A synthesis of the phenolic lipid, 3-[(Z)-pentadec-8-enyl] catechol, (15:1)-urushiol

Article abstract of DOI:10.1016/S0009-3084(02)00125-1

A synthesis of (15:1)-urushiol, urushiol monoene, 3-[(Z)-pentadec-8-enyl] catechol, 1,2-dihydroxy-3-[(Z)-pentadec-8-enyl] benzene, one of the toxic principles of Rhus toxicodendron and of Rhus vernicifera is described. 6-Chlorohexan-1-ol protected at the OH group with ethyl vinyl ether reacted with 2,3-dimethoxybenzaldehyde in the presence of lithium to give, after removal of the protective group with methanolic 4-toluenesulphonic acid, 1-(2,3-dimethoxyphenyl) heptane-1,7-diol. Catalytic hydrogenolysis in ethanol with palladium-carbon selectively afforded 7-(2,3-dimethoxyphenyl)heptane-1-ol accompanied by a small proportion of the 7-(3-methoxyphenyl)heptane-1-diol, formed by demethoxylation. Reaction of the dimethoxy compound with boron tribromide resulted in both bromination and demethylation to give 7-(2,3-dihydroxyphenyl) heptylbromide. This bromide in tetrahydrofuran (THF) containing hexamethylphosphoric triamide reacted with excess lithium oct-1-yne to give 3-(pentadec-8-enyl)catechol which, by catalytic hydrogenation in ethyl acetate containing quinoline, selectively formed the required cis product, 3-[(Z)-pentadec-8-enyl]catechol which was identical chromatographically and spectroscopically with urushiol monoene separated from the natural product.

Full text of DOI:10.1016/S0009-3084(02)00125-1

Chemistry and Physics of Lipids 120 (2002) 101ꢀ108
/
www.elsevier.com/locate/chemphyslip
A synthesis of the phenolic lipid, 3-[(Z)-pentadec-8-enyl]
catechol, (15:1)-urushiolꢀ
John H.P. Tyman *, Brian G. Schofield, Choong H. Khor
Department of Chemistry, Brunel University, Uxbridge, Middlesex UB8 3PH, UK
Received 22 May 2002; received in revised form 5 August 2002; accepted 6 August 2002
Abstract
A synthesis of (15:1)-urushiol, urushiol monoene, 3-[(Z)-pentadec-8-enyl] catechol, 1,2-dihydroxy-3-[(Z)-pentadec-8-
enyl] benzene, one of the toxic principles of Rhus toxicodendron and of Rhus vernicifera is described. 6-Chlorohexan-1-
ol protected at the OH group with ethyl vinyl ether reacted with 2,3-dimethoxybenzaldehyde in the presence of lithium
to give, after removal of the protective group with methanolic 4-toluenesulphonic acid, 1-(2,3-dimethoxyphenyl)
heptane-1,7-diol. Catalytic hydrogenolysis in ethanol with palladiumꢀcarbon selectively afforded 7-(2,3-dimethox-
/
yphenyl)heptane-1-ol accompanied by a small proportion of the 7-(3-methoxyphenyl)heptane-1-diol, formed by
demethoxylation. Reaction of the dimethoxy compound with boron tribromide resulted in both bromination and
demethylation to give 7-(2,3-dihydroxyphenyl) heptylbromide. This bromide in tetrahydrofuran (THF) containing
hexamethylphosphoric triamide reacted with excess lithium oct-1-yne to give 3-(pentadec-8-enyl)catechol which, by
catalytic hydrogenation in ethyl acetate containing quinoline, selectively formed the required cis product, 3-[(Z)-
pentadec-8-enyl]catechol which was identical chromatographically and spectroscopically with urushiol monoene
separated from the natural product.
