, 43, and 45 have been
previously described, as has their characterization.18 Compounds 41 and 44 have been previously
reported.Error! Bookmark not defined.
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(E)-ethyl-3-(2,8-bis(trifluoromethyl)quinolin-4-yl)acrylate (46). Aryl bromide 16 (1.22 g, 3.55
mmol), Pd(OAc)2 (0.015 g, 0.071 mmol), and Pꢀ(oꢀtoly)3 (0.097 g, 0.319 mmol) were dissolved in ethyl
acrylate/Et3N (1:1 v/v, 2.5 mL/2.5 mL). The reaction was heated to reflux for 4 h and then cooled to rt
and poured onto ice (25 mL). The mixture was partitioned between EtOAc and H2O. The aqueous phase
extracted with EtOAc (3 X 15 mL). The combined organic extracts were washed with sat. aq. NaCl (20
mL), dried over MgSO4, and concentrated in vacuo. Flash chromatography over silica gel (30:70
EtOAcꢀHexanes) gave 46 as a lightꢀyellow solid (0.927 g, 72%). mp 105–107 °C; 1H NMR (500 MHz,
CDCl3) δ 8.42ꢀ8.37 (m, 2 H), 8.21 (d, J = 8.0 Hz, 1 H), 7.93 (s, 1 H), 7.80 (t, J = 8.0 Hz, 1 H), 6.73 (d, J
13
= 15.4 Hz, 1 H), 4.35 (q, J = 6.8 Hz, 2 H), 1.38 (t, J = 7.4 Hz, 3 H); C NMR (125 MHz, CDCl3) δ
165.4, 148.3 (q, JCꢀF = 35.6 Hz), 144.1, 142.9, 138.3, 137.2, 132.1, 129.5 (q, JCꢀF = 6.1 Hz), 127.7,
127.1, 123.4 (q, JCꢀF = 274 Hz), 121.1 (q, JCꢀF = 275.6 Hz), 117.8, 114.8, 61.4, 14.2; HRMS-ESI: m/z
calcd. for C16H11F6NO2 [M+H]+ 364.0767, found 364.0767.
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(E)-3-(2,8-bis(trifluoromethyl)quinolin-4-yl)prop-2-en-1-ol (17). Ester 46 was dissolved in
PhMe (1.3 mL) and cooled to –78 °C. DIBAL (0.29 mL, 0.296 mmol, 1.0 M in hexane) was added
dropwise over a period of ca. 2 min, and the resulting mixture was stirred at –78 °C for 10 min. before
warming to 0 °C (iceꢀwater bath). The mixture was stirred for 2 h at 0 °C then warmed to room
temperature. Sat. aq. NH4Cl (1.0 mL) was added, and the mixture was partitioned between CH2Cl2 and
H2O. The aqueous phase was extracted with CH2Cl2 (3 X 5 mL), and the combined organic extracts
were washed with sat. NaCl (5 mL), dried over MgSO4, filtered and concentrated in vacuo. Flash
chromatography over silica gel (40:60 EtOAcꢀHexanes) gave 17 as a white solid (0.034 g, 78%). mp
123–124 °C; 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.2 Hz, 1 H), 8.16 (d, J = 7.3 Hz, 1 H), 7.85 (s,
1 H), 7.72 (t, J = 7.79 Hz, 1 H), 7.42 (dt, J = 16.0 Hz, 1.8 Hz, 1 H), 6.70 (dt, J = 15.5 Hz, 4.5 Hz, 1 H),
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4.55ꢀ4.52 (m, 2 H), 1.73 (t, J = 5.9 Hz, 1 H); C NMR (100 MHz, CDCl3) δ 148.3 (q, JCꢀF = 35.2 Hz),
145.6, 144.1, 138.3, 129.3, 129.1 (q, JCꢀF = 65.8 Hz), 128.0, 127.2, 127.0, 123.6 (q, JCꢀF = 273.8 Hz),
123.2, 121.3 (q, JCꢀF = 275.8 Hz),114.1, 62.9; HRMS-ESI: m/z calcd. for C14H9F6NO [M+H]+
322.0661, found 322.0664.
