An efficient and facile synthesis of capsaicin-like compounds as agonists of the TRPV1 receptor

Article abstract of DOI:10.1002/ejoc.200600135

A new versatile synthetic route is described for the preparation of capsaicin-like molecules which contain an α-hydroxy ketone functional group mimicking the amide functional group in the capsaicin structure. The key reaction in this synthesis was the formation of α-(dimethylamino) alkanenitriles as intermediates. These nitriles were successfully prepared from both aliphatic and aromatic aldehydes by reaction with dimethylamine and aqueous sodium cyanide. Treatment of the nitriles with lithium diisopropylamide (LDA) followed by reaction with various aldehydes led to the formation of α-hydroxy ketone compounds, examples of which include 2-hydroxy-1-(4- hydroxy-3-methoxyphenyl)dodecan-3-one, (5R)- and (5S)-2-hydroxy-1-(4-hydroxy-3- methoxyphenyl)-5,9-dimethyldec-8-en-3-one, representing novel capsaicin-like molecules. Formation of (4-benzyloxy-3-methoxyphenyl)-acetaldehyde was also described from the Wittig reaction of 4-benzyloxy-3-methoxybenzadehyde with an ylide reagent (methoxymethyl)triphenylphosphonium bromide followed by acid hydrolysis to form the title compound. This aldehyde represents a useful precursor for the synthesis of capsaicin-like structures. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200600135

FULL PAPER
DOI: 10.1002/ejoc.200600135
An Efficient and Facile Synthesis of Capsaicin-Like Compounds as Agonists of
the TRPV1 Receptor
Van H. Tran,[a] Ravi Kantharaj,[a] Basil D. Roufogalis,[a] and Colin C. Duke*[a]
Keywords: α-Hydroxy ketone / Wittig reaction / Aldol reactions / Capsaicin / TRPV1
A new versatile synthetic route is described for the prepara-
tion of capsaicin-like molecules which contain an α-hydroxy
ketone functional group mimicking the amide functional
group in the capsaicin structure. The key reaction in this syn-
thesis was the formation of α-(dimethylamino)alkanenitriles
as intermediates. These nitriles were successfully prepared
from both aliphatic and aromatic aldehydes by reaction with
dimethylamine and aqueous sodium cyanide. Treatment of
the nitriles with lithium diisopropylamide (LDA) followed by
reaction with various aldehydes led to the formation of α-
hydroxy ketone compounds, examples of which include 2-
hydroxy-1-(4-hydroxy-3-methoxyphenyl)dodecan-3-one,
(5R)- and (5S)-2-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-
5,9-dimethyldec-8-en-3-one, representing novel capsaicin-
like molecules. Formation of (4-benzyloxy-3-methoxyphenyl)-
acetaldehyde was also described from the Wittig reaction of
4-benzyloxy-3-methoxybenzadehyde with an ylide reagent
(methoxymethyl)triphenylphosphonium bromide followed by
acid hydrolysis to form the title compound. This aldehyde
represents a useful precursor for the synthesis of capsaicin-
like structures.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
pounds with modified structures, particularly the thiourea
derivatives, exhibited even more potent activity than capsa-
icin in increasing 45Ca2+ influx in DRG neurones.[11]
Introduction
Capsaicin, the main pungent principle in “hot” chilli
peppers of the Capsicum family, was identified with an ini-
tial action to activate the “capsaicin receptor” or vanilloid
ion-channel receptor (TRPV1) in the sensory nervous sys-
tem.[1–4] One well known property of capsaicin is to excite
some, but not all, sensory neurones and by doing so, capsa-
icin evokes an inward depolarizing current which is associ-
ated with a conductance increase, and the sensation of
“burning”.[1,5] Exposure to capsaicin results in activation,
followed by desensitization, of lightly myelinated or unmy-
elinated primary afferent fibers.[2] The latter is believed to
account for the antinociceptive effect observed in a number
of analgesic models.[6–9]
Structure–activity relationship studies on capsaicin-like
compounds have been extensively investigated and have in-
volved modification of three regions of the capsaicin struc-
ture: the aromatic region (A region),[10] the amide func-
tional group (B region)[11] and the hydrophobic side chain
(C region)[12] (Figure 1). In the amide functional group in
Figure 1. Structures of capsaicin and [6]-gingerol.
We have discovered [6]-gingerol [5-hydroxy-1-(4-hydroxy-
particular, the carbonyl and the amino group were either 3-methoxyphenyl)decan-3-one] (Figure 1), a pungent prin-
interchanged or replaced with an urea or thiourea group.[11] ciple of the rhizome of ginger (Zingiber officinale) activates
It was shown that almost all compounds containing amide, capsaicin-sensitive receptor isolated from dorsal root gan-
“reversed” amide, urea or thiourea functional groups exhib- glia of neonatal rats. This activation was abolished by the
ited potent activity in increasing 45Ca2+ influx in dorsal TRPV1 antagonist capsaizepine.[13] [6]-Gingerol, however,
root ganglion (DRG) neurons.[11] In some cases, com- contains a chemically labile β-hydroxy ketone (B region)
group, which is prone to dehydration to form [6]-shogaol
[1-(4-hydroxy-3-methoxyphenyl)dec-4-en-3-one].[14] Intro-
[a] Faculty of Pharmacy, University of Sydney,
NSW 2006, Australia
duction of an α-hydroxy ketone functional group at the B
region to replace the amide group in capsaicin, and β-hy-
Fax: +612-93514391
E-mail: colind@pharm.usyd.edu.au
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Synthesis of Capsaicin-Like Compounds as Agonists of the TRPV1 Receptor
FULL PAPER
droxy ketone group in [8]-gingerol [5-hydroxy-1-(4-hydroxy- nitriles 5 and 6 were prepared from optically pure (R)- and
3-methoxyphenyl)dodecan-3-one] not only improves chemi- (S)-3,7-dimethyl-6-octenal enantiomers, respectively, which
cal stability of the compound but also retains agonistic ac- were commercially available. Lithium derivatives of aro-
tivity on the TRPV1 from rat isolated DRG neurons.[15]
matic α-(dimethylamino)alkanenitriles proved to be more
We report here the synthesis of a novel class of TRPV1 reactive than those of aliphatic α-(dimethylamino)alkaneni-
agonists containing an α-hydroxy ketone functional group, triles in the condensation reaction (step ii, Scheme 1; step
via aldol condensation of an aldehyde with an α-(dimeth- iv, Scheme 2), which was carried out at a temperature of
ylamino)alkanenitrile intermediate. The latter is obtained not higher than –50 °C, as above this temperature polymeri-
from the reaction of aliphatic or aromatic aldehydes with sation may occur. Yields were moderate in most cases, and
dimethylamine and aqueous sodium cyanide. This concise products were readily purified by normal-phase silica gel
and versatile synthetic route allowed us to obtain com- short-column vacuum chromatography as described in the
pounds with the α-hydroxy ketone functional group at C1 Exp. Sect.
