Advanced
Short and Efficient Synthesis of Licochalcone B and D Through Acid-Mediated Claisen-Schmidt Condensation
Short and Efficient Synthesis of Licochalcone B and D Through Acid-Mediated Claisen-Schmidt Condensation
Bulletin of the Korean Chemical Society. 2013. Dec, 34(12): 3906-3908
Copyright © 2013, Korea Chemical Society
  • Received : September 06, 2013
  • Accepted : September 25, 2013
  • Published : December 20, 2013
Download
PDF
e-PUB
PubReader
PPT
Export by style
Article
Author
Metrics
Cited by
TagCloud
About the Authors
Zengtao Wang
Zhiguo Liu
School of Pharmacy, Wenzhou Medical College, 1210 University Town, Wenzhou, Zhejiang 325035, China
Yongkai Cao
Suresh Paudel
Goo Yoon
College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 534-729, Korea
Seung Hoon Cheon

Abstract
Keywords
PPT Slide
Lager Image
PPT Slide
Lager Image
PPT Slide
Lager Image
Experimental Section
General Experiments. All solvents were purchased from OCI (Seoul, Korea). Reagents were obtained from Alfa Aesar or Aldrich and were used without further purification. Silica gel plates (F254; Merck, Germany) and silica gel 60 (70-230 mesh; Merck) were used for analytical and column chromatography, respectively. Melting points were determined in capillary tubes using a capillary melting point apparatus and are not corrected. Nuclear magnetic resonance (NMR) spectra 300 MHz for 1 H-NMR, 75 MHz for 13 C-NMR were recorded on a Varian Unity Plus 300 spectrometer, which were performed using CDCl 3 or dimethylsulfoxide (DMSO)- d 6 as a solvent at room temperature. Chemical shift (δ) was expressed in ppm relative to tetramethylsilane used as an internal standard, coupling constant ( J ) values are estimated in hertz (Hz) and spin multiples are given as s (singlet), d (doublet), dd (double doublets), m (multiplet), and br (broad). The mass spectra (MS) were acquired in positive mode over 100:600 m/z range using a Varian 1200L triple quadrupole mass spectrometer equipped with electrospray ionization (ESI) source. Compounds were visualized by ultraviolet light.
Compound 4. To a suspended solution of 2,3,4-trihydroxybenzaldehyde (1.2 g, 8 mmol) in dichloromethane (10 mL) was added N,N -diisopropylethylamine (2.8 mL, 17 mmol), and stirred for 15 min at 0 ℃. Methoxymethyl chloride (1.3 mL, 17 mmol) was then added drop-wise. The mixture was stirred at 0 ℃ for 15 min then at room temperature for 1 h. The reaction mixture was poured into water and extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-EtOA c = 10:1) to afford 2-hydroxy-3,4-bis(methoxymethoxy)benzaldehyde (1.37 g, 71%) as a white solid. mp 55-56 ℃. LCEIMS: m/z = 241 [M-H] . 1 H-NMR (CDCl 3 )δ 11.30 (1H, s), 9.75 (1H, s), 7.28 (1H, d, J = 8.7 Hz), 6.82 (1H, d, J = 8.7 Hz), 5.30 (2H, s), 5.20 (2H, s), 3.64 (3H, s), 3.51 (3H, s). 13 C-NMR (CDCl 3 ) δ 195.05, 157.07, 156.07, 133.23, 130.15, 116.83, 107.05, 97.91, 94.52, 57.19, 56.49.
Compound 5. To a stirred solution of 4 (1.37 g, 5.7 mmol) in DMF (14 mL) was added to a suspension of NaH (344 mg, 60% in oil, 8.6 mmol) in DMF (16 mL) under cooling with ice-water. After being stirred at the same temperature for 30 min, followed by CH 3 I (0.54 mL, 8.6 mmol) at room temperature, and the mixture was stirred at same temperature overnight, which was quenched with an aqueous NH 4 Cl solution (saturated), then extracted with ethyl acetate (EtOAc) and the combined organic layer was washed with water and brine, dried over MgSO 4 , filtered and concentrated under reduced pressure to give a crude oil, which was purified by silica gel chromatography (hexane-EtOAc = 10:1) to give a colorless oil liquid (1.38 g, 95%). 1 H-NMR (300 MHz, CDCl 3 ) δ 10.25 (1H, d, J = 0.6 Hz), 7.60 (1H, d, J = 9.0 Hz), 7.01 (1H, dd, J = 9.0, 0.9 Hz), 5.28 (2H, s), 5.17 (2H, s), 4.01 (3H, s), 3.63 (3H, s), 3.52 (3H, s). 13 C-NMR (CDCl 3 ) δ 188.26, 157.08, 156.49, 138.94, 124.05, 123.93, 110.79, 98.36, 94.41, 62.29, 56.97, 56.17.
