Concise total synthesis of honokiol via Kumada cross coupling

Accepted Manuscript Concise total synthesis of honokiol via Kumada cross coupling Jada Srinivas, Parvinder Pal Singh, Yogesh Kumar Varma, Irfan Hyder, H.M. Sampath Kumar PII: DOI: Reference:

S0040-4039(14)00709-6 http://dx.doi.org/10.1016/j.tetlet.2014.04.084 TETL 44546

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Received Date: Revised Date: Accepted Date:

12 June 2013 23 April 2014 23 April 2014

Please cite this article as: Srinivas, J., Singh, P.P., Varma, Y.K., Hyder, I., Sampath Kumar, H.M., Concise total synthesis of honokiol via Kumada cross coupling, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet. 2014.04.084

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Graphical Abstract Concise total synthesis of Honokiol via Kumada cross coupling Jada Srinivas,1 Parvinder Pal Singh,2 Yogesh Kumar Varma,1 Irfan Hyder,1 H. M. Sampath Kumar*,1

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Concise total synthesis of honokiol via Kumada cross coupling Jada Srinivas,1 Parvinder Pal Singh,2 Yogesh Kumar Varma,1 Irfan Hyder,1 H. M. Sampath Kumar*,1 1

Natural Products Chemistry Division, Indian Institute of Chemical Technology, CSIR, Hyderabad, India 500 607. 2Indian Institute of Integrative Medicine,CSIR, Jammu-Tawi, India 180001

Abstract— A concise four-step efficient synthesis of honokiol 1 in 68% overall yield is described here. The present method involves tetrakis(triphenylphosphine)palladium [Pd(Ph3)4] catalyzed Kumada coupling in two key steps. First coupling generates biaryl backbone intermediate 5 and second generates 2,4′-O-dimethylhonokiol 3. Final demethylation under AlCl3/DMS condition affords honokiol in quantitative yield. Keywords: Honokiol, Kumada coupling, Tetrakis(triphenylphosphine)palladium, Demethylation Honokiol 1 is an unsymmetrical biaryl neolignan isolated originally from Magnoliae officinalis1 and also from Magnoliae abovota.2 Honokiol rich extracts have long been used in the traditional Chinese and Japanese medicine system for the treatment of various of ailments. Honokiol itself has been explored for various biological activities and shown various potent activities3-7 such as anxiolytic, antithrombotic and anti-depressant, antiemetic, antibacterial, antiviral, anticancer and antiinflammatory. Till now, honokiol was obtained through natural sources but its isolation has been quite cumbersome because of the presence of its other constitutional isomer magnolol 2 which has similar Rf value.8 In view its potential pharmacological importance, world wide effort has been made to evolve new synthetic routes for this compound, as an alternative to the natural source and also, in order to explore the possibility of generating the diversity around the scaffold through appropriate chemistry.9-12 The interesting pharmacological profiles of these unsymmetrical biaryl compounds led to the development of various synthetic routes. Till date four synthetic strategies have been developed for honokiol and still there is a need to evolve simple and high yielding strategy for its preparation.

OH

OH

OH

OH

1 (Honokiol )

2 (Magnolol)

Fig 1: Structures of biaryl neolignans

The first synthesis of honokiol was reported by Tobinaga et al., in 1986 with overall yield of 15.6% in 4 steps, which employed Grignard reaction with quinol acetate to provide biphenyl compound followed by Claisen rearrangement.9 The second synthesis was reported by Esumi et al., in 2004 with overall yield of 21% in 14 steps which employed Suzuki–Miyaura coupling as a key step.10 The third synthesis was reported by Chen and Liu with improved yields (32%), which involved Suzuki cross-coupling as a key step.11 The fourth method was developed by Denton et al., in 2010 wherein honokiol was synthesized in four steps with overall yield of 55%.12 Moreover, two more methods were reported in

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the literature for the synthesis of 4′-O-methyl honokiol.13-14 In continuation of our recent finding towards the synthesis of novel biaryl neolignan and their analogs,15 we envisioned that synthesis of honokiol could be achieved in concise manner with good overall yield from economical and simple commercially available starting material as per the retro-synthetic scheme shown in Fig 2. As per our strategy, we started our synthetic route from commercially available starting materials viz., 2-bromoanisole 6 and 4-iodoanisiole 7. In our strategy, the key step is Kumada C-C bond forming cross coupling reaction which generates the required biaryl backbone.16

