Lamellodysidines A and B, Sesquiterpenes Isolated from the Marine

Aug 25, 2017 - Faculty of Fisheries and Marine Science, Sam Ratulangi University, Kampus Bahu, Manado 95115, Indonesia. § Naturalis Biodiversity Cent...
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Lamellodysidines A and B, Sesquiterpenes Isolated from the Marine Sponge Lamellodysidea herbacea Masumi Torii,† Hikaru Kato,† Yuki Hitora,† Esther D. Angkouw,‡ Remy E. P. Mangindaan,‡ Nicole J. de Voogd,§ and Sachiko Tsukamoto*,† †

Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan Faculty of Fisheries and Marine Science, Sam Ratulangi University, Kampus Bahu, Manado 95115, Indonesia § Naturalis Biodiversity Center, P.O. Box 9517, 2300 RA Leiden, The Netherlands ‡

S Supporting Information *

ABSTRACT: Four new sesquiterpenes, lamellodysidines A and B, O,Odimethyllingshuiolide A, and 11-epi-O,O-dimethyllingshuiolide A (1−4), were obtained from the marine sponge, Lamellodysidea herbacea, collected in Indonesia. Their planar structures were elucidated by analysis of spectroscopic data. The absolute configurations of the new compounds were determined by the calculated ECD spectra. Compound 1 has a unique carbon framework, and 2 is a new nitrogenous sesquiterpene.

M

arine sponges are known to be rich sources of biologically active and structurally unique compounds.1,2 A large number of marine natural products have been discovered from the order of Dictyoceratida,3 which is wellknown as a rich source of structurally highly diverse terpenes including sesterterpenes,4−7 norsesterterpenes,8 sesquiterpene quinones,9−11 and furan-containing terpenes.12−14 The chemical diversity of terpenes reported from Dictyoceratida is fascinating from the viewpoints of pharmacological properties and biosynthetic studies, and continuous efforts to explore new chemical scaffolds from natural sources are in great demand.15 In our ongoing research into novel metabolites from marine sponges, we found that an extract of the sponge, L. herbacea, collected in Indonesia showed cytotoxic and antimicrobial activities, and we isolated 2-(2′-bromophenoxy)-3,4,5,6-tetrabromophenol16 and 2-(2′,4′-dibromophenoxy)-4,6-dibromophenol17 as the biologically active entities. Together with these metabolites, four new sesquiterpenes, lamellodysidines A and B, O,O-dimethyllingshuiolide A, and 11-epi-O,O-dimethyllingshuiolide A (1−4), and a known sesquiterpene, O-methyl nakafuran-8 lactone18 (5), were isolated. Compound 1 is the first natural product found to possess an unprecedented bridged polycyclic skeleton, and 2 is a new nitrogen-containing sesquiterpene.

Hz, H-1)), and three methyls (δH 0.78 (s, H-14), 0.81 (d, J = 7.3 Hz, H-15), and 1.14 (s, H-13)) (Table 1). The 13C NMR and DEPT spectra indicated the presence of a carbonyl carbon (δC 178.2, C-9), two protonated olefin carbons (δC 132.5 (C10) and 135.8 (C-11)), two methylenes (δC 33.4 (C-7) and 39.4 (C-6)), four methines (δC 38.5 (C-3), 47.1 (C-4), 60.7 (C2), and 99.4 (C-1)), three methyls (δC 15.8 (C-13), 17.2 (C15), and 18.6 (C-14)), and three additional quaternary carbons (δC 49.0 (C-5), 51.6 (C-12), and 57.7 (C-8)) (Table 1). The planar structure of 1 was determined by detailed analysis of 2D NMR spectroscopic data. The COSY spectrum revealed the presence of two spin systems, H-1/H-2/H-3(/H-10/H-11)/H4/H-15 and H-6/H-7 (Figure 1a). The HMBC correlations from H-7 to C-2 and C-8, from H-13 to C-5, C-8, C-11, and C12, and from H-14 to C-4, C-5, C-6, and C-12 established a

