An expedient synthesis of honokiol and its analogues as potential neuropreventive agents

Article abstract of DOI:10.1016/j.bmcl.2011.11.030

An efficient synthesis of honokiol with Suzuki-Miyaura cross coupling obtained an overall yield of 45%. The proposed approach successfully synthesized several structurally similar alkyl, alkenyl and alkynyl analogues, seven of which showed potential neuropreventive activity against MPP⁺-induced and CHP/TBHP oxidative stress induced neuroblastoma cell death.

Full text of DOI:10.1016/j.bmcl.2011.11.030

Bioorganic & Medicinal Chemistry Letters 22 (2012) 216–221
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
An expedient synthesis of honokiol and its analogues as potential
neuropreventive agents
Subhankar Tripathi a,b, , Ming-Huan Chan b, , Chinpiao Chen a,
⇑
⇑
a Department of Chemistry, National Dong Hwa University, Hualien 97401, Taiwan
b Institute of Pharmacology and Toxicology, Tzu Chi University, Hualien, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of honokiol with Suzuki–Miyaura cross coupling obtained an overall yield of 45%.
The proposed approach successfully synthesized several structurally similar alkyl, alkenyl and alkynyl
analogues, seven of which showed potential neuropreventive activity against MPP+-induced and CHP/
TBHP oxidative stress induced neuroblastoma cell death.
Received 2 August 2011
Revised 21 October 2011
Accepted 9 November 2011
Available online 16 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Honokiol
Neuropreventive
Parkinson’s disease
Suzuki–Miyaura cross coupling
Claisen rearrangement
The search for natural sources of chemical entities with thera-
peutic and chemo-preventive activities has been a major focus of
scientific research in recent decades. Most of these natural prod-
ucts have complex structural features that inhibit rapid industrial
synthesis. Therefore, reports of structurally simple small molecule
natural products (SMNPs)1 with wide-spectrum biological activi-
ties and low toxicity are exceptionally rare in the literature.
Honokiol, a biphenolic neolignan that is isolated from the stem
bark of Magnolia species precisely meets these criteria and is
known to exhibit a wide range of biological activities, including
anticancer,2 anti-inflammatory,3 anti-viral,4 and anxiolytic proper-
ties.5 One recently discovered biological activity of honokiol has
motivated a recent surge of biological studies of the compound.
Symptoms of Parkinson’s disease (PD), which is a motor control
disorder, include akinesia, tremor, and rigidity, which are largely
attributable to a dopamine (DA) deficit in the putamen and caudate
nucleus, which is caused by dysfunction and neurodegeneration of
the dopaminergic neurons in the substantia nigra.6,7 This neurode-
generative disorder is characterized by several abnormalities,
including inflammation,8–11 mitochondrial dysfunction,12,13 iron
accumulation and oxidative stress.14–16 Considerable evidence sug-
gests that cellular oxidative damage in PD might also be caused by
nitric oxide (NO).17,18 Indeed, both human and animal studies of PD
reveal high levels of neuronal and inducible NO synthase (NOS) in
the substantia nigra.19,20
The compounds honokiol and magnolol significantly decrease
Amyloid b peptide (Ab)-induced cell death.21 Their neuroprotective
effects may involve reductions in reactive oxygen species (ROS)
production, intracellular calcium and caspase-3 activity. The syn-
thetic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP) causes a Parkinsonian syndrome in humans and animals.
Formation of ROS (e.g., superoxide or hydroxyl radicals)22 induced
by its active metabolite, 1-methyl-4-phenyl pyridinium (MPP+),
suggests that oxidative stress underlies MPTP neurotoxicity. An
MPTP-based animal model can therefore reveal compounds that
mitigate ROS effects and have potential use as neuroprotective
agents for treating PD.23 This study explores the neuroprotective
activity of honokiol and its analogues against oxidative stress
forced by CHP/TBTH and MPP+-induced neuroblastoma cell death.