(14), C2 (17, 18 and 19), or C3 (16) on the side chain. Of
particular interest is the series of compounds 17, 18 and 19,
which may be viewed as novel capsaicin analogues in which
the amide (NHCO) group is replaced by an α-hydroxy
ketone [CH(OH)CO] group. We also report the synthesis of
compounds with the “reversed” α-hydroxy ketone func-
tional group (20 and 22), where the hydroxy and ketone
groups are interchanged in their positions on the side chain
compared with the corresponding “parent” compounds 14,
and 16.
The tetrahydropyran-2-yl (THP) group was used as pro-
tecting group in Scheme 1 for its facile removal, which oc-
curred simultaneously with the conversion of the α-(dimeth-
ylamino)alkanenitriles to α-hydroxy ketone in aqueous ox-
alic acid.[16] The THP group was, however, unsuitable for
the synthesis of compounds 17, 18 and 19 according to
Scheme 2, because it would be cleaved by acid hydrolysis
(step iii, Scheme 2) of 10 to form 11. In this case a benzyl
group, readily removed by catalytic hydrogenation, was
used to protect the phenolic OH group.[17]
All synthetic routes described in this study can accom-
modate compounds with a double bond in the side chain,
which can be hydrogenated to produce saturated congeners
for structure-activity relationship study. Of particular inter-
est is the synthesis of 18 and 19 (Scheme 2 and Figure 2),
which contain a double bond at the methyl end of the side
chain, representing similar structure to the capsaicin mole-
cule. The protecting benzyl group was effectively removed
by palladium-catalyzed hydrogen transfer in cyclohexene
(step viii, Scheme 2).[18]
Results and Discussion
The synthetic routes as described in Scheme 1 and
Scheme 2 have resulted in compounds having an α-hydroxy
ketone functional group at C1 (14), C2 (17, 18, 19) or C3
(16) on the side chain relative to the aromatic moiety as
shown in Figure 2. These compounds, particularly 17, 18
and 19, represent novel capsaicin hybrid structures in which
the α-hydroxy ketone replaced the amide group in the cap-
All aldehydes used in this study are commercially avail-
saicin molecule (Figure 1). The synthetic route as described able except for (4-benzyloxy-3-methoxyphenyl)acetaldehyde
in Scheme 1 also allowed for the preparation of the so (11), which was obtained by Wittig reaction of 4-benzyloxy-
called “reversed” α-hydroxy ketone compounds 20 and 22, 3-methoxybenzaldehyde (i.e. vanillin benzyl ether) with a
in which the hydroxy and carbonyl group interchange their phosphorus ylide reagent generated from (methoxymethyl)-
position on the side chain compared with the correspond- triphenylphosphonium bromide and potassium tert-butox-
ing compounds 14 and 16, respectively (Figure 2). Struc- ide, as described in Scheme 2 (step ii). This aldehyde repre-
tures of the intermediate compounds are shown in Figure 3. sents a useful precursor for the synthesis of capsaicin hybrid
The formation of α-(dimethylamino)alkanenitriles 3–6 of structures in which the nitrogen atom in capsaicin structure
aliphatic aldehydes, as shown in step i of Scheme 1, from is replaced by an alcohol moiety to form an α-hydroxy
nonanal, decanal, (3R)-3,7-dimethyl-6-octenal and (3S)-3,7- ketone functional group that mimics the amide group in the
dimethyl-6-octenal, and α-(dimethylamino)alkanenitriles 7 capsaicin structure. The synthetic route described for the
and 8 from aromatic aldehydes, including 3-methoxy-4- preparation of α-hydroxy ketones in this study resulted in a
[(tetrahydro-2H-pyran-2-yl)oxy]benzaldehyde (1) and 3- racemic mixture, which allows for further isolation of op-
{3-methoxy-4-[(tetrahydro-2H-pyran-2-yl)oxy]phenyl}-2-prop- tically pure enantiomers for enantiospecific investigation of
enal (2), were achieved essentially in quantitative yield. The the compounds on the TRPV1 receptor.
Scheme 1. Reagents and conditions: (i) aq. NaHSO3, MeOH/H2O: 9:1, NH(CH3)2, aq. NaCN, room temp., 16 h, 4: 94%; (ii) 1.3 equiv.
LDA, THF, –80 °C to room temp., 2 h, then 1 equiv. of 1, –80 °C, 5 h; (iii) aq. oxalic acid, THF, reflux, 1.5 h followed by chromatography
14: 74%.
