Total Syntheses of Malabaricones B and C via a Cross-Metathesis

Jun 5, 2017 - ... C via a Cross-Metathesis Strategy. Kshama Kundu and Sandip K. Nayak. Bio-Organic Division, Bhabha Atomic Research Centre, Trombay, ...
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Total Syntheses of Malabaricones B and C via a Cross-Metathesis Strategy Kshama Kundu and Sandip K. Nayak* Bio-Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India S Supporting Information *

ABSTRACT: The malabaricones A−D belong to the class of diarylnonanoids isolated from the Myristicaceae family of plants. Although malabaricone C displayed various interesting biological activities, its isolation remains tedious due to its close chemical similarity to malabaricones A, B, and D. Therefore, development of an efficient synthesis route has become essential to cater to the need of large amounts of malabaricone C for its pharmacological profiling. So far there is only one report of the synthesis of malabaricone C through a lengthy sequence of reactions. We have developed an efficient and short route for the syntheses of malabaricones B and C, which will also provide a convenient access to all other members of the malabaricone family. Synthesis of an important building block, ω-aryl heptyl bromide, employed in the synthesis was realized by adopting a cross-metathesis reaction as the key step.

T

he malabaricones constitute an important class of natural products isolated from the Myristicaceae family of plants.1 Four species of the Myristica genus, M. ceylanica, M. dactyloides, M. malabarica, and M. fragrans, are found in Sri Lanka and the southern part of India.2 All these species have been used as folk medicine for many years.3,4 Owing to their interesting pharmacological profile, the chemical constituents of M. f ragrans and M. dactyloides have been studied extensively. This has led to the isolation of various compounds including diarylnonanoids, which are referred to as malabaricones.5−11 Among these natural products, malabaricones B and C displayed various interesting biological activities including nematocidal,12 antiinflammatory,13 antioxidant,14 anti-quorum sensing,15 antimicrobial,16 antifungal,17 antipromastigote,18 acetylcholinestearase inhibitory,19 antiproliferative,20 and cytotoxicity21 effects against human cancer cell lines, antihypertensive effects,22 and gastroprotective properties against stomach ulceration.23 In addition, these molecules also exhibited blood-brain-barrier permeability.24 In our laboratory, fruit rinds of M. malabarica have been used as a source of malabaricone C.14b However, its isolation in pure form has always remained a laborious task because of the close chemical similarity it shares with malabaricones A, B, and D (Figure 1). A mechanistic probe into its pharmacological profile may require a significant amount of malabaricone C, which prompted the development of a practical route for its synthesis. Olefin cross-metathesis has emerged as an essential tool in organic synthesis for the formation of carbon−carbon bonds.25 The efficacy of this reaction has been manifested in the total synthesis of a wide range of natural products.26 Herein, the total syntheses of malabaricones B and C via a cross-metathesis © 2017 American Chemical Society and American Society of Pharmacognosy

Figure 1. Structures of malabaricones A−D.

reaction between allylarenes and 6-bromohex-1-ene (2) as a key step are disclosed.

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RESULTS AND DISCUSSION As shown in Figure 1, malabaricone C contains a 3,4dihydroxyphenyl group and a 2,6-dihydroxybenzoyl moiety linked by a spacer comprising eight methylene units.27 So far, there is only one report by Tsuda et al.28 on the synthesis of malabaricone C (11 steps), wherein aldol reaction of 2benzyloxy-6-hydroxyacetophenone with 7-(3,4dimethoxyphenyl)heptanal was used as a key step to form the corresponding β-hydroxy ketone. The hydroxy ketone on dehydration, followed by catalytic hydrogenation and demethylation, led to the formation of malabaricone C. The required 7-arylheptanal was derived from 1,6-hexanediol using a lengthy sequence of reactions (six steps). This prompted the development of an efficient and concise route toward the total synthesis of malabaricone C. Received: December 5, 2016 Published: June 5, 2017 1776

DOI: 10.1021/acs.jnatprod.6b01119 J. Nat. Prod. 2017, 80, 1776−1782

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Scheme 1. Retrosynthesis Analysis for the Synthesis of Malabaricone C

Scheme 2. Attempted Route to the Synthesis of a Malabaricone Analogue

The first retrosynthesis analysis of malabaricone C is illustrated in Scheme 1 (route A). The two key steps in the retrosynthesis are (i) alkylation of the aromatic β-keto ester (derived from 2′,6′-dimethoxyacetophenone) with 2 and (ii) cross-metathesis of the allylarene 3a with the terminal alkene substituted β-keto ester. Before embarking on the actual synthesis of malabaricone C, a compound that is a close

structural analogue, i.e., 9-(4-hydroxyphenyl)-1-phenylnonan-1one (12b), was chosen as a model target for the optimization of the different synthesis steps. Accordingly, alkylation of ethyl benzoylacetate (5) with 2, using NaH/THF, afforded 6 in 51% yield. A cross-metathesis reaction of 6 with 2 equiv of 4-allylanisole (3b), using Grubbs I catalyst, yielded the homocoupled products 7 and 8, along with 1777

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Scheme 3. Syntheses of (7-Bromoheptyl)arene Intermediates 4a/4b via a Cross-Metathesis Strategy

Scheme 4. Total Syntheses of Malabaricones B and C

Table 1. NMR Spectroscopic Data of Malabaricone C19b (19a) and Malabaricone B19b (19b) malabaricone B natural product

a1

pos

δC

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

209.7 45.8 25.8 30.3 30.5 30.5 30.6 33.0 36.1 131.0 130.3 116.0 156.2 116.0 130.3 111.5 163.4 108.4 136.9 108.4 163.4

a

δH (J in Hz) 3.11, 1.67, 1.35, 1.35, 1.35, 1.35, 1.55, 2.49,

t (8.0) m m m m m m t (8.0)

