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DOI: 10.1055/s-0033-1339292
Transition-Metal-Catalyzed Regio- and Diastereoselective 1,4-Conjugate Addition of Zerumbone Using Boronic Acids: A Simple Route toward Novel Zerumbone Derivatives
Publication History
Received: 15 April 2013
Accepted after revision: 27 May 2013
Publication Date:
12 July 2013 (online)
Abstract
A straightforward method for the synthesis of novel derivatives of zerumbone via palladium- and rhodium-catalyzed regio- and diastereoselective 1,4-conjugate addition using boronic acids is developed. The reaction is general for aryl boronic acids containing both electron-donating and electron-withdrawing groups.
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Natural products represent a rich source of new molecules with pharmacological or biological properties, which are often lead compounds for the development of new drugs.[1] Many well-known drugs listed in modern pharmacopoeia have their origin in Nature.[2] The inspiration for drug development since the discovery of penicillin can be mainly attributed to natural products.[3]
Zerumbone (1) is a monocyclic sesquiterpene containing a cross-conjugated dienone system, with potent biological activity, and is abundantly available from the essential oil of wild ginger, Zingiber zerumbet Smith (Figure [1]).[4] This natural product demonstrates a wide spectrum of biological activity including antitumor,[5] anti-inflammatory,[6] anticancer[7] and anti-HIV.[8] Moreover, most of the derivatives of zerumbone reported so far also show intriguing biological properties.[9] Studies have revealed that the rhizome oil of the Zingiber zerumbet plant that grows in southern India contains about 80% zerumbone, and this compound can be easily obtained by simple distillation and recrystallization techniques.[10] The great abundance, attractive reactivity[11] and interesting biological properties make zerumbone a very important phytochemical. Based on the above facts concerning zerumbone and its derivatives, we have developed new synthetic methods for its derivatization with the aim of enhancing its biological properties.
A literature survey indicated that there were no reports on transition-metal-catalyzed synthetic transformations of zerumbone. It has been documented that zerumbone undergoes conjugate additions,[12] transannular ring-contraction,[13] ring-expansion,[14] asymmetric induction reactions,[15] etc. Most of the conjugate addition reactions of zerumbone reported so far suffer from drawbacks such as long reaction times (4–5 days), and a lack of generality, stereoselectivity and regioselectivity.[11] This prompted us to investigate conjugate addition reactions under transition-metal catalysis on this challenging sesquiterpene. Rhodium-catalyzed conjugate addition of organometallic compounds to α,β-unsaturated ketones plays a pivotal role in organic synthesis. Most of the rhodium-catalyzed reactions reported so far are mild, general and, most importantly, highly stereoselective.[16] Palladium-catalyzed 1,4-conjugate addition reactions of boronic acids to cyclic/ acyclic enones are also known, albeit they are not as common as those mediated by rhodium.[17] Herein, we disclose our efforts toward developing a new and general route to synthesize novel zerumbone derivatives via palladium- and rhodium-catalyzed 1,4-conjugate additions using organoboronic acids.
In an initial reaction, zerumbone (1)[18] (1 equiv) was treated with phenylboronic acid (2a) (2 equiv) in the presence of tris(dibenzylideneacetone)dipalladium-chloroform [Pd2(dba)3·CHCl3] (5 mol%), cesium carbonate (Cs2CO3) (2 equiv) and triphenylphosphine (PPh3) (10 mol%) in toluene at 80 °C for 24 hours. The reaction afforded the corresponding 1,4-conjugate addition product 3a in 25% yield (Scheme [1]).
The structure and stereochemistry of the product 3a was confirmed unambiguously by single crystal X-ray analysis (Figure [2]).[19]
In order to find a suitable catalytic system, detailed screening studies were carried out using different catalysts, ligands, and bases. Our efforts toward optimizing the various reaction parameters are listed in Table 1. An investigation of the base revealed that cesium carbonate was more effective than potassium carbonate (K2CO3) and triethylamine (Et3N) (Table 1, entries 1, 4 and 5). We next turned our attention to ligand effects. From the ligands screened, triphenylphosphine was found to be the best (Table 1, entries 1, 8 and 9). Unfortunately, the palladium-catalyzed 1,4-conjugate addition reactions did not give the desired product in more than 30% yield.
a Reaction conditions: zerumbone (1 equiv), phenylboronic acid (2 equiv), Pd catalyst (5 mol%), ligand (10 mol%), base (1 equiv), toluene (2 mL).
b Yield of isolated product.
c Reaction carried out in the presence of H2O (0.01 mL).
d Reaction carried out in a sealed tube.
e DMF was used as the solvent.
f Reaction carried out in the presence of H2O (0.01 mL) and CHCl3 (2 mL).
We next turned our attention to the 1,4-conjugate addition of zerumbone using boronic acids under rhodium catalysis. In a test reaction, zerumbone (1) was treated with phenylboronic acid (2a) in the presence of the rhodium(I) catalyst, [Rh(acac)(cod)], which afforded the 1,4-addition product 3a in 34% yield (Scheme [2]).
The rhodium-catalyzed 1,4-conjugate addition reaction required a detailed optimization study to find the best conditions (Table 2). The reaction temperature proved to have a very important outcome (Table 2, entries 1–4); a yield of 61% was obtained when the reaction was performed at 100 °C (Table 2, entry 4). Various catalysts including [Rh(acac)(cod)], [Rh(Cl)(cod)]2, [Rh(OH)(cod)]2 and [Rh(Cl)(coe)2]2 were screened from which [Rh(acac)(cod)] gave the highest yield (Table 2, entries 5–9). Other parameters such as the ligand and solvent were also investigated. Addition of a ligand led to a reduction in the yield (Table 2, entries 9 and 10). Of the solvents tested, a mixture of 1,4-dioxane–water (3:1) gave a superior result compared to N,N-dimethylformamide and toluene. The optimized conditions were as follows: a 1:2 mixture of zerumbone–boronic acid, [Rh(acac)(cod)] (10 mol%) and 1,4-dioxane–H2O (3:1, 2 mL) as the solvent.
a Reaction conditions: zerumbone (1 equiv), phenylboronic acid (2 equiv), rhodium catalyst, solvent (2 mL).
b Yield of isolated product.
c Reaction carried out in the presence of BINAP (10 mol%).
d Reaction carried out in the presence of Ph3P (10 mol%).