Few approaches5c,24 for synthesizing honokiol 1 have been doc-
umented, and a simple high-yield strategy is still needed. This
study therefore developed a general method for synthesizing hon-
okiol 1 and several of its analogues for use in biological screening.
Retrosynthesis of 1 and its analogues reveals that the biphenolic
core is easily formed by Suzuki–Miyaura cross coupling between
the respective bromo aromatic compounds and aryl boronates or
boronic acids (Scheme 1). Hence, if the flexibility of the substitu-
ents of bromo aromatic compounds is maintained, coupling of
the same boronate 4 would enable synthesis of numerous ana-
logues that are structurally similar to honokiol 1 and would reveal
whether interacting functional groups exhibit typical biological
activities.
⇑
Corresponding authors. Tel.: +886 3 863 3597; fax: +886 3 863 0475.
E-mail address: chinpiao@mail.ndhu.edu.tw (C. Chen).
Present address: Vivekananda Mahavidyalaya, Burdwan, West Bengal 713 103,
India.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.11.030

S. Tripathi et al. / Bioorg. Med. Chem. Lett. 22 (2012) 216–221
217
R2
R3
R1
Suzuki
Miyaura
O
O
Br
B
B
OTHP
A
+
OH
B
A
MeO
3 = alkyl or
functionalized alkyl
HO
4
R
R1, R2 = allyl, propyl
or propargyl
Scheme 1. Retrosynthesis of honokiol and its analogues.
Commercially available 4-allylanisole 9 was used to synthesize
the known 2-bromo-4-allyl anisole 225 in a two-step process with
70% isolated yield. In accordance with procedures reported in the
literature,26b the other coupling component, pinacol boronate 4,
was easily obtained with an excellent yield from the corresponding
known boronic acid.26a In this study, the first attempt at cross
coupling of 2 with 4 in the presence of the Pd(II) catalyst under
Suzuki–Miyaura conditions failed to yield the desired product. In-
stead, a mixture of cis and trans isomers was obtained, presumably
via isomerization of the double bond of the allyl substituent of the
coupled product (Scheme 2). This process required the temporary
functionalization of the terminal double bond before the coupling
reaction to prevent isomeratization resulting from its interaction
with the Pd(II) catalyst. Fortunately, the Suzuki–Miyaura cross cou-
pling of dihydroxylated bromo compound 3 with 4 under the same
reaction conditions efficiently produced 5 in a nearly quantitative
yield. The terminal double bond was smoothly regenerated by an
iodide-induced demesylation–iodination–deiodination sequence
in the presence of Zn in DMF at an elevated temperature on the
crude dimesylated derivative of 5, which eventually produced the
phenol 6 with associated THP deprotection in situ.
2.5 equiv of BBr3. Therefore, honokiol 1 was synthesized (Scheme
2) at a sufficiently high overall yield (45%) for industrial synthesis.
Although Lewis and co-workers24c reported a similar approach for
synthesizing 1, the method described here is superior in terms of
the simplicity and efficiency of the intermediate synthetic steps,
which are essential for large-scale production of this synthetic
product.
Honokiol analogues were synthesized using the same method.
However, the position and functionality of the substituents of the
two aromatic rings were varied in order to determine an appropri-
ate screening for biological activity. The two strategies were (i)
using the same biphenolic framework reported in 1 but syntheti-
cally modifying the allyllic substituents and (ii) varying the posi-
tion of the aromatic coupling with flexibile positioning and
judicious synthetic modification of the substituents. Although the
hydrogenated derivatives 13, 14 and 195c,24b were also obtainable
by hydrogenation of 1, their exclusive synthetic has not been
reported in the literature.
Hydrogenation of 9 followed by bromination yielded the de-
sired chromatographically unstable bromo compound, which was
subjected to Suzuki–Miyaura cross coupling with 4 to furnish 10.
