A concise synthesis of honokiol

Article abstract of DOI:10.1016/j.tet.2010.08.005

Two approaches to the synthesis of the plant-derived biaryl neolignan honokiol are described. The second approach provided the natural product in either four steps with 34% overall yield or five steps and 55% overall yield.

Full text of DOI:10.1016/j.tet.2010.08.005

Tetrahedron 66 (2010) 8029e8035
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A concise synthesis of honokiol
y
*
Ross M. Denton , James T. Scragg, Adrià M. Galofré, Xiechao Gui, William Lewis
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
Article history:
Received 18 May 2010
Received in revised form 14 July 2010
Accepted 3 August 2010
Available online 7 August 2010
Two approaches to the synthesis of the plant-derived biaryl neolignan honokiol are described. The
second approach provided the natural product in either four steps with 34% overall yield or five steps and
55% overall yield.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Honokiol
Natural products
Suzuki coupling
Neolignans
1. Introduction
to the development of a concise and robust synthesis of hono-
kiol, which we developed to make material available for
Honokiol-(1) (Fig. 1) is one of a family of biaryl neolignans
originally isolated from Magnoliae officinalis1 and more recently
from Magnoliae obovata.2 Honokiol-containing extracts of the
stems and bark of these plants have long been used in tradi-
tional Chinese and Japanese medicine for the treatment of a va-
riety of ailments. In 1975 the muscle relaxing properties of
honokiol were described.3 Since this time, a substantial body of
literature describing the biological activity of the natural product
in vitro and in vivo has appeared. Perhaps the most significant
findings of these wide-ranging studies are concerned with
honokiol’s anticancer4 and neurotrophic activity.5 At present
natural honokiol is obtained by extraction of magnolia bark;
however, the isolation is complicated by the fact that the natural
product is often isolated with its constitutional isomer magno-
lol-(3). Separation requires either HPLC,6 electromigration7 or
chemical derivatisation.8 Despite the considerable interest in the
biological activity of honokiol in recent years there was, until
recently, only two reported total syntheses of the natural
product. The first,9 reported in 1986, proceeds in four steps with
an overall yield of 16% whilst the second reported synthesis
proceeds in an improved 21% overall yield but required 14
steps.5c The recent report of a shorter and higher yielding route,
32%, which features a Suzuki cross-coupling as a key step10
prompts us to report the results of our own studies pertaining
biological study.
3'
4' OH
5'
2'
1'
OH
OH
8'
2
1
9'
3
4
6'
7'
6
5
7
9
8
1
honokiol-(
)
chavicol-(2)
OH
OH
OH
OH
OH
magnolol-(3)
dunnianol-(4)
Figure 1. Honokiol-(1) and related neolignan natural products.
Our initial synthesis plan for honokiol is outlined in Scheme 1 in
retrosynthetic form. The proposed route relies on the recently de-
veloped rhodium-catalysed direct arylation of phenols for the
construction of the biaryl bond11 (7þ8/6) and Claisen and Claisen/
Cope rearrangements to introduce the two allyl groups at the C5
and C50 positions, respectively. The ortho-tert-butyl group present
* Corresponding author. Tel.: þ44 115 9514194; fax: þ44 115 9513564; e-mail
address: ross.denton@nottingham.ac.uk (R.M. Denton).
y
Corresponding author for X-ray crystal structures.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.08.005

8030
R.M. Denton et al. / Tetrahedron 66 (2010) 8029e8035
in starting material 6 is necessary to prevent both unwanted
Claisen rearrangement occurring at C3 and to ensure mono-
arylation during the direct arylation process.
FriedeleCrafts alkylation in the presence of alkenes and of the
possibility for nucleophilic capture of the derived tert-butyl car-
bocation by the adjacent aromatic ring. We therefore began by
establishing that a retro alkylation reaction was viable on substrate
10, which lacked the allyl groups.
sigmatropic
OH
OH
rearrangements
O
O
OH
OH
OH
OH
retro Friedel
(a)
Crafts alkylation
honokiol-(1)
5
11
10
allylation
demethylation
OMe
Scheme 3. Reagents and Conditions: (a) AlCl3, toluene:CH3NO2 (10:1), 60 ꢀC, 2 h 63%.
OH
OMe
direct
arylation
OH
Heating a solution of 10 and AlCl3 in toluene and nitromethane13
to 60 ꢀC afforded a good yield of biaryl 11. No products arising from
recapture of the tert-butyl group were observed in the 1H NMR
spectrum of the crude reaction mixture presumably because the
solvent acts as an irreversible tert-butyl cation scavenger.12 We then
turned our attention to the removal of the tert-butyl blocking group
from substrate 9 to complete the synthesis of honokiol (Scheme 4).
Br
7
8
6
Scheme 1. Synthesis plan for honokiol.
2. Results and discussion 1dRhodium-catalysed direct
arylation approach
OH
OH
OH
OH
a or b
The synthesis began with the rhodium-catalysed direct aryla-
tion of phenol 8 with bromide 7 according to the general protocol of
Bedford and co-workers (Scheme 2) to afford the expected biaryl in
45% isolated yield.11 Given that the reaction reaches full conversion
with respect to the phenol the moderate yield obtained reflects the
difficulty in separating the product from the excess bromide 7 used.
X
9
1
honokiol-( )
Scheme 4. Reagents and Conditions: (a) AlCl3, toluene:CH3NO2 (10:1), 60 ꢀC, 2 h. (b)
AlCl3, toluene, rt, 2 h.
