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DOI: 10.1055/s-0039-1690794
Total Synthesis of (±)-Cassumunins A–C and Curcumin Analogues
F.A.K. gratefully acknowledges Science and Engineering Research Board, Department of Science and Technology, New Delhi for financial support.
Publication History
Received: 18 December 2019
Accepted after revision: 19 December 2019
Publication Date:
27 January 2020 (online)
Abstract
A full account of the total synthesis of (±)-cassumunins A–C – superior antioxidants and anti-inflammatory agents – is given. Two novel approaches were developed for synthesizing cassumunins. The total synthesis of cassumunins A and B was accomplished in five linear steps from a known aldehyde in good overall yields of 50 and 43%, respectively, featuring a cascade [3,3]-sigmatropic shift (the Claisen rearrangement) and Heck cross-coupling reaction. Consequently, the total synthesis of cassumunin C was accomplished in three linear steps from a known alcohol with an overall yield of 53%. The key features involved in this synthesis are tandem [3,3]-sigmatropic shift, SN2′ reaction, and aldol condensation. Moreover, a total of eighteen symmetrical and unsymmetrical curcumin analogues were synthesized.
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Key words
total synthesis - Claisen rearrangement - SN2′ reaction - cassumunins A–C - curcumin - Heck reaction - aldol condensationTraditionally, curcumin (1; Figure [1]) is a globally popular herbal drug, isolated from turmeric, the rhizome of Curcuma longa L. (Zingiberaceae), by Vogel et al. in 1842.[1] Turmeric contains three curcuminoids such as curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Out of these three compounds, curcumin is the most abundant and is well known for being an extremely biologically potent component.[2] In the past decade, numerous biological investigations have been carried out on curcumin and it was found to be the best chemopreventive drug that can cure frequently existing cancers such as stomach, lung, breast, duodenal, prostate and colon cancers, and leukemia.[2] Also, it has other biological activities such as antioxidant, anti-inflammatory, antiarthritis, cardiotoxicity, antidiabetic, and neurotoxicity.[2]
In 1993, Masuda et al. isolated three new curcuminoids from the rhizome of tropical ginger, Zingiber cassumunar and named as (±)-cassumunins A–C, having superior antioxidant and anti-inflammatory properties in comparison to curcumin.[4] Subsequently, in 1998, they synthesized cassumunins A and B in nine linear steps in an overall yield of 20 and 26%, respectively (Scheme [1]). Cassumunins A–C are more active against cell death in thymocyte system of the rat, induced by H2O2 in comparison to curcumin.[5]
In 2014, Chen et al. synthesized cassumunin C in seven linear steps in an overall yield of 11.7% by using aromatic propargylation, stereoselective reduction of alkynylphenol, and Reimer–Tiemann reaction as key steps (Scheme [1]).[6] Because of remarkable antioxidant, anti-inflammatory activities, and attractive molecular architecture, we were prompted to synthesize (±)-cassumunins A–C and herein report straightforward as well as efficient approaches leading to good overall yield of 50, 43, and 53%, respectively.
Cassumunins have curcumin core structure with phenylbutenylated moiety.[4] [5] Retrosynthetic analysis of 5 and 6 is depicted in Scheme [2]. Cassumunins A and B could be assembled via an aldol condensation reaction between 13 and 8 or 9 followed by usual deprotection of O-Boc. The compound 8 or 9 could be accessed via Heck cross-coupling of 10 and the corresponding methoxy-substituted bromobenzenes. Compound 10 was expected to be synthesized from 11 through usual Boc protection. Terminal olefin 11 could be obtained by [3,3]-sigmatropic shift (the Claisen rearrangement) of 12, which was expected to be prepared from commercially available vanillin.
As shown in Scheme [3], we commenced our synthetic investigation towards cassumunins A and B from aldehyde 12, which was prepared by following the known procedure with slight modification via alkylation between commercially available vanillin and crotyl bromide in the presence of K2CO3/DMF in good yield (96%).[7] Aldehyde 12 was subjected to [3,3]-sigmatropic shift (the Claisen rearrangement) at 180 °C in a sealed tube to give 11 in excellent yield (95%).[8] The free hydroxyl group of compound 11 was protected by using (Boc)2O and DMAP/Et3N/CH2Cl2, which furnished O-Boc protected compound 10 in good yield (97%). The corresponding methoxy-substituted aryl group was familiarized by Heck cross-coupling reaction with olefin derivative 10, in the presence of a catalytic amount of Pd(OAc)2 and Cs2CO3/PhMe to afford compound 8 or 9 in good yield of 84 and 82%, respectively.[9] Preparation of cassumunin A (5) from 8 through condensation reaction with 13 [10] followed by deprotection of the O-Boc group by using B2O3/B(OMe)3/10% HCl furnished two products cassumunin A (5) and O-Boc protected cassumunin A (5a) in 32 and 46% yield, respectively.[11] Similarly, preparation of cassumunin B (6) from 9 via aldol condensation reaction with 13 [10] followed by deprotection of O-Boc group by using B2O3/B(OMe)3/10% HCl[11] gave two products, cassumunin B (6) and the O-Boc protected cassumunin B (6a) in 5 and 48% yield, respectively. Therefore, a small modification in our retrosynthetic synthesis was done by first deprotecting the O-Boc group followed by aldol condensation reaction. Compound 8 and 9 were subjected to standard O-Boc deprotection condition TFA/CH2Cl2, which were unsuccessful. A significant transformation of 8 and 9 to 14 and 15 was observed by using K2CO3/MeOH/H2O[12] (3:1) at 80 °C in excellent yield of 97 and 94%, respectively. Compounds 5 and 6 were accomplished by performing aldol condensation reaction between 13 [10] and 14 or 15 in the presence of B2O3/B(OMe)3/10% HCl[11] at 80 °C in good yield of 66 and 61%, respectively.
The retrosynthetic analysis of 7 is depicted in Scheme [4]. We anticipated that cassumunin C could be secured via aldol condensation between aldehyde 16 and diketone 13. Compound 16 could be derived from 17 via [3,3]-sigmatropic shift of 17, it was expected to be prepared via SN2′ reaction between vanillin and 18 under Mitsunobu reaction conditions.
As shown in Scheme [5], we commenced our synthesis from compound 17, which was prepared from alcohol 18 via SN2′ reaction under Mitsunobu reaction conditions in the presence of vanillin (19o) and Et3N/DEAD/PPh3 to furnish aldehyde 17 in excellent yield (91%).[13] [14] Alcohol 18 was prepared by following the known procedure by trapping the lithiated arene with crotonaldehyde.[15] Compound 17 was subjected to the rearrangement reaction in a sealed tube at 148 °C/PhMe to afford 16 in excellent yield (89%).[13] Preparation of compound 7 from 16 through aldol condensation with compound 13 [10] in the presence of B2O3/B(OMe)3/10% HCl[11] at 80 °C furnished 7 in good yield (65%).
Based on the product formed and previous literature reports,[13] [16] a plausible mechanism for the formation 17 is proposed in Scheme [6]. First, intermediate A was formed from alcohol 18 under Mitsunobu reaction conditions. After that, vanillin reacted with intermediate A via SN2′ reaction leading to compound 17.
Since cassumunins possess curcumin core, we explored the synthesis of new[17] derivatives of curcumin. Symmetrical curcumin analogues were prepared according to known literature procedure as depicted in Scheme [7].[11a] [18] Curcumins 1a–f were prepared by using commercially available aldehydes 19a–f. Concisely, in the presence of a base, aldehyde derivatives were condensed with boric anhydride complex, which was prepared in situ from acetylacetone and B2O3. Curcumins 1g–k were prepared from known aldehydes 19g–k [19] [20] [21] [22] [23] having different substituents on the aromatic ring and are present in various natural products and drugs.
In order to synthesize some novel unsymmetrical curcumin analogues, standard procedure[10] [11] as depicted in Scheme [8] was used. The fragment 13 was prepared using known method and the same was extended for the preparation of previously unknown 13a. Condensation of various aldehydes 19h,l,m,n,e or 11 with 13 or 13a in the presence of B2O3 and base furnished 1l–r, after acidic workup in moderate to good yields.
In summary, we have accomplished an improved total synthesis for (±)-cassumunins A–C in good overall yields of 50, 43 and 53%, respectively. The key features involved in our approaches are [3,3]-sigmatropic shift (the Claisen rearrangement), Heck cross-coupling reaction, SN2′ reaction, and aldol condensation. Our two approaches are straightforward for (±)-cassumunins A–C with the minimum number of steps and high overall yields. Additionally, we have synthesized new[17] curcumin analogues (18 analogues) by following the known literature procedures.
All reactions were performed in oven-dried glass apparatus. Commercial grade solvents were distilled before use. The reactions were monitored by TLC by using Merck silica gel GF 254 on microscopic slides coated with silica gel and visualization of the spots was accomplished by exposure to UV light and iodine. Melting points were obtained in open capillary tubes using a Gallenkamp instrument and are uncorrected. Purification of products carried out by Biotage flash chromatography or column chromatography using Merck silica gel (100–200 or 200–400) with combinations of EtOAc and hexane solvent system as the eluent. IR spectra were recorded as neat solids or liquids using a Bruker Alpha-p ATR FT-IR spectrophotometer. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded at ambient temperature using a Bruker Avance III 400 MHz spectrometer. The samples for NMR were prepared by dissolving the products in CDCl3 or DMSO-d 6 and TMS was used as an internal standard. Chemical shift (δ) are reported in ppm with reference to the signal for TMS (0 ppm). Coupling constants (J) are reported in Hz. Standard abbreviations are used to report the multiplicities. The 13C NMR chemical shifts are assigned by fixing the central signal of CDCl3 at 77.00 ppm. High-resolution mass spectrometry (HRMS) was performed on Agilent spectrometer using electrospray ionization (ESI-TOF).
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(E)-1-(3,4-Dimethoxyphenyl)but-2-en-1-ol (18)[15]
Compound 18 was prepared according to the known literature procedure.[15] To a stirred solution of bromoveratrole (1.0 g, 4.60 mmol) in anhyd THF (10 mL) at –78 °C under N2 atmosphere was added dropwise n-BuLi (1.6 M in hexane, 3.0 mL, 5.52 mmol). After stirring for 40 min at –78 °C, a solution of crotonaldehyde (322 mg, 4.60 mmol) in anhyd THF (5 mL) was added dropwise over a period of 10 min. The resulting reaction mixture was stirred for 3 h. After complete conversion of the starting material (monitored by TLC), the reaction mixture was quenched by adding sat. aq NH4Cl (1 mL) at –78 °C, then the mixture was diluted with H2O (30 mL) and the aqueous layer was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100–200 mesh) to afford alcohol 18 as a colorless liquid; yield: 900 mg (94%); Rf = 0.25 (15% EtOAc in hexane, silica gel TLC).
IR (neat): 3619, 2961, 2843, 1688, 1590, 1513, 1454, 1257, 1142 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.85 (d, J = 2.0 Hz, 1 H), 6.80 (dd, J = 8.3, 2.0 Hz, 1 H), 6.75 (d, J = 8.3 Hz, 1 H), 5.62 (dd, J = 6.4, 5.4 Hz, 2 H), 5.03–4.91 (m, 1 H), 3.79 (s, 3 H), 3.78 (s, 3 H), 2.85–2.72 (m, 1 H), 1.65 (d, J = 4.9 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 148.7, 148.0, 136.2, 133.6, 126.6, 118.1, 110.8, 109.2, 77.5, 76.8, 74.5, 55.7, 55.6, 17.5.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C12H16O3Na: 231.0992; found: 231.0996.
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(E)-4-{[4-(3,4-Dimethoxyphenyl)but-3-en-2-yl]oxy}-3-methoxybenzaldehyde (17)
To a stirred solution of alcohol 18 (350 mg, 1.68 mmol) in anhyd THF (20 mL) at 0 °C under N2 atmosphere was added vanillin (19o; 255 mg, 1.68 mmol), Et3N (254 mg, 2.52 mmol), and PPh3 (660 mg, 2.52 mmol). Subsequently, DEAD was added to the reaction mixture (438 mg, 2.52 mmol) over a period of 30 min. The resulting reaction mixture was allowed to warm to rt and stirred for the next 24 h. After complete conversion of the starting material (monitored by TLC), excess of THF was evaporated under reduced pressure. The residue was purified over silica gel column chromatography [before packing the column, 100–200 mesh silica gel was neutralized with 1% Et3N in hexane (50 mL)] to afford the Mitsunobu product 17 as a colorless liquid; yield: 520 mg (91%); Rf = 0.50 (30% EtOAc in hexane, silica gel TLC).