6.97, d (8.0) 6.69, d (8.0) 6.69, d (8.0) 6.97, d (8.0)

6.35, d (8.0) 7.19, t (8.0) 6.35, d (8.0)

malabaricone C synthetic

δC 210.0 45.7 25.9 30.3 30.5 30.5 30.6 33.0 36.1 135.1 130.3 116.2 156.2 116.2 130.3 111.7 163.4 108.6 136.9 108.6 163.4

a

natural product

δH (J in Hz) 3.10, 1.66, 1.33, 1.33, 1.33, 1.33, 1.55, 2.49,

δC 209.7 45.8 25.8 30.5 30.6 30.6 30.3 32.9 36.3 135.8 116.6 146.0 144.0 116.2 120.7 111.5 163.4 108.4 136.8 108.4 163.4

t (7.5) m m m m m m t (7.5)

6.97, d (8.5) 6.68, d (8.5) 6.68, d (8.5) 6.97, d (8.5)

6.35, d (8.0) 7.19, t (8.0) 6.35, d (8.0)

a

δH (J in Hz) 3.12, 1.67, 1.36, 1.36, 1.36, 1.36, 1.56, 2.45,

t (8.0) m m m m m m t (8.0)

6.62, d (2.0)

6.67, d (8.0) 6.48, dd (8.0, 2.0)

6.35, d (8.0) 7.20, t (8.0) 6.35, d (8.0)

synthetica δC 210.0 45.8 25.9 30.5 30.6 30.6 30.3 32.9 36.3 136.0 116.7 146.1 144.1 116.4 120.8 111.7 163.4 108.6 137.0 108.6 163.4

δH (J in Hz) 3.10, 1.65, 1.31, 1.31, 1.31, 1.31, 1.53, 2.43,

t (7.5) m m m m m m t (7.5)

6.60, d (2.0)

6.66, d (8.0) 6.47, dd (8.0, 2.0)

6.34, d (8.0) 7.19, t (8.0) 6.34, d (8.0)

H and 13C NMR spectra recorded at 500 and 125 MHz, respectively, in methanol-d4 for both natural product and synthetic sample.

the targeted cross-coupled product ethyl 2-benzoyl-9-(4methoxyphenyl)non-7-enoate (9), as the major product (63%) (Scheme 2). Hydrolysis of 9 with 10% aqueous NaOH solution, followed by in situ decarboxylation under acidic conditions, afforded 9-(4-methoxyphenyl)-1-phenylnon7-en-1-one (10) in high yield (85%).

However, catalytic hydrogenation of 10 with 10% Pd−C/H2 (1 atm) led to the unwanted concomitant reduction of the carbonyl and olefinic functions to afford 1-methoxy-4-(9phenylnonyl)benzene (11) as the sole product in 86% yield. Lowering the catalyst loading (3% Pd−C) and reducing the reaction time failed to induce chemoselectivity toward 12a, and 1778

