Synthetic approach to the chemical isostere of o -methyl honokiol

Article abstract of DOI:10.1055/s-0031-1290076

We established a synthetic method for the chemical isostere of the structurally unique natural product, 4-O-methyl honokiol by replacing two allyl groups with two different alkyl groups with the aim of developing synthetic analogues of the chemical isoste

Full text of DOI:10.1055/s-0031-1290076

LETTER
311
Synthetic Approach to the Chemical Isostere of O-Methyl Honokiol
Synthesis of the
C
he
m
i
n
stere of
O
-
M
g
ethyl
H
onok
h
iol ua Cui, Hak Sung Kim*
Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University,
344-2 Shinyong-Dong, Iksan, Jeonbuk 570-749, South Korea
Fax +82(63)8431581; E-mail: hankidad@wku.ac.kr
Received 19 September 2011
dunnianol.10 We were interested in synthesizing the chem-
ical isostere of O-methyl honokiol by replacing the C-3
atom with a nitrogen atom. Herein we describe the synthe-
sis of the chemical isostere of O-methyl honokiol with the
Abstract: We established a synthetic method for the chemical isos-
tere of the structurally unique natural product, 4¢-O-methyl honoki-
ol by replacing two allyl groups with two different alkyl groups with
the aim of developing synthetic analogues of the chemical isostere.
The key steps in this synthetic route are the Suzuki–Miyaura cou- stepwise introduction of two allyl groups.
pling reaction for the formation of the phenylpyridine moiety and
the Stille coupling reaction for the stepwise introduction of two allyl
groups.
3'
OMe
OMe
4'
2'
OH
OH
2
1'
Key words: honokiol, 4¢-O-methyl honokiol, chemical isostere,
Suzuki–Miyaura coupling, Stille coupling
1
5'
3
4
N
6'
6
5
Structurally fascinating natural products may serve as
subjects for new potential approaches in drug design.
Honokiol, isolated from Magnolia sp., has been exten-
sively studied because of its versatile bioactivities such as
anticancer1 and neurotrophic activity.2 O-Methyl honoki-
ol (Figure 1), a honokiol analogue found in the extract of
Magnolia virginiana leaves3 and Magnolia officinalis
stem bark,4 shows bioactivities similar to those of hono-
kiol, including anti-inflammatory effects5 and neuropro-
tective activity,6 therefore, even this compound has
gained interest in terms of its application in drug design.
In 1985, Tobinaga and co-workers reported the first total
synthesis of honokiol,7 and recently Denton and co-work-
ers presented a concise alternative synthetic method of
honokiol8 and O-methyl honokiol (1).9 Also this group
has accomplished the synthesis of the relevant compound
4'-O-methyl honokiol (1)
O-methyl honokiol isostere 2
Figure 1 Structure of honokiol analogues
In the retrosynthetic analysis shown in Scheme 1, the tar-
get isostere 2 could be prepared by halogenative allylation
on the key intermediate 3, which may be prepared by a
simple procedure like successive O-methylation and
monoiodination from bromobiphenyl 4. Coupling of pyri-
dine moiety 5 with a commercially available phenyl-
boronic acid via Suzuki–Miyaura reaction11 could yield 4.
Bromoiodopyridine 5 was synthesized from the commer-
cially available bromopyridone 6 in five steps by using
simple processes (Scheme 2). The bromoiodopyridone 712
was obtained by iodination of bromopyridone 6 using N-
OMe
OMe
OH
OBn
Stille coupling
selective monoiodination
N
N
I
Br
2
3
OH
OBn
OH
I
OH
Suzuki–Miyaura coupling
N
N
+
HO
B
Br
Br
OH
4
5
Scheme 1 Retrosynthetic analysis
SYNLETT 2012, 23, 311–313
x
x.
x
x.
2
0
1
2
Advanced online publication: 03.01.2012
DOI: 10.1055/s-0031-1290076; Art ID: U06911ST
© Georg Thieme Verlag Stuttgart · New York