Then the compound 10 was ultimately converted to the partially-
and fully-hydrogenated analogues 13 and 14 in high yield follow-
ing the simple reaction sequence of THP deprotection, allylation,
rearrangement and demethylation by BBr3 (Scheme 3).
The other partially-hydrogenated analogue 19, an allyl group,
was generated at a later stage from its diol precursor 17, by the
same method used to generate the parent compound (Scheme 4).
The greater acidity of phenol compared to alcohol was exploited
The ortho allylic substituent was successfully incorporated by
the quantitative Et2AlCl-catalyzed Claisen rearrangement27 of the
allylic ether 7 in hexanes at room temperature. The final demeth-
ylation step by BBr3 was optimized by performing the reaction at
various temperatures with various equivalents of BBr3 because
prolonged exposure of the BBr3 to substrate produced inseparable
impurities that adversely affected the final yield. The reaction fin-
ished within 25 min with 90% yield at room temperature and with
OTHP
OTHP
OMe
OMe
OMe
Br
ii
+
(complex inseparable mixture)
84% (appox.)
2
OTHP
iii
OMe
OMe
Br
i
ii
OH
OH
OH
3
OH
5
OH
OR1
OH
O
OMe
OMe
iv
v
8: R1 = Me
vi
6
1: R1 = H
7
Scheme 2. Synthesis of compound 1. Reagents and conditions: (i) OsO4, 91%; (ii) Compound 4, PdCl2(dppf), DME, Na2CO3, 99%; (iii) (a) MsCl, TEA; (b) Zn, NaI, 85%; (iv) allyl
bromide, K2CO3, acetone; (v) Et2AlCl, 100%; (vi) BBr3, 90%.

218
S. Tripathi et al. / Bioorg. Med. Chem. Lett. 22 (2012) 216–221
OH
OH
OR1
OR
OH
OMe
OMe
v
iii
i
14
9
12 : R1 = Me
10: R = THP
ii
iv
13: R1 = H
11: R = allyl
Scheme 3. Synthesis of compounds 13 and 14. Reagents and conditions: (i) (a) H2, Pd/C, MeOH; (b) Br2, AcOH; (c) 4, PdCl2(dppf), 65%; (ii) (a) PTSA, MeOH; (b) allyl bromide,
K2CO3, acetone; (iii) Et2AlCl, 99%; (iv) BBr3, 88%; (v) H2, Pd/C, MeOH, 99%.
OR2
O
OH
R
OR1
OMe
OMe
iv
i
ii
5
OH
OH
18 : R1 = Me, R2 = Ms
19 : R1 = R2 = H
OH
15
OH
v
16 : R = allyl
iii
17 : R = propyl
Scheme 4. Synthesis of compound 19. Reagents and conditions: (i) (a) PTSA; (b) allyl bromide, 89%; (ii) Et2AlCl, 98%; (iii) H2, Pd/C, MeOH, 100%; (iv) (a) MsCl, TEA; (b) NaI,
DMF, Zn, 85%; (v) (a) BBr3; (b) NaOH, 87%.
OH
OR
O
OMe
iv
ii
i
15
O
O
O
O
O
O
21 : R = Me,
iii
22
:
R = H
20
OR
OMOM
OMOM
OR
v
HO
HO
24: R = MOM
25: R = H
vi
23
Scheme 5. Synthesis of compound 25. Reagents and conditions: (i) COCl2, 99%; (ii) Et2AlCl, 98%; (iii) BBr3, 96%; (iv) (a) MOMBr; (b) NaOH, 83%; (v) (a) NaIO4; (b) CBr4, PPh3;
(c) t-BuLi, 67%; (vi) HCl, 92%.
to obtain the allyl ether 15 with excellent yield and chemoselectiv-
ity; after rearrangement and hydrogenation, the desired propyl
group was installed at the ortho position of 15. The allyl group
was then regenerated as before, and the subsequent removal of
phenolic protections gave 19 in a satisfactory overall yield.