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constant J is reported in Hz. Microanalysis was performed with a Vario Micro elemental analyzer. All commercially available chemicals were used without further purification. Dichloromethane was distilled over CaH2, toluene was dried over Na, and tetrahydrofuran was dried over Na-benzophenone ketyl prior to use. Ethyl 2-Benzoyloct-7-enoate (6). To a stirred suspension of NaH (150 mg, 6.25 mmol) in dry THF (5 mL) was added dropwise a solution of ethyl benzoylacetate (5, 960 mg, 5.00 mmol) in dry THF (5 mL). After stirring the reaction mixture at ambient temperature for 2 h, 6-bromohex-1-ene (2, 900 mg, 5.52 mmol) was added slowly and refluxed for 24 h. The reaction mixture was cooled to ambient temperature and quenched with 10% aqueous NH4Cl solution (10 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL), and the combined extract was washed with brine (2 × 5 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (hexanes/EtOAc = 98:2) to afford the title compound (700 mg, 51%) as a colorless, thick oil: Rf = 0.50 (hexanes/EtOAc = 97:3); IR (neat) νmax 3073, 2929, 2858, 1736, 1687, 1640, 1597, 1580, 1448, 1368, 1270, 1025, 1000, 912 cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.00− 7.98 (2H, m), 7.59 (1H, app t, J = 7.5 Hz), 7.50−7.46 (2H, m), 5.82− 5.74 (1H, m), 5.00−4.92 (2H, m), 4.28 (1H, t, J = 7.0 Hz), 4.14 (2H, q, J = 7.2 Hz), 2.07−1.98 (4H, m), 1.46−1.36 (4H, m), 1.17 (3H, t, J = 7.2 Hz); 13C NMR (CDCl3, 125 MHz) δ 195.2, 170.0, 138.6, 136.4, 133.4, 128.7, 128.5, 114.5, 61.3, 54.3, 33.4, 28.8, 28.7, 27.1, 14.0; anal. C 74.63, H 8.02%, calcd for C17H22O3, C 74.42, H 8.08%. Ethyl 2-Benzoyl-9-(4-methoxyphenyl)non-7-enoate (9). To a solution of 6 (274 mg, 1.00 mmol) in dry CH2Cl2 (0.2 M) was added successively 3b (296 mg, 2.00 mmol) and Grubbs 1 catalyst (41 mg, 5 mol %). The resulting mixture was stirred at ambient temperature for 18 h. After completion of the reaction, CH2Cl2 was removed in vacuo, and the crude residue was purified by silica gel column chromatography (hexanes/EtOAc = 98:2 to 9:1) to afford compounds 7, 8, and 9. As geometrical isomers of these compounds could not be separated by column chromatography, the E/Z ratio was calculated on the basis of their 1H NMR data.31 9: Colorless, thick oil; yield (248 mg, 63%); E/Z = 5:1; Rf = 0.33 (hexanes/EtOAc = 19:1); IR (neat) νmax 2934, 2859, 1732, 1683, 1601, 1512, 1448, 1369, 1250, 1176, 1099, 1031, 833, 768 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.96 (2H, d, J = 8.0 Hz), 7.56 (1H, app t, J = 7.3 Hz), 7.45 (2H, app t, J = 7.8 Hz), 7.05 (2H, d, J = 8.5 Hz), 6.80 (2H, d, J = 8.5 Hz), 5.53−5.40 (2H, m), 4.25 (1H, t, J = 7.0 Hz), 4.15−4.10 (2H, m), 3.76 (3H, s), 3.29 (0.33H, d, J = 7.5 Hz), 3.23 (1.67H, d, J = 6.5 Hz), 2.15−2.00 (0.65H, m), 2.02−1.95 (3.35H, m), 1.44−1.33 (4H, m), 1.16−1.13 (3H, m); 13C NMR (CDCl3, 125 MHz) δ 195.2, 170.0, 157.8, 136.4, 133.4, 133.1, 131.1, 130.0, 129.6, 129.3, 129.1, 128.8, 128.7, 128.5, 113.8, 113.8, 61.3, 55.2, 54.3, 54.3, 38.1, 32.5, 32.1, 29.5, 29.2, 28.8, 28.8, 27.3, 27.1, 26.9, 14.0; anal. C 76.41, H 7.39%, calcd for C25H30O4, C 76.11, H 7.67%. 1,4-Bis(4-methoxyphenyl)but-2-ene (7). Colorless solid; E/Z = 6:1; mp 59−60 °C (lit.31 mp 61−64 °C); Rf = 0.58 (hexanes/EtOAc = 19:1); IR (CHCl3) νmax 3008, 2902, 2835, 1610, 1584, 1510, 1463, 1300, 1245, 1176, 1106, 1034, 968, 811, 755 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.15−7.10 (4H, m), 6.86−6.84 (4H, m), 5.68−5.67 (0.30H, m), 5.64−5.63 (1.70H, m), 3.80 (6H, s), 3.46 (0.57H, d, J = 5.5 Hz), 3.31 (3.43H, d, J = 5.0 Hz); 13C NMR (125 MHz, CDCl3) δ 158.0, 132.9, 130.6, 129.5, 129.3, 129.2, 114.0, 113.9, 55.3, 55.3, 38.1, 32.6; anal. C 80.54, H 7.25%, calcd for C18H20O2, C 80.56, H 7.51%. Diethyl 2,13-Dibenzoyltetradec-7-enedioate (8). Colorless, thick oil; E/Z = 8:3; Rf = 0.15 (hexanes/EtOAc = 19:1); IR (neat) νmax 3060, 2923, 2853, 1736, 1686, 1598, 1580, 1511, 1448, 1368, 1249, 1021 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.98 (4H, d, J = 7.5 Hz), 7.60−7.57 (2H, m), 7.49−7.46 (4H, m), 5.34−5.33 (1.45H, m), 5.32− 5.30 (0.55H, m), 4.28 (2H, t, J = 7.2 Hz), 4.14 (4H, q, J = 7.0 Hz), 2.01−1.95 (8H, m), 1.40−1.35 (8H, m), 1.17 (6H, t, J = 7.