(2S,3S)-3-(2,8-bis(trifluoromethyl)quinolin-4-yl)oxiran-2-yl)methanol (18). A 25 mL round
bottom was charged was crushed 4Ǻ mol sieves (0.025 g), flamed dried under high vacuum, and then
cooled to – 20 °C under an Ar atmosphere. To this flask was added CH2Cl2 (4 mL) and LꢀDIPT (0.027
g, 0.118 mmol). The mixture was stirred for 5 min, and Ti(OꢀiꢀPr)4 (0.031 mL, 0.105 mmol) was added
dropꢀwise over a period of ca. 2 min. This mixture was stirred 10 min. tꢀBuOOH (0.21 mL, 1.05 mmol,
5.0 M in decane) was added dropꢀwise over a period of ca. 5 min, and the mixture stirred 30 min.
Allylic alcohol 17 (0.085 g, 0.264 mmol) was dissolved in CH2Cl2 (0.5 mL) and added to the reaction
mixture dropꢀwise over a period of ca. 5 min. The reaction was stirred at –20 °C for 38 h. The reaction
was quenched by addition of 30% NaOH in sat. NaCl (1.0 mL) and Et2O (3 mL), followed by warming
to rt. After stirring an additional 15 min, MgSO4 and celite were added. Stirring was continued an
additional 10 min before the reaction mixture was filtered over a tightlyꢀpacked pad of celite, followed
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by concentration of the filtrate in vacuo. Flash chromatography over silica gel (60:40 EtOAcꢀHexane)
gave 18 as a white solid (0.068 g, 77%). Recrystallization from Et2O/hexanes (70% recovery) led to an
> 99:1 er [determined by HPLC, chiral ODꢀH column, 80:20 hexanesꢀiꢀPrOH, 0.35 mL/min, λ = 254
1
2
3
4
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6
7
8
1
nm, tR(major) = 20.6 min, tR(minor) = 22.5 min]; mp 126–127 °C; H NMR (500 MHz, CDCl3) δ 8.34
9
(d, J = 8.0 Hz, 1 H), 8.20 (J = 7.4 Hz, 1 H), 7.81 (s, 1 H), 7.79 (t, J = 7.4 Hz, 1H), 4.67 (d, J = 1.7 Hz, 1
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H), 4.19ꢀ4.16 (m, 1 H), 4.06ꢀ4.04 (m, 1 H), 3.23ꢀ3.22 (m, 1 H), 1.83 (brs, 1 H); C NMR (100 MHz,
CDCl3) δ 148.8 (q, JCꢀF = 35.6 Hz), 146.2, 143.3, 129.5 (q, JCꢀF = 30.7 Hz), 129.2 (q, JCꢀF = 6.1 Hz),
127.7, 127.2, 127.1, 123.4 (q, JCꢀF = 273.1 Hz), 121.1 (q, JCꢀF = 275.6 Hz), 113.4, 62.5, 60.2, 51.8;
HRMS-ESI: m/z calcd. for C14H9F6NO2 [M+Na]+ 360.0430, found 360.0443.
(±)-3-(2,8-bis(trifluoromethyl)quinolin-4-yl)oxiran-2-yl)methanol [(±)ꢀ18]. Allylic alcohol 17
(0.092 g, 0.286 mmol) was dissolved in CH2Cl2 (5.0 mL) and cooled to 0 °C. NaHCO3 (0.024 g, 0.286
mmol) and mꢀCPBA (0.123 g, 0.716 mmol) were then added, and the reaction was warmed to rt and
stirred for 14 h. The reaction was quenched with 1 M Na2SO3 (4 mL) and diluted with H2O (5 mL). The
layers were partitioned between CH2Cl2 and H2O. The aqueous phase was extracted with CH2Cl2 (3 x
10 mL). The combined organic extracts were washed with sat. aq. NaHCO3 (10 mL), and sat. aq. NaCl
(10 mL). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. Flash
chromatography over silica gel (60:40 EtOAcꢀHexanes) gave (±)ꢀ18 as a white solid (0.084 g, 87%, and
50:50 er [determined by HPLC, chiral ODꢀH column, 80:20 hexanesꢀiꢀPrOH, 0.35 mL/min, λ = 254 nm,
tR = 21.4 min, tR = 23.3 min]); spectral data was identical to that of 18.
