Enantiodivergence in the Biosynthesis of Bromotyrosine Alkaloids

Jan 13, 2017 - The isolation of bromotyrosine alkaloids, some of which are enantiomers of previously isolated compounds, has highlighted a possible ...
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Enantiodivergence in the Biosynthesis of Bromotyrosine Alkaloids from Sponges? Kavita Ragini,† Jane Fromont,‡ Andrew M. Piggott,† and Peter Karuso*,† †

Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW 2109, Australia Department of Aquatic Zoology, Western Australian Museum, Western Australia 6106, Australia

‡

S Supporting Information *

ABSTRACT: The isolation of bromotyrosine alkaloids, some of which are enantiomers of previously isolated compounds, has highlighted a possible enantiodivergence in their biosynthesis. Two new (1, 2) and six known bromotyrosine alkaloids (4−9), and the enantiomer (10) of a known compound, have been isolated from a Western Australian marine sponge, Pseudoceratina cf. verrucosa. The compounds inhibited the growth of multidrug-resistant and methicillin-resistant Staphylococcus aureus with comparable activity to vancomycin. In addition, one possible artifact of extraction (3) containing an ethoxy group was isolated. From analysis of the known bromotyrosine alkaloids, a biogenesis is proposed that explains the formation of antipodal natural products within this family of sponges.

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EtOAc partition of the aqueous ethanolic extract yielded 10 bromotyrosine-derived metabolites: two new compounds, pseudoceratinamide A (1) and pseudoceratinamide B (2), one artifact of isolation (3), six known compounds, (−)-purealidin R (4),5 aplysamine 2 (5),17 purpuramine I (6),3 araplysillin I (7),18 ianthesine B (8),19 and (−)-purealin (9),20 and one enantiomer of a known compound, 10.21 The structures of 1−10 were determined by analysis of their spectroscopic data, including UV, ECD, NMR, and HRESI(+)MS. Pseudoceratinamide A (1) was obtained as a levorotatory ([α]20D −10) solid with a protonated molecule isotopic cluster [M + H]+ at m/z 656/658/660/662/664 in the ratio 1:4:6:4:1, suggesting the presence of four bromine atoms. The molecular formula of 1 was assigned as C18H16Br4N2O5 based on HRESIMS of the [M + Na]+ adduct ion. The 1H NMR spectrum of 1 (DMSO-d6) showed the presence of 10 different signals. Because 1 was isolated in only a small quantity, not all carbons could be accounted for in the 1D 13C NMR spectrum, but together with the HMBC and HSQC spectra, one amide carbonyl (δC 158.8, νmax 1668 cm−1), eight nonprotonated carbons, four methines, three methylenes, and one methyl were assigned in addition to an NH (δH 8.54) and an OH (δH 6.39). Comparison of the NMR data for 1 (Table 1) with those reported for (−)-purealidin R (4)5 suggested that the two compounds contain identical spiro-cyclohexadienyl-isoxazoline moieties. The COSY NMR spectrum of 1 revealed a second

f all the marine invertebrates, sponges have been shown to be the most significant source of marine natural products.1 Marine sponges from the order Verongida are characterized by the production of bromotyrosine-derived alkaloids.2 Chemical modification occurring in both the side chains and aromatic rings of these alkaloids gives rise to a suite of biosynthetically related compounds with a diverse range of bioactivities,3 such as aplysamine 7 (anticancer),4 purealidin Q (EGFR kinase inhibition),3 and purpurealidin B (antibacterial).3 Another interesting aspect of these alkaloids is the isolation of antipodal congeners from closely related sponges. For example, (+)-purealidin R was isolated from Psammaplysilla purea5 and (−)-purealidin R from Pseudoceratina sp.6 In the unrelated oroidin alkaloids, this phenomenon has recently been suggested (and challenged) to arise from biosynthetic enantiodivergence,7−10 in parallel to the concept of enantiodivergent synthesis, which has been common in organic chemistry since the mid 1980s.11,12 This phenomenon may be about as common in terrestrial as marine natural products,13 with even a few examples of antipodal natural products produced by the same organism.14 During our investigations into brominated alkaloids from Australian sponges,15 we have previously reported the isolation of new and known alkaloids from a Pseudoceratina purpurea16 collected in New South Wales. Herein, we extend this work to investigate a Pseudoceratina cf. verrucosa collected from the remote northern coast of Western Australia. Chemical dereplication (HPLC-ESIMS) showed P. verrucosa to be rich in brominated alkaloids, including compounds with molecular weights not previously reported. Reversed-phase HPLC of the © 2017 American Chemical Society and American Society of Pharmacognosy