OMe
OMe
OH
OH
Unfortunately, repeated attempts under a variety of reaction
conditions were uniformly unsuccessful. In the first instance the
conditions depicted in Scheme 3 were employed. We were frus-
trated to observe that subjection of substrate 9 to the same
conditions resulted in decomposition of 9. Analysis of 1H NMR
and 13C NMR spectra of the crude reaction mixture indicated that
the tert-butyl group was intact but a complex mixture of prod-
ucts had formed. It was apparent from the spectra that a cycli-
sation had occurred between the hydroxyl group at position
C40and the allyl side chain at position C50.14 When 9 was sub-
jected to the AlCl3 in toluene at room temperature similar deg-
radation was observed after 2 h. In a further experiment we
examined the stability of commercial honokiol to AlCl3 in tolu-
ene-d8 at both room temperature and 60 ꢀC. We were disap-
pointed again to observe the disappearance of the CH2 resonance
for the C50 allyl group suggesting that the unwanted cyclisation,
as well as other reactions, had occurred at both room tempera-
ture and 60 ꢀC. Given that honokiol was unstable to the initial
reaction conditions employed for cleavage of the blocking group
we returned to the AlCl3 nitromethane complex, which is known
to promote retro FriedeleCrafts alkylation under milder reaction
conditions.13 We began by establishing that honokiol was stable
to this reagent for at least 16 h at room temperature in toluene-
d8. However, when 9 was treated with 1, 3 or 10 equiv of the AlCl3
nitromethane complex at room temperature no reaction was
observed. Frustratingly, heating the reaction mixture to 60 ꢀC
resulted in decomposition. Given these difficulties and the in-
stability of the product above room temperature this route
was abandoned and a revised synthesis plan was developed
(Scheme 5).
a
Br
7
8
6
b, c
OH
O
OH
O
d
9
5
Scheme 2. Reagents and conditions: (a) [RhCl(COD)]2 10 mol %, P(NMe2)3 30 mol %,
Cs2CO3, toluene, reflux, 18 h, 45%. (b) BCl3$SMe2, DCE, reflux, 18 h, 66%. (c) Allyl bro-
mide, Cs2CO3, DMF, 15 h, 92%. (d) DMF, microwave, 200 ꢀC, 50 min, 49%.
Demethylation of biaryl 6 was then effected using BCl3$SMe2
affording the corresponding diol. Double allylation of this material
was achieved in excellent yield using allyl bromide and Cs2CO3 in
DMF affording rearrangement precursor 5. We were pleased to
observe that the latter compound underwent clean Claisen and
Claisen/Cope rearrangements upon heating to 200 ꢀC in the mi-
crowave to afford tert-butyl honokiol 9 in moderate yield. At this
point of the synthesis all that remained was a retro FriedeleCrafts
alkylation12 reaction to remove the tert-butyl blocking group
from C3. We were conscious of the lack of precedent for retro

R.M. Denton et al. / Tetrahedron 66 (2010) 8029e8035
8031
O
Claisen
OH
OH
rearrangement
OH
OH
O
OMe
OMe
a
deprotection
honokiol-(1)
12
18
16
c
Suzuki
coupling
allylation
OH
OMe
OMe
lithiation
OH
B(OH)2
OMe
b
Br
13
15
14
Scheme 5. Revised synthesis plan for honokiol.
19
d
3. Results and discussion 2dSuzuki coupling approach
The revised synthesis plan relies on a Suzuki cross-coupling
between boronic acid 14 and bromophenol 13. We recognized that
this strategy was dependant on the identification of cross-coupling
conditions that would not isomerise the potentially sensitive allyl
group. However, in our previous synthesis of dunnianol-(4)15 we
established that Suzuki couplings with 14 were possible without
isomerisation of the C5 allyl group (Scheme 6). Boronic acid 14 was
prepared from commercially available 15 via directed ortho-lith-
iation.16 This high yielding procedure is convenient and should find
application in the synthesis of other oligomeric natural products
derived from chavicol-(2). With the boronic acid in hand we fo-
cused on the Suzuki cross-coupling of 14 with bromophenol 13 (see
Scheme 7). Given our previous success in a similar system15 we
were surprised and frustrated to discover that the Suzuki cross-
coupling of 13 and 14 under identical conditions was met with
substantial alkene isomerisation (Table 1, entry 1).
OH
OH
OH
OH
20
honokiol-(1)
Scheme 7. Reagents and conditions: (a) Allyl bromide, K2CO3, acetone, reflux, 18 h,
99%. (b) BCl3$SMe2, DCE, reflux, 18 h, 47%. (c) 1,2-Dichlorobenzene, microwave, 200 ꢀC,
15 min, 86%. (d) BCl3$SMe2, DCE, reflux, 18 h, 91%.
Table 1
Conditions screened for Suzuki coupling of 16 and 17
Entry
Pd source
10 mol %
Ligand
Base
Solvent
(10:1)
Ratio
30 mol %
5 equiv
16:17a
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
d
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
d
Na2CO3
Na2CO3
Na2CO3
K2CO3
Na2CO3
K2CO3
Na2CO3
K2CO3
Na2CO3
K2CO3
KF
iPrOH/H2O
DMF/H2O
3:2
3:10
3:8
OH
OH
OMe
OH
OMe
OMe
a
CH3CN/H2O
iPrOH/H2O
iPrOH/H2O
iPrOH/H2O
iPrOH/H2O
iPrOH/H2O
iPrOH/H2O
iPrOH/H2O
1,4-Dioxane/H2O
THF/H2O
B(OH)2
3:4
Traceb
Traceb
1:6
d
Br
Pd(PPh3)4
Pd(PPh3)4
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
d
9:2
3:2
14
13
17
16
9
PPh3
PPh3
S-Phos
S-Phos
PPh3
S-Phos
10
11
12
13
14
3:2
Scheme 6. Reagents and conditions: (a) For conditions see entry 12 of Table 1, 15 h,
1:0c
1:0
94%.