# 2002 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Phenolic lipid; Urushiol; 3-Alkenylcatechol; Rhus genus; Synthesis; Alkynes
1. Introduction
(Nagase and Miyakoshi, 1997, 1998) and histori-
cally a material of great antiquity (Tyman, 1979;
Snyder, 1989). Structurally related substances are
also found in the saps of species found in Burma,
Taiwan and Vietnam. The related genus, namely
poison or ground ivy, (Rhus toxicodendron) is
found mainly in North America and contains
similar phenolic lipids. Early studies (Majima,
1922) indicated the heterogeneous nature of R.
vernicifera and later chromatographic and struc-
tural work (Sunthankar and Dawson, 1954; Symes
and Dawson, 1954) on R. toxicodendron led to the
Rhus vernicifera, the lacquer tree, indigenous
notably in Japan, China, and Korea, is a source of
urushi and the enzyme laccase, both of which have
a current commercial and an historical interest in
the economy and culture of those countries
ꢀ Long chain phenols, part 36.
* Corresponding author. Tel./fax: ꢁ
E-mail address: jhptyman@hotmail.com (J.H.P. Tyman).
/
44-20-8878-6314
0009-3084/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 0 0 9 - 3 0 8 4 ( 0 2 ) 0 0 1 2 5 - 1

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/
isolation of the saturated, the 8-monoene, the 8,11-
diene and 8,11,14-triene constituents (Fig. 1 aꢀd)
and from R. vernicifera a, b, c and e.
The quantitative composition and also the
isolation of the 8,11,14-triene from R. vernicifera
was effected by GC and GC/MS studies (Tyman
and Matthews, 1982; Tyman et al., 1993). Other
capillary GC analyses of R. vernicifera (Du et al.,
1984) have indicated greater complexity and in
dimethoxybenzaldehyde (2) which, in the presence
of lithium, was reacted with 6-chlorohexane-1-ol
(protected at the OH group by ethyl vinyl ether) to
give, after protective group removal, 7-(2,3-di-
methoxyphenyl)heptane-1,7-diol (3). Catalytic hy-
/
drogenolysis with PdÃ
(2,3-dimethoxyphenyl)heptan-1-ol (4, Rꢂ
Bromination and demethylation then smoothly
gave 1-bromo-7-(2,3-dihydroxyphenyl)-heptane
/C in ethanol afforded 7-
/OMe).
(5), alkylation of which with excess lihthio-oct-1-
yne yielded 1,2-dihydroxy-3-(pentadec-8-ynyl)ben-
addition to aꢀe, an 8Z, 11E-diene, an 8Z, 11E,
/
13Z-triene and a number of C17 constituents have
been identified. More recently, capillary GC and
supercritical fluid chromatography (Bartus et al.,
1994) and pyrolysis GC (Kawanobe, 1996) have
been studied.
zene (6). Selective catalytic reduction with PdÃ
ethanol containing quinoline afforded, in excellent
yield, urushiol monoene, (15:1)-urushiol (1b; Rꢂ
R1ꢂ
OMe), which was spectroscopically and
/
C in
/
/
chromatographically identical with the natural
product.
Reagents: (i) Me2SO4, K2CO3, Me2CO; (ii) Li,
THF, Cl(CH2)6OCHMe(OEt); EtOH, HCl; (iii)
For structure/property studies the usage of pure
constituents is advantageous and, since the isola-
tion of these by chromatography of the natural
product is laborious and the constituents are
subject to degradation, synthesis becomes a viable
alternative. Furthermore, recent interest in artifi-
cial urushi (Ikeda et al., 2001; Nagase and
Miyakoshi, 1997) suggests that synthetic analo-
gues could be of significance in structure/property
studies. Apart from its polymer technology (Vogl,
2000; Bartus et al., 1994), urushiol has a wood
preservative use (Sato and Saito, 1996), medical
applications (Wakida, 1992) and anticancer po-
tential (Hong et al., 1999).
A synthesis of urushiol monoene had been
described in an earlier preliminary communication
(Tyman and Khor, 1974) although no experimen-
tal details were given; this present account supplies
this information (Scheme 1). In our route, depicted
in Scheme 1, o-vanillin was converted to 2,3-
PdÃ
BBr3, ꢃ
HMPT; (vi) PdÃ
/
C, EtOH, H3Oꢁ; (iv) CHCl3, PBr3, 0 8C;
/
80 8C; H3Oꢁ (v) 3LiCÅ
BaSO4, H2, EtOAc, quinoline.