3-(2,8-bis(trifluoromethyl)quinolin-4-yl)prop-2-yn-1-ol (19). To a suspension of CuI (0.037 g,
0.198 mmol) in Et3N (82 mL) was added propargylic alcohol (0.21 mL, 3.64 mmol), and the mixture
was stirred for 5 min. Aryl bromide 16 (1.14 g, 3.31 mmol) and PdCl2(PPh3)2 (0.092 g, 0.132 mmol)
were added and the mixture was heated to reflux for 4 h and then cooled to rt. The reaction was filtered
through a tightlyꢀpacked pad of Celite and rinsed with CH2Cl2 (75 mL). The filtrate was washed with
sat. aq. NaCl (50 mL), dried over MgSO4, filtered, and partially concentrated in vacuo until Et3NH+
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precipitated out of solution. The suspension was filtered, washed with EtOAc (50 mL), and concentrated
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in vacuo. Flash chromatography over silica gel (40:60 EtOAcꢀHexanes) gave 19 as an offꢀwhite solid
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5
6
1
(0.845 g, 80%). mp 106–108 °C; H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 7.3 Hz, 1 H), 8.18 (d, J =
7
8
9
6.8 Hz, 1 H), 7.89 (s, 1 H), 7.76 (t, J = 7.7 Hz, 1 H), 4.69 (d, J = 5.9 Hz, 2 H), 1.89 (t, J = 6.4 Hz, 1 H);
13C NMR (100 MHz, CDCl3) δ 148.1 (q, JCꢀF = 36.1 Hz), 143.6, 131.8, 130.2, 129.7 (q, JCꢀF = 5.8 Hz),
129.1 (q, JCꢀF = 30.3 Hz), 128.6, 127.9, 123.4 (q, JCꢀF = 273.8 Hz), 121.0 (q, JCꢀF = 275.8 Hz), 120.4,
99.3, 80.3, 51.6; HRMS-ESI: m/z calcd. for C14H7F6NO [M+H]+ 320.0505, found 320.0511.
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(Z)-3-(2,8-bis(trifluoromethyl)quinolin-4-yl)prop-2-en-1-ol (20). A 5 mL round bottom flask was
charged with alkyne 19 (0.090 g, 0.282 mmol) and Lindlar's catalyst (0.020 g, 0.183 mmol). Anhydrous
MeOH (1.2 mL) and quinoline (0.021 mL, 0.183 mmol) were added, and a balloon containing H2 was
attached to the flask. The reaction was stirred at rt for 17 h and subsequently filtered through a tightlyꢀ
packed pad of celite. The mixture was concentrated in vacuo. Flash chromatography over silica gel
1
(40:60 EtOAcꢀHexanes) gave 20 as a white solid (0.074 g, 82%). mp 53–55 °C; H NMR (400 MHz,
CDCl3) δ 8.24 (d, J = 8.2 Hz, 1 H), 8.18 (d, J = 6.8 Hz, 1 H), 7.73 (t, J = 7.4 Hz, 1 H), 7.59 (s, 1 H),
7.02 (dd, J = 11.91 Hz, 0.9 Hz, 1 H), 6.39 (dt, J = 11.9 Hz, 6.4 Hz, 1 H), 4.28ꢀ4.25 (m, 2 H), 1.57 (brs, 1
13
H); C NMR (100 MHz, CDCl3) δ 147.9 (q, JCꢀF = 35.2 Hz), 145.0, 143.7, 137.0, 129.2 (q, JCꢀF = 5.8
Hz), 129.0, 127.7, 128.6 (overlapped q), 127.3, 125.4, 123.6 (q, JCꢀF = 272.9 Hz), 121.2 (q, JCꢀF = 275.8
Hz), 117.4, 59.3; HRMS-ESI: m/z calcd. for C14H9F6NO [M+H]+ 322.0661, found 322.0672.
tert-butyl-(5S,6S)-6-(2,8-bis(trifluoromethyl)quinolin-4-yl)-5,6-dihydroxyhexyl)carbamate (30).