KF
KF
Na2CO3
THF/H2O
THF/H2O
9:4
3:2
Initial changing of solvents to either DMF or acetonitrile did not
suppress isomerisation (entries 2 and 3). However, reactions car-
ried out in the absence of Pd(OAc)2 (entries 5 and 6) resulted in
markedly less isomerised product. For this reason Pd(PPh3)4 was
next examined (entries 7 and 8); unfortunately, the isomerised
alkene was still obtained under these conditions. Changing the
palladium source to Pd2(dba)3 was also ineffective with both so-
dium and potassium carbonate (entries 9 and 10). Work carried out
by Liu and Chen on the cross-coupling of 4-hydroxyboronic acid
and 4-allyl-2-bromo-1-methoxybenzene10 identified conditions
using S-Phos17 and KF combined with Pd2(dba)3 (entry 11);
a modification of the solvent system afforded a slight increase in
the yield (entry 12). Efforts to switch to a cheaper phosphine ligand
and a cheaper base (entries 13 and 14, respectively) both resulted
in isomerisation of the product. The data shows that S-Phos, KF
and Pd2(dba)3 are required for efficient cross-coupling without
a
Ratio determined by integration of C7 and C9 resonances of 16 and 17,
respectively from the 1H NMR spectrum of the crude reaction mixture.
b
As no source of palladium was added to the reaction mixture no coupling
occurred, however, trace amounts of 14 with isomerisation of the double bond were
visible on the 1H NMR spectrum of the crude reaction mixture.
c
Protocol of Liu and Chen.10
isomerisation of the sensitive alkene.10 Under these conditions 16
was obtained in 94% isolated yield with no detectable
isomerisation.
The synthesis of honokiol was then completed as follows. The
free hydroxyl group of 16 was allylated and ether 18 underwent
Claisen-rearrangement and deprotection on treatment with
BCl3$SMe2 to afford honokiol in moderate yield with the remainder
of the mass-balance being 20. This procedure, although slightly

8032
R.M. Denton et al. / Tetrahedron 66 (2010) 8029e8035
ꢀ
lower yielding than an existing method, benefits from the use of
2.5 equiv of single boron halide reagent.18 Alternatively, if a higher
yield is desired the thermal Claisen rearrangement provided
product 19 in 86% yield. Conversion of 19 to honokiol was achieved
in excellent yield using BCl3$SMe2. The synthetic material (Fig. 2)
was identical to a natural sample in all respects.19
wire, filtered and distilled and stored over activated 4 A molecular
sieves. N,N,N0,N0-Tetramethylethylene-1,2-diamine (TMEDA) was
dried over calcium hydride powder, filtered and distilled and stored
ꢀ
ꢀ
over activated 4 A molecular sieves. Activation of 4 A molecular
sieveswasachievedbyheatingto200 ꢀCunderhighvacuumfor15 h.
Microwave reactions were carried outon a CEMExplorer microwave.
Reactions were monitored using thin layer chromatography (TLC) on
PolygramÒ SIL G/UV254 0.25 mm silica gel precoated sheets with
fluorescent indicator. Sheets were visualised using ultra-violet light
(254 nm) and/or anisaldehyde or KMnO4 solutions, as appropriate.
Flash chromatography was performed using Fluorochem silica gel
60, 35e70 m, unless otherwise noted. Infrared spectra were recorded
on a PerkineElmer 1600 FTIR instrument as dilute chloroform so-
lutions or as neat solids using an ATR accessory. 1H and 13C NMR
spectra were recorded on a Bruker DPX 400 as dilute solutions in the
indicated deuterated solvent. All chemical shifts (d) are reported in
parts per million (ppm) relative to residual solvent peaks. All
chemical shifts are reported relative to chloroform (dH¼7.27 ppm,
dC¼77.0 ppm). Coupling constants (J) are reported in hertz and are
recorded after averaging. The multiplicity of a 1H NMR signal is
designated by one of the following abbreviations: s¼singlet,
d¼doublet, t¼triplet, m¼multiplet, br¼broad signal. 13C multiplici-
ties were assigned using a DEPT sequence. Where appropriate;
HMQC, HMBC and NOE experiments were performed to aid assign-
ment. Assignments of protons (e.g., ortho, para) are made with re-
specttothehydroxylormethoxygroups.Massspectrawereacquired
on a VG micromass 70E, VG Autospec or Micromass LCTOF. Melting
points were acquired on a StuartÒ SMP3 melting point apparatus.
Figure 2. Crystal structure representation of honokiol.20
4. Conclusion
5.2. Honokiol 1
In conclusion we have developed a short (four steps) route to
honokiol-(1) that proceeds in 34% overall yield from commercially
available starting materials. We have prepared ca. 100 mg of hon-
okiol-(1) in a single run using this route. Finally, if a higher overall
yield is required the thermal rearrangement of 20 can be performed
resulting in 55% overall yield, the highest yielding route to date, at
the cost of one additional step to the synthesis.