IR (neat): 2967, 1703, 1591, 1513, 1456, 1259, 1142, 1071 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.76 (s, 1 H), 7.41–7.31 (m, 2 H), 7.01 (d, J = 8.3 Hz, 1 H), 6.93–6.83 (m, 2 H), 6.75 (d, J = 8.3 Hz, 1 H), 6.53 (d, J = 16.1 Hz, 1 H), 6.13 (dd, J = 6.8, 16.1 Hz, 1 H), 5.05 (quint, J = 6.4 Hz, 1 H), 3.88 (s, 3 H), 3.83 (s, 3 H), 3.81 (s, 3 H), 1.58 (d, J = 6.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 190.8, 153.0, 150.2, 149.1, 149.0, 131.4, 130.0, 129.1, 127.3, 126.5, 119.9, 113.8, 111.0, 109.4, 108.7, 76.1, 55.9, 55.88, 55.80, 21.7.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H23O5: 343.1540; found: 343.1544.
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(E)-3-[1-(3,4-Dimethoxyphenyl)but-2-en-1-yl]-4-hydroxy-5-methoxybenzaldehyde (16)
The Mitsunobu product 17 (400 mg, 1.17 mmol) was taken in a sealed tube and PhMe was added (5 mL) to it at rt under N2 atmosphere. The resulting reaction mixture was heated to 148 °C and allowed to stir for 24 h. After complete conversion of the starting material (monitored by TLC), excess of PhMe was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [before packing the column, 100–200 mesh silica gel was neutralized with 1% Et3N in hexane (50 mL)] to afford the rearrangement product 16 as a colorless liquid; yield: 358 mg (89%); Rf = 0.45 (30% EtOAc in hexane, silica gel TLC).
IR (neat): 3384, 2934, 2842, 1677, 1591, 1505, 1448, 1250, 11376, 1027 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.79 (s, 1 H), 7.31 (s, 2 H), 6.95–6.65 (m, 3 H), 6.38 (br s, 1 H), 5.92 (ddd, J = 16.0, 7.0, 2.0 Hz, 1 H), 5.44 (ddd, J = 16.0, 7.0, 2.0 Hz, 1 H), 5.05 (d, J = 7.3 Hz, 1 H), 3.94 (s, 3 H), 3.85 (s, 3 H), 3.82 (s, 3 H), 1.75 (d, J = 6.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 191.2, 148.9, 148.8, 147.6, 147.0, 135.4, 132.0, 130.4, 129.0, 127.5, 127.2, 120.2, 111.9, 111.0, 106.9, 56.3, 55.88, 55.85, 46.2, 18.0.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H23O5: 343.1540; found: 343.1533.
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(±)-Cassumunin C (7)[4] [6]
To a stirred solution of B2O3 (10.0 mg, 0.146 mmol) was added diketone 13 (34 mg, 0.15 mmol) in anhyd EtOAc (3 mL) at rt under N2 atmosphere and the reaction mixture was heated to 80 °C and stirred for 30 min, whereupon a yellow precipitate was observed. Excess of EtOAc was evaporated under reduced pressure, the residue was rinsed with hexane, and dried under reduced pressure. To the resulting boric anhydride complex was added aldehyde 16 (100 mg, 0.29 mmol), EtOAc (3 mL) and B(OMe)3 (60 mg, 1.17 mmol), then reaction mixture was heated to 80 °C and allowed to stir for 30 min. After 30 min, piperidine [10 mg dissolved in EtOAc (0.5 mL), 0.012 mmol], was added dropwise at 80 °C to the mixture. After complete conversion of the starting material (as monitored by TLC), the reaction was quenched with aq 10% HCl (5 mL) and stirred for 30 min at 80 °C. The aqueous layer was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (5 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 200–400 mesh) to afford cassumunin C (7) as a yellow colored solid foam; yield: 106 mg (65%); mp 89–91 °C; Rf = 0.35 (35% EtOAc in hexane, silica gel TLC).
IR (neat): 3398, 2935, 1575, 1502, 1436, 1260, 1132, 1027 cm–1.
1H NMR (400 MHz, CDCl3): δ = 16.07 (br s, 1 H), 7.57 (d, J = 16.0 Hz, 1 H), 7.56 (d, J = 16.0 Hz, 1 H), 7.09 (dd, J = 8.1, 2.2 Hz, 1 H), 7.03 (d, J = 1.5 Hz, 1 H), 6.97 (d, J = 1.7 Hz, 1 H), 6.95 (s, 1 H), 6.92 (d, J = 8.1 Hz, 1 H), 6.80 (d, J = 8.0 Hz, 1 H), 6.76 (s, 2 H), 6.47 (d, J = 16.0 Hz, 1 H), 6.43 (d, J = 16.0 Hz, 1 H), 6.08 (br s, 2 H), 5.91 (ddd, J = 15.0, 7.0, 1.5 Hz, 1 H), 5.80 (s, 1 H), 5.46 (ddd, J = 15.0, 7.0, 1.5 Hz, 1 H), 5.01 (br d, J = 7.3 Hz, 1 H), 3.91 (s, 3 H), 3.91 (s, 3 H), 3.85 (s, 3 H), 3.82 (s, 3 H), 1.75 (d, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 183.5, 183.1, 148.8, 147.9, 147.5, 146.9, 146.8, 145.4, 141.1, 140.5, 135.8, 132.3, 130.5, 127.7, 127.2, 126.7, 123.3, 122.9, 121.8, 121.5, 120.3, 114.9, 112.0, 111.0, 109.7, 107.3, 101.1, 56.1, 56.0, 55.9, 46.3, 18.1.
HRMS (ESI-TOF): m/z [M + K]+ calcd for C33H34O8K: 597.1885; found: 597.1895.
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4-(But-2-en-1-yloxy)-3-methoxybenzaldehyde (12)[7]
Compound 12 was prepared according to the known literature procedure.[7] To a stirred solution of vanillin (19o; 1.0 g, 6.58 mmol) in anhyd DMF (10 mL) at 0 °C under N2 atmosphere was added K2CO3 (1.82 g, 13.14 mmol). After stirring for 10 min at 0 °C, ~85% trans-crotyl bromide (1.15 g, 8.54 mmol) was added. The resulting mixture was allowed to warm to rt and stirred for next 1 h. Then it was quenched H2O (30 mL) and the aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel 200–400 mesh) to afford the alkylation product mixture 12 as E:Z (81:19); colorless liquid; yield: 1.30 g (96%); Rf = 0.60 (10% EtOAc in hexane, silica gel TLC).
IR (neat): 2936, 1681, 1586, 1507, 1455, 1400, 1255, 1127, 973 cm–1.
1H NMR (400 MHz, CDCl3): δ (E:Z mixture) = 9.85–9.84 (m, 2 H), 7.52–7.37 (m, 4 H), 6.98 (d, J = 7.8 Hz, 2 H), 5.99–5.81 (m, 2 H), 5.81–5.61 (m, 2 H), 4.70–4.51 (m, 4 H), 3.93 (s, 6 H), 1.84–1.61 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 190.9, 153.7, 149.9, 149.8, 131.8, 130.0, 130.0, 129.3, 126.7, 125.0, 124.7, 111.7, 109.1, 77.4, 77.1, 76.8, 69.7, 64.8, 56.0, 17.9, 13.4.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H15O3: 207.1016; found: 207.1016.
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3-(But-3-en-2-yl)-4-hydroxy-5-methoxybenzaldehyde (11)
The alkylation product 12 (390 mg, 1.89 mmol), was taken in a sealed tube and PhMe was added (1 mL) under N2 atmosphere. The resulting reaction mixture was heated to 180 °C and stirred for 24 h. After complete conversion of the starting material (as monitored by TLC), excess of PhMe was evaporated under reduced pressure. The residue was purified by flash chromatography (silica gel, 200–400 mesh) and isolated with 8–10% EtOAc in hexane as eluent to afford the rearrangement product 11 as a colorless liquid; yield: 372 mg (95%); Rf = 0.50 (10% EtOAc in hexane, silica gel TLC).
IR (neat): 3156, 2967, 1663, 1637, 1588, 1427, 1365, 1263, 1193, 1143, 1056 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.81 (s, 1 H), 7.34 (d, J = 1.5 Hz, 1 H), 7.30 (d, J = 1.5 Hz, 1 H), 6.41 (br s, 1 H), 6.06 (ddd, J = 5.9, 10.5, 16.9 Hz, 1 H), 5.26–5.02 (m, 2 H), 3.98–3.93 (m, 4 H, OCH3 merged with 1 H), 1.38 (d, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 191.2, 148.9, 146.9, 141.4, 131.4, 129.1, 125.8, 113.8, 106.8, 56.2, 35.7, 19.0.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H15O3: 207.1016; found: 207.1019.
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2-(But-3-en-2-yl)-4-formyl-6-methoxyphenyl tert-Butyl Carbonate (10)
To a stirred solution of the rearrangement product 11 (350 mg, 1.70 mmol) in anhyd CH2Cl2 (5 mL) under N2 atmosphere was added DMAP (20 mg, 0.17 mmol), Et3N (257 mg, 2.55 mmol), and Boc2O (0.6 mL, 2.55 mmol) at 0 °C for 1 h. After complete conversion of the starting material (as monitored by TLC), all volatiles were evaporated under reduced pressure and the residue was purified by flash chromatography (silica gel, 200–400 mesh) to afford the Boc protected product 10 as a colorless liquid; yield: 502 mg (97%); Rf = 0.50 (10% EtOAc in hexane, silica gel TLC).
IR (neat): 2977, 1761, 1695, 1594, 1463, 1427, 1381, 1254, 1123, 1056 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.89 (s, 1 H), 7.33 (s, 1 H), 7.35 (s, 1 H), 5.95 (ddd, J = 6.1, 10.5, 17.1 Hz, 1 H), 5.15–5.00 (m, 2 H), 3.88 (s, 3 H), 3.79 (quint, J = 8.0 Hz, 1 H), 1.52 (s, 9 H), 1.34 (d, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 191.3, 152.2, 150.3, 143.0, 140.8, 139.4, 134.5, 123.6, 114.4, 108.6, 83.8, 56.2, 36.2, 27.5, 19.3.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H23O5: 307.1540; found: 307.1547.
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tert-Butyl (E)-{2-[4-(3,4-Dimethoxyphenyl)but-3-en-2-yl]-4-formyl-6-methoxyphenyl} Carbonate (8)
To a stirred solution of olefin 10 (200 mg, 0.65 mmol) in anhyd PhMe (5 mL) under N2 atmosphere was added bromoveratrole (170 mg, 0.78 mmol), Cs2CO3 (425 mg, 1.30 mmol), Pd(OAc)2 (29 mg, 0.13 mmol), and PPh3 (70 mg, 0.26 mmol) at rt. The resulting reaction mixture was heated to 110 °C and stirred for 18 h. After complete conversion of the starting material (as monitored by TLC), the crude reaction mixture was filtered through a short Celite pad and the residue was purified by flash chromatography (silica gel 200–400 mesh) to afford the Heck coupled product 8 as a colorless liquid; yield: 242 mg (84%); Rf = 0.25 (15% EtOAc in hexane, silica gel TLC).
IR (neat): 2975, 1761, 1695, 1593, 1513, 1460, 1383, 1256, 1131, 1030 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.92 (s, 1 H), 7.44 (d, J = 1.5 Hz, 1 H), 7.37 (d, J = 1.5 Hz, 1 H), 6.94–6.85 (m, 2 H), 6.84–6.74 (m, 1 H), 6.42 (d, J = 16.0 Hz, 1 H), 6.20 (dd, J = 16.0, 8.0 Hz, 1 H), 4.99–3.93 (m, 1 H), 3.92 (s, 3 H), 3.90–3.85 (m, 6 H), 1.50 (s, 9 H), 1.48 (d, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 191.3, 152.3, 150.4, 149.0, 148.5, 143.1, 139.7, 134.6, 130.7, 130.3, 129.2, 123.6, 119.3, 111.1, 108.6, 83.9, 56.2, 55.9, 55.8, 35.7, 27.5, 20.0.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C25H31O7: 443.2064; found: 443.2067.
