Asymmetric synthesis and absolute configuration assignment of a new type of bedaquiline analogue

Article abstract of DOI:10.3390/molecules201219846

Bedaquiline is the first FDA-approved new chemical entity to fight multidrug-resistant tuberculosis in the last forty years. Our group replaced the quinoline ring with a naphthalene ring, leading to a new type of triarylbutanol skeleton. An asymmetric synthetic route was established for our bedaquiline analogues, and the goal of assigning their absolute configurations was achieved by comparison of experimental and calculated electronic circular dichroism spectra, and was confirmed by the combined use of circular dichroism and NMR spectroscopy.

Full text of DOI:10.3390/molecules201219846

Article
Asymmetric Synthesis and Absolute Configuration
Assignment of a New Type of Bedaquiline Analogue
Chang-Jiang Qiao 1,2, Xiao-Kui Wang 2, Fei Xie 2, Wu Zhong 2,* and Song Li 1,2,
*
Received: 3 November 2015 ; Accepted: 7 December 2015 ; Published: 11 December 2015
Academic Editor: Wim Dehaen
1
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road,
Shenyang 110016, China; qchj2004@163.com
Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology
and Toxicology, 27 Taiping Road, Beijing 100850, China; wxkcaptain@163.com (X.W.);
xiefei0058@aliyun.com (F.X.)
2
*
Correspondence: lis.lisong@gmail.com (S.L.); zhongwu@bmi.ac.cn (W.Z.); Tel.: +86-10-6693-2624 (W.Z.)
Abstract: Bedaquiline is the first FDA-approved new chemical entity to fight multidrug-resistant
tuberculosis in the last forty years. Our group replaced the quinoline ring with a naphthalene ring,
leading to a new type of triarylbutanol skeleton. An asymmetric synthetic route was established for
our bedaquiline analogues, and the goal of assigning their absolute configurations was achieved by
comparison of experimental and calculated electronic circular dichroism spectra, and was confirmed
by the combined use of circular dichroism and NMR spectroscopy.
Keywords: antituberculosis; asymmetric synthesis; bedaquiline analogues; absolute configuration
assignment
1. Introduction
Tuberculosis is a widespread infectious disease that threatens one-third of the World
population [1]. Most of these infections have no symptoms, a situation known as latent tuberculosis,
and almost 10% of these latent infections will progress to the active disease [2]. The emergence of
multidrug-resistant tuberculosis (MDR-TB) and extensive-drug resistant tuberculosis (XDR-TB) has
invalidated the current commercially available medicines, such as isoniazid, rifampin, pyrazinamide,
ethambutol and streptomycin [3]. Therefore, to stop the prevalence of tuberculosis, new drugs with
novel mechanisms of action are urgently needed.
Bedaquiline, which targets the adenosine triphosphate synthase (ATPase) M. tuberculosis [4], was
approved by the FDA to specifically treat MDR-TB. Because of its novel mechanism, bedaquiline
does not have cross-resistance with current antituberculosis drugs. Many efforts have been made
by scientists to locate the exact binding domain of bedaquiline in M. tuberculosis ATPase [5–9].
Most recently, in 2015, the X-ray crystal structures of a mycobacterial C9 ring with and without a
bedaquiline molecule were reported, and it was suggested that bedaquiline blocked the ion-binding
sites of the c-subunits [10].
During the development of bedaquiline, the structure-activity relationship (SAR) has always
been the focus of scientists’ attention. Originally, the group led by Koen Andries at Janssen
Pharmaceutica selected bedaquiline from more than 200 analogues [11] and, later, from over
500 compounds with a modulation on the aliphatic side chain; a total of 200 compounds with
increased flexibility around the two stereogenic centers were synthesized and tested against
Gram-positive bacteria to expand the diarylquinoline’s (DARQ’s) antibacterial spectrum [12].
Another group also greatly contributed to probing the SAR of bedaquiline by dividing bedaquiline
into four quarters and modifying every quarter to evaluate the biologically active motifs [13–17].
Molecules 2015, 20, 22272–22285; doi:10.3390/molecules201219846
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Molecules 2015, 20, 22272–22285
All the above modifications were based on the DARQ skeleton, but there is no confirmed proof
that the quinoline ring is indispensable for anti-tuberculosis activity. Therefore, our group attempted
to replace the quinoline ring with a naphthalene ring. As a result, the DARQ skeleton was changed
into a triarylbutanol (TARB) skeleton. A series of substituted TARB compounds were synthesized
and evaluated for MIC90, and most of them exhibited a comparable or even better inhibitory effect
against M. tuberculosis H37Rv than bedaquiline (Figure 1) [18]. In accordance with Koen Andries’s
results, the (1R, 2S) and (1S, 2R) mixture was superior to the (1S, 2S) and (1R, 2R) one.
Figure 1. Structure of bedaquiline and our designed analogues of the TARB skeleton.
To continue our research on determining which type of optical isomer of our analogues played
a critical role in antituberculosis activity, we need to build a general asymmetric synthetic route to
generate the four respective optical isomers and assign their absolute configurations (ACs).
2. Results and Discussion
2.1. Synthesis of Four Optical Isomers
After a thorough investigation into the asymmetric synthesis of bedaquiline, we found that only
two asymmetric synthetic routes were available, reflecting the difficulty of building two vicinal chiral
centers at sterically hindered positions surrounded by three bulky aryl groups [19]. Because we
needed to obtain all four types of optical isomers, we proposed our asymmetric synthetic route based
on the research of Chandrasekhar’s group [20], starting with the synthesis of TM-05 as a starting
material (Scheme 1).