To a solution of 18 (200 mg, 0.713 mmol) in DCE (5 mL) was
added BCl3$SMe2 (1.12 mL, 1.78 mmol of a 2.00 M solution in
CH2Cl2) and the solution was heated to reflux for 18 h. The reaction
was cooled to room temperature and H2O (5 mL) was added. The
reaction was stirred for a further 15 min before being diluted with
CH2Cl2 (20 mL), washed with brine (3ꢂ20 mL), dried over MgSO4
and concentrated in vacuo. Purification by flash chromatography
(petrol/EtOAc, 3:1) gave 1 (89.5 mg, 47%) as a colourless solid, mp
85e87 ꢀC, literature mp 84e86 ꢀC9, Rf 0.32 (petrol/EtOAc, 3:1). A
crystal suitable for X-ray analysis was obtained by slow evaporation
from a petrol/EtOAc solution. IR: nmax (CHCl3) 3595, 3550, 3081,
3010, 2979, 5960, 2927, 2855, 1638, 1609, 1588, 1490, 1261, 1177,
5. Experimental
5.1. General
All glassware were flame-dried or oven-dried and allowed to cool
undera streamofnitrogenbefore use. Coolingtoꢁ78 ꢀC waseffected
using dry ice-acetone mixtures. Degassing was achieved by purging
nitrogen through the appropriate solution for 10 min. The petrol
used refers to the fraction with bp 40e60 ꢀC. Commercial solvents
and reagents were used as supplied with the following exceptions.
Tetrahydrofuran (THF) was pre-dried over sodium wire and distilled
under an atmosphere of nitrogen from sodium benzophenone ketyl
or obtained from a solvent tower, where degassed THF was passed
998, 910 cmꢁ1. 1H NMR: (400 MHz, CDCl3)
d
7.24 (1H, dd, J¼7.4, 2.4,
ArHmeta), 7.22 (1H, d, J¼2.4, ArHmeta), 7.07 (1H, dd, J¼7.7, 2.2, ArH-
meta), 7.04 (1H, d, J¼2.2, ArHmeta), 6.93 (1H, J¼7.4, ArHortho), 6.91 (1H,
J¼7.7, ArHortho), 6.05 (1H, ddt, J¼17.1, 10.1, 6.4, ArCH2CHCH2), 5.98
(1H, ddt, J¼17.0, 9.9, 6.8, ArCH2CHCH2), 5.24 (1H, dd, J¼10.1, 1.6,
ArCH2CHCH2cis), 5.23 (1H, dd, J¼17.1, 1.6, ArCH2CHCH2trans), 5.10
(1H, dd, J¼9.9, 1.6, ArCH2CHCH2cis), 5.08 (1H, dd, J¼17.0, 1.6,
ArCH2CHCH2trans), 5.07 (1H, br s, ArOH), 5.06 (1H, br s, ArOH), 3.48
(2H, d, J¼6.4, ArCH2CHCH2), 3.36 (2H, d, J¼6.8, ArCH2CHCH2). 13C
through two columns of activated alumina and a 7
m filter under
a4 barpressure. Diethylether(Et2O)waspre-driedoversodiumwire
and distilled under an atmosphere of nitrogen from sodium benzo-
phenone ketyl or obtained from a solvent tower, where degassed
ether was passed through two columns of activated alumina and
NMR: (100 MHz, CDCl3) d 153.9 (Cq), 150.7 (Cq), 137.8 (CH), 135.9
(CH), 132.2 (Cq), 131.1 (CH), 130.2 (Cq), 129.6 (CH), 128.8 (CH), 128.5
(CH), 127.7 (Cq), 126.3 (Cq), 116.9 CH2), 116.6 (CH), 115.6 (CH), 115.5
(CH2), 39.4 (CH2), 35.2 (CH2). HRMS: (ESIþ) m/z calculated for
C18H18O2Na 289.1191, m/z found 289.1199.
a7 mfilterundera4 barpressure. Toluenewaspre-driedoversodium
wire and distilled under an atmosphere of nitrogen from sodium
benzophenone ketyl or obtained from a solvent tower, where
degassed toluene was passed through two columns of activated
To a solution of 19 (28.0 mg, 0.100 mmol) in DCE (1 mL) was
added BCl3$SMe2 (0.100 mL, 0.200 mmol of a 2.00 M solution in
CH2Cl2) and the solution was heated to reflux for 18 h. The reaction
was cooled to room temperature and H2O (5 mL) was added. The
reaction was stirred for a further 15 min before being diluted with
CH2Cl2 (10 mL), washed with brine (3ꢂ10 mL), dried over MgSO4
and concentrated in vacuo. Purification by flash chromatography
(petrol/EtOAc, 3:1) gave 1 (24.2 mg, 91%) as a colourless solid. Data
matched that previously recorded.
alumina and a 7
m filter under a 4 bar pressure. Dichloromethane
(CH2Cl2) was distilled from calcium hydride powder or purchased as
ꢀ
analytical grade and stored over activated 4 A molecular sieves.
Dimethylformamide (DMF) was dried over calcium hydride powder,
ꢀ
filtered and distilled under reduced pressure onto activated 4 A
molecular sieves. Trimethylborate (B(OMe)3) was dried over sodium

R.M. Denton et al. / Tetrahedron 66 (2010) 8029e8035
8033
5.3. 2-40-Bis(allyloxy)-3-tert-butylbiphenyl 5
ArCH2CHCH2trans), 5.09 (1H, br s, ArOH), 5.04 (1H, dd, J¼10.1, 1.6,
ArCH2CHCH2cis), 3.45 (2H, d, J¼6.4, ArCH2CHCH2), 3.33 (2H, d,
J¼6.9, ArCH2CHCH2), 1.41 (9H, s, ArC(CH3)3). 13C NMR: (100 MHz,
To a solution of 10 (100 mg, 0.413 mmol) in DMF (5 mL) was
added Cs2CO3 (269 mg, 0.826 mmol), allyl bromide (71.9
mL,
CDCl3) d 154.0 (Cq), 149.4 (Cq), 138.0 (CH), 135.0 (CH), 131.6 (CH),
0.826 mmol) and the solution was stirred at room temperature for
15 h. MeOH (5 mL) was added and the reaction was stirred for
a further 15 min. The reaction was diluted with H2O (20 mL),
washed with Et2O (3ꢂ20 mL), the organics were combined, dried
over MgSO4 and concentrated in vacuo. Purification by flash chro-
matography (petrol/EtOAc, 5:1) gave 5 (122 mg, 92%) as a colourless
solid, mp 56e58 ꢀC, Rf 0.73 (petrol/EtOAc, 5:1). IR: nmax (CHCl3)
3084, 3010, 2961, 2873, 1648, 1608, 1513, 1485, 1463, 1433, 1405,
130.9 (Cq), 129.7 (Cq), 129.0 (CH), 128.4 (Cq), 127.8 (CH), 126.5 (Cq),
126.5 (CH), 119.7 (Cq), 116.9 (CH2), 116.7 (CH), 115.4 (CH2), 39.8
(CH2), 35.2 (CH2), 34.9 (Cq), 29.6 (CH3). HRMS: (ESIþ) m/z calculated
for C22H26O2Na 345.1825, m/z found 345.1830.