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 195.3, 170.1, 136.3, 133.4, 130.4, 130.2, 129.7, 128.7, 128.6, 114.6, 61.3, 54.3, 32.2, 29.5, 29.3, 28.8, 27.3, 27.1, 26.9, 14.0; anal. C 73.58, H 7.91%, calcd for C32H40O6, C 73.82, H 7.74%.

11 was obtained as the sole product (84%). Thus, an alternative plan for the synthesis of malabaricone C had to be developed. The revised strategy (Scheme 1; route B) began with the preparation of 4-(7-bromoheptyl)-1,2-dimethoxybenzene (4a), which served as a key building block in the synthesis. To this end, cross-metathesis reaction of 2 with 4-allyl-1,2-dimethoxybenzene (3a; 2 equiv), using Grubbs 1 catalyst (5 mol %), afforded a statistical mixture of all three possible alkenes 13, 14, and 15a (Scheme 3). Gratifyingly, the targeted unsymmetrical alkene 15a could be readily purified by column chromatography (SiO2) in 32% yield (based on 2). However, catalytic hydrogenation of 15a with 10% Pd−C/H2 (1 atm) led to reduction of both the olefinic and bromo functions. Optimized conditions for chemoselective reduction of the olefinic group in the presence of bromide were established [3% Pd−C/H2 (1 atm); 1.5 h] to afford 4-(7-bromoheptyl)-1,2-dimethoxybenzene (4a) in 85% yield. Next, we focused on the synthesis of the dimethoxyphenyl βketo ester 1, an important intermediate in the total synthesis. To this end, reaction of 2′,6′-dimethoxyacetophenone (16) with diethyl carbonate in the presence of NaH afforded ethyl 3(2,6-dimethoxyphenyl)-3-oxopropanoate (1) in 94% yield (Scheme 4). However, alkylation of 1 with 4a using NaH/ THF failed and only starting materials were recovered. However, use of KI29 as additive initiated the reaction, and the target alkylated β-keto ester 17a was obtained in 42% yield. The poor yield of the reaction could be explained by the reduction in electrophilicity of the benzylic carbonyl group by the two-electron-donating o-methoxy groups, compounded by steric hindrance at the alkylating center. Compound 17a underwent smooth alkaline hydrolysis and in situ decarboxylation to afford 1-(2,6-dimethoxyphenyl)-9-(3,4dimethoxyphenyl)nonan-1-one (18a) in 95% yield. Finally, compound 18a was demethylated with BBr3 (8 equiv) in CH2Cl2 to afford 1-(2,6-dihydroxyphenyl)-9-(3,4dihydroxyphenyl)nonan-1-one (19a; malabaricone C) in 78% yield, along with a small amount (6%) of 9-(3,4-dihydroxyphenyl)-1-(2-hydroxy-6-methoxyphenyl)nonan-1-one (19c). The NMR spectroscopic data of synthesized 19a were in agreement with those reported for natural malabaricone C19b (Table 1). Thus, the total synthesis of malabaricone C was accomplished in six steps in 8.5% overall yield. Using the same strategy, synthesis of malabaricone B19b (19b) was accomplished in 11.7% overall yield via the cross-metathesis reaction of 4-allylanisole (3b) with 2 (Scheme 4). In summary, a practical method for the total syntheses of malabaricones B and C was developed via a cross-metathesis reaction as a key step. The methodology can also be used in the synthesis of all other members of the malabaricone series including malabaricone A30 and malabaricone D. The biological activity of malabaricones is currently under study, and the results thereof will be reported in due course.

