This Issue is Dedicated to Professor George R. Waller on the Occasion of his 80th Birthday Volume 3. Issue 9. Pages 1377-1564. 2008 ISSN 1934-578X (printed); ISSN 1555-9475 (online) www.naturalproduct.us
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Natural Product Communications
EDITOR-IN-CHIEF DR. PAWAN K AGRAWAL Natural Product Inc. 7963, Anderson Park Lane, Westerville, Ohio 43081, USA
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2008 Vol. 3 No. 9 1473 - 1478
Natural Product Communications
Cembranoid Diterpenes from the Soft Corals Sarcophyton sp. and Sarcophyton glaucum Daniela Grotea, Kamel H. Shakera, Hesham S. M. Solimanb, Muhammmad M. Hegazic and Karlheinz Seiferta* a
University of Bayreuth, Organic Chemistry, NW II, D-95440 Bayreuth, Germany
b
Helwan University, Faculty of Pharmacy, Pharmacognosy Department, P.O. Box 11795, Ain-Helwan, Cairo, Egypt c
Suez Canal University, Faculty of Science, Marine Science Department, Ismailia, Egypt
karlheinz.seifert@universität-bayreuth.de Received: January 31st, 2008; Accepted: June 23rd, 2008
Two new cembrane diterpenes, 17-hydroxysarcophytoxide (1) and 7β-acetoxy-8α-hydroxydeepoxysarcophine (2), together with 7β,8α-dihydroxydeepoxysarcophine (3), sarcophytonin A (4) and (-)-β-elemene (5) have been isolated from the soft coral Sarcophyton sp. 7β-Hydroxy-8α-methoxydeepoxysarcophytoxide (6) and 7α,8β-dihydroxydeepoxysarcophytoxide (7) have been obtained from the soft coral Sarcophyton glaucum. The structures were determined primarily by NMR spectroscopy. Keywords: Soft corals, Sarcophyton, Alcyonacea, cembranoid diterpenes.
Soft corals belonging to the genus Sarcophyton (order Alcyonacea, family Alcyoniidae) have been shown to be a valuable source of structurally diverse cembrane diterpenoids [1-4]. Many of these cembranoids exhibit interesting biological activities, including cytotoxicity towards various cancer cell lines [5-8] and to fertilized sea urchin eggs [9], antifouling activity [10], antiinflammatory [11], HIVinhibitory [12] and inhibitory activity of JB6 cell transformation [13]. This paper describes the isolation and structure determination of two new cembrane diterpenes, 17-hydroxysarcophytoxide (1) and 7β-acetoxy-8αhydroxydeepoxysarcophine (2), together with the cembranoids 3, 4 and the sesquiterpene (-)-β-elemene (5) from Sarcophyton sp. and two further cembranoids 6 and 7 from S. glaucum. The fresh soft corals of Sarcophyton sp. and S. glaucum were cut and exhaustively extracted with methanol. The crude methanolic extracts were purified by silica gel column chromatography to yield the pure compounds.
17-Hydroxysarcophytoxide {1, [α ]D : + 51 (CHCl3)} showed in the HR-ESI-MS the [M+Na+] ion peak at m/z 341.2095, which is in agreement with the molecular formula C20H30O3Na. 1H and 13C NMR spectra (Table 1) indicated the presence of 1 containing three tertiary methyl (C-18, C-19, C-20), two oxymethines (C-2, C-7), two oxymethylenes (C-16, C-17), and six methylene (C-5, C-6, C-9, C-10, C-13, C-14) carbons, one O-substituted quaternary carbon (C-8), two methine olefines (C-3, C-11) and four quaternary olefinic carbons (C-1, C-4, C-12, C-15). The correlations of 1H-1H COSY revealed four proton-proton networks, H3-18/H-3/H-2, H2-5/H2-6/H-7, H2-9/H2-10/H-11 and H2-13/H2-14. These data together with the HMBC cross peaks between H3-18/C-4, H3-18/C-3, H3-18/ C-5, H3-19/C-7, H3-19/C-8, H3-19/C-9, H3-20/C-11, H3-20/C-12, H3-20/C-13, H-2/C-1 and H2-14/C-1 confirm the connections from C-1 to C-14 of the 14-membered ring of 1. Further 1H-1H COSY signals between H2-16 and H-2, H2-17 and H-14 (δH 1.72), and HMBC couplings H2-17/C-15, H2-17/C-16, H2-17/C-1 and H-2/C-15 suggested the structure of 17-hydroxysarcophytoxide (1). 26
1474 Natural Product Communications Vol. 3 (9) 2008
Grote et al.