312
M. Cui, H. S. Kim
LETTER
be simple, however, the monoiodination step was found to
be problematic.
BnBr, Ag2CO3
toluene
reflux, 3 h
O
O
NIS
MeCN
I
reflux, 2 h
HN
HN
The main side reaction in the monoiodination process was
the di-iodination at the two ortho positions of the methoxy
group, for which various reaction conditions were at-
tempted. As shown in Table 1,14 the best selectivity and
yield for C-5¢ monoiodination were achieved by treatment
with iodine in the presence of silver sulfate, a method pat-
ented by Sy.15
82%
90%
Br
6
Br
7
(4-hydroxyphenyl)boronic acid
Pd(dppf)Cl2, K2CO3
H2O, dioxane
OH
OBn
OBn
I
reflux, 3 h
N
N
In the Stille coupling,16 the more reactive iodo group
yielded a faster allylation reaction speed (Scheme 3).
Along with the successful one pot-allylation in moderate
yield (60%), we were able to distinguish the iodo group
from the bromo group for the stepwise introduction of two
allyl groups, which gave the diallyl compound 10 from the
monoallyl compound 9 in good yield. The final process,
debenzylation, was not successful. Double-bond migra-
tion occurred under mild acidic conditions such as in the
presence of trifluoroacetic acid (TFA)17 and HBr/AcOH,18
which were regular procedures for the O-debenzylation.
Fortunately, reductive debenzylation using lithiated di-
tert-butylbiphenyl(DTBB)19,20 was successful in furnish-
ing the final target 2.
80%
Br
5
Br
4
OMe
I
OMe
DMS, NaH
THF
r.t., overnight
OBn
OBn
I2, Ag2SO4
MeOH
r.t., 2 h
N
N
92%
80%
Br
8
Br
3
Scheme 2 Synthesis of the key intermediate 3
iodosuccinimide. The pyridone moiety was converted into
O-benzylpyridine 5 by O-benzylation of benzyl bromide
in the presence of silver carbonate as a base. The coupling
reaction of compound 5 with commercially available (4-
hydroxyphenyl)boronic acid was accomplished by using
the Suzuki–Miyaura coupling,13 to readily obtain 3-phe-
nylpyridine 4 in 80% yield. The successive O-methylation
and monoiodination from 3-phenylpyridine 4 seemed to
As shown in Scheme 2, two different halogen groups in 3-
phenylpyridine 3 can exist as mechanistic attractive sub-
stituents for introducing two different alkyl groups on the
basis of their unique differences in chemical reactivity,
which may have great chemical merit for their synthetic
application in the development of a variety of analogues.
allyltributyltin
allyltributyltin
Pd(PPh3)4
OMe
Pd(PPh3)4
DMF
OMe
OBn
OBn
Br
benzene
110 °C, 3 h
130 °C, 2.5 h
N
N
I
80%
72%
Br
3
9
OMe
OMe
Li, DTBB
THF
–78 °C, 5 min
OBn
OBn
N
N
79%
10
2
Scheme 3 Synthesis of O-methyl honokiol isostere 2
Table 1 Iodination of 3-(4-Methoxyphenyl)pyridine 9a
Entry
Reagents
NaI, NaOCl, NaOH
NaI, I2, H2O
NIS, H2SO4
NIS, I2
Solvent
MeOH
NH4OH
AcOH
Time (h)
Product
Yield (%)
1
2
3
4
5
1
20
20
2
3¢,5¢-diiodo product
3¢,5¢-diiodo product
3¢,5¢-diiodo product
3¢,5¢-diiodo product
5¢-monoiodo product
61
46
70
37
80
MeOH
MeOH
I2, Ag2SO4
1.5
a Reaction temperature: r.t.
Synlett 2012, 23, 311–313
© Thieme Stuttgart · New York

LETTER
Synthetic of the Chemical Isostere of O-Methyl Honokio
313
(5) Oh, J. H.; Kang, L. L.; Ban, J. O.; Kim, Y. H.; Kim, K. H.;
Han, S. B.; Hong, J. T. Chem. Biol. Interact. 2009, 180, 506.
(6) Lee, J. W.; Lee, Y. K.; Lee, B. J.; Nam, S.-Y.; Lee, S. I.;
Kim, Y. H.; Kim, K. H.; Oh, K.-W.; Hong, J. T. Pharmacol.
Biochem. Behav. 2010, 95, 35.
OMe
I
OMe
R2
OBn
N
OBn
stepwise introduction
of two alkyl groups
N
(7) Takeya, T.; Okubo, T.; Tobinaga, S. Chem. Pharm. Bull.
Br
R1
R1, R2 = alkyl
1986, 34, 2066.
(8) Denton, R. M.; Scragg, J. T.; Galofré, A. M.; Gui, X.-C.;
Lewis, W. Tetrahedron 2010, 66, 8029.
(9) Denton, R. M.; Scragg, J. T.; Saska, J. Tetrahedron Lett.
2011, 52, 2554.
Scheme 4 The applicability of the successive introduction of two
different alkyl groups
(10) Denton, R. M.; Scragg, J. T. Synlett 2010, 633.
(11) Chen, C.-M.; Liu, Y.-C. Tetrahedron Lett. 2009, 50, 1151.
(12) Angela, M.; Rodriguez, J. F.; Sanz-Tejedor, M. A.; Garcia-
Ruano, J. L. Synlett 2003, 1678.
(13) For recent reviews of Suzuki–Miyaura coupling, see:
(a) Suzuki, A. Proc. Jpn. Acad., Ser. B. 2004, 80, 359.
(b) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002,
58, 9633.
In conclusion, we achieved the synthesis of a structurally
unique isostere 2 of O-methyl honokiol in total eight steps
with 19.8% overall yield. Evaluation of the biological ac-
tivity of the target compound 2 is under way for develop-
ing the derivatives.
(14) (a) Cowart, M.; Faghih, R.; Curtis, M. P.; Gfesser, G. A.;
Bennani, Y. L.; Black, A. L.; Pan, L.; Marsh, K. C.; Sullivan,
J. P.; Esbenshade, T. A.; Fox, G. B.; Hancock, A. A. J. Med.
Chem. 2005, 48, 38. (b) Pu, Y.-M.; Grieme, T.; Gupta, A.;
Plata, D.; Bhatia, A. V.; Cowart, M.; Ku, Y.-Y. Org. Process
Res. Dev. 2005, 9, 45.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
(15) Sy, W.-W. Tetrahedron Lett. 1993, 34, 6223.
(16) (a) Heguaburu, V.; Mandolesi Sa, M.; Schapiro, V.;
Pandolfi, E. Tetrahedron Lett. 2008, 49, 6787. (b) Vaz, B.;
Alvarez, R.; R. de Lera, A. J. Org. Chem. 2002, 67, 5040.
(c) Hoyt, S. B.; London, C.; Park, M. Tetrahedron Lett.
2009, 50, 1911.
This research was supported by Wonkwang University in 2010.
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Synlett 2012, 23, 311–313

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