Synthesis of Magnolignan, a New Pigment Lightening Component, via a Suzuki-Miyaura Reaction

Narita, Shuhei; Ogura, Tetsuhiro; Usuki, Toyonobu

doi:https://doi.org/10.1155/2013/686242

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Research Article | Open Access

Volume 2013 | Article ID 686242 | https://doi.org/10.1155/2013/686242

Synthesis of Magnolignan, a New Pigment Lightening Component, via a Suzuki-Miyaura Reaction

Shuhei Narita,¹Tetsuhiro Ogura,¹and Toyonobu Usuki¹

Academic Editor: Lorenzo Cerretani

Received25 Apr 2012

Revised10 Jul 2012

Accepted10 Jul 2012

Published07 Aug 2012

Abstract

Magnolignan, 2,2′-dihydroxy-5,5′-dipropyl-biphenyl (1), is a down-regulator of melanin synthesis that inhibits the maturation of tyrosinase. In this study, a concise total synthesis of 1 was achieved in five steps with 50% overall yield starting from commercially available trans-anethole (2) via a Suzuki-Miyaura reaction.

1. Introduction

Various treatments with melanin synthesis inhibitors, lasers, and chemical peels have been investigated to achieve lightening effects for pigmented skin in the field of cosmetics. In particular, melanin synthesis inhibitors, such as hydroquinone, have been shown to be an effective treatment of melasma and a prophylactic agent for hyperpigmentation [1]. Melanin synthesis inhibitors have been widely used as lightening components in cosmetic formulations. While hydroquinone has a remarkable lightening effect, its strong bleaching action causes skin irritation. Therefore, alternative hydroquinone derivatives that have a mild or nonirritating effect have been investigated.

Researchers at Kanebo Cosmetics Co. Ltd., Japan, have proved that compounds with a biphenol framework are extraordinarily effective as melanin synthesis inhibitors [2]. Structure-activity relationship (SAR) studies of biphenol compounds strongly suggested that 2,2′-dihydroxy-5,5′-dipropyl-biphenyl (1, Figure 1), also known as magnolignan or tetrahydromagnolol, has a greater lightening effect than the natural products magnolol and honokiol, which are isolated from the bark of Magnolia officinalis or M. obovata [3]. The lightening effect of magnolignan 1 was validated by several bioassays, such as the de novo melanin synthesis [4], the tyrosine hydroxylase assay [5], and melanin measurements [6]. For these studies, the new lightening compound 1 was synthesized using the oxidative coupling method previously reported by Sartori and co-workers [7]. Here, in this paper, a concise total synthesis of magnolignan 1 is described. The key step in the synthesis is a Suzuki-Miyaura reaction [8] in water.

2. Experimental

2.1. General Procedures

All nonaqueous reactions were conducted under an atmosphere of nitrogen with magnetic stirring. Tetrahydrofuran (THF), dichloromethane (CH₂Cl₂), acetonitrile (MeCN), and diethyl ether (Et₂O) were dried by distillation and stored over activated molecular sieves. Dehydrated methanol (MeOH) was purchased from Kanto Chemical (Tokyo, Japan). Dimethyl sulfoxide (DMSO) was purchased from Wako Pure Chemical Industries (Osaka, Japan). All reagents were obtained from commercial suppliers and used without further purification unless otherwise stated. Analytical thin layer chromatography (TLC) was performed on silica gel 60 F₂₅₄ plates produced by Merck. Column chromatography was performed with acidic Silica gel 60 (spherical, 40–50 μm) or neutral Silica gel 60N (spherical, 40–50 μm) produced by Kanto Chemical.