The relative configurations at C-2, C-7 and C-8 were also determined by comparing the 13C NMR chemical shifts with those of (+)-(2S,7S,8S)- and (-)-(2R,7S,8S)-sarcophytoxide [16]. The 13C NMR shifts in CDCl3 of the C-2, C-7, C-8 and C-19-signals (δc 83.8, 61.9, 59.8, 16.9) are in good agreement with those of (+)-sarcophytoxide (δc 83.7, 61.9, 59.8, 17.0) [17], but not with (-)-sarcophytoxide (δc 85.3, 62.3, 60.1, 16.4) [16]. The absolute stereochemistry of (+)-(2S,7S,8S)-sarcophytoxide was confirmed by X-ray analysis [17] and chemical correlations [16]. The (7S,8S) relative configuration of 1 indicated the trans-epoxide. 17-Hydroxysarcophytoxide (1) has a similar structure to lobophynin B, which is 17-acetoxysarcophytoxide, which has been isolated from the soft coral Lobophyton schoedei [14].
Figure 1: Selected NOE correlations in 17-hydroxysarcophytoxide (1).
The relative configuration of 17-hydroxysarcophytoxide (1) was determined by ROESY experiments. NOEs from H-7 to H-11, H-7 to H-3 and from H-11 to H3-19 showed that H-7 and H3-19 were α-oriented. The ROESY cross peak between H2 and H3-18 assigned the β-orientation of H-2, H3-18 and the trans-configuration of the 3,4 double bond (Figure 1). The (3E)- and the (11E)-configurations could be determined by comparison of the 13C chemical shifts of the C-18 and C-20 methyl signals (δc 15.6 and 15.1) with literature values [8,14,15]. The stereo formula in Figure 1 has been drawn with Chem 3D Ultra 9.0. The minimized energy was calculated with MM2 (Molecular Mechanics).
The [M+Na+] ion at 399.2155 of the HR-ESI-MS of 7β-acetoxy-8α-hydroxydeepoxysarcophine (2) gave the molecular formula C22H32O5Na. The 1H-1H COSY experiment of 2 allowed the assignment of the proton correlations H-14 (δH 2.50)/H-2/H-3/ H3-18, H2-5/H2-6/H-7, H2-9/H2-10/H-11/H3-20, and H2-13/H2-14. These data together with HMBC cross peaks between H3-18/C-3, H3-18/C-4, H3-18/C-5,
18
H
O
7
O
8
3 19
H
15
1
OH OH
17 12
1
20
H
2
H
O
HO
O
AcO
16
O
O
OH
4
3 1
14 9
5
3
12
7 11
H
13
15
5 H
O
HO OMe
H
O
HO OH
6
7
O
Cembrane diterpenoids from Sarcophyton sp.
Natural Product Communications Vol. 3 (9) 2008 1475
Table 1: 1H- and 13C NMR spectroscopic data of compounds 1, 2, 4 and 6, and 13C NMR spectroscopic data of compounds 3and 7 (CDCl3). pos. 1 2 3 4 5
1 δH
5.58 m 5.24 d (10.0) 2.32 m
1 δC 137.6 83.8 125.4 140.0 37.7
6 7 8 9 10 11 12 13 14 15 16 17 18 19
1.86 m , 1.62, m 2.68 dd (4.1, 3.9)
4.67 m, 4.72 m 4.26 s 1.81 s 1.25 s
25.3 61.9 59.8 39.8 23.5 123.9 136.4 36.8 26.2 131.6 75.8 56.8 15.6 16.9
20
1.57 s
15.1
2.10 m, 0.98 m 2.21 m, 1.87 m 5.09 dd (9.8, 5.8) 1.91 m 2.59 m, 1.72 m
2 δH
2 δC 163.5 78.8 122.2 142.3 35.3
3 δC 162.5 79.0 121.5 143.3 35.4
24.8 76.1 75.0 37.3 23.7 124.2 135.9 36.5 25.9 122.2 174.9 8.9 16.2 24.8
27.9 72.6 78.1 39.1 24.8 124.0 135.0 36.3 26.0 122.9 174.6 9.0 16.0 26.5
1.64 s
15.1
15.8
2.08 s
20.9, 170.6
5.55 d (10.3) 4.80 d (10.3) 2.15 m, 1.91 m 1.88 m, 1.82 m 4.98 d (10.9) 1.82 m 1.59 m 2.23 m 2.05 m 4.92 br.d (8.7) 2.16 m, 1.95 m 2.79 m, 2.50 m 1.82 s 1.92 s 1.07 s
AcO-7 MeO-8
