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Article

Asymmetric Synthesis and Absolute Configuration Assignment of a New Type of Bedaquiline Analogue

by
Chang-Jiang Qiao
1,2,
Xiao-Kui Wang
2,
Fei Xie
2,
Wu Zhong
2,* and
Song Li
1,2,*
1
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China
2
Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China
*
Authors to whom correspondence should be addressed.
Molecules 2015, 20(12), 22272-22285; https://doi.org/10.3390/molecules201219846
Submission received: 3 November 2015 / Revised: 4 December 2015 / Accepted: 7 December 2015 / Published: 11 December 2015
(This article belongs to the Section Medicinal Chemistry)
Browse Figures
Versions Notes

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.

Graphical Abstract

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 [5,6,7,8,9]. 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 [13,14,15,16,17].
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.
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Figure 1. Structure of bedaquiline and our designed analogues of the TARB skeleton.
Figure 1. Structure of bedaquiline and our designed analogues of the TARB skeleton.
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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).
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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, (+)-DIPT, tBuOOH, 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.
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, (+)-DIPT, tBuOOH, 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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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.
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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%.
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%.
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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 (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.
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Figure 2. Comparison of experimental ECD spectra and calculated ECD spectra of the four TM-05 optical isomers.
Figure 2. Comparison of experimental ECD spectra and calculated ECD spectra of the four TM-05 optical isomers.
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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: [email protected]). Crystal structures of the two corresponding stereoisomers were attached in Supplementary Materials (Figure S10).
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Figure 3. Induced CD spectra of in situ formed Mo-complex of 10a.
Figure 3. Induced CD spectra of in situ formed Mo-complex of 10a.
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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 (1R, 2S)/(1S, 2R) group of TM-05, the Ph(o)/E and A/Ha′ correlations should be observed, and the 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 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) 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. 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.
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Figure 4. 1D NOESY spectra of TM-05-c.
Figure 4. 1D NOESY spectra of TM-05-c.
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Figure 5. 1D NOESY spectra of TM-05-d.
Figure 5. 1D NOESY spectra of TM-05-d.
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Table
Table 1. Proton chemical shifts and coupling constants in CDCl3 of TM-05-c and TM-05-d.
Table 1. Proton chemical shifts and coupling constants in CDCl3 of TM-05-c and TM-05-d.
Compound TM-05-cCompound TM-05-d
Protonδ (ppm)J (Hz)Protonδ (ppm)J (Hz)
N(CH3)2,Hb,Hb’1.88–2.04mN(CH3)2,Hb,Hb’1.93–2.06m
Ha′2.17t (12.9)Ha’2.32t (12.0)
Ha2.47d (14.3)Ha2.49d (14.3)
OCH34.05sOCH33.00s
L6.04sL5.86s
Ph(m, p)6.86–6.88mM6.46s
Ph(o),M7.12–7.14mPh(p),F,G,D7.20–7.25m
F7.31t (7.6)Ph(m),H7.34–7.42m
I,C7.45–7.50mC,J7.51–7.55m
D,J7.57–7.61mI7.77d (8.1)
G7.67d (8.1)B7.86s
E,H7.87–7.92mPh(o),E7.91–7.97m
B8.03sA8.34s
K8.65d (8.7)K8.52d (8.7)
A8.75s

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 (ΔG) using Boltzmann statistics. The final ECD spectra were obtained by averaging all the simulated ECD spectra of the calculated conformers according to Boltzmann distribution.

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 white solid. 1H-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 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 × 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.
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 obtained without column chromatography. 1H-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.
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. [Astec® Cyclobond® I 2000 RSP (250 mm × 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 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: https://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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MDPI and ACS Style

Qiao, C.-J.; Wang, X.-K.; Xie, F.; Zhong, W.; Li, S. Asymmetric Synthesis and Absolute Configuration Assignment of a New Type of Bedaquiline Analogue. Molecules 2015, 20, 22272-22285. https://doi.org/10.3390/molecules201219846

AMA Style

Qiao C-J, Wang X-K, Xie F, Zhong W, Li S. Asymmetric Synthesis and Absolute Configuration Assignment of a New Type of Bedaquiline Analogue. Molecules. 2015; 20(12):22272-22285. https://doi.org/10.3390/molecules201219846

Chicago/Turabian Style

Qiao, Chang-Jiang, Xiao-Kui Wang, Fei Xie, Wu Zhong, and Song Li. 2015. "Asymmetric Synthesis and Absolute Configuration Assignment of a New Type of Bedaquiline Analogue" Molecules 20, no. 12: 22272-22285. https://doi.org/10.3390/molecules201219846

APA Style

Qiao, C.-J., Wang, X.-K., Xie, F., Zhong, W., & Li, S. (2015). Asymmetric Synthesis and Absolute Configuration Assignment of a New Type of Bedaquiline Analogue. Molecules, 20(12), 22272-22285. https://doi.org/10.3390/molecules201219846

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