Facile Synthesis of Licochalcone C

Abstract

Licochalcone C was synthesized from commercially available 2,4-dihydroxybenzaldehde by using regioselective $Al_2O_3$-mediated C-prenylation followed by conventional Claisen-Schmidt condensation in basic condition.

Introduction

Glycyrrhiza inflata is the main species in licorice and contains several licochalcones showing various biological properties, including antibacterial,1 antitumor,2 anti-inflammatory, 3 and antioxidative4 activities. Of which licochalcone C (1) has been known as antioxidant based on the results that it reduces the production of superoxide radicals and consequently reduces the activity of inducible nitric oxide synthase (iNOS) via inhibition of nuclear facor kappa B (NF-kB) activation.5 Licochalcone C also has been known as strong inhibitor against PTP1B enzyme.6 However, the study of biological activities for licochalcone C has not been fully elucidated because of the low isolated yield (15 mg) from 2 kg of powdered Glycyrrhiza glabra.5 Also, the chemical synthesis of licochalcone C in the literature has been reported by only two, but one procedure7 used commercially unavailable starting material and the other synthesis8 showed a low total yield (6% with 4 steps).

Water-accelerated [3,3]-sigmatropic rearrangement reaction has been introduced in the licochalcone A synthesis9 in our group, and also utilized for the synthesis of licochalcone D10 and E.11 As long as the necessity of large quantities of licochalcone C for its biological studies, the synthetic challenge is required by using water-accelerated [3,3]-sigmatropic rearrangement reaction or other methods.

 

Results and Discussion

Water-accelerated [3,3]-sigmatropic rearrangement of chalcone 2 produced regioselectively only 3 in licochalcone A synthesis,9 however, chalcone 4 failed to give the desired product 5 for licochalcone C synthesis in every efforts with different conditions and protecting groups (Scheme 1). It is noteworthy that only the MOE protected 4 produced the desired product 5 in the [3,3]-sigmatropic rearrangement condition, but it was also decomposed in the course of the deprotection step.

Scheme 1.Regioselective prenylation in water-accelerated [3,3]- sigmatropic rearrangement reaction.

Figure 1.Structure of licochalcones C, A, D and E.

Regioselective C-prenylation of phenol 6 is a key step in the licochalcone C synthesis, and several attempts instead of sigmatropic rearrangement were applied with prenylating agent 7 in various conditions as shown in Table 1. n-BuLi (entry 1)12 or DBU condition (entry 2)13 showed no expected product, however prenylation promoted by aluminum oxide (entry 3)14 produced the desired product 8 in 21% yield. Aluminum oxide complex with BaO (entry 4) or ZnO (entry 5) also gave the same product in similar yield. Friedel-Crafts reaction using Lewis acids (entries 6-8)15 did not give the prenylated product. Strong base condition using KOH (entries 9-10)16 gave only undesired regioisomer 9.

Table 1.C-Prenylation reaction of phenol 6

Licochalcone C is synthesized from the C-prenylated product 8 prepared using Al2O3, thus regioselective protection of 8 to 10 in 95% yield followed by methylation using K2CO3 with MeI to give 11 in 81% yield, and base-mediated Claisen-Schmidt condensation with acetophenone 12 allowed the chalcone 13 in 59% yield (Scheme 2). Finally, pyridinium p-toluenesulfonate (PPTs)-mediated deprotection produced the licochalcone C in 69% yield, without having any decomposed problems. The synthetic licochalcone C was crystallized as yellow needles and mp was 197-199 ℃, which was never reported in the previous reports. Even though 1H NMR data of the product were well matched with the references,5,8 but the 13C NMR data were quite different with those in the reference.8 There are 14 sp2 with 5 sp3 carbons in the reference, while we reports 15 sp2 with 4 sp3 carbons in the 13C NMR data.

Scheme 2.Synthesis of licochalcone C (1).

In summary, we prepared licochalcone C by using Al2O3- mediated C-prenylation, regioselective protection and methylation, followed by conventional Claisen-Schmidt condensation in basic condition. Direct water-accelerated [3,3]- sigmatropic rearrangement reaction of chalcones could not be employed in the licochalcone C synthesis due to the decomposition problems, however we found the regioselective C-prenylation using Al2O3 for a new additional licochalcone C synthesis

 

Experimental

All chemicals were purchased from Sigma-Aldrich Chemicals and were used without further purification unless noted otherwise. NMR spectra were recorded at Varian Mercury- 300 MHz FT-NMR and 75 MHz for 13C, with the chemical shift (δ) reported in parts per million (ppm) relative to TMS and the coupling constants (J) quoted in Hz. CDCl3 was used as a solvent and an internal standard. Mass spectra were recorded using a JMS-700 (JEOL) spectrometer. Melting points were measured on a MEL-TEMP II apparatus and were uncorrected. Thin-layer chromatography (TLC) was performed on DC-Plastikfolien 60, F254 (Merck, layer thickness 0.2 mm) plastic-backed silica gel plates and visualized by UV light (254 nm) or staining with p-anisaldehyde.