Subsequently, the scope of the reaction was explored under the optimized conditions using different substituted phenylboronic acids. In all cases, the desired 1,4-addition product was formed in moderate to good yield. The results are shown in Table 3.
It is noteworthy that functionalized boronic acids such as 2b–l could be used in this 1,4-conjugate addition process, which should make it valuable for further development toward biologically important zerumbone derivatives. Unfortunately, the reaction did not work with heteroaryl boronic acids such as pyridinyl and thienyl boronic acids.
a Reaction conditions: zerumbone (1 equiv), boronic acid (2 equiv), [Rh(acac)(cod)] (10 mol%), 1,4-dioxane–H2O (3:1, 2 mL).
b Yield of isolated product.
The first step of the proposed mechanism[16a] involves transmetallation followed by the addition of the organometallic species to the double bond of the enone in a regio- and stereoselective manner. Subsequent hydrolysis of the Rh–O bond furnishes the conjugate addition product 3a (Scheme [3]). The selective formation of a single diastereoisomer is mainly due to the steric hindrance resulting from the methyl group at C-2 and the distorted structure of the conjugated double bonds in the parent molecule, zerumbone.
In conclusion, we have developed a straightforward, catalytic and general method for the synthesis of novel zerumbone derivatives, via rhodium(I)-catalyzed 1,4-conjugate additions using various boronic acids. The addition across the enone moiety of zerumbone took place in a regio- and diastereoselective manner. A comparative study of the reactivity of organopalladium and organorhodium reagents toward this 1,4-conjugate addition reaction showed that, in most cases, the organopalladium reagents were inferior in terms of reactivity compared to organorhodium reagents. The synthesized molecules are expected to have high synthetic utility for the preparation of a number of biologically relevant molecules. Biological evaluation of the newly synthesized molecules is under way in our laboratory.
All chemicals were of the best grade commercially available and were used without further purification. All the solvents were purified according to standard procedures; anhydrous solvents were obtained according to literature methods and were stored over molecular sieves. Analytical thin-layer chromatography was performed on Merck glass plates coated with silica gel (silica gel 60 F254, 0.25 mm) containing CaSO4 as the binder. Gravity column chromatography was performed using Merck silica gel (100–200 mesh), eluting with mixtures of hexane–EtOAc. Melting points were determined with a Buchi melting point apparatus and are uncorrected. IR spectra were recorded on a Bruker Alpha FT-IR spectrophotometer. 1H NMR and 13C NMR spectra were recorded on Bruker Avance DPX 300 and Bruker AV 500 spectrometers using CDCl3 as the solvent. 1H NMR chemical shifts (δ) are reported in parts per million (ppm) downfield from SiMe4 (δ = 0.0 ppm), and relative to the signal of the residual protonated solvent (δ = 7.25 ppm, singlet). Multiplicities are given as follows: s (singlet), d (doublet), br d (broad doublet), ddd (doublet of double doublets), t (triplet) and m (multiplet). Coupling constants (J) are reported in Hz. 13C NMR chemical shifts (δ) are reported in parts per million (ppm) downfield from SiMe4 (δ = 0.0 ppm), and relative to the signal of CDCl3 (δ = 77.03 ppm, triplet). High-resolution mass spectrometry was performed under ESI conditions at a resolution of 61800 using a Thermo Scientific Exactive mass spectrometer.
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(2E,6E,10E)-2,6,9,9-Tetramethylcycloundeca-2,6,10-trienone (Zerumbone) (1);[12a] Isolation
Dried rhizomes of Z. zerumbet Smith (2.0 kg) were ground into a powder and then extracted with acetone (3 × 3 L) at r.t. Removal of the solvent under reduced pressure gave the crude acetone extract (50 g), which was further subjected to column chromatography on silica gel. The column was eluted with hexane and then 2% EtOAc–hexane to remove less polar compounds. Further elution with 5% EtOAc–hexane, evaporation of the fractions containing the desired product and, recrystallization of the residue (26 g) from distilled hexane gave zerumbone (1).
Yield: 25.1 g (50%); white crystalline solid; mp 65–67 °C; Rf = 0.44 (EtOAc–hexane, 1:9).
IR (KBr): 3026, 2964, 2924, 2856, 1656 (bis-enone), 1455, 1431, 1386, 1363, 1299, 1264, 1211, 1183, 1166, 1104, 1062, 1023, 966, 949, 906, 848, 827, 697, 627, 576, 533 cm–1.
1H NMR (500 MHz, CDCl3): δ = 6.01–5.81 (m, 3 H), 5.26–5.21 (m, 1 H), 2.37–2.20 (m, 5 H), 1.90–1.86 (m, 1 H), 1.76 (s, 3 H), 1.51 (s, 3 H), 1.18 (s, 3 H), 1.05 (s, 3H).
13C NMR (125 MHz, CDCl3): δ = 204.2, 160.7, 148.7, 137.9, 136.2, 127.1, 124.9, 42.4, 39.4, 37.8, 29.4, 24.4, 24.1, 15.2, 11.7.
HRMS (ESI): m/z [M + Na]+ calcd for C15H22ONa: 241.1568; found: 241.1567.
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1,4-Conjugate Addition; General Procedure
Zerumbone (1) (1 equiv), boronic acid 2a (2 equiv) and [Rh(acac)(cod)] (10 mol%) were added to a Schlenk tube and the contents degassed. The mixture was dissolved in 1,4-dioxane–H2O (3:1, 2 mL) and stirred at 100 °C for 12–24 h under an Ar atm. After completion of the reaction (as indicated by TLC analysis), the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (EtOAc–hexane) to afford the product.