O
O
3
3
2
Br
Br
Br
Br
g
Br
CHO
h
Br
OEt
OH
OCH3
f
OH
OCH3
(2 , 3
(2 , 3
i
OH
j
2
CHO
OH
OCH3
O
OCH3
O
(2 , 3
(2 , 3
)
)
)
)
(
(
)
)
3
4
2
1
4
Br
2
5
1
Br
Br
Br
o
Br
l
k
n
m
HO
O
HO
O
HO
O
CHO
O
OH
O
O
HO
OH
(
(
)
)
(1 isomers)
(1 isomers)
(4 isomers)
(4 isomers)
(5 isomers)
(5 isomers)
(2 isomers)
(2 isomers)
Ha, Ha'
Hb, Hb'
N
3
2
1
OH
3
4
4
B
A
Br
Br
Br
q
r
J
p
*
Br
K
L
HO
HO
O
HO
O
I
CH2OH
OE
O
N
OTs
C
H
D
M
F
G
(4 isomers)
(4 isomers)
(4 isomers)
(4 isomers)
: mixture of
: mixture of
and
and
Scheme 1. Asymmetric synthesis of four isomers of TM-05. Reagents and conditions: (f) NaHMDS,
(EtO)2P(O)CH2CO2Et, THF, 0 ˝C to r.t., 2 h, 87%; (g) DIBAL-H, CH2Cl2, r.t., 2 h, 76%; (h) Ti(OiPr)4,
t
(+)-DIPT, BuOOH, 4 Å zeolite, CH2Cl2, ´20 ˝C, 4 h, 60%; (i) PhMgBr, CuI, THF, ´20 ˝C, 3 h, 60%;
(j) NaIO4, CH2Cl2, r.t., 3 h; (k) 1-naphthylmagnesium bromide, THF, 0 ˝C, 2 h, 62% over 2 steps;
(l) DMP, CH2Cl2, r.t., 2 h, 95%; (m) allylzinc bromide, THF, r.t., 5 min, 60%; (n) OsO4, NMO,
THF/water/acetone (1:1:1), r.t., 8 h; (o) NaIO4, CH2Cl2, r.t., 3 h; (p) NaBH4, CH3OH, r.t., 3 h, 50%
over 3 steps; (q) TsCl, DMAP, pyridine, r.t., 16h, 58%; (r) HNMe2, THF.
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Molecules 2015, 20, 22272–22285
To prepare the desired starting material naphthaldehyde 6 (Scheme 2), 3-hydroxy-2-naphthoic
acid (1) was first brominated by excess bromine at positions 4 and 7, followed by selective
debromination with tin powder in an acidic environment to generate the 7-monobromo-substituted
naphthoic acid 3 [21]. Treatment of naphthoic acid 3 with the methylation reagent dimethyl sulfate
yielded the methoxy ester compound 4, which was reduced by LiAlH4 to give the corresponding
methoxy alcohol compound 5. After oxidation of 5 using Dess-Martin periodinane (DMP) reagent,
naphthaldehyde 6 was obtained in a high overall yield of 54% over five steps.
Br
COOH
OH
COOH
OH
Br
COOH
OH
a
b
c
3
2
1
Br
Br
Br
CHO
Br
COOCH3
OCH3
CH2OH
OCH3
e
d
OCH3
6
5
4
Scheme 2. Synthesis of naphthaldehyde 6. Reagents and conditions: (a) Br2, HOAc, reflux, 3 h, 91%;
(b) tin powder, concentrated HCl, HOAc, reflux, 3 h, 93%; (c) K2CO3, (CH3O)2SO2, acetone, reflux,
10 h, 86%; (d) LiAlH4, THF, r.t., 8 h, 78%; (e) DMP, CH2Cl2, r.t., 1 h, 95%.
After we obtained starting material 6, we followed Chandrasekhar’s procedure special attention
to the problem of the low solubility of compounds 13a and 13b. Trans-allyl alcohol 8 as
a Sharpless epoxidation standard substrate was easily regioselectively synthesized from 6 by
Horner-Wadsworth-Emmons olefination and subsequent reduction with DIBAL-H. Asymmetric
epoxidation is a critical step in controlling the final products’ optical purity. Active powdered 4 Å
molecular sieves made trans-allyl alcohol 8 convert completely into epoxy alcohol 9a with 87% e.e.
when using L-(+)-diisopropyl tartrate (DIPT) and to 9b with 97% e.e. when using D-(´)-DIPT [22].
Once the epoxy ring of epoxy alcohol 9a was regioselectively opened in the presence of active
CuI and freshly prepared Grignard reagent [23], the stereochemistry of the biaryl-substituted tertiary
carbon of diol 10a would remain unchanged. Cleavage of the diol was effectively and conveniently
performed by treatment with NaIO4-impregnated silica gel to convert the diol 10a into the aldehyde
11a [24]. The introduction of the third aryl group to form the TARB skeleton was achieved through
the attack of 1-naphthylmagnesium bromide to aldehyde 11a, followed by oxidation with DMP to
yield the keto compound 13a.
After the first chiral center was enantioselectively constructed in 9a, the diastereomers of 14a
resulting from the second chiral center could be differentiated by physical properties, such as their
molecular polarity which facilitates the isolation process. Therefore, the keto compound 13a was
converted to the allylic compound 14a without any stereoselective control. Compound 13a has a very
low solubility in most commonly used solvents, such as dichloromethane, THF and ethyl acetate.
This physical property is very different from the synthetic intermediate of bedaquiline, and created a
large obstacle for the next step because we needed to use as little as possible of the solvent THF for
allylation [25]. Finally, allylation with freshly prepared allylzinc bromide [26] was achieved using
crude product 13a without purification. The classic method for the oxidative cleavage of olefin
compounds using OsO4 and NaIO4 was applied to 14a [27], affording the triaryl aldehyde 16a. After
the triaryl aldehyde 16a was reduced to an alcohol by NaBH4, O-tosylation and displacement of the
tosyl group with dimethylamine were conducted to produce the mixture 19a.
To obtain optical purity-enriched final isomers, we made many attempts to investigate the proper
isolation steps of 14a, 16a, 17a, 18a and 19a, excluding compound 15a due to the complexity of
dealing with three chiral centers. Eventually, we found that compound 19a gave the best result
when using dichloromethane as the eluent for glass column silica gel chromatography. For the sake
of convenience, we defined the upper spot on the TLC plate (CH2Cl2/MeOH = 50:1) as TM-05-a
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Molecules 2015, 20, 22272–22285
(Rf = 0.3), and the lower spot as TM-05-b (Rf = 0.25). The epoxy alcohol 9b went through the same
synthetic procedures as 9a, and compound 19b was thus obtained. Regarding 19b, the upper spot
TM-05-c (Rf = 0.3, CH2Cl2/MeOH = 50:1) and the lower spot TM-05-d (Rf = 0.25, CH2Cl2/MeOH =
50:1) were defined.