Melting point was measured by an AS one ATM-01 apparatus. Infrared (IR) spectra were recorded on a JASCO FT-IR 4100 spectrometer and are reported in wavenumbers (cm⁻¹). ¹H and ¹³C NMR spectra were recorded on a JEOL JNM-EXC 300 spectrometer (300 MHz) or on a JEOL JNM-ECA 500 spectrometer (500 MHz). ¹H NMR data are reported as follows: chemical shift (δ, ppm), integration, multiplicity (s, singlet; d, doublet; t, triplet; m, multiplet), coupling constants (J) in Hz, and assignments. ¹³C NMR data are reported in terms of chemical shift (δ, ppm). EI-LRMS (GC-MS) spectra were recorded on a Shimadzu GCMS QP-5050 instrument. EI-HRMS spectra were recorded on a JEOL JMS-700 instrument.

2.2. 1-Methoxy-4-Propylbenzene (3)

To a suspension of 10% Pd/C (0.101 g) in MeOH (30 mL) under atmosphere of hydrogen was added 1-methoxy-4-(1-propenyl)benzene 2 (1.00 g, 6.75 mmol). After stirring for 3 h at room temperature, the reaction mixture was filtered through a pad of Celite with MeOH. Concentration in vacuo afforded 3 (0.957 g, 6.37 mmol, 94%) as a colorless oil; 0.48 (hexane/EtOAc = 20 : 1); IR (neat) 2947, 2063, 1879, 1610, 1509, 1456, 1248, 1179, 1110, 1038, 821, 748, 699, 553 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.10 (2H, d, Hz, ArH), 6.83 (2H, d, Hz, ArH), 3.87 (3H, s, OMe), 2.51 (2H, t, Hz, CH₂), 1.54–1.64 (2H, m, CH₂), 0.92 (3H, t, Hz, CH₃); ¹³C NMR (75 MHz, CDCl₃) δ 157.8, 134.9, 129.4, 113.7, 55.3, 37.2, 24.9, 13.9; GC-MS (m/z) calcd for C₁₀H₁₄O [M]⁺ 150.10, found 150.05.

2.3. 2-Bromo-1-Methoxy-4-Propylbenzene (4)

To a solution of -bromosuccinimide (0.498 g, 2.80 mmol, 1.2 eq) in MeCN (8.75 mL) was added 1-methoxy-4-propylbenzene 3 (0.351 g, 2.34 mmol, 1.0 eq). After stirring for 3 h at room temperature, the reaction mixture was concentrated in vacuo, and washed with CCl₄. Concentration in vacuo afforded 4 (0.521 g, 2.27 mmol, 97%) as a colorless oil; 0.61 (hexane/EtOAc = 20 : 1); IR (neat) 2957, 1602, 1495, 1262, 1187, 1150, 1054, 887, 808, 747, 714, 672, 595, 556 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.36 (1H, d, Hz, ArH), 7.06 (1H, dd, , 2.1 Hz, ArH), 6.81 (1H, d, Hz, ArH), 3.87 (3H, s, OMe), 2.51 (2H, t, Hz, CH₂), 1.54–1.64 (2H, m, CH₂), 0.92 (3H, t, Hz, CH₃); ¹³C NMR (75 MHz, CDCl₃) δ 153.9, 136.4, 133.2, 128.4, 111.9, 111.4, 56.3, 36.8, 24.6, 13.7; GC-MS (m/z) calcd for C₁₀H₁₃BrO [M]⁺ 228.01, found 227.95; EI-HRMS (m/z) calcd for C₁₀H₁₂BrO [M-H]⁻ 227.0072, found 227.0072.

