Concise and practical approach for the synthesis of honokiol, a neurotrophic agent

Article abstract of DOI:10.1016/j.tetlet.2020.152229

An improved method has been developed for the synthesis of honokiol using a readily available p-bromophenol as a precursor. The key step involved in this method is ortho-lithiation facilitated by methoxymethyl ether (MOM). Other important steps are ortho-allyl phenyl ether Claisen rearrangement and a Suzuki coupling for the construction of biaryls. This method does not require pre-functionalization of aromatic ring with bromide for the generation of arylboronic acid.

Full text of DOI:10.1016/j.tetlet.2020.152229

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Concise and practical approach for the synthesis of honokiol, a neurotrophic
agent
P. Rasvan Khan, Taufiqueahmed Mujawar, P. Shekhar, G. Shankar, BV.
Subba Reddy, Ravi Subramanyam
PII:
S0040-4039(20)30696-1
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152229
TETL 152229
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
5 June 2020
4 July 2020
8 July 2020
Please cite this article as: Rasvan Khan, P., Mujawar, T., Shekhar, P., Shankar, G., Subba Reddy, BV.,
Subramanyam, R., Concise and practical approach for the synthesis of honokiol, a neurotrophic agent,
Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152229
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Graphical Abstract
Concise and practical approach for the synthesis of
honokiol, a neurotrophic agent
Leave this area blank for abstract info.
OMOM
B(OH)2
OH
OH
2
OH
OH
(1)
Honokiol
Br
3
Br

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Concise and practical approach for the synthesis of honokiol,
a neurotrophic agent
P. Rasvan Khan, a Taufiqueahmed Mujawar,a P. Shekhar,a G. Shankar,a B V Subba Reddy,a*
Ravi Subramanyama
aFluoro & Agrochemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad –500 007, India. E-mail:
basireddy@iict.res.in
bColgate Palmolive Technology Center, 909 River Road, Piscataway, NJ, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An improved method has been developed for the synthesis of honokiol using a
readily available p-bromophenol as a precursor. The key step involved in this
method is ortho-lithiation facilitated by methoxymethyl ether (MOM). Other
important steps are ortho-allyl phenyl ether Claisen rearrangement and a Suzuki
coupling for the construction of biaryls. This method does not require pre-
functionalization of aromatic ring with bromide for the generation of arylboronic
acid.
Available online
Keywords:
ortho-Lithiation, Claisen rearrangement, Suzuki
cross-coupling, honokiol
Introduction
The extracts of Magnolia have been used in Chinese traditional medicine for the treatment of
gastrointestinal disorders, allergic diseases and anxiety.1 Honokiol (1) was isolated originally from the stem
and bark extracts of Magnoliae officinalis along with its structural isomer magnolol as two primary actives.
Till date, honokiol was obtained from natural sources. However, the isolation of honokiol in pure form has
become quite difficult due to its low concentration in the extract, the presence of closely related isomers
and seasonal variations affecting its level.2 Subsequently, honokiol was also isolated from Magnoliae
obovata3 and Magnolia garrettii.4 Interest in honokiol stems from the fact that it exhibits a broad spectrum
of biological activities such as anti-tumour,5 anti-inflammatory,6 anti-viral7 and neurotrophic activity.8
Honokiol can readily cross the blood brain barrier and blood-cerebrospinal fluid barrier.9 The natural
occurrence of honokiol is too low (2-3%).10 Therefore, the synthesis of honokiol has attracted the attention
of many synthetic chemists. As a result, numerous methods have been developed for the synthesis of
honokiol.11 However, most of these methods involve the use of BBr3 or BCl3 for demethylation or for
Claisen rearrangement, which limit their use in large scale synthesis. Indeed, the formation of biaryls and
the cross-coupling of allyl and aryl groups are the major challenges for the scale-up. Interestingly, there is a
report on direct arylation of ortho-tert-butylphenol with p-bromoanisole to afford the biaryl ring using 10
12
mol% [RhCl(COD)]2 and 30 mol% P(NMe2)3. This method typically requires demethylation and de-tert-
butylation from aromatic ring. Inspired by its inherent biological activity, we reported the synthesis of
honokiol involving Grignard reaction and Claisen rearrangement as key steps.13 However, we encountered
some difficulties in the demethylation of aryl methyl ethers when performed in large scale. In addition, the
honokiol was formed as a mixture of two regioisomers during the Claisen rearrangement, which limits its

