A concise synthesis of 4′-O-methyl honokiol

Article abstract of DOI:10.1016/j.tetlet.2011.03.031

A concise and protecting group free synthesis of the naturally occurring neolignan 4′-O-methyl honokiol is developed. The key biaryl bond is constructed by 1,2-addition of an aryl Grignard reagent to a dienone followed by rearrangement.

Full text of DOI:10.1016/j.tetlet.2011.03.031

Tetrahedron Letters 52 (2011) 2554–2556
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A concise synthesis of 40-O-methyl honokiol
⇑
Ross M. Denton , James T. Scragg, Jan Saska
School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
a r t i c l e i n f o
a b s t r a c t
A concise and protecting group free synthesis of the naturally occurring neolignan 40-O-methyl honokiol
is developed. The key biaryl bond is constructed by 1,2-addition of an aryl Grignard reagent to a dienone
followed by rearrangement.
Article history:
Received 25 January 2011
Revised 18 February 2011
Accepted 7 March 2011
Available online 11 March 2011
Ó 2011 Published by Elsevier Ltd.
Keywords:
40-O-Methyl honokiol
Natural products
Dienone addition/rearrangement
Neolignans
Members of the genus Magnolia, from the family Magnoliaecae,
have been used in traditional folk medicine for the treatment of a
variety of ailments such as gastrointestinal disorders, allergic dis-
eases and anxiety.1 In 1991, 40-O-methyl honokiol (1) was isolated
from the leaves of Magnolia virginiana2 and later from the stem
bark of Magnolia officinalis3 and leaves of Magnolia garrettii.4 Along
with 1 were isolated, amongst others, honokiol (2),5 Magnolol (3),5
and syringin (8)6 (Fig. 1). These compounds exhibit interesting bio-
logical properties7 and have, therefore, attracted the attention of
synthetic chemists.8,9 Initial biological studies of 1 identified
potent anti-fungal and anti-bacterial activities,2 while subsequent
reports have appeared on the anti-inflammatory10 and neurotro-
phic11 activities of the natural product. The only synthesis of 1
reported to date was by Fukuyama and co-workers8b which pro-
ceeded in 3% overall yield over 15 steps. Herein, we report an alter-
native protecting group free synthesis of the natural product which
we have developed to make synthetic material available for biolog-
ical testing.
Our initial synthetic plan is outlined in Scheme 1 in retrosyn-
thetic form. The proposed route is inspired by Tobinaga’s 1986 syn-
thesis of honokiol (2)8a and involves a 1,2-addition of the Grignard
reagent derived from 10 to dienone 12 followed by rearrangement
to construct the key biaryl bond.12 The two required coupling part-
ners, 10 and 12, are derived from iodophenol 11 via a Claisen rear-
rangement and from oxidative dearomatisation of the phenol
derived from 13, respectively.
R
OMe
OH
R
3'
6'
OH
R
4' R'
5'
OMe
O
OH
2'
1'
2
R'
3
4
1
6
I
I
MeO
OH
OH
OMe
5
O
OH
10
+
11
HO
O
OH
O
OMe
1 R=H, R'=OMe
2 R=H, R'=OH
3 R=OH, R'=H
4 R=OH, R'=CH2CHCH2
5 R=OMe, R'=CH2CHCH2
6 R=OMe, R'=CHCHCHO
8 R=CH2OH
9 R=CHO
1
OAc
Figure 1. Structures of aromatic natural products isolated from Magnolia virgini-
ana,1 Magnolia officinalis2 and Magnolia garrettii.3
12
13
⇑
Corresponding author. Tel.: +44 115 9514194; fax: +44 115 9513564.
E-mail address: ross.denton@nottingham.ac.uk (R.M. Denton).
Scheme 1. Retrosynthesis of 40-O-methyl honokiol (1).
0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.03.031