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V. H. Tran, R. Kantharaj, B. D. Roufogalis, C. C. Duke
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Scheme 2. Reagents and conditions: (i) NaH, DMF, PhCH2Br, room temp., 30 min, followed by chromatography, 9: 92%; (ii) 1 equiv.
(methoxymethyl)triphenylphosphonium bromide, 1.5 equiv. potassium tert-butoxide, 0 °C, 30 min, followed by chromatography, 10: 78%;
(iii) THF/HCl, reflux, followed by chromatography, 11: 60%; (iv) 1 equiv. 4 [or (vii) 1 equiv. 5], 1.3 equiv. LDA, THF, –80 °C to room
temp., 2 h, then 1 equiv. 11, –80 °C, 5 h; (v) aq. oxalic acid, THF, reflux, 1.5 h, followed by chromatography, 12: 85% or 13: 78%; (vi)
H2, Pd-C, EtOAc, room temp., 4 h, followed by chromatography, 17: 92%; (viii) EtOH/cyclohexene: 2:1, Pd-C, reflux, 3 h, followed by
chromatography, 18: 80%.
Figure 2. Structures of α-hydroxy ketone compounds.
Figure 3. Structures of intermediate compounds.
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Synthesis of Capsaicin-Like Compounds as Agonists of the TRPV1 Receptor
FULL PAPER
and are uncorrected. 1H and 13C spectra were recorded with Varian
Gemini 300 BB spectrometer [300 MHz, δ = 0 ppm (TMS), in
CDCl3]. Chemical shifts are expressed in ppm (δ relative to TMS
as internal reference). J values are given in Hz. MS were measured
with ThermoFinnigan PolarisQ ion trap MS/MS system by elec-
tron impact (EI), or by chemical ionization (CH4). All experiments
sensitive to air and/or to moisture were carried out under nitrogen.
Analytical thin-layer chromatography (TLC) was performed on sil-
ica gel pre-coated TLC plates (Merck, 60, F254). Chromatographic
purification was carried out by short-column vacuum chromatog-
Preliminary investigation of the α-hydroxy ketones de-
scribed in this study for activity on the TRPV1 receptor
in isolated dorsal root ganglion (DRG) neurons in culture,
showed that these compounds, at 10 µ, evoked [Ca2+
]
i
transients in Fura-2 loaded DRG neurons.[15] The acti-
vation of the receptor by these α-hydroxy ketones exclu-
sively occurred in capsaicin-sensitive neurones and was an-
tagonised by capsazepine, a capsaicin receptor antago-
nist.[15]
The discovery of the series of α-hydroxy ketones as novel raphy using Merck silica gel (60 H). Anhydrous tetrahydrofuran
(THF) was freshly distilled from sodium hydride under nitrogen.
Anhydrous dichloromethane (CH2Cl2) was distilled from P2O5 un-
der nitrogen. Anhydrous dimethylformamide (DMF) was distilled
from CaH2 under nitrogen.
TRPV1 agonists was a result of combining structural fea-
tures of capsaicin and gingerol molecules in the develop-
ment of TRPV1 agonists. Molecular comparison of the
TRPV1 agonists using molecular modelling as described in
the Exp. Sect. showed that the molecular structures, par-
ticularly regions “A” and “B”, superimposed well to one
another (Figure 4) indicating that these molecules could act
on the same active site on TRPV1. These findings provide
a model for further drug design and structure–activity rela-
tionship analysis of α-hydroxy ketones as TRPV1 agonists.
Materials: Benzyl bromide, n-butyllithium, (3R)- and (3S)-3,7-di-
methyl-6-octenal, decanal, 3,4-dihydro-2H-pyran, anhydrous di-
methylamine, 2-(4-hydroxy-3-methoxyphenyl)ethanol, 4-hydroxy-3-
methoxycinnamaldehyde, nonanal, and vanillin were purchased
from Sigma–Aldrich. Pyridinium p-toluenesulfonate was prepared
as described in the literature.[19]
General Procedure for Short-Column Vacuum Chromatography: The
chromatography was carried out using normal-phase Merck silica
gel 60 H, which was packed under vacuum in a sintered funnel to
form a tightly packed silica bed.[20] To this bed a solution of the
compound in dichloromethane was loaded and eluted with stepwise
gradient of increased polarity of the mobile phase consisting of
hexane and ethyl acetate. Fractions were successively collected and
analysed by thin-layer chromatography (TLC). Fractions that had
a similar chromatographic profile were combined and the solvent
evaporated. Samples were subsequently characterised using NMR
and mass spectrometry.
3-Methoxy-4-(tetrahydropyran-2-yloxy)benzaldehyde (1). General
Procedure: To a solution of vanillin (5.0 g, 0.033 mol) and pyridin-
ium p-toluenesulfonate (0.1 g, 0.004 mol) in anhydrous dichloro-
methane (50 mL) was added dropwise 3,4-dihydro-2H-pyran (3 g,
0.036 mol). The mixture was stirred at room temperature for
24 h.[19] The solvent was removed under reduced pressure to give a
residue which was purified by normal-phase short-column vacuum
chromatography as described above to afford a colourless liquid,
Figure 4. Low-energy conformers of capsaicin, [8]-gingerol and α-
hydroxy ketone compounds. The molecules of the TRPV1 agonists
were constructed, energy minimisation and superimposed using
Maestro version 6.0.107, MM share version 1.2.014, Shrodinger,
L.L.C.
