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Oct 11, 2017 - folk medicine for the treatment of hepatic and gallbladder diseases in China.4 Penchinones A−D have the unique structural feature of ...
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Article Cite This: J. Org. Chem. 2017, 82, 11566-11572

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Total Synthesis and Anti-inflammatory Evaluation of Penchinone A and Its Structural Analogues Yongguk Oh,† Yeon Jeong Jang,† Mijin Jeon,† Hyung Sik Kim,† Jong Hwan Kwak,† Kyu Hyuck Chung,† Suhkneung Pyo,*,† Young Hoon Jung,*,†,‡ and In Su Kim*,† †

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea Biocenter, Gyeonggido Business & Science Accelerator (GBSA), Suwon 16229, Republic of Korea

‡

S Supporting Information *

ABSTRACT: The first total synthesis and biological evaluation of penchinone A and its structural analogues are described. The key steps for the preparation of penchinone A derivatives involve the oxime-directed palladium(II)catalyzed oxidative acylation, Claisen rearrangement, and base-mediated olefin migration. This transformation efficiently provides a range of allyl-substituted biaryl ketones with siteselectivity and functional group compatibility. In addition, all synthetic compounds were screened for anti-inflammatory activity against nitric oxide (NO), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6) with lipopolysaccharide (LPS)-induced RAW264.7 cells. Generally, a range of penchinone A derivatives potently inhibited NO, TNF-α, and IL-6 productions, compared to dexamethasone as a positive control. Notably, penchinone A (8g) and its derivatives (8e and 8f) were found to exhibit anti-inflammatory activity stronger than that of dexamethasone.

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INTRODUCTION Lignans have been known as the important class of naturally occurring phenylpropanoid dimers and play a crucial role in the biological defense of plants against external pathogens and pests.1 In addition, these compounds have been known to possess a variety of pharmacological effects, such as antiinflammatory, antitumoral, antimitotic, antiviral, antiatherosclerotic activities, etc.2 Although the framework of lignans consists only of two phenylpropane (C6−C3) units, lignans exhibit a wide range of structural diversity by the linkage patterns derived from the oxidative coupling of two C6−C3 units. Penchinones A−D were first isolated from the hepatoprotective portion of the water decoction of Penthorum chinense Pursh by Xiong and co-workers in 2015 (Figure 1).3 Traditionally, Penthorum chinense Pursh has been used as a folk medicine for the treatment of hepatic and gallbladder

diseases in China.4 Penchinones A−D have the unique structural feature of two pairs of cis−trans isomers with rearranged carbon skeletons. Notably, the presence of 1,2-bisacyl and internal trans-allyl groups on penchinone A encourages organic and medicinal chemists to synthesize this complex molecule. Biaryl ketones have been recognized as crucial structural motifs in biologically active compounds and functional materials.5 Recently, the transition-metal-catalyzed oxidative acylation reactions of sp2 C−H bonds have been intensively studied for the construction of biaryl ketones.6 For example, our group first reported the Rh(III)-catalyzed oxidative acylation of benzamides using aryl aldehydes as acyl sources to afford biaryl ketone compounds.7 Later, the Pd(II)-catalyzed acylation reactions of aromatic compounds using various acyl surrogates such as aldehydes, alcohols, ethers, and toluene derivatives were also explored under oxidative conditions.8 Generally, tert-butyl hydroperoxide (TBHP) was widely used as an oxidant to generate the acyl radical intermediates, delivering the acyl moiety on sp2 C−H bonds. In continuation of our recent works on the discovery of biologically active compounds based on catalytic C−H functionalization,9 we herein describe the first total synthesis of penchinone A and its structural analogues via the Pd(II)-catalyzed oxidative acylation of ketoximes with aldehydes. In addition, all synthetic compounds

Figure 1. Structure of penchinone A and its derivatives.

Received: September 2, 2017 Published: October 11, 2017

© 2017 American Chemical Society

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DOI: 10.1021/acs.joc.7b02212 J. Org. Chem. 2017, 82, 11566−11572

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The Journal of Organic Chemistry Scheme 1. Synthesis of Ketoxime 5a

Table 1. Selected Optimization of Reaction Conditionsa

entry

catalyst (mol %)

additive (mol %)

solvent

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13c 14d 15e 16f

[RhCp*Cl2]2 (2.5) [RhCp*Cl2]2 (2.5) [RhCp*Cl2]2 (2.5) Pd(OAc)2 (5) Pd(OAc)2 (5) Pd(OAc)2 (5) Pd(OAc)2 (5) Pd(OTf)2 (5) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10)

AgSbF6 (10) AgSbF6 (10), Ag2CO3 (200) AgSbF6 (10), Ag2CO3 (200) TBHP (200) TBHP (300) TBHP (400) TBHP (300), AcOH (200) TBHP (300) TBHP (300) TBHP (300) TBHP (300) TBHP (300) TBHP (300) TBHP (300) TBHP (300) TBHP (300)

