Sweritranslactones A–C: Unusual Skeleton Secoiridoid Dimers via [4

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Cite This: J. Org. Chem. 2017, 82, 13263−13267

Sweritranslactones A−C: Unusual Skeleton Secoiridoid Dimers via [4 + 2] Cycloaddition from Swertiamarin Lu Liu,#,† Guan-Ling Xu,#,† Xiao-Xia Ma,#,† Afsar Khan,‡ Wen-Hong Tan,† Zhu-Ya Yang,† and Zhi-Hong Zhou*,† †

Yunnan Key Laboratory of Dai and Yi Medicines, Yunnan University of Traditional Chinese Medicine, Kunming 650500, People’s Republic of China ‡ Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan S Supporting Information *

ABSTRACT: Skeleton-diversity-oriented chemical conversion from pure natural products is a valuable method to obtain natural product-like compounds, especially those with novel architecture. The application of phytochemical methods to iridoids yielded three novel secoiridoid dimers: sweritranslactones A−C (1−3). These molecules possess a 6/6/6/6/6/6-fused hexacyclic skeleton and were obtained from swertiamarin, one of the major constituents of the genus Swertia, via a [4 + 2] cycloaddition and intramolecular nucleophilic addition under aqueous conditions. The structures were established based on extensive spectroscopic characterization and X-ray crystallographic diffraction analysis.

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INTRODUCTION Limited sources of bioactive compounds is a critical restriction in biological research and drug discovery.1,2 Natural products, especially those possessing novel skeletons, are recognized as “privileged structures” in the drug discovery process3 due to their possession of multiple chiral centers, fused polycyclic systems, multiple degrees of unsaturation, or the inclusion of heteroatoms. However, novel compounds are not easy to obtain using traditional phytochemical methods. Many approaches have been used to obtain privileged structures, including the diversity-oriented chemical modification of natural extracts.4−6 In general, natural extracts have common characteristics, including sharing similar functional groups for addition reactions7 or the Mannich reaction.8 Previous reports have described the chemical synthesis of novel dimers using nonenzyme-mediated dimerization.9 Secoiridoids contain alkene, carbonyl, and hydroxyl groups,10 rendering them amenable to hydrolysis, keto−enol tautomerism, and nucleophilic addition reactions. The secoiridoid swertiamarin, one of the major constituents isolated from the genus Swertia, has shown various biological activities.11,12 It can be transformed chemically into a conjugated diene and can be subjected to [4 + 2] cycloaddition to produce diverse novel skeletons upon heating in water. On the basis of the above hypothesis, we subjected swertiamarin to boiling water for 6 h, until the starting material could not be detected by HPLC. Investigations of the transformed products led to the isolation of three secoiridoid dimers with novel skeletons: sweritranslactones A−C (1−3) (Figure 1). These compounds possess © 2017 American Chemical Society

Figure 1. Structures of compounds 1−3.

6/6/6/6/6/6-fused hexacyclic skeletons from [4 + 2] cycloaddition and intramolecular nucleophilic addition reactions. Their structures were established based on extensive spectroscopic methods and X-ray crystallographic diffraction analysis. Plausible transformation pathways of the novel compounds are also proposed.

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RESULTS AND DISCUSSION Sweritranslactone A (1) was obtained as colorless cubic crystals (acetone). Its molecular formula was determined to be C19H20O7 by HREIMS at m/z 360.1215 [M]+ (calcd for C19H20O7, 360.1204) with ten double bond equivalents. The IR spectrum revealed the presence of double bond (1618 and 1402 cm−1) and lactone carbonyl (1710 cm−1) groups. The 13C Received: September 21, 2017 Published: November 16, 2017 13263

DOI: 10.1021/acs.joc.7b02383 J. Org. Chem. 2017, 82, 13263−13267

Article

The Journal of Organic Chemistry Table 1. 13C (150 MHz) and 1H (600 MHz) NMR Spectroscopic Data of 1−3 (chloroform-d1) 1

2

3

no.

