Highly efficient synthesis of capsaicin analogues by condensation of vanillylamine and acyl chlorides in a biphase H2O/CHCl3 system

Article abstract of DOI:10.1016/j.tet.2009.04.046

Highly efficient synthesis of capsaicin analogues was developed using condensation of vanillylamine with acyl chlorides in a biphase H₂O/CHCl₃ system under mild conditions. For C4-C18 aliphatic or aromatic acyl chlorides, the yields were up to 93-96% with high purity after a simple work-up procedure, and only 1-1.16 equiv of acyl chloride was needed in the reaction.

Full text of DOI:10.1016/j.tet.2009.04.046

Tetrahedron 65 (2009) 5409–5412
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly efficient synthesis of capsaicin analogues by condensation of vanillylamine
and acyl chlorides in a biphase H2O/CHCl3 system
*
*
Bo Wang, Fan Yang, Yi-Fan Shan, Wen-Wei Qiu , Jie Tang
Institute of Medicinal Chemistry, Department of Chemistry, East China Normal University, Shanghai 200062, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly efficient synthesis of capsaicin analogues was developed using condensation of vanillylamine
with acyl chlorides in a biphase H2O/CHCl3 system under mild conditions. For C4–C18 aliphatic or
aromatic acyl chlorides, the yields were up to 93–96% with high purity after a simple work-up procedure,
and only 1–1.16 equiv of acyl chloride was needed in the reaction.
Received 20 January 2009
Received in revised form 8 April 2009
Accepted 14 April 2009
Available online 18 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Capsaicin analogue
Vanillylamine
Acylation
1. Introduction
The most convenient method for preparation of capsaicinoids is
by selective acylation of vanillylamine with acyl chloride. However,
Fruits of the red pepper (Capsicum spp.) have been used for
centuries for their medicinal effects, primarily for stomach disor-
ders and as topical counterirritants for relief of pain and in-
flammation.1,2 These fruits contain capsaicin analogues (also called
capsaicinoids) with a common structure comprising a group of acid
amides of vanillylamine and fatty acids. In recent years, a wide
variety of physiological and biological activities of capsaicinoids
have been reported, including stimulation of the cardiovascular and
respiratory systems, application as anti-nociceptive and anti-in-
flammatory analgesics, and use as neurotoxic drugs or enhancers of
adrenal catecholamine secretion.3–5 Individual capsaicinoids can be
isolated from red peppers by TLC or HPLC techniques. However, the
relative content of the components depends on the species and
sort, and total concentrations can be very low. For example, it has
been reported that capsaicin analogues with long alkyl side chains
(C14–C20) have no pungency, but still stimulate adrenaline release
and increase fat metabolism.6–8 Unfortunately, these long-chain
non-pungent capsaicin analogues are minor components in pep-
pers and are hard to isolate from natural capsaicin. Thus, chemical
synthesis of capsaicin analogues has been motivated by the search
for spicy substitutes for natural capsaicin and the development of
non-irritant drugs, antioxidants, and other useful substances.
vanillylamine is poorly soluble in anhydrous systems, and acyl
chloride is easily hydrolysed when water is present, so it is very
difficult to obtain a satisfactory yield. The first analogues of capsaicin,
vanillylamides of saturated C2–C12 fatty acids and 10-undecylenic
acid were synthesised by Nelson by acylation of vanillylamine with
acyl chlorides or acid anhydrides in dry ether.9 Although 2 equiv of
vanillylamine was used, the yield was only 44–83%. Janusz et al.
liberated the HCl from vanillylamine HCl in an aqueous soda solution
and avoided using excess vanillylamine, but obtained yields of only
27–69% for DMF, THF or ether as co-solvent.10 Kobata et al. reported
the enzymatic synthesis of capsaicin analogues by reaction of
vanillylamine HCl with fatty acid methyl esters, but only 8–28% yield
was obtained.11 Koreishi et al.12 and Castillo et al.13 reported the
acylase- or lipase-catalysed synthesis of capsaicins with higher
yields. Nevertheless, from an economic point of view, highly efficient
base-catalysed condensation of vanillylamine and acyl chlorides is
still the most practical method for preparation of capsaicin ana-
logues. Here we report a highly efficient method for synthesis of
capsaicin analogues by interfacial reaction of vanillylamine–H2O
with acyl chloride–CHCl3 (Scheme 1).
