The stereochemistry of baishouwubenzophenone, a

Journal of Molecular Structure 1125 (2016) 370e373

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Journal of Molecular Structure journal homepage: http://www.elsevier.com/locate/molstruc

The stereochemistry of baishouwubenzophenone, a unique atropisomer from C. wilfordii Zhixu Zhou a, b, Zhiqiang Wang c, Linwei Li a, Ke Zhang a, Qing Peng a, Shuyun Wang a, Jinhui Wang a, Jian Huang a, **, Tiemin Sun a, * a b c

Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang 110016, PR China School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, PR China College of Chemistry & Chemical Engineering, Harbin Normal University, Harbin 150025, PR China

a r t i c l e i n f o

a b s t r a c t

Article history: Received 21 January 2016 Received in revised form 3 July 2016 Accepted 4 July 2016 Available online 7 July 2016

Baishouwubenzophenone (1), possessing a unique atropisomeric feature, has been isolated from the roots of Cynanchum wilfordii. The congested structure makes it showing optical activity and consequently the absolute configuration was identified by experimental CD and computational approaches. Configurational assignment was further confirmed by exciton chirality method. The structural features in baishouwubenzophenone molecule allow it to be a potential atropisomeric ligand in asymmetric synthesis. © 2016 Elsevier B.V. All rights reserved.

Keywords: Baishouwubenzophenone Absolute configuration TDDFT ECD Atropisomeric ligand

1. Introduction The genus Cynanchum, containing the largest number among the 180 species in Asclepiadacease, is distributed around the world [1]. Cynanchum wilfordii, belonging to the family Apocynaceae, is a famous traditional medicine used as a blood tonic, enriching vitality and enhancing immunity [2]. According to the current knowledge, more than 300 compounds have been isolated from Cynanchum species, including steroids, alkaloids, terpenes, flavonoids, benzophenones, polysaccharides, and steroidal glycosides [1]. Among these, baishouwubenzophenone was often regarded as an important active component. Baishouwubenzophenone (1, Fig. 1) was isolated from the roots of C. wilfordii. Although the compound has been reported previously [3], the stereochemistry has not been investigated in spite of the obvious existence of steric effects. Many compounds with similar planar structures or substructures to baishouwubenzophenone were reported, such as graphisin A (2) [4], sutural element

* Corresponding author. ** Corresponding author. E-mail address: [email protected] (T. Sun). http://dx.doi.org/10.1016/j.molstruc.2016.07.008 0022-2860/© 2016 Elsevier B.V. All rights reserved.

of Balanol (3) [5,6], ortho-benzoylbenzoic acid (4) [7], however no enough attention was paid to their stereochemistry. In our research, we have found that baishouwubenzophenone showed unique optical activity which aroused our interest of its stereochemistry. We assumed that the two phenyl rings in the molecular structure are flanked by two ortho substituents thus exhibiting hindered rotation about the Ar-CO-Ar group. Moreover, the most of atropisomeric compounds used in asymmetric synthesis are derived from biaryls, such as the BINOL [8e12], BINAP [8,13] and their derivatives, while the use of non-biaryl atropisomeric ligands in asymmetric catalysis is in its infancy [14e16]. Some benzophenone-derived diphosphine ligands, such as DPBP (2,20 -bis(diphenylphosphino)benzophenone) [17], which could be controlled into a single enantiomeric conformation, have been used in asymmetric synthesis. It is reported that the levels of enantioselectivity observed with the benzophenonebased catalyst are superior to those observed with BINAP-based catalytic systems in asymmetric ketone hydrogenation [18]. In the present paper, we tried to investigate the stereochemistry of baishouwubenzophenone systematically, considering that the atropisomeric feature and multiple hydroxyl groups would allow it to be potential as an atropisomeric ligand in asymmetric synthesis. The chemical structure of 1 as well as the absolute configuration (AC) was elucidated by spectroscopic methods, electronic circular

Z. Zhou et al. / Journal of Molecular Structure 1125 (2016) 370e373

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Chemistry, Shenyang Pharmaceutical University, Shenyang, China. 2.3. Extraction and isolation Air-dried roots of C. wilfordii (20 kg) were extracted three times by 95% ethanol (3 100 L) after refluxing for 3 h. The combined EtOH extracts were concentrated in vacuo to yield a residue (920 g), which was suspended in water and extracted successively with light-petroleum, chloroform, ethyl acetate and n-butyl alcohol. Part of the ethyl acetate extract was subjected to column chromatography over silica gel and using a CHCl3 e MeOH gradient (from 100:0 / 94:6 v/v) to afford 76 mg of baishouwubenzophenone. 2.4. Computational details Fig. 1. Structures of baishouwubenzophenone and its analogs.