δC, type

δH (J in Hz)

δC, type

δH (J in Hz)

δC, type

δH (J in Hz)

1 3 4 5 6

96.3, CH 64.1, CH 131.6, C 152.6, C 25.7, CH2

5.81, s, 1H 4.89, d (3.6, 1H)

64.6, CH 67.1, CH 52.9, C 140.1, C 24.4, CH2

4.71, overlap 4.71, overlap

72.5, CH 64.1, CH 133.1, C 150.3, C 24.0, CH2

4.06, brs, 1H 4.86, d (6.0, 1H)

7 8 9 10

66.2, 73.4, 49.1, 17.7,

11 3′ 4′ 5′ 6′

160.6, C 154.6, CH 106.8, C 71.2, C 33.8, CH2

7′ 8′ 9′ 10′

63.6, 27.5, 39.3, 32.5,

11′

163.5, C

CH2 CH C CH3

CH2 CH CH2 CH2

2.90, dt (14.4, 5.2, 1H), 2.56, dt (14.4, 5.2, 1H) 4.52, t (5.2, 2H) 3.97, q (6.4, 1H) 0.97, d (6.4, 3H)

7.85, s, 1H

2.24, dd (13.2, 5.2, 1H), 1.95, dd (13.6, 3.2, 1H) 4.46, dd (13.2, 5.2, 1H), 4.40, m, 1H 2.35, m, 1H 1.92, d (3.2, 1H), 1.17, t (12.0, 1H) 2.26, m, 1H, 1.02, d (3.6, 1H)

66.0, CH2 130.2, CH 124.6, C 114.7, CH2

2.94, m, 2H 4.42, m, 2H 6.69, dd (11.2, 17.6, 1H) 5.28, d (11.1, 1H), 5.20, d (17.6, 1H)

66.0, CH2 139.0, CH 50.6, C 118.7, CH2

170.6, C 69.1, CH 128.6, C 155.4, C 26.0, CH2

2.73, m, 2H

162.7, C 69.3, CH 130.7, C 155.8, C 25.9, CH2

66.6, 65.4, 42.2, 35.1,

5.52, 3.80, 2.97, 2.19,

66.7, 66.0, 42.9, 35.6,

CH2 CH CH CH2

4.95, s, 1H

m, m, m, m,

161.1, C

1H, 5.49, m, 1H 1H 1H 2H

CH2 CH CH CH2

2.53, t (6.0, 2H) 4.41, overlap, 2H 5.76, dd (10.8, 17.6, 1H) 5.28, d (10.9, 1H), 5.18, d (17.6, 1H)

4.76, s, 1H

2.71, t (6.4, 2H) 4.50, m, 2H 3.79, brs, 1H 2.91, t (2.4, 1H) 2.27, dd (6.0, 14.4, 1H), 2.16, dd (3.0, 14.4, 1H)

161.4, C

and C-5′ were linked by an oxygen bridge. The HMBC correlations of H-8 with C-1, C-8′, C-3 (δC 64.1), and C-5 (δC 152.6); of H3-10 with C-9; and of H-3 with C-5 led to the establishment of D and E rings, among which C-3 and C-8 were linked by an oxygen bridge. The presence of the F ring was identified by cross peaks of H2-7 with C-11 (δC 160.6), of H2-6 with C-4 (δC 131.6), and of H-3 with C-11. Thus, the planar structure of 1 was established as a secoiridoid dimer derivative with a 6/6/6/6/6/6-fused hexacyclic architecture together with an oxygen bridge, a carbon−oxygen bridge, and two δ-lactone rings, which is unprecedented. The two chiral quaternary carbons in the structure of compound 1 and the lack of effective correlations in the ROESY spectrum resulted in a failure to elucidate the relative configuration of 1. However, colorless cubic crystals of 1 were obtained in acetone, which enabled successful X-ray crystallographic analysis. The crystallographic data (CCDC 946642) of 1 corroborated the planar structure and clarified the relative configuration of 1 (Figure 2) as 1S*,3R*,8R*,9R*,5′S*,8′S*. Sweritranslactone B (2), colorless cubic crystals (acetone), was assigned the molecular formula C19H18O6 based on its molecular ion peak in HREIMS at m/z 342.1095 [M]+ (calcd 342.1098) with 11 double bond equivalents. The 13C NMR and DEPT data (Table 1) revealed 19 carbon resonance signals, containing six methylenes (one terminal alkene carbon), six tertiary carbons (five sp3 carbons and one sp2 carbon), and seven quaternary carbons (two lactone carbons, four double bond carbons, and one sp3 carbon). The remaining six degrees of unsaturation were indicative of a hexacyclic ring system. In the 1H−1H COSY spectrum, the cross peaks of H-3 (δH 4.71)/H-9′ (δH 2.97)/H-8′ (δH 3.80)/H2-10′ (δH 2.19)/H-1 (δH 4.71), H2-6 (δH 2.94)/H2-7 (δH 4.42), H-8 (δH 6.69)/H210 (δH 5.28, 5.20), and H2-6′ (δH 2.73)/H2-7′ (δH 5.52/5.49) suggested the existence of four isolated spin systems: (C-3/C9′/C-8′/C-10′/C-1), (C-6/C-7), (C-8/C-10), and (C-6′/C-7′) (Figure 3). In the HMBC spectrum, the correlations of H2-7