Fig 2: Retro-synthetic strategy for synthesis of honokiol

First, the 2-bromoanisole 6 was converted into organomagnesium intermediate and then treated with second coupling partner 4-iodoanisole 7 under Kumada C-C bond formation condition where tetrakis (triphenylphosphine) palladium {Pd(Ph3)4} was used as a source of Pd catalyst. This coupling generates the biaryl backbone intermediate 5 in a 85% yields.17 The biaryl intermediate 5 was then treated with bromine in the presence of hydrogen peroxide in acetic acid 18 gave unsymmetrical biaryl, 3′,5-dibromo2,4′-dimethoxy biphenyl 4 in 96% yield.19 The 3′,5-dibromo-2,4′-dimethoxy biphenyl 4 was converted into organomagesium species and then treated with allyl bromide under Kumada coupling condition catalyzed by Pd(PPh3)4 gave 86% of coupled product, 3′,5-diallyl-2,4′dimethoxy biphenyl 3.20 Finally honokiol 1 was obtained in near quantitative yields of 97% by

demethylation of compound AlCl3/dimethyl sulfide.21

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using

Fig 3: Scheme for the synthesis of honokiol

In summary, we have developed a concise fourstep route for the total synthesis of honokiol in high yield starting from inexpensive starting materials like 2-bromo anisole and 4iodoanisole. The overall yield obtained here (68%) is far superior to earlier reported procedures by Tobinaga9 (15 %), Esumi10 (21% in 14 steps), Chen11 (32%), Denton12 (55%). Prominent features include the two Kumada coupling steps catalyzed by Pd(PPh3)4 to generate biaryl and allyl biaryl units, high yielding bromination with Br/H2O2/AcOH and effective demethylation with AlCl3/DMS. Advantages in terms of minimal reaction steps, high overall yields and in expensive starting materials makes the present method a convenient alternative to currently available routes for the synthesis of honokiol. Acknowledgement JS and YKV thank CSIR-New Delhi for the award of fellowships. This work was partly supported by 12th FYP DENOVA (CSC0205).

References and notes 1. Fujita, M.; Itokawa, H.; Sashida, Y. Chem. Pharm. Bull. 1972, 20, 212. 2. Fukuyama, Y.; Otoshi, Y.; Miyoshi, K.; Nakamura, K.; Kodama, M.; Nagasawa, M.;

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3.

4.

5.

6.

7.

8.

Hasegawa, T.; Okazaki, H.; Sugawara, M. Tetrahedron 1992, 48, 377. a). Beom Seok, C.; Yong M, L.; Young, K.; Kihwan, B.; Chong Pyoung, C. Planta Medica 1998, 64, 367. b). Jongsung, L.; Eunsun, J.; Sungran, H.; Deokhoon, P.; Anthony, A.; Roy, H. Cosmetics & Toiletries 2009, 124, 53-54, 56-58, 60. c). Kun-Yen, H.; Chi-Cheng, C. T.; JiingSheng, H.; Chun-Ching, L. Phytotherapy Research 2001, 15(2), 139. d). Kyu Ho, B.; Kim, Y.; Kwan,Y. K.; Sun, M.; Kyun, M. N.; Young Ha, R.; Jong Pill, L.; Hwan, K. B. Archives of Pharmacal Research 2000, 23, 46. e). Ui-Joung, Y.; Quan Cheng, C.; Wen-Yi, J.; Ik-Soo, L.; Jong-Pill, H, L.; Min-Jung, C.; Byung-Sun, M.; Ki-Hwan, B. Journal of Natural Products 2007, 70, 1687. a). Kong, Z.; Tzeng, S.; Liu, Y. Bioorganic Medicinal Chemistry Letters 2005, 15, 163 and references cited therein. b). Ahn, K.W.; Sethi, G.; Shishodia, S.; Sung, B.; Arbiser, J. L.; Aggarwal, B. B. Mol. Cancer Res. 2006, 4, 621. c). Amblard, F.; Govindarajan, B.; Lefkove, B.; Rapp, K. L.; Detorio, M.; Arbisera, J. L.; Schinazib, R. F. Bioorganic Medicinal Chemistry Letters 2007, 17, 4428. (a) Matsuda, H.; Kageura, T.; Oda, M.; Morikawa, T.; Sakamoto, Y.; Yoshikawa, M. Chem. Pharm. Bull. 2001, 49, 716. b). Liou, K. -T.; Shen, Y. -C.; Chen, C. -F.; Tsao, C. -M.; Tsai, S. -K. Eur. J. Pharmacol. 2003, 475, 19. c). Tse, K. -W.; Wan, C. -K.; Shen, X. -L.; Yang, M.; Fong, W. -F. Biochem. Pharmacol. 2005, 70, 1443. Amblard, F.; Govindarajan, B.; Lefkove, B.; Rapp, K. L.; Detorio, M.; Arbiser, J. L.; Schinazi, R. F. Bioorg. Med. Chem. Lett. 2007, 17, 4428. Fukuyama, Y.; Nakade, K.; Minoshima, Y.; Yokoyama, R.; Zhai, H.; Mitsumoto, Y. Bioorg. Med. Chem. Lett. 2002, 12, 1163. Liu, L.; Wu, X.; Fan, L.; Chen, X.; Hu, Z. Analytical and Bioanalytical Chemistry 2006, 384, 1533.