Fig. 2. Possible configurations of 1, hydrogen atoms are omitted.

dichroism (ECD), and theoretical calculations.

The conformational searching was performed using the Spartan 08 program with the MMFF94. Then all of the possible conformers were optimized at B3LYP level of theory using 6-311 þ G(d, p) basis sets. Relative population of each conformer was valued on the basis of Boltzmann weighting factor at 298 K. The geometries used for the ECD calculation are optimized by DFT calculations at the B3LYP/6-311 þ G(d, p) levels. The ECD were then simulated by the TDDFT method at the level of CAM-B3LYP/ TZVP. ECD curves were generated by Specdis using half bandwidth of 0.25 eV. To generate the final spectrum of ECD, all the simulated spectra of the lowest energy conformations were averaged according to the Boltzmann distribution theory in which their Gibbs free energy (G) was adopted.

2. Experimental details 3. Results and discussion

2.1. General remarks Column chromatography: Silica gel (200e300 mesh; Qingdao Marine Chemical Group, Co.); ODS (30e50 mm; YMC CO. Ltd. Japan). Mass spectra were recorded on Varian QFT-ESI and Bruker microTOFQ-Q mass spectrometer (for HR-ESIMS). NMR spectra were recorded on Bruker AV-300 and Bruker AV-600 spectrometers (Bruker, Germany), TMS as internal standard, d in ppm, J in Hz; CD spectrum were gotten on Biologic MOS-450 CD spectrometer. 2.2. Plant material The roots of C. wilfordii were purchased from Changfu medicines Ltd (Anhui), China, in July 2007 and identified by Prof. Qishi Sun of Shenyang Pharmaceutical University. The voucher sample (WF20070713) was deposited in the Department of Natural Products

3.1. Structure confirmation Baishouwubenzophenone (1) was obtained as colorless needles, [[a]D ¼ 30 (c ¼ 0.1 M, MeOH)]. The molecular formula of 1 was determined as C16H14O6 by its HR-ESI-MS (m/z 301.0710 [M H]-, calcd for C16H13O6 301.0712). The UV absorption at 285 nm suggesting the existence of phenolic hydroxyl chromophore, The IR bands at 3442, 3419, 2926, 2856, 1629 and 1620 cm1 suggested the presence of OH, CH3 and carbonyl chromophore. The 1H NMR spectrum (300 MHz, DMSO-d6) showed the presence of two methyls at dH 2.21 (3H, s, phenyl-CH3) and 2.52 (3H, s, COCH3), four protons of aromatic ring at dH 6.44 (1H, d, J ¼ 9 Hz, H-5), 6.75 (1H, d, J ¼ 8.7 Hz, H-30 ), 6.69 (1H, J ¼ 8.7 Hz, H-40 ), 7.71 (1H, d, J ¼ 8.9 Hz, H4), four hydroxyl group at dH 8.50 (1H, s, C50 eOH), 9.31 (1H, s, C6eOH), 10.30 (1H, s, C20 eOH), 12.88 (1H, s, C2eOH). The 13C NMR

Fig. 3. Relatively stable conformers of R and S configurations.

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Table 1 Relative free energies and populations of the conformations of R and S. conformera DG (kcal mol1) P%

S-1 S-2 S-3 S-4 R-1 R-2 R-3 R-4 a

0 0.31 0.50 0.63 0 0.31 0.50 0.63

42.2 25.0 18.2 14.6 42.2 25.0 18.2 14.6

m

4.659 4.910 7.442 4.157 4.659 4.910 7.442 4.158

Dihedral ( ) C2eC1eC7eC10

C1eC7eC10 eC60

26.9 9.4 27.9 12.7 26.9 9.4 27.9 12.7

40.9 113.2 38.1 119.5 40.9 71.8 38.1 65.6

See Fig. 3 for the structures of the conformers.