NMR and DEPT data (Table 1) revealed 19 carbon resonance signals due to one methyl, six methylenes, five tertiary carbons (four sp3 carbons and one sp2 carbon), and seven quaternary carbons (two lactone carbons, three double bond carbons, and two sp 3 carbons). The aforementioned functionalities accounted for four double bond equivalents, suggesting that compound 1 possessed a hexacyclic skeleton. Detailed interpretation of 2D NMR spectroscopic data, including 1H−1H COSY, HSQC, and HMBC, enabled the establishment of the planar structure of 1. In the 1H−1H COSY spectrum, cross peaks of H2-7′ (δH 4.46, 4.40)/H2-6′ (δH 2.24, 1.95), H2-9′ (δH 1.92, 1.17)/H-8′ (δH 2.35)/H2-10′ (δH 2.26, 1.02)/H-3 (δH 4.89), H2-6 (δH 2.90, 2.56)/H2-7 (δH 4.52), and H-8 (δH 3.97)/H3-10 (δH 0.97) suggested the presence of four key fragments: (C-7′/C-6′), (C-9′/C-8′/C-10′/C-3), (C-6/C7), and (C-8/C-10) (Figure 2). In the HMBC spectrum, the correlations of H2-7′ with C-11′ (δC 163.5); of H2-6′ with C-4′ (δC 106.8); of H2-9′ with C-6′ (δC 33.8), C-4′, and C-9 (δC 49.1); of H-8′ with C-1 (δC 96.3); and of H-1 (δH 5.81) with C-8′ (δC 27.5), C-5′ (δC 71.2), and C-3′ (δC 154.6) indicated the presence of A, B, and C rings (Figure 2), among which C-1

Figure 2. Key HMBC and 1H−1H COSY correlations and ORTEP drawing of 1. 13264

DOI: 10.1021/acs.joc.7b02383 J. Org. Chem. 2017, 82, 13263−13267

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The Journal of Organic Chemistry

Figure 4. Key HMBC and 1H−1H COSY correlations and ORTEP drawing of 3.

with C-3′ (δC 69.3) demonstrated the existence of rings D, E, and F, among which one oxygen bridge linked C-3′ and C-8′. As was seen in 2, the ethenyl group located at C-9 was corroborated by the HMBC correlations of H2-10 with C-9 and of H-8 with C-1 (δC 72.5). Therefore, the planar structure of 3 was elucidated as a novel-skeleton 6/6/6/6/6/6-fused hexacyclic secoiridoid dimer derivative. As for 2, the ROESY spectrum failed to establish the relative configuration of 3. However, colorless cubic crystals of 3 were obtained successfully in acetone. Subsequent X-ray crystallographic analysis (CCDC 1048152) confirmed the relative configuration of 3 as 1S*,3R*,9S*,3′S*,8′R*,9′R*. The plausible transformation pathways of 1−3 from swertiamarin are presented in Scheme 1. Under heating conditions, swertiamarin can undergo selective hydrolysis, decarboxylation, and keto−enol tautomerism equilibrium reactions to produce four key intermediates: X11, X12, X21 and X22. A [4 + 2] cycloaddition13,14 between a conjugated diene and a substituted dienophile formed a substituted cyclohexene system upon heating. Compound 1 can be formed from X11 and X21 via double [4 + 2] cycloaddition and intramolecular nucleophilic addition. Compounds 2 and 3 can be produced by the reactions of X21 and X11, as well as X22 and X12, via a [4 + 2] cycloaddition, intramolecular nucleophilic addition, and intramolecular dehydration. It is noteworthy that natural product-like novel molecular skeletons can be obtained from swertiamarin, an easily accessed molecule isolated from the genus Swertia. The structure of swertiamarin suggested that heating would effect a [4 + 2] cycloaddition to generate a cyclohexene ring system. Combined with the characteristic hydroxyl, carbonyl, and poly double bonds, these experiments resulted in further chemical skeleton diversity, leading to the isolation of the three novel skeletons of sweritranslactones A−C (1−3). The structures of these compounds were established on the basis of extensive 1D and 2D NMR techniques, as well as X-ray crystallographic diffraction analysis. Similar methods can be applied to compounds possessing characteristic chemical reactivity to generate diverse natural product-like compounds.