DCE DCE THF DCE DCE DCE DCE DCE DCE THF 1,4-dioxane MeOH DCE DCE DCE DCE

N.R. N.R. N.R. 38 51 50 32 31 61 25 21 trace 55 60 48 43

Reaction conditions: 5a (0.2 mmol), 6a (0.6 mmol), catalyst (quantity noted), additive (quantity noted), solvent (1 mL) under air at 80 °C for 20 h in pressure tubes. bIsolated yield by flash column chromatography. cThe reaction was carried out at 120 °C. d6a (1 mmol, 5 equiv) was used. eThe reaction was carried out under N2 atmosphere. fThe reaction was carried out under air using 4 Å molecular sieves. a

was further acetylated to afford a separable mixture of transadduct 5a (71%) and cis-adduct 5b (14%), respectively. Next, we performed the ketoxime-directed catalytic oxidative acylation of 5a using p-anisaldehyde (6a) as a model substrate (Table 1). As shown in entry 1, no coupling reaction between 5a and 6a under cationic Rh(III) catalysis was observed. In addition, treatment of Ag2CO3 as an external oxidant was found to be ineffective in this transformation (Table 1, entries 2 and 3). To our delight, this coupling reaction was detected by using Pd(II) catalyst and TBHP oxidant to provide our desired product 7a in 38% yield (Table 1, entry 4). Increasing the amount of TBHP to 3 equiv provided an improved yield (51%) of the acylated adduct 7a (Table 1, entries 5 and 6). Further screening of additive and Pd salts was found to be less effective in this reaction (Table 1, entries 7 and 8). Notably, an increased loading of Pd(OAc)2 to 10 mol % resulted in increased reactivity, giving 7a in 61% yield (Table 1, entry 9).

were evaluated for inhibitory activity against nitric oxide (NO), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6) with lipopolysaccharide (LPS)-induced RAW264.7 cells10 and were found to potently inhibit NO, TNF-α, and IL-6 productions without affecting the viability of RAW264.7 cells, competitive with well-known dexamethasone as a positive control.

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RESULTS AND DISCUSSION The total synthesis of penchinone A was initiated by the formation of ketoxime 5a (Scheme 1). Allylation of phydroxyacetophenone (1) followed by subsequent Claisen rearrangement afforded ortho-allylated phenol 2 in 71% yields in two steps. Olefin migration of 2 was performed by treatment with KOtBu, providing internal olefin 3 with a ratio of E:Z = 5:1 in 95% yield. The reaction of 3 with O-methyl hydroxylamine hydrochloride smoothly provided p-hydroxy ketoxime 4, which 11567

DOI: 10.1021/acs.joc.7b02212 J. Org. Chem. 2017, 82, 11566−11572

Article

The Journal of Organic Chemistry Scheme 2. Synthesis of Penchinone A Derivatives via C−H Acylation and Hydrolysis

Table 2. Inhibitory Effects of the Synthesized Compounds 7a−g and 8a−g on NO, TNF-α, and IL-6 in LPS-Induced RAW264.7 Cellsa IC50 value (μM) compounds 7a 7b 7c 7d 7e 7f 7g a

NO 7.60 6.26 2.73 2.78 5.77 4.95 4.16

± ± ± ± ± ± ±

0.07 0.02 0.01 0.02 0.02 0.01 0.07

TNF-α 11.16 8.66 5.89 6.96 8.97 4.32 6.24

± ± ± ± ± ± ±

0.06 0.07 0.01 0.02 0.07 0.02 0.02

IC50 value (μM) IL-6

compounds

± ± ± ± ± ± ±

8a 8b 8c 8d 8e 8f 8g dexamethasone

8.68 5.60 4.26 4.14 6.88 3.23 5.96

0.06 0.01 0.02 0.02 0.02 0.02 0.01

NO 4.38 5.40 2.00 6.21 1.81 0.94 1.01 1.76

± ± ± ± ± ± ± ±

0.02 0.01 0.02 0.03 0.01 0.01 0.01 0.02

TNF-α 9.16 7.66 4.05 6.86 3.77 3.20 3.12 4.52

± ± ± ± ± ± ± ±

0.04 0.01 0.00 0.02 0.02 0.03 0.01 0.02

IL-6 7.66 6.53 2.15 7.70 3.10 2.07 2.10 3.92

± ± ± ± ± ± ± ±

0.01 0.01 0.03 0.01 0.01 0.01 0.04 0.01

IC50 value (μM): 50% inhibition concentration for NO, TNF-α, and IL-6 production. The results are reported as the mean value ± SEM for n = 3.

coupled with ketimine 5a (Scheme 2). The p-OH-substituted benzaldehyde 6b was found to display moderate reactivity furnishing the biaryl ketone 7b in 51% yield. The acylation reaction of meta-substituted benzaldehydes 6c and 6d showed relatively decreased reactivity under the current reaction conditions to afford the corresponding products 7c and 7d. Additionally, 3,4-disubstituted substrate 6e also underwent the C−H acylation reaction to deliver the desired adduct 7e in 34% yield. Notably, o-hydroxybenzaldehyde (6f) was also tolerable in this transformation to provide 7f, albeit resulting in low yield (21%). Moreover, this method can be successfully applied to a highly substituted benzaldehyde 6g to yield 7g as a synthetic precursor of penchinone A (8g). To construct penchinone A and its structural analogues, we performed the acid-mediated hydrolysis of all acylated compounds 7a−g. Acetyl and imine moieties were readily removed by using 0.5 M HCl in MeOH/

Subsequently, various solvents were screened, and 1,2-dichloroethane (DCE) solvent was found to be most effective (Table 1, entries 10−12). Furthermore, we performed the control experiments to increase the yield of 7a, but no improvement of acylated product 7a was observed, as shown in entries 13 and 14. Finally, this reaction was also carried out either under N2 atmosphere or by using molecular sieves, and no improved yield of both reactions was observed (Table 1, entries 15 and 16). Meanwhile, the C−H acylation reaction of phenol compound 4 was also examined under various reaction conditions. However, no formation of the corresponding adduct was detected, presumably due to the tight bidentate coordination of both hydroxy and olefin functionality to a Pd(II) center. With the optimal reaction conditions for the oxidative C−H acylation reaction in hand, various aryl aldehydes 6b−g were 11568