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tert-Butyl (E)-{4-Formyl-2-methoxy-6-[4-(2,4,5-trimethoxyphenyl)but-3-en-2-yl]phenyl} Carbonate (9)
To a stirred solution of olefin 10 (200 mg, 0.65 mmol) in anhyd PhMe (5 mL) under N2 atmosphere was added 1-bromo-2,4,5-trimethoxybenzene (193 mg, 0.79 mmol), Cs2CO3 (425 mg, 1.30 mmol), Pd(OAc)2 (29 mg, 0.13 mmol), and PPh3 (69 mg, 0.26 mmol) at rt. Then, the resulting reaction mixture was heated to 110 °C and stirred for 15 h. After complete conversion of the starting material (as monitored by TLC), the crude reaction mixture was filtered through a short Celite pad and the residue was purified by flash chromatography (silica gel 200–400 mesh) to afford the Heck coupled product 9 as a colorless liquid; yield: 253 mg (82%); Rf = 0.25 (15% EtOAc in hexane, silica gel TLC).
IR (neat): 2970, 2841, 1760, 1696, 1595, 1511, 1457, 1386, 1260, 1130, 1035 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.92 (s, 1 H), 7.45 (d, J = 2.0 Hz, 1 H), 7.36 (d, J = 2.0 Hz, 1 H), 6.94 (s, 1 H), 6.78 (dd, J = 16.0, 2.0 Hz, 1 H), 6.49 (s, 1 H), 6.20 (dd, J = 16.0, 8.0 Hz, 1 H), 4.04–3.94 (m, 1 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.83 (s, 3 H), 3.82 (s, 3 H), 1.51 (s, 9 H), 1.48 (d, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 191.5, 152.3, 151.1, 150.5, 149.2, 143.4, 143.1, 140.2, 134.6, 130.9, 123.8, 123.6, 118.1, 109.7, 108.5, 97.8, 83.8, 56.7, 56.5, 56.2, 56.1, 36.2, 27.5, 20.2.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C26H33O8: 473.2170; found: 473.2168.
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(±)-Cassumunin A (5)[4] [5] and tert-Butyl {2-[(E)-4-(3,4-Dimethoxyphenyl)but-3-en-2-yl]-4-[(1E,4Z,6E)-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-3-oxohepta-1,4,6-trien-1-yl]-6-methoxyphenyl)} Carbonate (5a)
To a stirred solution of B2O3 (16.0 mg, 0.23 mmol) in anhyd EtOAc (5 mL) was added diketone 13 [10] (105 mg, 0.45 mmol) at rt under N2 atmosphere and the reaction mixture was heated to 80 °C and stirred for 30 min, whereupon a yellow precipitate was observed. Excess of EtOAc was evaporated under reduced pressure, the residue was rinsed with hexane, and dried under reduced pressure. To the resulting boric anhydride complex was added aldehyde 8 (200 mg, 0.45 mmol), EtOAc (5 mL), and B(OMe)3 (94 mg, 0.90 mmol) at the same temperature under N2 atmosphere and the mixture was heated to 80 °C and stirred for 15 min. Then piperidine [19 mg dissolved in EtOAc (0.5 mL), 0.23 mmol] was added dropwise at the same temperature and stirred for 2 h. After complete conversion of the starting material (as monitored by TLC), the reaction was quenched with aq 10% HCl (5 mL) and stirred for 30 min. The mixture was allowed to stir at 80 °C for 12 h. The aqueous layer was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (5 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel 200–400 mesh) to afford cassumunin A (5) and the O-Boc protected cassumunin A 5a.
#
Compound 5
Yellow colored solid foam; yield: 80 mg (32%); mp 96–98 °C; Rf = 0.35 (35% EtOAc in hexane, silica gel TLC).
For the spectral data of 5, vide infra.
#
Compound 5a
Yellow colored solid foam; yield: 138 mg (46%); mp 88–90 °C; Rf = 0.45 (35% EtOAc in hexane, silica gel TLC).
IR (neat): 3413, 2966, 2841, 1756, 1579, 1507, 1452, 1254, 1130, 1030 cm−1.
1H NMR (400 MHz, CDCl3): δ = 15.92 (br s, 1 H), 7.60 (d, J = 16.0 Hz, 1 H), 7.58 (d, J = 16.0 Hz, 1 H), 7.12 (dd, J = 8.1, 2.0 Hz, 1 H), 7.08 (d, J = 2.0 Hz, 1 H), 7.07–7.03 (m, 1 H), 7.00 (d, J = 2.0 Hz, 1 H), 6.96–6.86 (m, 3 H), 6.83–6.76 (m, 1 H), 6.53 (d, J = 16.0 Hz, 1 H), 6.48 (d, J = 16.0 Hz, 1 H), 6.38 (d, J = 16.0 Hz, 1 H), 6.21 (dd, J = 16.0, 6.1 Hz, 1 H), 5.93 (br s, 1 H), 5.83 (s, 1 H), 3.94–3.90 (m, 4 H, OCH3 merged with 1 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.87 (s, 3 H), 1.50 (s, 9 H), 1.45 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 184.4, 182.0, 151.8, 151.0, 149.0, 148.5, 148.0, 146.8, 141.0, 139.8, 139.3, 133.4, 131.2, 130.5, 128.8, 127.5, 124.0, 123.0, 121.8, 120.3, 119.3, 114.9, 111.1, 109.7, 108.9, 108.7, 101.4, 83.6, 56.1, 56.0, 55.9, 55.8, 35.8, 27.6, 20.0.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C38H43O10: 659.2851; found: 659.2846.
#
(±)-Cassumunin B (6)[4] [5] and tert-Butyl {4-[(1E,4Z,6E)-5-Hydroxy-7-(4-hydroxy-3-methoxyphenyl)-3-oxohepta-1,4,6-trien-1-yl]-2-methoxy-6-[(E)-4-(2,4,5-trimethoxyphenyl)but-3-en-2-yl]phenyl} Carbonate (6a)
To a stirred solution of B2O3 (13 mg, 0.80 mmol) in anhyd EtOAc (5 mL) was added diketone 13 [10] (84 mg, 0.36 mmol) at rt under N2 atmosphere and the reaction mixture was heated to 80 °C and stirred for 30 min, whereupon a yellow precipitate was observed. Excess of EtOAc was evaporated under reduced pressure and the residue was rinsed with hexane, and dried under reduced pressure. To the resulting boric anhydride complex was added aldehyde 9 (170 mg, 0.36 mmol), EtOAc (5 mL), and B(OMe)3 (75 mg, 0.72 mmol) at the same temperature and the mixture was stirred at 80 °C for 15 min. Then piperidine [15 mg dissolved in EtOAc (0.5 mL), 0.18 mmol] was added dropwise at the same temperature and stirred for 2 h. After complete conversion of the starting material (as monitored by TLC), the reaction was quenched with aq 10% HCl (5 mL) and stirred for 30 min. The reaction mixture was allowed to stir from 80 °C for 12 h. The aqueous layer was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (5 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (200–400 mesh) to afford cassumunin B 6 and the O-Boc protected cassumunin B 6a.
#
Compound 6
Yellow colored solid foam; yield: 10 mg (5%); mp 98–100 °C; Rf = 0.35 (35% EtOAc in hexane, silica gel TLC).
For the spectral data of 6, vide infra.
#
Compound 6a
Yellow colored solid foam; yield: 120 mg (48%); mp 86–88 °C; Rf = 0.45 (35% EtOAc in hexane, silica gel TLC).
IR (neat): 3392, 2952, 2838, 1747, 1677, 1592, 1508, 1452, 1255, 1139, 1028 cm–1.
1H NMR (400 MHz, CDCl3): δ = 15.96 (br s, 1 H), 7.60 (d, J = 16.0 Hz, 1 H), 7.56 (d, J = 16.0 Hz, 1 H), 7.09 (dt, J = 1.8, 4.2 Hz, 2 H), 7.04–7.01 (m, 1 H), 7.00–6.94 (m, 2 H), 6.94–6.87 (m, 1 H), 6.84–6.74 (m, 1 H), 6.57–6.40 (m, 3 H), 6.21 (dd, J = 6.2, 15.8 Hz, 1 H), 6.04 (br s, 1 H), 5.82 (s, 1 H) 3.91 (s, 4 H, OCH3 merged with 1 H), 3.88 (s, 6 H), 3.84 (s, 3 H), 3.82 (s, 3 H), 1.51 (s, 9 H), 1.46 (d, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 184.3, 182.0, 151.7, 151.1, 151.0, 149.1, 148.0, 146.8, 143.4, 141.0, 139.9, 139.7, 139.6, 133.4, 131.4, 127.5, 123.9, 123.2, 122.9, 121.7, 120.4, 118.3, 114.9, 109.7, 108.8, 101.3, 97.9, 83.5, 56.7, 56.5, 56.1, 56.0, 55.9, 36.2, 27.5, 20.1.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C39H45O11: 689.2956; found: 689.2946.
#
(E)-3-[4-(3,4-Dimethoxyphenyl)but-3-en-2-yl]-4-hydroxy-5-methoxybenzaldehyde (14)
To a stirred solution of compound 8 (100 mg, 0.23 mmol) in MeOH/H2O (3:1, 2 mL) under N2 atmosphere was added K2CO3 (280 mg, 2.03 mmol). Then, the resulting reaction mixture was heated to 80 °C and stirred for 8 h. After complete conversion of the starting material (as monitored by TLC), excess of MeOH was evaporated under reduced pressure. The aqueous layer was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (5 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel 200–400 mesh, 40% EtOAc in hexane) to afford 14 as a colorless liquid; yield: 75 mg (97%); Rf = 0.35 (33% EtOAc in hexane, silica gel TLC).
IR (neat): 2955, 1676, 1591, 1506, 1449, 1251, 1136, 1026, 964 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.81 (s, 1 H), 7.41 (d, J = 1.5 Hz, 1 H), 7.30 (d, J = 2.2 Hz, 1 H), 6.94–6.86 (m, 2 H), 6.79 (d, J = 8.1 Hz, 1 H), 6.60 (br s, 1 H), 6.41 (d, J = 16.0 Hz, 1 H), 6.29 (dd, J = 16.0, 8.0 Hz, 1 H), 4.10 (quint, J = 6.8 Hz, 1 H), 3.92 (s, 3 H), 3.88 (s, 3 H), 3.85 (s, 3 H), 1.48 (d, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 191.2, 149.03, 149.01, 148.5, 147.0, 131.7, 131.4, 130.5, 129.1, 128.7, 125.6, 119.2, 111.2, 108.7, 106.9, 56.2, 55.9, 55.8, 35.3, 19.7.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H23O5: 343.1540; found: 343.1546.
#
(E)-4-Hydroxy-3-methoxy-5-[4-(2,4,5-trimethoxyphenyl)but-3-en-2-yl]benzaldehyde (15)
To a stirred solution of compound 9 (80 mg, 0.17 mmol) in MeOH/H2O (3:1, 2 mL), under N2 atmosphere was added K2CO3 (210 mg, 1.50 mmol). Then the resulting reaction mixture was heated to 80 °C for 8 h. After complete conversion of the starting material (as monitored by TLC), excess of MeOH was evaporated under reduced pressure. The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 200–400 mesh, 30% EtOAc in hexane) to afford 15 as a colorless liquid; yield: 59 mg (94%); Rf = 0.30 (33% EtOAc in hexane, silica gel TLC).
IR (neat): 2925, 1678, 1593, 1507, 1452, 1274, 1203, 1137, 1028 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.82 (s, 1 H), 7.42 (d, J = 2.0 Hz, 1 H), 7.30 (d, J = 2.0 Hz, 1 H), 6.97 (s, 1 H), 6.78 (dd, J = 16.0, 1.5 Hz, 1 H), 6.49 (s, 1 H), 6.40 (br s, 1 H), 6.28 (dd, J = 16.0, 8.0 Hz, 1 H), 4.11 (quint, J = 8.0 Hz, 1 H), 3.96 (s, 3 H), 3.88 (s, 3 H), 3.85 (s, 3 H), 3.82 (s, 3 H), 1.49 (d, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 191.3, 151.1, 149.2, 148.9, 147.0, 143.4, 132.0, 131.6, 129.1, 125.9, 123.2, 118.3, 109.7, 106.8, 97.9, 56.7, 56.6, 56.3, 56.1, 35.9, 19.9.
HRMS (ESI-TOF): m/z [M + K]+ calcd for C21H24O6K: 411.1204; found: 411.1205.