2.4. 1-Methoxy-4-Propyl-2-(4,4,5,5-Tetramethyl-[1,3,2]Dioxaborolan-2-yl)Benzene (5)

To a mixture of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (47.7 mg, 0.0655 mmol, 5 mol%), bis(pinacolato)diboron (399 mg, 1.57 mmol, 1.2 eq), and potassium acetate (386 mg, 3.93 mmol, 3.0 eq) was added 2-bromo-1-methoxy-4-propylbenzene 4 (300 mg, 1.31 mmol, 1.0 eq) in DMSO (4.5 mL). After stirring for 24 h at 80°C, the reaction mixture was diluted with toluene and quenched with H₂O. The aqueous layer was then extracted with toluene. The combined organic layers were washed with H₂O, dried over Na₂SO₄, and concentrated in vacuo. Purification by silica gel column chromatography (hexane/EtOAc = 20 : 1) afforded 5 (110.3 mg, 0.399 mmol, 31%), 6 (17.0 mg, 0.0616 mmol, 5%), and 4 (69.3 mg, 0.303 mmol, 23%). 5 was obtained as a brown oil; 0.4 (hexane/EtOAc = 5 : 1); IR (neat) 3517, 2967, 1736, 1602, 1348, 1148, 1037, 963, 915, 853, 819, 752, 676, 581 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.47 (1H, d, Hz, ArH), 7.19 (1H, dd, , 2.4 Hz, ArH), 6.78 (1H, d, Hz, ArH), 3.80 (3H, s, OMe), 2.52 (2H, t, Hz, CH₂), 1.55–1.64 (2H, m, CH₂), 1.35 (12H, s, Bpin), 0.92 (3H, t, Hz, CH₃); ¹³C NMR (75 MHz, CDCl₃) δ 162.5, 136.8, 136.7, 132.4, 110.5, 83.5, 56.0, 55.6, 37.1, 24.9, 13.9; GC-MS (m/z) calcd for C₁₆H₂₅BO₃ [M]⁺ 276.18, found 275.95; EI-HRMS (m/z) calcd for C₁₆H₂₅BO₃ [M]⁺ 276.1897, found 276.1895.

2.5. 2,-Dimethoxy-5,5′-Dipropyl-Biphenyl (6)

To a mixture of 2-bromo-1-methoxy-4-propylbenzene 4 (41.3 mg, 0.180 mmol, 1.0 eq), 1-methoxy-4-propyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzene 5 (49.6 mg, 0.180 mmol, 1.0 eq), and tetrakis(triphenylphosphine)palladium(0) (10.4 mg, 9.00 μmoL, 5 mol%) was added potassium carbonate (74.6 mg, 0.54 mmol, 3.0 eq) in THF (2.0 mL). After stirring for 8 h at reflux, the reaction mixture was concentrated in vacuo and extracted with CH₂Cl₂. The combined organic layers were washed with H₂O, dried over Na₂SO₄, and concentrated in vacuo. Purification by silica gel column chromatography (hexane/EtOAc = 20 : 1) afforded 6 (7.7 mg, 0.0258 mmol, 14%) as a yellow oil; 0.38 (hexane/EtOAc = 10 : 1); IR (neat) 2955, 2052, 1727, 1605, 1497, 1244, 1175, 1141, 1037, 893, 809, 757, 634, 511 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.11 (2H, dd, , 2.3 Hz, ArH), 7.06 (2H, d, Hz, ArH), 6.88 (2H, d, Hz, ArH), 3.74 (6H, s, OMe), 2.55 (4H, t, Hz, CH₂), 1.57–1.70 (4H, m, CH₂), 0.95 (6H, t, Hz, CH₃); ¹³C NMR (75 MHz, CDCl₃) δ 155.2, 134.5, 131.7, 128.3, 127.8, 111.1, 56.0, 37.3, 24.8, 14.0; GC-MS (m/z) calcd for C₂₀H₂₆O₂ [M]⁺ 298.19, found 298.20; EI-HRMS (m/z) calcd for C₂₀H₂₆O₂ [M]⁺ 298.1933, found 298.1930.