R. M. Denton et al. / Tetrahedron Letters 52 (2011) 2554–2556
2555
PhI(OAc)2 in the presence of acetic acid afforded 12 in a yield of
60% (90% with respect to recovered starting material).14
We next examined the synthesis of Grignard reagent precursor
10 (Scheme 3). To this end, allylation of 11 afforded Claisen rear-
rangement precursor 15 in excellent yield.
O
OMe
OH
(a)
(b)
OAc
Unfortunately, the rearrangement of the latter to form 16
proved low yielding under both thermal conditions and in the
presence of Lewis acids (Table 1).
13
14
12
Scheme 2. Reagents and conditions: (a) BCl3ꢀSMe2, 1,2-DCE, reflux, 18 h, 89%;
Subjection of 15 to either microwave or conventional heating in
either DMF or 1,2-dichlorobenzene afforded only low yields (max-
imum 30%, Table 1, entry 1) of rearranged product with the rest of
the mass being unreacted starting material. The use of BCl3ꢀSMe2 in
1,2-DCE afforded a mixture of 11 and 16 in a 1:1 ratio.15 Work car-
ried out by Ollevier and Mwene-Mjeba has shown that Claisen
rearrangements can be catalysed with Bi(OTf)3 in MeCN, however,
it has also been shown that significant cleavage of the allyl group
occurs, and in our hands only a trace amount of product was ob-
tained using this method.16 Finally, heating 15 on water did not af-
ford any rearranged product.17
(b) PhI(OAc)2, AcOH, 8 h, 60%.
OH
O
OH
OMe
(a)
(b)
I
I
I
I
11
15
16
10
These unsatisfactory results led us to develop an alternative
route in which the allyl group was introduced by nucleophilic dis-
placement of a benzylic halide (Scheme 4).
Scheme 3. Reagents and conditions: (a) allyl bromide, K2CO3, acetone, reflux, 1 h,
98%; (b) see Table 1.
To this end alcohol 17 was brominated using the catalytic Appel
conditions recently developed in our laboratory.18 Thus, the
bromophosphonium salt responsible for the bromination of 17
was generated from catalytic triphenylphosphine oxide using oxa-
lyl bromide as the stoichiometric reagent. A subsequent copper-
catalysed nucleophilic substitution reaction with bromide 18 and
vinyl magnesium chloride then afforded bromide 19.19
With both of the required coupling partners in hand the synthe-
sis was completed by coupling of the Grignard reagent derived
from bromide 19 with dienone 12 in satisfactory yield. This step
occurs presumably, via acetate elimination and a 1,2-shift of the
aryl group to afford 1 upon work-up (Scheme 5).20
In conclusion, we have developed a concise (three steps in the
longest linear sequence) protecting group free synthesis of 40-O-
methyl honokiol (1)21 in an overall yield of 11%. The spectroscopic
data for the synthetic material were in excellent agreement with
those of the natural product.22
Table 1
Conditions used for the Claisen rearrangement of 15
Entry
Lewis acid/solvent
Time
Temperature (°C)
Yield (%) 16
1
2
3
4
5
6
7
DMF
DMF
50 min
24 h
50 min
24 h
2 h
24 h
200a
160b
200a
185c
90b
30
16
24
Trace
43
1,2-Dichlorobenzene
1,2-Dichlorobenzene
BCl3ꢀSMe2/1,2-DCE
Bi(OTf)3/MeCN
H2O
85b
Trace
—
24 h
100b
a
b
c
Reactions carried out in a microwave reactor.
Reactions carried out in an oil bath.
Reaction carried out in a sand bath.
OMe
Br
OMe
Br
OMe
(a)
(b)
OH
Br
Acknowledgements
Br
This work was supported financially by The University of
Nottingham (New Researcher’s Fund NF5012) and could not have
been completed without the help of Dr. Mick Cooper, Graham
Coxhill, Shazad Aslam and Kevin Butler from the Analytical
Services Department.
17
18
19
Scheme 4. Reagents and conditions: (a) (COBr)2, Ph3PO (15 mol %), CHCl3, 5 h, 63%;
(b) CH2CHMgCl, CuI (10 mol %), 2,20-bipyridine (10 mol %), benzene, 0 °C to rt, 6 h,
64%.
Supplementary data
The synthesis began with the preparation of dienone 12
(Scheme 2). Thus, demethylation of 13 with BCl3ꢀSMe2 afforded
14 in excellent yield.13 Subsequent oxidative dearomatisation with
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.031.
OMe
OMe
OH
O
OMe
BrMgO
(a)
+
OAc
OAc
Br
12
1
19
20
Scheme 5. Reagents and conditions: (a) (i) Mg, 1,2-dibromoethane, Et2O, reflux, 1 h; (ii) Et2O, 0 °C, 30 min; (iii) NH4Cl, 10 min, 50%.