5.6. 3-tert-Butylbiphenyl-2,40-diol 10
To a solution of 6 (100 mg, 0.390 mmol) in DCE (5 mL) was
added BCl3$SMe2 (0.293 mL, 0.585 mmol of 2.00 M solution in
CH2Cl2) and the solution was heated to reflux for 18 h. The re-
action was cooled to room temperature and H2O (5 mL) was
added. The reaction was stirred for a further 15 min before being
diluted with CH2Cl2 (20 mL), washed with brine (3ꢂ20 mL), dried
over MgSO4 and concentrated in vacuo. Purification by flash
chromatography (petrol/EtOAc, 9:1) gave 10 (62.3 mg, 66%) as
a colourless solid, mp 100e102 ꢀC, Rf 0.13 (petrol/EtOAc, 9:1). IR:
1287, 1239, 1178, 1059, 995, 833 cmꢁ1. 1H NMR: (CDCl3)
d 7.51 (2H,
d, J¼9.0, ArHmeta), 7.31 (1H, dd, J¼7.6, 1.8, ArHmeta), 7.17 (1H, dd,
J¼7.6, 1.8, ArHmeta), 7.08 (1H, dd, J¼7.6, 7.6, ArHpara), 6.97 (2H, d,
J¼9.0, ArHortho), 6.10 (1H, ddt, J¼17.6, 10.6, 1.6, ArOCH2CHCH2), 5.77
(1H, ddt, J¼17.4, 10.4, 1.6, ArOCH2CHCH2), 5.45 (1H, dd, J¼17.6, 1.6,
ArOCH2CHCH2trans), 5.32 (1H, dd, J¼10.6, 1.6, ArOCH2CHCH2cis), 5.18
(1H, dd, J¼17.4, 1.6, ArOCH2CHCH2trans), 5.09 (1H, dd, J¼10.4, 1.6,
ArOCH2CHCH2cis), 4.59 (2H, d, J¼5.2, ArOCH2CHCH2), 3.93 (2H, d,
J¼5.2, ArOCH2CHCH2), 1.44 (9H, s, ArC(CH3)3). 13C NMR: (100 MHz,
nmax (CHCl3) 3595, 3543, 3154, 2960, 1514, 1171, 888 cmꢁ1
.
1H
CDCl3)
d
157.6 (Cq), 155.4 (Cq), 143.1 (Cq), 133.7 (CH), 133.7 (Cq),
NMR: (400 MHz, CDCl3)
d
7.34 (2H, d, J¼8.6, ArHmeta), 7.29 (1H, dd,
133.1 (CH), 132.2 (Cq), 129.7 (CH), 129.4 (CH), 125.8 (CH), 123.2 (CH),
117.5 (CH2), 116.3 (CH2), 114.5 (CH), 72.5 (CH2), 68.7 (CH2), 35.0 (Cq),
30.6 (CH3). HRMS: (ESIþ) m/z calculated for C22H26O2Na 345.1825,
m/z found 345.1830.
J¼7.8, 1.6, ArHmeta), 7.05 (1H, dd, J¼7.8, 1.6, ArHmeta), 6.97 (2H, d,
J¼8.6, ArHmeta), 6.91 (1H, dd, J¼7.8, 7.8, ArHpara), 5.40 (1H, br s,
ArOH), 4.83 (1H, br s, ArOH), 1.45 (9H, s, ArC(CH3)3). 13C NMR:
(100 MHz, CDCl3)
d 155.5 (Cq), 151.2 (Cq), 136.1 (Cq), 131.0 (CH),
129.5 (Cq), 128.4 (Cq), 128.1 (CH), 126.4 (CH), 119.8 (CH), 116.3
(CH), 34.9 (Cq), 29.6 (CH3). HRMS: (ESIþ) m/z calculated for
C16H18O2Na 265.1199, m/z found 265.1198.
5.4. 3-tert-Butyl-40-methoxybiphenyl-2-ol 611b
To a solution of 8 (0.102 mL, 0.666 mmol) in toluene (10 mL)
were added
1.70 mmol), P(NMe2)3 (36.3
(32.8 mg, 66.6 mol) and the solution was heated to reflux for
7
(0.125 mL, 0.999 mmol), Cs2CO3 (368 mg,
5.7. Biphenyl-2,40-diol 1121
m
L, 0.200 mmol) and [RhCl(COD)]2
m
To a solution of 10 (50.0 mg, 0.207 mmol) in toluene (1 mL) and
CH3NO2 (0.1 mL) was added AlCl3 (136 mg, 1.03 mmol) and the
solution was heated to 60 ꢀC for 2 h. The reaction was diluted with
EtOAc (5 mL), washed with H2O (3ꢂ5 mL), dried over MgSO4 and
concentrated in vacuo. Purification by flash chromatography (pet-
rol/EtOAc, 3:1) gave 11 (24.2 mg, 63%) as a colourless solid, mp
161e163 ꢀC, literature mp 162e163 ꢀC21, Rf 0.33 (petrol/EtOAc, 3:1).