O
NH2 . HCl
N
H
R
H2O/CHCl3
NaHCO3
+ RCOCl
HO
HO
OCH3
OCH3
* Corresponding authors. Fax: þ86 21 62232764.
E-mail address: jtang@chem.ecnu.edu.cn (J. Tang).
Scheme 1.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.046

5410
B. Wang et al. / Tetrahedron 65 (2009) 5409–5412
Table 1
Effect of temperature on the condensation reactiona
O
NH2 . HCl
N
H
C17H35
H2O/CHCl3
NaHCO3
+ C17H35COCl
HO
HO
OCH3
OCH3
Run
T (ꢀC)
Isolated yield (%)
1
2
3
12
18
25
88
96
96
a
Reaction conditions: vanillylamine hydrochloride (28.04 mmol), stearoyl chloride (28.04 mmol), NaHCO3 as base (91.7 mmol), reaction time 30 min.
2. Results and discussion
molar ratio to 1.16:1 increased the yield of the product N-(4-hy-
droxy-3-methoxybenzyl)butanamide to 93% (run 4, Table 2).
During condensation of acyl chloride and vanillylamine, which
can be freed from its HCl in aqueous NaHCO3, esterification of the
phenolic hydroxyl and hydrolysis of the acyl chloride can occur, as
well as the expected acylation of the amino group to produce the
target compound. Hence, there are three competing reactions in
this system. To inhibit side reactions, a biphase H2O/CHCl3 system
was used. The reaction rate was adjusted by controlling the tem-
perature and altering the reactant molar ratio.
2.3. Condensation of vanillylamine with various acyl
chlorides in H2O/CHCl3
Under optimum reaction conditions, condensation of vanillyl-
amine with various acyl chlorides was assayed. The results are
summarised in Table 3.
The results show that all theacyl chlorides selectively reacted with
vanillylamine at the NH2 position in the biphase system to produce
the corresponding capsaicin derivatives. Regardless of the acyl chlo-
rides used (saturated, unsaturated or aromatic) the yield isolated was
93–96%. We consider that the critical point for the excellent yield is
the use of a biphase system, which slows down the rate of acyl
chloride hydrolysis. Although Janusz et al. liberated the HCl from
vanillylamine HCl in the same aqueous solution, they used DMF/THF
as the organic solvent, which mixed with the water to form a homo-
geneous reaction system, and thus the reaction gave a lower yield.10
Owing to the special stability of benzoyl chloride, a yield of 96%
of acylation product was obtained, and 2-Cl-substituted benzoyl
chloride gave likewise excellent result, 94% yield.
2.1. Effect of temperature on condensation
Condensation with stearoyl chloride was used as the model re-
action. The free vanillylamine base was dissolved in aqueous NaHCO3
and added dropwise to a solution of stearoyl chloride in chloroform
at different temperatures. The results are listed in Table 1.
The results in Table 1 reveal that when the reaction was carried
out at 12 ꢀC, only 88% yield of N-(4-hydroxy-3-methoxybenzyl)-
octadecanamide was obtained (run 1, Table 1). TLC analysis revealed
that stearic acid was formed. This suggests that the reaction rate was
slower at lower temperature, leading to the hydrolysis of stearoyl
chloride. For reaction at 18 ꢀC, satisfactory results were obtained (run
2, Table 1). A further increase in temperature to 25 ꢀC did not in-
crease the yield. Therefore, the temperature of subsequent reactions
was controlled at approximately 20 ꢀC.
It is worth noting that the free vanillylamine base is soluble in
water and insoluble in CHCl3, so it reacts with acyl chloride, which
is soluble in CHCl3, at the interface. A schematic drawing of this
two-phase system is shown in Figure 1.
Since all these capsaicin derivatives are soluble in chloroform, the
product can easily be separated after the reaction by decantation.