Figure 3. Key HMBC and 1H−1H COSY correlations and ORTEP drawing of 2.

with C-11 (δC 170.6), of H2-6 with C-4 (δC 52.9) and C-9 (δC 124.6), of H-3 with C-11 and C-5 (δC 140.1), and of H-1 with C-5 and C-3 (δC 67.1) led to the identification of rings A, B, and C (Figure 3). Simultaneously, one oxygen bridge was found between C-1 and C-3. The HMBC correlations of H-3 with C-3′ (δC 69.1) and C-5′ (δC 155.4), of H-3′ with C-5′ and C-11′ (δC 161.1), of H-8′ with C-5′, of H-7′ with C-11′, and of H2-6′ with C-4′ (δC 128.6) and C-9′ (δC 42.2) indicated the presence of rings D/E and F. The oxygen bridge between C-3′ and C-8′ was supported by the HMBC correlations of H-3′ with C-8′ (δC 65.4) and of H-8′ with C-3′. Furthermore, an ethenyl group was proposed at C-9, which was verified by HMBC correlations of H2-10 with C-9 and of H-8 with C-1 (δC 64.6). Hence, the planar structure of 2 was elucidated as a secoiridoid dimer derivative possessing a novel 6/6/6/6/6/6fused hexacyclic skeleton with two oxygen bridges. The relative configuration of 2 was established by X-ray crystallography due to a lack of evidence from the ROESY spectrum. The crystallographic data (CCDC 1048153) of 2 supported the planar structure and elucidated the relative configuration of 2 (Figure 3) as 1S*,3R*,4S*,3′S*,8′S*,9′S*. Sweritranslactone C (3) shared the molecular formula of 2, C19H18O6, as obtained by the HREIMS ion peak at m/z 342.1097 [M]+ (calcd 342.1098). The 13C NMR and DEPT data (Table 1) revealed similar carbon types in 3 as those in 2, with minor differences in the chemical shifts in the 13C NMR spectrum. Comprehensive interpretation of the 2D NMR spectroscopic data permitted the establishment of the planar structure of 3, another novel skeleton with different bond topology compared to 2. The 1H−1H COSY correlations of H-3 (δH 4.86)/H2-10′ (δH 2.27, 2.16)/H-8′ (δH 3.79)/H-9′ (δH 2.91)/H-1 (δH 4.06), H26 (δH 2.53)/H2-7 (δH 4.41), H2-6′ (δH 2.71)/H2-7′ (δH 4.50), and H-8 (δH 5.76)/H2-10 (δH 5.28, 5.18) suggested the presence of four isolated spin systems: (C-3/C-10′/C-8′/C-9′/ C-1), (C-6/C-7), (C-6′/C-7′), and (C-8/C-10) (Figure 4). Rings A, B, and C were revealed by the HMBC correlation of H2-7 with C-11 (δC 162.7), of H2-6 with C-4 (δC 133.1) and C9 (δC 50.6), of H-3 with C-11 and C-5 (δC 150.3), and of H-1 with C-5 and C-3 (δC 64.1). Similarly, an oxygen bridge was proposed between C-1 and C-3 based on the above correlations. Furthermore, the correlations of H2-7′ with C11′ (δC 161.4) and C-5′ (δC 155.8); of H2-6′ with C-4′ (δC 130.7) and C-9′ (δC 42.9); of H-3′ with C-5′, C-8′ (δC 66.0), and C-11′; of H-9′ with C-4′ and C-6′ (δC 25.9); and of H-1

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EXPERIMENTAL SECTION

General Experimental Procedures. Optical rotations were measured on a JASCO P-1020 polarimeter. All the 1D and 2D NMR spectra were recorded on Bruker DRX-400 spectrometer. HREI-MS analyses were carried out on Waters AutoSpec Premier P776 mass spectrometer. Silica gel (100−200 and 200−300 mesh, Qingdao Marine Chemical Co., Ltd., China) was used for column chromatography. Fractions were monitored by TLC (GF 254, Qingdao Marine Chemical Co., Ltd.), and spots were visualized by 10% H2SO4/EtOH reagent.