DOI: 10.1021/acs.joc.7b02212 J. Org. Chem. 2017, 82, 11566−11572

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The Journal of Organic Chemistry acetone at 80 °C to furnish the corresponding products 8a−g in moderate to good yields. The spectroscopic data (1H NMR and 13C NMR) and physical properties of the synthesized penchinone A (8g) were in full agreement with the reported values.3 Synthetic penchinone A and its derivatives (7a−g and 8a−g) were evaluated for in vitro inhibitory activity against nitric oxide (NO), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6) as cell signaling cytokines involved in the inflammation process (Table 2). Inflammation has been known as an early response of host against pathogenic challenge.11 In this process, activated inflammatory cells can secrete increased amounts of NO, prostaglandins, and cytokines such as IL-1β, IL-6, and TNF-α. In our experiment, the anti-inflammatory activity was determined by enzyme-linked immunosorbent assay (ELISA) using LPS-induced RAW264.7 cells and represents the 50% inhibition concentration of compounds compared with LPSstimulated cells (see Figure S1 in Supporting Information for dose-dependent cell viability data of 7a−g and 8a−g). A commercial anti-inflammatory drug, dexamethasone, was selected as a positive control.12 A range of compounds (7c, 7d, 8c, and 8e−g) exhibited comparable inhibitory activity with dexamethasone. In particular, penchinone A (8g) and its structural analogue (8f) were found to display most potent inhibitory activities (IC50 = 1.01 ± 0.01 μM for 8g and IC50 = 0.94 ± 0.01 μM for 8f) against NO production, stronger than that of a positive control (see Figure S2 in Supporting Information for dose-dependent NO production inhibition data). Moreover, compounds (8c and 8e−g) were found to induce higher inhibition activity than that of dexamethasone against TNF-α and IL-6 productions (see Figures S3 and S4 in Supporting Information for dose-dependent TNF-α and IL-6 production inhibition data). On the basis of the structure− activity relationship (SAR) between synthetic compounds (8c and 8e−g), we believe that the o-hydroxy and/or m-methoxy groups on the left ring of penchinone A are very crucial for antiinflammatory activity.

1-(4-(allyloxy)phenyl)ethan-1-one (2.8 g, 16 mmol, 100 mol %) was stirred in o-xylene (16 mL) for 18 h at 220 °C. The resulting mixture was cooled to room temperature, diluted with EtOAc (20 mL), and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes/EtOAc = 6:1) to afford 2 (2.0 g, 71%) as a white solid. 1-(3-Allyl-4-hydroxyphenyl)ethan-1-one (2). 2.0 g (71%); white solid; mp = 115.8−116.4 °C; 1H NMR (400 MHz, CDCl3) δ 7.79−7.77 (m, 2H), 7.04 (s, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.07−5.97 (m, 1H), 5.16−5.13 (m, 2H), 3.45 (d, J = 6.4 Hz, 2H), 2.57 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ 198.3, 159.4, 135.8, 131.5, 130.0, 129.3, 126.1, 116.9, 115.6, 34.7, 26.4; IR (KBr) υ 3262 (OH), 1672 (CO) cm−1; HRMS (orbitrap, ESI) calcd for C11H13O2 [M + H]+ 177.0910, found 177.0905. Experimental Procedure and Characterization Data for the Synthesis of 3. To an oven-dried round-bottom flask (100 mL) charged with 2 (1.8 g, 10 mmol, 100 mol %) and THF (40 mL) was added KOtBu (4.5 g, 40 mmol, 400 mol %) under air at room temperature. The reaction mixture was stirred for 8 h at 80 °C. The resulting mixture was extracted with EtOAc (100 mL). The organic layer was washed with saturated NH4Cl solution (2 × 60 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes/EtOAc = 5:1) to afford 3 (1.7 g, 95%) as a white solid. 1-(4-Hydroxy-3-(prop-1-en-1-yl)phenyl)ethan-1-one (3). 1.7 g (95%, E:Z = 5:1); white solid; mp = 107.3−109.1 °C; 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.72 (dd, J = 8.4, 2.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.66 (dd, J = 16.0, 1.6 Hz, 1H), 6.35−6.26 (m, 1H), 2.59 (s, 3H), 1.90 (dd, J = 6.8, 1.6 Hz, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ 198.7, 158.0, 129.8, 129.1, 129.0, 128.4, 125.4, 124.7, 115.7, 26.4, 19.0; IR (KBr) υ 3282 (OH), 1651 (CO) cm−1; HRMS (orbitrap, ESI) calcd for C11H13O2 [M + H]+ 177.0910, found 177.0909. Experimental Procedure and Characterization Data for the Synthesis of 4. To an oven-dried round-bottom flask (100 mL) charged with 3 (1.1 g, 6 mmol, 100 mol %), O-methyl hydroxylamine hydrochloride (0.6 g, 7.2 mmol, 120 mol %), and NaOAc (0.98 g, 12 mmol, 200 mol %) was added MeOH (12 mL) under air. The reaction mixture was stirred for 4 h at room temperature. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was washed with saturated NH4Cl solution (2 × 30 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes/EtOAc = 15:1) to afford 4 (1.08 g, 87%) as a white solid. (Z)-1-(4-Hydroxy-3-((E)-prop-1-en-1-yl)phenyl)ethan-1-one O-Methyl Oxime (4). 1.08 g (87%, E:Z = 5:1); white solid; mp = 105.8−107.3 °C; 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 15.2 Hz, 1H), 6.27−6.18 (m, 1H), 5.83 (br s, 1H), 3.98 (s, 3H), 2.20 (s, 3H), 1.89 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.9, 153.5, 131.8, 128.9, 125.9, 125.4, 125.2, 123.9, 115.7, 61.8, 19.0, 12.9; IR (KBr) υ 3323 (OH), 1654 (CN), 968 (N−O) cm−1; HRMS (orbitrap, ESI) calcd for C12H16NO2 [M + H]+ 206.1176, found 205.1173. Experimental Procedure and Characterization Data for the Synthesis of 5a and 5b. To an oven-dried round-bottom flask (100 mL) charged with 4 (0.62 g, 3 mmol, 100 mol %), acetyl chloride (0.94 g, 12 mmol, 400 mol %), and N,N-diisopropylethylamine (0.94 g, 12 mmol, 400 mol %) was added CH2Cl2 (6 mL) under air at room temperature. The reaction mixture was stirred for 6 h at 60 °C. The resulting mixture was extracted with EtOAc (30 mL). The organic layer was washed with saturated NH4Cl solution (2 × 20 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes/EtOAc = 20:1) to afford a separable mixture of 5a (0.53 g, 71%) and 5b (0.11 g, 14%), respectively. 4-((E)-1-(Methoxyimino)ethyl)-2-((E)-prop-1-en-1-yl)phenyl Acetate (5a). 0.53 g (71%, E-isomer); colorless oil; 1H NMR (700 MHz, CDCl3) δ 7.76 (d, J = 2.1 Hz, 1H), 7.49 (dd, J = 8.4, 2.1 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.39 (dd, J = 16.1, 2.1 Hz, 1H), 6.32−