/
CC6Hl3, THF,
/
2. Experimental procedures
2.1. Extraction of material
R. toxicodendron, poison ivy, in the form of
twigs and leaves was kindly supplied by J. Keesing
from the Japanese Garden at the Royal Botanic
Garden at Kew, Surrey, UK. R. vernicifera was
obtained through the agency of the Japanese
Trade Centre, London, from Dr M. Sato, Indus-
trial Research Institute, Sendai, Japan.
Fig. 1. Formulae of some of the constituents of urushiol from R. vernicifera and R. toxicodendron (Rꢂ
/
R1ꢂ
OH).
/

J.H.P. Tyman et al. / Chemistry and Physics of Lipids 120 (2002) 101ꢀ
/
108
103
Scheme 1. Synthesis of urushiol monoene.
2.2. Chromatography
natural urushiol were analysed on a 2% PEGA
column.
Analytical TLC was performed on slides (2.5ꢄ
/
7.5ꢄ0.25 mm) coated with silica gel GF-254
/
2.3. Spectroscopy
(Merck) with solvents as indicated and plates
were visualised by spraying with 0.1% ethanolic
Rhodamine 6G and viewing under long wave UV
light.
Infrared spectra were recorded on a Perkinꢀ
/
Elmer Model 700 as neat liquid films on sodium
chloride discs and on a Unicam SP200 instrument.
1H NMR spectra were recorded on a Varian T60
spectrometer with tetramethylsilane as internal
standard. Mass spectra were determined on AEI
Argentation TLC was carried out on silica gel G
containing 10% silver nitrate with similar visuali-
sation. Argentated preparative and analytical
plates were prepared by slurrying silica gel G
with aqueous silver nitrate solution containing
10% AgNO3 on the weight of silica gel G used in
a volume of water approximately double the
weight of silica gel G. Spreading was then carried
out as rapidly as possible on slides or preparative
plates on described equipment (Tyman and Hig-
MS9 and Hitachiꢀ
/
PerkinꢀElmer RMS4 instru-
/
ments.
2.4. Synthesis of intermediates and final product
Starting materials were obtained from Aldrich
Chemical Co. 6-Chlorohexanol was prepared (Co-
leman and Bywaters, 1944) from readily available
hexane-1,6-diol.
don, 1972). For preparative TLC, plates 20ꢄ
cm were used with similar viewing.
Column chromatography was carried out with
silica gel MFC (100ꢀ200 mesh) (British Drug
/
20
/
2.4.1. HO-protected 6-chlorohexan-1-ol
Houses, Poole, Dorset). GC of all intermediates
was carried out with a Pye 104 (model 64)
To ethyl vinyl ether (37.0 g, 0.50 mol), cooled to
0 8C, containing 4-toluenesulphonic acid (35 mg),
6-chlorohexan-1-ol (3.44 g, 0.025 mol), was added
dropwise over 20 min, during which the tempera-
ture was kept at 0 8C. The cooling bath was
removed and further catalyst (25 mg) added, after
equipped with FID on glass columns (5ꢄ
/
1/4 in.)
120
mesh) with nitrogen (7 psi) as carrier gas at
containing 3% SE30 on diatomite C (100ꢀ
/
220 8C. The methyl ethers of synthetic and

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J.H.P. Tyman et al. / Chemistry and Physics of Lipids 120 (2002) 101ꢀ108
/
which the mixture was stirred for 1 h. The mixture
was then cooled below 5 8C and, after TLC
monitoring for completion of reaction, saturated
aqueous potassium carbonate (5 ml) was added
with vigorous stirring followed by solid K2CO3 to
remove water. After drying, the mixture was
filtered, the solid washed with diethyl ether and
the filtrate evaporated to remove solvent and
excess ethyl vinyl ether to leave the adduct as a
Repeated preparations gave yields consistently
from 86 to 97%. By GC, retention time 4.65 min
(SE30, 220 8C).