2.6. 2-Methoxy-5-Propylphenylboronic Acid (7)

To a solution of 2-bromo-1-methoxy-4-propylbenzene 4 (200 mg, 0.873 mmol, 1.0 eq) in THF (3.6 mL) was added 1.6 M n-BuLi in hexane (0.709 mL, 1.135 mmol, 1.3 eq) at −78°C. After stirring for 5 min, triisopropyl borate (0.586 mL, 2.619 mmol, 3.0 eq) was added at −78°C and the mixture was allowed to warm up to room temperature. After stirring for 13 h at room temperature, the reaction mixture was acidified with 10% HCl aq. and extracted with EtOAc. The combined organic layers were washed with H₂O, dried over Na₂SO₄, and concentrated in vacuo. Purification by silica gel column chromatography (hexane/EtOAc = 13 : 1) afforded 7 (114.6 mg, 0.591 mmol, 68%) and 3 (23.6 mg, 0.157 mmol, 18%). 7 was obtained as a colorless powder; 0.33 (hexane/EtOAc = 3 : 1); mp 71°C; IR (KBr) 3801, 3358, 2926, 2355, 1607, 1415, 1338, 1229, 1155, 1097, 1043, 788, 679, 555 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.64 (1H, d, Hz, ArH), 7.23 (1H, d, Hz, ArH), 6.84 (1H, d, Hz, ArH), 3.89 (3H, s, OMe), 2.55 (2H, t, Hz, CH₂), 1.56–1.68 (2H, m, CH₂), 0.93 (3H, t, Hz, CH₃); ¹³C NMR (75 MHz, CDCl₃) δ 162.8, 136.8, 135.3, 132.8, 109.9, 77.3, 55.6, 37.1, 24.9, 13.9; EI-HRMS (m/z) calcd for C₁₀H₁₅BO₃ [M]⁺ 194.1114, found 194.1095.

2.7. 2,-Dimethoxy-5,5′-Dipropyl-Biphenyl (6)

To a mixture of 2-bromo-1-methoxy-4-propylbenzene 4 (50.5 mg, 0.220 mmol, 1.0 eq) and 2-methoxy-5-propylphenylboronic acid 7 (55.4 mg, 0.287 mmol, 1.3 eq) were added palladium(II) acetate (0.01 mg, 0.437 μmoL, 0.2 mol%), potassium carbonate (75.0 mg, 0.546 mmol, 2.5 eq), and tetrabutylammonium bromide (70.0 mg, 0.218 mmol, 1.0 eq) in H₂O (0.23 mL). The reaction mixture was degassed by freeze/pump/thaw techniques. After stirring for 2 h at 70°C, the reaction mixture was cooled to room temperature, diluted with H₂O, and then extracted with EtOAc. The combined organic layers were washed with H₂O, dried over Na₂SO₄, and concentrated in vacuo. Purification by silica gel column chromatography (hexane/EtOAc = 80 : 1) afforded 6 (63.7 mg, 0.213 mmol, 98%).

2.8. 2,-Dihydroxy-5,5′-Dipropyl-Biphenyl (1)

To a solution of 2,2′-dimethoxy-5,5′-dipropyl-biphenyl 6 (24.2 mg, 0.081 mmol, 1.0 eq) in CH₂Cl₂ (1.4 mL) was added 1 M boron tribromide in CH₂Cl₂ (0.406 mL, 0.406 mmol, 5.0 eq) at −78°C, then allowed to warm up to room temperature. After stirring for 1.5 h, the reaction mixture was quenched carefully with 10% HCl aq. at 0°C and extracted with Et₂O. The combined organic layers were washed with H₂O, dried over Na₂SO₄, and concentrated in vacuo. Purification by silica gel column chromatography (hexane/EtOAc = 20 : 1) afforded 1 (18.3 mg, 0.068 mmol, 83%) as a colorless powder; 0.43 (hexane/EtOAc = 3 : 1); mp 144°C; IR (KBr) 3206, 2963, 2923, 2855, 1494, 1415, 1226, 1113, 887, 818, 797, 598, 534, 436 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.13 (2H, dd, , 2.3 Hz, ArH), 7.06 (2H, d, Hz, ArH), 6.95 (2H, d, Hz, ArH), 2.57 (4H, t, Hz, CH₂), 1.60–1.67 (4H, m, CH₂), 0.95 (6H, t, Hz, CH₃); ¹³C NMR (125 MHz, CDCl₃) δ 151.0, 136.0, 131.1, 130.0, 123.4, 116.5, 37.3, 24.9, 14.0; EI-HRMS (m/z) calcd for C₁₈H₂₂O₂ [M]⁺ 270.1620, found 270.1613.

