Hedychins A and B, 6,7-Dinorlabdane Diterpenoids with a Peroxide

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Letter Cite This: Org. Lett. 2018, 20, 704−707

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Hedychins A and B, 6,7-Dinorlabdane Diterpenoids with a Peroxide Bridge from Hedychium forrestii Qing Zhao,† Jie-Jie Gao,† Xu-Jie Qin,‡ Xiao-Jiang Hao,*,‡ Hong-Ping He,*,†,‡ and Hai-Yang Liu*,‡ †

Yunnan University of Traditional Chinese Medicine, Kunming 650500, China State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China

‡

S Supporting Information *

ABSTRACT: Hedychins A (1) and B (2), two unprecedented 6,7-dinorlabdane ditepenoids with a peroxide bridge, were obtained from the rhizomes of Hedychium forrestii. Their structures and absolute configurations were unequivocally established by a combination of spectroscopic data and X-ray single-crystal diffractions. Their plausible biosynthetic pathway was proposed. Compound 2 exhibited cytotoxicity against HepG2 and XWLC-05 cell lines with IC50 values of 8.0 and 19.7 μM, respectively.

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pecies of the genus Hedychium (Zingiberaceae) have been proven to be a rich source of diverse diterpenoids, some of which exhibited various biological effects, such as cytotoxic, anti-inflammatory, and antibacterial activities.1 Hedychium forrestii Diels is widely distributed in some provinces in south China.2 Its rhizomes can be used as folk medicine for the treatment of dyspepsia, gastrofrigid, metrorrhagia, menoxenia, headache, rheumatic pain and other diseases in Southeast China.3 Our previous investigations involving Hedychium genus resulted in a number of labdane-type diterpenoids, such as yunnancoronarins A−C, villosumcoronarin, hedychenone, and 7-hydroxyhedychenone.4 Among these diterpenoids, yunnancoronarins A−C showed significant cytotoxic activities to A549, K562, and KB cell lines.4b,d Furthermore, yunnancoronarin A has an inhibitory ratio of 54.27% to H22 tumors in ICR mice at the dosage of 50 mg/kg/day for 7 days.4f As a part of our continuous effort to search for more bioactive molecules from Hedychium genus, the rhizomes of H. forrestii collected from Yunnan Province of China were investigated, and this has led to two novel dinorlabdane diterpenoids, hedychins A (1) and B (2) (Figure 1). Although labdane-type norditerpenoids with the loss of the carbons from the side chain at C-9 were quite common,5 this is the first example of the degradation of their C-6 and C-7 replaced by the construction of a peroxide bridge in both 1 and 2, which links C-5 and C-8. Compound 2 showed certain cytotoxic activity against HepG2 and XWLC-05 cell lines. Herein, the details of the structural elucidation and bioactivities of these isolates are described. Hedychin A (1), [α]22 D = +132.2 (MeOH, c 2.1), was isolated as colorless needle crystals (PE/acetone, 3:1, v/v). It displayed positive color reaction to Huber and Fröhlke reagent for peroxides on TLC.6 Furthermore, compound 1 contained a furanoid fragment based on a positive Ehrlich test.7 Its © 2018 American Chemical Society

Figure 1. Structures of 1 and 2.

molecular formula was determined to be C18H26O5 by HREIMS data (m/z 322.1775 [M]+; calcd for 322.1780), requiring six indices of hydrogen deficiency (IHD). Its IR spectrum revealed the presence of β-substituted furan rings (1504 and 876 cm−1).8 The 1H NMR spectrum of 1 displayed monosubstituted furan ring protons at δH 6.48 (H-14, br s), 7.51 (H-15, br s), and 7.52 (H-16, br s), four methyls linked to quaternary carbon at δH 1.29 (H-17, s), 1.06 (H-18, s), 0.93 (H-19, s), and 1.57 (H-20, s), and three oxymethines at δH 3.53 (s, H-5), 4.76 (H-11, dd, J = 8.0, 6.9 Hz), and 4.99 (H-12, d, J = 8.0 Hz). The 13C NMR and HSQC spectra showed 18 carbons, including a monosubstituted furan ring [δC 128.5 (s, C-13), 109.5 (d, C-14), 140.1 (d, C-15), and 144.2 (d, C-16)], four methyls [δC 27.6 (q, C-17), 33.2 (q, C-18), 21.2 (q, C-19), and 15.6 (q, C-20)], and three oxymethines [δC 92.3 (d, C-5), 79.1 (d, C-11), and 77.2 (d, C-12)], together with a ketal carbon (δC Received: December 8, 2017 Published: January 17, 2018 704