Received: November 11, 2016 Published: January 13, 2017 215

DOI: 10.1021/acs.jnatprod.6b01038 J. Nat. Prod. 2017, 80, 215−219

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Table 1. NMR Data (DMSO-d6, 1H 600 MHz, 13C 150 MHz) for Compounds 1−3 pseudoceratinamide A (1) positiona 1 2 3 4 5 6 7 8 9 1′ 2′ 3′ 4′ 5′ 6′ 7′ 8′ 3-OMe 1′-NH 1-OH a

δC, type 73.5, 113.1, 147.1, 120.9, 131.2, 90.2, 39.2, 154.5, 158.8, 40.5, 33.0, 131.1, 131.9, 118.5, 151.5, 118.5, 131.9, 59.6,

CH C C C CH C CH2 C C CH2 CH2 C CH C C C CH CH3

δH (J in Hz) 3.89, s

6.56, d (0.9) 3.58, d (18.0), 3.18, d (18.0)

3.30, m 2.63, t (7.0) 7.30, s

7.30, 3.63, 8.54, 6.39,

s s t (5.8) br s

pseudoceratinamide B (2) δC, type 73.6, 113.0, 147.1, 121.1, 131.2, 90.1, 39.7, 154.5, 158.8, 40.5, 33.4, 131.4, 132.7, 109.0, 152.6, 116.3, 129.0, 59.8,

CH C C C CH C CH2 C C CH2 CH2 C CH C C CH CH CH3

δH (J in Hz) 3.89, d (7.9)

6.57, d (0.9) 3.58, d (17.8), 3.18, d (17.8)

3.30b 2.65, t (7.4) 7.30, d (2.0)

6.85, 6.99, 3.63, 8.54, 6.37,

d (8.2) dd (8.2, 2.0) s t (5.8) d (7.9)

compound 3 δC, type 73.6, 113.1, 147.1, 120.8, 131.3, 90.1, 39.5, 154.5, 158.8, 38.7, 33.1, 23.0, 91.8, 171.0, 186.0, 57.8, 15.2, 59.6,

CH C C C CH C CH2 C C CH2 CH2 CH2 C C C CH2 CH3 CH3

δH (J in Hz) 3.90, d (7.0)

6.56, s 3.59, d (18.0), 3.18, d (18.0)

3.11, m 1.75, m 1.45, m; 1.33, m

3.36, 1.07, 3.63, 8.55, 6.37,

m; 3.13, m t (7.0) s t (6.0) d (7.0)

See Figure 1 for locant numbering. bObscured by H2O signal.