#
(±)-Cassumunin A (5)[4] [5]
To a stirred solution of B2O3 (7 mg, 0.01 mmol) was added diketone 13 [10] (48 mg, 0.20 mmol) in anhyd EtOAc (3 mL) was added at rt under N2 atmosphere. Then the reaction mixture was heated to 80 °C and stirred for 30 min, whereupon a yellow precipitate was observed. Excess of EtOAc was evaporated under reduced pressure, the residue was rinsed with hexane, and dried under reduced pressure. To the resulting boric anhydride complex was added aldehyde 14 (60 mg, 0.17 mmol), EtOAc (3 mL), and B(OMe)3 (35 mg, 0.34 mmol) at rt under N2 atmosphere, then reaction mixture was heated to 80 °C for 15 min. Then piperidine [7 mg dissolved in EtOAc (0.5 mL), 0.08 mmol], was added dropwise at 80 °C and stirred for 2 h. After complete conversion of the starting material (as monitored by TLC), the reaction was quenched with aq 10% HCl (5 mL) and the mixture was stirred for 30 min at 80 °C. The aqueous layer was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (5 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel 200–400 mesh, 45% EtOAc in hexane) to afford cassumunin A (5) as a yellow solid foam; yield: 63 mg (66%); mp 96–98 °C; Rf = 0.35 (35% EtOAc in hexane, silica gel TLC).
IR (neat): 3400, 2950, 2840, 1573, 1500, 1435, 1256, 1128, 1028 cm–1.
1H NMR (400 MHz, CDCl3): δ = 16.07 (br s, 1 H), 7.58 (d, J = 16.0 Hz, 1 H), 7.56 (d, J = 16.0 Hz, 1 H), 7.09 (d, J = 2.2 Hz, 1 H), 7.07 (s, 1 H), 7.01 (s, 1 H), 6.93 (s, 2 H), 6.91 (d, J = 8.0 Hz, 2 H), 6.79 (d, J = 8.8 Hz, 1 H), 6.46 (dd, J = 15.8, 7.0 Hz, 2 H), 6.38 (br s, 1 H), 6.29 (dd, J = 16.0, 5.9 Hz, 1 H), 6.12 (br s, 2 H), 5.80 (s, 1 H), 4.05 (quint, J = 8.0 Hz, 1 H), 3.91 (s, 3 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.86 (s, 3 H), 1.46 (d, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 183.4, 183.2, 149.0, 148.4, 147.9, 146.9, 146.7, 145.3, 141.0, 140.5, 131.9, 131.8, 130.7, 128.5, 127.6, 127.0, 122.7, 122.9, 121.7, 121.5, 119.2, 114.9, 111.2, 109.7, 108.7, 107.3, 101.2, 56.1, 56.0, 55.9, 35.5, 19.8.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C33H35O8: 559.2326; found: 559.2341.
#
(±)-Cassumunin B (6)[4] [5]
To a stirred solution of B2O3 (7.0 mg, 0.01 mmol) in anhyd EtOAc (3 mL) was added diketone 13 [10] (45 mg, 0.19 mmol) at rt under N2 atmosphere. Then, the reaction mixture was heated to 80 °C and stirred for 30 min, whereupon a yellow precipitate was observed. Excess of EtOAc was evaporated under reduced pressure, the residue was rinsed with hexane, and dried under reduced pressure. To the resulting boric anhydride complex was added aldehyde 15 (60 mg, 0.16 mmol), EtOAc (3 mL), and B(OMe)3 (34 mg, 0.32 mmol) at rt under N2 atmosphere and the mixture was stirred at 80 °C for 15 min. Then, piperidine [7 mg, dissolved in EtOAc (0.5 mL), 0.08 mmol] was added dropwise at 80 °C and stirred for 2 h. After complete conversion of the starting material (as monitored by TLC), the reaction was quenched with aq 10% HCl (5 mL), and the mixture was stirred for 30 min at 80 °C . The aqueous layer was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (5 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel 200–400 mesh, 45% EtOAc in hexane) to afford cassumunin B (6) as a yellow solid foam; yield: 58 mg (61%); mp 98–100 °C; Rf = 0.35 (35% EtOAc in hexane, silica gel TLC).
IR (neat): 3406, 2938, 2844, 1754, 1508, 1504, 1446, 1266, 1200, 1126, 1028 cm–1.
1H NMR (400 MHz, CDCl3): δ = 16.07 (br s, 1 H), 7.59 (d, J = 16.0 Hz, 1 H), 7.57 (d, J = 16.0 Hz, 1 H), 7.11 (d, J = 2.2 Hz, 1 H), 7.09 (s, 1 H), 7.03 (d, J = 1.5 Hz, 1 H), 6.99 (s, 1 H), 6.94 (d, J = 1.8 Hz, 1 H), 6.92 (d, J = 8.0 Hz, 1 H), 6.79 (dd, J = 16.1, 1.5 Hz, 1 H), 6.51 (s, 1 H), 6.46 (d, J = 16.0 Hz, 2 H), 6.30 (dd, J = 16.0, 6.6 Hz, 1 H), 6.14 (br s, 1 H), 6.05 (br s, 1 H), 5.80 (s, 1 H), 4.07 (quint, J = 8.0 Hz, 1 H), 3.93 (s, 3 H), 3.92 (s, 3 H), 3.89 (s, 3 H), 3.86 (s, 3 H), 3.83 (s, 3 H), 1.48 (d, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 183.5, 183.1, 151.1, 149.1, 147.9, 146.8, 146.7, 145.3, 143.5, 141.1, 140.4, 132.2, 132.1, 127.7, 127.0, 126.9, 122.8, 121.7, 121.5, 118.5, 114.8, 109.7, 107.3, 101.09, 97.94, 56.8, 56.6, 56.1 (2 C), 55.95, 36.0, 20.0.
HRMS (ESI-TOF): m/z [M + K]+ calcd for C34H36O9K: 627.1991; found: 627.1982.
#
Compounds 1a–k; General Procedure A
To a stirred solution of acetylacetone (1.0 equiv) in anhyd EtOAc (2.5 mL) was added B2O3 (0.50 equiv). The solution was stirred for 30 min at 80 °C to get a white boric anhydride complex. Excess of EtOAc was evaporated under reduced pressure, the residue was rinsed with hexane (2 mL), and dried under reduced pressure. To the resulting boric anhydride complex was added the respective aldehyde 19a–k (2.0 equiv), EtOAc (2 mL), and B(OMe)3 (2.0 equiv) at ambient temperature under N2 atmosphere and the reaction mixture was heated to 80 °C and stirred for 15 min to obtain a transparent solution. After 15 min, n-BuNH2 [0.2 equiv, dissolved in EtOAc (0.5 mL)] was added dropwise at the same temperature. Then the reaction allowed to stir for 24 h. After complete conversion of the starting material (as monitored by TLC), the reaction was quenched with aq 10% HCl (5 mL) and stirred for 30 min. The aqueous layer was extracted with EtOAc (3 × 15–25 mL), the combined organic layers were washed with brine (3 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100–200 mesh), by using combinations of solvents such as MeOH, EtOAc, CH2Cl2, and hexane as eluents to afford 1a–k.
#
(1E,4Z,6E)-1,7-Bis(2,4-dichlorophenyl)-5-hydroxyhepta-1,4,6-trien-3-one (1a)
General procedure A described above was followed when acetylacetone (34 mg, 0.35 mmol), B2O3 (12 mg, 0.17 mmol), and B(OMe)3 (71 mg, 0.69 mmol) reacted with 2,4-dichlorobenzaldehyde (19a; 120 mg, 0.69 mmol) and n-BuNH2 (5 mg, 0.07 mmol) at 80 °C to afford 1a as a yellow solid; yield: 71 mg (49%); mp 177–179 °C; Rf = 0.50 (15% CH2Cl2 in hexane, silica gel TLC).
IR (neat): 3088, 2355, 2204, 2162, 1949, 1635, 1578, 1468, 1384, 1306, 1140, 1103, 1048, 970, 1864, 815 cm–1.
1H NMR (400 MHz, CDCl3): δ = 15.67 (br s, 1 H), 7.98 (d, J = 16.0 Hz, 2 H), 7.59 (d, J = 8.4 Hz, 2 H), 7.45 (d, J = 2.4 Hz, 2 H), 7.29–7.27 (m, 2 H), 6.60 (d, J = 15.8 Hz, 2 H), 5.88 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 182.8, 136.2, 135.7, 135.4, 131.7, 130.1, 128.2, 127.5, 126.7, 102.0.
HRMS (ESI-TOF): m/z calcd for C19H13Cl4O2 [M + H]+: 412.9664; found: 412.9655.
#
(1E,4Z,6E)-1,7-Bis(2-ethoxy-3-methoxyphenyl)-5-hydroxyhepta-1,4,6-trien-3-one (1b)
General procedure A described above was followed when acetylacetone (28 mg, 0.28 mmol), B2O3 (10 mg, 0.14 mmol), and B(OMe)3 (40 mg, 0.55 mmol) reacted with 2-ethoxy-3-methoxybenzaldehyde (19b; 100 mg, 0.55 mmol) and n-BuNH2 (4 mg, 0.06 mmol) at 80 °C h to afford 1b as a yellow solid; yield: 68 mg (57%); mp 100–102 °C; Rf = 0.50 (15% EtOAc in hexane, silica gel TLC).
IR (neat): 2974, 2934, 2892, 1621, 1573, 1471, 1444, 1386, 1296, 1259, 1212, 1179, 1137, 1070, 1027 cm–1.
1H NMR (400 MHz, CDCl3): δ = 15.89 (br s, 1 H), 7.99 (d, J = 16.0 Hz, 2 H), 7.19 (d, J = 7.8 Hz, 2 H), 7.05 (t, J = 8.0 Hz, 2 H), 6.92 (d, J = 8.1 Hz, 2 H), 6.68 (d, J = 16.0 Hz, 2 H), 5.86 (s, 1 H), 4.08 (q, J = 7.3 Hz, 4 H), 3.86 (s, 6 H), 1.42 (t, J = 7.3 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 183.6, 153.3, 147.6, 135.6, 129.5, 125.3, 124.0, 119.1, 113.7, 101.4, 69.7, 55.8, 15.6.
HRMS (ESI-TOF): m/z calcd for C25H29O6 [M + H]+: 425.1959; found: 425.1957.
#
(1E,4Z,6E)-1,7-Bis(3-bromophenyl)-5-hydroxyhepta-1,4,6-trien-3-one (1c)[17]
General procedure A described above was followed when acetylacetone (40 mg, 0.40 mmol), B2O3 (14 mg, 0.20 mmol), and B(OMe)3 (83 mg, 0.81 mmol) reacted with 3-bromobenzaldehyde (19c; 150 mg, 0.81 mmol) and n-BuNH2 (6 mg, 0.08 mmol) at 80 °C to afford 1c as a yellow solid; yield: 90 mg (52%); mp 139–141 °C; Rf = 0.60 (15% EtOAc in hexane, silica gel TLC).
IR (neat): 3057, 2340, 2150, 1633, 1563, 1471, 1412, 1306, 1270, 1199, 1137, 1069 cm–1.
1H NMR (400 MHz, CDCl3): δ = 15.75 (br s, 1 H), 7.69 (s, 2 H), 7.57 (d, J = 15.5 Hz, 2 H), 7.47 (dd, J = 15.8, 7.7 Hz, 4 H), 7.28–7.24 (m, 2 H), 6.60 (d, J = 15.8 Hz, 2 H), 5.83 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 182.9, 139.0, 137.0, 132.9, 130.6, 130.4, 126.9, 125.2, 123.1, 102.3.
HRMS (ESI-TOF): m/z calcd for C19H15Br2O2 [M + H]+: 432.9433; found: 432.9428.
#
(1E,4Z,6E)-1,7-Bis(4-ethylphenyl)-5-hydroxyhepta-1,4,6-trien-3-one (1d)
General procedure A described above was followed when acetylacetone (112 mg, 1.1 mmol), B2O3 (39 mg, 0.56 mmol), and B(OMe)3 (230 mg, 2.23 mmol) reacted with 4-ethylbenzaldehyde (19d; 300 mg, 2.23 mmol) and n-BuNH2 (16 mg, 0.22 mmol) at 80 °C to afford 1d as a yellow solid; yield: 182 mg (49%); mp 169–171 °C; Rf = 0.50 (15% EtOAc in hexane, silica gel TLC).
IR (neat): 2966, 2389, 2304, 2196, 2121, 2068, 2002, 1940, 1628, 1594, 1325, 1182, 1138 cm–1.
1H NMR (400 MHz, CDCl3): δ = 15.99 (br s, 1 H), 7.64 (d, J = 15.8 Hz, 2 H), 7.47 (d, J = 8.1 Hz, 4 H), 7.22 (m, 4 H), 6.58 (d, J = 15.9 Hz, 2 H), 5.8 (s, 1 H), 2.67 (q, J = 7.6 Hz, 4 H), 1.24 (t, J = 7.4 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 183.4, 146.8, 140.5, 132.5, 128.5, 128.2, 123.1, 101.6, 28.8, 15.3.