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CONCLUSION We described the first total synthesis and anti-inflammatory evaluation of penchinone A and its structural derivatives via the oxime-directed palladium(II)-catalyzed oxidative acylation, the Claisen rearrangement, and base-mediated olefin migration. This transformation efficiently provides an array of allylsubstituted biaryl ketones with site-selectivity and functional group compatibility. In addition, all synthetic compounds were screened for inhibitory activity against NO, TNF-α, and IL-6 productions with LPS-induced RAW264.7 cells. Notably, penchinone A (8g) and its derivatives (8e and 8f) were found to display potent anti-inflammatory activity stronger than that of dexamethasone as a positive control.

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EXPERIMENTAL SECTION

Experimental Procedure and Characterization Data for the Synthesis of 2. To an oven-dried round-bottom flask (100 mL) charged with p-hydroxyacetophenone (1) (2.7 g, 20 mmol, 100 mol %), K2CO3 (5.5 g, 40 mmol, 200 mol %), and MeCN (20 mL) was added allyl bromide (2.1 mL, 24 mmol, 120 mol %) under air at room temperature. The reaction mixture was stirred for 6 h at 60 °C. The resulting mixture was extracted with EtOAc (100 mL). The organic layer was washed with saturated NH4Cl solution (2 × 60 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes/EtOAc = 2:1) to afford the 1-(4-(allyloxy)phenyl)ethan-1-one (3.5 g, 99%) as a colorless oil. Next, 11569

DOI: 10.1021/acs.joc.7b02212 J. Org. Chem. 2017, 82, 11566−11572

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The Journal of Organic Chemistry