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RESULTS AND DISCUSSION Lamellodysidine A (1) has the molecular formula of C15H20O3, which was determined by HRESIMS. The 1H NMR spectrum showed a Z-olefin (δH 5.80 (H-11) and 6.18 (H-10), 3JHH = 8.2 Hz), a methine bearing two oxygen atoms (δH 5.24 (d, J = 3.8 © 2017 American Chemical Society and American Society of Pharmacognosy

Received: July 16, 2017 Published: August 25, 2017 2536

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Table 1. 1H NMR and 13C NMR Data (600/150 MHz, CDCl3) for 1 and 2 1 no.

δC, type

1 2 3 4 5 6α 6β

99.4, 60.7, 38.5, 47.1, 49.0, 39.4,

CH CH CH CH C CH2

7α 7β 8 9 10 11 12 13 14 15

33.4, CH2 57.7, C 178.2, C 132.5, CH 135.8, CH 51.6, C 15.8, CH3 18.6, CH3 17.2, CH3

and NOE may be observed among these pairs. In spite of the hemiacetal substructure, 1 does not convert into the 1R-epimer in CDCl3 or CD3OD. The 1S-epimer would cause steric hindrance between the hydroxy group at C-1 and the olefin at C-10. The experimental ECD spectrum of 1 matched the calculated spectrum of 1S,2S,3S,4R,5S,8S,12R-1 (Figure 1c). Thereby, the structure of 1 was determined including the absolute configuration. Lamellodysidine B (2) has a molecular formula of C17H23NO3, shown by HRESIMS. The 1H NMR spectrum indicated the presence of two olefinic protons (δH 5.82 (s, H-2) and 5.73 (brd, J = 5.8 Hz, H-8)), three deshielded protons (δH 3.50 (d, J = 17.0 Hz, H-2′a), 4.11 (d, J = 17.0 Hz, H-2′b), and 4.17 (brs, H-10)), and three methyls (δH 0.79 (d, J = 6.7 Hz, H13), 0.99 (s, H-14), and 1.61 (s, H-15)) (Table 1). The 13C NMR spectra indicated the presence of two carbonyl carbons (δC 173.4 (C-1) and 175.4 (C-1’)), two double bonds (δC 123.6 (CH, C-2)/166.5 (C, C-3) and 139.4 (C, C-7)/124.3 (CH, C-8)), three methyls (δC 20.7 (C-13), 20.9 (C-15), and 26.5 (C-14)), four methylenes (δC 27.4 (C-4), 27.6 (C-11), 43.5 (C-5), and 44.0 (C-2’)), three methines (δC 30.5 (C-9), 40.1 (C-12), and 68.3 (C-10)), and a quaternary carbon (δC 40.8 (C-6)) (Table 1). The presence of spin systems, H-10/H9(/H-8)/H-11/H-12/H-13 and H-4/H-5, was indicated by the COSY spectrum (Figure 2a). Key HMBC cross-peaks, H-4α/

2 δH, mult (J in Hz)

no.

δC, type

5.24, 2.28, 2.64, 1.68,

1 2 3 4α 4β 5α 5β

173.4, C 123.6, CH 166.5, C 27.4, CH2

6 7 8 9 10 11α 11β 12 13 14 15 1’ 2’a 2’b

40.8, C 139.4, C 124.3, CH 30.5, CH 68.3, CH 27.6, CH2

d (3.8) d (3.8) m m

1.58, m 1.79, td (12.6, 4.6) 1.68, m 2.38, m

6.18, brt (8.2) 5.80, dd (8.2, 1.0) 1.14, s 0.78, s 0.81, d (7.3)

43.5, CH2

40.1, CH 20.7, CH3 26.5, CH3 20.9, CH3 175.4, C 44.0, CH2

δH, mult (J in Hz) 5.82, s 2.44, brd (12.1) 2.11, brt (12.1) 1.41, brt (12.5) 1.71, m

5.73, 2.65, 4.17, 1.22, 1.02, 1.48, 0.79, 0.99, 1.61,

brd (5.8) m brs m m m d (6.7) s s

3.50, d (17.0) 4.11, d (17.0)

Figure 2. (a) COSY and key HMBC correlations of 2, (b) the possible structures, A and B, and (c) key NOEs observed in two stable conformers 2a and 2b. Dashed black line: hydrogen bond.