HRMS (ESI-TOF): m/z calcd for C23H25O2 [M + H]+: 333.1849; found: 333.1847.
#
(1E,4Z,6E)-1,7-Di(biphenyl-4-yl)-5-hydroxyhepta-1,4,6-trien-3-one (1e)
General procedure A described above was followed when acetylacetone (36 mg, 0.36 mmol), B2O3 (12 mg, 0.18 mmol), and B(OMe)3 (74 mg, 0. 72 mmol) reacted with [1,1′-biphenyl]-4-carbaldehyde (19e; 130 mg, 0.72 mmol) and n-BuNH2 (5 mg, 0.07 mmol) at 80 °C to afford 1e as a yellow solid; yield: 95 mg (62%); mp 258–260 °C; Rf = 0.50 (15% CH2Cl2 in hexane, silica gel TLC).
IR (neat): 3033, 2924, 2853, 1636, 1596, 1553, 1485, 1453, 1408, 1136 cm–1.
1H NMR (400 MHz, CDCl3): δ = 15.96 (br s, 1 H), 7.37 (d, J = 15.6 Hz, 2 H), 7.65–7.62 (m, 12 H), 7.46 (t, J = 7.3 Hz, 4 H), 7.38 (d, J = 7.3 Hz, 2 H), 6.68 (d, J = 15.7 Hz, 2 H), 5.88 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 183.2, 142.8, 140.1, 133.9, 128.9, 128.6, 127.8, 127.5, 127.0, 123.9, 101.9.
HRMS (ESI-TOF): m/z calcd for C31H25O2 [M + H]+: 429.1849; found: 429.1857.
#
(1E,4Z,6E)-1,7-Bis(2-bromophenyl)-5-hydroxyhepta-1,4,6-trien-3-one (1f)
General procedure A described above was followed when acetylacetone (41 mg, 0.40 mmol), B2O3 (14 mg, 0.20 mmol), and B(OMe)3 (83 mg, 0.81 mmol) reacted with 2-bromobenzaldehyde (19f; 150 mg, 0.81 mmol) and n-BuNH2 (6 mg, 0.08 mmol) at 80 °C to afford 1f as a yellow solid; yield: 105 mg (60%); mp 138–140 °C; Rf = 0.50 (15% EtOAc in hexane, silica gel TLC).
IR (neat): 2089, 2050, 1994, 1629, 1556, 1523, 1463, 1431, 1021 cm–1.
1H NMR (400 MHz, CDCl3): δ = 15.71 (br s, 1 H), 8.02 (d, J = 15.8 Hz, 2 H), 7.63 (dd, J = 9.9, 8.4 Hz, 4 H), 7.33 (t, J = 7.7 Hz, 2 H), 7.25–7.19 (m, 2 H), 6.57 (dd, J = 15.8, 1.7 Hz, 2 H), 5.91 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 183.0, 139.1, 134.9, 133.5, 131.0, 127.7, 126.7, 125.6, 101.7.
HRMS (ESI-TOF): m/z calcd for C19H14Br2O2Na [M + Na]+: 454.9253; found: 454.9267.
#
(1E,4Z,6E)-5-Hydroxy-1,7-bis(2-methoxynaphthalen-1-yl)hepta-1,4,6-trien-3-one (1g)[17]
General procedure A described above was followed when acetylacetone (27 mg, 0.27 mmol), B2O3 (9 mg, 0.14 mmol), and B(OMe)3 (55 mg, 0.54 mmol) reacted with 2-methoxy-1-naphthaldehyde[19] (19g; 100 mg, 0.54 mmol) and n-BuNH2 (4 mg, 0.05 mmol) at 80 °C to afford 1g as a yellow solid; yield: 75 mg (64%); mp 155–157 °C; Rf = 0.50 (15% EtOAc in hexane, silica gel TLC).
IR (neat): 2932, 2849, 2509, 2357, 2197, 1616, 1553, 1510, 1463, 1261, 1141, 1093 cm–1.
1H NMR (400 MHz, CDCl3): δ = 16.25 (br s, 1 H), 8.36 (d, J = 16.0 Hz, 2 H), 8.25 (d, J = 8.8 Hz, 2 H), 7.84–7.76 (m, 4 H), 7.52 (ddd, J = 8.6, 6.6, 1.5 Hz, 2 H), 7.37 (t, J = 7.8 Hz, 2 H), 7.28–7.23 (m, 2 H), 6.91 (d, J = 16.8 Hz, 2 H), 5.92 (s, 1 H), 4.00 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 184.1, 156.8, 133.5, 132.8, 131.5, 129.3, 129.0, 128.6, 127.4, 123.9, 123.5, 117.4, 112.8, 102.4, 56.2.
HRMS (ESI-TOF): m/z calcd for C29H25O4 [M + H]+: 437.1747; found: 437.1745.
#
(1E,4Z,6E)-1,7-Bis(2-bromo-3,4,5-trimethoxyphenyl)-5-hydroxyhepta-1,4,6-trien-3-one (1h)
General procedure A described above was followed when acetylacetone (22 mg, 0.22 mmol), B2O3 (7 mg, 0.11 mmol), and B(OMe)3 (45 mg, 0.44 mmol) reacted with 2-bromo-3,4,5-trimethoxybenzaldehyde[20] (19h; 120 mg, 0.44 mmol) and n-BuNH2 (4 mg, 0.05 mmol) at 80 °C to afford 1h as a yellow solid; yield: 98 mg (72%); mp 137–139 °C; Rf = 0.50 (15% EtOAc in hexane, silica gel TLC).
IR (neat): 2937, 2834, 1625, 1568, 1477, 1424, 1391, 1342, 1285, 1200, 1106, 1004 cm–1.
1H NMR (400 MHz, CDCl3): δ = 15.74 (br s, 1 H), 7.99 (d, J = 16.0 Hz, 2 H), 6.95 (s, 2 H), 6.47 (d, J = 16.0 Hz, 2 H), 5.93 (s, 1 H), 3.92 (s, 6 H), 3.90 (6 H), 3.89 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 183.0, 152.8, 151.2, 144.8, 139.1, 130.2, 126.0, 113.2, 105.9, 101.0, 61.2, 61.0, 56.2.
HRMS (ESI-TOF): m/z calcd for C25H27Br2O8 [M + H]+: 613.0067; found: 613.0062.
#
(1E,4Z,6E)-5-Hydroxy-1,7-bis(2,4,6-tribromo-3-methoxyphenyl)-hepta-1,4,6-trien-3-one (1i)
General procedure A described above was followed when acetylacetone (27 mg, 0.27 mmol), B2O3 (9 mg, 0.13 mmol), and B(OMe)3 (56 mg, 0.54 mmol) reacted with 2,4,6-tribromo-3-methoxybenzaldehyde[21] (19i; 200 mg, 0.54 mmol) and n-BuNH2 (4 mg, 0.05 mmol) at 80 °C to afford 1i as a yellow solid; yield: 150 mg (69%); mp 209–211 °C; Rf = 0.50 (30% MeOH in CH2Cl2, silica gel TLC).
IR (neat): 3409, 2926, 2253, 2127, 1643, 1448, 1411, 1350, 1022 cm–1.
1H NMR (400 MHz, CDCl3/DMSO-d 6, 3:1): δ = 7.69 (s, 2 H), 7.38 (d, J = 16.0 Hz, 2 H), 6.41 (d, J = 16.1 Hz, 2 H), 5.77 (s, 1 H), 3.73 (s, 6 H).
13C NMR (100 MHz, CDCl3/DMSO-d 6, 3:1): δ = 182.2, 154.1, 138.1, 136.8, 135.9, 132.4, 120.3, 118.1, 102.6, 60.5.
HRMS (ESI-TOF): m/z calcd for C21H15Br6O4 [M + H]+: 804.6065; found: 804.6035.
#
(1E,3Z,6E)-3-Hydroxy-5-oxohepta-1,3,6-triene-1,7-diyl)bis(2-methoxy-5,1-phenylene) Diacetate (1j)
General procedure A described above was followed when acetylacetone (39 mg, 0.39 mmol), B2O3 (13 mg, 0.19 mmol), and B(OMe)3 (79 mg, 0.77 mmol) reacted with 5-formyl-2-methoxyphenyl acetate[22] (19j; 150 mg, 0.77 mmol) and n-BuNH2 (6 mg, 0.08 mmol) at 80 °C to afford 1j as a yellow solid; yield: 93 mg (53%); mp 155–157 °C; Rf = 0.50 (15% EtOAc in hexane, silica gel TLC).
IR (neat): 2941, 1763, 1630, 1593, 1508, 1460, 1415, 1369, 1297, 1259, 1195, 1154, 1125, 1031 cm–1.
1H NMR (400 MHz, CDCl3): δ = 15.99 (br s, 1 H), 7.54 (d, J = 16.0 Hz, 2 H), 7.34 (dd, J = 8.4, 1.8 Hz, 2 H), 7.26 (d, J = 2.2 Hz, 2 H), 6.93 (d, J = 8.1 Hz, 2 H), 6.43 (d, J = 16.0 Hz, 2 H), 5.71 (s, 1 H), 3.83 (s, 6 H), 2.32 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 183.1, 168.8, 151.3, 140.0 139.3, 128.2, 127.8, 127.7, 122.7, 121.8, 101.7, 55.9, 20.6.
HRMS (ESI-TOF): m/z calcd for C25H25O8 [M + H]+: 453.1544; found: 453.1542.
#
(1E,4Z,6E)-1,7-Bis(5-bromo-2,4-dimethoxyphenyl)-5-hydroxyhepta-1,4,6-trien-3-one (1k)
General procedure A described above was followed when acetylacetone (41 mg, 0.40 mmol), B2O3 (14 mg, 0.20 mmol), and B(OMe)3 (83 mg, 0.81 mmol) reacted with 5-bromo-2,4-dimethoxybenzaldehyde[23] (19k; 200 mg, 0.81 mmol) and n-BuNH2 (6 mg, 0.08 mmol) at 80 °C to afford 1k as a yellow solid; yield: 114 mg (51%); mp 192–195 °C; Rf = 0.40 (30% EtOAc in hexane, silica gel TLC).
IR (neat): 2941, 2842, 1589, 1498, 1460, 1386, 1295, 1208, 1144, 1059, 1026, 972, 816 cm–1.
1H NMR (400 MHz, CDCl3): δ = 16.08 (br s, 1 H), 7.83 (d, J = 16.0 Hz, 2 H), 7.70 (s, 2 H), 6.54 (d, J = 16.0 Hz, 2 H), 6.44 (s, 2 H), 5.77 (s, 1 H), 3.93 (s, 6 H), 3.31 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 183.4, 159.0, 158.0, 133.8, 132.1, 123.0, 118.1, 102.6, 101.6, 96.0, 56.3, 55.8.
HRMS (ESI-TOF): m/z calcd for C23H23Br2O6 [M + H]+: 552.9856; found: 552.9844.
#
Compounds 13 and 13a; General Procedure B
To a stirred solution of acetylacetone (2.2 equiv) in anhyd EtOAc (30 mL) was added B2O3 (2.0 equiv). The solution was stirred for 30 min at 80 °C to get a white boric anhydride complex. Excess of EtOAc was evaporated under reduced pressure, the residue was rinsed with hexane, and dried under reduced pressure. To the resulting boric anhydride complex was added aldehydes 19o or 19g [19] (1.0 equiv) EtOAc (30 mL) and B(OMe)3 (0.4 equiv) at rt under N2 atmosphere and the reaction mixture was heated to 80 °C and stirred for 15 min to obtain a transparent solution. After 15 min, n-BuNH2 [0.35 equiv dissolved in EtOAc (2.0 mL)], was added dropwise at the same temperature. Afterwards, the mixture was heated to 110 °C for 3 h. After complete conversion of the starting material (as monitored by TLC), the reaction was quenched with aqa 10% HCl (5 mL) and stirred for 30 min. The aqueous layer was extracted with EtOAc (3 × 50 mL), the combined organic layers were washed with brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100–200 mesh) using EtOAc and hexane as eluents to afford 13 and 13a.