2,4-Dihydroxy-3-(3-methylbut-2-en-1-yl)benzaldehyde (8). To a 2,4-dihydroxybenzaldehyde (6) (100 mg, 0.66 mmol), Al2O3 (5 g, 49 mmol) in diethyl ether (50 mL) was added 1-bromo-3-methyl-2-butene (7) under nitrogen atmosphere and stirred for 72 h at rt. Al2O3 was filtered by glass filter. The reaction mixture was extracted with CH2Cl2, dried over anhydrous Na2SO4, concentrated in vacuo, and purified by silica gel flash column chromatography (EtOAc/hexane = 1/5) to give a clean white solid (30 mg, 21%). Rf 0.42 (EtOAc/hexane = 1/3); mp 119-121 ℃; 1H NMR (300 MHz, CDCl3) δ 11.70 (1H, s), 9.64 (1H, s), 7.28 (1H, d, J = 9.0 Hz), 6.65 (1H, br s), 6.47 (1H, d, J = 9.0 Hz), 5.25 (1H, t, J = 6.3 Hz), 3.42 (2H, d, J = 6.0 Hz), 1.82 (3H, s), 1.75 (3H, s). 13C NMR (75 MHz, CDCl3) δ 194.4, 162.3, 161.6, 135.5, 133.4, 120.7, 115.0, 114.0, 108.8, 25.8, 21.5, 18.0.

2-Hydroxy-3-(3-methylbut-2-en-1-yl)-4-[(tetrahydro-2H-pyran-2-yl)oxy]benzaldehyde (10). To a 2,4-dihydroxy- 3-(3-methylbut-2-en-1-yl)benzaldehyde (8) (34 mg, 0.16 mmol), PPTs (4 mg, 0.02 mmol) in CH2Cl2 (3 mL) was added slowly DHP (16 mg, 0.19 mmol) under nitrogen atmos-phere and stirred for 4 h at rt. The reaction mixture was extracted with CH2Cl2, dried over anhydrous MgSO4, concentrated in vacuo, and purified by silica gel flash column chromatography (EtOAc/hexane = 1/3) to give a yellow solid (47 mg, 95%). Rf 0.70 (EtOAc/hexane = 1/3); mp 40 ℃ ; 1H NMR (300 MHz, CDCl3) δ 11.45 (1H, s), 9.68 (1H, s), 7.30 (1H, d, J = 8.7 Hz), 6.77 (1H, d, J = 8.7 Hz), 5.23 (1H, t, J = 6.9 Hz), 4.94 (1H, t, J = 4.8 Hz), 3.81 (1H, d, t, J = 11.1, 2.7 Hz), 3.61 (2H, d, J = 7.2 Hz), 3.39 (1H, t, J = 7.8 Hz), 1.78 (3H, s), 1.71 (6H, m), 1.67 (3H, s). 13C NMR (75 MHz, CDCl3) δ 194.6, 161.3, 160.9, 133.0, 131.6, 121.8, 117.7, 115.7, 106.4, 95.8, 61.9, 30.1, 25.8, 25.1, 21.8, 18.4, 17.9.

2-Methoxy-3-(3-methylbut-2-en-1-yl)-4-[(tetrahydro-2H-pyran-2-yl)oxy]benzaldehyde (11). To a 2-hydroxy-3-(3-methylbut-2-en-1-yl)-4-[(tetrahydro-2H-pyran-2-yl)oxy]-benzaldehyde (10) (540 mg, 1.86 mmol) in acetone (15 mL) was added slowly K2CO3 (514 mg, 3.72 mmol) under nitrogen atmosphere and stirred for 10 min at rt. MeI (0.13 mL, 2.23 mmol) was added slowly to this reaction mixture and stirred for 3.5 h at rt. After completion of reaction, the solvent was evaporated. The reaction mixture was extracted with CH2Cl2, dried over anhydrous Na2SO4, concentrated in vacuo, and purified by silica gel flash column chromatography (EtOAc/hexane = 1/7) to give a yellow liquid (459 mg, 81%). Rf 0.70 (EtOAc/hexane = 1/3); 1H NMR (300 MHz, CDCl3) δ 10.18 (1H, s), 7.69 (1H, d, J = 9.0 Hz), 6.99 (1H, d, J = 9.0 Hz), 5.19 (1H, t, J = 6.9 Hz), 4.94 (1H, t, J = 4.8 Hz), 3.87 (3H, s), 3.63 (2H, d, J = 7.2 Hz), 3.49 (3H, m), 1.79 (3H, s), 1.73 (5H, m), 1.69 (3H, s). 13C NMR (75 MHz, CDCl3) δ 188.9, 162.3, 161.0, 131.5, 128.3, 124.3, 123.2, 122.5, 110.3, 95.9, 62.9, 62.0, 30.7, 25.5, 25.1, 22.8, 18.5, 18.0.