2.4.4. 7-(2,3-Dimethoxyphenyl)heptan-1-ol (4,
Rꢂ
The purified diol (10.03 g, 0.037 mol) in ethanol
(200 ml) containing 10% PdÃC (1.01 g) was
/OMe)
/
hydrogenated at 15 psi in a Parr hydrogenator
with agitation over 16 h. Because of slow uptake of
hydrogen, further catalyst (0.5 g) and ethanol (5
ml), containing eight drops cone, HCl) were
introduced into the hydrogenation flask. Follow-
ing further agitation and TLC monitoring, the
mixture was released to atmospheric pressure
under a nitrogen atmosphere, filtered to remove
catalyst and the filtrate slightly basified with 5%
aqueous sodium bicarbonate, prior to evaporation
of the ethanol. The residual oil in diethyl ether was
washed with sodium hydroxide solution, with
aqueous sodium chloride, dried (Na2SO4), filtered
and the solvent removed to afford an oil (7.2 g,
76%). The product was further purified, by va-
cuum distillation under nitrogen, to give five
fractions the main fraction being the fourth, (4.7
colourless oil (45.7 g, 88%); dH (CCl4) 1.0ꢀ
(14H, t, m, 2Me, 4CH2), 3.10ꢀ3.55 (4H, 2t, CH2O,
CH2Cl), 4.45 (1H, OCHO).
/1.80
/
2.4.2. 2,3-Dimethoxybenzaldehyde (2)
2,3-Dimethoxybenzaldehyde was prepared by
the methylation of o-vanillin (27.2 g) with di-
methyl sulphate (27.7 g) in benzene (caution toxic)
(150 ml) containing anhydrous potassium carbon-
ate (50 g) and obtained as pale yellow crystals,
m.p. 53ꢀ
s, 2OMe), 6.95ꢀ
CHO).
/
55 8C in 98.7% yield; dH (CCl4) 3.95 (6H,
/7.40 (3H, m, 3HAr), 13.60 (1H, s,
2.4.3. 1-(2,3-Dimethoxyphenyl)heptane-1,7-diol
(3)
A solution of 2,3-dimethoxybenzaldehyde (16.6
g, 0.1 mol) and the above adduct (25.02 g, 0.12
mol) in THF (20 ml) was slowly added to lithium
as 0.2 mm cubes (1.735 g, 0.23 mol) covered with
THF while the temperature was maintained below
g, 70%), b.p. 131ꢀ
preferably, by column chromatography on silica
gel and elution with chloroform/ethylacetate. Re-
/
136 8C/0.02ꢀ0.04 mmHg, or,
/
peated preparations gave crude yields of 76.5ꢀ
and of purified product 50ꢀ56%. By TLC,
(CHCl3ÃEtOAc, 70:30), Rf 0.28.
/80%
/
10 8C and the mixture then stirred at ꢃ
/
20 8C for
/
16 h. After removal of excess lithium by decanting
the mixture through glass wool, the filtrate was
diluted with diethyl ether, washed with saturated
ammonium chloride solution and the ethereal
layer dried (MgSO4) and evaporated to constant
weight. The residual oil in ethanol (50 ml),
containing cone. HCl (1 ml), was then stirred at
The crude product (4.0 g) in chloroform (4.0 g)
was chromatographed on silica gel (MFC, 180 g)
and eluted with 6ꢄ
ethylacetate(E) of compositions, 100C, 80Cꢀ
120E, 75Cꢀ25E, 3ꢄ70Cꢀ30E, to give six frac-
/
250 ml of chloroform(C)ꢀ
/
/
/
/
/
tions, respectively, the 4th of which contained the
product (1.80 g, 45%) also present in small amount
in the 3rd and 5th fractions; dH (CCl4), 1.35 (10H,
s, 5CH2), 2.55 (2H, t, CH2Ar), 2.65 (1H, s, OH,
exch. D2O), 3.45 (2H, t, CH2OH), 3.75 (6H. s,
35ꢀ40 8C for 5 h, diluted with water and ex-
/
tracted with diethyl ether. The combined extracts
were washed with 0.5 M sodium hydroxide, dried
(MgSO4) and the ether evaporated to afford the
crude product as a pale yellow oil (24 g, 89.5%);
the crude diol was purified by vacuum distillation,
2MeO), 6.50ꢀ ,
6.95 (3H, m, HAr); nmax (cmꢃ1
/
NaCl disc), 3350 (OH), 2930, 2850 (CH2), 1590,
1580, 1470, 1420, 1265, 1220, 1170, 1080, 1060,
1010, 745; m/z 252 (Mꢁ), 122 (base peak). By GC,
retention time 4.05 min (SE30, 220 8C).