Figure 1. (a) COSY and key HMBC correlations of 1, (b) key NOEs observed in 1, and (c) experimental ECD spectrum (MeCN) of 1 and calculated ECD spectrum of 1S,2S,3S,4R,5S,8S,12R-1 with B3LYP/ TZVP.

C-3, C-6, and C-10, H-14/C-5, C-6, C-7, and C-12, and H-15/ C-6, C-7, and C-8 showed the presence of a bicyclo[4.2.2]decane skeleton in 2 (Figure 2a). Furthermore, HMBC crosspeaks, H-2/C-1, C-3, C-4, and C-10, H-2′a/C-1 and C-1′, and H-2′b/C-10 and C-1′, showed a glycine moiety attached through an amide linkage at C-1 (Figure 2a). Considering the molecular formula, two possible structures, A and B, were suggested (Figure 2b). Chemical shift calculations based on quantum chemistry were conducted for A and B, and their standard deviations of differences between the calculated and experimental values were 2.2 and 6.0 ppm, respectively (Table 2). Among the differences, C-3 and C-10 for B showed large

tricyclic carbon skeleton. Additional HMBC correlations from H-1 and H-7 to C-9 demonstrated the presence of a γhydroxylated γ-lactone fused to the tricyclic skeleton, which completed the tetracyclic structure of 1 (Figure 1a). From the nature of the fused-ring system together with NOE correlations, H-1/H-3, H-10/H-15, H-2/H-4, and H-2/H-7α, the relative configurations of 1 were unambiguously assigned (Figure 1b). Although the chemical shifts of H-4 and H-7α were completely overlapped at δH 1.68, the calculated distances of H-2/H-4 and H-2/H-7α were 2.5 and 2.2 Å, respectively, 2537

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Table 2. Experimental 13C NMR Data (150 MHz, CDCl3) of 2 and Calculated Data Based on ωB97X-D/6-31G* for Possible Structures A and B 2

a

A

B

no.

δexp

δcalcd

δcalcd−δexp

δcalcd

δcalcd−δexp

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 1′ 2′ SDa

173.4 123.6 166.5 27.4 43.5 40.8 139.4 124.3 30.5 68.3 27.6 40.1 20.7 26.5 20.9 175.4 44.0

173.9 123.5 167.2 27.0 43.5 40.4 142.4 126.4 33.1 68.6 28.2 39.5 20.7 26.4 22.0 168.5 47.8

0.5 −0.1 0.7 −0.4 0.0 −0.4 3.0 2.1 2.6 0.3 0.6 −0.6 0.0 −0.1 1.1 −6.9 3.8 2.2

171.9 123.4 150.5 30.7 45.5 39.7 142.6 125.4 37.7 83.9 31.4 36.1 22.4 26.5 21.6 175.8 47.9

−1.4 −0.2 −16.0 3.3 2.0 −1.1 3.2 1.1 7.2 15.6 3.8 −4.0 1.7 0.0 0.7 0.4 3.9 6.0

Figure 3. Experimental ECD spectra (MeOH) of 2 and 5 and calculated spectra of 6S,9R,10R,12R-2 and 6S,9R,10R,12R-5 with the BHandHLYP/TZVP level. The wavelengths were corrected by +10 nm and +20 nm for 2 and 5, respectively.