#
(1E,4Z)-5-Hydroxy-1-(4-hydroxy-3-methoxyphenyl)hexa-1,4-dien-3-one (13)[10]
General procedure B described above was followed when acetylacetone (3.3 mL 32.0 mmol), B2O3 (2.0 g, 28.94 mmol), and B(OMe)3 (600 mg, 5.90 mmol) reacted with vanillin (19o; 2.2 g 14.47 mmol) and n-BuNH2 (390 mg, 5.06 mmol) at 80 to 110 °C afford 13 as a yellow solid; yield: 1.7 g (50%); mp 140–142 °C (Lit.[10] mp 143.5–145.5 °C); Rf = 0.50 (20% EtOAc in hexane, silica gel TLC).
IR (neat): 3213, 1626, 1566, 1509, 1421, 1272, 1148, 1021, 930 cm–1.
1H NMR (400 MHz, CDCl3): δ = 15.49 (br s, 1 H), 7.53 (d, J = 16.1 Hz, 1 H), 7.17–7.04 (m, 1 H), 7.01 (s, 1 H), 6.92 (d, J = 8.1 Hz, 1 H), 6.32 (d, J = 15.4 Hz, 1 H), 6.01 (br s, 1 H), 5.63 (s, 1 H), 3.92 (s, 3 H), 2.15 (s, 3 H).
#
(1E,4Z)-5-Hydroxy-1-(2-methoxynaphthalen-1-yl)hexa-1,4-dien-3-one (13a)
General procedure B described above was followed when acetylacetone (2.6 mL 25.52 mmol), B2O3 (1.6 g, 23.20 mmol), and B(OMe)3 (480 mg, 4.64 mmol) reacted with 2-methoxy-1-naphthaldehyde[19] (19g; 2.160 g, 11.60 mmol) and n-BuNH2 (300 mg, 4.06 mmol) at 80 to 110 °C to afford 13a as a yellow solid; yield: 1.0 g (32%); mp 142–144 °C; Rf = 0.50 (15% EtOAc in hexane, silica gel TLC).
IR (neat): 3056, 2839, 1620, 1581, 1506, 1459, 1430, 1336, 1246, 1148, 1083, 1023 cm–1.
1H NMR (400 MHz, CDCl3): δ = 15.52 (br s, 1 H), 8.34–8.09 (m, 2 H), 7.88–7.72 (m, 2 H), 7.52 (ddd, J = 1.5, 7.0, 8.7 Hz, 1 H), 7.37 (dt, J = 1.0, 7.3 Hz, 1 H), 7.33–7.15 (m, 1 H), 6.82 (d, J = 16.1 Hz, 1 H), 5.69 (s, 1 H), 4.00 (s, 3 H), 2.18 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 197.6, 177.9, 156.5, 133.0, 132.7, 131.3, 129.0, 128.6, 127.9, 127.3, 123.9, 123.3, 117.4, 112.8, 101.2, 56.2, 27.0.
HRMS (ESI-TOF): m/z calcd for C17H17O3 [M + H]+: 269.1172; found: 269.1170.
#
Compounds 1l–r; General Procedure C
To a stirred solution of diketone derivative 13 or 13a (1.0 equiv) in anhyd EtOAc (2.5 mL) was added B2O3 (2.0 equiv). The solution was stirred for 30 min at 80 °C to get an orange-red boric anhydride complex. Excess of EtOAc was evaporated under reduced pressure, the residue was rinsed with hexane, and dried under reduced pressure. To the resulting boric anhydride complex was added the respective aldehyde 19h,l,m,n,e or 11 (1.0 equiv) EtOAc (2 mL) and B(OMe)3 (2.0 equiv) at r.t. under N2 atmosphere and the reaction mixture was heated to 80 °C and stirred for 15 min to obtain a transparent orange-red solution. After 15 min, piperidine [0.4 equiv dissolved in EtOAc (0.5 mL)] was added dropwise at the same temperature. Then the reaction mixture was stirred for 2 h. After complete conversion of the starting material (as monitored by TLC), the reaction was quenched with aq 10% HCl (5 mL) and stirred for 30 min. The aqueous layer was extracted with EtOAc (3 × 15–25 mL), the combined organic layers were washed with brine (3 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100–200 mesh) using EtOAc and hexane as eluents to afford 1l–r.
#
(1E,4Z,6E)-7-(2-Bromo-3,4,5-trimethoxyphenyl)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)hepta-1,4,6-trien-3-one (1l)
General procedure C described above was followed when compound 13 (120 mg, 0.51 mmol), B2O3 (70 mg, 1.02 mmol), and B(OMe)3 (105 mg, 1.02 mmol) reacted with 2-bromo-3,4,5-trimethoxybenzaldehyde[20] (19h; 140 mg, 0.51 mmol) and piperidine (17 mg, 0.20 mmol) at 80 °C to afford 1l as a yellow solid; yield: 160 mg (63%); mp 149–151 °C; Rf = 0.50 (30% EtOAc in hexane, silica gel TLC).
IR (neat): 3403, 2939, 2054, 1625, 1577, 1511, 1475, 1427, 1390, 1344, 1273, 1205, 1166, 1134, 1110, 1004 cm–1.
1H NMR (400 MHz, CDCl3): δ = 15.91 (br s, 1 H), 7.91 (d, J = 15.8 Hz, 1 H), 7.61 (d, J = 15.8 Hz, 1 H), 7.12 (dd, J = 8.1, 1.4 Hz, 1 H), 7.05 (d, J = 1.0 Hz, 1 H), 6.96–6.92 (m, 2 H), 6.48 (dd, J = 15.40, 9.5 Hz, 2 H), 5.93 (br s, 1 H), 5.87 (s, 1 H), 3.94 (s, 3 H), 3.93 (s, 3 H), 3.91 (s, 3 H), 3.90 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 184.3, 181.9, 152.8, 151.2, 148.0, 146.8, 144.7, 141.2, 138.6, 130.4, 127.5, 126.0, 123.0, 121.7, 114.8, 113.1, 109.6, 105.9, 101.2, 61.2, 61.0, 56.2, 55.9.
HRMS (ESI-TOF): m/z calcd for C23H24BrO7 [M + H]+: 491.0700; found: 491.0696.
#
(1E,4Z,6E)-5-Hydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(2,4,6-tribromo-3-hydroxyphenyl)hepta-1,4,6-trien-3-one (1m)
General procedure C described above was followed when compound 13 (80 mg, 0.34 mmol), B2O3 (47 mg, 0.68 mmol), and B(OMe)3 (70 mg, 0.68 mmol) reacted with 2,4,6-tribromo-3-hydroxybenzaldehyde[21] (19l; 122 mg, 0.34 mmol) and piperidine (12 mg, 0.14 mmol) at 80 °C to afford 1m as a yellow solid; yield: 120 mg (61%); mp 99–101 °C; Rf = 0.50 (50% EtOAc in hexane, silica gel TLC).
IR (neat): 3482, 3073, 2962, 1627, 1572, 1510, 1432, 1374, 1268, 1204, 1175, 1133, 1029 cm–1.
1H NMR (400 MHz, CDCl3/DMSO-d 6, 3:1): δ = 15.98 (br s, 1 H), 8.78 (br s, 1 H), 8.30 (br s, 1 H), 7.94 (d, J = 3.0 Hz, 1 H), 7.82 (d, J = 16.0 Hz, 1 H), 7.68 (dd, J = 16.0, 2.6 Hz, 1 H), 7.56 (d, J = 3.0 Hz, 1H), 7.29 (s, 1 H), 7.11 (d, J = 8.0 Hz, 1 H), 6.71 (d, J = 16.0 Hz, 2 H), 6.06 (s, 1 H), 4.12 (s, 3 H).
13C NMR (100 MHz, CDCl3/DMSO-d 6, 3:1): δ = 186.0, 179.2, 150.7, 149.1, 147.6, 142.0, 137.2, 136.1, 135.1, 132.3, 126.6, 123.2, 121.1, 115.5, 113.1, 112.6, 111.1, 110.1, 102.0, 55.8.
HRMS (ESI-TOF): m/z calcd for C20H16Br3O5 [M + H]+: 572.8542; found: 572.8517.
#
(1E,4Z,6E)-1-(2-Bromo-3,4,5-trimethoxyphenyl)-5-hydroxy-7-(2-methoxynaphthalen-1-yl)hepta-1,4,6-trien-3-one (1n)
General procedure C described above was followed when compound 13a (100 mg, 0.37 mmol), B2O3 (52 mg, 0.75 mmol), and B(OMe)3 (77 mg, 0.75 mmol) reacted with 2-bromo-3,4,5-trimethoxybenzaldehyde[20] (19h; 102 mg, 0.37 mmol) and piperidine (13 mg, 0.15 mmol) at 80 °C to afford 1n as a yellow solid; yield: 126 mg (65%); mp 118–122 °C; Rf = 0.40 (30% EtOAc in hexane, silica gel TLC).
IR (neat): 2939, 2839, 1769, 1620, 1560, 1512, 1473, 1428, 1391, 1344, 1269, 1200, 1105, 1006 cm–1.
1H NMR (400 MHz, CDCl3): δ = 15.98 (br s, 1 H), 8.37 (d, J = 16.0 Hz, 1 H), 8.24 (d, J = 8.6 Hz, 1 H), 8.01 (d, J = 15.6 Hz, 1 H), 7.86 (d, J = 9.2 Hz, 1 H), 7.80 (d, J = 8.0 Hz, 1 H), 7.54–7.51 (m, 1 H), 7.39 (t, J = 8.0 Hz, 1 H), 7.31–7.25 (m, 1 H), 7.02–6.97 (m, 2 H), 6.51 (d, J = 15.5 Hz, 1 H), 5.94 (s, 1 H), 4.03 (s, 3 H), 3.89 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 184.6, 182.3, 156.9, 152.8, 151.2, 144.7, 138.6, 134.1, 132.8, 131.7, 130.5, 129.1, 129.0, 128.67, 127.4, 126.2, 123.9, 123,4, 117.2, 113.2, 112.7, 105.9, 101.8, 61.2, 61.0, 56.28, 56.23.
HRMS (ESI-TOF): m/z calcd for C27H26BrO6 [M + H]+: 525.0907; found: 525.0901.
#
(1E,4Z,6E)-5-Hydroxy-7-(2-methoxynaphthalen-yl)-1-(3,4,5-trimethoxyphenyl)hepta-1,4,6-trien-3-one (1o)
General procedure C described above was followed when compound 13a (100 mg, 0.37 mmol) B2O3 (52 mg, 0.75 mmol), and B(OMe)3 (77 mg, 0.75 mmol) reacted with 3,4,5-trimethoxybenzaldehyde (19m; 72 mg, 0.37 mmol) and piperidine (13 mg, 0.15 mmol) at 80 °C to afford 1o as a yellow solid; yield: 81 mg (49%); mp 145–148 °C; Rf = 0.50 (30% EtOAc in hexane, silica gel TLC).
IR (neat): 2938, 2837, 2312, 2270, 2188, 2168, 1985, 1625, 1582, 1504, 1460, 1263, 1129 cm–1.
1H NMR (400 MHz, CDCl3): δ = 16.08 (br s, 1 H), 8.35 (d, J = 15.9 Hz, 1 H), 8.22 (d, J = 8.6 Hz, 1 H), 7.84 (d, J = 9.0 Hz, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.58 (d, J = 15.8 Hz, 1 H), 7.53–7.50 (m, 1 H), 7.40–7.36 (m, 1 H), 7.29–7.25 (m, 1 H), 6.98 (d, J = 16.0 Hz, 1 H), 6.77 (s, 2 H), 6.55 (d, J = 15.6 Hz, 1 H), 5.89 (s, 1 H), 4.01 (s, 3 H), 3.89 (s, 9H).
13C NMR (100 MHz, CDCl3): δ = 184.2, 182.9, 156.8, 153.4, 140.2, 139.9, 133.8, 132.8, 131.6, 130.6, 129.1, 129.0, 128.6, 127.4, 123.9, 123.6, 123.4, 117.2, 112.7, 105.1, 102.0, 61.0, 56.2, 56.1.
HRMS (ESI-TOF): m/z calcd for C27H27O6 [M + H]+: 447.1802; found: 447.1799.
#
(1E,4Z,6E)-1-(2,4-Dimethoxyphenyl)-5-hydroxy-7-(2-methoxynaphthalen-1-yl)hepta-1,4,6-trien-3-one (1p)
General procedure C described above was followed when compound 13a (80 mg, 0.30 mmol), B2O3 (41 mg, 0.60 mmol), and B(OMe)3 (62 mg, 0.60 mmol) reacted with 2,4-dimethoxybenzaldehyde (19n; 50 mg, 0.30 mmol) and piperidine (10 mg, 0.12 mmol) at 80 °C to afford 1p as a yellow solid; yield: 62 mg (50%); mp 141–144 °C; Rf = 0.50 (30% EtOAc in hexane, silica gel TLC).