1
5.9 g, 76% yield. H NMR (CDCl3): δ = 1.78–1.56 (m, 3 H), 2.15–
1.85 (m, 3 H), 3.68–3.59 (m, 1 H), 3.88 (s, 3 H), 3.94–3.89 (m, 1
H), 5.57 (m, 1 H), 7.27 (d, J = 8.7 Hz, 1 H), 7.44–7.41 (m, 2 H),
9.86 (s, 1 H) ppm.
Conclusions
In summary, it was demonstrated that α-(dimethylamino)-
alkanenitriles, derived from various aldehydes including ali-
phatic and aromatic aldehydes, are versatile intermediates
for the synthesis of α-hydroxy ketone compounds to mimic
the amide functional group in the capsaicin molecule. As a
result, representative compounds with the α-hydroxy ketone
functional group at the C1, C2 or C3 position on the side
chain relative to the aromatic moiety were synthesised. The
synthetic routes described in this study allowed for the syn-
thesis of the respective α-hydroxy ketones and their “re-
versed” α-hydroxy ketone congeners for further structure-
activity relationship studies on the activation of the TRPV1
receptor in a drug discovery and development program.
3-[3-Methoxy-4-[(tetrahydropyran-2-yl)oxy]phenyl]-2-propenal (2):
The synthesis was accomplished according to the general procedure
as described for 1 starting with 4-hydroxy-3-methoxycinnamal-
dehyde (2 g, 0.011 mol). The product was purified by normal-phase
short-column vacuum chromatography as described above to afford
a yellowish solid, 2.0 g, 70% yield, m.p. 91–92 °C. 1H NMR
(CDCl3): δ = 1.78–1.58 (m, 3 H), 2.10–1.86 (m, 3 H), 3.68–3.61 (m,
1 H), 3.89 (s, 3 H), 3.99–3.90 (m, 1 H), 5.50 (m, 1 H), 6.66–6.58
(dd, J = 15.8, 7.7 Hz, 1 H), 7.19–7.09 (m, 3 H), 7.44 (d, J = 15.8 Hz,
1 H), 9.67 (d, J = 7.7 Hz, 1 H) ppm.
α-(Dimethylamino)nonyl Cyanide (3). General Procedure: To a
stirred solution of NaHSO3 (1.0 g, 0.01 mol) in water (2 mL) was
added nonanal (2 g, 0.014 mol) in MeOH (30 mL), followed by the
addition of anhydrous dimethylamine (0.7 g, 0.016 mol) in cold
MeOH (20 mL). The mixture was cooled on ice prior to the ad-
dition of an aqueous solution of NaCN (0.8 g, 0.016 mol). The
mixture was stirred at room temperature overnight[21,22] and then
extracted with Et2O (2×50 mL). The organic portions were washed
Experimental Section
General: Solid compounds were recrystallised from ethyl acetate/n-
hexane and melting points were taken with a hot stage microscope
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V. H. Tran, R. Kantharaj, B. D. Roufogalis, C. C. Duke
FULL PAPER
with water (20 mL) and evaporated under reduced pressure to give
a colourless oil, 2.6 g, 95% yield. The product was used for the
next reaction without further purification. H NMR (CDCl3): δ =
0.88 (t, J = 6.8 Hz, 3 H), 1.39–1.20 (m, 10 H), 1.52–1.40 (m, 2 H),
1.80–1.62 (m, 2 H), 2.31 (s, 6 H), 3.50–3.45 (m, 1 H) ppm.
1 H), 6.93 (d, J = 8 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 14.1,
22.7, 23.8, 29.0, 29.3 (3C), 29.4, 31.9, 37.8, 56.0, 79.4, 109.1, 114.6,
121.2, 130.0, 146.1, 147.1 ppm. MS (CI): m/z (%) = 337 (10)
[M+29]+, 309 (100) [M+1]+, 291 (15), 151 (8). MS (EI): m/z (%)
= 308 (8) [M], 151 (100), 55 (8). C18H28O4 (308.20): calcd. C 70.10,
H 9.15, O 20.75; found C 70.11, H 9.20, O 20.69.
1
α-(Dimethylamino)decyl Cyanide (4): The synthesis was ac-
complished according to the general procedure as described for 3
3-Hydroxy-1-(4-hydroxy-3-methoxyphenyl)dodec-1-en-4-one (15):
starting with decanal (2 g, 0.013 mol). A colourless oil, 2.6 g, 94%
The synthesis was accomplished according to the general procedure
yield. H NMR (CDCl3): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.39–1.20 as described for 14 by aldol condensation between 2 (1 g,
(m, 12 H), 1.52–1.40 (m, 2 H), 1.80–1.62 (m, 2 H), 2.31 (s, 6 H), 0.004 mol) and 3 (0.8 g, 0.004 mol). The product was purified by
1
3.50–3.45 (m, 1 H) ppm.
short-column vacuum chromatography as described above to afford
a yellowish oil, 0.8 g, 62% yield. H NMR (CDCl3): δ = 0.86 (t, J
1
(R)-α-(Dimethylamino)-3,7-dimethyl-6-octenyl Cyanide (5): The syn-
thesis was accomplished according to the general procedure as de-
scribed for 3 starting with (+)-(R)-3,7-dimethyl-6-octenal (citronel-
= 6.8 Hz, 3 H), 1.25 (m, 10 H), 1.63 (m, 2 H), 2.66–2.46 (m, 2 H),
3.91 (s, 3 H), 4.74–4.69 (m, 1 H), 5.70 (s, 2 H), 5.95–5.87 (dd, J =
15, 7.7 Hz, 1 H), 6.76 (d, J = 15 Hz, 1 H), 6.85–7.0 (m, 3 H) ppm.