2.2. Determination of Optical Purity
According to the Sharpless epoxidation empirical rule [28], compound 9a should be (2S, 3S)
enriched in the enantiomer, whereas compound 9b should be enriched in the (2R, 3R) one. However,
their absolute configurations needed to be verified, as discussed in Section 2.3. Their optical purities
were determined by chiral HPLC, and the HPLC spectra are available in the Supplementary
Materials. Compound 9a had an e.e. value of 87%, while compound 9b had a much higher e.e. value of
97%. Because, the stereochemistry of the biaryl-substituted tertiary carbons in 19a and 19b stemmed
from the epoxy alcohols 9a and 9b, the four isomers after isolation should have the same optical
purity as that of 9a and 9b, respectively. This speculation was firmly confirmed by the optical purity
of TM-05-a (e.e. = 87%) and its enantiomer TM-05-c (e.e. = 97%). Therefore, based on these highly
coherent data, we claim that TM-05-b possessed an e.e. value of 87% and TM-05-d 97%.
2.3. Absolute Configuration Assignment
2.3.1. AC Assignment by Electronic Circular Dichroism (ECD) Spectroscopy
Because every final optical isomer of TM-05-a–TM-05-d has a heavy atom, bromine, anchored
to the naphthalene ring, their ACs could be determined if two single crystals from two group of
enantiomers were obtained. However, all of our attempts at growing single crystals failed. While
we were searching for other methods to assign ACs, ECD caught our attention. In recent years, ECD
spectroscopy has been proven reliable and has been broadly used for the determination of the ACs
of chiral compounds, by simply matching the calculated ECD curve with the experimental one [29].
Three aromatic chromophores surrounding the two chiral carbons make it possible to apply the ECD
method to our AC analysis.
As shown in Figure 2, we observe a good match between TM-05-a and (1R, 2S), TM-05-b and (1R,
2R), TM-05-c and (1S, 2R) and TM-05-d and (1S, 2S). The experimental ECD spectra were recorded
at a concentration of 0.2´1.0 mg/mL in methanol, and the quantum chemical calculations were only
conducted for two diastereomers, (1R, 2S) and (1R, 2R), because the calculated ECD spectra of their
respective enantiomers could be easily plotted by showing mirror symmetry along the wavelength
axis. Computational details are described in the following experimental section. According to
these satisfactorily matched ECD spectra, (1R, 2S), (1R, 2R), (1S, 2R) and (1S, 2S) were assigned to
TM-05-a–TM-05-d, respectively.
Figure 2. Comparison of experimental ECD spectra and calculated ECD spectra of the four TM-05
optical isomers.
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Molecules 2015, 20, 22272–22285
2.3.2. AC Corroboration by the Combined Use of Circular Dichroism and NMR Spectroscopy
In spite of the agreement achieved between the computational and experimental ECD spectra,
the ECD method is not 100% accurate because the calculated ECD spectra is only a simulation and
cannot reflect all of the actual molecular properties in the solvent [30]. Therefore, the above results
need to be corroborated.
To confirm the calculated results, we tried to assign the ACs step-by-step. First, we tested
the Mo2(OAc)4-induced CD spectrum of compound 10a according to the previously described
procedure [31], specifically used for the AC assignment of optically active 1,2-diols. According to
the empirical rule proposed by Snatzke [32], the negative Cotton effect IV at ca. 310 nm observed
in the Mo2(OAc)4-induced CD (DMSO) spectrum reflects a negative torsional angle (OH)-C-C-(OH).
For steric reasons, the conformation of the diol 10a prefers the bulky diaryl group pointing away
from the remaining acylate moieties. As shown in Figure 3, the 2R configuration in 10a was
concluded, and, considering the phenyl located on the reverse side of the secondary hydroxyl
group, the AC of 10a can be defined as (2R, 3R), as expected when using L-(+)-(DIPT). Actually,
we also tried to grow single crystals for 10a and 10b, but unfortunately both turned out to be
the racemate of two stereoisomers in acetone. CCDC-1417941 and CCDC-1417940 contains the
supplementary crystallographic data for 10a and 10b. These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK; Fax: +44 1223 336033; E-mail: deposit@ccdc.cam.ac.uk). Crystal structures of the
two corresponding stereoisomers were attached in Supplementary Materials (Figure S10).
Figure 3. Induced CD spectra of in situ formed Mo-complex of 10a.
Based on the Sharpless epoxidation empirical rule and the Mo2(OAc)4-induced CD spectrum
result, compound 10a was unequivocally assigned as (2R, 3R) and 10b was supposed to be (2S, 3S).
To further clarify the AC of the final isomers, 1H-NMR and 2D NMR (NOESY or ROESY) experiments
were performed on TM-05-c and TM-05-d and the proton chemical shift values and coupling
constants of TM-05-c and TM-05-d are summarized in Table 1. Because the structural difference
between bedaquiline and our final compounds is so small and according to the overlay results of
the crystal structure of bedaquiline from the PDB database (ID: 4V1F) and the optimized conformer
of (1R, 2S) isomer of TM-05 (Figure S9), it is reasonable to assume that they will have similar
characteristic correlation peaks in their 2D NOESY or ROESY spectra. Specifically, in the spectra of the
1
(1R, 2S)/(1S, 2R) group of TM-05, the Ph(o)/E and A/Ha correlations should be observed, and the
1
Ph(o)/Ha and A/E correlations should be absent; conversely, regarding the (1R, 2R)/(1S, 2S) group
of TM-05, the Ph(o)/Ha and A/E correlations should appear, while Ph(o)/E and A/Ha should
1
1
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Molecules 2015, 20, 22272–22285
disappear [33]. However, in the 2D NOESY spectrum (Figure S5) of TM-05-c and the 2D ROESY
spectrum (Figure S6) of TM-05-d, the respective characteristic correlation peaks were submerged in
the noise signals. Therefore, 1D NOESY experiments at specific proton chemical shifts were carried
out. For TM-05-c (Figure 4, full spectra are in the Supplementary Materials), irradiation of the Ph(o)
1
and Ha protons induced an enhancement of the integration of proton E by 0.93% and proton A by
1.54%, respectively, and it is noteworthy that the irradiation of proton A did not affect proton E.