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(2E,6E)-4,4,7,11-Tetramethyl-10-phenylcycloundeca-2,6-dienone (3a)
Yield: 28.5 mg (70%); white crystalline solid; mp 65–70 °C; Rf = 0.46 (EtOAc–hexane, 1:9).
IR (KBr): 3024, 2959, 2938, 2871, 1693, 1628, 1452, 1383, 1301, 1042, 999, 840, 743, 701 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.38–7.33 (m, 4 H), 7.27–7.24 (m, 1 H), 6.35–6.27 (m, 2 H), 5.11 (dd, J 1 = 11.5 Hz, J 2 = 4.0 Hz, 1 H), 3.42 (br d, J = 8.5 Hz, 1 H), 2.72 (ddd, J 1 = 13.0 Hz, J 2 = 6.5 Hz, J 3 = 2.5 Hz, 1 H), 2.31 (t, J = 12.5 Hz, 1 H), 2.03–1.99 (m, 1 H), 1.97–1.90 (m, 2 H), 1.55 (t, J = 12.0 Hz, 1 H), 1.49 (s, 3 H), 1.24 (s, 3 H), 1.22 (s, 3 H), 1.05–0.99 (m, 1 H), 0.93 (d, J = 5.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 202.8, 151.3, 143.8, 137.8, 128.5, 128.4, 128.2, 126.4, 122.2, 53.9, 46.2, 41.7, 40.0, 38.1, 28.9, 24.7, 23.1, 16.8, 7.4.
HRMS (ESI): m/z [M + Na]+ calcd for C21H28ONa: 319.2038; found: 319.2037.
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(2E,6E)-4,4,7,11-Tetramethyl-10-(p-tolyl)cycloundeca-2,6-dienone (3b)
Yield: 30.5 mg (71%); pale yellow viscous liquid; Rf = 0.56 (EtOAc–hexane, 1:9).
IR (neat): 2921, 2853, 1738, 1690, 1624, 1599, 1454, 1379, 1264, 1118, 1040, 810, 699, 647 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.26–7.13 (m, 4 H), 6.35–6.20 (m, 2 H), 5.09 (br d, J = 7.5 Hz, 1 H), 3.36 (br d, J = 8.1 Hz, 1 H), 2.67 (ddd, J 1 = 13.0 Hz, J 2 = 6.5 Hz, J 3 = 2.5 Hz, 1 H), 2.35 (s, 3 H), 2.31 (t, J = 13.2 Hz, 1 H), 2.02–1.84 (m, 3 H), 1.57–1.50 (m, 1 H), 1.48 (s, 3 H), 1.24 (s, 3 H), 1.22 (s, 3 H), 1.05–0.96 (m, 1 H), 0.91 (d, J = 6.6 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 203.3, 151.5, 140.7, 137.9, 136.1, 129.2, 129.1, 128.8, 128.7, 128.4, 122.2, 54.1, 45.9, 41.7, 40.1, 38.1, 29.1, 24.7, 23.1, 21.0, 16.9, 7.6.
HRMS (ESI): m/z [M + Na]+ calcd for C22H30ONa: 333.2194; found: 333.2183.
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4-[(4E,8E)-2,6,6,9-Tetramethyl-3-oxocycloundeca-4,8-dien-1-yl]benzaldehyde (3c)
Yield: 28 mg (63%); colorless viscous liquid; Rf = 0.29 (EtOAc–hexane, 1:9).
IR (neat): 2920, 2852, 1736, 1682, 1654, 1600, 1511, 1457, 1420, 1254, 1120, 1041, 846, 698, 645 cm–1.
1H NMR (500 MHz, CDCl3): δ = 10.01 (s, 1 H), 7.87 (d, J = 8.0 Hz, 2 H), 7.51 (d, J = 8.0 Hz, 2 H), 6.31 (s, 2 H), 5.08 (dd, J 1 = 11.5 Hz, J 2 = 4.0 Hz, 1 H), 3.48 (br d, J = 8.5 Hz, 1 H), 2.67 (ddd, J 1 = 9.0 Hz, J 2 = 6.5 Hz, J 3 = 2.0 Hz, 1 H), 2.31 (t, J = 12.5 Hz, 1 H), 2.06–1.89 (m, 3 H), 1.54–1.48 (m, 1 H), 1.47 (s, 3 H), 1.25 (s, 3 H), 1.24 (s, 3 H), 1.12–1.00 (m, 1 H), 0.93 (d, J = 6.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 202.5, 191.8, 152.1, 151.1, 137.6, 135.1, 130.1, 130.0, 129.4, 129.2, 127.9, 122.6, 53.6, 46.7, 41.2, 40.2, 38.1, 29.1, 24.5, 23.2, 16.9, 7.6.
HRMS (ESI): m/z [M + Na]+ calcd for C22H28O2Na: 347.1987; found: 347.1980.
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(2E,6E)-10-(3-Acetylphenyl)-4,4,7,11-tetramethylcycloundeca-2,6-dienone (3d)
Yield: 33 mg (71%); pale yellow viscous liquid; Rf = 0.27 (EtOAc–hexane, 1:9).
IR (neat): 2957, 2929, 2855, 1689, 1628, 1453, 1362, 1269, 1173, 1043, 999, 844, 794, 699, 588 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.94 (s, 1 H), 7.84 (d, J = 7.5 Hz, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.47 (t, J = 7.5 Hz, 1 H), 6.37–6.29 (m, 2 H), 5.11 (dd, J 1 = 11.5 Hz, J 2 = 4.0 Hz, 1 H), 3.47 (br d, J = 9.0 Hz, 1 H), 2.72 (ddd, J 1 = 13.0 Hz, J 2 = 6.5 Hz, J 3 = 2.5 Hz, 1 H), 2.64 (s, 3 H), 2.36–2.28 (m, 1 H), 2.05–1.90 (m, 3 H), 1.52 (t, J = 12.0 Hz, 1 H), 1.49 (s, 3 H), 1.25 (s, 3 H), 1.23 (s, 3 H), 1.05 (m, 1 H), 0.91 (d, J = 6.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 202.3, 197.8, 151.7, 144.5, 137.7, 137.6, 133.0, 128.6, 127.9, 127.8, 126.8, 122.4, 53.7, 46.2, 41.6, 40.0, 38.1, 29.3, 26.4, 24.7, 23.2, 16.7, 7.4.