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EXPERIMENTAL SECTION

General Experimental Procedures. Melting points were determined using a Buchi M-560 melting point apparatus. Unless otherwise noted, all reactions were carried out under an argon atmosphere. IR spectra were recorded on a Bruker Tensor II FTIR spectrophotometer. The 1H and 13C NMR spectra were recorded with 300 and 500 MHz spectrometers. NMR spectroscopic data are reported as follows: chemical shifts are reported in ppm and calibrated relative to CDCl3 (δH = 7.26, δC = 77.00); multiplicities of the peaks are reported as s = singlet, bs = broad singlet, d = doublet, t = triplet, app t = apparent triplet, q = quartet, m = multiplet. The coupling 1779

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m), 1.53−1.47 (4H, m); 13C NMR (CDCl3, 125 MHz) δ 130.2, 129.7, 33.8, 32.3, 32.2, 31.6, 28.1, 28.0, 26.3; anal. C 40.39, H 6.36%, calcd for C10H18Br2, C 40.30, H 6.09%. 4-(7-Bromoheptyl)-1,2-dimethoxybenzene (4a). To a solution of 15a (800 mg, 2.55 mmol) in CH2Cl2/EtOH (1:5, 50 mL) was added 3% Pd−C (18 mg), and the mixture was stirred at ambient temperature under hydrogen (1 atm). After 1.5 h, the mixture was passed through a pad of Celite, and the eluate was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (hexanes/EtOAc = 97:3) to afford the title compound (683 mg, 85%) as a colorless, thick oil: Rf = 0.58 (hexanes/EtOAc = 19:1); IR (neat) νmax 2929, 2853, 1590, 1514, 1463, 1416, 1261, 1155, 1030, 850, 803, 763, 725 cm−1; 1H NMR (CDCl3, 500 MHz) δ 6.79 (1H, d, J = 8.0 Hz), 6.72−6.71 (2H, m), 3.88 (3H, s), 3.86 (3H, s), 3.41 (2H, t, J = 7.0 Hz), 2.55 (2H, t, J = 7.8 Hz), 1.87−1.84 (2H, m), 1.62−1.58 (2H, m), 1.44−1.43 (2H, m), 1.35−1.33 (4H, m); 13C NMR (CDCl3, 125 MHz) δ 148.7, 147.0, 135.3, 120.0, 111.7, 111.1, 55.8, 55.7, 35.4, 33.8, 32.7, 31.4, 28.9, 28.5, 28.0; anal. C 57.03, H 7.48%, calcd for C15H23BrO2, C 57.15, H 7.35%. Ethyl 3-(2,6-Dimethoxyphenyl)-3-oxopropanoate (1). A solution of 16 (3.000 g, 16.65 mmol) in dry toluene (50 mL) was added dropwise to a solution containing diethyl carbonate (3.90 g, 33.0 mmol) and NaH (600 mg, 25.0 mmol) in toluene (5 mL). The reaction mixture was initially stirred at room temperature and then refluxed at 110 °C. After 1 h the mixture was cooled to ambient temperature and quenched with 3 N aqueous HCl solution (10 mL). The aqueous layer was extracted with EtOAc (3 × 40 mL), and the combined organic extracts were washed with brine (2 × 20 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (hexanes/EtOAc = 3:1) to afford the title compound (3.95 g, 94%) as a colorless solid: keto/enol = 10:1; mp 68−69 °C (lit.34 mp 63−70 °C); Rf = 0.35 (hexanes/EtOAc = 4:1); IR (neat) νmax 3020, 2841, 1739, 1704, 1595, 1474, 1433, 1407, 1367, 1254, 1217, 1112, 1035, 993, 943 cm−1; 1H NMR (CDCl3, 500 MHz) δ 12.33 (0.09H, s), 7.30 (1H, t, J = 8.5 Hz), 6.56 (2H, d, J = 8.5 Hz), 4.25 (0.18H, q, J = 7.5 Hz), 4.16 (1.82H, q, J = 7.5 Hz), 3.81 (8H, s), 1.32 (0.27H, t, J = 7.5 Hz), 1.23 (2.73H, t, J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 195.6, 167.1, 157.3, 131.6, 131.0, 103.9, 94.4, 60.9, 60.0, 56.0, 55.8, 51.0, 14.2, 14.0; anal. C 62.21, H 6.39%, calcd for C15H16O5, C 61.90, H 6.39%. Ethyl 2-(2,6-Dimethoxbenzoyl)-9-(3,4-dimethoxyphenyl)nonanoate (17a). To a stirred suspension of NaH (48 mg, 2.0 mmol) in dry THF (10 mL) was added dropwise a solution of compound 1 (400 mg, 1.59 mmol) in THF (5 mL). After stirring the reaction mixture for 1.5 h at ambient temperature, KI (332 mg, 2.00 mmol) and 4a (555 mg, 1.76 mmol) were added slowly, and the mixture was refluxed for 24 h. The reaction mixture was cooled to ambient temperature and quenched with 10% aqueous NH4Cl solution (15 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL), and the combined organic extracts were washed with brine (2 × 10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (hexanes/EtOAc = 7:3) to afford the title compound (327 mg, 42%) as a colorless, thick oil: keto/enol = 4:1; Rf = 0.31 (hexanes/EtOAc = 85:15); IR (neat) νmax 2925, 2852, 1736, 1707, 1592, 1514, 1463, 1260, 1234, 1154, 1112, 1028 cm−1; 1H NMR (CDCl3, 500 MHz) δ 12.74 (0.20H, s), 7.31−7.26 (1H, m), 6.79 (1H, d, J = 8.5 Hz), 6.72−6.68 (2H, m), 6.57 (0.40H, d, J = 8.5 Hz), 6.54 (1.60H, d, J = 8.5 Hz), 4.28 (0.40H, q, J = 7.0 Hz), 4.15−4.06 (1.60H, m), 3.93 (0.80H, t, J = 7.5 Hz), 3.88−3.86 (6H, m), 3.79−3.78 (6H, m), 2.55−2.48 (2H, m), 1.94−1.87 (2H, m), 1.60−1.54 (2H, m), 1.35−1.30 (8H, m), 1.16 (3H, t, J = 7.0 Hz); 13C NMR (CDCl3, 125 MHz) δ 198.7, 169.7, 157.2, 148.8, 147.0, 135.6, 131.3, 120.1, 119.1, 111.8, 111.3, 104.0, 103.9, 60.8, 60.5, 56.0, 55.8, 35.5, 31.6, 29.3, 29.2, 29.2, 28.0, 27.5, 14.0; anal. C 69.48, H 7.46%, calcd for C28H38O7, C 69.11, H 7.87%. 1-(2,6-Dimethoxyphenyl)-9-(3,4-dimethoxyphenyl)nonan-1one35 (18a). Following the procedure adopted for compound 10, alkaline hydrolysis and in situ decarboxylation of 17a (250 mg, 0.513