1194 (C−O), 964 (N−O) cm−1; HRMS (orbitrap, ESI) calcd for C21H22NO5 [M + H]+ 368.1492, found 368.1495. 5-(4-Hydroxy-3-methoxybenzoyl)-4-((E)-1-(methoxyimino)ethyl)-2-((E)-prop-1-en-1-yl)phenyl Acetate (7e). Yield 54.1 mg (34%); red sticky oil; 1H NMR (400 MHz, CD3OD) δ 7.69 (s, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.16 (dd, J = 8.0, 2.0 Hz, 1H), 7.12 (s, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.50−6.49 (m, 2H), 3.85 (s, 3H), 3.69 (s, 3H), 2.32 (s, 3H), 2.03 (s, 3H), 2.03−1.92 (m, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 197.0, 170.7, 155.7, 153.3, 149.0, 148.4, 139.2, 135.9, 133.6, 131.9, 130.7, 127.2, 126.3, 124.7, 124.5, 115.7, 113.2, 62.0, 56.3, 20.6, 19.0, 15.1; IR (KBr) υ 3404 (OH), 1762 (CO), 1652 (CN), 1195 (C−O), 965 (N−O) cm−1; HRMS (orbitrap, ESI) calcd for C22H24NO6 [M + H]+ 398.1598, found 398.1600. 5-(2-Hydroxybenzoyl)-4-((E)-1-(methoxyimino)ethyl)-2-((E)prop-1-en-1-yl)phenyl Acetate (7f). Yield 30.9 mg (21%); yellow sticky oil; 1H NMR (400 MHz, CDCl3) δ 11.86 (s, 1H), 7.62 (s, 1H), 7.43 (ddd, J = 8.8, 7.2, 1.6 Hz, 1H), 7.24 (dd, J = 8.0, 1.6 Hz, 1H), 7.11 (s, 1H), 7.00 (dd, J = 8.4, 1.2 Hz, 1H), 6.76 (ddd, J = 9.0, 7.2, 0.8 Hz, 1H), 6.46−6.33 (m, 2H), 3.67 (s, 3H), 2.34 (s, 3H), 2.08 (s, 3H), 1.94 (d, J = 4.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 201.7, 168.9, 162.4, 152.8, 147.3, 136.5, 136.0, 133.8, 132.6, 132.3, 131.0, 126.0, 123.6, 123.2, 120.5, 118.9, 118.0, 61.9, 21.0, 19.1, 14.1; IR (KBr) υ 3401 (OH), 1765 (CO), 1630 (CN), 1192 (C−O), 965 (N−O) cm−1; HRMS (orbitrap, ESI) calcd for C21H22NO5 [M + H]+ 368.1492, found 368.1508. 5-(2,4-Dihydroxy-3-methoxybenzoyl)-4-((E)-1(methoxyimino)ethyl)-2-((E)-prop-1-en-1-yl)phenyl Acetate (7g). Yield 29.8 mg (18%); yellow sticky solid; 1H NMR (700 MHz, CD3OD) δ 7.72 (s, 1H), 7.11 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 2.8 Hz, 2H), 6.31 (d, J = 9.1 Hz, 1H), 3.86 (s, 3H), 3.67 (s, 3H), 2.33 (s, 3H), 2.09 (s, 3H), 1.94−1.93 (m, 3H); 13C{1H} NMR (175 MHz, CD3OD) δ 201.9, 170.7, 158.5, 158.3, 154.7, 148.6, 138.0, 136.1, 134.9, 133.7, 132.0, 130.0, 127.0, 124.5, 124.1, 115.7, 108.9, 62.0, 60.8, 20.6, 19.0, 14.3; IR (KBr) υ 3396 (OH), 1754 (C O), 1614 (CN), 1191 (C−O), 963 (N−O) cm−1; HRMS (orbitrap, ESI) calcd for C22H24NO7 [M + H]+ 414.1547, found 414.1554. Typical Procedure for the Synthesis of Penchinone A Derivatives via Acidic Hydrolysis (8a−g). To an oven-dried sealed tube charged with 7a (76.3 mg, 0.2 mmol, 100 mol %) were added 0.5 M HCl (1 mL) and MeOH/acetone (1 mL, 1:1) under air at room temperature. The reaction mixture was stirred for 4 h at 80 °C. The reaction mixture was cooled to room temperature, quenched with saturated NaHCO3 solution (1 mL) to make pH 7 of reaction mixture, and then extracted with EtOAc (2 × 10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes/ EtOAc = 3:1) to afford 8a (32.9 mg) in 53% yield. (E)-1-(4-Hydroxy-2-(4-methoxybenzoyl)-5-(prop-1-en-1-yl)phenyl)ethan-1-one (8a). Yield 32.9 mg (53%); white solid; mp = 177.2−178.6 °C; 1H NMR (400 MHz, CD3OD) δ 8.04 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.72 (dd, J = 16.0, 1.6 Hz, 1H), 6.68 (s, 1H), 6.55−6.46 (m, 1H), 3.84 (s, 3H), 2.47 (s, 3H), 1.94 (dd, J = 6.4, 1.6 Hz, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 199.1, 199.0, 165.2, 159.4, 142.5, 132.5, 131.3, 130.5, 129.6, 129.2, 127.1, 125.9, 115.9, 114.7, 56.0, 26.8, 19.1; IR (KBr) υ 3295 (OH), 1671 (CO) cm−1; HRMS (orbitrap, ESI) calcd for C19H19O4 [M + H]+ 311.1278, found 311.1290. (E)-1-(4-Hydroxy-2-(4-hydroxybenzoyl)-5-(prop-1-en-1-yl)phenyl)ethan-1-one (8b). Yield 42.2 mg (71%); white solid; mp = 233.1−234.9 °C; 1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.57 (d, J = 8.8, 2H), 6.78 (d, J = 8.8 Hz, 2H), 6.71 (dd, J = 16.0, 1.6 Hz, 1H), 6.67 (s, 1H), 6.54−6.45 (m, 1H), 2.47 (s, 3H), 1.94 (dd, J = 6.8, 1.6 Hz, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 199.2, 199.0, 163.8, 159.5, 142.7, 132.9, 130.5, 130.1, 129.5, 129.1, 127.1, 126.0, 116.1, 116.0, 26.9, 19.1; IR (KBr) υ 3289 (OH), 1676 (CO) cm−1; HRMS (orbitrap, ESI) calcd for C18H17O4 [M + H]+ 297.1121, found 297.1122. (E)-1-(4-Hydroxy-2-(3-methoxybenzoyl)-5-(prop-1-en-1-yl)phenyl)ethan-1-one (8c). Yield 24.9 mg (40%); brown sticky oil; 1 H NMR (700 MHz, CD3OD) δ 8.04 (s, 1H), 7.31−7.28 (m, 2H), 7.12−7.10 (m, 2H), 6.72 (dd, J = 16.1, 1.4 Hz, 1H), 6.71 (s, 1H),

