Efficient synthesis of neurotrophic honokiol using Suzuki-Miyaura reactions

Article abstract of DOI:10.1016/j.tetlet.2014.09.040

Efficient synthesis of honokiol (1) was accomplished using two kinds of Suzuki-Miyaura reactions. The first Suzuki-Miyaura reaction was employed to couple 2-bromophenol (6) with 4-hydroxyphenylboronic acid (5), giving rise to biphenol 4, and the second co

Full text of DOI:10.1016/j.tetlet.2014.09.040

Tetrahedron Letters 55 (2014) 6001–6003
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Tetrahedron Letters
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Efficient synthesis of neurotrophic honokiol using Suzuki–Miyaura
reactions
⇑
⇑
Kenichi Harada , Chiharu Arioka, Akina Miyakita, Miwa Kubo, Yoshiyasu Fukuyama
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2014
Revised 29 August 2014
Accepted 8 September 2014
Available online 16 September 2014
Efficient synthesis of honokiol (1) was accomplished using two kinds of Suzuki–Miyaura reactions. The
first Suzuki–Miyaura reaction was employed to couple 2-bromophenol (6) with 4-hydroxyphenylboronic
acid (5), giving rise to biphenol 4, and the second coupling was used to introduce allyl groups at 5- and
30-positions of honokiol. The total synthesis of 1 was completed in 74% yield over five steps from 6, or in
83% yield over four steps from biphenol 4.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Honokiol
Neolignan
Suzuki–Miyaura reaction
Neurotrophic activity
A neolignan honokiol (1) was isolated from several species of
Magnolia plants such as Melilotus officinalis,1 Magnolia obovata,2
and Magnolia garrettii.3 (Fig. 1) In spite of its simple biphenyl struc-
ture having two hydroxy and two allyl groups, a number of diverse
biological activities were detected; antioxidant,4 antitumor,5 anti-
inflammatory,6 and antiemetic7 activities. In addition, we have
found that honokiol exhibits a significant neurite outgrowth and
neuroprotective activities in the primary cultured rat cortical neu-
rons at concentration ranging from 0.1 to 10 l
M.8 Moreover, our
structure–activity relationship study revealed that 40-hydroxy
and 5-allyl groups of 1 were crucial for neurotrophic activity.9 In
addition, honokiol was found to prevent learning and memory
impairment and cholinergic deficit in SAMP8 mice; therefore, hon-
okiol would be a therapeutic agent for various neurodegenerative
disorders such as Alzheimer’s disease and Parkinson’s disease.10
Owing to its useful pharmacological activities, synthetic studies
on 1 have been done by several research groups. In 1986, Tobinaga
and co-workers reported the first synthesis of 1.11 In 2004, we
reported the second synthesis of 1 by the Suzuki–Miyaura reaction
to connect between two kinds of arenes as a key step.9 Short syn-
theses have been followed by Liu,12 Denton,13 Chen,14 and Reddy.15
In this Letter, we report the development of a new efficient synthe-
sis of 1, which is superior to the previously reported procedures.
Figure 1. Structure of honokiol (1).
Our new synthetic strategy focused on constructing the carbon
skeleton of 1 by employing two kinds of Suzuki–Miyaura reactions.
(Scheme 1) Two allyl groups would be introduced by coupling of
dibromide 2 with allyl boronate. The dibromide would be derived
from biphenol 4 by regioselective dibromination. Although biphe-
nol 4 is commercially available from Sigma–AldrichÒ (PH002104),
4 could be obtained in one step by Suzuki–Miyaura reaction of
2-bromophenol (6) and hydroxyphenylboronic acid (5). Very
recently, Kumar et al. reported a concise total synthesis of 1, which
was similar to our new route with regard to the regioselective
dibromination at 5- and 30-positions on biphenol derivative.16
However, we have individually established this synthetic route,
and thus report our own procedure for 1.
The synthesis of 1 commenced with the preparation of biphenol
4. (Scheme 2) The Suzuki–Miyaura coupling of 2-bromophenol (6)
with 4-hydoroxyphenylboronic acid (5) was carried out with
Pd(OAc)2, DPPF, and K2CO3 in THF at 70 °C to give 4 in 89% yield.17
⇑
Corresponding authors. Tel.: +81 88 602 8436; fax: +81 88 655 3051 (K.H.); tel.:
+81 88 602 8435; fax: +81 88 655 3051 (Y.F.).
E-mail addresses: kenichi@ph.bunri-u.ac.jp (K. Harada), fukuyama@ph.bunri-u.
ac.jp (Y. Fukuyama).
http://dx.doi.org/10.1016/j.tetlet.2014.09.040
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