IR (neat): 3056, 3004, 2939, 2837, 1599, 1506, 1460, 1269, 1206, 1130, 1033, 968 cm–1.
1H NMR (400 MHz, CDCl3): δ = 16.21 (br s, 1 H), 8.31 (d, J = 16.0 Hz, 1 H), 8.24 (d, J = 8.6 Hz, 1 H), 7.93 (d, J = 15.9 Hz, 1 H), 7.85–7.78 (m, 2 H), 7.54–7.48 (m, 2 H), 7.38 (t, J = 7.7 Hz, 1 H), 7.30 (d, J = 9.5 Hz, 1 H), 6.96 (d, J = 16.0 Hz, 1 H), 6.66 (d, J = 16.0 Hz, 1 H), 6.52 (dd, J = 8.8, 2.2 Hz, 1 H), 6.46 (d, J = 2.2 Hz, 1 H), 5.86 (s, 1 H), 4.02 (s, 3 H), 3.88 (s, 3 H), 3.84 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 185.0, 182.7, 162.7, 159.9, 156.6, 136.0, 133.0, 132.8, 131.3, 130.2, 129.4, 129.1, 128.6, 127.3, 123.9, 123.5, 122.5, 117.6, 117.2, 112.8, 105.4, 101.7, 98.4, 56.2, 55.52, 55.50.
HRMS (ESI-TOF): m/z calcd for C26H24O5Na [M + Na]+: 439.1516; found: 439.1516.
#
(1E,4Z,6E)-7-(Biphenyl-4-yl)-5-hydroxy-1-(2-methoxynaphthalen-1-yl)hepta-1,4,6-trien-3-one (1q)
General procedure C described above was followed when compound 13a (85 mg, 0.32 mmol), B2O3 (44 mg, 0.63 mmol), and B(OMe)3 (65 mg, 0.63 mmol) reacted with [1,1′-biphenyl]-4-carbaldehyde (19e; 58 mg, 0.32 mmol) and piperidine (11 mg, 0.13 mmol) at 80 °C to afford 1q as a yellow solid; yield: 68 mg (49%); mp 187–190 °C; Rf = 0.50 (15% EtOAc in hexane, silica gel TLC).
IR (neat): 3035, 2938, 2839, 2160, 1622, 1557, 1510, 1463, 1348, 1267, 1184, 1138, 972 cm–1.
1H NMR (400 MHz, CDCl3): δ = 16.0 (br s, 1 H), 8.37 (d, J = 15.9 Hz, 1 H), 8.24 (d, J = 8.5 Hz, 1 H), 7.86 (d, J = 9.0 Hz, 1 H), 7.76 (d, J = 7.6 Hz, 1 H), 7.71 (d, J = 15.9 Hz, 1 H), 7.63–7.61 (m, 6 H), 7.54 (ddd, J = 8.4, 7.0, 1.2 Hz, 1 H), 7.46 (t, J = 7.3 Hz, 2 H), 7.41–7.35 (m, 2 H), 7.30 (d, J = 9.0 Hz, 1 H), 7.01 (d, J = 16.0 Hz, 1 H), 6.68 (d, J = 16.0 Hz, 1 H), 5.91 (s, 1 H), 4.03 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 184.5, 182.8, 156.8, 142.7, 140.2, 139.7, 134.1, 133.9,132.8, 131.6, 129.2, 129.0, 128.9, 128.66, 128.60, 127.8, 127.5, 127.4, 127.0, 124.1, 123.9, 123.4, 117.3, 112.7, 102.1, 56.2.
HRMS (ESI-TOF): m/z calcd for C30H25O3 [M + H]+: 433.1798; found: 433.1796.
#
(1E,4Z,6E)-7-[3-(But-3-en-2-yl)-4-hydroxy-5-methoxyphenyl]-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)hepta-1,4,6-trien-3-one (1r)
General procedure C described above was followed when compound 13 (50 mg, 0.21 mmol), B2O3 (30 mg, 0.43 mmol), and B(OMe)3 (44 mg, 0.43 mmol) reacted with 3-(but-3-en-2-yl)-4-hydroxy-5-methoxybenzaldehyde (11; 43 mg, 0.21 mmol) and piperidine (7.0 mg, 0.08 mmol) at 80 °C to afford 1r as a yellow solid; yield: 52 mg (59%); mp 179–181 °C; Rf = 0.50 (30% EtOAc in hexane, silica gel TLC).
IR (neat): 3417, 2961, 1578, 1503, 1442, 1278, 1205, 1136, 965, 837 cm–1.
1H NMR (400 MHz, DMSO-d 6): δ = 16.37 (br s, 1 H), 9.69 (s, 1 H), 9.25 (s, 1 H), 7.56 (dd, J = 16.1, 2.2 Hz, 2 H), 7.33 (d, J = 1.5 Hz, 1 H), 7.24 (d, J = 1.5 Hz, 1 H), 7.16 (dd, J = 8.4, 1.8 Hz, 1 H), 7.07 (d, J = 2.2 Hz, 1 H), 6.84 (d, J = 8.8 Hz, 1 H), 6.78 (d, J = 5.9 Hz, 1 H), 6.74 (d, J = 5.1 Hz, 1 H), 6.11 (s, 1 H), 6.09–6.02 (m, 1 H), 5.08–5.01 (m, 2 H), 3.88 (s, 3 H), 3.85 (s, 4 H, CH3O merged with 1 H), 1.28 (d, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 183.2, 183.1, 149.3, 147.9, 147.6, 146.0, 142.2, 140.9, 140.6, 131.9, 126.3, 125.7, 123.0, 121.3, 121.1, 121.0, 115.6, 113.1, 111.3, 108.6, 100.6, 55.9, 55.6, 35.4, 19.2.
HRMS (ESI-TOF): m/z calcd for C25H27O6 [M + H]+: 423.1802; found: 423.1805.
#
2-Methoxy-1-naphthaldehyde (19g)[19]
Compound 19g was prepared according to the known literature procedure.[19]
Mp 80–82 °C (Lit.[19] mp 82.2–83.1 °C).
IR (neat): 3004, 2954, 2881, 1657, 1582, 1511, 1430, 1252, 949 cm–1.
1H NMR (400 MHz, CDCl3): δ = 10.85 (s, 1 H), 9.26 (d, J = 8.8 Hz, 1 H), 7.99 (d, J = 9.3 Hz, 1 H), 7.73 (d, J = 8.3 Hz, 1 H), 7.59 (t, J = 7.8 Hz, 1 H), 7.46–7.28 (m, 1 H), 7.21 (d, J = 9.3 Hz, 1 H), 3.98 (s, 3 H).
#
2-Bromo-3,4,5-trimethoxybenzaldehyde (19h)[20]
Compound 19h was prepared according to the known literature procedure.[20]
Mp 68–70 °C (Lit.[20] mp 70.5–71.5 °C).
IR (neat): 3075, 2993, 2937, 2851, 1680, 1566, 1460, 1381, 1317, 991 cm–1.
1H NMR (400 MHz, CDCl3): δ = 10.26 (s, 1 H), 7.28 (s, 1 H), 3.96 (s, 3 H), 3.89 (s, 6 H).
#
2,4,6-Tribromo-3-methoxybenzaldehyde (19i)[21]
Compound 19i was prepared according to the known literature procedure.[21]
Mp 109–111 °C (Lit.[21] mp 113 °C).
IR (neat): 3068, 2942, 2881, 2781, 1697, 1530, 1451, 1407, 1329, 1022, 919 cm–1.
1H NMR (400 MHz, CDCl3): δ = 10.15 (s, 1 H), 7.88 (s, 1 H), 3.91 (s, 1 H).
#
5-Formyl-2-methoxyphenyl Acetate (19j)[22]
Compound 19j was prepared according to the known literature procedure.[22]
Mp 84–86 °C (Lit.[22] mp 85–86 °C).
IR (neat): 2840, 1764, 1687, 1600, 1509, 1439, 1374, 1270, 1186, 1112, 908 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.83 (s, 1 H), 7.73 (dd, J = 8.6, 2.2 Hz, 1 H), 7.56 (d, J = 2.0 Hz, 1 H), 7.05 (d, J = 8.8 Hz, 1 H), 3.89 (s, 3 H), 2.31 (s, 3 H).
#
2,4,6-Tribromo-3-hydroxybenzaldehyde (19l)[21]
Compound 19l was prepared according to the known literature procedure.[21]
Mp 117–119 °C (Lit.[21] mp 119.5 °C).
IR (neat): 3383, 2878, 1694, 1544, 1434, 1364, 1287, 1172, 867 cm–1.
1H NMR (400 MHz, CDCl3): δ = 10.17 (s, 1 H), 7.84 (s, 1 H), 6.39 (br s, 1 H).
#
5-Bromo-2,4-dimethoxybenzaldehyde (19k)[23]
Compound 19k was prepared according to the known literature procedure.[23]
Mp 130–132 °C (Lit.[23] mp 134–138 °C).
IR (neat): 2944, 2856, 1660, 1584, 1460, 1394, 1269, 1156, 1012, 891 cm–1.
1H NMR (400 MHz, CDCl3): δ = 10.19 (s, 1 H), 7.94 (s, 1 H), 6.41 (s, 1 H), 3.94 (s, 3 H), 3.92 (s, 3 H).
#
#
Acknowledgment
M.A.H. thanks CSIR for providing a fellowship [09/1001(0016)/2014-EMR-I].
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0039-1690794.