3. Results and Discussion

Starting with commercially available trans-anethole (2), the synthesis of 1 involved hydrogenation, bromination, boronation, Suzuki-Miyaura reaction, and demethylation, as illustrated in Scheme 1. Initially, direct bromination of 2 using N-bromosuccinimide (NBS) was intended as the first step in the synthesis. However, this reaction did not proceed. Therefore, alkene 2 was reduced by H₂ with Pd/C to gave alkane 3 in 94% yield [9]. Obtained 3 was then converted to bromide 4 in good yield (70–80%, data not shown) using NBS and HBF₄/Et₂O in MeCN at −20°C to room temperature [10]. However, the product was a mixture of monobromide 4 and the dibromide compound. It was thought that acidic condition prompted the reactivity of the bromination. Therefore, the reaction was attempted with 1.2 equivalents of NBS without additives in MeCN at room temperature. The desired compound 4 was obtained as a single product in 97% yield [11].

Next, the transformation of bromide 4 into arylboronate ester 5 was pursued. Unfortunately, in a one pot reaction using (Bpin)₂ in the presence of 5 mol% PdCl₂(dppf) and AcOK in DMSO at 80°C, compound 5 was obtained in only 31% yield along with biaryl compound 6 in 5% yield and recovered starting material 4 in 23% yield [12]. Although the yield for compound 6 could not be improved in this reaction, biaryl product 6 was synthesized in 14% yield through a Suzuki-Miyaura cross-coupling reaction between 4 and 5 in the presence of 5 mol% Pd(PPh₃)₄ and K₂CO₃ in THF under reflux condition [13].

As an alternative strategy, arylboronic acid 7 was prepared from bromide 4 as a precursor for the Suzuki-Miyaura reaction (Scheme 1). Bromide 4 was thus converted into 7 with n-BuLi and triisopropyl borate in 68% yield, with alkane 3 as a by-product in 18% yield [14]. The Suzuki-Miyaura cross-coupling reaction between 4 and 7 then afforded biaryl product 6 in 98% yield using 0.2 mol% Pd(OAc)₂ in H₂O at 70°C in the presence of one equivalent of tetrabutylammonium bromide (TBAB) as a phase transfer catalyst [15]. This reaction was achieved as an eco-friendly system with a high yield. Finally, removal of the methyl group from 6 using BBr₃ in CH₂Cl₂ at −78°C to room temperature gave the desired magnolignan 1 in 83% yield [16]. Synthetic 1 was fully assigned by spectroscopic analysis, including ¹H NMR, ¹³C NMR, IR, and EI-HRMS [3].

In conclusion, the total synthesis of magnolignan 1, a new skin lightening component for use in cosmetics, was achieved in five steps with overall 50% yield. An aqueous Suzuki-Miyaura reaction was the key step in the synthesis. The palladium-catalyzed Suzuki-Miyaura reaction in H₂O was achieved with excellent yield, and can be considered an eco-friendly reaction. Through variation of the Suzuki-Miyaura coupling precursors, this synthetic strategy is well suited for the preparation of a wide range of magnolignan derivatives for use in further SAR studies.

Acknowledgments

The authors are grateful to Ms. Yasuko Shimizu, Sophia University, for measurement of the high-resolution mass spectra, and to Ms. Emiko Okano, Sophia University, for measurement of the NMR spectra (500 MHz).

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Copyright © 2013 Shuhei Narita et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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