An earlier fraction in the vacuum distillation of
the main product and also a band with higher Rf in
b.p. 190ꢀ
/
210 8C/0.1ꢀ
/
0.3 mmHg; dH (CCl4) 1.05ꢀ
/
1.80 (10H, m, 5CH2), 3.05 (2H, s, 2OH, D2O
exch.) 3.45 (2H, t, CH2OH), 3.75 (6H s, 2OMe),
4.55 (1H, t, CH(OH)), 6.65ꢀ7.05 (3H, m, HAr).
/

J.H.P. Tyman et al. / Chemistry and Physics of Lipids 120 (2002) 101ꢀ
/
108
105
prep TLC, was concluded, from spectroscopic
evidence, to be a 2-demethoxylation product,
ride, dried (Na2SO4) and the ether removed in
vacuo to leave a pale oil; dH (60 MHz, CCl4) 0.80ꢀ
0.98 (3H, t, Me), 1.32 (18H, s, (CH2)9, 1.92ꢀ2.32
(4H, m, 2CH2CHÄ), 2.44ꢀ2.66 (2H, t, CH2Ar),
6.48ꢀ
6.68 (3H, m, HAr); nmax (cmꢃ1, NaCl disc)
3450 (OH), 2800, 2650 (CH2), 2000 (CÅC), 1475
(CÃH, def.), 830 (CÃH, arom.). By TLC, (CHCl3Ã
/
namely 7-(3-methoxyphenyl)heptan-1-ol (4, Rꢂ
/
/
H); m/z 222 (Mꢁ) 220, 192, 147, 135, 122 (base
peak), 121, 91, 78, 7741, 39, 28, 18. By GC,
retention time 3.15 min (SE30, 220 8C).
/
/
/
/
/
/
/
2.4.5. 7-(2,3-Dihydroxyphenyl)heptyl bromide (5)
7-(2,3-Dimethoxyphenyl)heptan-1-ol (l.79 g,
0.0071 mol) in dry chloroform (50 ml) was treated
with phosphorus tribromide (2.36 g, 0.0087 mol) in
chloroform (10 ml) and the temperature of the
stirred mixture kept at 0 8C. Then, after 4 h at
ambient temperature with TLC monitoring, for-
mation of the bromide, 7-(2,3-dimethoxyphe-
nyl)heptyl bromide was complete. To the
mixture, boron tribromide (4.7 g) was added and
after 7 days, during which the progress of
demethylation was followed by TLC and GC,
the mixture was carefully diluted with ice/water,
and the chloroform solution washed with water
until neutral, dried (Na2SO4) and the chloroform
removed in vacuo to leave a faintly pink coloured
oil (1.58 g, 77.5%) which was purified by prep TLC
EtOAc, 95:5) Rf 0.53. By GC, retention time 20.4
min. (SE30, 220 8C).
2.4.7. 3-[(8Z)-Pentadecenyl]catechol (1b)
3-(Pentadec-8-ynyl)catechol (0.155 g, 0.0049
mol) in ethyl acetate (3 ml) containing 5% PdÃ
/
BaSO4 (0.16 g) and quinoline (one drop) in
methanol (1.5 ml) was hydrogenated at ambient
pressure and temperature until the required uptake
of hydrogen (11 ml) had been consumed. The
mixture was filtered, the catalyst was washed with
diethyl ether and the filtrate then washed with
dilute HCl, followed by sodium chloride solution,
dried and the ether evaporated to give an oil; dH
(60 mHz, CCl4), 0.08ꢀ
m, (CH2)9, 1.80ꢀ2.20 (4H, m, 2CH2CHÄ
2.72 (2H, t, CH2Ar), 5.00ꢀ5.40 (2H, bs, OH, exch.