Standard deviation.

differences (16.0 and 15.6 ppm, respectively). These results excluded the possibility of B, and A was more plausible for the structure of 2. The NOE correlations, H-4β/H-10 and H-8/H10, indicated that H-4β, H-8, and H-10 were β-oriented, whereas the correlations at H-2/H-4α, H-2/H-5α, and H-5α/ H-12 disclosed α-orientations of these protons (Figure 2c). Conformational analyses revealed that A was comprised of two major conformers (2a and 2b) caused by flipping of C-11−C12−C-13 with an almost 1:1 ratio (51.5 and 42.9% of the Boltzmann distribution, respectively). Both conformers satisfied all of the above NOEs. In addition, the NOE correlation H-9/ H-2′a (δH 3.50) was possible for A (both 2a and 2b) but not for B. Thus, the possibility of B was completely excluded. Thus, the structure of 2 including the relative configuration was determined, and, based on the structural relationship, 2 was a congener of O-methyl nakafuran-8 lactone18 (5). Although 5 was originally isolated from a Dysidea sp. marine sponge collected in the South China Sea, the absolute configuration was not reported.18 Therefore, the ECD spectra of 2 and 5 were calculated with a configuration of 6S,9R,10R,12R for both of them, and the calculated spectra showed negative Cotton effects around 250 nm similar to their experimental spectra (Figure 3). Therefore, the absolute configurations of 2 and 5 were confirmed to be 6S,9R,10R,12R. Compounds 3 and 4 were obtained as an inseparable mixture in the ratio of 1:1, which was indicated by the presence of two sets of slightly shifted signals in the 13C NMR spectrum (Table 2). This suggested two possibilities for 3 and 4: a mixture of structurally related isomers or an equilibrium mixture. A comprehensive analysis of 2D NMR spectra (Table 3) and HRESIMS data showed that the relative structures of 3 and 4 corresponded to those of 11-epimers of O,O-dimethyllingshuiolide A19 (6) (3R*,5R*,6S*). The cis relationship between Me-14 and Me-15 was indicated by the 13C chemical shift of C15 (δC 19.5) (3 and 4). Due to the γ-effect of these methyl groups in the cis isomer, C-15 is shielded more in the cis isomer (δC 20.9−21.1) than in the trans isomer (δC 26.3−26.6).19,20

Table 3. 1H NMR and 13C NMR Data (600/150 MHz, CDCl3) for 3/4 no.

δC, type

1 2 3 4α 4β 5 6 7 8

144.92/144.86, C 124.18/124.13, CH 72.91/72.90, CH 31.94/31.91, CH2

9 10 11 12 13 14 15 3-OMe 11-OMe

139.29/139.26, C 141.49/141.46, CH 102.35/102.34, CH 171.2, C 19.1, CH3 15.57/15.56, CH3 19.5, CH3 56.0, CH3 56.86/56.85, CH3

28.19/28.17, CH 40.9, C 33.8, CH2 20.47/20.45, CH2

δH, mult (J in Hz) 5.64, 3.54, 1.65, 1.50, 1.98,

d (4.2) brs m ddd (13.3, 13.3, 4.3) m

1.62, m 1.98, m 2.27, dt (16.5, 6.4) 6.72, s 5.69, s 1.69, 0.87, 0.82, 3.31, 3.54,

d (5.8) d (6.8) s s s

NOE correlations, H-4α/H-14, H-4α/3-OMe, and H-4β/H-15, assigned the relative configuration of the cyclohexene moiety of 3/4 (Figure 4a), which was the same as that of 6. The magnitude of the coupling constant, 4.3 Hz, between H-3 and H-4β clearly showed the gauche and anti configurations for H3/H-4β and 3-OMe/H-4β, respectively. These results suggested that 3 and 4 were (1) 11-epimers with the same absolute configurations for the cyclohexene moieties or (2) diastereomers with the same absolute configurations of C-11 together with the enantiomeric configurations in the cyclohexene moieties. The ECD spectrum of a mixture of 3 and 4 (1:1), 2538