HRMS (ESI): m/z [M + Na]+ calcd for C23H30O2Na: 361.2143; found: 361.2131.
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(2E,6E)-10-(4-Benzoylphenyl)-4,4,7,11-tetramethylcycloundeca-2,6-dienone (3e)
Yield: 36 mg (68%); colorless viscous liquid; Rf = 0.32 (EtOAc–hexane, 1:9).
IR (neat): 3028, 2957, 2934, 2869, 1692, 1658, 1627, 1603, 1449, 1382, 1313, 1279, 1177, 1042, 1000, 923, 855, 738, 703, 625 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.83–7.81 (m, 4 H), 7.60 (t, J = 7.5 Hz, 1 H), 7.53–7.44 (m, 4 H), 6.33 (s, 2 H), 5.12 (dd, J 1 = 11.5 Hz, J 2 = 4.5 Hz, 1 H), 3.51 (br d, J = 8.5 Hz, 1 H), 2.75 (ddd, J 1 = 13.0 Hz, J 2 = 6.5 Hz, J 3 = 2.0 Hz, 1 H), 2.35–2.30 (m, 1 H), 2.07–2.03 (m, 1 H), 2.00–1.91 (m, 2 H), 1.58 (t, J = 12.0 Hz, 1 H), 1.49 (s, 3 H), 1.25 (s, 3 H), 1.23 (s, 3 H), 1.05–1.01 (m, 1 H), 0.95 (d, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 202.2, 195.9, 151.8, 148.8, 137.9, 137.6, 136.2, 132.2, 130.3, 129.8, 128.3, 128.2, 127.9, 122.4, 53.6, 46.4, 41.7, 40.1, 38.1, 28.9, 24.6, 23.1, 16.8, 7.4.
HRMS (ESI): m/z [M + Na]+ calcd for C28H32O2Na: 423.2300; found: 423.2293.
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(2E,6E)-10-(4-Bromophenyl)-4,4,7,11-tetramethylcycloundeca-2,6-dienone (3f)
Yield: 20 mg (40%); pale yellow viscous liquid; Rf = 0.45 (EtOAc–hexane, 1:9).
IR (neat): 2958, 2934, 2870, 1693, 1628, 1488, 1453, 1407, 1382, 1302, 1264, 1077, 1008, 817, 720, 556 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.46 (d, J = 8.5 Hz, 2 H), 7.21 (d, J = 8.5 Hz, 2 H), 6.29 (s, 2 H), 5.08 (dd, J 1 = 11.5 Hz, J 2 = 4.0 Hz, 1 H), 3.36 (dd, J 1 = 8.0 Hz, J 2 = 1.0 Hz, 1 H), 2.66 (ddd, J 1 = 13.0 Hz, J 2 = 6.5 Hz, J 3 = 2.0 Hz, 1 H), 2.30 (t, J = 12.5 Hz, 1 H), 2.03–1.99 (m, 1 H), 1.92–1.82 (m, 2 H), 1.50 (t, J = 12.5 Hz, 1 H), 1.47 (s, 3 H), 1.23 (s, 3 H), 1.21 (s, 3 H), 1.05–0.99 (m, 1 H), 0.90 (d, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 202.5, 151.7, 142.8, 137.6, 131.6, 130.1, 127.9, 122.3, 120.3, 53.7, 45.8, 41.7, 40.0, 38.0, 28.9, 24.7, 23.1, 16.7, 7.3.
HRMS (ESI): m/z [M + Na]+ calcd for C21H27BrONa: 397.1143; found: 397.1137.
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(2E,6E)-4,4,7,11-Tetramethyl-10-[4-(trifluoromethyl)phenyl]cycloundeca-2,6-dienone (3g)
Yield: 30 mg (60%); white crystalline solid; mp 104–106 °C; Rf = 0.49 (EtOAc–hexane, 1:9).
IR (neat): 3041, 2920, 2853, 1738, 1693, 1624, 1453, 1418, 1382, 1325, 1264, 1163, 1122, 1069, 1042, 999, 845, 715, 668, 646 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.62 (d, J = 8.0 Hz, 2 H), 7.45 (d, J = 8.0 Hz, 2 H), 6.32 (s, 2 H), 5.10 (dd, J 1 = 11.5 Hz, J 2 = 4.0 Hz, 1 H), 3.47 (br d, J = 9.0 Hz, 1 H), 2.70 (ddd, J 1 = 9.0 Hz, J 2 = 6.6 Hz, J 3 = 2.5 Hz, 1 H), 2.31 (t, J = 13.0 Hz, 1 H), 2.05–2.01 (m, 1 H), 1.96–1.89 (m, 2 H), 1.53–1.48 (m, 1 H), 1.49 (s, 3 H), 1.24 (s, 3 H), 1.23 (s, 3 H), 1.09–1.04 (m, 1 H), 0.92 (d, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 202.6, 152.0, 147.8, 137.6, 129.1, 128.8, 127.9, 125.5, 125.4, 125.2, 122.4, 53.6, 46.3, 41.6, 40.2, 38.0, 28.9, 24.5, 23.1, 16.8, 7.5.
HRMS (ESI): m/z [M + Na]+ calcd for C22H27F3ONa: 387.1912; found: 387.1904.
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(2E,6E)-10-(4-Methoxyphenyl)-4,4,7,11-tetramethylcycloundeca-2,6-dienone (3h)
Yield: 26 mg (60%); colorless viscous liquid; Rf = 0.44 (EtOAc–hexane, 1:9).