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The Journal of Organic Chemistry Scheme 1. Proposed Transformation Pathways of Compounds 1−3 from Swertiamarin

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Preparation of Diversity-Skeleton Molecules from Swertiamarin and Isolation. The mixture of swertiamarin (120 g) and water (350 g) was heated under reflux conditions for 6 h to obtain aqueous mixture (300 g) and precipitation fraction (16 g). The precipitation fraction (10 g) was subjected to medium pressure liquid chromatography column with gradient elution (MeOH/H2O, v/v, from 50% to 100% MeOH) to get five fractions A−E on the basis of TLC detection. Fr. C (0.7 g) was chromatographed on a silica gel column (10 g) to yield 15 subfractions (Fr. C1−C15). Fr. C10 (0.3 g) was subjected to silica gel chromatography (2 g) to get compound 1 (3 mg). Compound 2 (5 mg) was obtained from Fr. D (0.26 g) by silica gel chromatography and preparative TLC, respectively. Fr. E (0.2 g) was chromatographed on a silica gel column (10 g) to get 8 subfractions (Fr. E1-E8), and then Fr. E5 was further purified by preparative TLC to yield compound 3 (3 mg). Sweritranslactone A (1). Colorless cubic crystals (acetone); mp = 182−183 °C; [α]18D −12.5 (c 0.20, acetone); 1H and 13C NMR data: see Table 1; HR-EI-MS m/z 360.1215 [M]+ (calcd for C19H20O7, 360.1204). Sweritranslactone B (2). Colorless cubic crystals (acetone); mp = 213-214 °C; [α]18D −5.7 (c 0.30, acetone); 1H and 13 C NMR data: see Table 1; HR-EI-MS m/z 342.1095 [M]+ (calcd for C19H18O6+, 342.1098). Sweritranslactone C (3). Colorless cubic crystals (acetone); mp = 220−221 °C; [α]17D −3.9 (c 0.34, CHCl3); 1H and 13 C NMR data: see Table 1; HR-EI-MS m/z 342.1097 [M]+ (calcd for C19H18O6+, 342.1098).

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02383. The details of isolation and experimental procedures and original MS and NMR spectra (PDF) Crystallographic file for 1 (CIF) Crystallographic file for 2 (CIF) Crystallographic file for 3 (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Zhi-Hong Zhou: 0000-0003-2144-2804 Author Contributions #

These authors contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The work was financially supported by the National Science Foundation (NSF) of China (no. 81060338), the Project of 13266

DOI: 10.1021/acs.joc.7b02383 J. Org. Chem. 2017, 82, 13263−13267

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The Journal of Organic Chemistry Scientific Research Fund of Yunnan Provincial Education Department (no. 2017ZZX290), the NSF of Yunnan Province (no. 2010CD072), the key laboratory training program in Yunnan (2017DG006), and the key Project of Applied Basic Research of Yunnan Province (no. 2013FA040).

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REFERENCES

(1) Harvey, A. L. Drug Discovery Today 2008, 13, 894. (2) Cragg, G. M.; Grothaus, P. G.; Newman, D. J. Chem. Rev. 2009, 109, 3012. (3) Ramallo, I. A.; Salazar, M. O.; Mendez, L.; Furlan, R. L. E. Acc. Chem. Res. 2011, 44, 241. (4) Chen, Y.-H.; Sun, X.-L.; Guan, H.-S.; Liu, Y.-K. J. Org. Chem. 2017, 82, 4774. (5) Yuan, P.; Liu, X.; Yang, X.; Zhang, Y.; Chen, X. J. Org. Chem. 2017, 82, 3692. (6) Galloway, R. W. R. J. D.; Isidro-Llobet, A.; Spring, D. R. Nat. Commun. 2010, 1, 80. (7) Lindner, S.; et al. Chem. Biol. 2014, 21, 1452. (8) Heravi, M.; et al. Curr. Org. Chem. 2014, 18, 2857. (9) Wang, T.; Hoye, T. R. Nat. Chem. 2015, 7, 641. (10) Dinda, B.; Debnath, S.; Harigaya, Y. Chem. Pharm. Bull. 2007, 55, 689. (11) Patel, T. P.; Soni, S.; Parikh, P.; Gosai, J.; Chruvattil, R.; Gupta, S. J. Evidence-Based Complementary Altern. Med. 2013, 2013, 358673. (12) Vaidya, H. B.; Goyal, R. K.; Cheema, S. K. J. Pharmacol. Pharmacother. 2014, 5, 232. (13) Yang, X.-W.; Li, Y.-P.; Su, J.; Ma, W.-G.; Xu, G. Org. Lett. 2016, 18, 1876. (14) Zhao, N.; Ren, X.; Ren, J.; Lü, H.; Ma, S.; Gao, R.; Li, Y.; Xu, S.; Li, L.; Yu, S. Org. Lett. 2015, 17, 3118.

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DOI: 10.1021/acs.joc.7b02383 J. Org. Chem. 2017, 82, 13263−13267