Figure 1. Key HMBC, COSY, and ROESY correlations of 1−3. 1

spin system indicative of an aminoethylene unit (δH 8.54, t, J = 5.8 Hz, NH; 3.30, m, CH2; 2.63, t, J = 7.0 Hz, CH2). The remaining pair of equivalent aryl protons (δH 7.30, s, 2 × CH), two bromine atoms, and one hydroxy group could be accommodated by a symmetrically substituted dibromophenol moiety. HMBC correlations from H-2′ to C-4′/C-8′ and ROESY correlations from H-2′ to H-4′/H-8′ (Figure 1) positioned the aminoethylene group between the two aryl protons, necessitating the phenolic hydroxy group be positioned ortho to each bromine. An amide linkage between the aminoethylene and spiroisoxazoline moieties was confirmed by HMBC correlations from H-1′ and 1′-NH to the C-9 carbonyl carbon (δC 158.8). The remaining 2D NMR correlations (Figure 1) were the same as those reported for 45 and confirmed the structure of 1 as shown. Pseudoceratinamide B (2) was obtained as a levorotatory ([α]20D −4) solid with a UV spectrum (λmax 250 and 290 nm) similar to 1. ESIMS analysis revealed a protonated molecule [M + H]+ isotopic cluster at m/z 579/581/583/585 in the ratio 1:3:3:1, suggesting the presence of three bromine atoms. The molecular formula of 2 was assigned as C18H17Br3N2O5 based on HRESIMS. The NMR data for 2 were very similar to those for 1 (Table 1), with the only significant difference being the presence of an extra aromatic proton with an ortho-coupling in 2 (δH 6.85, d, J = 8.2 Hz), in place of the two equivalent metacoupled protons (H-4′/H-8′) in 1, indicative of a 7′-debromo analogue. Analysis of key 2D NMR correlations (Figure 1) and

H NMR coupling constants confirmed the structure of 2 as shown. Compounds 1 and 2 both showed negative specific rotations and negative Cotton effects at 250 and 290 nm in their ECD spectra, which match the ECD spectrum of 7,18 suggesting they share the same 1S,6R configuration. Although the enantiomer of 1 has tentatively been isolated as a base-catalyzed degradation product of 19-deoxy-11-oxofistularin 3,22 this is the first report of its isolation as a natural product. Compound 3 was obtained as a levorotatory ([α]20D −1.4) solid with a slightly different UV spectrum (λmax 228, 242, and 287 nm) from 1 and 2. ESIMS analysis of 3 showed a protonated molecule [M + H]+ isotopic cluster at m/z 564/ 566/568 in the ratio 1:2:1, suggesting the presence of two bromine atoms. The molecular formula of 3 was assigned as C18H23Br2N5O6 based on HRESIMS. The 13C NMR spectrum of 3 (Table 1) displayed signals for 18 carbons, including one amide carbonyl carbon (δC 158.8), eight nonprotonated carbons, two methines, five methylenes and two methyls, similar to those previously reported for 14-oxoaerophobin 2 (11),23 with the only significant differences being the presence of an additional ethoxy moiety (δH 1.07, t, J = 7.0 Hz, CH3; 3.36/3.13, m, CH2O) and the absence of the aminoimidazolone methine proton. HMBC correlations from H-2′, H-3′, and H-7′ to C-4′ (Figure 1) confirmed the structure of 3 to be the 4′ethoxy adduct of 11. As no similar ethyl or methyl ethers have been reported in the literature, it is likely that 3 is the reaction 216

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product of an electrophilic natural product, such as 3a or 3c, with EtOH, the extraction solvent (Scheme 1). HPLC-ESIMS Scheme 1. Proposed Abiotic Synthesis of 3 from Putative Intermediate 3a′ or 3c