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R. M. Denton et al. / Tetrahedron Letters 52 (2011) 2554–2556
13. Denton, R. M.; Scragg, J. T. Synlett 2010, 633–635.
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21. 40-O-Methyl honokiol (1). To a suspension of Mg turnings (90.4 mg, 3.72 mmol)
in Et2O (1 mL) was added 19 (9.00 mL, 2.13 mmol of a 0.237 M solution in
Et2O) dropwise over 30 min and the solution was stirred for 30 min. To a
solution of 12 (100 mg, 0.520 mmol) in Et2O (2.5 mL) at 0 °C was added the
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previously prepared Grignard reagent (0.390 mL, 0.390 mmol of
a 0.1 M
solution in Et2O) and the solution was stirred for 30 min before being
warmed to rt. The reaction mixture was quenched with NH4Cl (2.5 mL of a
1 M aqueous solution) and the solution was stirred for a further 30 min before
being diluted with Et2O (10 mL), washed with NH4Cl (3 ꢁ 10 mL of a 1 M
aqueous solution) and brine (3 ꢁ 10 mL), dried over MgSO4 and concentrated
under reduced pressure. Purification by flash chromatography (petroleum
ether/EtOAc, 9:1) gave 1 (73.2 mg, 50%) as a colourless oil, Rf 0.71 (petroleum
ether/EtOAc, 9:1). IR: mmax (CHCl3) 3549, 3081, 3011, 2979, 2929, 2839, 1639,
1606, 1491, 1467, 1441, 1286, 1248, 1177, 1052, 1030, 919 cmꢂ1 1H NMR:
.
(400 MHz, CDCl3) d 7.30 (1H, dd, J = 8.3, 2.2 Hz, ArHmeta), 7.25 (1H, d, J = 2.2 Hz,
ArHmeta), 7.07 (1H, dd, J = 8.1, 1.9 Hz, ArHmeta), 7.04 (1H, d, J = 1.9 Hz, ArHmeta),
6.97 (1H, d, J = 8.3 Hz, ArHortho), 6.92 (1H, d, J = 8.1 Hz, ArHortho), 6.07–5.94 (2H,
m, ArCH2CHCH2, ArCH2CHCH2), 5.13 (1H, brs, ArOH), 5.13–5.05 (4H, m,
ArCH2CHCH2, ArCH2CHCH2), 3.98 (3H, s, ArOCH3), 3.45 (2H, d, J = 6.7 Hz,
ArCH2CHCH2), 3.37 (2H, d, J = 6.8 Hz, ArCH2CHCH2). 13C NMR: (100 MHz,
CDCl3) d 157.0 (Cq), 150.8 (Cq), 137.8 (CH), 136.5 (CH), 132.1 (Cq), 130.5 (CH),
130.2 (CH), 129.8 (Cq), 129.0 (Cq), 128.8 (CH), 127.9 (CH), 127.8 (Cq), 115.8
(CH2), 115.5 (CH, CH2), 111.0 (CH), 55.5 (CH3), 39.4 (CH2), 34.3 (CH2). HRMS:
(ESI+) m/z Calcd for C19H20O2Na 303.1356, m/z, found: 303.1342.
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22. The 13C resonances at 129.8 and 115.5 were originally assigned as CH and Cq,
respectively (Ref. 2). However, our DEPT data and assignments made by others
on similar structures indicate that these assignments are in error and should be
129.8 (Cq) and 115.5 (CH).