2.2. Influence of reactant molar ratio
It was found that the acyl chloride/vanillylamine molar ratio
influenced the reaction selectivity (Table 2). For long-chain acyl
chlorides such as stearoyl chloride, which have good hydrophobic
property and it could present stably in the aqueous system, equi-
molar amounts of the acyl chloride and vanillylamine HCl gave an
excellent result (run 1, Table 2). When a 10% molar excess of the acyl
chloride was used, only 87% yield was obtained (run 2, Table 2) and
a diacyl by-product compound was produced. For short-chain acyl
chlorides such as butyryl chloride, equimolar amounts of the acyl
chloride and vanillylamine gave an 89% yield (run 3, Table 2) owing
to its hydrophility and it may hydrolyse partially in the aqueous
system, so a slight excess of acyl chloride was needed. A change in
Table 3
a
Condensation of vanillylamine with acyl chlorides in H2O/CHCl3
O
NH2 . HCl
N
H
R
H2O/CHCl3
NaHCO3
+ RCOCl
HO
HO
OCH3
OCH3
Run
Acyl chloride
RCOCl/vanillylamine
HCl molar ratio
Isolated yield (%)
1
2
3
4
5
6
7
8
CH3(CH2)16COCl
CH3(CH2)14COCl
CH3(CH2)12COCl
CH3(CH2)10COCl
CH3(CH2)8COCl
(CH3)2CH(CH2)6COCl
CH3(CH2)6COCl
CH3(CH2)4COCl
CH3(CH2)2COCl
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1.01:1
1.16:1
1:1
96
95
95
95
95
95
94
94
93
96
96
94
Table 2
Influence of molar ratio on the condensation reactiona
Run RCOCl
RCOCl/vanillylamine HCl molar ratio Isolated yield (%)
1
2
3
4
CH3(CH2)16COCl
CH3(CH2)16COCl 1.10:1
CH3(CH2)2COCl
CH3(CH2)2COCl
1:1
96
87
89
93
9
10
11
12
CH3(CH2)7CH]CH(CH2)7COCl
C6H5COCl
2-ClC6H4COCl
1:1
1.16:1
1:1
1:1
a
a
Reaction conditions: vanillylamine hydrochloride (28.04 mmol), NaHCO3 as base
(91.7 mmol); temperature 20 ꢀC; reaction time 30 min.
Reaction conditions: vanillylamine hydrochloride (28.04 mmol), NaHCO3 as base
(91.7 mmol), temperature 20 ꢀC, reaction time 30 min.

B. Wang et al. / Tetrahedron 65 (2009) 5409–5412
5411
Water
J¼1.5 Hz, ArH-2), 6.76 (1H, dd, J¼8.0,1.5 Hz, ArH-6), 5.62 (1H, br s, OH),
5.59 (1H, s, NH), 4.35 (2H, d, J¼6.0 Hz, H-7), 3.88 (3H, s, OCH3), 2.19 (2H,
t, J¼7.5 Hz, H-20), 1.65 (2H, m, H-30), 1.29–1.25 (24H, m, H-40–150), 0.88
(3H, t, J¼7.0 Hz, H-160); MS (EI): m/z 391 [M]þ, 195, 152, 137.
Water
4.2.4. N-(4-Hydroxy-3-methoxybenzyl)tetradecanamide
White solid; mp 76–78 ꢀC [lit14 76–77 ꢀC]; yield 9.63 g (94.6%); 1H
Chloroform
Chloroform
NMR (500 MHz, CDCl3):
d
6.86 (1H, d, J¼8.0 Hz, ArH-5), 6.81 (1H, d,
J¼1.5 Hz, ArH-2), 6.76 (1H, dd, J¼8.0, 1.5 Hz, ArH-6), 5.64 (1H, s, OH),
5.60 (1H, s, NH), 4.35 (2H, d, J¼5.5 Hz, H-7), 3.88 (3H, s, OCH3), 2.19
(2H, t, J¼7.0 Hz, H-20),1.64 (2H, m, H-30),1.29–1.25 (20H, m, H-40–130),
0.88 (3H, t, J¼7.0 Hz, H-140); MS (EI): m/z 363 [M]þ, 195, 152, 137.
Figure 1. Schematic drawing of the condensation reaction.
3. Conclusions
We developed a highly efficient biphase reaction system for the
preparation of vanillylamides with near equimolar acyl chlorides
under mild conditions. This method avoids the hydrolysis of acyl
chloride and diacylation of vanillylamine and improves the yield to
93–96%. High-purity capsaicinoid products were obtained after
a simple work-up procedure.