comparison of known (+)- and (−)-spiroisoxazolines with the araplysillins revealed several inconsistencies in the literature that suggest the published structures of araplysillin-I, araplysillin-II, and several other analogues are incorrect. The original report for araplysillins-I and -II noted negative specific rotations, but no comment was made regarding the absolute configuration in the text.18 The authors arbitrarily depicted the 1R,6S configuration for both compounds, which is now known to be inconsistent with negative specific rotations in this class of compounds. Some subsequent compounds (araplysillins IV and V, araplysillin N-formamide, and araplysillin N-oxide)28 were also drawn with 1R,6S configurations, despite the authors assigning 1S,6R configurations in the text based on their negative specific rotations and negative Cotton effects. Likewise, 19-hydroxyaraplysillin-I N-sulfamate29 and araplysillin-I N-sulfamate29 were depicted with 1R,6S configurations, despite the authors tentatively assigning 1S,6R configurations based on their negative specific rotations. Therefore, we propose that the structures of the above-mentioned araplysillins and their analogues with negative specific rotations and negative Cotton effects should be revised to reflect a common 1S,6R absolute configuration. A thorough review of the literature for all known spiroisoxazolines for which ECD and specific rotation are reported has revealed an absolute correlation between the sign of the specific rotation and the Cotton effect at 250 and 290 nm. The most interesting feature of our compounds is that they all share the same 1S,6R absolute configurations (negative Cotton effects at 290 and 250 nm and negative specific rotations), whereas the majority of this class of alkaloids have 1R,6S configurations (positive Cotton effects and positive specific rotations). Indeed, 10 is the enantiomer of the same compound isolated from Aplysina f ulva.21 This suggests there is an enantiodivergent step in the biosynthesis of this class of alkaloids that leads to increased structural diversity.8 This is most likely to occur at the dearomatization step (Figure 2), which is catalyzed by a monooxygenase (possibly a cytochrome P45030). Starting from tyrosine, deamination (aminotransferase), methylation (methylase), bromination (bromoperoxidase), and conversion of the keto group (oximinotransferase) yields an oxime. To generate the spiroisoxazoline, it is believed that a monooxygenase epoxidizes the aromatic ring, which can cyclize to give the isoxazoline (Figure 2).8 The enantiotopic epoxidation is an interesting enantiodivergent desymmetrization that leads to two closely related sets of antipodes, and sometimes actual enantiomers such as 4, 9 and 10, being

analysis of the crude extract showed a minor peak with a protonated molecule isotopic cluster at m/z 517.9/519.9/521.9 (Supporting Information, Figure S23), corresponding to a monoisotopic molecular weight mass of 516.96 and a molecular formula of C16H17Br2N5O5, consistent with structure 3a or 3a′. No evidence of 3b or 3c was obtained from LCMS analysis of the crude extract. These data suggest it is plausible that 3a′ could have reacted with EtOH, a weak nucleophile, to produce 3 abiotically. A similar biogenetic proposal, involving highly reactive intermediates, such as 2-aminoimidazolones, has been proposed by Al-Mourabit and Potier in relation to the biosynthesis of oroidin alkaloids.24 Enantioselective HPLC analysis of 3 with α-cyclodextrin in the mobile phase25 revealed two peaks in a 1:1 ratio (Figure S24), suggesting 3 is a mixture of C-4′ epimers. Despite being a mixture of diastereomers, no doubling of signals was observed in the 1H and 13C NMR spectra of 3 (Figure S15), most likely due to the flexibility of the molecule resulting in little interaction between the remote chiral centers. This phenomenon was also observed with 8,19 which contains a terminal amino acid found to be a 7:3 mixture of the L- and D-forms, yet only showed one set of NMR signals and eluted as a single peak on HPLC. Compound 10 was identified as the previously reported natural product based on comparison of NMR data and mass spectrometry.22 However, our measured specific rotation ([α]D −9) was not consistent with the rotation published for the 1R,6S enantiomer of 10 ([α]D +140),21 suggesting our compound could be a scalemic mixture. Enantioselective HPLC analysis of 10 (Figure S28) yielded a single peak, suggesting that 10 is enantiomerically pure. While it is unclear why the absolute values of these specific rotations do not match, it is noteworthy that many related structures (e.g., purealidin B, purealidin P, purealidin Q, purealidin T, purealidin U, and purpurealidin A)3,5,26 also have specific rotations with magnitudes less than 10 deg cm2 g−1. It is also well known that specific rotations can be highly dependent on the counterion, and it is possible that the compound isolated by Molinski, which was purified by HPLC without the addition of an acid, was a natural salt, whereas ours is the free acid (purified using TFA; pKa = 0.25).21 The electronic circular dichroism (ECD) spectra of 4 and 7− 10 (Supporting Information) all showed negative Cotton effects at 255 and 290 nm, which agreed with those reported for (−)-aeroplysinin-1 (12), whose absolute configuration has been established unequivocally as 1S,6R through ECD and X-ray crystallography.27 In addressing the absolute configuration of 7, 217

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biogenesis that explains the formation of antipodal natural products within this family of sponges.