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9. Takeya, T.; Okubo, T.; Tobinaga, S. Chem. Pharm. Bull. 1986, 34, 2066. 10. Esumi, T.; Makado, G.; Zhai, H.; Shimizu, Y.; Mitsumoto, Y.; Fukuyamaa, Y. Bioorganic & Medicinal Chemistry Letters 2004, 14, 2621. 11. Chen, C. M.; Liu, Y. –C. Tetrahedron Letters 2009, 50, 1151. 12. a). Denton, R. M.; Scragg, J. T.; Galofré, A. M.; Gui, X.; Lewis W. Tetrahedron 2010, 66, 8029. 13. Denton, R. M.; Scragg, J. T.; Saska, J. Tetrahedron Letters 2011, 52, 2554. 14. Kwak, J. H.; Cho, Y. A.; Jang, J. Y.; Seo, S. –Y.; Lee, H.; Hong, J. T.; Han, S. B.; Lee, K.; Kwak, Y. –S.; Jung, J. K. Tetrahedron 2011, 67, 9401. 15. Jada S.; Reddy, D. M.; Singh, P. P.; Kumar, S.; Malik, F.; Sharma, A.; Khan, I. A.; Qazi, G. N.; Kumar, H. M. S. European Journal of Medicinal Chemistry 2012, 51, 35. 16. Negishi, E. –I.; Takahashi, T.; King, A. O. Organic Syntheses 1993, Coll. Vol. 8, 430 (1988, Vol. 66, 67). 17. Synthesis of 2,4′-dimethoxy biphenyl (5): To a suspension of Mg turnings (800 mg, 33 mmol) and catalytic amount of iodine in dry THF (20 ml) was added 2-bromo anisole 6 (5.00 g, 27 mmol) dropwise over 10 min and the solution was stirred till the generation of Grignard reagent. This Grignard reagent was then added slowly to a solution containing 4-iodoanisole 7 (6.30 g,27 mmol) and tetrakis (triphenylphosphine) palladium (310 mg, 0.27 mmol) in Et2O (15 ml) at 0 oC. After the addition, the reaction mixture was stirred for 30 min before being warmed to rt and continuously stirred for 7-8 h. The reaction mixture was quenched with NH4Cl solution and then extracted with Et2O (20 ml x 3), washed with brine (15 ml x 3), dried over NaSO4 and concentrated under reduced pressure. Purification via flash column chromatography of the residue afforded 4.88 g (85%) of 2,4′-dimethoxy biphenyl 5. 1H NMR (200 MHz, CDCl3): δ 3.81 (s, 3H), 3.89 (s, 3H), 6.93-7.04 (m,