DOI: 10.1021/acs.orglett.7b03836 Org. Lett. 2018, 20, 704−707

Letter

Organic Letters 109.4, s, C-8). The above-mentioned information accounted for three out of the required six IHDs, and 1 was thus proposed to have another bicyclic system. 1 should be a labdane-type dinorditerpenoid according to the fact that a series of diterpenoids have been reported from the genus Hedychium. Table 1. 1H (500 MHz) and 13C (125 MHz) NMR Data of 1 in Acetone-d6 and 2 in Methanol-d4 1

2

no.

δH (mult., J in Hz)

δC

δH (mult., J in Hz)

δC

Figure 3. Key ROESY correlations of 1 and 2.

1α 1β 2α 2β 3α 3β 4 5 8 9 10 11 12 13 14 15 16 17 18 19 20

1.17 2.26 1.30 1.66 1.35 1.46

38.9

2.06 1.23 1.49 1.76 1.37 1.21

35.1

with H-9 suggested that the two protons were α-oriented, and rings A and B of 1 were trans-fused. Also, ROESY correlations of H-9α with H3-17 and H-11 suggested these protons were cofacial. Fortunately, the single crystals of 1 were obtained in petroleum ether/acetone (3:1, v/v) and then subjected to an Xray diffraction experiment (CCDC 907918) with Cu Kα radiation, which further confirmed the structure and absolute configuration of 1 (Figure 4).

(m) (m) (m) (m) (m) (m)

3.53 (s) 2.00 (d, 6.9) 4.76 (dd, 8.0, 6.9) 4.99 (d, 8.0) 6.48 7.51 7.52 1.29 1.06 0.93 1.57

(br s) (br s) (br s) (s) (s) (s) (s)

18.3 41.2 34.7 92.3 109.4 56.5 37.9 79.1 77.2 128.5 109.5 140.1 144.2 27.6 33.2 21.2 15.6

(m) (m) (m) (m) (m) (m)

4.12 (s) 1.87 (d, 4.5) 4.31 (dd, 4.5, 3.1) 4.96 (d, 3.1) 6.50 7.49 7.45 1.70 1.00 1.08 1.40

(d, 1.2) (br s) (d, 1.2) (s) (s) (s) (s)

19.5 35.4 35.6 90.1 109.9 58.9 38.3 76.4 79.3 123.0 111.4 142.1 143.9 25.0 30.4 28.0 23.2

The planar structure of 1 was established by its 1H−1H COSY and HMBC experiments (Figure 2). The 1H−1H COSY

Figure 4. Crystal structure of 1.

Hedychin B (2), [α]17 D = −16.8 (MeOH, c 2.45), was obtained as a colorless block (methanol−water, 2:1, v/v). It had the same molecular formula (C18H26O5) as that of 1 by HRESI-MS. Detailed analysis of 1H−1H COSY, HMQC, and HMBC spectra of 2 indicated that its planar structure was identical with that of 1, except for the β-configuration of H-5. This was further supported by the ROESY correlation of H320β with H-5 (Figure 3). Finally, the structure and relative configuration of 2 was unambiguously determined by X-ray crystallography (CCDC 907917) using Cu Kα radiation (Figure 5). Hedychins A (1) and B (2) represent an unprecedented 6,7dinorlabdane ditepenoid skeleton conjugated with a peroxide bridge, which aroused our interest in their plausible biogenesis. Biosynthetically, compounds 1 and 2 may be biogenetically derived from a labdane-type diterpenoid, 7-hydroxyhedychenone (3), which was obtained from H. forrestii as an abundant component (Scheme 1).4b In brief, the epoxidation of the double bond between C-11 and C-12 in 3 could give 3a, which is further enolized to 3b. Then, 3b is oxidized by singlet oxygen to give key intermediate 3c, which contains a peroxy bridge. 3c is isomerized to 3d, which undergoes Baeyer−Villiger oxidation to get 3e. 3e undergoes oxidation at C-6 and ring-opening reaction to get 3f, whose hydroxy group at C-8 attacks C-12 followed by ring opening of the epoxide group to obtain 3h. 3h is subsequently transformed into 3i by pyruvate decarboxylase. Finally, 3i is decarboxylated to yield 1 and 2, in which the