6.27 (m, 1H), 3.99 (s, 3H), 2.33 (s, 3H), 2.21 (s, 3H), 1.90 (dd, J = 7.0, 2.1 Hz, 3H); 13C{1H} NMR (175 MHz, CDCl3) δ 169.3, 154.0, 148.1, 134.7, 130.5, 129.1, 125.4, 124.4, 124.2, 122.6, 62.0, 21.0, 19.0, 12.7; IR (KBr) υ 1759 (CO), 1654 (CN), 1197 (C−O), 963 (N−O) cm−1; HRMS (orbitrap, ESI) calcd for C14H18NO3 [M + H]+ 248.1281, found 248.1280. 4-((E)-1-(Methoxyimino)ethyl)-2-((Z)-prop-1-enyl)phenyl Acetate (5b). 0.11 g (14%, Z-isomer); colorless oil; 1H NMR (700 MHz, CDCl3) δ 7.57 (d, J = 2.1 Hz, 1H), 7.55 (dd, J = 8.4, 2.1 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.29 (dd, J = 11.2, 1.4 Hz, 1H), 5.90− 5.85 (m, 1H), 3.98 (s, 3H), 2.27 (s, 3H), 2.21 (s, 3H), 1.77 (dd, J = 7.0, 2.1 Hz, 3H); 13C{1H} NMR (175 MHz, CDCl3) δ 169.1, 154.0, 149.1, 134.3, 130.4, 129.5, 128.2, 125.7, 124.2, 122.3, 62.1, 21.0, 14.7, 12.8; IR (KBr) υ 1759 (CO), 1651 (CN), 1197 (C−O), 959 (N−O) cm−1; HRMS (orbitrap, ESI) calcd for C14H18NO3 [M + H]+ 248.1281, found 248.1280. Typical Procedure for the C−H Acylation of 5a with Aldehydes (7a−g). To an oven-dried sealed tube charged with 5a (98.9 mg, 0.4 mmol, 100 mol %), Pd(OAc)2 (9.0 mg, 0.04 mmol, 10 mol %), and TBHP (0.24 mL, 1.2 mmol, 300 mol %, 5 M in decane) were added p-anisaldehyde (6a) (163.4 mg, 1.2 mmol, 300 mol %) and DCE (2 mL) under air at room temperature. The reaction mixture was stirred for 20 h at 80 °C. The reaction mixture was cooled to room temperature and extracted with EtOAc (2 × 15 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes/ EtOAc = 10:1) to afford 7a (93.1 mg) in 61% yield. 5-(4-Methoxybenzoyl)-4-((E)-1-(methoxyimino)ethyl)-2-((E)prop-1-en-1-yl)phenyl Acetate (7a). Yield 93.1 mg (61%); orange sticky oil; 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.8 Hz, 2H), 7.58 (s, 1H), 7.12 (s, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.45−6.34 (m, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 2.32 (s, 3H), 2.02 (s, 3H), 1.93 (d, J = 5.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.8, 169.0, 163.4, 154.3, 147.1, 138.0, 134.8, 132.3, 132.0, 130.8, 130.7, 126.4, 123.8, 123.7, 113.7, 61.8, 55.5, 21.0, 19.1, 15.2; IR (KBr) υ 1762 (CO), 1718 (CO), 1658 (CN), 1197 (C−O), 965 (N−O) cm−1; HRMS (orbitrap, ESI) calcd for C22H24NO5 [M + H]+ 382.1649, found 382.1652. 5-(4-Hydroxybenzoyl)-4-((E)-1-(methoxyimino)ethyl)-2-((E)prop-1-en-1-yl)phenyl Acetate (7b). Yield 74.9 mg (51%); white solid; mp = 132.0−133.6 °C; 1H NMR (700 MHz, CD3OD) δ 7.69 (s, 1H), 7.59 (d, J = 9.1 Hz, 2H), 7.10 (s, 1H), 6.80 (d, J = 9.1 Hz, 2H), 6.49−6.48 (m, 2H), 3.66 (s, 3H), 2.32 (s, 3H), 2.03 (s, 3H), 1.93 (d, J = 4.9 Hz, 3H); 13C{1H} NMR (175 MHz, CD3OD) δ 197.2, 170.7, 163.8, 155.4, 148.5, 139.4, 135.7, 133.6, 133.3, 131.9, 130.4, 127.2, 124.6, 124.5, 116.1, 61.9, 20.6, 19.0, 14.9; IR (KBr) υ 3341 (OH), 1763 (CO), 1716 (CO), 1650 (CN), 1195 (C−O), 964 (N− O) cm−1; HRMS (orbitrap, ESI) calcd for C21H22NO5 [M + H]+ 368.1492, found 368.1493. 5-(3-Methoxybenzoyl)-4-((E)-1-(methoxyimino)ethyl)-2-((E)prop-1-en-1-yl)phenyl Acetate (7c). Yield 74.8 mg (49%); brown sticky oil; 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.34 (q, J = 1.6 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.23 (dt, J = 7.6, 1.2 Hz, 1H), 7.17 (s, 1H), 7.07 (ddd, J = 8.0, 2.8, 1.2 Hz, 1H), 6.46−6.35 (m, 2H), 3.82 (s, 3H), 3.72 (s, 3H), 2.33 (s, 3H), 2.02 (s, 3H), 1.93 (d, J = 4.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.8, 169.0, 159.7, 154.1, 147.1, 139.3, 137.6, 135.0, 132.7, 130.9, 129.4, 126.3, 124.1, 123.7, 122.5, 119.6, 113.3, 61.8, 55.6, 21.0, 19.1, 15.1; IR (KBr) υ 1769 (C O), 1721 (CO), 1668 (CN), 1193 (C−O), 964 (N−O) cm−1; HRMS (orbitrap, ESI) calcd for C22H24NO5 [M + H]+ 382.1649, found 382.1654. 5-(3-Hydroxybenzoyl)-4-((E)-1-(methoxyimino)ethyl)-2-((E)prop-1-en-1-yl)phenyl Acetate (7d). Yield 58.8 mg (40%); white solid; mp = 129.0−130.2 °C; 1H NMR (700 MHz, CD3OD) δ 7.71 (s, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.15 (s, 1H), 7.09−7.07 (m, 2H), 6.97 (ddd, J = 7.7, 2.1, 1.4 Hz, 1H), 6.50−6.49 (m, 2H), 3.66 (s, 3H), 2.33 (s, 3H), 2.02 (s, 3H), 1.95−1.94 (m, 3H); 13C{1H} NMR (175 MHz, CD3OD) δ 198.2, 170.7, 158.8, 155.2, 148.6, 140.6, 139.2, 135.8, 134.0, 132.1, 130.5, 126.9, 124.7, 124.6, 121.6, 121.1, 116.5, 62.0, 20.6, 19.0, 14.6; IR (KBr) υ 3385 (OH), 1768 (CO), 1651 (CN), 11570