9-(4-Methoxyphenyl)-1-phenylnon-7-en-1-one (10). A mixture of 9 (200 mg, 0.507 mmol) and 10% aqueous NaOH (2 mL) was stirred at 65 °C for 6 h, whereupon TLC showed complete consumption of 9. The mixture was acidified carefully with aqueous 3 N HCl (5 mL), upon which decarboxylation to 10 occurred. The aqueous layer was extracted with EtOAc (3 × 10 mL), and the combined organic extracts were washed with brine (2 × 5 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (hexanes/EtOAc = 97:3) to afford the title compound (140 mg, 85%) as a colorless, thick oil: E/Z = 13:3; Rf = 0.56 (hexanes/EtOAc = 19:1); IR (neat) νmax 3060, 3002, 2930, 2853, 1682, 1610, 1582, 1511, 1448, 1360, 1299, 1245, 1177, 1107, 1036, 969, 818, 750, 691, 656 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.96 (2H, d, J = 8.5 Hz), 7.57− 7.54 (1H, m), 7.48−7.45 (2H, m), 7.10 (2H, d, J = 8.0 Hz), 6.83 (2H, d, J = 8.0 Hz), 5.56−5.46 (2H, m), 3.79 (3H, s), 3.33 (0.38H, d, J = 7.5 Hz), 3.26 (1.62H, d, J = 6.5 Hz), 2.96 (2H, t, J = 7.5 Hz), 2.18− 2.14 (0.39H, m), 2.05−2.02 (1.61H, m), 1.77−1.71 (2H, m), 1.58− 1.39 (4H, m); 13C NMR (CDCl3, 75 MHz) δ 200.5, 157.8, 137.1, 132.9, 131.4, 129.4, 129.2, 128.6, 128.1, 113.8, 55.3, 38.6, 38.2, 32.6, 32.3, 29.5, 29.3, 29.0, 28.9, 27.1, 24.2; anal. C 81.82, H 8.31%, calcd for C22H26O2, C 81.95, H 8.13%. 1-Methoxy-4-(9-phenylnonyl)benzene (11). To a solution of 10 (140 mg, 0.434 mmol) in CH2Cl2/EtOH (1:5, 20 mL) was added 3% Pd−C (10 mg), and the mixture was stirred at ambient temperature under hydrogen (1 atm). After 2 h the reaction mixture was passed through a pad of Celite, and the eluate was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (hexanes/EtOAc = 97:3) to afford the title compound (113 mg, 84%) as a colorless, thick oil: Rf = 0.57 (hexanes/EtOAc = 19:1); IR (neat) νmax 3061, 3026, 2925, 2852, 1610, 1511, 1460, 1298, 1244, 1176, 1113, 1037, 823 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.30−7.26 (2H, m), 7.19−7.16 (3H, m), 7.10 (2H, d, J = 8.8 Hz), 6.83 (2H, d, J = 8.8 Hz), 3.80 (3H, s), 2.61 (2H, t, J = 7.8 Hz), 2.55 (2H, t, J = 7.8 Hz), 1.63−1.56 (4H, m), 1.38−1.30 (10H, m); 13C NMR (CDCl3, 125 MHz) δ 157.6, 142.9, 135.1, 129.2, 128.4, 128.2, 125.5, 113.7, 55.2, 36.0, 35.0, 31.7, 31.5, 29.5, 29.5, 29.3, 29.2; anal. C 85.10, H 9.57%, calcd for C22H30O, C 85.11, H 9.74%. 4-(7-Bromohept-2-en-1-yl)-1,2-dimethoxybenzene (15a). Following a similar procedure to that used for compound 9, the cross-metathesis reaction of 2 (1.63 g, 10.0 mmol) and 3a (3.56 g, 20.0 mmol) afforded a mixture of products. The crude product was purified by silica gel column chromatography (hexanes/EtOAc = 99:1 to 90:10) to afford pure 13, 14, and 15a. 15a: Colorless, thick oil; yield (1.0 g, 32%); E/Z = 8:3; Rf = 0.57 (hexanes/EtOAc = 19:1); IR (neat) νmax 3000, 2934, 2835, 1590, 1514, 1463, 1336, 1262, 1234, 1139, 1028, 970, 853, 807, 763 cm−1; 1H NMR (CDCl3, 500 MHz) δ 6.80 (1H, d, J = 7.5 Hz), 6.72−6.70 (2H, m), 5.61−5.55 (1H, m), 5.51− 5.46 (1H, m), 3.87 (3H, s), 3.86 (3H, s), 3.44−3.39 (2H, m), 3.35 (0.55H, d, J = 7.0 Hz), 3.28 (1.45H, d, J = 7.0 Hz), 2.21−2.16 (0.55H, m), 2.08−2.05 (1.45H, m), 1.91−1.85 (2H, m), 1.57−1.50 (2H, m); 13 C NMR (CDCl3, 125 MHz) δ 148.8, 147.2, 133.4, 130.7, 129.8, 129.7, 129.0, 126.0, 120.2, 120.0, 111.8, 111.6, 111.2, 55.9, 55.7, 38.5, 33.6, 32.9, 32.2, 32.2, 31.4, 29.6, 28.0, 27.8, 26.2; anal. C 57.64, H 6.52%, calcd for C15H21BrO2, C 57.52, H 6.76%. 1,4-Bis(3,4-dimethoxyphenyl)but-2-ene32 (13). Colorless solid; E/Z = 4:1; mp 81−82 °C; Rf = 0.14 (hexanes/EtOAc = 19:1); IR (CHCl3) νmax 3019, 2936, 2835, 1591, 1513, 1464, 1417, 1333, 1261, 1189, 1138, 1029, 971, 940, 853, 805, 753, 666 cm−1; 1H NMR (CDCl3, 500 MHz) δ 6.82−6.80 (2H, m), 6.77−6.72 (4H, m), 5.73−5.71 (0.42H, m), 5.67−5.66 (1.58H, m), 3.86 (9.66H, s), 3.85 (2.34H, s), 3.47 (0.78H, d, J = 5.5 Hz), 3.32 (3.22H, d, J = 4.5 Hz); 13 C NMR (CDCl3, 125 MHz) δ 148.9, 147.4, 133.4, 130.5, 129.2, 120.3, 120.1, 112.0, 111.4, 56.0, 55.8, 38.5, 33.0; anal. C 72.97, H 7.12%, calcd for C20H24O4, C 73.15, H 7.37%. 1,10-Dibromodec-5-ene33 (14). Colorless, thick oil; E/Z = 11:2; Rf = 0.86 (hexanes/EtOAc = 19:1); IR (neat) νmax 2934, 2855, 1454, 1437, 1282, 1249, 1199, 968, 735 cm−1; 1H NMR (CDCl3, 500 MHz) δ 5.41−5.39 (0.31H, m), 5.38−5.36 (1.69H, m), 3.41 (4H, t, J = 7.0 Hz), 2.09−2.06 (0.61H, m), 2.04−2.00 (3.39H, m), 1.89−1.83 (4H, 1780