Figure 2. 1H−1H COSY and key HMBC correlations of 1 and 2.

spectrum revealed three spin systems (C-1−C-2−C-3, C-9−C11−C-12, and C-14−C-15) as drawn with bold bonds (blue). The HMBC correlations from H-16 to C-15 and from H-12 to C-13/C-14/C-16 suggested that the furan ring was linked to C12. The key HMBC correlations from H3-20 to C-1/C-5/C-10 and from H3-18/H3-19 to C-3/C-4/C-5 constructed ring A. Similarly, the HMBC correlations from H3-17 to C-8/C-9 and from H-12 to C-8 led to the establishment of ring C. In addition, the construction of ring B with a peroxide bridge between C-5 and C-8 was indicated by their downfield 13C shifts and two additional oxygen atoms in the molecular formula of 1. The relative configuration of 1 was assigned by a ROESY experiment (Figure 3). ROESY correlation of H3-20 with H319β and H-12 indicated that both of the methyl group at C-10 and H-12 were β-oriented. Likewise, ROESY correlation of H-5 705

DOI: 10.1021/acs.orglett.7b03836 Org. Lett. 2018, 20, 704−707

Letter

Organic Letters Accession Codes

CCDC 907917−907918 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. Figure 5. Crystal structure of 2.

ORCID

Scheme 1. Plausible Biogenetic Pathways for 1 and 2

Xu-Jie Qin: 0000-0002-0853-0028 Xiao-Jiang Hao: 0000-0001-9496-2152 Hai-Yang Liu: 0000-0002-1050-6254 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (Nos. 81460533, 81060262, and 31570363), Natural Science Foundation of Yunnan Province (2015FA031), and Yunnan Provincial Science and Technology Department-Applied Basic Research Joint Special Funds of Yunnan University of Traditional Chinese Medicine (2017FF116(-011)). The authors are also grateful to Prof. Xiao-Qiong He (Kunming Medical University) and Dr. GuoYing Zuo (Research Center of Natural Medicine, Clinical School of Kunming General Hospital of Chengdu Military Command) for cytotoxic and antibacterial screenings, respectively.

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electron-withdrawing effect of the α-peroxide bond may be the driving force of decarboxylation. The novel structures of 1 and 2, especially the cyclic peroxide moiety, encouraged us to investigate their pharmacological activities because many natural peroxides revealed significant pharmacological activities.9 For example, artemisinin containing a peroxide bridge is a famous antimalarial medicine. Therefore, antibacterial and cytotoxic screenings of 1 and 2 were performed. Both 1 and 2 were evaluated for their antibacterial activities against Staphylococcus aureus, Pseudomonas aeruginosa, MRSA (methicillin-resistant Staphylococcus aureus) 92#, and MRSA 98#. However, both of them only exhibited weak antibacterial effects (see SI Table S1). Subsequently, the screening of their cytotoxicities showed that 2 was cytotoxic against HepG2 and XWLC-05 cell lines with IC50 values of 8.0 and 19.7 μM, respectively (SI Table S2).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03836. Detailed descriptions of the experimental procedure; UV, IR, MS, and NMR spectra for compounds 1 and 2 (PDF) 706

DOI: 10.1021/acs.orglett.7b03836 Org. Lett. 2018, 20, 704−707

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Organic Letters (8) Chandra Sharma, S.; Tandon, J. S.; Dhar, M. M. Phytochemistry 1976, 15, 827−828. (9) (a) Tu, Y. Y. Angew. Chem., Int. Ed. 2016, 55, 2−19. (b) Wu, Y. W.; Tang, W.; Zuo, J. P. Sci. Bull. 2016, 61, 37−41. (c) Wang, P.; Li, R. J.; Liu, R. H.; Jian, K. L.; Yang, M. H.; Yang, L.; Kong, L. Y.; Luo, J. Org. Lett. 2016, 18, 832−835. (d) Jimenez-Romero, C.; Rodriguez, A. D.; Nam, S. Org. Lett. 2017, 19, 1486−1489.

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DOI: 10.1021/acs.orglett.7b03836 Org. Lett. 2018, 20, 704−707