P(tꢀBu)3 (0.058 mL, 0.24 mmol), Et3N (0.42 mL, 3.00 mmol), and DMF (2.4 mL) were added to a
mixture of aryl bromide 16 (0.412 g, 1.2 mmol), alkene 27 (0.289 g, 1.45 mmol), and Pd(OAc)2 (0.027
g, 0.12 mmol). The mixture was heated to 110 °C for 7 h. Upon cooling to rt, the reaction was quenched
by addition of H2O. The mixture was partitioned between Et2O and H2O, and the aqueous phase was
extracted with Et2O (3 X 15 mL). The combined organic extracts were washed with sat. aq. NaCl, dried
with MgSO4, filtered, and concentrated in vacuo. Flash chromatography over silica gel (30:70 EtOAcꢀ
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The Journal of Organic Chemistry
Hexanes) gave the semiꢀpurified Heck product as an orange oil that was used directly in the subsequent
transformation. To a solution of ADmixꢀα (0.273 g, 1.1g/mmol) and methansulfonamide (0.07 g, 0.744
mmol) in tꢀBuOH(1.2 mL) and H2O (1.2 mL) at 0 °C was added semiꢀpurified olefin (0.115 g, 0.248
mmol) dissolved in tꢀBuOH (1.0 mL, 0.5 mL wash). The reaction was stirred for 40 h at 0 °C. Sodium
sulfite (0.320 g) was added and the reaction was allowed to warm to room temperature, and stirring was
continued for an additional hour. The mixture was then partitioned between Et2O and H2O, and the
aqueous phase extracted with Et2O (3 x 15 mL). The combined organic extracts were washed with sat.
aq. NaCl, dried with MgSO4, filtered, and concentrated in vacuo. Flash chromatography over silica gel
(30:70 to 80:20 EtOAcꢀHexanes) yielded 30 as a white solid (0.04 g, 6.7 % over 2 steps). mp 127–128
°C; 1H NMR (400 MHz, CDCl3): δ 8.23 (d, J = 7.79 Hz, 1 H), 8.16 (d, J = 7.33Hz, 1 H), 8.02 (s, 1 H)
7.72 (t, J = 7.79 Hz, 1 H), 5.35 (d, J = 4.12 Hz, 1 H), 4.61 (brs, 1 H), 3.82ꢀ3.804 (m, 1 H), 3.13 (brs, 2
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13
H), 1.71ꢀ1.53 (m, 3 H), 1.50ꢀ1.39 (m, 12 H, apparent singlet at 1.41); C NMR (125 MHZ, CDCl3): δ
156.8, 150.8, 148.1 (q, JC-F = 36.2 Hz), 143.8, 129.5 (q, JC-F = 30.6 Hz), 128.7 (q, JC-F = 4.8 Hz), 127.2,
127.1, 126.9, 123.5 (q, JC-F = 271.5 Hz), 121.3 (q, JC-F = 274 Hz), 115.9, 79.7, 74.6, 72.2, 39.6, 33.1,
29.9, 28.3, 22.4; HRMS-ESI: m/z calcd. for C22H26F6N2O4 [M+Na]+ 519.1689, found 519.1709.
Protodehalogenation product 29 (2,8-bis(trifluoromethyl)quinoline) was also isolated as an orange solid
during the Heck coupling between 16 and 27. mp 73–75 °C; 1H NMR (600 MHz, CDCl3): δ 8.41 (d, J =
8.25 Hz, 1 H), 8.16 (d, J = 7.56 Hz, 1 H), 8.09 (d, J = 8.25 Hz, 1 H), 7.82 (d, J = 8.25 Hz, 1 H), 7.22 (t,
J = 7.56 Hz, 1 H); 13C NMR (150 MHZ, CDCl3): δ 148.5 (q, JC-F = 35.4 Hz), 143.6, 138.3, 132.1, 129.2
(q, JC-F = 5.91 Hz), 129.1, 129.0 (q, JC-F = 31.0 Hz), 127.3, 123.5 (q, JC-F = 275.0 Hz), 121.2 (q, JC-F
275.0 Hz), 117.8; HRMS-ESI: m/z calcd. for C11H5F6N [M+Na]+ 288.0218, found 288.0217.
=
tert-butyl (4-(2S,3S)-3-(2,8-bis(trifluoromethyl)quinolin-4-yl)oxiran-2-yl)butyl)carbamate (31).
Diol 30 (0.038 g, 0.076 mmol) was dissolved in CH2Cl2 (1.3 mL). Trimethylorthoacetate (0.03 mL,
0.229 mmol) and PPTS (0.003 g, 15 mol%) were added and the reaction mixture was stirred for 12 h
and then concentrated in vacuo. The resulting yellow oil was dissolved in CH2Cl2 (1.3 mL) and cooled
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to 0 °C. Acetyl bromide (0.017 mL, 0.229 mmol) was added dropwise dropꢀwise over a period of ca. 2
min, and the reaction was warmed to rt and stirred 6 h. The mixture was concentrated in vacuo, and the
resulting orange residue was dissolved in MeOH (1.3 mL). K2CO3 (0.031 g, 0.229 mmol) was added and
the heterogeneous mixture was stirred for 10 h. The mixture was then evaporated, dissolved in H2O (5
mL), and extracted with Et2O (3 X 10 mL). The combined organic extracts were washed with sat. aq.