- Supporting Information
-
References
- 1a Vogel AJr, Pelletier J. J. Pharm. 1815; 1: 289
- 1b Vogel AJr. J. Pharm. Chem. 1842; 3: 20
- 1c Gupta SC, Patchva S, Koh W, Aggarwal BB. Clin. Exp. Pharmacol. Physiol. 2012; 39: 283
- 1d Priyadarsini KI. Molecules 2014; 19: 20091
- 1e Maurent K, Vanucci-Bacque C, Saffon-Merceron N, Baltas M, Bedos-Belval F. J. Nat. Prod. 2017; 80: 1623
- 1f Joseph AI, Luis PB, Schneider C. J. Nat. Prod. 2018; 81: 2756
- 1g Kunihiro AG, Luis PB, Brickey JA, Frye JB, Chow H.-HS, Schneider C, Funk JL. J. Nat. Prod. 2019; 82: 500
- 1h Lin X, Ji S, Li R, Dong Y, Qiao X, Hu H, Yang W, Guo D, Tu P, Ye M. J. Nat. Prod. 2012; 75: 2121
- 1i Jirasek P, Amslinger S, Heilmann J. J. Nat. Prod. 2014; 77: 2206
- 1j Wohlmuth H, Deseo MA, Brushett DJ, Thompson DR, MacFarlane G, Stevenson LM, Leach DN. J. Nat. Prod. 2010; 73: 743
- 2a Duvoix A, Blasius R, Delhalle S, Schnekenburger M, Morceau F, Hennry E, Dicato M, Diederich M. Cancer Lett 2005; 223: 181
- 2b Tima S, Ichikawa H, Ampasavate C, Okonogi S, Anuchapreeda S. J. Nat. Prod. 2014; 77: 948
- 2c Anand P, Sundaram C, Jhurani S, Kunnumakkara AB, Aggarwal BB. Cancer Lett. 2008; 267: 133
- 3a Arezki A, Chabot GG, Quentin L, Scherman D, Jaouen G, Brul E. Med. Chem. Commun. 2011; 2: 190
- 3b Minassi A, Sanchez-Duffhues G, Collado JA, Munoz E, Appendino G. J. Nat. Prod. 2013; 76: 1105
- 4a Masuda T, Jitoe A, Nakatani N. Chem. Lett. 1993; 189
- 4b Masuda T, Jitoe A. J. Agric. Food Chem. 1994; 42: 1850
- 5a Masuda T, Matsumura H, Oyama Y, Takeda Y, Jitoe A, Kida A, Hidaka K. J. Nat. Prod. 1998; 61: 609
- 5b Masuda T, Jitoe A, Kida A, Takeda Y. Nat. Prod. Lett. 1997; 10: 13
- 6 Dai Y, He Y, Wang Y, Jiang H, Li Z, Chen W. Synthesis 2014; 46: 3041
- 7 Mukinja J, Jankovic N, Ratkovic Z, Bogdanovic G, Bugarcic Z. Mol. Divers. 2016; 20: 591
- 8a Acevedo O, Armacost K. J. Am. Chem. Soc. 2010; 132: 1966
- 8b Gajewski JJ. Acc. Chem. Res. 1997; 30: 219
- 8c Ito S, Kitamura T, Arulmozhiraja S, Manabe K, Tokiwa H, Suzuki Y. Org. Lett. 2019; 21: 2777
- 9a Eggen M, Mossman CJ, Buck SB, Nair SK, Bhat L, Ali SM, Reiff EA, Boge TC, Georg GI. J. Org. Chem. 2000; 65: 7792
- 9b Dieck A, Heck RF. J. Am. Chem. Soc. 1974; 96: 1133
- 9c Dounay AB, Overman LE. Chem. Rev. 2003; 103: 2945
- 9d Beletskaya IP, Cheprakov AV. Chem. Rev. 2000; 100: 3009
- 10a Ryu EK, Choe YS, Lee K-H, Choi Y, Kim B-T. J. Med. Chem. 2006; 49: 6111
- 10b Liang B, Shao W, Zhu C, Wen G, Yue X, Wang R, Quan J, Du J, Bu X. ACS Chem. Biol. 2016; 11: 425
- 10c Lee I, Yang J, Lee JH, Choe YS. Bioorg. Med. Chem. Lett. 2011; 21: 5765
- 11a Feng JY, Liu A-Q. J. Agric. Food Chem. 2009; 57: 11041
- 11b Lozada-Garcia MC, Enriquez RG, Ramirez-Apan TO, Nieto-Camacho A, Palacios-Espinosa JF, Custodio-Galvan Z, Soria-Arteche O, Perez-Villanueva J. Molecules 2017; 22: 633
- 11c Qiu X, Liu Z, Shao W-Y, Liu X, Jing D-P, Yu Y-J, An L-K, Huang SL, Bu X-Z, Huang Z-S, Gu L-Q. Bioorg. Med. Chem. 2008; 16: 8035
- 12a Chakrabarty M, Kundu T, Harigaya Y. Synth. Commun. 2006; 36: 2069
- 12b Nakamura K, Nakajima T, Kayahara H, Nomura E, Taniguchi H. Tetrahedron Lett. 2004; 45: 495
- 13 Hou S, Li X, Xu J. J. Org. Chem. 2012; 77: 10856
- 14a Manivel P, Rai NP, Jayashankara VP, Arunachalam PN. Tetrahedron Lett. 2007; 48: 2701
- 14b Fletcher S. Org. Chem. Front. 2015; 2: 739
- 14c Shirai A, Miyata O, Tohnai N, Miyata M, Procter DJ, Sucunza D, Naito T. J. Org. Chem. 2008; 73: 4464
- 15 Jagtap PR, Cisarova I, Jahn U. Org. Biomol. Chem. 2018; 16: 750
- 16 Webster S, Schaefer L, Barker G, Lee A-L. Synlett 2015; 26: 2673
- 17a Compound 1c is reported in: Alleyne Cargill H. Jr, Dhandapani KM, Wen K, Ma M, Hu W. U.S. Patent Appl. Publ. US 20150087705 A1 20150326, 2015
- 17b Compound 1g is reported in: Chen P-T, Chen Z-t, Hou W-C, Yu L-C, Chen R-P. Sci. Rep. 2016; 6: 29760
- 18a Zuo Y, Huang J, Zhou B, Wang S, Shao W, Zhu C, Lin L, Wen G, Wang H, Du J, Bu X. Eur. J. Med. Chem. 2012; 55: 346
- 18b Qiu X, Du Y, Lou B, Zuo Y, Shao W, Huo Y, Huang J, Yu Y, Zhou B, Du J, Fu H, Bu X. J. Med. Chem. 2010; 53: 8260
- 18c Kabalka GW, Yao M-L. J. Organomet. Chem. 2009; 694: 1638
- 19a Iguchi H, Uchida S, Koyama Y, Takata T. ACS Macro Lett. 2013; 2: 527
- 19b Jang K, Miura K, Koyama Y, Takata T. Org. Lett. 2012; 14: 3088
- 20a Sun W, Yuan Y, Lee B, Jun H-S, Shin D, Seo S-Y. Synlett 2018; 29: 326
- 20b Li Y-J, Qin Y-J, Makawana JA, Wang Y-T, Zhang Y-Q, Zhang Y-L, Yang M-R, Jiang A-Q, Zhu H-L. Bioorg. Med. Chem. 2014; 22: 4312
- 21a Khan FA, Ahmad S, Kodipelli N, Shivange G, Anindya R. Org. Biomol. Chem. 2014; 12: 3847
- 21b Osuna MR, Aguirre G, Somanathan R, Molins E. Tetrahedron: Asymmetry 2002; 13: 2261
- 22 Naidu AB, Ganapathy D, Sekar G. Synthesis 2010; 3509
- 23 AbuSalim DI, Merfeld ML, Lash TD. J. Org. Chem. 2013; 78: 10360
-
References
- 1a Vogel AJr, Pelletier J. J. Pharm. 1815; 1: 289
- 1b Vogel AJr. J. Pharm. Chem. 1842; 3: 20
- 1c Gupta SC, Patchva S, Koh W, Aggarwal BB. Clin. Exp. Pharmacol. Physiol. 2012; 39: 283
- 1d Priyadarsini KI. Molecules 2014; 19: 20091
- 1e Maurent K, Vanucci-Bacque C, Saffon-Merceron N, Baltas M, Bedos-Belval F. J. Nat. Prod. 2017; 80: 1623
- 1f Joseph AI, Luis PB, Schneider C. J. Nat. Prod. 2018; 81: 2756
- 1g Kunihiro AG, Luis PB, Brickey JA, Frye JB, Chow H.-HS, Schneider C, Funk JL. J. Nat. Prod. 2019; 82: 500
- 1h Lin X, Ji S, Li R, Dong Y, Qiao X, Hu H, Yang W, Guo D, Tu P, Ye M. J. Nat. Prod. 2012; 75: 2121
- 1i Jirasek P, Amslinger S, Heilmann J. J. Nat. Prod. 2014; 77: 2206
- 1j Wohlmuth H, Deseo MA, Brushett DJ, Thompson DR, MacFarlane G, Stevenson LM, Leach DN. J. Nat. Prod. 2010; 73: 743
- 2a Duvoix A, Blasius R, Delhalle S, Schnekenburger M, Morceau F, Hennry E, Dicato M, Diederich M. Cancer Lett 2005; 223: 181
- 2b Tima S, Ichikawa H, Ampasavate C, Okonogi S, Anuchapreeda S. J. Nat. Prod. 2014; 77: 948
- 2c Anand P, Sundaram C, Jhurani S, Kunnumakkara AB, Aggarwal BB. Cancer Lett. 2008; 267: 133
- 3a Arezki A, Chabot GG, Quentin L, Scherman D, Jaouen G, Brul E. Med. Chem. Commun. 2011; 2: 190
- 3b Minassi A, Sanchez-Duffhues G, Collado JA, Munoz E, Appendino G. J. Nat. Prod. 2013; 76: 1105
- 4a Masuda T, Jitoe A, Nakatani N. Chem. Lett. 1993; 189
- 4b Masuda T, Jitoe A. J. Agric. Food Chem. 1994; 42: 1850
- 5a Masuda T, Matsumura H, Oyama Y, Takeda Y, Jitoe A, Kida A, Hidaka K. J. Nat. Prod. 1998; 61: 609
- 5b Masuda T, Jitoe A, Kida A, Takeda Y. Nat. Prod. Lett. 1997; 10: 13
- 6 Dai Y, He Y, Wang Y, Jiang H, Li Z, Chen W. Synthesis 2014; 46: 3041
- 7 Mukinja J, Jankovic N, Ratkovic Z, Bogdanovic G, Bugarcic Z. Mol. Divers. 2016; 20: 591
- 8a Acevedo O, Armacost K. J. Am. Chem. Soc. 2010; 132: 1966
- 8b Gajewski JJ. Acc. Chem. Res. 1997; 30: 219
- 8c Ito S, Kitamura T, Arulmozhiraja S, Manabe K, Tokiwa H, Suzuki Y. Org. Lett. 2019; 21: 2777
- 9a Eggen M, Mossman CJ, Buck SB, Nair SK, Bhat L, Ali SM, Reiff EA, Boge TC, Georg GI. J. Org. Chem. 2000; 65: 7792
- 9b Dieck A, Heck RF. J. Am. Chem. Soc. 1974; 96: 1133
- 9c Dounay AB, Overman LE. Chem. Rev. 2003; 103: 2945
- 9d Beletskaya IP, Cheprakov AV. Chem. Rev. 2000; 100: 3009
- 10a Ryu EK, Choe YS, Lee K-H, Choi Y, Kim B-T. J. Med. Chem. 2006; 49: 6111
- 10b Liang B, Shao W, Zhu C, Wen G, Yue X, Wang R, Quan J, Du J, Bu X. ACS Chem. Biol. 2016; 11: 425
- 10c Lee I, Yang J, Lee JH, Choe YS. Bioorg. Med. Chem. Lett. 2011; 21: 5765
- 11a Feng JY, Liu A-Q. J. Agric. Food Chem. 2009; 57: 11041
- 11b Lozada-Garcia MC, Enriquez RG, Ramirez-Apan TO, Nieto-Camacho A, Palacios-Espinosa JF, Custodio-Galvan Z, Soria-Arteche O, Perez-Villanueva J. Molecules 2017; 22: 633
- 11c Qiu X, Liu Z, Shao W-Y, Liu X, Jing D-P, Yu Y-J, An L-K, Huang SL, Bu X-Z, Huang Z-S, Gu L-Q. Bioorg. Med. Chem. 2008; 16: 8035
- 12a Chakrabarty M, Kundu T, Harigaya Y. Synth. Commun. 2006; 36: 2069
- 12b Nakamura K, Nakajima T, Kayahara H, Nomura E, Taniguchi H. Tetrahedron Lett. 2004; 45: 495
- 13 Hou S, Li X, Xu J. J. Org. Chem. 2012; 77: 10856
- 14a Manivel P, Rai NP, Jayashankara VP, Arunachalam PN. Tetrahedron Lett. 2007; 48: 2701
- 14b Fletcher S. Org. Chem. Front. 2015; 2: 739
- 14c Shirai A, Miyata O, Tohnai N, Miyata M, Procter DJ, Sucunza D, Naito T. J. Org. Chem. 2008; 73: 4464
- 15 Jagtap PR, Cisarova I, Jahn U. Org. Biomol. Chem. 2018; 16: 750
- 16 Webster S, Schaefer L, Barker G, Lee A-L. Synlett 2015; 26: 2673
- 17a Compound 1c is reported in: Alleyne Cargill H. Jr, Dhandapani KM, Wen K, Ma M, Hu W. U.S. Patent Appl. Publ. US 20150087705 A1 20150326, 2015
- 17b Compound 1g is reported in: Chen P-T, Chen Z-t, Hou W-C, Yu L-C, Chen R-P. Sci. Rep. 2016; 6: 29760
- 18a Zuo Y, Huang J, Zhou B, Wang S, Shao W, Zhu C, Lin L, Wen G, Wang H, Du J, Bu X. Eur. J. Med. Chem. 2012; 55: 346
- 18b Qiu X, Du Y, Lou B, Zuo Y, Shao W, Huo Y, Huang J, Yu Y, Zhou B, Du J, Fu H, Bu X. J. Med. Chem. 2010; 53: 8260
- 18c Kabalka GW, Yao M-L. J. Organomet. Chem. 2009; 694: 1638
- 19a Iguchi H, Uchida S, Koyama Y, Takata T. ACS Macro Lett. 2013; 2: 527
- 19b Jang K, Miura K, Koyama Y, Takata T. Org. Lett. 2012; 14: 3088
- 20a Sun W, Yuan Y, Lee B, Jun H-S, Shin D, Seo S-Y. Synlett 2018; 29: 326
- 20b Li Y-J, Qin Y-J, Makawana JA, Wang Y-T, Zhang Y-Q, Zhang Y-L, Yang M-R, Jiang A-Q, Zhu H-L. Bioorg. Med. Chem. 2014; 22: 4312
- 21a Khan FA, Ahmad S, Kodipelli N, Shivange G, Anindya R. Org. Biomol. Chem. 2014; 12: 3847
- 21b Osuna MR, Aguirre G, Somanathan R, Molins E. Tetrahedron: Asymmetry 2002; 13: 2261
- 22 Naidu AB, Ganapathy D, Sekar G. Synthesis 2010; 3509
- 23 AbuSalim DI, Merfeld ML, Lash TD. J. Org. Chem. 2013; 78: 10360