(150 MHz, DMSO-d6) showed the presence of two methyls signals at dC 26.26 (C-9), 30.78 (C-10), two conjugated carbonyls at dC 203.13 (C-8) and 203.24 (C-7), two aromatic group skeletons at dC 107.57 (C-5), 111.58 (C-1), 112.42 (C-3), 115.86 (C-10 ), 117.45 (C-30 ), 118.20 (C-40 ), 130.26 (C-60 ), 132.29 (C-4), 147.04 (C-20 ), 148.03 (C-50 ), 162.36 (C-6), 162.57 (C-2). Based on the aforementioned analysis and literature values [3], compound 1 was identified as baishouwubenzophenone. 3.2. Conformational analyses Due to the sterically restricted rotation of the two substituted phenyl ring, there existed two possible configurations for baishouwubenzophenone: R or S configuration (Fig. 2). To identify the AC of the compound, ECD spectrum analysis and theoretical calculation were employed here. Because of the conformational characteristic of a molecule can significantly affect its chiroptical properties at the working temperature; thence, it is necessary to perform conformational search before ECD calculation to define the stable conformers. Initial conformational searches for R and S configurations were carried out using Monte Carlo searching together with the MMFF94 [19]. Conformers occurring within 4 kcal/mol energy window from the particular global minimum were chosen for further geometrical optimization and energy calculation at the DFT/B3LYP/6-311 þ G** level of theory under polarizable continuum model (PCM) [20,21] in the program package Gaussian 09 [22]. Four stable low-energy conformations of S configurations and R configurations were obtained, respectively (Fig. 3 and Table 1). The gross conformational changes for the two possible configurations are mainly by the rotations of the single bonds connecting the two phenyl ring, or rather, the changes of dihedral angles

C2eC1eC7eC10 and C1eC7eC10 eC60 . S-1 is more stable than S-2, which may be due to the intramolecular hydrogen bonds (HB) shown in Fig. 3. The bond length of HB1 HB2 and HB3 in S-1 is 1.67, 1.81 and 1.60 Å, respectively; whereas, only two HBs are in S-2, well within the range of 5%) for the referred MO have been listed in Table S1. In addition, baishouwubenzophenone molecule contains two

Fig. 4. (A) Experimental ECD of baishouwubenzophenone, and simulated ECDs for R and S configurations. (B) Application of the CD ECM to baishouwubenzophenone.


individual chromophores (two phenyl rings), which are likely to interact via exciton coupling, therefore the experimental ECD may be explained by exciton chirality method (ECM) that is widely used in ECD analysis. The ECM enables one to determine the AC in a nonempirical manner without reference [27]. As inferred from the ECD theoretical result, the first positive CE at 308 nm and the second negative CE at 336 nm in the experimental spectrum could be regarded as the so called bisignate CEs, which may be derived from a slight exciton coupling of the two phenyl rings, although the first positive CE is so weak. The negative exciton chirality (72) gives compound 1 an S configuration (Fig. 4B), which is consistent with the conclusion obtained from ECD theoretical calculations. 4. Conclusions This article reports the structural identification of baishouwubenzophenone, a unique atropisomer. The planar structure was confirmed by comparing its NMR data with the literature and the AC was determined by experimental ECD and quantum chemical calculations. The result showed that baishouwubenzophenone possessed an S configuration. The AC was further confirmed by exciton chirality method. The unique atropisomeric feature and multiple hydroxyl groups in baishouwubenzophenone molecule would allow it to be potential as an atropisomeric ligand in asymmetric synthesis. Acknowledgments Financial support of this research was provided by the Program for Innovative Research Team of the Ministry of Education, Program for Liaoning Innovative Research Team in University, Key Projects of the National Science and Technology Pillar Program (2012BAI30B02), National Natural Science Foundation (U1170302, 81303270) and Shenyang pharmaceutical university scientific research fund (ZCJJ2013407). The theoretical calculations were conducted on the ScGrid and Deepcomp7000 the Supercomputing Center, Computer Network Information Center of Chinese Academy of Sciences. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.molstruc.2016.07.008. References [1] Y. Jiang, H.G. Choi, Y. Li, Y.M. Park, J.H. Lee, D.H. Kim, J.-H. Lee, J.K. Son, M. Na, S.H. Lee, Chemical constituents of Cynanchum wilfordii and the chemotaxonomy of two species of the family Asclepiadacease, C. wilfordii and C. auriculatum, Arch. Pharmacal. Res. 34 (2011) 2021e2027. [2] L. Shan, R.-H. Liu, Y.-H. Shen, W.-D. Zhang, C. Zhang, D.-z. Wu, L. Min, J. Su, X.K. Xu, Gastroprotective effect of a traditional Chinese herbal drug “Baishouwu” on experimental gastric lesions in rats, J. Ethnopharmacol. 107 (2006) 389e394. [3] S. Gong, C. Liu, S. Liu, Y. Du, W. Kang, X. Dong, Studies on constituents of chinese traditional drug baishouwu (cynanchum auriculatum royle ex wight),

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