1
For TM-05-d (Figure 5), irradiation of the Ha proton increased the integration of proton Ph(o) by
1.86%, and irradiation of proton A greatly enhanced proton E and Ph(o) by 8.05%, indicating that
protons A, E and Ph(o) are sterically close. These 1D NOESY results matched perfectly with the
characteristic correlations mentioned above; therefore, we concluded that TM-05-c belonged to the
(1R, 2S)/(1S, 2R) group of TM-05, and TM-05-d belonged to the (1R, 2R)/(1S, 2S) group. Considering
the AC of the tertiary carbon defined by the Mo2(OAc)4-induced CD spectra, the ACs of TM-05-a,
TM-05-b, TM-05-c and TM-05-d were unambiguously determined as (1R, 2S), (1R, 2R), (1S, 2R) and
(1S, 2S), respectively, which are in accordance with the ECD method results.
Figure 4. 1D NOESY spectra of TM-05-c.
Figure 5. 1D NOESY spectra of TM-05-d.
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Molecules 2015, 20, 22272–22285
Table 1. Proton chemical shifts and coupling constants in CDCl3 of TM-05-c and TM-05-d.
Compound TM-05-c
Compound TM-05-d
Proton
δ (ppm)
J (Hz)
Proton
δ (ppm)
J (Hz)
N(CH3)2,Hb,Hb’
1.88–2.04
2.17
m
t (12.9)
N(CH3)2,Hb,Hb’
1.93–2.06
2.32
m
t (12.0)
1
Ha
Ha’
Ha
2.47
d (14.3)
Ha
2.49
d (14.3)
OCH3
4.05
s
OCH3
3.00
s
L
6.04
s
m
m
t (7.6)
m
m
L
M
5.86
6.46
7.20–7.25
7.34–7.42
7.51–7.55
7.77
7.86
7.91–7.97
8.34
s
s
m
m
m
d (8.1)
s
m
s
Ph(m, p)
Ph(o),M
6.86–6.88
7.12–7.14
7.31
7.45–7.50
7.57–7.61
7.67
Ph(p),F,G,D
Ph(m),H
F
I,C
D,J
G
E,H
B
C,J
I
B
Ph(o),E
A
d (8.1)
m
7.87–7.92
8.03
s
K
A
8.65
8.75
d (8.7)
s
K
8.52
d (8.7)
3. Experimental Section
3.1. General Information
Unless otherwise noted, all reactions were performed under an atmosphere of nitrogen. Except
for L-(+)-DIPT, D-(´)-DIPT and Ti(OiPr)4 from Sigma-Aldrich Co. Ltd (Beijing, China), all other
reagents and solvents were purchased from common commercial suppliers. Only THF and CH2Cl2
needed to be distilled according to standard procedures: CH2Cl2 by CaH2 and THF by LiAlH4. NMR
spectra were recorded on a Bruker ARX400 spectrometer (Bruker Inc., Karlsruhe, Germany) with
Me4Si as an internal standard. Mass spectra were obtained on an 1260-G6230A LC-MS spectrometer
(Agilent, Santa Clara, CA, USA). ECD spectra were recorded in a quartz cuvette with a 1-mm optical
path length using a Jasco J-815 CD spectrometer (Jasco Inc., Tokyo, Japan). All quantum computations
were performed using the Gaussian 09 program package on an IBM cluster machine located at the
High Performance Computing Center of Peking Union Medical College.
3.2. Computational Details
We selected the (1R, 2S) and (1R, 2R) configurations for quantum chemical calculations. The
initial conformation search was carried out using the MMFF94 molecular mechanics force field via the
MOE software package. The resulting eight conformers (Figure S7) for (1R, 2S) and six conformers
(Figure S8) for (1R, 2R), within a 5-kJ/mol window, were optimized in the framework of density
functional theory (DFT) using the Becke 3-Lee-Yang-Parr (B3LYP) exchange-correlation functional at
the 6-31G (d) basis set level (see supporting information). All of these conformers were verified as
the true minima of the potential energy surface by showing no imaginary frequency. Solvent effects
of methanol were considered by using the polarizable continuum model (PCM). Oscillator strengths
and rotational strengths in both dipole length (Rlen) and dipole velocity (Rvel) representations of the
60 lowest electronic transitions were calculated for each conformer. Every conformer’s ECD spectra
was simulated by using a Gaussian function with Rvel and a bandwidth σ = 0.45 eV. Equilibrium
populations of conformers at 298.15 K were calculated from their relative free energies (∆G) using
Boltzmann statistics. The final ECD spectra were obtained by averaging all the simulated ECD spectra
of the calculated conformers according to Boltzmann distribution.
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Molecules 2015, 20, 22272–22285
3.3. Synthesis and Characterization
4,7-Dibromo-3-hydroxy-2-naphthoic acid (2). At room temperature, a suspension of 3-hydroxy-2-
naphthoic acid 1 (50 g, 266 mmol) in acetic acid (500 mL) was mechanically stirred for 10 min.
A solution of bromine (34 mL, 665 mmol) in acetic acid (200 mL) was then added dropwise through a
dropping funnel. Then the mixture was heated to reflux for 3 h. After cooling to room temperature,
the reaction was quenched with 3000 mL of ice water. The yellow solid was filtered and dried to give
a crude product of 2 (84 g, 91%) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6): δ = 3.63 (br. s),
7.84 (dd, J = 9.2, 2.0 Hz, 1H), 7.98 (d, J = 9.0 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 8.63 (s, 1H) ppm. HRMS
´
´
(ESI): [M ´ H] , found 344.8591. C11H5Br2O3 requires 344.8585.