IR (neat): 2919, 2851, 1735, 1687, 1607, 1511, 1457, 1419, 1378, 1248, 1117, 1038, 832, 700, 646 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.25 (d, J = 8.5 Hz, 2 H), 6.90 (d, J = 8.5 Hz, 2 H), 6.34–6.26 (m, 2 H), 5.10 (dd, J 1 = 12.0 Hz, J 2 = 4.0 Hz, 1 H), 3.82 (s, 3 H), 3.34 (br d, J = 9.0 Hz, 1 H), 2.68 (ddd, J 1 = 9.0 Hz, J 2 = 7.0 Hz, J 3 = 2.5 Hz, 1 H), 2.30 (t, J = 12.5 Hz, 1 H), 2.01–1.97 (m, 1 H), 1.92–1.83 (m, 2 H), 1.54 (t, J = 12.0 Hz, 1 H), 1.47 (s, 3 H), 1.23 (s, 3 H), 1.21 (s, 3 H), 1.03–0.97 (m, 1 H), 0.91 (d, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 203.5, 158.2, 151.5, 137.9, 135.7, 129.4, 128.3, 122.1, 113.8, 55.3, 54.2, 45.5, 41.6, 40.1, 38.1, 29.0, 24.9, 23.1, 16.9, 7.5.
HRMS (ESI): m/z [M + Na]+ calcd for C22H30O2Na: 349.2143; found: 349.2137.
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3-Methyl-5-[(4E,8E)-2,6,6,9-tetramethyl-3-oxocycloundeca-4,8-dienyl]benzaldehyde (3i)
Yield: 13 mg (30%); pale yellow viscous liquid; Rf = 0.28 (EtOAc–hexane, 1:9).
IR (neat): 2956, 2926, 2855, 2724, 1696, 1627, 1601, 1454, 1348, 1264, 1144, 1044, 999, 862, 701, 668, 564 cm–1.
1H NMR (500 MHz, CDCl3): δ = 10.02 (s, 1 H), 7.65 (s, 1 H), 7.58 (s, 1 H), 7.39 (s, 1 H), 6.36–6.30 (m, 2 H), 5.11 (dd, J 1 = 11.5 Hz, J 2 = 4.0 Hz, 1 H), 3.45 (br d, J = 9.0 Hz, 1 H), 2.71 (ddd, J 1 = 13.3 Hz, J 2 = 7.0 Hz, J 3 = 2.5 Hz, 1 H), 2.48 (s, 3 H), 2.31 (t, J = 12.5 Hz, 1 H), 2.06–2.02 (m, 1 H), 1.99–1.91 (m, 2 H), 1.63 (s, 3 H), 1.54–1.51 (m, 1 H), 1.26 (s, 3 H), 1.23 (s, 3 H), 1.05–1.02 (m, 1 H), 0.91 (d, J = 6.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 202.2, 192.2, 151.8, 144.9, 139.1, 137.6, 135.3, 133.7, 129.0, 127.9, 126.3, 122.4, 53.7, 46.1, 41.6, 40.0, 38.1, 28.9, 24.6, 23.2, 21.2, 16.8, 7.4.
HRMS (ESI): m/z [M + Na]+ calcd for C23H30O2Na: 361.2143; found: 361.2131.
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(2E,6E)-10-(2,5-Dimethoxyphenyl)-4,4,7,11-tetramethylcycloundeca-2,6-dienone (3j)
Yield: 24.4 mg (50%); white crystalline solid; mp 138–140 °C; Rf = 0.34 (EtOAc–hexane, 1:9).
IR (neat): 2956, 2928, 2871, 1693, 1629, 1612, 1586, 1503, 1458, 1367, 1291, 1208, 1154, 1039, 837, 798, 632 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.15 (d, J = 8.5 Hz, 1 H), 6.53–6.45 (m, 3 H), 6.22 (d, J = 16.0 Hz, 1 H), 5.08 (dd, J 1 = 11.5 Hz, J 2 = 4.0 Hz, 1 H), 3.93 (s, 3 H), 3.86 (br d, J = 9.5 Hz, 1 H), 3.81 (s, 3 H), 2.60 (ddd, J 1 = 13.5 Hz, J 2 = 7.0 Hz, J 3 = 2.0 Hz, 1 H), 2.30 (t, J = 12.5 Hz, 1 H), 1.94–1.82 (m, 3 H), 1.47 (s, 3 H), 1.41 (t, J = 12.0 Hz, 1 H), 1.26 (s, 3 H), 1.21 (s, 3 H), 0.91–0.89 (m, 1 H), 0.83 (d, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 203.4, 159.4, 158.5, 150.1, 137.5, 128.7, 128.0, 124.3, 122.2, 103.7, 98.9, 55.4, 55.2, 51.6, 41.9, 40.0, 38.0, 37.0, 29.1, 23.8, 22.8, 16.7, 7.2.
HRMS (ESI): m/z [M + Na]+ calcd for C23H32O3Na: 379.2249; found: 379.2242.
#
(2E,6E)-10-(Biphenyl-4-yl)-4,4,7,11-tetramethylcycloundeca-2,6-dienone (3k)
Yield: 38 mg (75%); colorless viscous liquid; Rf = 0.44 (EtOAc–hexane, 1:9).
IR (neat): 3028, 2958, 2934, 2869, 1693, 1628, 1486, 1452, 1382, 1366, 1301, 1042, 1001, 843, 755, 697, 562 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.61–7.56 (m, 4 H), 7.45–7.39 (m, 4 H), 7.35–7.32 (m, 1 H), 6.37–6.28 (m, 2 H), 5.12 (dd, J 1 = 11.0 Hz, J 2 = 3.5 Hz, 1 H), 3.46 (br d, J = 9.0 Hz, 1 H), 2.76 (ddd, J 1 = 13.5 Hz, J 2 = 6.5 Hz, J 3 = 2.5 Hz, 1 H), 2.32 (t, J = 22.5 Hz, 1 H), 2.06–2.01 (m, 1 H), 1.99–1.90 (m, 2 H), 1.59 (t, J = 11.5 Hz, 1 H), 1.45 (s, 3 H), 1.25 (s, 3 H), 1.23 (s, 3 H), 1.05–1.01 (m, 1 H), 0.96 (d, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 202.7, 151.6, 151.4, 142.9, 142.8, 140.8, 139.5, 137.8, 128.9, 128.8, 128.7, 128.2, 127.2, 127.1, 127.0, 126.9, 122.3, 53.9, 45.9, 41.7, 40.1, 38.2, 28.9, 24.8, 23.1, 16.8, 7.6.