The versatility of intermediate 15 was confirmed by the finding
that its vicinal diol moiety could be transformed into a terminal al-
kyne through oxidative cleavage with periodate and application of
Corey–Fuchs protocol28 to the resultant aldehyde. This strategy
again failed at the BBr3 demethylation stage, which obtained a
mixture of unidentifiable products, possibly because of the
bromination29 of the terminal alkyne by BBr3. Other demethylation
methods such as those using TMSI,30 AlBr3-EtSH31 and LiI32 in
collidine and others were also attempted but resulted in either a
mixture of products or the complete recovery of starting material.
Finally, 15 was protected as a cyclic carbonate 20, which was con-
verted to two phenolic hydroxyl groups by Claisen rearrangement
and demethylation by BBr3. The phenolic hydroxyl groups of 22
were further protected as their MOM ethers (23), which were
implemented by Corey–Fuchs protocol to produce a terminal
alkyne 24 in excellent yield. Final acid treatment to remove
MOM protection successfully produced the desired analogue 25
(Scheme 5).
The intermediate 12 was used as the starting material for the
synthesis of the other alkyne analogue, 29. The 12 was converted
to diol 26 in excellent yield by successive methylation and dihydr-
oxylation with OsO4. To avoid further complications in the final
demethylation stage, the methyl ethers were cleaved after the diol

S. Tripathi et al. / Bioorg. Med. Chem. Lett. 22 (2012) 216–221
219
OMe
OR
OH
OMe
OH
OR
iv
i
ii
12
OH
O
O
OH
O
26
29
27: R = H
28: R = MOM
iii
Scheme 6. Synthesis of compound 29. Reagents and conditions: (i) (a) MeI; (b) OsO4, 89%; (ii) (a) COCl2; (b) BBr3, 86%; (iii) MOMBr, 90%; (iv) (a) NaOH, (b) NaIO4, (c) CBr4,
PPh3; (d) t-BuLi, (e) HCl, 56%.
OR
OMe
OH
OH
1
1
i
2
6
A
2
3
iv
A
+
A
A
3
Br
B
4
OR1
B
B
30
OH
OH
31 : R = Me, R1 = THP
34
35
ii
32 : R = R1 = H
iii
33 : R = R1 = allyl
Scheme 7. Synthesis of compounds 34 and 35. Reagents and conditions: (i) 4, PdCl2(dppf), DME, Na2CO3, 80%; (ii) (a) PTSA; (b) BBr3, 90%; (iii) allyl bromide, 87%; (iv) Et2AlCl.
OMe
OMe
R1O
OR2
R1O
OMe
i
ii
iv
Br
38: R1= THP
39: R1= Allyl
40: R1 = H, R2 = Me
41: R1 = Ms, R2 = Me
42
v
iii
37
36
vi
: R1 = R2 = H
Scheme 8. Synthesis of compound 42. Reagents and conditions: (i) (a) H2, Pd/C, MeOH; (b) NBS; (ii) 4, PdCl2(dppf), DME, 89%; (iii) (a) PTSA; (b) allyl bromide, 94%; (iv)
Et2AlCl, 96%; (v) MsCl, TEA, 95%; (vi) (a) BBr3; (b) NaOH, 80%.
26 had been protected by formation of its carbonate derivative, and
the target alkyne analogue 29 was produced following the same
reactions used to generate 25 (Scheme 6).
The bromo compound 44 was prepared in three steps from 3634
in excellent overall yield. The steps were sequential dihydroxyla-
tion, acetonide protection and regioselective bromination by NBS.