NaCl, dried with MgSO4, filtered, and concentrated in vacuo. Flash chromatography over silica gel
(35:65 EtOAcꢀHexanes) yielded 31 as a white solid (0.01 g, 27 %). mp 93–95 °C; 1H NMR (400 MHz,
CDCl3): δ 8.31 (d, J = 8.24 Hz, 1 H), 8.19 (d, J = 7.33 Hz, 1 H), 7.80ꢀ7.76 (m, 2 H), 4.57 (brs, 1 H),
4.30 (d, J = 1.83 Hz, 1 H), 3.18ꢀ3.17 (m, 2 H), 2.97 (tdd, J = 2.97 Hz, 5.04 Hz, 2.29 Hz, 1 H), 1.99ꢀ1.94
(m, 1 H), 1.87ꢀ1.80 (m, 1 H), 1.46ꢀ1.39 (m, 4 H), 1.47 (s, 9 H); 13C NMR (100 MHz, CDCl3): δ 156.1,
148.8 (q, JC-F = 35.2 Hz), 146.7, 143.3, 129.6 (q, JC-F = 30.3 Hz), 129.1 (q, JC-F = 4.8 Hz), 127.6, 127.4,
126.9, 123.5 (q, JC-F = 272.9 Hz), 121.1 (q, JC-F = 275.8 Hz), 113.3, 79.3, 63.3, 54.9, 40.2, 31.8, 30.0,
28.5, 23.2; HRMS-ESI: m/z calcd for C22H24F6N2O3 [M+Na]+ 501.1583, found 501.1603.
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(R)-2-((S)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)-methyl)piperidin-1-ium
chloride
[(+)ꢀ1]. A solution of 31 (0.004 g, 0.008 mmol) in CH2Cl2 (0.2 mL) was cooled to 0 °C (iceꢀwater bath).
TFA (3.3 ꢁL, 0.043 mmol) was then added dropwise dropꢀwise over a period of ca. 2 min. The mixture
was allowed to warm to rt and stirred for 30 min. It was then quenched by the addition of sat. aq.
NaHCO3 until pH = 7, followed by extraction of the aqueous phase with CH2Cl2 (3 x 5 mL). The
combined organic extracts were washed with sat. NaCl, dried over MgSO4, and concentrated in vacuo.
The resulting orange oil was dissolved in MeOH (0.5 mL). Freshly ground K2CO3 (0.002 g, 0.016
mmol) was added, and the reaction was heated at 50 °C for 3 h. The solution was filtered, washed with
Et2O (2 mL), and concentrated in vacuo. The resulting lightꢀyellow solid was dissolved in Et2O (2 mL)
and cooled in an iceꢀwater bath. Dry HCl gas was then bubbled through the solution until it was
saturated. The resulting solid was filtered and dried under vacuum to afford [(+)ꢀ1] as a yellow solid
(0.003 g, 88%). Spectral data was identical to that previously reported.11
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(E)-2-(6-(4,4,5,5-tetramethyl-methyl-1,3,2-dioxaborolan-2-yl)hex-5-en-1-yl)isoindoline-1,3-
1
2
dione (40). Nꢀ(5ꢀhexynyl)phthalimide (0.15 g, 0.66 mmol), 4ꢀ(dimethylamino)benzoic acid (0.005 g, 5
mol%), and pinacol borane (0.28 mL, 1.98 mmol) were dissolved in octane (0.6 mL), and stirred at 100
°C for 12 h. The mixture was then cooled to rt and concentrated in vacuo. Flash chromatography over
3
4
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7
8
9
1
silica gel (0:100 to 30:70 EtOAcꢀHexanes) gave 40 as a white solid (0.185 g, 79%). mp 51–53 °C; H
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NMR (400 MHz, CDCl3) δ 7.85ꢀ7.80 (m, 2 H), 7.72ꢀ7.68 (m, 2 H), 6.57 (dt, J = 17.86 Hz, 6.87 Hz, 1
H), 5.41 (dt, J = 17.86Hz, 1.37 Hz, 1 H), 3.67 (t, J = 7.33 Hz, 2 H), 2.21ꢀ2.15 (m, 2 H), 1.71ꢀ1.64 (m, 2
H), 1.49ꢀ1.43 (m, 2 H), 1.24 (s, 12 H); 13C NMR (125 MHz, CDCl3) δ 168.3, 153.6, 133.8, 132.1,
123.1, 80.0, 37.8, 35.3, 28.2, 25.5, 24.8, 24.7; HRMS-ESI: m/z calcd. for C20H26BNO4 [M+Na]+
378.1851, found 378.1868.