HRMS (ESI): m/z [M + Na]+ calcd for C27H32ONa: 395.2351; found: 395.2344.
#
(2E,6E)-4,4,7,11-Tetramethyl-10-(naphthalen-1-yl)cycloundeca-2,6-dienone (3l)
Yield: 40 mg (85%); pale yellow viscous liquid; Rf = 0.45 (EtOAc–hexane, 1:9).
IR (neat): 3047, 2960, 2935, 2870, 1693, 1629, 1511, 1472, 1381, 1299, 1264, 1042, 997, 846, 795, 779, 729, 677, 565 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.34 (d, J = 8.5 Hz, 1 H), 7.94 (d, J = 8.0 Hz, 1 H), 7.85 (d, J = 8.0 Hz, 1 H), 7.66–7.63 (m, 1 H), 7.56–7.48 (m, 3 H), 6.63 (d, J = 16.0 Hz, 1 H), 6.41 (d, J = 16.0 Hz, 1 H), 5.19 (dd, J 1 = 11.5 Hz, J 2 = 4.0 Hz, 1 H), 4.45 (br d, J = 9.5 Hz, 1 H), 2.75 (ddd, J 1 = 13.5 Hz, J 2 = 7.0 Hz, J 3 = 2.5 Hz, 1 H), 2.38 (t, J = 12.5 Hz, 1 H), 2.24–2.18 (m, 1 H), 2.01–1.94 (m, 2 H), 1.55 (s, 3 H), 1.43 (t, J = 7.5 Hz, 1 H), 1.41 (s, 3 H), 1.27 (s, 3 H), 1.15–1.05 (m, 1 H), 0.91 (d, J = 6.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 203.1, 151.9, 138.8, 138.2, 134.5, 132.6, 129.6, 127.9, 127.2, 126.2, 125.3, 125.2, 122.4, 121.9, 51.8, 41.7, 40.4, 40.1, 38.1, 29.0, 25.3, 23.3, 16.9, 7.9.
HRMS (ESI): m/z [M + Na]+ calcd for C25H30ONa: 369.2194; found: 369.2188.
#
#
Acknowledgment
The authors thank the Council of Scientific and Industrial Research (CSIR), New Delhi, [12th FYP Project, ORIGIN (CSC 0108) and NAPAHA CSC (0130)] for financial assistance. A.K.R. and N.J. thank the CSIR and UGC for research fellowships. We thank Ms. Soumini Mathew, Mr. Vipin M. G., Mr. Arun Thomas and Ms. Viji for the NMR spectral and HRMS data.
Supporting Information
- for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.
- Supporting Information
-
References
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- 1b Itokawa H, Morris-Natschke SL, Akiyama T, Lee KH. J. Nat. Med. 2008; 62: 263
- 2 Strohl WR. Drug Discovery Today 2000; 5: 39
- 3 Newman DJ, Cragg GM. J. Nat. Prod. 2007; 70: 461
- 4a Dev S. Tetrahedron 1960; 8: 171
- 4b Damodaran NP, Dev S. Tetrahedron Lett. 1965; 1977
- 4c Dev S, Anderson JE, Cormier V, Damodaran NP, Roberts JD. J. Am. Chem. Soc. 1968; 90: 1246
- 4d Hall SR, Nimgirawath S, Raston CL, Sittatrakkul A, Thadaniti S, Thirasasana N, White AH. Aust. J. Chem. 1981; 34: 2243
- 4e Fransworth NR, Bunyapraphatsara N. Thai Medical Plants . Prachachon; Bangkok: 1992: 261
- 4f Sawada S, Yokoi T, Kitayama T. Aroma Res. 2002; 9: 34; and references cited therein
- 5a Murakami A, Tanaka T, Lee JY, Surh YJ, Kim HW, Kawabata K, Nakamura Y, Jiwajinda S, Ohigashi H. Int. J. Cancer 2004; 110: 481
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- 6a Ozaki Y, Kawahara N, Harada M. Chem. Pharm. Bull. 1991; 39: 2353
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- 6c Szabolcs A, Tiszlavicz L, Kaszaki J, Pósa A, Berkó A, Varga IS, Boros I, Szüts V, Lonovics J, Takács T. Pancreas 2007; 35: 249
- 6d Murakami A, Ohigashi H. Int. J. Cancer 2007; 121: 2357
- 6e Murakami A, Miyamoto M, Ohigashi H. Biofactors 2004; 21: 95
- 7a Aggarwal BB, Ajaikumar BK, Harikumar KB, Sheeja TT, Sung B, Anand P. Planta Med. 2008; 74: 1560; and references cited therein
- 7b Taha MM, Abdul AB, Abdullah R, Ibrahim TA, Abdelwahab SI, Mohan S. Chem. Biol. Interact. 2010; 186: 295