Removal of acetonide followed by Suzuki coupling gave the desired
biphenolic core in the analogue 51. Similar synthetic processes
smoothly produced the diallyl compound 52. We attempted to
cleave the methyl ether of 52 by BBr3 or by other established meth-
ods to obtain 51, but we did not succeed. Involvement of allyl
groups in the BBr3 reaction by initiating side reactions was sus-
pected. After its diol functionality was protected by forming its
cyclic carbonate derivative 45 as described above, Suzuki coupling
performed at a reduced temperature with a shortened reaction
time produced the coupled product 47 in 70% yield. Thereafter,
the precursor bromo compound was demethylated. Under pro-
longed exposure to the basic Suzuki conditions at high tempera-
tures, concomitant deprotection of cyclic carbonate reduced
overall yield. The remaining steps in synthesizing 51 resulted in
high yield and are elucidated in Scheme 9. The study hypothesis
was further supported by evidence that totally hydrogenated
derivative of 52 underwent smooth demethylation by BBr3, which
produced analogue 53 in excellent yield (Scheme 10, A). Analogue
55 was synthesized from commercially available bisphenol 54
using established procedures4 (Scheme 10, B).
The next set of analogues was prepared by changing the Suzuki
coupling, and the precursor bromo compounds were selected
accordingly. Therefore, the synthesis of analogues 34 and 35 began
with commercially available 3-bromo anisole 30 as the Suzuki cou-
pling precursor (Scheme 7). The Suzuki coupling product 31 was
fully deprotected to bisphenol 32, which, on allylation and Claisen
rearrangement, produced two chromatographically-separable
isomers in a 3:2 ratio and with allylic moieties in different posi-
tions in the aromatic ring A. The structure of the two regioisomers
was fully elucidated by their respective 1H NMR spectra. The
appearance of a clear singlet peak at 7.01 ppm was attributed to
the aromatic proton H-6 located between the phenolic hydroxyl
group and the aryl substituent. Although the structure was identi-
cal to that of 35, the signal from the H-3 proton of compound 34 in
ring A appeared as a triplet owing to coupling with the two adja-
cent ortho protons, which was indeed observed from its 1H NMR.
The Suzuki coupling precursors for the remaining analogues
with 4,40-biphenolic cores (42, 51, and 53), were synthesized as
described in the literature. Thus, bromo compound 37,33 obtained
in two steps from known 3-allyl anisole 3634 by sequential hydro-
genation and bromination was subjected to Suzuki–Miyaura cross
coupling with 4 to furnish 38, which was ultimately converted to
the partially-hydrogenated analogue 42 in good yield following
the simple reaction sequence, THP deprotection, allylation,
rearrangement and demethylation by BBr3 (Scheme 8).
Since phenolic compounds are known to exert cytoprotective
effects, the aim of this study was to investigate whether the new
synthetic biphenolic neolignans are neuroprotective. For this pur-
pose, two in vitro models of neuronal death were performed: (1)
the SH-SY5Y human neuroblastoma cells exposed to cumene

220
S. Tripathi et al. / Bioorg. Med. Chem. Lett. 22 (2012) 216–221
OR1
OMe
OMe
OMe
O
O
iii
ii
v
i
O
Br
O
Br
HO
45: R1= Me
36
OH
O
iv
43
: R1 = H
46
44
OR1
OMs
OMs
OH
OH
O
O
ix
O
viii
vii
OR2
OH
O
47: R1= H, R2 = THP
50
vi
49
51
48: R1 = Ms, R2 = allyl
Scheme 9. Synthesis of compounds 51. Reagents and conditions: (i) OsO4, 91%; (ii) (a) acetone, PTSA; (b) NBS, 86%; (iii) (a) PTSA; (b) COCl2, 88%; (iv) BBr3, 94%; (v) 4,
PdCl2(dppf), DME, 70%; (vi) (a) MsCl, TEA; (b) PTSA, (c) allyl bromide, 79%; (vii) (a) NaOH, (b) MsCl, TEA; (c) Zn, NaI, 76%; (viii) Et2AlCl, 97%; (ix) NaOH, 90%.