Compound 6b.
Method A: A solution of 4-hydroxyacetophenone ( 6a ) (5 g, 36.8 mmol) in dry THF (50 mL) was added to a slurry of BaO (3 eq) and A1 2 O 3 (3 eq, basic or neutral Type T or E for thin layer chromatography; Merck) in dry ether-hexane (55 mL, 1:1). After 2 h, the solvent was evaporated and 2 eq of prenyl bromide in CH 2 Cl 2 (90 mL) was added. After 4 days the solid was filtered off and washed with 1% HOAc- EtOAc. The combined organic layers were evaporated and compound 6b was obtained as a white-pale yellow crystalline solid (2.63 g, 35%) over silica gel column using mixtures of hexanes and EtOAc (10:1 to 7:1) as eluent.
Method B : Compound 6a (25 g) in 150 mL dioxane was added to a stirred fresh solution of 2-methyl-3-buten-2-ol (20 g) and 12.5 mL BF 3 ·OEt 2 in 100 mL dioxane, and stirring was continued for 5 h at room temperature. Ether (250 mL) was added and the resulting solution was extracted with water (3 × 500 mL). The remaining organic layer was dried over MgSO 4 before evaporation to dryness. The crystalline residue was extracted with hexane (5 × 50 mL), which dissolved the reaction products and left behind most unchanged starting material. After evaporation of the solvent in vacuo the crude residue was purified by flash chromatography (hexane:EtOAc = 10:1) to give 6b (4.65 g, 31%) based on recovered compound 6a (15 g, 60%).
Method C : 4-Hydroxyacetophenone ( 6a , 2 g, 14.7 mmol) was dissolved in aqueous potassium hydroxide (0.82 g in 8 mL water, 14.7 mmol) solution at room temperature. To this solution, 3,3-dimethylallyl bromide (3.5 g, 23.7 mmol) and aqueous potassium hydroxide (0.82 g in 8 mL water, 14.7 mmol) were added simultaneously, in portion-wise over 1 h and the reaction mixture was stirred for 48 h at around 45 ℃. After completion of the reaction (monitored by TLC), the reaction mass was basified further with potassium hydroxide (0.82 g in 8 mL water, 14.7 mmol) and extracted with toluene (2 × 10 mL) to remove O -prenylated product. The aqueous layer was then acidified with acetic acid at ice water bath temperature to pH 5.0 and was extracted with ethyl acetate (3 × 10 mL). The organic layer was dried over anhydrous MgSO 4 and evaporated under reduced pressure to obtain the product (1.82 g). The crude product obtained was column chromatographed on silica gel (hexane-EtOAc = 10:1) to afford the pure product (6b, 1.41 g, 47%).
Compound 6b: mp 81-83 ℃. LC-EIMS: m/z = 203 [MH] . 1 H-NMR (CDCl 3 ) δ 7.79(1H, d, J = 2.1 Hz), 7.75 (1H, dd, J = 8.4, 2.1 Hz), 7.43 (1H, s, br), 6.91 (1H, d, J = 8.4 Hz), 5.30-5.36 (1H, m), 3.40 (2H, d, J = 4.2 Hz), 2.57 (3H, s), 1.76 (6H, s). 13 C-NMR (CDCl 3 ) δ 198.68, 159.73, 134.17, 130.76, 129.36, 128.81, 127.86, 121.29, 115.17, 28.80, 26.18, 25.69, 17.78.
Licochalcone B and D (1 and 2). Compound 5 (1.0 eq) and intermediate 6a or 6b (1.1 eq) were dissolved in anhydrous EtOH, cooled by ice-water bath, then anhydrous 2.0 M HCl-EtOH (6 eq) was added slowly to the stirred solution. The mixture was continuously stirred for 15-20 h at 0 °C. When the starting martial 6a or 6b disappeared (monitored by TLC), then the mixture was kept stirring at room temperature for 8-12 h. HCl and EtOH solvent were removed under reduced pressure, and the residue was then extracted with EtOAc, washed with H 2 O, saturated aqueous NaHCO 3 solution, and H 2 O. After the extracted organic layer was dried over MgSO 4 , and filtered, the solvent was removed under reduced pressure. Licochalcone B ( 1 ) or licochalcone D ( 2 ) was obtained as a yellow solid after silica gel column chromatography using mixture of chloroformmethanol- acetic acid (200:4:1) as an eluent.