6002
K. Harada et al. / Tetrahedron Letters 55 (2014) 6001–6003
Scheme 1. Retrosynthetic analysis of 1.
Next, bromination of 4 in CS2 afforded dibromide 2 in 63% yield
with complete regioselectivity.18 According to the synthetic plan,
the direct Suzuki–Miyaura allylation of dibromide was examined,
together with Kumada reaction and Stille reaction. However, all
the reactions examined gave a small amount of honokiol along
with the mono-allylated compounds 7 and 8, due to the instability
of dibromide 2 and low reactivity toward the oxidative addition of
Pd(0) and Ni(0) in the Ni- and Pd-catalyzed cross couplings.
In order to improve the stability and reactivity of 2, two
hydroxy groups were acetylated to give 3 in 96% yield. (Scheme 3)
As a result, the Suzuki–Miyaura reaction of 3 proceeded cleanly to
afford the desired product 9 as a mixture of mono-acetates, which
was produced by partial hydrolysis of acetate groups. Therefore,
the crude mixture 9 was treated with LiAlH4 without purification,
then purificated by SiO2 column chromatography to give rise to
honokiol, quantitatively.19
Scheme 3. Suzuki–Miyaura reaction of diacetate 3 and complete total synthesis of
1.
Finally, the brominating step was optimized. (Scheme 4) The
yield was increased up to 83% as two step yield by directly
acetylating the crude mixture of 2 without purification.20 As
results, the total synthesis of honokiol was accomplished in 74%
from 2-bromophenol over 5 steps, or in 83% from commercially
available biphenol 4 over 4 steps. Our synthesis is simple and pre-
parative procedure with only three purifications, and the highest
yield among all of the syntheses reported to date. A large scale
synthesis of honokiol (1) using this methodology can be made to
supply sample amount enough to perform in vivo experiments
for the development of 1 as a drug for the treatment of neurode-
generative diseases.
Scheme 4. Optimization of the procedure from 4 to 3.
Acknowledgments
We thank Dr Yasuko Okamoto for measuring mass spectra. This
work was supported by a Grant from the Tokushima Bunri
University for Education Reform and Collaborative Research (No.
TBU2013-2-2) and a Grant from MEXT-Senryaku for the Promotion
and Mutual Aid Corporation for Private Schools of Japan.
Scheme 2. Preparation and direct allylation of dibromide 2.

