Hedyorienoids A and B, Two Sesquiterpenoid Dimers Featuring

Aug 16, 2018 - (2) The plants of the Chloranthaceae family have three genera of Chloranthus, Sarcandra, and Hedyosmum in China.(3) The genera of ...
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Letter Cite This: Org. Lett. 2018, 20, 5435−5438

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Hedyorienoids A and B, Two Sesquiterpenoid Dimers Featuring Different Polycyclic Skeletons from Hedyosmum orientale Yao-Yue Fan, Yi-Li Sun, Bin Zhou, Jin-Xin Zhao, Li Sheng, Jing-Ya Li,* and Jian-Min Yue* State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People’s Republic of China

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S Supporting Information *

ABSTRACT: Hedyorienoids A (1) and B (2), two sesquiterpenoid dimers, were isolated and characterized from Hedyosmum orientale. Compound 1 was an unprecedented heterodimer of two different classes of sesquiterpenoids furnished by forming an unusual 1,3-dioxolane ring, while compound 2 possessed a new dimerization pattern of two guaiane-type sesquiterpenoids. Biosynthetic pathways for 1 and 2 were proposed with the coexisting monomers chloranthalactone A (3) and hedyosumin A (4) as the precursors. Compounds 2 and 3 showed significant NF-κB inhibitory activity.

D

isolation, structural elucidation, plausible biogenetic pathways, and bioactive evaluation of compounds 1−4.

imeric sesquiterpenoids (DSs), which possessed more fascinating structures and exhibited more potent biological activities than their monomeric precursors in previous research,1 have been attracting considerable attention from the scientific communities of natural products and organic synthesis.2 The plants of the Chloranthaceae family have three genera of Chloranthus, Sarcandra, and Hedyosmum in China.3 The genera of Chloranthus and Sarcandra have been found to be rich sources of bioactive DSs, which are mainly Diels−Alder adducts of two molecular lindenane-type sesquiterpenoids,1a,4 while only a limited number of monomeric sesquiterpenoid analogues have been identified from Hedyosmum genus so far.5 Our preliminary study on Hedyosmum orientale Merr. et Chun, the only species occurring in China, led to the isolation of three rare tetracyclic guaianolides,5c which have been synthesized recently.6 In continuing our efforts to search for structurally diverse and biologically important DSs from the Chloranthaceae plants, a sample of the twigs and leaves of H. orientale collected from the Hainan Province of China was reinvestigated, which afforded two unprecedented DSs, hedyorienoids A (1) and B (2). It is noteworthy that compound 1 possessed an unprecedented heterodimeric framework of a lindenane and an aromadendrane sesquiterpenoid furnished by forming an unusual 1,3dioxolane ring, and compound 2 featured a new dimerization pattern of two guaiane-type sesquiterpenoids tied together by forming a new carbon−carbon bond. Their structures, including absolute configurations, were unequivocally established by extensive spectroscopic data analysis and X-ray crystallography study. The plausible biosynthetic pathways for compounds 1 and 2 were proposed with the concomitant sesquiterpenoids, chloranthalactone A (3),7 and hedyosumin A (4)5c as the precursors. All of the compounds were evaluated in several biological assays, and compounds 2 and 3 exhibited siginificant NF-κB inhibitory activity. Herein, we elaborate the © 2018 American Chemical Society

Hedyorienoid A (1), colorless crystals, was assigned the molecular formula C30H40O6 by high-resolution electrospray ionization mass spectrometry (HRESIMS) ion at m/z 495.2750 [M − H]− (calcd for C30H39O6, 495.2747) and 13 C nuclear magnetic resonance (NMR) data, requiring the presence of 11 double bond equivalents (DBEs). The IR spectrum revealed the attendance of hydroxyl (3282 cm−1) and carbonyl (1760 cm−1) groups. The 1H NMR data of 1 (Table 1) exhibited characteristic signals for four methyl singlets (δH 1.25, 1.08, 1.03, and 0.54) and an exocyclic vinyl group (δH 5.04 and 4.73, both d, J = 2.0 Hz). The 13C NMR spectrum of 1 resolved 30 carbon signals, which were classified by DEPT Received: July 25, 2018 Published: August 16, 2018 5435