Licochalcone B (1, 62%): mp 196-198 ℃. LC-EIMS: m/z = 285 [M-H] . 1 H-NMR (DMSO- d 6 ) δ 8.00 (2H, d, J = 8.7 Hz), 7.84 (1H, d, J = 15.9 Hz), 7.66 (1H, d, J = 15.9 Hz), 7.33 (1H, d, J = 8.7 Hz), 6.88 (2H, d, J = 8.7 Hz), 6.62 (1H, d, J = 8.4 Hz), 3.77 (3H, s). 13 C-NMR (DMSO- d 6 ) δ 187.27, 172.53, 162.01, 149.90, 148.63, 138.47, 138.28, 130.92, 129.56, 119.48, 119.02, 118.53, 115.41, 111.82, 60.79.
Licochalcone D (2, 57%): mp 112-114 ℃. LC-EIMS: m/z = 353 [M-H] . 1 H-NMR (CDCl 3 ) δ 7.92 (1H, d, J = 15.6 Hz), 7.87 (1H, s), 7.85 (1H, d, J = 5.1 Hz), 7.54 (1H, d, J = 15.6 Hz), 7.20 (1H, d, J = 9.0 Hz), 6.89 (1H, d, J = 9.0 Hz), 6.78 (1H, d, J = 8.7 Hz), 5.65 (3H, br), 5.32-5.37 (1H, m), 3.87 (3H, s), 3.44 (2H, d, J = 7.5 Hz), 1.81 (3H, s), 1.80 (3H, s). 13 CNMR (CDCl 3 ) δ 189.34, 158.91, 147.24, 146.95, 138.73, 136.60, 135.70, 131.22, 131.09, 128.97, 127.08, 121.04, 120.74, 120.35, 115.65, 111.88, 62.27, 29.82, 25.82, 17.97.
Acknowledgements
This study was financially supported by Chonnam National University, 2011. We also thank the Korea Basic Science Institute (KBSI), Gwangju branch, for performing the NMR and analytical experiments.
References
Saitoh T. , Shibata S. 1975 Tetrahedron Lett. 16 4461 -    DOI : 10.1016/S0040-4039(00)91092-X
Kajiyama K. , Demizu S. , Hiraga Y. , Kinoshita K. , Koyama K. , Takahashi K. , Tamura Y. , Okada K. , Kinoshita T. 1992 Phytochemistry 31 3229 -    DOI : 10.1016/0031-9422(92)83481-D
Yoon G. , Jung Y. D. , Cheon S. H. 2005 Chem. Pharm. Bull. 53 694 -    DOI : 10.1248/cpb.53.694
Park E. J. , Park H. R. , Lee J. S. , Kim J. W. 1998 Planta. Med. 64 464 -    DOI : 10.1055/s-2006-957485
Yoon G. , Kang B. Y. , Cheon S. H. 2007 Arch. Pharm. Res. 30 313 -    DOI : 10.1007/BF02977611
Furusawa J.-I. , Funakoshi-Tago M. , Mashino T. , Tago K. , Inoue H. , Sonoda Y. , Kasahara T 2009 Int. Immunopharmacol. 9 499 -    DOI : 10.1016/j.intimp.2009.01.031
Tanifuji S. , Aizu-Yokota E. , Funakoshi-Tago M. , Sonoda Y. , Inoue H. , Kasahara T. 2010 Int. Immunopharmacol. 10 769 -    DOI : 10.1016/j.intimp.2010.04.007
Li Y.-J. , Chen J. , Li Y. , Li Q. , Zheng Y.-F. , Fu Y. , Li P. 2011 J. Chromatogr. A 1218 8181 -    DOI : 10.1016/j.chroma.2011.09.030
Kim S.-J. , Jun J.-G. 2013 Bull. Korean Chem. Soc. 34 54 -    DOI : 10.5012/bkcs.2013.34.1.54
Saito S. , Kawabata J. 2005 Tetrahedron 61 8101 -    DOI : 10.1016/j.tet.2005.06.040
Liu Z. , Lee W. , Kim S.-N. , Yoon G. , Cheon S. H. 2011 Bioorg. Med. Chem. Lett. 21 3755 -    DOI : 10.1016/j.bmcl.2011.04.057
Helesbeux J.-J. , Duval O. , Ruilet D. , Seraphin D. , Rondeau D. 2003 Tetrahedron 59 5091 -    DOI : 10.1016/S0040-4020(03)00733-6
Rao G. V. , Swamy B. N. , Chandregowda V. , Reddy G. C. 2009 Eur. J. Med. Chem. 44 2239 -    DOI : 10.1016/j.ejmech.2008.05.032
Kromann H. , Larsen M. , Boesen T. , Schønning K. , Nielsen S. F. 2004 Eur. J. Med. Chem. 39 993 -    DOI : 10.1016/j.ejmech.2004.07.004