7-Bromo-3-hydroxy-2-naphthoic acid (3). Compound 2 (70 g, 202 mmol), tin powder (23.9 g, 202 mmol)
and 250 mL of concentrated HCl were successively added into acetic acid (800 mL). The mixture was
heated to reflux for 3 h. After cooling to room temperature, the reaction was quenched with ice water
(1000 mL) and the solid was filtered and dried to afford 3 (50 g, 93%) as a yellow solid. 1H-NMR
(400 MHz, DMSO-d6): δ = 3.37 (br. s), 7.37 (s, 1H), 7.64 (dd, J = 9.0, 2.0 Hz, 1H), 7.76 (d, J = 9.0 Hz, 1H),
´
´
8.28 (d, J = 2.0 Hz, 1H), 8.54 (s, 1H) ppm. HRMS (ESI): [M ´ H] , found 264.9502. C11H6BrO3
requires 264.9500.
Methyl 7-bromo-3-methoxy-2-naphthoate (4). To a solution of 3 (200 g, 750 mmol) in acetone (2000 mL),
anhydrous K2CO3 (757 g, 5475 mmol) and dimethyl sulfate (236 g, 1872 mmol) were added at room
temperature with mechanical stirring. After refluxing for 10 h, the reaction was cooled to room
temperature. The insoluble K2CO3 was filtered and washed with EtOAc. The combined filtrate was
concentrated under reduced pressure and extracted with EtOAc and water. The combined organic
layer was washed with water and brine, dried with Na2SO4 and rotary evaporated to give 4 (190 g,
86%) as a pale yellow solid. 1H-NMR (400 MHz, CDCl3): δ = 3.95 (s, 3H), 3.99 (s, 3H), 7.17 (s, 1H),
7.57 (dd, J = 8.7, 2.0 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 8.18 (s, 1H) ppm. HRMS
(ESI): calcd. for C13H11BrO3Na+ [M + Na]+ 316.9789, found 316.9785.
7-Bromo-3-methoxy-2-naphthalenemethanol (5). To a suspension of LiAlH4 (8.36 g, 220 mmol) in THF
(100 mL), a solution of 4 (59 g, 200 mmol) in THF (500 mL) was added dropwise via a dropping
funnel at room temperature. After stirring for 8 h, water (20 mL) was added dropwise with vigorous
stirring to quench the reaction. The mixture was filtrated through a plug of Celite and rinsed with
EtOAc. The combined filtrate was dried with Na2SO4 and concentrated to give 5 (46 g, 78%) as a
1
white solid. H-NMR (400 MHz, CDCl3): δ = 3.97 (s, 3H), 4.82 (s, 2H), 7.09 (s, 1H), 7.50 (dd, J = 8.8,
2.0 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.9 (s, 1H) ppm. GC-MS m/z: 266 (M+).
7-Bromo-3-methoxy-2-naphthaldehyde (6). To a solution of 5 (10 g, 37.4 mmol) in CH2Cl2 (150 mL) at
˝
0 C, Dess-Martin periodinane (DMP: 24 g, 56.6 mmol) was added slowly. After stirring for 1 h at
room temperature, the reaction mixture was quenched with saturated aqueous Na2S2O3 (50 mL) and
saturated aqueous NaHCO3 (50 mL). The aqueous phase was extracted with CH2Cl2. The combined
organic layer was washed with water and brine, dried with Na2SO4 and rotary evaporated. The crude
product underwent silica gel chromatography (eluent: EtOAc/hexane = 1:10) to yield 6 (9.4 g, 95%)
as a yellow solid. 1H-NMR (400 MHz, DMSO-d6): δ = 4.01 (s, 3H), 7.58 (s, 1H), 7.72 (dd, J = 8.8, 2.0 Hz,
1H), 7.86 (d, J = 8.8 Hz, 1H), 8.35 (m, 2H), 10.46 (s, 1H) ppm. GC-MS m/z: 264 (M+).
Ethyl (E)-3-(7-bromo-3-methoxynaphthalen-2-yl)acrylate (7). To a solution of triethyl phosphonoacetate
˝
(6.78 g, 30.3 mmol) in THF (10 mL) at 0 C, NaHMDS (14.2 mL, 28.4 mmol, 2.0 M in THF) was added
slowly and stirred for 30 min at room temperature. A solution of 6 (5 g, 19 mmol) in THF (10 mL) was
added dropwise to the above reaction mixture and then stirred for another 2 h. The reaction mixture
was quenched with water, concentrated under reduced pressure and extracted with EtOAc. The
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Molecules 2015, 20, 22272–22285
combined organic layer was washed with water and brine, dried with Na2SO4, rotary evaporated
and crystallized to give 7 (5.5 g, 87%) as a white solid. 1H-NMR (400 MHz, DMSO-d6): δ = 1.28
(t, J = 7.2 Hz, 3H), 3.98 (s, 3H), 4.22 (q, J = 7.0 Hz, 2H), 6.78 (d, J = 16.2 Hz, 1H), 7.47 (s, 1H), 7.62
(dd, J = 8.7, 2.0 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.94 (d, J = 16.2 Hz, 1H), 8.10 (d, J = 2.0 Hz, 2H), 8.33
(s, 1H) ppm. HRMS (ESI): [M + Na]+, found 357.0096. C16H15BrO3Na+ requires 357.0102.