H3-19/C-7, H3-19/C-8, H3-19/C-9, H3-20/C-11, H3-20/C-12, H3-20/C-13, H2-14/C-1 and H2-14/C-2 suggested that 2 possessed a cembrane skeleton with a 14-membered ring. HMBC correlations between H3-17/C-15, H3-17/C-16 and H3-17/C-1 revealed the position of the 17-methyl group and the lactone ring. The acetoxy group is located at C-7. This could be deduced from the HMBC cross peak H-7/CH3CO-7. The relative stereochemistry of 2 was elucidated by ROESY experiments. The NOE cross peaks between H-3 and H-7 revealed that they were α-oriented. The β-orientation of H-2 methine, H-10 (δ 2.23), H3-18, H3-19 and H3-20 was supported by strong NOE interactions between H-2/H3-18, H-10 (δ 2.23)/H3-19 and H-10 (δ 2.23)/H3-20). The (3E)- and (11E)configurations were determined in the same way as for compound 1 on the basis of 13C NMR chemical shifts of the C-18 and C-20 methyl carbons (δc 16.2 and 15.1) [8,14,15]. 7β-Acetoxy-8α-hydroxydeepoxysarcophine (2) and 7β,8α-dihydroxydeepoxysarcophine (3) have previously been obtained by treatment of (+)-sarcophine with 1% p-TsOH in HOAc [18]. The relative configuration of (+)-sarcophine was elucidated by X-ray analysis [19] and the absolute configuration by CD spectroscopy [18]. Since the 26 optical rotations of the natural products 2 { [α ]D :
+ 89 (CHCl3)} and 3 { [α ]D : + 103 (CHCl3)} are similar to those of the semi synthetic compounds 2 {[α]D: + 87 (CHCl3)} and 3 {[α]D : + 100 (CHCl3)} 27
4 δH
5.48 m 5.06 d (10.0) 2.28 m, 2.15 m 2.35 m, 2.05 m 4.83 m
4 δC 133.9 83.9 125.7 140.4 39.1
4.47 m 1.62 s 1.67 s 1.56 s
24.7 125.5 133.2 40.3 23.4 123.9 135.4 37.1 25.8 127.1 78.3 10.1 14.9 15.0
1.58 s
15.5
2.10 m, 1.89 m 2.03 m 4.98 dd (7.5, 7.1) 1.91 m 2.35 m, 1.84 m
6 δH
6 δC 133.5 83.9 126.7 139.5 35.7
7 δC 133.3 84.0 126.8 139.1 35.6
4.47 br.s 1.61 s 1.79 s 1.11 s
26.6 72.7 79.5 31.2 23.3 124.4 135.6 36.5 25.0 127.7 78.5 10.2 15.6 18.4
26.7 72.9 75.5 37.0 23.6 124.2 135.8 36.7 25.3 127.9 78.5 10.0 16.0 24.2
1.60 s
15.7
15.4
3.16 s
49.2
5.52 m 5.13 d (10.1) 2.12 m, 2.36 ddd (13.1, 13.0, 3.3) 1.41 m, 1.85 m 3.49 dd (9.9, 9.7) 1.82 m, 1.58 m 2.07 m 5.00 (t, 7.2) 1.92 m 2.46 m, 1.72 m
[18], the formulas of 2 and 3 represent the absolute configurations. The 1H and 13C NMR spectroscopic data of the natural product 2 are in good agreement with those of the partially synthesized compound [18]. 7β,8α-Dihydroxydeepoxysarcophine (3) (13C NMR data, Table 1) has been isolated before from Sarcophyton trocheliophorum, which was collected near Kenting, Taiwan [20]. The 1H and 13C NMR data are in agreement with those already reported [13,18,20]. The cembranoid diterpene 3 is cytotoxic against the cell line P-388 (murine lymphocytic leukaemia) with an ED50 3.27 μg/mL [20]. The enantiomeric mixture of sarcophytonin A (4) (1H and 13C NMR data, Table 1) has been obtained for the first time from the Ishigaki Island soft coral Sarcophyton glaucum [21]. The 1H and 13C NMR chemical shifts of 4, which were not thoroughly assigned in previous literature, were determined by COSY, HMQC and HMBC experiments in this 25 investigation. The optical rotation of 4 ( [α ]D : - 90, CHCl3) is similarly to that of Kobayashi et al. [21] ([α]D : - 92, CHCl3). Finally, our sample is a mixture of the (+) and (-) form in which the (-)-enantiomer is dominant. (-)-β-Elemene {5, [α ]24 : – 17 (CHCl3)} has been D identified from its physical, spectroscopic and library spectral data [22, 23, 24]. Compound 5 is cytoxic against the cell line P-388 with an ED50 0.92 μg/mL [25].