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EXPERIMENTAL SECTION

General Experimental Procedures. Optical rotations were measured on a Jasco P-1010 polarimeter (Jasco). UV measurements were performed on a SpectraMax M5 spectrophotometer (Molecular Devices). Circular dichroism spectra were acquired on a Jasco J-810 spectropolarimeter. Infrared spectra were recorded on a PerkinElmer Paragon 1000PC FTIR spectrometer or Nicolet iS10 FT-IR spectrometer (Thermo Scientific). 1H NMR and 13C NMR spectra were recorded in 5 mm Shigemi tubes on a Bruker Avance AVII 600 MHz spectrometer in DMSO-d6. All spectra were obtained at 25 °C, processed using Bruker Topspin 3.2, and referenced to residual solvent peaks (DMSO-d6, δH 2.49 and δC 39.52 ppm). Mass spectrometry was performed by electrospray ionization (ESI) in positive polarity mode on a Shimadzu LC-20A Prominence system coupled to an LCMS2010 EV single quadrupole mass spectrometer. High-resolution ESIMS experiments were carried out on an Agilent UHD Accurate Mass Q-TOF liquid chromatography mass spectrometer or a Bruker 7 T Fourier transform ion cyclotron resonance mass spectrometer. The samples were analyzed by direct infusion in positive polarity mode. HPLC separations were achieved on a Waters 600-MS system controller using a Shimadzu SPD-6AV UV−vis spectrophotometric detector and on a Gilson 506C HPLC system with a Gilson 215 liquid handling platform running UNIPOINT version 5.11 LC system software. Analytical and preparative HPLC were performed on Synergi Max-RP HPLC columns (Phenomenex, Sydney, Australia): Synergi 10 μm Max-RP 80 Å 250 × 4.6 mm and Synergi 10 μm MAX-RP 80 Å 250 × 21.2 mm, respectively. Biological Material. The sponge was collected by scuba from Dampier, Western Australia, in October 1998 at 3 m depth. The samples were frozen upon collection and stored at −20 °C. The sample was identified as Pseudoceratina cf. verrucosa (class Demospongiae, order Verongida, family Pseudoceratinidae). A voucher specimen with the registration number WAMZ3084 is in the collections at the Western Australia Museum. Another voucher specimen is deposited at the Department of Chemistry and Biomolecular Sciences, Macquarie University, also under the same number. Extraction and Isolation. The frozen sponge (141.6 g) was homogenized in EtOH (3 × 1 L), and the combined EtOH extracts were filtered and evaporated to approximately 1 L. The extract was partitioned with hexane (3 × 500 mL), EtOAc (3 × 500 mL), and 1BuOH (2 × 200 mL) to yield 0.51, 3.37, and 0.80 g of extracts, respectively. The EtOAc extract was subjected to gel permeation chromatography (Sephadex LH-20; 1:1 CHCl3−MeOH) to afford four fractions (F1−F4). Fraction F3 (258.2 mg) was passed through an Alltech high-capacity C18 solid-phase extraction cartridge using 90% CH3CN in H2O, and the resulting extract was purified on an RP HPLC column (Synergi Max-RP C12, 10 μm, 250 × 22 mm) using a gradient from 20% to 60% CH3CN in H2O to afford compounds 3 and 5−9. Fraction F4 (210.1 mg) was also passed through an Alltech high-capacity C18 solid-phase extraction cartridge using 90% CH3CN in H2O, and the resulting extract was purified on an RP HPLC column (Synergi Max-RP C12, 10 μm, 250 × 22 mm) using a gradient from 20% to 80% CH3CN in H2O to afford compounds 1, 2, 4, and 10. Enantioselective HPLC was carried out on a C18 analytical column (Gemini C18, 3 μm, 150 × 2.0 mm) with a gradient from 0% to 45% CH3CN in H2O containing a homochiral reagent: α-cyclodextrin (0.0004 wt %/vol), flow rate 1 mL/min, and UV detection at 290 nm. Pseudoceratinamide A (1): light brown, amorphous solid (0.7 mg); [α]20D −10 (c 0.35, MeOH); UV (MeOH) λmax (log ε) 250 (3.78), 292 (3.60) nm; ECD (c 0.1 mM, MeOH) λmax (Δε) 252 (−1.3), 292 (−1.3) nm; IR (neat film) νmax 3324 (br), 1668, 1596, 1541, 1273, 1204, 1134 cm−1; 1H and 13C NMR data, Table 1; ESIMS m/z 656, 658, 660, 663, 665 [M + H]+ isotopic cluster in the ratio 1:4:6:4:1; HRESIMS m/z 678.7692 [M + Na]+ (calcd for C18H16Br4N2O5Na, 678.7690).