(E)-2-(6-(2,8-bis(trifluoromethyl)quinolin-4-yl)hex-5-en-1-yl)isoindoline-1,3-dione (33). Aryl
bromide 16 (0.058 g, 0.168 mmol), pinacol boronate ester 40 (0.066 g, 0.185 mmol), Pd(OAc)2 (0.0015
g, 4 mol%), XPhos (0.013 g, 8 mol%), and Cs2CO3 (0.164 g, 0.504 mmol) were dissolved in THF (2.0
mL) and H2O (0.4 mL H2O), and heated to reflux for 5 h. After cooling to rt the reaction was partitioned
between Et2O and H2O. The aqueous phase was extracted with Et2O (3 x 15 mL), and the combined
organic extracts were washed with sat. aq. NaCl (20 mL), dried over MgSO4, filtered, and concentrated
in vacuo. Flash chromatography over silica gel (30:70 EtOAcꢀHexanes) gave 33 as a pale yellow solid
(0.064 g, 77%). Spectral data was identical to that previously reported.18
ACKNOWLEDGEMENTS
The authors thank Dr. John D. Knight and Nata Cisse for their assistance conducting some
preliminary experiments related to Scheme 3. We are grateful to James Korp of the University of
Houston for determining the Xꢀray crystal structures of 43 and 45. We thank Professor K. C. Nicolaou
(Rice University) for generously allowing us use of his laboratory for polarimetry measurements. We
also thank the NSF (NSF 1300652), the Welch Foundation (Eꢀ1806), and the University of Houston for
financial support.
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SUPPORTING INFORMATION
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NMR spectra for all new compounds, selected HPLC chromatograms, and crystallographic data
5
for compounds 43 and 45. This material is available free of charge via the Internet at http://pubs.acs.org.
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REFERENCES
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10 Brober, E.; Hofneinz, W.; Meili A.; (Hoffmann–La Roche), Eur. Pat. 553778, 1993.
11 Xie, Z.ꢀX.; Zhang, L.ꢀZ.; Ren, X.ꢀJ.; Tang, S.ꢀY.; Li, Y.; Chin. J. Chem. 2008, 26, 1272–1276.
12 Zhou, G.; Liu, X.; Liu, X.; Nie, H.; Zhang, S.; Chen, W. Adv. Synth.Catal. 2013, 355, 3575–3580.
13 Ding, J.; Hall, D. G. Angew. Chem. Int. Ed. 2013, 52, 8069–8073.
14 Schützenmeister, N.; Müller, M.; Reinscheid, U. M.; Griesinger, C.; Leonov, A. Chem. Eur. J. 2013,
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15 As part of this work, Hall and Ding determined that the synꢀmefloquines are also active against
Plasmodium falciparum; see reference 13.
16) Knight, J. D.; Sauer, S. J.; Coltart, D. M. Org. Lett. 2011, 13, 3118–3121.
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Wengryniuk, S. E.; Lim, D.; Coltart, D. M. J. Am. Chem. Soc. 2011, 133, 8714–8720.
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21) Generated from 17 using mꢀCPBA. See the Experimental section for details.
22) See the Supporting Information for details.
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23) Shi, Y. Acc. Chem. Res.2004, 37, 488–496.
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H.ꢀL.; Morikawa, K.; Wang, Z.ꢀM.;Xu, D.; Zhang, X.ꢀL. J. Org. Chem. 1992, 57, 2768–2771.
25) Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515–10530.
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27) Fraunhoffer, K. J.; Bachovhin, D. A.; White, M. C. Org. Lett., 2005, 7, 223ꢀ226.
28) See the Supporting Information within reference 18 for details.
29) Ho, H. E.; Asao, N.; Yamamoto, Y.; Jin, T. Org. Lett. 2014, 16, 4670–4673.
30) For preparation of 42 see: Yevglevskis, M.; Bowskill, C. R.; Chan, C. C. Y.; Heng, J. H.ꢀJ.;
Threadgill, M. D.; Woodman, T. J.; Lloyd, M. D. Org. Biomol. Chem., 2014, 12, 6737–6744.
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