4.2.5. N-(4-Hydroxy-3-methoxybenzyl)dodecanamide
White solid; mp 71–73 ꢀC [lit9 60–61 ꢀC]; yield 8.93 g (95.1%);
1H NMR (500 MHz, CDCl3):
d
6.86 (1H, d, J¼8.0 Hz, ArH-5), 6.81 (1H,
d, J¼1.5 Hz, ArH-2), 6.76 (1H, dd, J¼8.0, 1.5 Hz, ArH-6), 5.61 (1H, s,
OH), 5.59 (1H, s, NH), 4.35 (2H, d, J¼5.5 Hz, H-7), 3.88 (3H, s, OCH3),
2.19 (2H, t, J¼7.0 Hz, H-20), 1.65 (2H, m, H-30), 1.27 (16H, m, H-40, 50,
60, 70, 80, 90, 100, 110), 0.88 (3H, t, J¼7.0 Hz, H-120); MS (EI): m/z 335
[M]þ, 195, 151, 137.
4. Experimental
4.1. General remarks
4.2.6. N-(4-Hydroxy-3-methoxybenzyl)decanamide
Commercially available reagents and solvents were used with-
out further purification. Melting points were measured using
a Yanaco Mp 500 instrument and the thermometer was un-
corrected. 1H NMR spectra were recorded on a Bruker AM-500 MHz
spectrometer with tetramethylsilane as the internal standard. Mass
spectra were recorded by the EI method. All reactions were moni-
tored by TLC. Flash column chromatography was carried out with
silica gel at increased pressure.
White solid; mp 48–50 ꢀC [lit10 61–63 ꢀC]; yield 8.15 g (94.7%); 1H
NMR (500 MHz, CDCl3):
d
6.86 (1H, d, J¼8.0 Hz, ArH-5), 6.81 (1H, d,
J¼1.5 Hz, ArH-2), 6.76 (1H, dd, J¼8.0, 1.5 Hz, ArH-6), 5.65 (1H, s, OH),
5.62 (1H, s, NH), 4.35 (2H, d, J¼5.5 Hz, H-7), 3.88 (3H, s, OCH3), 2.19
(2H, t, J¼7.5 Hz, H-20),1.64 (2H, m, H-30),1.29–1.25 (12H, m, H-40–90),
0.87 (3H, t, J¼7.0 Hz, H-100); MS (EI): m/z 307 [M]þ, 195, 152, 137.
4.2.7. N-(4-Hydroxy-3-methoxybenzyl)isodecanamide
White solid; mp 62–64 ꢀC [lit14 64–65 ꢀC]; yield 8.13 g (94.5%);
4.2. General procedure
1H NMR (500 MHz, CDCl3):
d
6.86 (1H, d, J¼8.0 Hz, ArH-5), 6.81 (1H,
d, J¼1.5 Hz, ArH-2), 6.76 (1H, dd, J¼8.0, 1.5 Hz, ArH-6), 5.64 (1H, s,
OH), 5.60 (1H, s, NH), 4.35 (2H, d, J¼6.0 Hz, H-7), 3.88 (3H, s, OCH3),
2.19 (2H, t, J¼7.5 Hz, H-20), 1.65 (2H, m, H-30), 1.50 (1H, m, H-80),
1.32–1.26 (6H, m, H-40–60), 1.15 (2H, m, H-70), 0.85 (6H, d, J¼6.5 Hz,
H-90, 100); MS (EI): m/z 307 [M]þ.
To a solution of vanillylamine hydrochloride (5.3 g, 28.04 mmol)
in water (58 mL), NaHCO3 (7.7 g, 91.7 mmol) was added. The mixture
was stirred for 30 min at 20 ꢀC and then chloroform (80 mL) was
added. After stirring for 15 min, a solution of acyl chloride in chlo-
roform (20 mL) was added dropwise. The mixture was stirred for
30 min (monitored by TLC) and then heated to 35–40 ꢀC. The organic
layer was separated and the water layer was extracted with chloro-
form (3ꢁ20 mL). The organiclayerwaswashedwith2%HClandbrine
and then dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure and the residue was subjected to flash col-
umn chromatography (if needed) to yield the product as a solid.