13C NMR (CDCl3): δ = 14.1, 22.7, 23.7, 29.1, 29.2, 29.3, 31.8, 38.1,
55.9, 78.5, 108.5, 114.5, 120.7, 122.9, 128.6, 134.6, 146.1,
146.7 ppm. MS (CI): m/z (%) = 349 (15) [M + 29]+, 321 (60)
[M+1]+, 303 (100), 197 (50), 137 (40).
1
lal) (2 g, 0.013 mol). A colourless oil, 2.5 g, 92% yield. H NMR
(CDCl3): δ = 0.95–0.92 (m, 3 H), 1.58–1.18 (m, 4 H), 1.60 (s, 3 H),
1.84–1.62 (m, 4 H), 1.99 (m, 2 H), 2.30 (s, 3 H), 2.32 (s, 3 H), 3.60–
3.54 (m, 1 H), 5.08 (m, 1 H) ppm.
(S)-α-(Dimethylamino)-3,7-dimethyl-6-octenyl Cyanide (6): The syn-
thesis was accomplished according to the general procedure as de-
scribed for 3 starting with (–)-S-3,7-dimethyl-6-octenal (citronellal)
(2 g, 0.013 mol). A colourless oil, 2.6 g, 94% yield. 1H NMR
(CDCl3): δ = 0.95–0.92 (m, 3 H), 1.58–1.18 (m, 4 H), 1.60 (s, 3 H),
1.84–1.62 (m, 4 H), 1.99 (m, 2 H), 2.30 (s, 3 H), 2.32 (s, 3 H), 3.60–
3.54 (m, 1 H), 5.08 (m, 1 H) ppm.
3-Hydroxy-1-(4-hydroxy-3-methoxyphenyl)dodecan-4-one (16): To a
mixture of 15 (0.6 g, 0.002 mol) and 10% Pd-C as catalyst in ethyl
acetate (50 mL) was bubbled through a fine stream of H2 at room
temperature[15] for 4 h. The mixture was filtered, and solvent was
removed under reduced pressure to give a colourless residue which
was purified by short-column vacuum chromatography to afford
the title compound as colourless oil, 0.6 g, 96% yield. 1H NMR
(CDCl3): δ = 0.87 (t, J = 6.8 Hz, 3 H), 1.26 (s, 10 H), 1.58 (m, 2
H), 1.84–1.70 (m, 1 H), 2.15–2.04 (m, 1 H), 2.50–2.30 (m, 2 H),
2.80–2.60 (m, 2 H), 3.60 (d, J = 5 Hz, 1 H), 3.88 (s, 3 H), 4.14 (m,
1 H), 5.51 (s, 1 H), 6.71 (m, 2 H), 6.86 (d, J = 8.5 Hz, 1 H) ppm.
13C NMR (CDCl3): δ = 14.1, 22.7, 23.6, 29.1, 29.2, 29.3, 31.0, 31.8,
36.0, 37.9, 55.9, 75.6, 111.3, 114.4, 121.1, 133.1, 143.9, 146.5 ppm.
MS (EI): m/z (%) = [M] 322 (20), 150 (95), 137 (100). C19H30O4
(322.21): calcd. C 70.78, H 9.38, O 19.84; found C 70.85, H 9.42,
O, 19.73.
α-(Dimethylamino)-1-{3-methoxy-4-[(tetrahydropyran-2-yl)-
oxy]phenyl}acetonitrile (7): The synthesis was accomplished accord-
ing to the general procedure as described for 3 starting with 1 (2 g,
1
0.009 mol). A colourless oil, 2.3 g, 95% yield. H NMR (CDCl3):
δ = 2.10–1.60 (m, 6 H), 2.35 (s, 6 H), 3.60–3.50 (m, 1 H), 3.89 (s,
3 H), 3.96 (m, 1 H), 4.85 (s, 1 H), 5.50 (m, 1 H), 7.10 (m, 2 H),
7.13 (d, J = 8.7 Hz, 1 H) ppm.
(2E)-α-(Dimethylamino)-3-{3-methoxy-4-[(tetrahydropyran-2-yl)-
oxy]phenyl}-2-propenyl Cyanide (8): The synthesis was ac-
complished according to the general procedure as described for 3
starting 2 (1 g, 0.004 mol). A colourless oil, 1.1 g, 90% yield. 1H
NMR (CDCl3): δ = 1.75–1.58 (m, 3 H), 2.10–1.85 (m, 3 H), 2.37
(s, 6 H), 3.64–3.56 (m, 1 H), 3.88 (s, 3 H), 4.01–3.92 (m, 1 H), 4.44
(dd, J = 4.7, 1.9 Hz, 1 H), 5.44 (m, 1 H), 6.02–5.95 (dd, J = 16,
4.7 Hz, 1 H), 6.88 (dd, J = 16, 1.7 Hz, 1 H), 6.98–6.40 (m, 2 H),
7.12 (d, J = 8.7 Hz, 1 H) ppm.
4-Benzyloxy-3-methoxybenzaldehyde (9). General Procedure: To a
stirred suspension of NaH (60%, 0.6 g, 0.015 mol) in anhydrous
DMF (40 mL) at 0 °C under N2 was added slowly a solution of
vanillin (2 g, 0.013 mol) in anhydrous DMF (20 mL) followed by
benzyl bromide (2.4 g, 0.014 mol).[23] The mixture was stirred at
room temperature for a further 2 h, carefully quenched with cold
water, followed by diluted HCl (1 , 50 mL), then extracted with
diethyl ether (2 × 100 mL). The organic layers were combined,
washed with water (50 mL) then evaporated under reduced pressure
to give a residue which was purified by short-column vacuum
chromatography to give a colourless solid, 2.9 g, 92% yield, m.p.