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the simplified models, 11S-7 and 3R,5R,6S-8, were calculated and showed positive Cotton effects around 270 and 200 nm, respectively (Figure 4c). Because a mixture of 3 and 4 (1:1) showed no Cotton effect around 270 nm, the positive and negative Cotton effects due to 11S- and 11R-γ-methoxy butenolide moieties in 3/4, respectively, apparently canceled out, which clearly showed the 11-epimeric nature of 3/4. The absolute configurations of 3/4 were thereby concluded to be 3R,5R,6S, whereas the respective absolute configurations of C11 for 3 and 4 remain unknown. Because 3 and 4 are methyl ketals and MeOH was used in the extraction/isolation of these compounds, it is rather likely that the methyl ketals were formed from lingshuiolide A during the isolation process. Dendrolasin, which is a known sponge metabolite,21 may be the common precursor of the sesquiterpenes 1−5 isolated in this study (Scheme 1). Cyclization of dendrolasin followed by oxidation would afford allylic alcohol 9.20 Oxidation of 9 may yield lingshuiolide A (6), followed by methylation to form O,Odimethyllingshuiolide A/11-epi-O,O-dimethyllingshuiolide A (3/4). Acid catalyzed dehydration of 9 could yield an allylic cation intermediate 10. Deprotonation of 10 may afford a γhydroxybutenolide (11), which is converted to lamellodysidine A (1) via the intramolecular Diels−Alder reaction. Alternatively, cyclization of 10 could generate nakafuran-819,22 (12), followed by oxidation to form a keto acid intermediate 13. Condensation of 13 with MeOH could generate the ketal, Omethyl nakafuran-8 lactone (5). On the other hand, condensation of 13 with glycine followed by dehydration may produce lamellodysidine B (2). In this study, we isolated the structurally unique bridged polycyclic sesquiterpenes, 1 and 2. Although several polycyclic sesquiterpenes have been isolated from marine sponges to date,22−25 2 is a new nitrogenous sesquiterpene, and the skeleton of 1 is the first compound containing the unique bridged polycyclic framework. We succeeded in determination of the absolute configurations of 1−4 by interpretation of calculated ECD spectra. Biological activities of 1−5 were tested in our in-house screening including cytotoxicity, antimicrobial activities, inhibitory activity of the cholesterol ester accumu-

Figure 4. (a) Key NOEs and a coupling constant observed in the cyclohexene moiety of 3/4, (b) experimental ECD spectrum (MeOH) of 3/4, and (c) calculated ECD spectra of 11S-7 and 3R,5R,6S-8 with B3LYP/TZVP.

which was isolated in this study, showed a positive Cotton effect only around 200 nm (Figure 4b). In order to confirm the wavelength for Cotton effects due to the γ-oxygenated butenolide and cyclohexene moieties in 3/4, ECD spectra of Scheme 1. Plausible Route of Formation of 1−5