Figure 2. Proposed biogenesis of bromotyrosine alkaloids showing the enantiodivergent epoxidation of the symmetrical dibromomethoxybenzene intermediate and enantioconvergent electrocyclic ring opening involved in isoxazoline and oxepin formation, respectively.

produced by different species. There are also some 30 dihydrooxepin analogues known, all of which feature an αhydroxy group on the spiroisoxazoline, a feature that is not seen in any of the cyclohexadiene analogues. The oxepin can be formed from the common epoxide intermediate via an enantioconvergent thermally allowed disrotatory electrocyclic ring opening, followed by a 1,3-sigmatropic hydride shift and a second epoxidation that is trapped by the oxime to produce the dihydrooxepins (Figure 2). Compounds 1−10 were obtained in small quantities and were therefore only assayed against three strains of Staphylococcus aureus and one strain of Escherichia coli using the overlay TLC bioautography method31 (Table S1). All compounds showed moderate activity against the S. aureus strains, with new compounds 1 and 2 having significant activity minimum inhibitory quantity (MIQ, 0.31 μg) against methicillin-sensitive S. aureus. Compound 9 showed comparable activity to vancomycin (MIQ 0.63 μg) against multidrugresistant S. aureus, and compounds 2, 3, 5, 6, 7, and 9 showed comparable activity to vancomycin (MIQ 0.63 μg) against methicillin-resistant S. aureus. None of the compounds showed activity against E. coli. In summary, two new antimicrobial marine alkaloids, pseudoceratinamides A (1) and B (2), together with an artifact of extraction (3) and the enantiomer of a known compound (10), were isolated from the West Australian marine sponge P. cf. verrucosa. Their absolute configurations were determined by spectroscopic analysis and specific rotations/circular dichroism. This suggested that the original structures of the araplysillins depicted the incorrect enantiomers and that these structures and some others based on this precedent need to be revised. All compounds showed moderate activity against S. aureus but no activity against E. coli. Compound 9 showed good activity against multidrug-resistant strains of S. aureus. More interestingly, the isolation of these compounds, some of which are enantiomers of previously isolated compounds, has highlighted a possible enantiodivergent step in their biosynthesis. From analysis of the known bromotyrosine alkaloids, we propose a 218