DOI: 10.1021/acs.orglett.8b02340 Org. Lett. 2018, 20, 5435−5438

Letter

Organic Letters Table 1. 1H and

13

C NMR Data for Compounds 1 and 2

1a no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 1′ 2′

δH (mult, J (Hz)) 1.83 td (7.8, 3.9) α 0.84 td (8.7, 5.3) β 0.68 dd (8.7, 3.9) 2.00 m 3.44 dd (12.5, 6.7) α 2.60 dd (18.5, 6.7) β 2.46 dd (18.5, 12.5)

2b δC 23.6 15.7 23.7 151.8 50.2 22.4

4.30 s

157.6 110.1 85.5

4.41 d (6.2, 2H)

42.7 129.2 170.6 55.5

0.54 s 5.04 d (2.0) 4.73 d (2.0) 1.63 m α 1.88 m

17.5 106.6 49.3 28.7

β 1.53 m (overlap) 3′ 4′ 5′ 6′ 7′ 8′ 9′

10′ 11′ 12′ 13′ 14′ 15′

α 1.72 m β 1.53 m (overlap) 1.45 dd (10.5, 9.5) 0.38 dd (11.2, 9.5) 0.64 m α 1.96 m β 1.07 m β 2.13 ddd (13.4, 6.8, 2.8) α 1.22 m 1.70 m 1.08 s 1.03 s 1.25 s 5.31 d (3.0)

41.8 80.6 54.0 29.3

δH (mult, J (Hz)) 2.94 brs α 2.48 dd (18.9, 6.7) β 1.93 dd (18.9, 2.7)

β 2.91 d (14.6) α 2.70 d (14.6) 4.72 brd (6.6) β 2.07 dd (14.9, 6.6) α 1.72 m (overlap)

β 1.72 m (overlap) α 1.61 m 1.74 t (1.8) 1.45, s 2.74 m α 2.21 ddd (13.9, 8.2, 2.0) β 1.56 ddd (13.9, 8.5, 8.5) 2.75 m

α 2.55 brd (14.3) β 2.49 d (14.3)

δC 50.8 37.1 209.9 139.1 169.7 29.8 90.4 85.1 40.4 88.0 80.4 178.2 37.3 7.9 25.0

Figure 1. Key 1H−1H COSY, HMBC, and NOESY correlations of 1.

structural fragments as depicted with bold bonds (Figure 1A), which were then connected with the quaternary carbons and oxygen atoms by the HMBC correlations to furnish its framework. First, two proton-coupling sequences of H-1/H22/H-3 and H-5/H2-6 as revealed by the 1H−1H COSY crosspeaks were connected with the other elements in unit A by the HMBC correlation networks of H2-6/C-7, C-8, and C-11; H9/C-5 and C-8; H2-13/C-7, C-11, and C-12; H3-14/C-1, C-5, C-9, and C-10; and H2-15/C-3, C-4, and C-5 to construct a scaffold of lindenane-type sesquiterpenoid (Figure 1A). The lactone ring formed between the C-8 and C-12 was tentatively assigned by chemical shifts of the related carbons within this ring system.8 Then, in combination with the 1H−1H COSY results, the unit B in 1 was readily delineated to be an aromadendrane-type sesquiterpenoid by the key HMBC correlations of H3-12′ and H3-13′/C-6′, C-7′, and C-11′ and H3-14′/C-3′, C-4′, and C-5′ (Figure 1A). Furthermore, the functional groups and ring systems in the two monomeric sesquiterpenoids took 10 out of the 11 total DBEs, and the remaining one thus required the existence of an additional ring in the molecule to fuse units A and B. The presence of an unusual 1,3-dioxolane ring in 1 was finally indicated by the chemical shifts of C-8 (δC 110.1), C-9 (δC 85.5), C-15′ (δC 107.2), and H-15′ (δH 5.31, d, J = 3.0 Hz). Thus, the gross structure of 1 was established to be a heterodimeric sesquiterpenoid fused by the formation of an unique 1,3dioxolane ring as the liaison between the lindenane and aromadendrane sesquiterpenoids. The relative configuration of 1 was fixed by NOESY spectrum (Figure 1B). In unit A, the NOESY correlations of H3-14/H-2β, H-6β, and H-9 indicated that these protons were cofacial and arbitrarily assigned to be β-oriented, while H-2α, H-1, H-3, and H-5 were assigned to be α-oriented by the NOESY correlations of H-2α/H-1 and H-3 and the large coupling constant between H-5 and H-6β (J = 12.5 Hz). In unit B, the NOESY cross-peaks of H-1′/H-2′, H-6′, and H-9′α and H-6′/H-7′, H3-13′, and H3-14′ indicated that these protons were on the same side and were randomly assigned as α-oriented, while the NOESY correlations of H-10′/H-2′β, H5′, H-9′β, and H-15′ suggested that these protons were β-