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3; HRESITOFMS m/z 317.1729 [M + Na]+ (calcd for C17H26NaO4, 317.1708). O-Methyl nakaf uran-8 lactone (5): [α]22D −34 (c 8.0, CHCl3) (lit.18 [α]25D −58 (c 0.16, CHCl3); ECD (MeOH) λmax (Δε) 254 (−37.2), 224 (10.8), 213 (0.760) nm; 1H and 13C NMR data were superimposable on the reported data.18 Conformational Analyses and Chemical Shift Calculations for Two Possible Structures A and B of 2. Conformational searches and chemical shift calculations for A and B conducted in the current study were performed with the Spartan′16 software (Wave function Inc.) using a commercially available PC (operating system, Windows 7 Professional SP1 64-bit; CPU, QuadCore Core i7-3770 processor 3.40 GHz; RAM, 8 GB). Stable conformers up to 10 kcal/ mol for A and B were initially searched using the Merck molecular force field (MMFF) method.26 Stable conformers suggested were further optimized using the Hartree−Fock (HF)/3-21G and ωB97XD/6-31G*, and then duplicate conformers were manually removed. The resulting conformers were subjected to chemical shift calculations using ωB97X-D/6-31G*. The obtained chemical shifts were corrected using the Boltzmann distribution to give calculated 13C chemical shifts, which were evaluated by standard deviations (SD) against the experimental data of 2 (Table 2). ECD Calculations for 2. ECD calculations for 2 were conducted with Gaussian09 (Revision D.01 by Gaussian)27 on a PC (Operating System, CentOS a Linux; CPU, Intel Xeon E5-2603 v3 processors 1.60 GHz; RAM, 32 GB). We selected the dominant conformers of 2 capable of covering >90% of the population from the Boltzmann’s law. Time-dependent density functional theory (TDDFT) calculations were conducted at the BHandHLYP/TZVP level for these conformers. The resulting rotational strength data were converted to Gaussian curves (bandwidth sigma = 3500 cm−1) to obtain the ECD spectra of the different conformers. The wavelength of the respective spectra was corrected (+10 nm), and then the spectra were correctively summed to give the corresponding theoretical ECD spectrum (Figure 3). Conformational Analyses and ECD Calculations for 1, 3/4, 5, 7, and 8. These experiments were performed as previously described.28 ECD calculations were performed at the B3LYP/TZVP level for 1, 3/4, 7, and 8 and at the BHandHLYP/TZVP level for 5. The wavelength was corrected (+20 nm) for 5, while no wavelength correction was conducted for 1, 3/4, 7, and 8.

lation in macrophages, inhibitory activity of the RANKL− induced formation of multinuclear osteoclasts, and inhibitory activities of the ubiquitin−proteasome system (proteasome, E1, Ubc13 (E2)−Uev1A interaction, p53−Mdm2 (E3) interaction, and USP7). However, no significant activity was detected for these compounds.