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Pseudoceratinamide B (2): light brown, amorphous solid (0.7 mg); [α]20D −4 (c 0.35, MeOH); UV (MeOH) λmax (log ε) 250 (3.70), 290 (3.60) nm; ECD (c 0.06 mM, MeOH) λmax (Δε) 255 (−0.4), 289 (−0.4) nm; IR (neat film) νmax 3337 (br), 2977, 1733, 1635, 1418, 1254, 1208, 1159 cm−1; 1H and 13C NMR data, Table 1; ESIMS m/z 578, 580, 582, 584 [M + H]+ isotopic cluster in the ratio 1:3:3:1; HRESIMS m/z 600.8582 [M + Na]+ (calcd for C18H17Br3N2O5Na, 600.8585). Compound 3: light brown, amorphous solid (1.8 mg); [α]20D −1.4 (c 0.45, MeOH); UV (MeOH) λmax (log ε) 256 (3.48), 287 (3.30) nm; ECD (c 0.2 mM, MeOH) λmax (Δε) 256 (−0.2), 287 (−0.2) nm; IR (neat film) νmax 3313 (br), 2976, 1668, 1652, 1594, 1310, 1048 cm−1; 1H and 13C NMR data, Table 1; ESIMS m/z 564, 566, 568 [M + H]+ isotopic cluster in the ratio 1:2:1; HRESIMS m/z 564.0109 [M + H]+ (calcd for C18H24Br2N5O6, 564.0093). Compound 10: white, amorphous solid (1.0 mg); [α]20D −9 (c 0.4, MeOH) lit.21 +140 (c 0.04, MeOH); UV (MeOH) λmax (log ε) 230 (3.00), 290 (2.70) nm; ECD (c 0.07 mM, MeOH) λmax (Δε) 253 (−0.3), 290 (−0.3) nm; 1H NMR (DMSO-d6, 600 MHz) δ 8.54 (t, J = 5.7 Hz, NH), 6.57 (s, H-5), 6.36 (br s, 1-OH), 3.90 (s, H-1), 3.63 (s, OCH3), 3.40 (d, J = 18.1 Hz, H-7a), 3.20 (d, J = 18.1 Hz, H-7b), 3.15 (q, J = 6.7 Hz, H-1′), 2.21 (t, J = 7.4 Hz, H-3′), 1.67 (p, J = 7.1 Hz, H2′); ESIMS m/z 467, 469, 471 [M + H]+ isotopic cluster in the ratio 1:2:1.