4.2.8. N-(4-Hydroxy-3-methoxybenzyl)octanamide
White solid; mp 42–44 ꢀC [lit10 44–45 ꢀC]; yield 7.36 g (94.1%);
1H NMR (500 MHz, CDCl3):
d
6.86 (1H, d, J¼8.0 Hz, ArH-5), 6.81 (1H,
d, J¼1.5 Hz, ArH-2), 6.76 (1H, dd, J¼8.0, 1.5 Hz, ArH-6), 5.64 (1H, s,
OH), 5.62 (1H, s, NH), 4.35 (2H, d, J¼6.0 Hz, H-7), 3.88 (3H, s, OCH3),
2.19 (2H, t, J¼7.5 Hz, H-20), 1.65 (2H, m, H-30), 1.31–1.26 (8H, m, H-40,
50, 60, 70), 0.87 (3H, t, J¼7.0 Hz, H-80); MS (EI): m/z 279 [M]þ.
4.2.1. N-(4-Hydroxy-3-methoxybenzyl)octadecanamide
White solid; mp 93–95 ꢀC [lit14 90–91 ꢀC]; yield 11.28 g (96.0%);
4.2.9. N-(4-Hydroxy-3-methoxybenzyl)hexanamide
1H NMR (500 MHz, CDCl3):
d
6.86 (1H, d, J¼8.0 Hz, ArH-5), 6.81 (1H,
White solid; mp 58–60 ꢀC [lit10 54–55 ꢀC]; yield 6.58 g (93.6%);
d, J¼1.5 Hz, ArH-2), 6.76 (1H, dd, J¼8.0,1.5 Hz, ArH-6), 5.63 (1H, br s,
OH), 5.60 (1H, s, NH), 4.35 (2H, d, J¼5.5 Hz, H-7), 3.88 (3H, s, OCH3),
2.20 (2H, t, J¼7.5 Hz, H-20), 1.65 (2H, m, H-30), 1.30–1.26 (28H, m, H-
40–170), 0.88 (3H, t, J¼7.0 Hz, H-180); MS (EI): m/z 419 [M]þ.
1H NMR (500 MHz, CDCl3):
d
6.86 (1H, d, J¼8.0 Hz, ArH-5), 6.81 (1H,
d, J¼1.5 Hz, ArH-2), 6.76 (1H, dd, J¼8.0, 1.5 Hz, ArH-6), 5.64 (1H, s,
OH), 5.62 (1H, s, NH), 4.35 (2H, d, J¼5.5 Hz, H-7), 3.88 (3H, s, OCH3),
2.19 (2H, t, J¼7.5 Hz, H-20), 1.65 (2H, m, H-30), 1.32 (4H, m, H-40, 50),
0.88 (3H, t, J¼7.0 Hz, H-60); MS (EI): m/z 251 [M]þ.
4.2.2. N-(4-Hydroxy-3-methoxybenzyl)oleamide
White solid; mp 31–33 ꢀC [lit14 36 ꢀC]; yield: 11.2 g (95.8%); 1HNMR
4.2.10. N-(4-Hydroxy-3-methoxybenzyl)butanamide
(500 MHz, CDCl3):
d
6.86 (1H, d, J¼8.1 Hz, H-5), 6.80 (1H, d, J¼1.6 Hz,
White solid; mp 74–76 ꢀC [lit9 68–70 ꢀC]; yield 5.80 g (92.9%);
H-2), 6.76 (1H, dd, J¼8.0, 1.6 Hz, H-6), 5.64 (1H, br s, OH), 5.60 (1H, s,
NH), 5.37–5.30 (2H, m, CH]CH), 4.35 (2H, d, J¼5.6 Hz, NCH2), 3.88 (3H,
s, OCH3), 2.19 (2H, t, J¼7.5 Hz, H-20), 2.04–1.98 (2H, m, H-30), 1.66–1.62
(2H, m, H-40), 1.29–1.26 (22H, m, H-50–80, H-110–170), 0.88 (3H, t,
J¼7.1 Hz, H-180); MS (EI): m/z 417 [M]þ (16), 137 [MꢂRCONH]þ (100).
1H NMR (500 MHz, CDCl3):
d
6.86 (1H, d, J¼8.5 Hz, ArH-5), 6.81 (1H,
d, J¼1.5 Hz, ArH-2), 6.76 (1H, dd, J¼8.5, 1.5 Hz, ArH-6), 5.63 (1H, s,
OH), 5.61 (1H, s, NH), 4.36 (2H, d, J¼6.0 Hz, H-7), 3.88 (3H, s, OCH3),
2.18 (2H, t, J¼7.5 Hz, H-20), 1.68 (2H, q, J¼7.5 Hz, H-30), 0.96 (3H, t,
J¼7.5 Hz, H-40); MS (EI): m/z 223 [M]þ, 194, 152, 137.