DOI: 10.1021/acs.jnatprod.6b01119 J. Nat. Prod. 2017, 80, 1776−1782

Journal of Natural Products

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113.7, 55.3, 35.0, 34.0, 32.8, 31.6, 29.0, 28.6, 28.1; anal. C 58.61, H 7.69%, calcd for C14H21BrO, C 58.95, H 7.42%. Ethyl 2-(2,6-Dimethoxybenzoyl)-9-(4-methoxyphenyl)nonanoate (17b). Following the procedure adopted for compound 17a, alkylation of 1 (280 mg, 1.10 mmol) with 4b (340 mg, 1.19 mmol) gave a crude mixture, which on purification by silica gel column chromatography (hexanes/EtOAc = 85:15) afforded the title compound (281 mg, 56%) as a colorless, thick oil: keto/enol = 3:1; Rf = 0.37 (hexanes/EtOAc = 85:15); IR (neat) νmax 2928, 2835, 1738, 1703, 1593, 1512, 1472, 1371, 1251, 1176, 1113, 1034, 829, 784, 738 cm−1; 1H NMR (CDCl3, 500 MHz) δ 12.73 (0.25H, s), 7.31−7.26 (1H, m), 7.09−7.05 (2H, m), 6.82 (2H, d, J = 8.5 Hz), 6.57 (0.50H, d, J = 8.0 Hz), 6.54 (1.50H, d, J = 8.5 Hz), 4.28 (0.50H, q, J = 7.5 Hz), 4.14−4.08 (1.50H, m), 3.93 (0.75H, t, J = 7.5 Hz), 3.79−3.78 (9H, m), 2.55−2.47 (2H, m), 1.93−1.87 (2H, m), 1.35−1.25 (10H, m), 1.17 (3H, t, J = 7.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 198.7, 173.6, 169.7, 166.1, 157.6, 157.5, 157.2, 135.0, 135.0, 131.2, 130.6, 129.2, 129.2, 113.7, 104.3, 104.0, 103.9, 60.8, 60.5, 60.4, 60.3, 55.8, 55.8, 55.5, 55.2, 35.0, 35.0, 35.0, 31.7, 31.7, 31.7, 29.3, 29.2, 29.2, 29.1, 29.1, 28.0, 27.5, 26.9, 14.3, 14.0; anal. C 71.07, H 7.77%, calcd for C27H36O6, C 71.03, H 7.95%. 1-(2,6-Dimethoxyphenyl)-9-(4-methoxyphenyl)nonan-1-one (18b). Following the procedure adopted for compound 10, alkaline hydrolysis and in situ decarboxylation of 17b (250 mg, 0.548 mmol) afforded a crude mixture, which on purification by silica gel column chromatography (hexanes/EtOAc = 4:1) furnished the title compound (190 mg, 90%) as a colorless, thick oil: Rf = 0.55 (hexanes/EtOAc = 4:1); IR (neat) νmax 2925, 1703, 1593, 1511, 1469, 1248, 1113, 1035, 779 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.26−7.23 (1H, m), 7.09 (2H, d, J = 9.0 Hz), 6.82 (2H, d, J = 9.0 Hz), 6.55 (2H, d, J = 8.5 Hz), 3.79−3.78 (9H, m), 2.73 (2H, t, J = 7.3 Hz), 2.54 (2H, t, J = 8.0 Hz), 1.68−1.65 (4H, m), 1.39−1.30 (8H, m); 13C NMR (CDCl3, 125 MHz) δ 205.4, 157.6, 156.7, 135.0, 130.3, 129.2, 120.8, 113.7, 104.0, 55.8, 55.2, 44.8, 35.0, 31.7, 29.4, 29.2, 29.1, 23.5; anal. C 74.74, H 8.15%, calcd for C24H32O4, C 74.97, H 8.39%. 1-(2,6-Dihydroxyphenyl)-9-(4-hydroxyphenyl)nonan-1-one (malabaricone B) (19b). Following the procedure adopted for compound 19a, compound 18b (150 mg, 0.390 mmol) on demethylation with BBr3 (0.29 mL, 3.1 mmol) afforded a crude mixture, which on purification by silica gel column chromatography (hexanes/EtOAc = 3:2) furnished pure 19b and 19d. 19b (malabaricone B): Light yellow solid; yield (100 mg, 75%); mp 100−101 °C (lit.16 mp 102−103 °C); Rf = 0.25 (hexanes/EtOAc = 7:3); IR (CHCl3) νmax 3273, 2914, 2848, 1634, 1614, 1579, 1514, 1452, 1383, 1233, 1038, 963, 718 cm−1; for 1H and 13C NMR data see Table 1; anal. C 73.63, H 7.66%, calcd for C21H26O4, C 73.66, H 7.65%. 1-(2-Hydroxy-6-methoxyphenyl)-9-(4-hydroxyphenyl)nonan-1-one (19d). Light yellow thick oil; yield (1.5 mg, ∼1%); Rf = 0.30 (hexanes/EtOAc = 7:3); IR (CHCl3) νmax 3384, 3019, 2923, 2852, 1624, 1514, 1460, 1375 1237, 1041 cm−1; 1H NMR (CDCl3, 500 MHz) δ 13.30 (1H, s), 7.34 (1H, app t, J = 8.0 Hz), 7.04 (2H, d, J = 8.5 Hz), 6.75 (2H, d, J = 8.5 Hz), 6.58 (1H, d, J = 8.5 Hz), 6.39 (1H, d, J = 8.0 Hz), 4.69 (1H, bs), 3.89 (3H, s), 3.04 (2H, t, J = 7.5 Hz), 2.53 (2H, t, J = 7.5 Hz), 1.68−1.64 (4H, m), 1.33−1.26 (8H, m); 13C NMR (CDCl3, 125 MHz) δ 207.9, 164.7, 161.3, 153.5, 135.6, 135.2, 129.4, 115.1, 111.4, 111.0, 101.2, 55.6, 45.0, 35.0, 31.6, 29.5, 29.4, 29.4, 29.2, 24.6.