D2O), 5.23ꢀ5.40 (2H, t, CHÄCH, J, 5.5, Hz), 6.43
(3H, s, HAr); nmax (cmꢃ1, NaCl disc) 3400 (bs,
OH), 2900, 2840 (CH2), 1595 (CÃO), 1475 (CÃH,
def.), 835 (CÃH, arom.); the product was chroma-
/
0.98 (3H, t, Me), 1.32 (18H,
/
/
), 2.44ꢀ
/
/
(ethyl acetateꢀ
/
chloroform, 20:80); dH (CCl4) 1.40
/
/
(10H, s, 5CH2), 2.60 (2H, t, CH2Ar), 3.37 (2H, t,
CH2Br), 5.60 (2H, bs, OH, exch. D2O), 6.65 (3H,
s, HAr). The bromide (1.55 g) was also prepared
also from the heptanol (1.70 g) in dichloromethane
(17 ml) directly with boron tribromide (5.08 g) in
dichloromethane (7.5 ml) in 80% yield. Repeated
preparations gave yields of 80%, and above. By
/
/
/
tographically (TLC and GC) and spectroscopically
(IR and NMR) identical with natural (15:1)-
urushiol; by TLC on silica gel G (CHCl3Ã
90:10), Rf 0.56 for both synthetic and natural
urushiol; on silica gel G containing 10% AgNO3
/
EtOAc,
TLC, (CHCl3Ã
/
EtOAc, 80:20), Rf 0.61. By GC,
retention time 4.75 min (SE30, 220 8C).
(CHCl3Ã/EtOAc, 80:20), Rf 0.69 for both the
natural and synthetic monoene. By GC, retention
time, 17.3 min, natural mixture monoene, diene,
triene 17.5 min (SE30, 220 8C).
2.4.6. 3-(Pentadec-8-ynyl)catechol (6)
To 7-(2,3-dihydroxyphenyl)heptyl bromide
(0.5176 g, 0.00194 mol) in THF (1.5 ml), contain-
ing HMPT (1 ml), a solution of lithio oct-1-yne in
THF (10 ml) prepared from 1-octyne (1.365 g,
0.0124 mol) and 1 M n-butyl lithium in hexanes
(0.572 g, 0.0105 mol) was added under nitrogen at
The dimethyl ether (1b; Rꢂ
/
R1ꢂ
OMe) was
/
also obtained on an analytical scale from 7-(2,3-
dimethoxyphenyl)heptyl bromide derived from 4
with phosphorus tribromide by reaction with
lithio-1-octyne and catalytic hydrogenation of the
resultant alkyne. The bromide prepared from the
heptanol with phosphorus tribromide was reacted
in HMPT with excess lithio oct-1-yne and the
product purified by TLC, and catalytically hydro-
genated as for the catechol analogue to give 3-
[8(Z)-pentadecenyl]veratrole, which was chroma-
ꢃ50 8C and the stirred mixture maintained at
/
that temperature, before TLC monitoring and
completion of the reaction at ambient tempera-
ture. The mixture was diluted with water, neutra-
lised and extracted with ether. The combined
extracts were washed with aqueous sodium chlo-

106
J.H.P. Tyman et al. / Chemistry and Physics of Lipids 120 (2002) 101ꢀ108
/
tographically (GC and TLC) identical to the
methylated monoene in methylated natural urush-
iol.
monoene (31.8%, 9.5 min), diene (47.5%, 11.6 min)
and triene (15.8%, 14.0 min).