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EXPERIMENTAL SECTION

General Experimental Procedures. Optical rotations were measured on a JASCO DIP-1000 polarimeter in MeOH or CHCl3. UV spectra were measured on a JASCO V-550 spectrophotometer in MeCN or MeOH. ECD spectra were measured on a JASCO J-820 spectropolarimeter in MeCN or MeOH. IR spectra were recorded on a PerkinElmer Frontier FT-IR spectrophotometer. 1H and 13C NMR spectra were recorded on a Bruker Avance III 600 NMR spectrometer. Chemical shifts were referenced to the residual solvent peaks (δH 7.24 and δC 77.0 for CDCl3). HRESIMS spectra were measured on a Bruker BioTOFQ mass spectrometer. The preparative HPLC system comprised a Waters 515 HPLC pump, Waters 2489 UV/visible detector, and Pantos Unicorder U-228. Animal Material. The sponge, Lamellodysidea herbacea, was collected by scuba at a depth of 10 m in Manadotua Island, Indonesia, in December 2011 and soaked in EtOH immediately. A voucher specimen (RMNH POR 10908) of the sponge has been deposited in the Naturalis Biodiversity Center. Extraction and Isolation. The sponge (wet weight 52 g) was extracted with EtOH and MeOH. After evaporation, the residual aqueous solution was extracted with EtOAc and then n-BuOH. The EtOAc fraction was partitioned between n-hexane and 90% MeOH− H2O. The n-hexane fraction (148 mg) was purified by gel filtration HPLC (Asahipak GS-310P column, Asahi Chemical Industry Co., Ltd., 21.5 × 500 mm) with MeOH to yield 12 fractions (Frs. 1−12). Fr. 4 was further purified by C18 HPLC (COSMOSIL 5C18-AR-II column, Nacalai Tesque Inc., 20 × 250 mm) with MeOH/H2O (7:3) to yield 3/4 (1.0 mg). Fr. 6 was identified to be 5 (10.8 mg). The 90% MeOH−H2O fraction (186 mg) was purified by gel filtration HPLC (Asahipak GS-310P column, 21.5 × 500 mm) with MeOH, followed by purification by silica gel column chromatography with a stepwise gradient elution using n-hexane/EtOAc (4:1, 3:1, 2:1, 1:1, and 1:3) and MeOH to yield 10 fractions. The fraction (8.4 mg) that eluted with n-hexane/EtOAc (4:1 and 3:1) was purified by C18 HPLC (COSMOSIL 5C18-AR-II column, 20 × 250 mm) with MeOH/H2O (7:3) to yield 1 (1.7 mg). The n-BuOH fraction (144 mg) was purified by gel filtration HPLC (Asahipak GS-310P column, 21.5 × 500 mm) with MeOH, followed by purification by C18 column chromatography with a stepwise gradient elution using MeOH/H2O (1:1, 3:2, and 3:1) and MeOH to yield four fractions. The fraction (15 mg) that eluted with MeOH/H2O (1:1 and 3:2) was purified by C18 HPLC (COSMOSIL 5C18-AR-II column, 20 × 250 mm) with MeOH/ H2O (9:11) to yield 2 (6.1 mg). Lamellodysidine A (1): white solid; [α]23D −24 (c 1.3, MeOH); UV (MeOH) no absorption maximum above 210 nm; ECD (MeCN) λmax (Δε) 218 (−2.63), 208 (−5.36), 192 (1.44) nm; IR (film) νmax 3283, 3045, 2970, 2934, 2888, 1716, 1446, 1379, 1328, 1309, 1286, 1245, 1212, 1195, 1145, 1086, 996, 915 cm−1; 1H and 13C NMR data, Table 1; HRESITOFMS m/z 271.1278 [M + Na]+ (calcd for C15H20NaO3, 271.1310). Lamellodysidine B (2): pale yellow oil; [α]20D −133 (c 4.1, MeOH); UV (MeCN) λmax (log ε) 220 (2.8, sh) nm; ECD (MeOH) λmax (Δε) 246 (−8.92), 224 (−2.78), 206 (1.58) nm; IR (film) νmax 3407, 2966, 2933, 2877, 2852, 1661, 1603, 1428, 1386, 1308, 1249, 1136, 862 cm−1; 1H and 13C NMR data, Table 1; HRESITOFMS m/z 312.1581 [M + Na]+ (calcd for C17H23NNaO3, 312.1576). O,O-Dimethyllingshuiolide A/11-epi-O,O-dimethyllingshuiolide A (3 and 4, 1:1): white solid; [α]20D +38 (c 0.79, MeOH); UV (MeOH) no absorption maximum above 210 nm; ECD (MeOH) λmax (Δε) 207 (2.96) nm; IR (film) νmax 3242, 2961, 2927, 1768, 1661, 1445, 1366, 1337, 1206, 1157, 1079, 937, 859 cm−1; 1H and 13C NMR data, Table

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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.jnatprod.7b00610. 1D and 2D NMR spectra of 1−4; calculated UV spectra of 1, 2, 5, 7, and 8 (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Sachiko Tsukamoto: 0000-0002-7993-381X Author Contributions

M.T. and H.K. contributed equally to this work. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Prof. T. Nehira of Hiroshima University for his valuable advice on calculated ECD spectra and Prof. M. Namikoshi and Dr. K. Ukai of Tohoku Medical and Pharmaceutical University and Dr. H. Rotinsulu of Universitas Pembangunan for collecting the sponges. This work was 2540

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B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision A.02; Gaussian, Inc.: Wallingford, CT, 2009. (28) Kagiyama, I.; Kato, H.; Nehira, T.; Frisvad, J. C.; Sherman, D. H.; Williams, R. M.; Tsukamoto, S. Angew. Chem., Int. Ed. 2016, 55, 1128−1132.

supported by Grants-in-Aid for Scientific Research (Nos. 22406001 and 17H03994 to S.T.) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan.

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DOI: 10.1021/acs.jnatprod.7b00610 J. Nat. Prod. 2017, 80, 2536−2541