(E)-3-(7-Bromo-3-methoxynaphthalen-2-yl)prop-2-en-1-ol (8). DIBAL-H (360 mL, 360 mmol, 1.0 M in toluene)
˝
was added to a solution of 7 (60 g, 180 mmol) in CH2Cl2 (400 mL) at 0 C. After being stirred for
2 h at room temperature, the reaction mixture was quenched with saturated aqueous Rochelle’s
˝
salt (300 mL) at 0 C and the resulting suspension was stirred vigorously for 4 h. The reaction
mixture was filtrated and the aqueous phase was extracted with EtOAc. The combined organic layer
was washed with water and brine, dried with Na2SO4 and rotary evaporated. The crude product
underwent silica gel chromatography (eluent: EtOAc/hexane = 1:5) to afford 8 (40 g, 76%) as a pale
yellow solid. 1H-NMR (400 MHz, DMSO-d6): δ = 3.92 (s, 3H), 4.18 (m, 2H), 4.96 (t, J = 5.6 Hz, 1H),
6.53 (dt, J = 5.0, 16.0 Hz, 1H), 6.91(d, J = 16.0 Hz, 1H), 7.36 (s, 1H), 7.51 (dd, J = 2.0, 8.7 Hz, 1H), 7.75
(d, J = 8.7 Hz, 1H), 7.99(s, 1H), 8.08(d, J = 2.0 Hz, 1H) ppm.
(2S,3S)-3-(7-Bromo-3-methoxynaphthalen-2-yl)oxiran-2-yl]methanol (9a). (2R,3R)-3-(7-Bromo-3-methoxy-
naphthalen-2-yl)oxiran-2-yl]methanol (9b) Ti(OiPr)4 (2.43 g, 8.5 mmol) was added to a suspension of
powdered molecular sieves (4 Å, 2 g, 40% w/w based on substrate) in CH2Cl2 (30 mL). After stirring
for 5 min, L-(+)-DIPT (2.4 g, 10.2 mmol) in CH2Cl2 (10 mL) was added, and the reaction mixture
was then stirred for 30 min, followed by slow addition of a solution of 8 (5 g, 17 mmol) in 120 mL
of CH2Cl2. The resulting suspension was stirred for another 40 min and anhydrous tert-butyl
hydroperoxide (5.5 M in nonane, 6.2 mL, 34.1 mmol) was added at the same temperature and stirred
˝
for 4 h. After warming to 0 C, 20% aqueous NaOH saturated with NaCl (30 mL) was added and
the mixture was stirred for 1 h. The resulting slurry was filtered through a plug of Celite and rinsed
thoroughly with CH2Cl2. The organic layer was separated and the aqueous layer was extracted with
EtOAc. The combined organic layer was washed with water and brine, dried with Na2SO4 and rotary
evaporated. The crude product underwent silica gel chromatography (eluent: EtOAc/hexane = 1:5)
to produce 9a (87% e.e.) as a white solid (3.1 g, 60%). 1H-NMR (400 MHz, DMSO-d6): δ = 3.10
(m, 1H), 3.58 (m, 1H), 3.80 (ddd, J = 2.8, 5.6, 12.6 Hz, 1H), 3.95 (s, 3H), 4.16 (d, J = 1.7 Hz, 1H), 5.05
(t, J = 5.9 Hz, 1H), 7.40 (s, 1H), 7.56 (dd, J = 2.0, 8.8 Hz, 1H), 7.63 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 8.11
(d, J = 2.0 Hz, 1H) ppm. HRMS (ESI): [2 M + Na]+ , found 640.9968. C28H26Br2O6Na+ requires 640.9973.
9b (97% e.e.) was obtained with the same procedure as 9a using D-(´)-DIPT. HPLC [Chiralpak IC
˝
(250 mm ˆ 4.6 mm, 5 µ), IPA/hexane = 30%:70%, flow = 1.0 mL, T = 20 C, λ = 225 nm, tR = 7.1 min
(9b), 9.2 min (9a)].
(2R,3R)-3-(7-Bromo-3-methoxynaphthalen-2-yl)-3-phenylpropane-1,2-diol (10a) (2S,3S)-3-(7-Bromo-3-
methoxynaphthalen- 2-yl)-3-phenylpropane-1,2-diol (10b). A suspension of freshly prepared CuI (6 g,
˝
32 mmol) in THF (34 mL) was cooled to ´20 C, and PhMgBr (22 mL, 66 mmol, 3 M in Et2O) was
added via syringe and stirred for 1 h. A solution of 9a (2 g, 6.5 mmol) in THF (10 mL) was added and
˝
stirred. After 3 h, the reaction mixture was warmed to 0 C and quenched by a saturated aqueous
solution of NH4Cl (50 mL). After the reaction mixture was concentrated under reduced pressure and
extracted with EtOAc, the combined organic layer was washed with water and brine, dried with
Na2SO4 and rotary evaporated. The crude product underwent silica gel chromatography (eluent:
EtOAc/hexane = 1:5) to obtain 10a as a white solid (1.5 g, 60%). 1H-NMR (400 MHz, DMSO-d6):
δ = 3.20 (m, 1H), 3.32 (m, 1H), 3.83 (s, 3H), 4.38 (m, 1H), 4.53 (d, J = 9.5 Hz, 1H), 7.10–7.33 (m, 6H),
7.50 (dd, J = 2.0, 8.7Hz, 1H), 7.71 (d, J = 9.0 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 8.12 (s, 1H) ppm. HRMS
(ESI): [M + Na]+, found 409.0425. C20H19BrO3Na+ requires 409.0415.
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Molecules 2015, 20, 22272–22285
10b was obtained with the same procedure as 10a using 9b.
(2R)-2-(7-Bromo-3-methoxynaphthalen-2-yl)-1-(naphthalen-1-yl)-2-phenylethanol (12a) (2S)-2-(7-Bromo-3-
methoxynaphthalen-2-yl)-1-(naphthalen-1-yl)-2-phenylethanol (12b). To a solution of 10a (4 g, 10.3 mmol)
in CH2Cl2 (100 mL), NaIO4 impregnated over silica (33 g, 20 % w/w on silica) was added and stirred
for 3 h at room temperature. The reaction mixture was filtrated and rotary evaporated to give the
crude product 11a which was used immediately for the next reaction. All of the above 11a was
dissolved in THF (22 mL), and freshly prepared naphthyl Grignard reagent (22 mL, 44 mmol, 2 M
˝
in THF) was added slowly at 0 C and stirred for 2 h. A saturated aqueous solution of NH4Cl (50 mL)
was added to quench the reaction, and the aqueous layer was extracted with EtOAc. The combined
organic layer was washed with water and brine, dried with Na2SO4 and rotary evaporated. The crude
product underwent silica gel chromatography (eluent: EtOAc/hexane = 1:10) to obtain 12a as a white
solid (3.1 g, 62% over 2 steps).