IR: nmax (CHCl3) 3478, 3357, 2925, 2923, 2853, 1593, 1494, 1477,
18 h. The reaction was cooled to room temperature, acidified (1 M
HCl to pH 5), diluted with CH2Cl2 (20 mL), washed with brine
(3ꢂ20 mL), dried over MgSO4 and concentrated in vacuo. Purifi-
cation by flash chromatography (petrol/EtOAc, 9:1) gave
6
(76.8 mg, 45%) as a colourless solid, mp 118e120 ꢀC, Rf 0.48
(petrol/EtOAc, 9:1). IR: nmax (CHCl3) 3693, 3541, 3000, 2960, 2912,
2875, 2839, 1711, 1609, 1513, 1609, 1512, 1434, 1247, 1178, 1031,
909, 892 cmꢁ1
.
1H NMR: (400 MHz, CDCl3)
d
7.38 (2H, d, J¼8.8,
1274, 1196, 1175, 1101, 812 cmꢁ1. 1H NMR: (400 MHz, CDCl3)
d 7.36
ArHmeta), 7.29 (1H, dd, J¼7.7, 1.6, ArHortho), 7.07 (1H, dd, J¼7.7, 1.6,
ArHmeta), 7.04 (2H, d, J¼8.8, ArHmeta), 6.91 (1H, dd, J¼7.7, 7.7,
ArHpara), 5.43 (1H, br s, ArOH), 3.88 (3H, s, ArOCH3), 1.45 (9H, s,
(2H, d, J¼8.5, ArHmeta), 7.25e7.21 (2H, m, ArH), 7.00e6.95 (4H, m,
ArH), 5.31 (1H, br s, ArOH), 5.16 (1H, br s, ArOH). 13C NMR:
(100 MHz, CDCl3)
d 155.4 (Cq), 152.5 (Cq), 130.5 (CH), 130.2 (CH),
ArC(CH3)3). 13C NMR: (100 MHz, CDCl3)
d
159.3 (Cq), 151.0 (Cq),
129.3 (Cq), 128.8 (CH), 127.7 (Cq), 120.8 (CH), 116.2 (CH), 115.7 (CH).
HRMS: (ESIþ) m/z calculated for C12H10O2Na 209.0573, m/z found
209.0583.
135.9 (Cq), 130.6 (CH), 129.1 (Cq), 128.3 (Cq), 127.8 (CH), 126.1
(CH), 119.6 (CH), 114.7 (CH), 55.2 (CH3), 34.7 (Cq), 29.4 (CH3).
HRMS: (ESIþ) m/z calculated for C17H20O2Na 279.1356, m/z found
279.1325.
5.8. 50-Allyl-20-methoxybiphenol-4-ol 16
5.5. 3,50-Diallyl-3-tert-butylbiphenyl-2,40-diol 9
To a solution of 13 (199 mg, 1.15 mmol) in THF (10 mL) and H2O
(1 mL) were added 14 (330 mg, 1.72 mmol), KF (300 mg,
5.75 mmol),
A solution of 5 (30.0 mg, 93.1
mmol) in DMF (1.5 mL) was heated
2-dicyclohexylphosphino-20,60-dimethoxybiphenyl
at 200 ꢀC for 50 min using a microwave. The reaction was diluted
with H2O (5 mL) and, washed with Et2O (3ꢂ5 mL). The organics
were combined, dried over MgSO4 and concentrated in vacuo. Pu-
rification by flash chromatography (petrol/EtOAc, 3:1) gave 9
(14.7 mg, 49%) as a colourless solid, mp 73e75 ꢀC, Rf 0.26 (petrol/
EtOAc, 3:1). IR: nmax (CHCl3) 3595, 3543, 3081, 3009, 2961, 2916,
(142 mg, 0.345 mmol) and Pd2(dba)3 (66.1 mg, 0.115 mmol) and the
solution was heated to reflux and stirred for 15 h. The reaction was
cooled to room temperature, diluted with EtOAc (25 mL) and
washed with 1 M HCl (2ꢂ25 mL) and brine (2ꢂ25 mL), dried over
MgSO4 and concentrated in vacuo. Purification by flash chroma-
tography (petrol/EtOAc, 3:1) gave 16 (259 mg, 94%) as a yellow oil,
Rf 0.48 (petrol/EtOAc, 3:1). IR: nmax (CHCl3) 3596, 3082, 3009, 2935,
2837, 1731, 1639, 1613, 1591, 1518, 1496, 1256, 1174, 1044, 1029,
2872, 1730, 1638, 1611, 1502, 1485, 1432, 1258, 1171, 997, 918 cmꢁ1
.