1-Hydroxy-1-(4-hydroxy-3-methoxyphenyl)undecan-2-one (14). Ge-
neral Procedure: To a solution of diisopropylamine (1.5 mL,
0.01 mol) in dry THF (20 mL) at –80 °C under N2 was added drop-
wise n-butyllithium (2.5 , 4 mL, 0.01 mol). The mixture was
stirred for 30 min at 0 °C, cooled to –80 °C prior to the addition
of a solution of 4 (1.8 g, 0.009 mol) in THF (5 mL). The mixture
was stirred at –80 °C for 15 min then brought to room temperature
and further stirred for 2 h. To this mixture cooled to –80 °C was
added dropwise a solution of 1 (2.0 g, 0.007 mol) in THF (5 mL).
The mixture was stirred at –80 °C for 5 h, quenched with wet ether,
1
62–64 °C (ref.[24] m.p. 67 °C). H NMR (CDCl3): δ = 3.98 (s, 3 H),
5.28 (s, 2 H), 7.03 (d, J = 8 Hz, 1 H), 7.50–7.40 (m, 7 H), 9.87 (s,
1 H) ppm.
(E)- and (Z)-1-Benzyloxy-2-methoxy-4-(2-methoxyethenyl)benzene
(10): To a suspension of (methoxymethyl)triphenylphosphonium
bromide (4.0 g, 0.01 mol) in dry THF (50 mL) under N2 at 0 °C
extracted with Et2O (2 × 50 mL), washed with brine solution was added dropwise a solution of potassium tert-butoxide (1 ,
(20 mL) and evaporated to give a residue which was refluxed with
10 mL, 0.01 mol).[25] The reaction mixture was stirred for further
30 min followed by addition of a solution of 9 (2 g, 0.008 mol) in
aqueous oxalic acid[16,22] (30% w/v) in THF for 1.5 h. The resulting
mixture was then extracted with ethyl acetate (2×50 mL). After THF (6 mL). The mixture was stirred at room temperature for 6 h,
evaporation of solvent, crude product was purified by short-column
vacuum chromatography as described above to afford a colourless
solid, 1.6 g, 74% yield, m.p. 49–51 °C. 1H NMR (CDCl3): δ = 0.87
(t, J = 6.8 Hz, 3 H), 1.32–1.10 (m, 12 H), 1.58–1.42 (m, 2 H), 2.33
(m, 2 H), 3.87 (s, 3 H), 4.34 (d, J = 4 Hz, 1 H), 5.01 (d, J = 4 Hz,
quenched with cold water, acidified with diluted HCl (1 , 50 mL),
then extracted twice with ethyl acetate (2×50 mL). The organic
layers were combined, washed with water (50 mL) and evaporated
under reduced pressure to give a solid residue, which was purified
by short-column vacuum chromatography to give a mixture of (E)
1 H), 5.71 (s, 1 H), 6.72 (d, J = 2 Hz, 1 H), 6.86 (dd, J = 8, 2 Hz, and (Z) isomers as colourless oil, 1.7 g, 78 % yield. 1H NMR
2974
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2970–2976

Synthesis of Capsaicin-Like Compounds as Agonists of the TRPV1 Receptor
(CDCl3): δ = 3.66 (s, 3 H), 3.76 (s, 3 H), 3.88 (s, 6 H), 5.13–4.16 C19H28O4 (320.20): calcd. C 71.22, H 8.81, O 19.97; found C 70.87,
FULL PAPER
(m, 4 H), 5.73 (d, J = 15 Hz, 1 H), 6.04 (d, J = 9 Hz, 1 H), 6.68– H 8.82, O 20.31.
6.71 (dd, J = 6, 2 Hz, 1 H), 6.77–6.81 (m, 3 H), 6.91 (d, J = 15 Hz,
(2RS,5S)-2-Hydroxy-1-(4-hydroxy-3-methoxyphenyl)-5,9-dimethyl-
1 H), 6.98–7.02 (dd, J = 8, 2 Hz, 1 H), 7.24–7.44 (m, 10 H) ppm.
dec-8-en-3-one (19): Synthesis of the title compound was ac-
complished similar to that described for 18. The product was puri-
fied by short-column vacuum chromatography to afford a colour-
2-(4-Benzyloxy-3-methoxyphenyl)acetaldehyde (11): To the mixture
of 10 (1.0 g, 0.004 mol) in THF (40 mL) was added diluted HCl
(1 , 10 mL). The reaction mixture was reflux for 3 h under N2,
cold water added, then extracted twice with diethyl ether
(2×100 mL). The combined organic layer was washed with water
(50 mL) and removed under reduced pressure to afford a residue,
which was purified by column chromatography to give a colourless
1
less oil, 0.2 g, 82% yield. H NMR (CDCl3): δ = 0.91–0.88 (m, 3
H), 1.38–1.18 (m, 2 H), 1.57 (s, 3 H), 1.59 (s, 3 H), 2.10–1.90 (m,
3 H), 2.36–2.28 (m, 1 H), 2.51–2.42 (m, 1 H), 2.81–2.72 (m, 1 H),
3.10–3.03 (m, 1 H), 3.45–3.42 (m, 1 H), 3.88 (s, 3 H), 4.39–4.30 (m,
1 H), 5.10–5.02 (m, 1 H), 5.53 (s, 1 H), 6.70 (dd, J = 8, 2 Hz, 1 H),
6.78 (d, J = 2 Hz, 1 H), 6.83 (d, J = 8 Hz, 1 H) ppm. 13C NMR
(CDCl3): δ = 19.9, 25.5, 25.7, 28.9, 36.9, 39.8, 46.0, 55.9, 77.4, 77.9,
111.9, 114.3, 121.9, 124.1, 128.4, 131.8, 144.6, 146.5 ppm. MS (CI):
m/z (%) = 321 (25) [M+1]+, 303 (80), 225 (25), 166 (20), 137 (100).