K. Harada et al. / Tetrahedron Letters 55 (2014) 6001–6003
6003
1.74 mmol) at rt. After being stirred at 70 °C for 1.5 h, the reaction mixture
was filtered through CeliteÒ535RVS, washed with acetone, and concentrated in
vacuo. The residue was purified by SiO2 column chromatography eluted with
hexane/EtOAc (3:1 to 1:1) to give 4 (47.8 mg, 89%) as a colorless solid. Data of
4: 1H NMR (400 MHz, CD3OD): d 4.87 (2H, br s), 6.81 (2H, d, J = 8.8 Hz),
6.83–6.86 (2H, m), 7.07 (1H, ddd, J = 7.8, 7.4, 1.8 Hz), 7.18 (1H, dd, J = 8.0,
1.8 Hz), 7.37 (2H, d, J = 8.8 Hz); 13C NMR (100 MHz, CD3OD): d 115.8, 116.4,
116.8, 120.9, 128.4, 128.8, 129.9, 131.4, 155.1, 157.3; IR (ATR) 3383, 1608,
1517, 1455, 1362, 1102, 814 cmꢀ1; EI-MS m/z 186 [M+] (100), 169 (12), 157
(45); HR-EI-MS m/z: [M+] Calcd for C12H10O2 186.0681; Found 186.0683; mp
159.7–160.8 °C.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.09.
040.
References and notes
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M.; Hasegawa, T.; Okazaki, H.; Sugawara, M. Tetrahedron 1992, 48, 377–392.
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Tagashita, H.; Tsutsui, K.; Okada, H.; Kido, Y.; Yasui, Y.; Fukuishi, N.; Fukuyama,
Y.; Akagi, M. Brain Res. 2009, 1305, 108–117.
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Subramanyam, R. Tetrahedron Lett. 2014, 55, 1049–1051.
16. Srinivas, J.; Singh, P. P.; Varma, Y. K.; Hyder, I.; Kumar, H. M. S. Tetrahedron Lett.
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18. Hazlet, S. E.; Kornberg, H. A. J. Am. Chem. Soc. 1941, 63, 1890–1892.
19. To a solution of 3 (15.6 mg, 36.6
220 mol), and CsF (22.3 mg, 146
(8.5 mg, 7.36 mol). The reaction was stirred at 70 °C for 16 h, the reaction
l
mol), allylboronic acid pinacol ester (41.5
lL,
l
lmol) in THF (1.00 mL) was added Pd(PPh3)4
l
mixture was filtered through CeliteÒ 535RVS and concentrated in vacuo. The
residue (55.7 mg) was dissolved in THF (5.00 mL). LiAlH4 (55.7 mg, 1.47 mmol)
was added to the reaction mixture at 0 °C. The reaction mixture was stirred for
14 h at the same temperature. The reaction was quenched with aq. potassium
sodium tartrate solution and then extracted with EtOAc, washed with brine,
dried over Na2SO4, and concentrated in vacuo. The residue was purified by SiO2
column chromatography eluted with hexane/EtOAc (4:1) to give honokiol
(9.7 mg) as a colorless solid. The spectral data (1H NMR, 13C NMR, IR, MS) of
synthesized 1 was identical to those of the natural product and previous
synthesized 1 (Ref. 9).
20. To a solution of 4 (200 mg, 1.08 mmol) in CS2 (11.0 mL) was added bromine
(128 lL, 2.47 mmol) at 0 °C. The reaction mixture was stirred for 14 h at the
same temperature. The reaction was quenched with sat. Na2SO3 solution and
then extracted with DCM, washed with brine, dried over Na2SO4, and
concentrated in vacuo. The crude mixture (390 mg) was dissolved in
pyridine (11.0 mL). Ac2O (534 lL, 5.67 mmol) was added to the solution.
After being stirred for 10 h at rt, the reaction mixture was concentrated in
vacuo. The residue was purified by SiO2 column chromatography eluted with
toluene/EtOAc (13:1) to give diacetate 3 (554 mg, 83%) as a colorless solid. Data
of 3: 1H NMR (400 MHz, CDCl3): d 2.12 (3H, s), 2.38 (3H, s), 7.03 (1H, d
J = 8.3 Hz), 7.18 (1H, d, J = 8.4 Hz), 7.35 (1H, dd, J = 8.4, 2.1 Hz), 7.51 (1H, dd,
J = 8.3, 2.3 Hz), 7.52 (1H, d, J = 2.3 Hz), 7.66 (1H, d, J = 2.1 Hz); 13C NMR
(100 MHz, CDCl3): d 20.8, 20.8, 116.2, 119.5, 123.7, 124.8, 128.9, 132.1, 133.4,
133.5, 134.5, 135.5, 146.8, 148.0, 168.4, 169.0; IR (ATR) 1766, 1496, 1252, 859,
843, 592, 441 cmꢀ1; EI-MS m/z 430 [M+] (5), 428 [M+] (9), 426 [M+] (5), 344
(100); HR-EI-MS m/z: [M+] Calcd for C16H12O479Br2 425.9102; Found 425.9099;
mp 108.4–109.6 °C.
17. To a solution of 2-bromophenol (50.0 mg, 289
lboronic acid (80.0 mg, 580 mol) in THF (3.00 mL) was added Pd(OAc)2
(13.0 mg, 57.9 mol), DPPF (32.2 mg, 58.1 mol), and K2CO3 (240 mg,
lmol) and 4-hydroxypheny
l
l
l