- 7c Abdelwahab SI, Abdul AB, Mohan S, Taha MM, Syam S, Ibrahim MY, Mariod AA. Leukemia Res. 2011; 35: 268
- 7d Sung B, Prasad S, Yadav VR, Aggarwal BB. Nutr. Cancer. 2012; 64: 173
- 7e Abdelwahab SI, Abdul AB, Zain ZN, Hadi AH. A. Int. Immunopharmacol. 2012; 12: 594
- 8 Dai JR, Cardellina JH, McMahon JB, Boyd MR. Nat. Prod. Lett. 1997; 10: 115
- 9a Kitayama T, Yamamoto K, Utsumi R, Takatani M, Hill RK, Kawai Y, Sawada S, Okamoto T. Biosci. Biotechnol. Biochem. 2001; 65: 2193
- 9b Kitayama T, Iwabuchi R, Minagawa S, Shiomi F, Cappiello J, Sawada S, Utsumi R, Okamoto T. Bioorg. Med. Chem. Lett. 2004; 14: 5943
- 9c Kitayama T, Iwabuchi R, Minagawa S, Sawada S, Okumura R, Hoshino K, Cappiello J, Utsumi R. Bioorg. Med. Chem. Lett. 2007; 17: 1098
- 9d Ohinishi K, Irie K, Murakami A. Biosci. Biotechnol. Biochem. 2009; 73: 1905
- 9e Songsiang U, Pitchuanchom S, Boonyarat C, Hahnvajanawong C, Yenjai C. Eur. J. Med. Chem. 2010; 45: 3794
- 10 Baby S, Dan M, Thaha AR. M, Johnson AJ, Kurup R, Balakrishnapillai P, Lim CK. Flavour Fragr. J. 2009; 24: 301
- 11 Kitayama T. Biosci. Biotechnol. Biochem. 2011; 75: 199; and references cited therein
- 12a Kitayama T, Okamoto T, Hill RK, Kawai Y, Takahashi S, Yonemori S, Yamamoto Y, Ohe K, Uemura S, Sawada S. J. Org. Chem. 1999; 64: 2667
- 12b Ohe K, Miki K, Yanagi S, Tanaka T, Sawada S, Uemura S. J. Chem. Soc., Perkin Trans. 1 2000; 3627
- 13 Kitayama T, Yokoi T, Kawai Y, Hill RK, Morita M, Okamoto T, Yamamoto Y, Fokin VV, Sharpless KB, Sawada S. Tetrahedron 2003; 59: 4857
- 14 Kitayama T, Masuda T, Sakai K, Imada C, Yonekura Y, Kawai Y. Tetrahedron 2006; 62: 10859
- 15a Kitayama T, Masuda T, Kawai Y, Hill RK, Takatani M, Sawada S, Okamoto T. Tetrahedron: Asymmetry 2001; 12: 2805
- 15b Kitayama T, Furuya A, Moriyama C, Masuda T, Fushimi S, Yonekura Y, Kubo H, Kawai Y, Sawada S. Tetrahedron: Asymmetry 2006; 17: 2311
- 16a Sakai M, Hayashi H, Miyaura N. Organometallics 1997; 16: 4229
- 16b Takaya Y, Ogasawara M, Hayashi T, Sakai M, Miyaura N. J. Am. Chem. Soc. 1998; 120: 5579
- 16c Hayashi T. Synlett 2001; 879
- 16d Ramnauth J, Poulin O, Bratovanov SS, Rakhit S, Maddaford SP. Org. Lett. 2001; 3: 2571
- 16e Hayashi T, Takahashi M, Takaya Y, Ogasawara M. J. Am. Chem. Soc. 2002; 124: 5052
- 16f Hayashi T, Yamasaki K. Chem. Rev. 2003; 103: 2829
- 16g Navarre L, Pucheault M, Darses S, Genet JP. Tetrahedron Lett. 2005; 46: 4247
- 16h Edwards HJ, Hargrave JD, Penrose SD, Frost CG. Chem. Soc. Rev. 2010; 39: 2093
- 16i Zilaout H, van den Hoogenband A, de Vries J, Lange JH. M, Terpstra JW. Tetrahedron Lett. 2011; 52: 5934
- 17a Chen L, Li CJ. Chem. Commun. 2004; 2362
- 17b Lu X, Lin S. J. Org. Chem. 2005; 70: 9651
- 17c Gini F, Hessen B, Minnaard AJ. Org. Lett. 2005; 7: 5309
- 17d Yamamoto T, Iizuka M, Ohta T, Ito Y. Chem. Lett. 2006; 35: 198
- 17e Gini F, Hessen B, Feringa BL, Minnaard AJ. Chem. Commun. 2007; 710
- 18 See the experimental section.
- 19 Compound 3a was recrystallized from EtOAc–hexane to give crystals which were suitable for single crystal X-ray analysis (CCDC 910243). Unit cell parameters: a = 11.3478(5) Å, b = 12.8754(6) Å, c = 12.5373(6) Å, β = 95.178(2)°, space group = P21.