2.4.8. Extraction of urushiol from Rhus
toxicodendron
3. Results and discussion
Dried crushed twigs cut in 0.5ꢀ0 75 in. lengths
/
There have been a number of attempts to
synthesise urushiol constituents, commencing
with the saturated member (1a) and subsequently
the (15:1)-monoene. The dimethyl ether of the cis-
(7.30 g) were extracted in a Soxhlet apparatus
during 3 h with ethanol (300 ml), secondly with
(200 ml) and finally with (100 ml) until the final
ethanol extract was only faintly coloured. The first
two extracts afforded upon evaporation, 0.0608
and 0.1022 g, respectively, of crude urushiol which
monoene (1b, Rꢂ
/
R1ꢂ
OMe) was prepared (Was-
/
serman and Dawson, 1943) although not the
parent catechol; but its synthesis was claimed
from the debenzylation of a 1,8-diene intermediate
of 1 (Loev and Dawson, 1959) although the
product was not characterised chromatographicaly
or spectroscopically. Subsequently, the 2,3-diben-
was dissolved in diethyl ether to give a greenꢀ
/
brown solution. Prep TLC (chloroformꢀethyl
/
acetate, 90:10) gave a main band with Rf 0.67 of
mixed urushiol. Elution with 10% methanol in
ether and recovery afforded a product (0.0712 g)
having, by TLC comparison with the synthetic
product, an identical Rf of 0.69. Argentation TLC
zyl ether of urushiol itself (1, Rꢂ
/
R1ꢂ
OBn) was
/
separated on alumina into the dibenzylmonoene,
diene and triene each of which was debenzylated
by the same procedure in hot butanol with sodium
(Markiewitz and Dawson, 1965) a procedure likely
to cause some conjugation of the unsaturation. By
the use of 8-(2,3-dimethoxyphenyl)octanal, ob-
tained from urushiol dimethyl ether by ozonisa-
tion, a partial synthesis of the dimethyl ether of the
monoene, and later of the diene and triene, was
effected (Sato, 1973) through a Wittig reaction,
but without stereochemical characterisation. The
alkene group(s) can be formed by either a Wittig
reaction or by way of an alkyne precursor and
examples of both approaches have been given
(Tyman, 1979, 1996). Although the relative pro-
portion of cis/trans isomers is predictable by
operating under kinetic or thermodynamic con-
trol, the alkyne/alkene route generally seems to be
more specific. An acetylenic route afforded the
monoene but in low overall yield (Halim et al.,
1980). In this approach, 2,3-dimethoxyphenyl
lithium was reacted with 1,7-dibromoheptane to
give 1-bromo-7-(2,3-dimethoxyphenyl)heptane in
low yield1. Alkylation of this bromo derivative
(chloroformꢀethyl acetate, 80:20) separated the
monoene (Rf 0.69), diene (Rf 0.63) and triene (Rf
0.57) constituents.
/
2.4.9. Methylation of synthetic monoene and of
natural urushiol from Rhus toxicodendron
The synthetic monoene (0.010 g) in benzene
(0.50 ml) containing dimethyl sulphate (0.05 ml)
and potassium carbonate (0.20 g) was refluxed
during 2.5 h under nitrogen. The cooled mixture
was diluted with water, and after the addition of
diethyl ether, the upper solvent layer was sepa-
rated, dried and concentrated to give the dimethyl
ether as an oil. Methylation proceeds (TLC
monitoring) by way of the monomethyl ether
(1b; Rꢂ
/
OMe, R1ꢂ
OH) (Tyman and Matthews,
/
1977) which has properties reminiscent of the
‘hindered’ phenols.
In a similar way, the natural material (0.0016 g)
in benzene (0.20 ml) containing dimethyl sulphate
(002 ml) and potassium carbonate (0.10 g) was
methylated and worked up as before. By GC, the
retention time of the methylated synthetic mono-
ene was 9.45 min (2% PEGA, 200 8C) in agree-
ment with the methyl ether of the monoene in the
fully methylated natural product, for the constitu-
ents of which the per cent composition and
retention times were, saturated (4.8%, 8.8 min),
1
Halim et al. (1980) very kindly acknowledged (p. 2331) that
only the synthesis by Tyman and Khor appears to be
satisfactory but it is unfortunate that these experimental
details and yields have not been reported until now.

J.H.P. Tyman et al. / Chemistry and Physics of Lipids 120 (2002) 101ꢀ
/
108
107
with lithio oct-1-yne afforded 1,2-dimethoxy-3-
(pentadec-8-ynyl)benzene, which was catalytically
hydrogenated to the corresponding alkene. De-
methylation by way of trimethylsilyl iodide af-
forded, by way of the bis trimethylsilyl derivative,
the required product (15:1)-urushiol, (1b) in very
low overall yield. More recently the 8Z, 11Z, 14
and 8Z, 11E, 13E-trienes have been synthesised
(Miyakoshi et al., 1991) by a Wittig reaction of 8-
(2,3-diacetoxyphenyl)octanal with a C7 unsatu-
rated phosphoran which in the case of the 8Z,
11Z, 14-triene gave a 42% yield compared with
graphy or preparative TLC. Initially 7-(2,3-di-
methoxyphenyl)heptyl bromide (5) was prepared
with phosphorus tribromide but a further advan-
tage in the present route was the reaction of the
dimethoxy compound (4) with boron tribromide
alone at low temperature to effect both demethy-
lation and bromide formation to give (5).