12b was obtained with the same procedure as 12a using 10b.
(R)-2-(7-Bromo-3-methoxynaphthalen-2-yl)-1-(naphthalen-1-yl)-2-phenylethanone (13a) (S)-2-(7-Bromo-3-
methoxynaphthalen-2-yl)-1-(naphthalen-1-yl)-2-phenylethanone (13b). To a solution of 12a (6.65 g,
13.8 mmol) in CH2Cl2 (100 mL), Dess-Martin periodinane (DMP: 9 g, 21 mmol) was added slowly
and stirred for 2 h. After the reaction finished, 30 mL of asaturated aqueous solution of Na2S2O3
and 30 mL of a saturated aqueous solution of NaHCO3 were added and stirred for 1 h. After the
reaction mixture became clear, it was extracted by CH2Cl2 three times. The combined organic layer
was washed with water and brine, dried with Na2SO4 and rotary evaporated. 13a (6.3 g, 95%) was
1
obtained without column chromatography. H-NMR (400 MHz, CDCl3): δ = 3.80 (s, 3H), 6.33 (s, 1H),
7.10 (s, 1H), 7.19 (s, 1H), 7.33–7.60 (m, 10H), 7.78 (d, J = 1.7 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.94
(d, J = 8.1 Hz, 1H), 8.05 (d, J = 7.3 Hz, 1H), 8.58 (d, J = 8.4 Hz, 1H). HRMS (ESI): [M + Na]+, found
505.0616. C29H21BrO2Na+ requires 505.0602.
13b was obtained with the same procedure as 13a using 12b.
(1R)-1-(7-Bromo-3-methoxynaphthalen-2-yl)-2-(naphthalen-1-yl)-1-phenylpent-4-en-2-ol (14a), (1S)-1-(7-
Bromo-3-methoxynaphthalen-2-yl)-2-(naphthalen-1-yl)-1-phenylpent-4-en-2-ol (14b). After the freshly
prepared allylzinc bromide (83 mmol) was concentrated under reduced pressure, a solution of 13a
(2 g, 4.15 mmol) in THF (as little as possible) was poured into the allylzinc bromide’s bottle and stirred
for 5 min. A saturated aqueous solution of NH4Cl (50 mL) was added, and the aqueous layer was
extracted with EtOAc. The combined organic layer was washed with water and brine, dried with
Na2SO4 and rotary evaporated. The crude product underwent silica gel chromatography (eluent:
EtOAc/hexane = 1:20) to obtain 14a as a white solid (1.3 g, 60%).
14b was obtained with the same procedure as 14a using 13b.
(4R)-4-(7-Bromo-3-methoxynaphthalen-2-yl)-3-hydroxy-3-(naphthalen-1-yl)-4-phenylbutanal (16a), (4S)-4-
(7-Bromo-3-methoxynaphthalen-2-yl)-3-hydroxy-3-(naphthalen-1-yl)-4-phenylbutanal (16b). To a solution
of 14a (3.5 g, 6.7 mmol) and N-methyl morpholine-N-oxide (NMO: 3.9 g, 33.5 mmol) in
˝
THF/water/acetone (1:1:1, 30 mL) at 0 C, OsO4 (0.68 mL, 0.1 mmol, 4% in water) was added.
The reaction was warmed to room temperature and stirred for 8 h. A saturated aqueous solution
of Na2S2O3 (10 mL) was added and stirred for 30 min. The reaction mixture was concentrated under
reduced pressure and extracted with EtOAc. The combined organic layer was washed with water
and brine, dried with Na2SO4 and rotary evaporated to give crude product 15a which was used
immediately for the next reaction.
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Molecules 2015, 20, 22272–22285
All of the above 15a was dissolved in CH2Cl2, and NaIO4 impregnated over silica (25 g, 20%
w/w on silica) was added and stirred for 3 h at room temperature. The reaction mixture was filtrated
and rotary evaporated to give 16a without column chromatography.
16b was obtained with the same procedure as 16a using 14b.
(4R)-4-(7-Bromo-3-methoxynaphthalen-2-yl)-3-(naphthalen-1-yl)-4-phenylbutane-1,3-diol (17a), (4S)-4-
(7-Bromo-3-methoxynaphthalen-2-yl)-3-(naphthalen-1-yl)-4-phenylbutane-1,3-diol (17b). All of the above
˝
16a was dissolved in 30 mL of methanol, and NaBH4 (0.3 g, 8 mmol) was added slowly at 0 C. After
stirring at room temperature for 3 h, the reaction mixture was filtrated, rotary evaporated and passed
through silica gel chromatography column (eluent: EtOAc/hexane = 1:10) to give 17a (1.8 g, 50%
over 3 steps). ESI-MS m/z: 526 [M]+.
17b was obtained with the same procedure as 17a using 16b.
(4R)-4-(7-Bromo-3-methoxynaphthalen-2-yl)-3-hydroxy-3-(naphthalen-1-yl)-4-phenylbutyl
4-methyl-
benzenesulfonate (18a), (4S)-4-(7-Bromo-3-methoxynaphthalen-2-yl)-3-hydroxy-3-(naphthalen-1-yl)-4-
phenylbutyl 4-methylbenzenesulfonate (18b). 17a (1 g, 1.9 mmol) was dissolved in 38 mL of pyridine,
and 4-dimethylaminopyridine (DMAP: 0.47 g, 3.8 mmol) and TsCl (3.2 g, 19 mmol) were added
˝
slowly at 0 C. After stirring for 16 h at room temperature, the reaction mixture was quenched by
5 mL of water. Most of the pyridine was rotary evaporated and the rest of the reaction mixture was
extracted with EtOAc. The combined organic layer was washed with water and brine, dried with
Na2SO4 and rotary evaporated. The crude product underwent silica gel chromatography (eluent:
EtOAc/hexane = 1:10) to obtain 18a as a white solid (0.75 g, 58%). ESI-MS m/z: 698 [M + NH4]+.