1476 Natural Product Communications Vol. 3 (9) 2008
Grote et al.
Silica gel column chromatography of the methanol fraction of the crude extract of S. glaucum gave the 25 cembrane diterpene 6 { [α ]D : + 9 (CHCl3)}. The ESI-MS of 6 showed the [M+Na+] ion at m/z 357. The 1H and 13C NMR data (Table 1) indicated the presence of 7β-hydroxy-8α-methoxydeepoxysarcophytoxide (6). The 1H-1H COSY experiment allowed the assignment of the proton correlations H-2/H-3/H3-18, H2-5/H2-6/H-7, H2-9/H2-10/H-11/H320 and H2-13/H2-14. By combination of these data and HMBC cross peaks H3-18/C-3, H3-18/C-4, H3-18/C-5, H3-19/C-7, H3-19/C-8, H3-19/C-9, H3-20/C-11, H3-20/C-12, H3-20/C-13, H-14 (δH 2.46)/C-1 and H-14 (δH 2.46)/C-2, the 14-membered ring of 6 could be deduced. The positions of the 17methyl and the 16-methylene group were confirmed by the HMBC correlations between H2-16/C-2, H2-16/C-15, H2-16/C-1 and H3-17/C-15, H3-17/C-1. The methoxy group at C-8 was revealed by HMBC coupling between CH3O-8 and C-8. The relative stereochemistry of 7β-hydroxy-8αmethoxydeepoxysarcophytoxide (6) was established by ROESY experiments. The NOE interactions found between H-3/H-5 (δ 2.36), H-7/H-5 (δ 2.36), H-7/H11 assigned the α-position of H-3, H-5 (δ 2.36), H-7 and H-11. Due to the chemical shifts of C-18 and C-20 carbons (δC 15.6 and 15.7), the configurations of the 3 and 11 double bonds were found to have a trans-geometry, respectively [8,14,15]. The ROESY cross peaks between H3-20/H3-19 and H-2/H3-18 showed the β-orientation of H3-20, H3-19, H-2 and H3-18. Compound 6 was probably formed by epoxide ring opening of sarcophytoxide during the extraction of the coral material with methanol. 7α,8β-Dihydroxydeepoxysarcophytoxide {7, [α ]D : + 138 (CHCl3)} displayed in the ESI-MS spectrum a [M+Na+] ion peak at m/z 343. The 13C NMR data (Table 1) are in agreement with the previously published structure of 7, which has been obtained from the Okinawan soft coral Sarcophyton sp. [26].
determined with a Jasco® P-1020 polarimeter. NMR spectra were recorded in CDCl3 on a Bruker DRX 500 spectrometer at 500.13 MHz (1H) and 125.76 MHz (13C). Spectra were referenced to residual solvent signals (1H 7.24, 13C 77.0). ESI-MS and HR-ESI-MS spectra were obtained with a Micromass LCT spectrometer and MS with a Finnigan MAT 8500. GC-MS was carried out with a Varian 3700 gas chromatograph coupled to a Finnigan MAT 312 mass spectrometer. Animal material: The soft coral Sarcophyton sp. was collected in May 2001 from Gulf of Suez, Egypt, at a depth of 10-15 m. The soft coral S. glaucum was collected from the Red Sea at Hurgada, Egypt, in April 2002, at a depth of 10-15 m. Both soft coral species were identified by Dr M. M. Hegazi, Suez Canal University, Faculty of Science, Marine Science Department, Ismailia, Egypt. Voucher specimens are on deposit at the same department. Extraction and isolation: The fresh soft coral Sarcophyton sp. (2.5 kg) was cut into pieces and extracted exhaustively with MeOH. The solvent was removed under reduced pressure (temperature not exceeding 40°C). The residue (31.1 g) was fractionated by silica gel column chromatography with n-hexane and a n-hexane/EtOAc gradient. Fractions 10-25 (30 mg) were purified by prep. TLC (silica gel, n-hexane/EtOAc 20:3) to give compound 5 (3 mg). Prep. TLC (RP-18, MeOH/H2O 17:3) of fractions 40-58 (55 mg) afforded compounds 2 (5 mg) and 3 (3.5 mg). Fractions 62-70 (20 mg) were subjected to prep. TLC (silica gel, n-hexane/EtOAc 18:3.5) to yield compound 4 (3 mg). Compound 1 (2.5 mg) was isolated from fractions 73-81 (15 mg) by prep. TLC (silica gel, n-hexane/EtOAc 7:3).