Although the resulting dihydroxyphenyl com-
pound consumed 3 mol of lithio oct-1-yne at the
next stage, the 2,3-dithio salt of 7-(2,3-dihydrox-
yphenyl)heptyl bromide was soluble in the reaction
mixture and formation of the pentadecynyl pro-
duct (6) proceeded in excellent yield. By contrast,
the demethylation stage in the synthesis the Halim
et al. (1980) required two additional steps while in
the route adopted by Miyakoshi et al. (1991) the
catechol system was acetylated prior to Wittig
reaction and finally deacetylaion effected with
LiAlH4 in only moderate yield. We had in earlier
work found catalytic reduction with Lindlar’s
catalyst to be very slow and hence adopted the
yields of 65ꢀ
/
90% generally found in the alkyneꢀ
/
alkene route. The Wittig sequence described in-
volves the conversion of a terminal v-bromo to an
v-iodooctyl group and then to the oxo group in 8-
(2,3-diacetoxyphenyl)octanal, with some loss of
yield.
The low yield (22%) in the first stage lithium
reaction by Halim et al. (1980) with 1,7-dibromo-
heptane leading to 1-bromo-7-(2,3-dimethoxyphe-
nyl)heptane is probably attributable to Wurtz side
reactions and contrasts with that of 84% reported
by Miyakoshi et al. for the homologous 1,8-
dibromooctane, but may indicate the unpredict-
able character of this reaction. Wurtz side reaction
also occurs in Grignard reactions resulting in the
persistent by-product, dodecane-1,12-diol, which
was difficult to remove.
In our own work, this deviation was avoided by
using nucleophilic addition of 2,3-dimethoxyben-
zaldehyde to HO-protected 6-chlorohexan-1-ol in
the presence of lithium. This sequence had proved
highly effective for routes in the synthesis of the
monoenes of the phenolic lipid analogues cardanol
and cardol (Tyman, 1996) by way of the respective
3-methoxy or 3,6-dimethoxyphenylheptane-1,7-
diols.
method using PdÃ/C poisoned with quinoline
which was found to be capable of careful regula-
tion in selectively affording the cis-alkene without
reduction to the alkane. The derivation of a
satisfactory route to (5) also provides a method
towards the diene (1c) and triene (1d), by forma-
tion of 10-(2,3-dihydroxyphenyl)dec-2-yn-1-ol and
reaction of the derived bromide with magnesio
bromo derivatives of 1-pentyne and of pent-1-yn-
4-ene, followed by selective reduction, work
which will be described elsewhere. The same
procedure in the present synthesis with p-vanillin,
in place of the o-isomer, might be employed for
the 4-alkenylcatechols of the thitsiol series, the
saturated constituent of which, 1,2-dihydroxy-4-
pentadecylbenzene, has been synthesised (Tyman,
1973).
Selective catalytic hydrogenolysis of the second-
Phenolic lipids are a significant group in the
general family of lipids although their syntheses
have generally received little attention (Gunstone,
1999). Thus it is believed that the methodology
described in the present communication and
developed over the past two decades gives access
to range of intermediates and procedures for
the synthesis of structural isomers and C17 analo-
gues.
ary OH group in (3) with PdÃ
/
C proceeded in high
yield and thus it was unexpected to encounter
demethoxylation of the 2-methoxy group, albeit in
low yield, in the present work to give by-product,
7-(3-methoxyphenyl)heptane-1-ol (Tyman, 1975);
the consumption of hydrogen, allowing for some
adsorption by the catalyst, was found to be nearly
the theoretical volume. This minor by-product was
easily removable either by distillation, chromato-

108
J.H.P. Tyman et al. / Chemistry and Physics of Lipids 120 (2002) 101ꢀ108
/
Sato, M., 1973. Synthesis of 8,11-diene and 8,11,13-triene of
urushiol. Yakugaku 22, 349ꢀ350.
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