-
References
- 1a Chin Y.-W, Balunas MJ, Chai H.-B, Kinghorn AD. AAPS J. 2006; 8: E239
- 1b Itokawa H, Morris-Natschke SL, Akiyama T, Lee KH. J. Nat. Med. 2008; 62: 263
- 2 Strohl WR. Drug Discovery Today 2000; 5: 39
- 3 Newman DJ, Cragg GM. J. Nat. Prod. 2007; 70: 461
- 4a Dev S. Tetrahedron 1960; 8: 171
- 4b Damodaran NP, Dev S. Tetrahedron Lett. 1965; 1977
- 4c Dev S, Anderson JE, Cormier V, Damodaran NP, Roberts JD. J. Am. Chem. Soc. 1968; 90: 1246
- 4d Hall SR, Nimgirawath S, Raston CL, Sittatrakkul A, Thadaniti S, Thirasasana N, White AH. Aust. J. Chem. 1981; 34: 2243
- 4e Fransworth NR, Bunyapraphatsara N. Thai Medical Plants . Prachachon; Bangkok: 1992: 261
- 4f Sawada S, Yokoi T, Kitayama T. Aroma Res. 2002; 9: 34; and references cited therein
- 5a Murakami A, Tanaka T, Lee JY, Surh YJ, Kim HW, Kawabata K, Nakamura Y, Jiwajinda S, Ohigashi H. Int. J. Cancer 2004; 110: 481
- 5b Kirana C, McIntosh GH, Record IR, Jones GP. Nutr. Cancer 2003; 45: 218
- 6a Ozaki Y, Kawahara N, Harada M. Chem. Pharm. Bull. 1991; 39: 2353
- 6b Sulaiman MR, Perimal EK, Akhtar MN, Mohamad AS, Khalid MH, Tasrip NA, Mokhtar F, Zakaria ZA, Lajis NH, Israf DA. Fitoterapia 2010; 81: 855
- 6c Szabolcs A, Tiszlavicz L, Kaszaki J, Pósa A, Berkó A, Varga IS, Boros I, Szüts V, Lonovics J, Takács T. Pancreas 2007; 35: 249
- 6d Murakami A, Ohigashi H. Int. J. Cancer 2007; 121: 2357
- 6e Murakami A, Miyamoto M, Ohigashi H. Biofactors 2004; 21: 95
- 7a Aggarwal BB, Ajaikumar BK, Harikumar KB, Sheeja TT, Sung B, Anand P. Planta Med. 2008; 74: 1560; and references cited therein
- 7b Taha MM, Abdul AB, Abdullah R, Ibrahim TA, Abdelwahab SI, Mohan S. Chem. Biol. Interact. 2010; 186: 295
- 7c Abdelwahab SI, Abdul AB, Mohan S, Taha MM, Syam S, Ibrahim MY, Mariod AA. Leukemia Res. 2011; 35: 268
- 7d Sung B, Prasad S, Yadav VR, Aggarwal BB. Nutr. Cancer. 2012; 64: 173
- 7e Abdelwahab SI, Abdul AB, Zain ZN, Hadi AH. A. Int. Immunopharmacol. 2012; 12: 594
- 8 Dai JR, Cardellina JH, McMahon JB, Boyd MR. Nat. Prod. Lett. 1997; 10: 115
- 9a Kitayama T, Yamamoto K, Utsumi R, Takatani M, Hill RK, Kawai Y, Sawada S, Okamoto T. Biosci. Biotechnol. Biochem. 2001; 65: 2193
- 9b Kitayama T, Iwabuchi R, Minagawa S, Shiomi F, Cappiello J, Sawada S, Utsumi R, Okamoto T. Bioorg. Med. Chem. Lett. 2004; 14: 5943
- 9c Kitayama T, Iwabuchi R, Minagawa S, Sawada S, Okumura R, Hoshino K, Cappiello J, Utsumi R. Bioorg. Med. Chem. Lett. 2007; 17: 1098
- 9d Ohinishi K, Irie K, Murakami A. Biosci. Biotechnol. Biochem. 2009; 73: 1905
- 9e Songsiang U, Pitchuanchom S, Boonyarat C, Hahnvajanawong C, Yenjai C. Eur. J. Med. Chem. 2010; 45: 3794
- 10 Baby S, Dan M, Thaha AR. M, Johnson AJ, Kurup R, Balakrishnapillai P, Lim CK. Flavour Fragr. J. 2009; 24: 301
- 11 Kitayama T. Biosci. Biotechnol. Biochem. 2011; 75: 199; and references cited therein
- 12a Kitayama T, Okamoto T, Hill RK, Kawai Y, Takahashi S, Yonemori S, Yamamoto Y, Ohe K, Uemura S, Sawada S. J. Org. Chem. 1999; 64: 2667
- 12b Ohe K, Miki K, Yanagi S, Tanaka T, Sawada S, Uemura S. J. Chem. Soc., Perkin Trans. 1 2000; 3627
- 13 Kitayama T, Yokoi T, Kawai Y, Hill RK, Morita M, Okamoto T, Yamamoto Y, Fokin VV, Sharpless KB, Sawada S. Tetrahedron 2003; 59: 4857
- 14 Kitayama T, Masuda T, Sakai K, Imada C, Yonekura Y, Kawai Y. Tetrahedron 2006; 62: 10859
- 15a Kitayama T, Masuda T, Kawai Y, Hill RK, Takatani M, Sawada S, Okamoto T. Tetrahedron: Asymmetry 2001; 12: 2805
- 15b Kitayama T, Furuya A, Moriyama C, Masuda T, Fushimi S, Yonekura Y, Kubo H, Kawai Y, Sawada S. Tetrahedron: Asymmetry 2006; 17: 2311
- 16a Sakai M, Hayashi H, Miyaura N. Organometallics 1997; 16: 4229
- 16b Takaya Y, Ogasawara M, Hayashi T, Sakai M, Miyaura N. J. Am. Chem. Soc. 1998; 120: 5579
- 16c Hayashi T. Synlett 2001; 879
- 16d Ramnauth J, Poulin O, Bratovanov SS, Rakhit S, Maddaford SP. Org. Lett. 2001; 3: 2571
- 16e Hayashi T, Takahashi M, Takaya Y, Ogasawara M. J. Am. Chem. Soc. 2002; 124: 5052
- 16f Hayashi T, Yamasaki K. Chem. Rev. 2003; 103: 2829
- 16g Navarre L, Pucheault M, Darses S, Genet JP. Tetrahedron Lett. 2005; 46: 4247
- 16h Edwards HJ, Hargrave JD, Penrose SD, Frost CG. Chem. Soc. Rev. 2010; 39: 2093
- 16i Zilaout H, van den Hoogenband A, de Vries J, Lange JH. M, Terpstra JW. Tetrahedron Lett. 2011; 52: 5934
- 17a Chen L, Li CJ. Chem. Commun. 2004; 2362
- 17b Lu X, Lin S. J. Org. Chem. 2005; 70: 9651
- 17c Gini F, Hessen B, Minnaard AJ. Org. Lett. 2005; 7: 5309
- 17d Yamamoto T, Iizuka M, Ohta T, Ito Y. Chem. Lett. 2006; 35: 198
- 17e Gini F, Hessen B, Feringa BL, Minnaard AJ. Chem. Commun. 2007; 710
- 18 See the experimental section.
- 19 Compound 3a was recrystallized from EtOAc–hexane to give crystals which were suitable for single crystal X-ray analysis (CCDC 910243). Unit cell parameters: a = 11.3478(5) Å, b = 12.8754(6) Å, c = 12.5373(6) Å, β = 95.178(2)°, space group = P21.