1H NMR: (400 MHz, CDCl3)
d
7.22 (1H, dd, J¼7.9, 2.4, ArHmeta), 7.18
(1H, d, J¼2.1, ArHmeta), 7.07 (1H, d, J¼2.1, ArHmeta), 6.91 (1H, d, J¼7.9,
ArHortho), 6.86 (1H, d, J¼2.4, ArHmeta), 6.06 (1H, ddt, J¼17.4, 10.1, 6.4,
ArCH2CHCH2), 5.96 (1H, ddt, J¼18.0, 10.7, 6.9, ArCH2CHCH2), 5.33
(1H, br s, ArOH), 5.21 (1H, d, J¼18.0, 1.6, ArCH2CHCH2trans), 5.19 (1H,
dd, J¼10.7, 1.6, ArCH2CHCH2cis), 5.09 (1H, dd, J¼17.4, 1.6,
835 cmꢁ1. 1H MNR: (400 MHz, CDCl3)
d
7.43 (2H, d, J¼8.8, ArHmeta),
7.13 (1H, s, ArHmeta), 7.12 (1H, d, J¼7.4, ArHmeta), 6.92 (1H, d, J¼7.4,
ArHortho), 6.88 (2H, d, J¼8.8, ArHortho), 5.99 (1H, ddt, J¼17.0, 11.5, 6.7,
ArCH2CHCH2), 5.11 (1H, dd, J¼17.0, 1.9, ArCH2CHCH2trans), 5.07 (1H,
dd, J¼11.5, 1.9, ArCH2CHCH2cis), 4.80 (1H, br s, ArOH), 3.80 (3H, s,

8034
R.M. Denton et al. / Tetrahedron 66 (2010) 8029e8035
ArOCH3), 3.38 (2H, d, J¼6.7, ArCH2CHCH2). 13C NMR: (100 MHz,
nmax (CHCl3) 3594, 3556, 3082, 3060, 2979, 2905, 1639, 1611, 1516,
1493, 1331, 1260, 1171, 911, 839 cmꢁ1 1H NMR: (400 MHz, CDCl3)
CDCl3)
d
154.9 (Cq), 154.5 (Cq), 137.8 (CH), 132.3 (Cq), 131.2 (Cq),
.
131.0 (CH), 130.8 (CH), 130.2 (Cq), 128.1 (CH), 115.6 (CH2),114.9 (CH),
111.3 (CH), 55.7 (CH3), 39.4 (CH2). HRMS: (ESIþ) m/z calculated for
C16H16O2Na 263.1039, m/z found 263.1043.
d
7.36 (2H, d, J¼8.4, ArHmeta), 7.07 (1H, dd, J¼8.0, 2.0, ArHmeta), 7.04
(1H, d, J¼2.0, ArHmeta), 6.95 (2H, d, J¼8.4, ArHmeta), 6.92 (1H, d,
J¼8.0, ArHortho), 5.99 (1H, ddt, J¼16.8, 10.0, 6.8, ArCH2CHCH2), 5.21
(1H, br s, ArOH), 5.10 (1H, dd, J¼16.8, 1.6, ArCH2CHCH2trans),
5.07 (1H, dd, J¼10.0, 1.6, ArCH2CHCH2cis), 3.36 (2H, d, J¼6.8,
5.9. 5-Allyl-40-(allyloxy)-2-methoxybiphenyl 18
ArCH2CHCH2). 13C NMR: (100 MHz, CDCl3)
d 39.4 (CH2), 115.6 (CH),
To a solution of 16 (250 mg, 1.04 mmol) in acetone (5 mL) were
added K2CO3 (216 mg, 1.56 mmol) and allyl bromide (0.996 mL,
1.14 mmol) and the solution was heated to reflux for 18 h. The re-
action was cooled to room temperature and MeOH (10 mL) was
added. The reaction was stirred for a further 15 min before the
reaction was diluted with EtOAc (20 mL), washed with brine
(3ꢂ20 mL), dried over MgSO4 and concentrated in vacuo giving 18
(278 mg, 99%) as a colourless oil, Rf 0.68 (petrol/EtOAc, 3:1). IR: nmax
(CHCl3) 3072, 3009, 2960, 2938, 1736, 1670, 1639, 1515, 1495, 1266,
115.7 (CH2), 116.1 (CH), 127.7 (Cq), 128.9 (CH), 129.5 (Cq), 130.3
(CH), 130.5 (CH), 132.4 (Cq), 137.8 (CH), 150.8 (Cq), 155.3 (Cq).
HRMS: (ESIþ) m/z calculated for C15H14O2Na 249.0891, m/z found
249.0907.
Acknowledgements
This work was financially supported by The University of Not-
tingham (New Researcher’s Fund NF5012) and the Royal Society
(Research Grant RG090319).
1240, 1179, 1029, 997, 834 cmꢁ1. 1H NMR: (400 MHz, CDCl3)
d 7.49
(2H, d, J¼8.8, ArHmeta), 7.16 (1H, d, J¼2.0, ArHmeta), 7.13 (1H, dd,
J¼8.4, 2,0, ArHmeta), 6.99 (2H, d, J¼8.8, ArHortho), 6.93 (1H, d, J¼8.4,
ArHortho), 6.11 (1H, ddt, J¼17.2, 10.4, 5.2, ArOCH2CHCH2), 6.00 (1H,
ddt, J¼16.8, 10.0, 6.8, ArCH2CHCH2), 5.47 (1H, dd, J¼17.2, 1.2,
ArOCH2CHCH2trans), 5.33 (1H, dd, J¼10.4, 1.2, ArOCH2CHCH2cis), 5.12
(1H, dd, J¼16.8, 1.6, ArCH2CHCH2trans), 5.09 (1H, dd, J¼10.0, 1.6,
ArCH2CHCH2cis), 4.60 (2H, d, J¼5.2, ArOCH2CHCH2), 3.84 (3H, s,
ArOCH3), 3.40 (2H, d, J¼6.8, ArCH2CHCH2). 13C NMR: (100 MHz,
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.08.005.
References and notes
CDCl3)
d 157.7 (Cq), 154.9 (Cq), 137.8 (CH), 133.5 (Cq), 132.3 (Cq),
1. (a) Fujita, M.; Itokawa, H.; Sashida, Y. Chem. Pharm. Bull. 1972, 20, 212e213;
131.2 (Cq), 131.0 (CH), 130.6 (CH), 130.3 (Cq), 128.0 (CH), 117.7 (CH2),
115.6 (CH2),114.3 (CH),111.4 (CH), 68.9 (CH2), 55.7 (CH3), 39.5 (CH2).