25
Experimental General experimental procedures: Silica gel 60 (0.040-0.063 mm, Merck) was used for column chromatography, and either reversed phase (RP-18 F254, Merck) or silica gel 60 (F254, Merck) aluminium plates for prep. TLC. The compounds were visualized either by UV light or by heating after spraying with vanillin/sulfuric acid. Optical rotations were
The fresh soft coral S. glaucum (2.14 kg) was sliced, homogenized with MeOH and directly extracted with MeOH. The solvent was removed under reduced pressure (temperature not exceeding 40°C). The residue (25.2 g) was separated by silica gel column chromatography with n-hexane and a n-hexane/EtOAc gradient. Fractions 25-32 (17 mg) were purified by prep. TLC (RP-18, MeOH/H2O 14:8) to obtain compound 6 (3 mg). Finally compound 7 (4 mg) was obtained by prep. TLC (RP18, MeOH/H2O 16:3) of fractions 35-45 (26 mg). 17-Hydroxysarcophytoxide (1)
[α ]26D : +51 (c 0.24, CHCl3).
Cembrane diterpenoids from Sarcophyton sp. 1
H NMR: Table 1. C NMR: Table 1. ESI-MS: m/z = 341 [M+Na+]. HR-ESI-MS: m/z [M+Na+] calcd for C20H30O3Na: 341.2093; found: 341.2095. 13
7β-Acetoxy-8α-hydroxydeepoxysarcophine (2)
[α ]26D : +89 (c 0.45, CHCl3).
Ref. [18], [α]D : +87 (c 0.01, CHCl3). 1 H NMR: Table 1. 13 C NMR: Table 1. ESI-MS: m/z = 399 [M+Na+]. HR-ESI-MS: m/z [M+Na+] calcd for C22H32O5Na: 399.2147; found: 399.2155.
Natural Product Communications Vol. 3 (9) 2008 1477
MS (EI, 70 eV) m/z (%): 286 [M+] (7), 271 (5), 203 (9), 175 (15), 163 (18), 149 (21), 136 (26), 135 (44), 121 (15), 107 (19), 93 (27), 91 (37), 67 (57). (-)-β-Elemene (5)
[α ]24D : –17 (c 0.2, CHCl3).
Ref. [22]: [α]D : – 14.5 (c 1.0, CHCl3). 13 C NMR (125 MHz, CDCl3): 150.4 (C-11), 150.3 (CH-1), 147.7 (C-4), 112.0 (CH2-3), 109.2 (CH2-2), 108.2 (CH2-12), 52.7 (CH-5), 45.7 (CH-7), 39.9 (CH2-9), 39.8 (C-10), 32.9 (CH2-6), 26.8 (CH2-8), 24.8 (CH3-15), 21.1 (CH3-13), 16.6 (CH3-14). GC-MS (EI, 70 eV): m/z (%) = 204 [M+] (5), 189 (32), 161 (38), 147 (51), 133 (32), 121 (52), 107 (65), 93 (96), 81 (100), 68 (71), 55 (37), 41 (45).
7β,8α-Dihydroxydeepoxysarcophine (3)
[α ]27D : +103 (c 0.15, CHCl3). Ref. [18], [α]D : +100
7β-Hydroxy-8α-methoxydeepoxysarcophytoxide (6)
1
[α ]25D : +9 (c 0.1, CHCl3).
(c 0.01, CHCl3). H NMR: Table 1. 13 C NMR: Table 1. ESI-MS: m/z = 357 [M+Na+].
1
Sarcophytonin A ( ± 4)
7α,8β-Dihydroxydeepoxysarcophytoxide (7)
[α ]
[α ]25D : +138 (c 0.5, CHCl3).
25 D :
-90 (c 0.98, CHCl3). Ref. [21], [α]D : – 92 (c 2.3, CHCl3). 1 H NMR: Table 1. 13 C NMR: Table 1.
H and 13C NMR: Table 1. ESI-MS: m/z = 357 [M+Na+].
Ref. [26], [α]D : +140 (c 0.48, CHCl3). 13 C NMR: Table 1. ESI-MS: m/z = 343 [M+Na+].
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