mmol) gave a crude mixture, which on purification by silica gel column chromatography (hexanes/EtOAc = 7:3) afforded the title compound (202 mg, 95%) as a colorless, thick oil: Rf = 0.46 (hexanes/EtOAc = 4:1); IR (neat) νmax 2928, 1707, 1592, 1514, 1469, 1254, 1029, 727 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.26−7.23 (1H, m), 6.79 (1H, d, J = 9.0 Hz), 6.72−6.71 (2H, m), 6.55 (2H, d, J = 8.5 Hz), 3.88 (3H, s), 3.86 (3H, s), 3.78 (6H, s), 2.73 (2H, t, J = 7.5 Hz), 2.55 (2H, t, J = 8.0 Hz), 1.68−1.65 (2H, m), 1.60−1.58 (4H, m), 1.35−1.32 (6H, m); 13 C NMR (CDCl3, 125 MHz) δ 205.4, 156.7, 148.8, 147.0, 135.6, 130.3, 120.7, 111.8, 111.2, 104.0, 55.9, 55.8, 44.8, 35.6, 31.7, 29.4, 29.3, 29.1, 23.5; anal.C 72.56, H 8.07%, calcd for C25H34O5, C 72.44, H 8.27%. 1-(2,6-Dihydroxyphenyl)-9-(3,4-dihydroxyphenyl)nonan-1one (malabaricone C) (19a). To a stirred solution of 18a (150 mg, 0.362 mmol) in dry CH2Cl2 (15 mL) at −40 °C was added BBr3 (0.27 mL, 2.9 mmol), and stirring continued at −20 °C for 2 h and then at ambient temperature for 16 h, when TLC showed complete consumption of 18a and the formation of two compounds. The reaction mixture was quenched with cold H2O (20 mL), the aqueous layer was extracted with CH2Cl2 (3 × 15 mL), and the combined organic extracts were washed with brine (2 × 10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (hexanes/EtOAc = 7:3 to 3:2) to afford pure 19a and 19c. 19a (malabaricone C): Light yellow solid; yield (101 mg, 78%); mp 118− 119 °C (lit.16 mp 117−118 °C); Rf = 0.23 (hexanes/EtOAc = 7:3); IR (CHCl3) νmax 3380, 3461, 3278, 2922, 2849, 1625, 1596, 1518, 1453, 1277, 1239, 1187, 1108, 1040, 946, 793 cm−1; for 1H and 13C NMR data see Table 1; anal. C 70.34, H 7.39%, calcd for C21H26O5, C 70.37, H 7.31%. 9-(3,4-Dihydroxyphenyl)-1-(2-hydroxy-6-methoxyphenyl)nonan-1-one (19c). Light yellow solid; yield 8 mg, 6%; mp 74−75 °C; Rf = 0.36 (hexanes/EtOAc = 7:3); IR (CHCl3) νmax 3386, 3019, 2927, 2854, 1623, 1598, 1518, 1461, 1436, 1353, 1281, 1237, 1218, 1184, 1089 cm−1; 1H NMR (CDCl3, 500 MHz) δ 13.31 (1H, s), 7.34 (1H, app t, J = 8.3 Hz), 6.77 (1H, d, J = 8.5 Hz), 6.70 (1H, d, J = 1.0 Hz), 6.61−6.57 (2H, m), 6.40 (1H, d, J = 8.0 Hz), 5.46−5.26 (2H, bs), 3.90 (3H, s), 3.04 (2H, t, J = 7.3 Hz), 2.49 (2H, t, J = 7.5 Hz), 1.68−1.65 (2H, m), 1.57−1.54 (2H, m), 1.36−1.29 (8H, m); 13C NMR (CDCl3, 125 MHz) δ 208.1, 164.5, 161.3, 143.4, 141.3, 136.0, 135.7, 120.7, 115.5, 115.2, 111.2, 110.8, 101.3, 55.6, 45.0, 35.1, 31.4, 29.3, 29.3, 29.2, 29.0, 24.5; anal. C 70.79, H 7.89%, calcd for C22H28O5, C 70.94, H 7.58%. 1-(7-Bromohept-2-en-1-yl)-4-methoxybenzene (15b). Following the procedure adopted for compound 15a, the cross-metathesis reaction of compound 2 (1.63 g, 10.0 mmol) with 3b (2.96 g, 20.0 mmol) gave a crude residue, which on purification by silica gel column chromatography (hexanes/EtOAc = 99:1 to 95:5) afforded pure 7, 14, and 15b. 15b: Colorless, thick oil; yield 1.04 g, 37%; E/Z = 5:1; Rf = 0.46 (hexanes/EtOAc = 98:2); IR (neat) νmax 2933, 2836, 1610, 1511, 1461, 1301, 1175, 1034, 970, 771 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.10 (2H, d, J = 8.5 Hz), 6.84 (2H, d, J = 8.5 Hz), 5.60−5.55 (1H, m), 5.49−5.43 (1H, m), 3.80 (3H, s), 3.44−3.40 (2H, m), 3.34 (0.34H, d, J = 7.0 Hz), 3.28 (1.66H, d, J = 7.0 Hz), 2.21−2.17 (0.34H, m), 2.08−2.04 (1.66H, m), 1.94−1.84 (2H, m), 1.59−1.5 (2H, m); 13 C NMR (CDCl3, 125 MHz) δ 157.9, 132.9, 130.7, 130.1, 129.7, 129.4, 129.2, 129.2, 113.9, 113.8, 55.3, 38.1, 33.8, 32.6, 32.4, 32.3, 31.6, 28.2, 28.0, 26.3; anal. C 59.66, H 6.47%, calcd for C14H19BrO, C 59.37, H 6.76%. 1-(7-Bromoheptyl)-4-methoxybenzene (4b). Following the procedure adopted for compound 4a, catalytic reduction of compound 15b (450 mg, 1.60 mmol) gave a crude mixture, which on purification by silica gel column chromatography (hexanes/EtOAc = 98:2) afforded the title compound (382 mg, 84%) as a colorless, thick oil: Rf = 0.47 (hexanes/EtOAc = 98:2); IR (neat) νmax 2934, 2835, 1608, 1510, 1461, 1440, 1300, 1246, 1175, 1107, 1034, 969, 818 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.10 (2H, d, J = 9.0 Hz), 6.83 (2H, d, J = 9.0 Hz), 3.79 (3H, s), 3.40 (2H, t, J = 7.0 Hz), 2.55 (2H, t, J = 8.0 Hz), 1.88−1.822 (2H, m), 1.62−1.57 (2H, m), 1.44−1.42 (2H, m), 1.37− 1.31 (4H, m); 13C NMR (CDCl3, 125 MHz) δ 157.7, 134.8, 129.2,

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.6b01119. Copies of 1H NMR and 13C NMR spectra of compounds 1, 4a, 4b, 6−11, 13, 14, 15a, 15b, 17a, 17b, 18a, 18b, 19a, 19b, 19c, and 19d (PDF) 1781

DOI: 10.1021/acs.jnatprod.6b01119 J. Nat. Prod. 2017, 80, 1776−1782

Journal of Natural Products

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AUTHOR INFORMATION

Corresponding Author

*Tel: +91-22-25592410. Fax: +91-22-25505326. E-mail: [email protected]. ORCID

Sandip K. Nayak: 0000-0001-8974-2200 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank Dr. S. Chattopadhyay, Director, Bio-Science Group, BARC, for his keen interest in the work.

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DOI: 10.1021/acs.jnatprod.6b01119 J. Nat. Prod. 2017, 80, 1776−1782