HRMS: (ESIþ) m/z calculated for C19H20O2H 286.1536, m/z found
286.1522.
For
a review of biologically active lignans and neolignans isolated from
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5.10. 3,50-Diallyl-20-methoxybiphenyl-4-ol 192
A solution of 18 (20.0 mg, 71.3 mmol) in 1,2-dichlorobenzene
4. (a) For recent studies, see Konoshima, T.; Kozuka, M.; Tokuda, H.; Nishino, H.;
Iwashima, A.; Haruna, M.; Ito, K.; Tanabe, M. J. Nat. Prod. 1991, 54, 816e822; (b)
Son, H. J.; Lee, H. J.; Yun-Choi, H. S.; Ryu, J. H. Planta Med. 2000, 66, 469e471; (c)
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(1.5 mL) was heated at 200 ꢀC for 15 min using a microwave. Pu-
rification by flash chromatography (gradial elution starting with
petrol increasing to petrol/EtOAc, 5:1) gave 19 (17.2 mg, 86%) as
a colourless oil, Rf 0.36 (petrol/EtOAc, 4:1). IR: nmax (CHCl3) 3599,
3080, 3010, 2955, 2936, 2908, 2838, 1639, 1611, 1585, 1512, 1466,
1435, 1301, 1247, 1176, 1035, 919 cmꢁ1. 1H NMR: (400 MHz, CDCl3)
d
7.32 (1H, dd, J¼8.2, 2.1, ArHmeta), 7.29 (1H, d, J¼2.0, ArHmeta), 7.12
(1H, s, ArHmeta), 7.11 (1H, dd, J¼8.1, 2.4, ArHmeta), 6.91 (1H, d, J¼8.1,
ArHortho), 6.86 (1H, d, J¼8.2, ArHortho), 6.12e5.94 (2H, m,
ArCH2CHCH2), 5.23 (1H, dd, J¼17.3, 1.6, ArCH2CHCH2trans), 5.19 (1H,
dd, J¼11.5, 1.6, ArCH2CHCH2cis), 5.11 (1H, dd, J¼17.2, 1.6, ArCH2-
CHCH2trans), 5.07 (1H, dd, J¼11.3, 1.6, ArCH2CHCH2cis), 5.04 (1H, br s,
ArOH), 3.80 (3H, s, ArOCH3), 3.47 (2H, d, J¼6.4, ArCH2CHCH2), 3.38
(2H, d, J¼6.8, ArCH2CHCH2). 13C NMR: (100 MHz, CDCl3)
d 154.8
(Cq), 153.3 (Cq). 137.8 (CH), 136.5 (CH), 132.3 (Cq), 131.5 (CH), 131.2
(Cq), 131.0 (CH), 130.4 (Cq), 129.0 (CH), 128.0 (CH), 124.7 (Cq), 116.6
(CH2),115.5 (CH2), 115.4 (CH), 111.3 (CH), 55.7 (CH3), 39.4 (CH2), 35.4
(CH2). HRMS: (ESIþ) m/z calculated for C19H20O2Na 303.1356, m/z
found 303.1356.
7. Wang, X.; Wang, Y.; Geng, Y.; Li, F.; Zheng, C. J. Chromatogr., A 2004, 1036,
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2008, 8, 990e992; (d) Oi, S.; Watanabe, S.-I.; Fukita, S.; Inoue, Y. Tetrahedron
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13. Masashi, T.; Haruo, Y.; Takehiko, Y. Synthesis 1978, 399e400.
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2006, 12, 6356e6365.
5.11. 5-Allylbiphenyl-2,40-diol 20
To a solution of 18 (200 mg, 0.713 mmol) in DCE (5 mL) was
added BCl3$SMe2 (1.12 mL, 1.78 mmol of a 2.00 M solution in
CH2Cl2) and the solution was heated to reflux for 18 h. The re-
action was cooled to room temperature and H2O (5 mL) was
added. The reaction was stirred for a further 15 min before being
diluted with CH2Cl2 (20 mL), washed with brine (3ꢂ20 mL), dried
over MgSO4 and concentrated in vacuo. Purification by flash
chromatography (petrol/EtOAc, 3:1) also gave 22 (94.9 mg, 49%) as
a colourless solid, mp 104e106 ꢀC, Rf 0.22 (petrol/EtOAc, 3:1). IR:
15. Denton, R. M.; Scragg, J. T. Synlett 2010, 4, 633e635.
16. For a similar lithiation on a diethylcarbamate, see Ref. 1d.

R.M. Denton et al. / Tetrahedron 66 (2010) 8029e8035
8035
17. For the first reported Suzuki cross-coupling using S-Phos see Walker, S. D.;
Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43,
1871e1876.
a discrepancy. Fukuyma and co-workers (Ref. 5c) report a peak at 7.20 ppm,
which given the other data we assume is a typographical error.
20. Crystallographic data (excluding structure factors) for 1 have been deposited
with the Cambridge Crystallographic Data Centre as supplementary publication
number CCDC 778234. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: þ44 1223
336033, e-mail: deposit@ccdc.cam.ac.uk or by visiting www.ccdc.cam.ac.uk/
data_request/cif.
18. Previous workers have used 2.0 equiv of BCl3 to effect the Claisen rearrange-
ment and then a further 2.5 equiv of BBr3 for cleavage of the methylether in
64% yield. In our experience the use of commercial BBr3 results in some bro-
mination of the C5 allyl group.
19. Natural honokiol was purchased from Aldrich. Examination of the 1H NMR data
for the synthetic material (Ref. 5c,10) and natural material revealed
21. Padwa, A.; Wisnieff, T. J.; Walsh, E. J. J. Org. Chem. 1989, 54, 299e308.