2
Tetrahedron
use for large scale synthesis. Therefore, there is a need for the development of an efficient and practical
approach for the synthesis of honokiol owing to its potent biological activity and natural scarcity. Hence,
we attempted a direct method for the ortho-lithiation of MOM protected phenyl ether to produce
arylboronic acid, which is a precursor for Suzuki coupling.
Results and Discussion
Following our interest on the large-scale synthesis, we herein report a concise and improved method for the
synthesis of honokiol starting from a readily available 4-bromophenol. Retro-synthetically, honokiol (1)
could be cleaved into two fragments aryl boronic acid 2 and 2-allyl-4-bromophenol 3. Both compounds 2
and 3 could in turn be prepared from a common precursor, 4-bromophenol 4 (Scheme 1).
OH
OH
OMOM
B(OH)2
OH
+
(1)
Br
Honokiol
2
3
OH
Br
4
Scheme 1. Retrosynthetic analysis of honokiol (1)
Accordingly, we began the synthesis of honokiol from 4-bromophenol. Thus the protection of 4-
bromophenol 4 with MOMCl using NaH in DMF at 0 C afforded the MOM ether 5 in 96% yield. Further
the cross-coupling of allyl bromide with arylmagnesium bromide, which is generated in situ from
compound 5 and magnesium in THF gave the 4-allyl derivative 6. ortho-Lithiation of compound 6 using n-
BuLi followed by borylation with B(OMe)3 at -78 C furnished the desired aryl boronic acid 2 in 88%
yield. On the other hand, the second key intermediate 3 was prepared in two steps from 4-bromophenol 4.
Treatment of compound 4 with allyl bromide using K2CO3 in acetone under reflux conditions gave the O-
allyl derivative 7 in 96% yield. The Claisen rearrangement of allyl aryl ether 7 under thermal conditions
afforded allyl derivative 3 in 97% yield. Finally, the cross-coupling of two key intermediates 2 and 3
followed by deprotection of MOM ether provided the desired honokiol (1). Accordingly, the Suzuki
coupling of boronic acid 2 with aryl bromide 3 using Pd(TPP)4 in the presence of K2CO3 in
toluene:EtOH:H2O under reflux conditions gave the unsymmetrical biaryl derivative 8 in 65% yield.
Deprotection of MOM group from compound 8 using TMSCl in methanol at 25 C afforded the honokiol
(1) in 85% yield. The spectral data and physical properties of honokiol are consistent with a natural product
(Scheme 2).

3
OMOM
OMOM
OMOM
B(OH)2
(c)
(b)
OH
(a)
Br
5
6
2
(d)
OH
Br
O
4
(e)
Br
Br
7
3
OH
OH
OH
MOMO
(f)
(g)
2
+
3
Honokiol (1)
8
Scheme 2. Synthesis of honokiol: (a) NaH, MOMCl, DMF, 0 °C, N2, 3h, 96%; (b) Mg, THF, rt then reflux, N2, 0 °C,
allyl bromide, then 70 °C, 2h, 91%; (c) n-BuLi, THF, N2, B(OMe)3, -78 °C, 2h, 88%; (d) K2CO3, acetone, N2, allyl
bromide, reflux, 4h, 95%; (e) 200-230 °C, 1h, 90%; (f) Pd(PPh3)4, N2, toluene:EtOH:H2O, K2CO3, reflux, 8h, 65%;
(g) TMSCl, MeOH, 0 °C to rt, 6h, 85%.
In summary, we have successfully demonstrated the total synthesis of honokiol in seven steps involving the
Suzuki coupling as a key step for the formation of biaryls. This method does not require pre-
functionalization of aromatic ring with bromide for making arylboronic acid. The use of MOM protection
does not require harsh conditions unlike demethylation for its removal. This method could be successfully
applied for the large-scale synthesis of honokiol.
Acknowledgements: Funding for conducting this research was provided by Colgate Palmolive Technology
Center, USA. The authors declare that there were no conflicts of interest. IICT/Pubs./2020/182.
Supplementary data
1
Characterization data, copies of H and 13C NMR spectrum of products are provided in supporting
information.
References and Notes
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B. Han, J. T. Hong, Pharmacology & Therapeutics 130 (2011) 157.
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3. Y. Fukuyama, Y. Otoshi, K. Miyoshi, K. Nakamura, M. Kodama, M. Nagasawa, T. Hasegawa, H. Okazaki, M. Sugawara,
Tetrahedron 48 (1992) 377.
4. W. Schuehly, W. Voith, H. Teppner, O..Kunert, J. Nat. Prod. 73 (2010) 1381.
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6. (a) H. Matsuda, T. Kageura, M. Oda, T. Morikawa, Y. Sakamoto, M. Yoshikawa, Chem. Pharm. Bull. 49 (2001) 716; (b)
K.-T. Liou, Y.-C. Shen, C.-F. Chen, C.-M. Tsao, S.-K. Tsai, Eur. J. Pharmacol. 475 (2003) 19; (c) K.-W. Tse, C.-K. Wan,
X.-L. Shen, M. Yang, W.-F. Fong, Biochem. Pharmacol. 70 (2005) 1443.
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Lett. 17 (2007) 4428.
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1163; (b) H. Zhai, K. Nakade, Y. Mitsumoto, Y. Fukuyama, Eur. J. Pharmacol. 474 (2003) 199; (c) T. Esmui, G. Makado,
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Chen, PLoS One. 6 (2011) e18490.
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4
Tetrahedron
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Volz, M. R. Grasso, G. W. O’Neil, Tetrahedron Lett. 54 (2013) 6125; (e) J. Srinivas, P. P. Singh, Y. K. Varma, I. Hyder, H.
M. S. Kumar, Tetrahedron Lett. 55 (2014) 4295; (f) K. Harada, C. Arioka, A. Miyakita, M. Kubo, Y. Fukuyama,
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1049.
Title: Concise and practical approach for the synthesis of honokiol, a neurotrophic agent
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that
could have appeared to influence the work reported in this article.
Highlights
 It describes an improved synthesis of honokiol.
 This method is practical and operationally simple.
 It is a highly convergent and scalable process.
 It is a first report on ortho-lithiation for honokiol.
Concise and practical approach for the synthesis of Leave this area blank for abstract info.
honokiol, a neurotrophic agent
OMOM
B(OH)2
OH
OH
2
OH
OH
(1)
Honokiol
Br
3
Br