DOI: 10.1021/acs.joc.7b02212 J. Org. Chem. 2017, 82, 11566−11572

Article

The Journal of Organic Chemistry 6.54−6.49 (m, 1H), 3.80 (s, 3H), 2.46 (s, 3H), 1.94 (dd, J = 6.3, 2.1 Hz, 3H); 13C{1H} NMR (175 MHz, CD3OD) δ 199.6, 199.0, 161.2, 159.7, 142.3, 139.9, 130.5, 129.6, 129.3, 127.3, 125.9 (two carbon overlap), 122.9, 120.1, 116.0, 114.1, 55.8, 26.6, 19.1; IR (KBr) υ 3274 (OH), 1670 (CO) cm−1; HRMS (orbitrap, ESI) calcd for C19H19O4 [M + H]+ 311.1278, found 311.1289. (E)-1-(4-Hydroxy-2-(3-hydroxybenzoyl)-5-(prop-1-en-1-yl)phenyl)ethan-1-one (8d). Yield 26.6 mg (45%); white solid; mp = 215.0−216.5 °C; 1H NMR (400 MHz, CD3OD) δ 8.04 (s, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.12−7.08 (m, 2H), 6.96 (ddd, J = 7.8, 2.8, 1.2 Hz, 1H), 6.74−6.70 (m, 1H), 6.70 (s, 1H), 6.55−6.46 (m, 1H), 2.47 (s, 3H), 1.94 (dd, J = 6.8, 2.0 Hz, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 199.9, 199.1, 159.7, 158.7, 142.5, 139.8, 130.5, 130.4, 129.6, 129.2, 127.3, 126.0, 121.5, 121.1, 116.3, 116.0, 26.6, 19.1; IR (KBr) υ 3346 (OH), 1668 (CO) cm−1; HRMS (orbitrap, ESI) calcd for C18H17O4 [M + H]+ 297.1121, found 297.1129. (E)-1-(4-Hydroxy-2-(4-hydroxy-3-methoxybenzoyl)-5-(prop1-en-1-yl)phenyl)ethan-1-one (8e). Yield 35.9 mg (55%); white solid; mp = 168.4−169.9 °C; 1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.01 (dd, J = 8.4, 2.0 Hz, 1H), 6.76− 6.70 (m, 2H), 6.69 (s, 1H), 6.54−6.45 (m, 1H), 3.87 (s, 3H), 2.47 (s, 3H), 1.94 (dd, J = 6.8, 1.6 Hz, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 199.2, 198.9, 159.4, 153.3, 149.0, 142.5, 130.5, 130.4, 129.7, 129.1, 127.1, 126.3, 126.0, 116.1, 115.5, 112.3, 56.3, 26.9, 19.1; IR (KBr) υ 3311 (OH), 1650 (CO) cm−1; HRMS (orbitrap, ESI) calcd for C19H19O5 [M + H]+ 327.1227, found 327.1239. (E)-1-(4-Hydroxy-2-(2-hydroxybenzoyl)-5-(prop-1-en-1-yl)phenyl)ethan-1-one (8f). Yield 36.3 mg (61%); white solid; mp = 100.7−102.6 °C; 1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 7.46 (ddd, J = 8.6, 6.8, 1.6 Hz, 1H), 7.07 (dd, J = 7.6, 1.6 Hz, 1H), 6.98 (dd, J = 8.4, 1.2 Hz, 1H), 6.79−6.73 (m, 2H), 6.72 (s, 1H), 6.58−6.49 (m, 1H), 2.51 (s, 3H), 1.96 (dd, J = 6.4, 1.6 Hz, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 205.2, 198.7, 163.3, 160.1, 140.7, 136.9, 133.1, 130.7, 129.3, 128.7, 127.5, 125.9, 121.5, 119.9, 118.7, 115.8, 26.5, 19.1; IR (KBr) υ 3276 (OH), 1671 (CO) cm−1; HRMS (orbitrap, ESI) calcd for C18H17O4 [M + H]+ 297.1121, found 297.1133. (E)-1-(2-(2,4-Dihydroxy-3-methoxybenzoyl)-4-hydroxy-5(prop-1-en-1-yl)phenyl)ethan-1-one (8g). Yield 41.2 mg (60%); white solid; mp = 111.2−113.9 °C; 1H NMR (700 MHz, CD3OD) δ 8.07 (s, 1H), 6.74−6.72 (m, 2H), 6.70 (s, 1H), 6.55−6.50 (m, 1H), 6.29 (d, J = 8.4 Hz, 1H), 3.90 (s, 3H), 2.52 (s, 3H), 1.96 (dd, J = 6.3, 1.4 Hz, 3H); 13C{1H} NMR (175 MHz, CD3OD) δ 203.8, 198.9, 159.5, 158.5, 158.3, 140.7, 136.0, 130.6, 129.9, 129.3, 128.9, 127.3, 125.9, 115.9, 115.4, 108.8, 60.8, 26.8, 19.1; IR (KBr) υ 3279 (OH), 1651 (CO) cm−1; HRMS (orbitrap, ESI) calcd for C19H19O6 [M + H]+ 343.1176, found 343.1179. Cell Culture and Cell Viability Assay. Murine RAW264.7 macrophage cell line was obtained from American Type Culture Collection (ATCC) and cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum and 1% penicillin−streptomycin at 37 °C in a humidified atmosphere containing 5% CO2. Cell viability was determined by 3-[4,5dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) reduction assay. In brief, RAW264.7 cells were preincubated overnight in 96-well plates at a density of 1 × 104 cells per well. After 24 h, cells were treated with various concentrations (0.1, 1, 10 μg/mL) of synthetic compounds for another 24 h. The mediums then were removed, and MTT was then added to each well at a final concentration of 0.5 mg/mL. The cells were incubated for 4 h at 37 °C, supernatants were removed, and dimethyl sulfoxide was added to each well. The optical density was measured at 540 nm using a microplate reader. Determination of Nitric Oxide. RAW264.7 cells were treated with compounds for 2 h, followed by the addition with LPS (1 μg/mL) for an additional 24 h. NO concentration in the culture supernatants was measured using a previously described assay system. The NO levels were used as an indicator of the amount of NO production. One hundred microliters of Griess regent (1% sulfanilamide in 5% phosphoric acid, 1% α-naphthylamide in H2O) in a 96-well plate,