18b was obtained with the same procedure as 18a using 17b.
(1R,2S)-1-(7-Bromo-3-methoxynaphthalen-2-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1- phenylbutan-2-ol
(TM-05-a) and (1R,2R)-1-(7-bromo-3-methoxynaphthalen-2-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-
phenylbutan-2-ol (TM-05-b). A solution of 18a (0.6 g, 0.9 mmol) in Me2NH (75 mL, 3 M in THF)
˝
was stirred at 45 C for 24 h. The reaction mixture was rotary evaporated and passes through a silica
gel chromatography column (eluent: EtOAc t/hexane = 1:5) to obtain the mixture of TM-05-a and
TM-05-b, namely 19a (0.4 g, 82%). Further purification of 19a through a silica gel chromatography
column (eluent: CH2Cl2) yielded the final products TM-05-a (0.15 g, 37.5%, Rf = 0.3, CH2Cl2/MeOH
= 50:1, 87% e.e.) and TM-05-b (0.1 g, 25%, Rf = 0.25, CH2Cl2/MeOH = 50:1, 97% e.e.). The mixture of
TM-05-c and TM-05-d, namely 19b (0.42 g, 86%) was obtained with the same procedure as 19a.
(1S,2R)-1-(7-Bromo-3-methoxynaphthalen-2-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1- phenylbutan-2-ol
(TM-05-c). TM-05-c (0.12 g, 28.6%, Rf = 0.3, CH2Cl2/MeOH = 50:1, 87% e.e.) was obtained
after purification of 19b through a silica gel chromatography column (eluent: CH2Cl2). 1H-NMR
(400 MHz, CDCl3): δ = 1.88–2.04 (m, 8H), 2.17 (t, J = 12.9 Hz, 1H), 2.47 (d, J = 14.3 Hz, 1H), 4.05
(s, 3H), 6.04 (s, 1H), 6.86–6.88 (m, 3H), 7.12–7.14 (m, 3H), 7.30–7.33 (t, J = 7.6 Hz, 1H), 7.45–7.50
(m, 2H), 7.57-7.61 (m, 2H), 7.67 (d, J = 8.1 Hz, 1H), 7.87–7.92 (m, 2H), 8.03 (s, 1H), 8.65 (d, J = 8.7 Hz,
1H), 8.75 (s, 1H). 13C-NMR (100 MHz, CDCl3): δ = 33.4, 44.7, 48.9, 55.9, 56.3, 82.4, 104.7, 116.8, 124.4,
125.1, 125.4, 125.5, 127.0, 127.4, 127.9, 128.0, 128.9, 129.8, 129.9, 130.1, 130.5, 131.6, 133.4, 134.7, 141.1,
+
142.2, 156.7 ppm. HRMS (ESI): [M + H]+, found 555.1769. C33H33BrNO2 requires 555.1728. [Astecr
Cyclobondr I 2000 RSP (250 mm ˆ 4.6 mm, 5 µ), MeOH:(50 µM CH3COONH4 aqueous solution) =
˝
80%:20%, flow = 0.8 mL, T = 20 C, λ = 225 nm, tR = 6.3 min (TM-05-a), 8.3 min (TM-05-c)].
(1S,2S)-1-(7-Bromo-3-methoxynaphthalen-2-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
(TM-05-d). TM-05-d (0.1 g, 23.8%, Rf = 0.25, CH2Cl2/MeOH = 50:1, 97% e.e.) was obtained
22282

Molecules 2015, 20, 22272–22285
after purification of 19b through a silica gel chromatography column (eluent: CH2Cl2). 1H-NMR
(400 MHz, CDCl3): δ = 1.93–2.06 (m, 8H), 2.32 (t, J = 12.0 Hz 1H), 2.49 (d, J = 14.3 Hz, 1H), 3.00 (s, 3H),
5.86 (s, 1H), 6.46 (s, 1H), 7.20–7.25 (m, 4H), 7.34–7.42 (m, 3H), 7.51–7.55 (m, 2H), 7.77 (d, J = 8.1 Hz,
1H), 7.86 (s, 1H), 7.91-7.97 (m, 3H), 8.34 (s, 1H), 8.52 (d, J = 8.7 Hz, 1H). 13C-NMR (100 MHz, CDCl3):
δ = 35.0, 42.0, 43.7, 54.4, 54.9, 104.6, 116.6, 124.0, 124.9, 125.7, 126.5, 127.4, 127.5, 128.6, 128.7, 128.9,
129.1, 129.2, 129.4, 129.6, 129.7, 131.1, 131.2, 131.4, 134.3, 138.1, 139.1, 155.2 ppm.
4. Conclusions
Asymmetric synthesis and AC assignment were achieved for our bedaquiline analogues with
a TARB skeleton. Comparison of theoretical and experimental ECD spectra is a very useful and
reliable tool to determine the AC and is especially suitable for our analogues, which are not very
flexible and have many chromophoric groups. The vicinal diol intermediate revealed its critical
role for our AC confirmation due to the special reactivity of the vicinal diol moiety. Moreover,
our results consolidated the generality of Sharpless epoxidation. Our NOESY spectra and existing
crystallographic data on the (1R, 2R) isomer of TM-05 strongly indicate that the replacement
of naphthalene did not alter the conformation of bedaquiline too much, which is a reasonable
explanation for our early bioactivity results. Further research to find the most bioactive isomers of
our analogues is ongoing.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/
20/12/19846/s1.
Acknowledgments: We are grateful for the financial support from the National Key Technologies R & D program
for the New Drugs (2015ZX09102007-006) to Wu Zhong. We appreciate the help from Wei Sun at the Chinese
Academy of Medical Sciences for the analysis of crystallographic data.
Author Contributions: Song Li, Wu Zhong and Chang-Jiang Qiao conceived and designed the experiments;
Chang-Jiang Qiao and Fei Xie performed the experiments; Chang-Jiang Qiao and Xiao-Kui Wang analyzed the
data; Chang-Jiang Qiao wrote the paper. All authors read and approved this final manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 2–19 are available from the authors.
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