MS (EI): m/z (%) = 320 (5) [M], 137 (100). C19H28O4 (320.20):
calcd. C 71.22, H 8.81, O 19.97; found C 71.40, H 8.85, O 19.75.
1
oil,[11] 0.6 g, 60% yield. H NMR (CDCl3): δ = 3.61 (d, J = 2 Hz,
2 H), 3.89 (s, 3 H), 5.15 (s, 2 H), 6.71 (dd, J = 8, 2 Hz, 1 H), 6.73
(d, J = 2 Hz, 1 H), 6.88 (d, J = 8 Hz, 1 H), 7.50–7.26 (m, 5 H),
9.72 (t, J = 2 Hz, 1 H) ppm.
1-(4-Benzyloxy-3-methoxyphenyl)-2-hydroxydodecan-3-one (12):
The synthesis was accomplished according to the general procedure
as described for 14 by an aldol condensation between 4 (0.25 g,
0.001 mol) and 11 (0.3 g, 0.001 mol). The product was purified by
short-column vacuum chromatography to give a colourless solid,
0.35 g, 85% yield. 1H NMR (CDCl3): δ = 0.88 (t, J = 6.8 Hz, 3 H),
1.26 (m, 12 H), 1.60 (m, 2 H), 2.55–2.37 (m, 2 H), 2.83–2.76 (dd,
J = 14, 7.4 Hz, 1 H), 3.09–3.03 (dd, J = 14, 4.6, Hz, 1 H), 3.41 (d,
J = 5 Hz, 1 H), 3.88 (s, 3 H), 4.41–4.30 (m, 1 H), 5.13 (s, 2 H),
6.70 (dd, J = 8, 2 Hz, 1 H), 6.82–6.79 (m, 2 H), 7.45–7.26 (m, 5 H)
ppm. MS (CI, NH4): m/z (%) = 430 (100) [M+18]+, 414 (35), 358
(25). MS (EI): m/z (%) = 412 (8) [M], 227 (40), 137 (35), 91 (100).
2-Hydroxy-1-(4-hydroxy-3-methoxyphenyl)undecan-1-one (20): The
synthesis was accomplished according to the general procedure as
described for 14 via aldol condensation between 7 (1 g, 0.003 mol)
and decyl aldehyde (0.5 g, 0.003 mol). The product was purified by
short-column vacuum chromatography to give a colourless solid,
1
0.8 g, 85% yield, m.p. 78–79 °C. H NMR (CDCl3): δ = 0.87 (t, J
= 6.8 Hz, 3 H), 1.24 (m, 12 H), 1.62–1.48 (m, 3 H), 1.84 (m, 1 H),
3.7 (m, 1 H), 3.97 (s, 3 H), 5.02 (m, 1 H), 6.20 (s, 1 H), 6.96 (d, J
= 8.2 Hz, 1 H), 7.48 (dd, J = 8.2, 2 Hz, 1 H), 7.53 (d, J = 2 Hz, 1
H) ppm. 13C NMR (CDCl3): δ = 14.2, 22.7, 24.9, 29.3, 29.4, 29.5,
29.5, 31.9, 36.61, 56.2, 72.7, 110.4, 114.1, 123.9, 126.4, 146.9,
151.1 ppm. MS (CI): m/z (%) = 337 (5) [M+29]+, 309 (25)
[M+1]+, 291 (100), 153 (8). MS (EI): m/z (%) = 308 (4) [M], 153
(100), 125 (10), 93 (20), 65 (15), 55 (14). C18H28O4 (308.20): calcd.
C 70.10, H 9.15, O 20.75; found C 70.20, H 9.18, O 20.62.
2-Hydroxy-1-(4-hydroxy-3-methoxyphenyl)dodecan-3-one (17): The
synthesis was accomplished according to the general procedure as
described for 16 starting 12 (0.35 g, 0.9 mmol). The product was
purified by short-column vacuum chromatography to give a colour-
1
less solid, 0.27 g, 92% yield, m.p. 46–48 °C. H NMR (CDCl3): δ
4-Hydroxy-1-(4-hydroxy-3-methoxyphenyl)dodec-1-en-3-one (21):
The synthesis was accomplished according to the general procedure
as described for 14 via aldol condensation between 8 (0.6 g,
0.002 mol) and nonyl aldehyde (0.3 g, 0.002 mol). The product was
purified by short-column vacuum chromatography to give a yellow-
ish oil, 0.4 g, 65% yield. 1H NMR (CDCl3): δ = 0.87 (t, J = 6.8 Hz,
3 H), 1.25 (m, 10 H), 1.62–1.38 (m, 3 H), 1.94–1.82 (m, 1 H), 3.68
(d, J = 5 Hz, 1 H), 3.96 (s, 3 H), 4.50–4.43 (m, 1 H), 6.05 (s, 1 H),
6.71 (d, J = 15.9 Hz, 1 H), 6.96 (d, J = 8.2 Hz, 1 H), 7.07 (d, J =
2 Hz, 1 H), 7.18 (dd, J = 8.2, 2 Hz, 1 H), 7.72 (d, J = 15.9 Hz, 1
H) ppm. 13C NMR (CDCl3): δ = 14.1, 22.7, 25.0, 29.3, 29.5, 29.6,
31.9, 34.6, 56.1, 75.6, 109.9, 114.9, 118.2, 123.8, 126.7, 144.9, 146.9,
148.8 ppm. MS (CI): m/z (%) = 361 (5) [M+41]+, 349 (15) [M+29]
+, 321 (100) [M+1]+, 303 (10). MS (EI): m/z (%) = 320 (10) [M],
177 (100), 145 (20), 77 (12), 43 (12).