incubated at room temperature for 15 min, and then measured at 550 nm using a Molecular Device microplate reader. Cytokine Determination by ELISA. RAW264.7 cells were pretreated with compounds, followed by the addition of LPS (1 μg/mL) to the cultures for 24 h. The concentration of the TNF-α and IL-6 in each sample was determined using DuoSet Elisa kit according to the manufacturer’s instructions. Statistical Analysis. Each result is reported as means ± SEM. All experiments were performed at least three times. For comparisons between two groups, the Student’s t test (SigmaPlot) was used. Multigroup comparisons of mean values were analyzed by one-way ANOVA (GraphPad program).

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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.joc.7b02212. Cell viability and dose-dependent inhibition data of compounds 7a−g and 8a−g and 1H and 13C NMR copies of all products (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. ORCID

Jong Hwan Kwak: 0000-0002-8327-3703 Suhkneung Pyo: 0000-0002-8333-6268 In Su Kim: 0000-0002-2665-9431 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by research grant commission of Gyeonggi Biocenter funded by Gyeonggi-do, Republic of Korea.

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REFERENCES

(1) For selected reviews, see: (a) Umezawa, T. Phytochem. Rev. 2003, 2, 371. (b) Landete, J. M. Food Res. Int. 2012, 46, 410. (c) Kassuya, C. A. L.; Leite, D. F. P.; de Melo, L. V.; Rehder, V. L. G.; Calixto, J. B. Planta Med. 2005, 71, 721. (2) For selected reviews, see: (a) Saleem, M.; Kim, H. J.; Ali, M. S.; Lee, Y. S. Nat. Prod. Rep. 2005, 22, 696. (b) Pan, J. Y.; Chen, S. L.; Yang, M. H.; Wu, J.; Sinkkonen, J.; Zou, K. Nat. Prod. Rep. 2009, 26, 1251. (3) He, Y.-C.; Peng, C.; Xie, X.-F.; Chen, M.-H.; Li, X.-N.; Li, M.-T.; Zhou, Q.-M.; Guo, L.; Xiong, L. RSC Adv. 2015, 5, 76788. (4) (a) Lu, Q.; Jiang, M. H.; Jiang, J. G.; Zhang, R. F.; Zhang, M. W. J. Agric. Food Chem. 2012, 60, 11097. (b) He, Y. C.; Zou, Y.; Peng, C.; Liu, J. L.; He, C. J.; Guo, L.; Xie, X. F.; Xiong, L. Fitoterapia 2015, 100, 7. (5) (a) Surburg, H.; Panten, J. Common Fragrance and Flavor Materials, 5th ed.; Wiley-VCH: Weinheim, Germany, 2006. (b) Deng, Y.; Chin, Y.-W.; Chai, H.; Keller, W. J.; Kinghorn, A. D. J. Nat. Prod. 2007, 70, 2049. (c) Romines, K. R.; Freeman, G. A.; Schaller, L. T.; Cowan, J. R.; Gonzales, S. S.; Tidwell, J. H.; Andrews, C. W.; Stammers, D. K.; Hazen, R. J.; Ferris, R. G.; Short, S. A.; Chan, J. H.; Boone, L. R. J. Med. Chem. 2006, 49, 727. (6) (a) Sharma, S.; Mishra, N. K.; Shin, Y.; Kim, I. S. Curr. Org. Chem. 2016, 20, 471. (b) Hummel, J. R.; Boerth, J. A.; Ellman, J. A. Chem. Rev. 2017, 117, 9163.

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DOI: 10.1021/acs.joc.7b02212 J. Org. Chem. 2017, 82, 11566−11572

Article

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DOI: 10.1021/acs.joc.7b02212 J. Org. Chem. 2017, 82, 11566−11572