3-{2-Methoxy-3-(3-methylbut-2-en-1-yl)-4-[(tetrahydro-2H-pyran-2-yl)oxy]phenyl}-1-{4-[(tetrahydro-2H-pyran-2-yl)oxy]phenyl}prop-2-en-1-one (13). To a 2-methoxy-3-(3-methylbut-2-en-1-yl)-4-[(tetrahydro-2H-pyran-2-yl)oxy]-benzaldehyde (11) (80 mg, 0.26 mmol), 1-[4-(teterahydro- 2H-pyran-2-yloxy)pheneyl]ethanone (12) (64 mg, 0.31 mmol) in EtOH (5 mL) was added KOH (59 mg, 1.05 mmol), and stirred for 6 h at rt. After completion of reaction, the solvent was evaporated. The reaction mixture was extracted with CH2Cl2, dried over anhydrous MgSO4, concentrated in vacuo, and purified by silica gel flash column chromatography (EtOAc/hexane = 1/4) to give a yellow liquid (75.5 mg, 59%). Rf 0.73 (EtOAc/hexane = 1/3); 1H NMR (300 MHz, CDCl3) δ 7.99 (2H, d, J = 9.0 Hz), 7.98 (1H, d, J = 15.3 Hz), 7.51 (1H, d, J = 8.4 Hz), 7.50 (1H, d, J = 16.5 Hz), 7.10 (2H, d, J = 9.0 Hz), 6.95 (1H, d, J = 8.1 Hz), 5.52 (1H, t, J = 3.0 Hz), 5.49 (1H, t, J = 3.0 Hz), 5.21 (1H, t, J = 6.9 Hz), 3.85 (2H, m), 3.76 (3H, s), 3.61 (2H, d, J = 7.2 Hz), 3.41 (2H, m), 1.89 (6H, m), 1.79 (3H, s), 1.72 (6H, m), 1.68 (3H, s). 13C NMR (75 MHz, CDCl3) δ 189.0, 160.5, 158.9, 157.7, 139.6, 132.0, 131.1, 130.4, 126.8, 124.7 123.0, 121.9, 120.9, 115.9, 110.4, 96.0, 95.9, 62.3, 62.0, 61.9, 30.3, 30.2, 25.8, 25.3, 25.1, 23.3, 18.6, 18.0.

3-[4-Hydroxy-2-methoxy-3-(3-methylbut-2-en-1-yl)phenyl]- 1-(4-hydroxyphenyl)prop-2-en-1-one; Licochalcone C (1). To a 3-{2-Methoxy-3-(3-methylbut-2-en-1-yl)-4-[(tetrahydro-2H-pyran-2-yl)oxy]phenyl}-1-{4-[(tetrahydro-2H-pyran-2-yl)oxy]phenyl}prop-2-en-1-one (13) (40 mg, 0.08 mmol) in MeOH (1 mL) was added PPTs (16 mg, 0.04 mmol), and stirred for 3 h at rt. After completion of reaction, the solvent was evaporated. The reaction mixture was extracted with CH2Cl2, dried over anhydrous MgSO4, concentrated in vacuo, and purified by silica gel flash column chromatography (EtOAc/hexane = 1/3) to give a yellow needles (18 mg, 69%). Rf 0.28 (EtOAc/hexane = 1/1); mp 197-199 ℃ ; 1H NMR (300 MHz, CDCl3) δ 8.00 (1H, d, J = 15.6 Hz, H-β), 7.97 (2H, d, J = 8.1 Hz), 7.49 (1H, d, J = 15.6 Hz, H-α), 7.46 (1H, d, J = 8.7 Hz), 6.93 (2H, d, J = 8.1 Hz), 6.68 (1H, d, J = 8.7 Hz), 6.06 (2H, br s, two OHs), 5.22 (1H, t, J = 6.6 Hz), 3.74 (3H, s), 3.44 (2H, d, J = 6.6 Hz), 1.83 (3H, s), 1.75 (3H, s). 13C NMR (75 MHz, CDCl3) δ 189.6, 160.3, 159.0, 158.3, 140.0, 135.4, 131.1, 130.9, 127.1, 121.3, 121.0, 120.9, 120.2, 115.4, 112.7, 62.6, 25.9, 23.2, 18.1; EIMS m/z 338 (M+), 323 (base), 308, 252, 121, 93, 65. HRMS (EI) calcd for C21H22O4 M+ 338.1518, found 338.1519.