= 0.88 (t, J = 6.8 Hz, 3 H), 1.26 (m, 12 H), 1.58 (m, 2 H), 2.56–
2.38 (m, 2 H), 2.84–2.77 (dd, J = 14, 7.4 Hz, 1 H), 3.09–3.03 (dd,
J = 14, 4.6 Hz, 1 H), 3.42 (d, J = 5 Hz, 1 H), 3.88 (s, 3 H), 4.42–
4.35 (m, 1 H), 5.53 (s, 1 H), 6.71 (dd, J = 8, 2 Hz, 1 H), 6.77 (d, J
= 2 Hz, 1 H), 6.85 (d, J = 8 Hz, 1 H) ppm. 13C NMR (CDCl3): δ
= 14.1, 22.7, 23.6, 29.2, 29.3, 29.4, 29.4, 31.9, 38.7, 39.9, 55.9, 77.4,
111.8, 114.4, 121.9, 128.4, 144.6, 146.5 ppm. MS (CI): m/z (%) =
323 (15) [M+1]+, 305 (70), 291 (12), 137 (100). MS (EI): m/z (%)
= [M] 322 (5), 137 (100). C19H30O4 (322.21): calcd. C 70.78, H
9.38, O 19.84; found C 71.04, H 9.46, O 19.50.
(2RS,5R)-2-Hydroxy-1-(4-hydroxy-3-methoxyphenyl)-5,9-dimethyl-
dec-8-en-3-one (18): The synthesis was accomplished according to
the general procedure as described for 14 via aldol condensation
between 5 (0.2 g, 0.001 mol) and 11 (0.3 g, 0.001 mol). The product
was purified by short-column vacuum chromatography to give a
colourless oil (13), 0.32 g, 78% yield. To this oil (0.32 g) was added
ethanol (10 mL), cyclohexene (5 mL) and Pd-C (10%, 0.02 g).[16]
The mixture was stirred under reflux for 3 h, filtered and the sol-
vent evaporated under reduced pressure to give an oil which was
purified by short-column vacuum chromatography to afford a
4-Hydroxy-1-(4-hydroxy-3-methoxyphenyl)dodecan-3-one (22): Hy-
drogenation of 21 (0.2 g) was carried out under H2 in the presence
of 10% Pd-C as described for 16. The product was purified by
short-column vacuum chromatography to give a colourless solid,
1
0.2 g, 95% yield, m.p. 40–41 °C. H NMR (CDCl3): δ = 0.87 (t, J
= 6.8 Hz, 3 H), 1.25 (m, 11 H), 1.54–1.36 (m, 2 H), 1.83–1.72 (m,
1 H), 2.80–2.65 (m, 2 H), 2.96–2.82 (m, 2 H), 3.43 (d, J = 5 Hz, 1
H), 3.87 (s, 3 H), 4.15–4.10 (m, 1 H), 5.50 (s, 1 H), 6.68–6.64 (m,
2 H), 6.84 (d, J = 8 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 14.1,
22.7, 24.8, 29.2, 29.4, 29.4, 29.5, 31.9, 33.7, 40.0, 55.9, 76.7, 111.0,
114.5, 120.8, 132.5, 143.9, 146.4 ppm. MS (EI): m/z (%) = 322 (40)
[M], 180 (40), 152 (45), 137 (100), 124 (40). C19H30O4 (322.21):
calcd. C 70.78, H 9.38, O 19.84; found C 70.79, H 9.38, O 19.83.
1
colourless oil, 0.2 g, 80% yield. H NMR (CDCl3): δ = 0.91–0.88
(m, 3 H), 1.38–1.18 (m, 2 H), 1.57 (s, 3 H), 1.59 (s, 3 H), 2.15–1.88
(m, 3 H), 2.36–2.26 (m, 1 H), 2.52–2.42 (m, 1 H), 2.81–2.72 (m, 1
H), 3.10–3.03 (m, 1 H), 3.45–3.42 (m, 1 H), 3.88 (s, 3 H), 4.39–4.30
(m, 1 H), 5.12–5.04 (m, 1 H), 5.53 (s, 1 H), 6.72 (dd, J = 8, 2 Hz,
1 H), 6.78 (d, J = 2 Hz, 1 H), 6.85 (d, J = 8 Hz, 1 H) ppm. 13C
NMR (CDCl3): δ = 19.9, 25.5, 25.7, 28.9, 37.0, 39.8, 45.9, 55.9,
77.4, 77.9, 111.9, 114.3, 121.9, 124.1, 128.4, 131.8, 144.6,
146.5 ppm. MS (CI): m/z (%) = 321 (30) [M+1]+, 303 (100), 165
Molecular Modeling: Molecular construction was carried out using
(15), 137 (80). MS (EI): m/z (%) = 320 (20) [M], 137 (100). Maestro version 6.0.107, MM share version 1.2.014, Shrodinger,
Eur. J. Org. Chem. 2006, 2970–2976
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2975

V. H. Tran, R. Kantharaj, B. D. Roufogalis, C. C. Duke
FULL PAPER
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atom of the major chain, 3rd and 7th atom of the major chain.
The best fit was selected from low-energy conformers.
Acknowledgments
Financial support was provided by Australian Research Council
and Thursday Plantation P/L in the Strategic Partnership with In-
dustry – Research and Training project. Bruce Tattam and Helen
Elimelakh are gratefully acknowledged for analysis of mass spectra
of the compounds.
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Received: February 16, 2006
Published Online: April 21, 2006
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Eur. J. Org. Chem. 2006, 2970–2976