4.2.3. N-(4-Hydroxy-3-methoxybenzyl)hexadecanamide
4.2.11. N-(4-Hydroxy-3-methoxybenzyl)benzoylamide
White solid; mp 83–85 ꢀC [lit15 79 ꢀC]; yield 10.43 g (95.1%); 1H
White solid; mp 142–144 ꢀC [lit9 140–142 ꢀC]; yield 6.75 g
NMR (500 MHz, CDCl3):
d
6.86 (1H, d, J¼8.0 Hz, ArH-5), 6.81 (1H, d,
(93.7%); 1H NMR (500 MHz, CDCl3):
d
7.78 (d, J¼7.7 Hz, 2H), 7.50

5412
B. Wang et al. / Tetrahedron 65 (2009) 5409–5412
(t, J¼7.2 Hz,1H), 7.42–7.45 (m, 2H), 6.90–6.84 (m, 3H), 6.33 (br s,1H,
OH), 5.61 (s, 1H, NH), 4.56 (d, J¼5.6 Hz, 2H, H-7), 3.89 (s, 3H, OCH3);
MS (EI): m/z 257 [M]þ, 152, 105, 77.
References and notes
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chemistry, Pharmacology, and Food Science of the Pungent Principle of Cap-
sicum Species. In The Alkaloids; Brossi, A., Ed.; Academic: New York, NY, 1984;
Vol. 23, Chapter 4.
3. Sancho, R.; Lucena, C.; Macho, A.; Calzado, M. A.; Blanco-Molina, M.; Minassi, A.;
Appendino, G.; Munoz, E. Eur. J. Immunol. 2002, 32, 1753–1763.
4. Kobata, K.; Toyoshima, M.; Kawamura, M.; Watanabe, T. Biotechnol. Lett. 1998,
20, 781–783.
5. Morita, A.; Iwasaki, Y.; Kobata, K.; Iida, T.; Higashi, T.; Oda, K.; Suzuki, A.;
Narukawa, M.; Sasakuma, S.; Yokogoshi, H.; Yazawa, S.; Tominaga, M.; Wata-
nabe, T. Life Sci. 2006, 79, 2303–2310.
6. Ohnuki, K.; Haramizu, S.; Oki, K.; Watanabe, T.; Yazawa, S.; Fushiki, T. Biosci.
Biotechnol. Biochem. 2001, 65, 2735–2740.
4.2.12. 2-Chloro-[N-(40-hydroxy-30-methoxybenzyl)]benzoylamide
White solid; mp 157–159 ꢀC; yield 7.81 g (95.7%); 1H NMR
(500 MHz, CDCl3):
d
7.68 (d, J¼7.6 Hz, 1H), 7.40–7.31 (m, 3H), 6.93
(s, 1H), 6.89–6.84 (m, 2H), 6.41 (br s, 1H, OH), 5.62 (s, 1H, NH), 4.58
(d, J¼5.6 Hz, 2H, NCH2), 3.89 (s, 3H, OCH3); 13C NMR (125 MHz,
CDCl3):
d 166.3 (C]O), 147.5, 145.4, 137.1, 130.7, 129.9, 129.8, 129.6,
128.8,127.1,119.7,115.2,111.5, 55.5, 42.2; MS (EI): m/z 291 [M]þ (61),
256 [MꢂCl]þ (10), 139 [2-ClC6H4CO]þ (100), 111 [2-ClC6H4]þ (30);
HRMS (EI) m/z calcd for C15H14ClNO3 291.0655, found 291.0662.
7. Watanabe, T.; Kawada, T.; Kato, T.; Harada, T.; Iwai, K. Life Sci. 1994, 54, 369–374.
8. Kim, K. M.; Kawada, T.; Ishihara, K.; Inoue, K.; Fushiki, T. Biosci. Biotechnol.
Biochem. 1997, 61, 1718–1723.
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We are grateful to the Laboratory of Organic Functional Mole-
cules, Sino-French Institute, ECNU for support.
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Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.04.046.