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(7) Beniddir, M. A.; Evanno, L.; Joseph, D.; Skiredj, A.; Poupon, E. Nat. Prod. Rep. 2016, 33, 820−842. (8) Ma, Z.; Wang, X.; Wang, X.; Rodriguez, R. A.; Moore, C. E.; Gao, S.; Tan, X.; Ma, Y.; Rheingold, A. L.; Baran, P. S.; Chen, C. Science 2014, 346, 219−224. (9) Sherman, D. H.; Tsukamoto, S.; Williams, R. M. Science 2015, 349, 149b. (10) Ma, Z.; Wang, X.; Wang, X.; Rodriguez, R. A.; Moore, C. E.; Gao, S.; Tan, X.; Ma, Y.; Rheingold, A. L.; Baran, P. S.; Chen, C. Science 2015, 349, 149−149. (11) Bartlett, P. A.; Meadows, J. D.; Ottow, E. J. Am. Chem. Soc. 1984, 106, 5304−5311. (12) McGarvey, G. J.; Hiner, R. N.; Matsubara, Y.; Oh, T. Tetrahedron Lett. 1983, 24, 2733−2736. (13) Finefield, J. M.; Sherman, D. H.; Kreitman, M.; Williams, R. M. Angew. Chem., Int. Ed. 2012, 51, 4802−4836. (14) Tsuda, M.; Kawasaki, N.; Kobayashi, J. Tetrahedron 1994, 50, 7957−7960. (15) Hao, E.; Fromont, J.; Jardine, D.; Karuso, P. Molecules 2001, 6, 130−141. (16) Gotsbacher, M. P.; Karuso, P. Mar. Drugs 2015, 13, 1389−1409. (17) Xynas, R.; Capon, R. J. Aust. J. Chem. 1989, 42, 1427−1433. (18) Longeon, A.; Guyot, M.; Vacelet, J. Experientia 1990, 46, 548− 550. (19) Okamoto, Y.; Ojika, M.; Kato, S.; Sakagami, Y. Tetrahedron 2000, 56, 5813−5818. (20) Nakamura, H.; Wu, H.; Kobayashi, J. i.; Nakamura, Y.; Ohizumi, Y.; Hirata, Y. Tetrahedron Lett. 1985, 26, 4517−4520. (21) Rogers, E. W.; Molinski, T. F. J. Nat. Prod. 2007, 70, 1191− 1194. (22) Mancini, I.; Guella, G.; Laboute, P.; Debitus, C.; Pietra, F. J. Chem. Soc., Perkin Trans. 1 1993, 1, 3121−3125. (23) Fendert, T.; Wray, V.; van Soest, R. W. M.; Proksch, P. Z. Naturforsch., C: J. Biosci. 1999, 54c, 246−252. (24) Al-Mourabit, A.; Potier, P. Eur. J. Org. Chem. 2001, 2001, 237− 243. (25) Szeman, J.; Ganzler, K. J. Chromatogr. A 1994, 668, 509−517. (26) Kobayashi, J. i.; Tsuda, M.; Agemi, K.; Shigemori, H.; Ishibashi, M.; Sasaki, T.; Mikami, Y. Tetrahedron 1991, 47, 6617−6622. (27) McMillan, J. A.; Paul, I. C.; Goo, Y. M.; Rinehart, K. L.; Krueger, W. C.; Pschigoda, L. M. Tetrahedron Lett. 1981, 22, 39−42. (28) Mani, L.; Jullian, V.; Mourkazel, B.; Valentin, A.; Dubois, J.; Cresteil, T.; Folcher, E.; Hooper, J. N. A.; Erpenbeck, D.; Aalbersberg, W.; Debitus, C. Chem. Biodiversity 2012, 9, 1436−1451. (29) Motti, C. A.; Freckelton, M. L.; Tapiolas, D. M.; Willis, R. H. J. Nat. Prod. 2009, 72, 290−294. (30) Stok, J. E.; Chow, S.; Krenske, E. H.; Soto, C. F.; Matyas, C.; Poirier, R. A.; Williams, C. M.; De Voss, J. J. Chem. - Eur. J. 2016, 22, 4408−4412. (31) Rahalison, L.; Hamburger, M.; Hostettmann, K.; Monod, M.; Frenk, E. Phytochem. Anal. 1991, 2, 199−203.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.6b01038. Bioassay results, NMR spectra, tabulated 2D NMR data, HRMS, UV and ECD data, enantioselective HPLC chromatograms (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: +61-2-9850-8290. Fax: +61-2-9850-8313. ORCID

Peter Karuso: 0000-0002-0217-6021 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Dr A. Dass (APAF, Macquarie University) and Dr. N. Proschogo (University of Sydney) for HRMS data. We also thank T. Malewska (Macquarie University) for assistance with the antibacterial assay. This work was funded, in part, by the Australian Research Council (FT130100142 to A.M.P. and DP130103281 to P.K. and A.M.P.) and Macquarie University (iMQRES to K.R.).

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REFERENCES

(1) Faulkner, D. J. Nat. Prod. Rep. 2001, 18, 1−49. (2) Peng, J.; Li, J.; Hamann, M. T., The Marine Bromotyrosine Derivatives. In The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.; Academic Press, 2005; Vol. 61, pp 59−262. (3) Tilvi, S.; Rodrigues, C.; Naik, C. G.; Parameswaran, P. S.; Wahidhulla, S. Tetrahedron 2004, 60, 10207−10215. (4) Tran, T. D.; Pham, N. B.; Fechner, G.; Hooper, J. N.; Quinn, R. J. J. Nat. Prod. 2013, 76, 516−523. (5) Kobayashi, J. i.; Honma, K.; Sasaki, T.; Tsuda, M. Chem. Pharm. Bull. 1995, 43, 403−407. (6) Salim, A. A.; Khalil, Z. G.; Capon, R. J. Tetrahedron 2012, 68, 9802−9807. 219

DOI: 10.1021/acs.jnatprod.6b01038 J. Nat. Prod. 2017, 80, 215−219