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4H), 7.30 (d, J = 5.4 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H); ESI MS: 214 (M+). 18. Wessel, T. 1997, US5654493. 19. Synthesis of 5,3′-dibromo-2,4′-dimethoxy biphenyl (4): To a solution of 2,4′dimethoxy biphenyl 5 (4 g, 18.6 mmol) and H2O2 (33% in H2O, 4.5 ml, 22.3 mmol) in acetic acid (15 ml) at 0 ºC was added bromine (1.15 ml, 21.8 mmol) dropwise. After completion of bromine addition the reaction mixture was left overnight. Then the reaction mixture was diluted with 100 ml of water and extracted with ethyl acetate (3 x 50 ml). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and evaporated in vacuum. The crude material was purified by flash chromatography to get pure 6.63 g of 5,3′dibromo-2,4′-dimethoxy biphenyl 4 with excellent yield of 96%. 1H NMR (200 MHz, CDCl3): δ 3.79 (s, 3H), 3.92 (s, 3H), 6.68 (d, J = 4.1 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 7.37-7.43 (m, 3H), 7.7 (d, J = 2.1 Hz, 1H); ESI-MS: 371.969 (M+). 20. Synthesis of 3′,5-diallyl-2,4′-dimethoxy biphenyl (3): To a suspension of Mg turnings (285 mg, 11.8 mmol), iodine (catalytic) in Et2O (15 ml) was added ,3′dibromo-2,4′-dimethoxy biphenyl 4 (2 g, 5.40 mmol) and the solution was stirred till the formation of Grignard reagent. This Grignard reagent was then slowly added to a solution containing allyl bromide (1.42 g, 11.8 mmol) and tetrakis (triphenylphosphine) palladium (124 mg, 0.1 mmol) at -8 oC in Et2O and stirred continuously for 1h at -8 oC and then warmed to rt. The reaction mixture was quenched with aqueous solution of NH4Cl and diluted with Et2O (20 ml). The organic layer was separated and washed with brine (3 x 10 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography gave 3′,5-diallyl-2,4′-dimethoxy biphenyl 3 with 86% yield (1.37 g). 1H NMR (200 MHz, CDCl3): δ 3.40 (d, J = 6.8 Hz, 2H), 3.50 (d, J = 6.3 Hz, 2H), 3.82 (s, 3H), 3.95 (s, 3H),

5.12-5.17 (m, 2H), 6.02-6.06 (m, 1H), 6.93 (dd, J = 7.2 & 4.0 Hz, 2H), 7.08 (dd, J = 8.4 & 1.7 Hz, 2H), 7.26 (s, 2H); 13C NMR (125 MHz, CDCl3): 34.3, 39.4, 57.0, 55.5, 111.0, 115.5, 115.8, 127.8, 127.9, 128.8, 129.0, 129.8, 130.2, 130.5, 132.1, 136.5, 137.8, 150.8, 157.0. ESI-MS: 294.22 (M+). 21. Synthesis of 3′,5-diallylbiphenyl-2,4′-diol (1): The solution of 3′,5-diallyl-2,4′dimethoxy biphenyl 3 (0.5 g, 1.69 mmol mmol) in DMS (2 ml) was added slowly to a solution of AlCl3 (678 mg, 5 mmol) in DMS (15 ml) at -5 oC and the temperature was maintained between -5 to 0 oC for 20 min. The reaction was then poured in ice cold water and extracted with EtOAc (20 ml x 3), washed with H2O (10 ml), dried over anhydrous Na2SO4 and concentrated in vacuo. Crystallization of the residue in ethyl acetate-hexane(3:7) afforded 1 in quantitative yield 97% (0.44 g). 1H NMR (200 MHz, CDCl3): δ 3.37 (d, J = 6.4 Hz, 2H), 3.48 (d, J = 6.3 Hz, 2H), 5.03–5.24 (m, 4H), 5.98–6.06 (m, 2H), 6.90–6.94 (m, 2H), 7.08 (d, J = 8.4 Hz, 2H), 7.3 (d, J = 7.1 Hz, 2H); 13C NMR (125 MHz, CDCl3): 151.09, 137.58, 133.24, 131.39, 131.16, 130.28, 129.87, 128.84, 128.54, 116.75, 115.84, 115.64, 39.37, 35.08; ESI-MS: 266 (M+).