54.9 32.5

45.8 138.7 131.5 31.6

27.7 23.4

4.50 dd (7.4, 2.5)

85.3 88.0

26.3

β 2.37 dd (14.3, 7.4)

40.0

α 1.64 m 48.6 21.1 16.6 28.9 26.1 107.2

6.34 6.02 1.63 1.32

s s brs s

90.0 139.5 171.5 125.3 11.9 24.6

a

Measured in CDCl3. bMeasured in methanol-d4.

and HSQC spectra as one carbonyl (δC 170.6), two double bonds (one exocyclic and one tetrasubstituted), four methyls, seven sp3 methylenes (one oxygenated), 10 sp3 methines (one oxygenated at δC 85.5 and an acetal at δC 107.2), and four sp3 quaternary carbons (one oxygenated at δC 80.6 and a ketal at δC 110.1). The diagnostic resonances of six highly upfieldshifted carbons [δC 29.3 (CH), 27.7 (CH), 23.7 (CH), 23.6 (CH), 21.1 (C), and 15.7 (CH2)] indicated the presence of two different substituted cyclopropane rings. The abovementioned evidence suggested that compound 1 was an analogue of DSs. The planar structure of 1 was constructed by detailed interpretation of the 2D NMR (1H−1H COSY and HMBC) spectra. The 1H−1H COSY correlations of 1 revealed three 5436

DOI: 10.1021/acs.orglett.8b02340 Org. Lett. 2018, 20, 5435−5438

Letter

Organic Letters oriented. The β-configured H-15′ was also deduced by the NOESY correlation between H-9 and H-15′. To confirm the structure assigned for compound 1, quality crystals were obtained from recrystallization in methanol, and the X-ray diffraction study (Cu Kα radiation) of 1 was successfully performed (Figure 2, CCDC 1855982). The X-ray

Figure 3. Key 1H−1H COSY, HMBC, and NOESY correlations of 2.

unprecedented dimerization pattern of two guaiane-type sesquiterpenoids. The relative configurations of the units A and B of two guaiane-type sesquiterpenoid motifs for 2 were mainly fixed by analysis of NOESY spectrum (Figure 3B), while the relative configurations at C-11 and C-3′ in the bridgeheads of two units A and B were left unassigned due to the lack of reliable NOESY correlations. Fortunately, a single-crystal X-ray diffraction study (Figure 2, CCDC 1855983) was successfully conducted by using an anomalous scattering of Cu Kα radiation, which not only completed the assignment of the relative configuration for 2, but also unambiguously determined its absolute configuration (1R,7R,8S,10R,11R,1′R,3′S,7′S,8′S,10′R) [Flack parameter = −0.05 (11)] .9 Biosynthetically, compound 1 could be derived from a coexisting major lindenane-type sesquiterpenoid, chloranthalactone A (3), and an aromadendrane sesquiterpenoid (Scheme 1A). Briefly, compound 3 would be oxidized to intermediate i with required stereochemistry by involving singlet oxygen via [2 + 2] cycloaddition.10 Cleavage of the peroxide bond of i would result in the formation of a diradical intermediate ii, which would be transformed into the key intermediate iii with desired vicinal cis-diol.11 The intermediate iv was presumed to be derived from a commonly existing aromadendrane sesquiterpenoid, such as spathulenol,12 via an oxidation sequence. Finally, the aldol condensation between two key intermediates iii and iv would produce the compound 1 with an unprecedented framework. A plausible biosynthetic pathway for compound 2 was also proposed with the coexisting guaiane-type sesquiterpenoid, hedyosumin A (4), as the precursor (Scheme 1B). The [2 + 2] heterocyclic addition of the ketone and the exocyclic double bond from two molecules of hedyosumin A would form the key intermediate v with an oxetane motif.13 Then, the cleavage of the strained C− O bond in the oxetane ring would generate a diradical intermediate vi,14 which was subsequently quenched by the free-radical reactions with two molecules of water to yield the sesquiterpenoid dimer 2 with a new carbon skeleton. Nuclear factor κB (NF-κB) is one of the key regulators of genes critically involved in the process of inflammation, immunity, aging, cell survival and apoptosis, and metabolic diseases.15 All the isolates were tested on a NF-κB pathway