i
ii
HO
OMe
44
A
B
HO
OH
52
53
i
HO
OH
HO
OH
54
55
Scheme 10. Synthesis of compounds 53 and 55. Reagents and conditions: (A) (i) (a) HCl; (b) 4, PdCl2(dppf), DME, Na2CO3; (c) MsCl, TEA; (d) Zn, NaI; (e) allyl bromide,
acetone; (f) Et2AlCl, 62%; (ii) (a) H2, MeOH; (b) BBr3, 92%. (B) (i) (a) allyl bromide, K2CO3; (b) BCl3, CH2Cl2.
hydroperoxide (CHP) and tert-butyl hydroperoxide (TBHP), for
oxidative stress; and (2) the SH-SY5Y human neuroblastoma cells
treated with 1-methyl-4-phenylpyridium (MPP+), for neurotox-
icity. Cell death was evaluated by 3-(4,5-dimethylthiazol-2-yl)-
2,5-diphenyltetrazolium bromide (MTT) assay. CHP and TBHP are
the lipophilic form of hydrogen peroxide that approaches to the
plasma membrane causing oxidative stress and lipid peroxidation,
participating in cellular damage or death.35–37 Three hours neuro-
blastoma cell exposure to CHP and TBHP at 300 lM, cell viability
was reduced to 64% and 72%, respectively, compared with control
(Fig. 1). Administration of seven synthesized neolignans, including
honokiol (1), 13, 14, 19, 25, 34 and 55 at 10 lM to SH-SY5Y cells
30 min prior to the commencement of CHP and TBHP exposure
for 3 h significantly prevented cell death (Fig. 1). Our results
showed that these honokiol derivatives have different potencies
and efficacies to prevent neuronal cell death provoked by oxidative
stress.
Figure 1. Effects of neolignans on cell viability exposed to oxidative stress in vitro.
SH-SY5Y cells were treated with honokiol analogues at 10 M, including honokiol
(1), 13, 14, 19, 25, 34, and 55, 30 min before exposure to CHP and TBHP (300 M) for
3 h. Cell viability was assessed by MTT assay. Results are expressed as mean SEM
Parkinsonian toxins are known to be particularly toxic to dopa-
minergic neuronal cells. The exposure of SH-SY5Y neuroblastoma
cells to MPP+ (1 mM) for 24 h reduced cell viability and resulted
in cytotoxicity.38 The following experimental model of neuropro-
tection was challenged by seven synthesized neolignans, including
honokiol (1), 13, 14, 19, 25, 34 and 55 at concentrations of 10 and
l
l
(n = 3). Cell viability in control cultures was treated as 100%.
P values were
calculated using ANOVA. ⁄Indicates a significant difference from the control group,
⁄p < 0.05. #p < 0.05 versus CHP or TBHP alone treated cell groups.
30
neolignans (10–30
l
M. The cells were treated by MPP+ at the same time as
lM) for 24 h. As Figure 2 shows, the neolignans
neolignans had two hydroxyl groups in the 2- and 40-positions,
and the allyl or propyl groups were in the 5- and 30-positions
(Fig. 3). Allyl groups were at the 5- and the 30-positions of honokiol
(1) whereas propyl groups were at these positions in neolignans
14. In neolignan 19, the allyl group was at the 5-position, and
moderated the cytotoxicity of MPP+ in the culture cells in a concen-
tration-dependent manner.39 The rates of cell survival in medium
that containing 30
lM neolignan 14, 19, 13, 34 or 25 and 1 mM
MPP+ were 91%, 87%, 83%, 79% and 80%, respectively. These

S. Tripathi et al. / Bioorg. Med. Chem. Lett. 22 (2012) 216–221
221
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.11.030.
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19
25
Figure 3. The structures of compounds 1, 13, 14, 19 and 25.
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is needed.
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The authors thank National Science Council of the Republic of
China (NSC 97-2811-B-320-004) for post-doctoral fellowship to
S.T. and financially supporting this work (NSC 97-2113-M-259-
002-MY3). Ted Knoy is appreciated for his editorial assistance.