Figure 2. ORTEP drawings of compounds 1 and 2.

crystallography result not only secured the above structural assignment for 1 but also established its absolute configuration (1R,3S,5S,8S,9S,10S,1′R,4′S,5′R,6′R,7′R,10′R,15′S) by the excellent Flack parameter [0.17 (10)].9 Hedyorienoid B (2) was obtained as colorless crystals. Its molecular formula was deduced to be C30H34O8 (14 DBEs) by (+)-HRESIMS ion at m/z 545.2151 [M + Na]+ (calcd for C30H34O8Na, 545.2146) and the 13C NMR data (Table 1). The IR spectrum of 2 showed absorptions of hydroxyl (3467 cm−1) and carbonyl (1767 and 1702 cm−1) groups. Thirty carbon resonances resolved in the 13C NMR spectrum (Table 1) were assigned by DEPT and HSQC spectra as three carbonyls (one keto and two esters), three double bonds (one exocyclic and two tetrasubstituted), four methyls, seven sp3 methylenes, five sp3 methines (two oxygenated), and five oxygenated sp3 quaternary carbons. The aforementioned evidence, and in particular the functional groups of 2, indicated it was likely a dimeric sesquiterpenoid that was skeletally different from the sesquiterpenoid dimers identified from the Chloranthaceae plants previously.1 The 1H−1H COSY correlations of H-1/H-2 and H-8/H-9 (Figure 3A), along with the network of HMBC cross-peaks of H-2/C-5; H-8/C-6, C-7, C-10, and C-12; H-9/C-1; H2-13/C-7, C-11, and C-12; H3-14/C-3, C-4, and C-5; and H3-15/C-1, C-9, and C-10 (Figure 3A), allowed the construction of the planar structure of unit A for 2 as a guaiane-type sesquiterpenoid bearing a characteristic 7,10-epoxy bridge (C-7 at δC 90.4 and C-10 at δC 88.0). Similarly, the unit B of a guaiane-type sesquiterpenoid framework for 2 was also identified. The units A and B were finally assembled via the C-13 and C-3′ bond by the key correlation of H-13/H-3′ in the 1H−1H COSY spectrum. Thus, the planar structure of 2 was established as an 5437

DOI: 10.1021/acs.orglett.8b02340 Org. Lett. 2018, 20, 5435−5438

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Organic Letters Notes

Scheme 1. Proposed Biosyntheses for Compounds 1 and 2

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the National Natural Science Foundation (Nos. 21532007, 21772213, 21772212, and 81673493) of the P. R. China is highly acknowledged.

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luciferase assay. Compounds 2 and 3 showed significant NF-κB inhibitory activities with IC50 values of 5.34 ± 2.21 and 2.84 ± 0.69 μM (Figure S1, Supporting Information), respectively, and compounds 1 and 4 were inactive.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02340. Experimental section; X-ray crystallographic data for 1 and 2; and 1D and 2D NMR, MS, and IR spectra of compounds 1 and 2 (PDF) Accession Codes

CCDC 1855982−1855983 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]. ORCID

Jian-Min Yue: 0000-0002-4053-4870 5438

DOI: 10.1021/acs.orglett.8b02340 Org. Lett. 2018, 20, 5435−5438