Preparation of a (+/-)-1,6-di-O-feruloyl-myo-inositol derivative: an efficient method for introduction of ferulic acid to 1,6-vicinal hydroxyl groups of myo-inositol.

Full text of DOI:10.1021/jo015629e

J . Org. Chem. 2001, 66, 7199-7201
7199
containing ferulic acid and myo-inositol as components
have not yet been discovered in nature.
P r ep a r a tion of a
(()-1,6-Di-O-fer u loyl-m yo-in ositol
Der iva tive: An Efficien t Meth od for
In tr od u ction of F er u lic Acid to 1,6-Vicin a l
Hyd r oxyl Gr ou p s of m yo-In ositol
Asao Hosoda,† Eisaku Nomura,† Kazuhiko Mizuno,‡ and
Hisaji Taniguchi*,†
Industrial Technology Center of Wakayama Prefecture,
60 Ogura, Wakayama 649-6261, J apan, and Department of
Applied Chemistry, College of Engineering, Osaka Prefecture
University, 1-1 Gakuen-cho, Sakai, Osaka 599-8531, J apan
In a previous paper, we reported the synthesis of seven
taniguti@wakayama-kg.go.jp
Received March 12, 2001
ester compounds consisting of ferulic acid and myo-
inositol and their inhibitory effect on 12-O-tetrade-
-
canoylphorbol-13-acetate (TPA)-induced superoxide (O2
)
generation by the use of differentiated HL-60 cells.9 In
this study, we found that only 3,4,5,6-tetra-O-acetyl-1,2-
di-O-[3-(4′-acetoxy-3′-methoxyphenyl)-2-propenoyl]-myo-
inositol (2) showed a distinct inhibitory activity. This
result suggests that the architecture having two feruloyl
groups at the vicinal positions of myo-inositol is essential
for the inhibitory activity.
Ferulic acid (1) can be synthesized by the reaction of
vanillin with malonic acid in the presence of an amine.1
However, this reaction requires a long reaction time for
completion and, hence, is impractical as a method for a
large scale preparation of 1.1 On the other hand, 1 is
known to occur in large amounts in various renewable
resources such as rice, wheat, and corn. Recently, we
have developed an efficient and practical method for the
mass production of 1 from the oily component of rice
bran.2 Since then, the synthetic applications of 1 and
related compounds have attracted considerable attention,
especially in the field of chemoprevention study. For
example, the ferulic acid derivative, ethyl 3-(4′-gerany-
loxy-3′-methoxyphenyl)-2-propenoate,2b in which the ger-
anyl group is attached to the phenolic hydroxyl group of
ethyl ferulate, was shown to have a suppressive effect
on the formation of a colonic tumor marker in rats.3
O-Tocopheryl succinyl O-ethyl ferulate was found to
reduce the replication rate of the HIV-1 virus in infected
cells in vitro by 80%.4
In the present paper, we report an efficient method for
the introduction of ferulic acid to the 1,6-vicinal hydroxyl
groups of (()-3,4-O-(1,1,3,3-tetraisopropyldisiloxanedi-
1,3-yl)-myo-inositol (TIPDS-myo-inositol, 4) and the effect
of intermolecular hydrogen bonding of 4 on the esterifi-
cation reaction.
The introduction of functional groups to the 1,6-vicinal
hydroxyl groups of myo-inositol has been performed
through 2,3:4,5-di-O-cyclohexlidene-myo-inositol as an
intermediate.10 However, the synthesis of this diketal
intermediate was difficult and troublesome: the reaction
of myo-inositol with cyclohexanone gave 1,2-O-cyclohexy-
lidene-myo-inositol and three diketals (1,2:3,4-, 1,2:4,5-,
and 2,3:4,5-di-O-cyclohexylidene-myo-inositol).11 The re-
action of myo-inositol with 1-ethoxycyclohexene in DMF
also gave the three diketals.12 In these reactions, the yield
of the 2,3:4,5-diketal was low, and the isolation of this
ester from the reaction mixture was tedious.
In contrast, the disiloxanyl derivative 3 can readily be
obtained from myo-inositol by consecutive regioselective
cyclohexylidenation and silylation reactions.13,14 The
reaction of 3 with 1 equiv of ethylene glycol in the
presence of a catalytic amount of p-toluenesulfonic acid
in CHCl3 at room temperature gave 4 as a white powder
in an 86% yield (Scheme 1). We then examined the
introduction of ferulic acid to the 1,6-vicinal hydroxyl
groups of 4.
myo-Inositol is also obtained from rice bran, and it
plays an important role in biological systems. D-myo-
Inositol-1,4,5-trisphosphate was found to act as an in-
tracellular second messenger for calcium mobilization.5,6
myo-Inositol hexaphosphate (IP6) was shown to have an
anticancer action in a variety of experimental tumor
models.7
Ferulic acid occurs usually as various ester or amide
derivatives in natural products,8 but the ester compounds
† Industrial Technology Center of Wakayama Prefecture.
‡ Osaka Prefecture University.
(1) (a) Adams, R.; Bockstahler, T. E. J . Am. Chem. Soc. 1952, 74,
5346-5348. (b) J ohnson, J . R. Organic Reactions; J ohn Wiley & Sons:
New York, 1942; Vol. 1, Chapter 8, pp 250-251.
(2) (a) Taniguchi, H.; Nomura, E.; Tsuno, T.; Minami, S.; Kato, K.;
Hayashi, C. J apanese Patent 2095088, Oct 2, 1996); U.S. Patent 5,-
288,902, Feb 22, 1994. (b) Taniguchi, H.; Hosoda, A.; Tsuno, T.; Maruta,
Y.; Nomura, E. Anticancer Res. 1999, 19, 3757-3762.
(3) Tsuda, H.; Park, C. B.; Takasuka, N.; Toriyama, H.; Sekine, K.;
Moore, M. A.; Nomura, E.; Taniguchi, H. Anticancer Res. 1999, 19,
3779-3782.
(4) Edeas, M. A.; Claise, C.; Vergnes, L.; Khalfoun, Y.; Barthelemy,
S.; Labidalle, S.; Lindenbaum, A. FEBS Lett. 1997, 418, 15-18.
(5) Berridge, M. J .; Irvine, R. F. Nature 1984, 312, 315-321.
(6) Berridge, M. J . Nature 1993, 361, 315-325.
(9) Hosoda, A.; Nomura, E.; Murakami, A.; Koshimizu, K.; Ohigashi,
H.; Mizuno, K.; Taniguchi, H. Bioorg. Med. Chem. Lett. 2000, 19, 1439-
1442.
(10) Watanabe, Y. In Studies in Natural Products Chemistry;
Rahman, A. U., Ed.; Elsevier Science: Amsterdam, 1996; Vol. 18, pp
391-456.
(11) Angyal, S. J .; Tate, M. E.; Gero, S. D. J . Chem. Soc. 1961, 4116-
4122.
(12) Garego, P. J .; Iversen, T.; J ohansson, R.; Lindberg, B. Carbo-
hydr. Res. 1984, 130, 322-326.
(13) Massy, D. J . R.; Wyss, P. Helv. Chim. Acta 1990, 73, 1037-
1057.
(14) Watanabe, Y.; Mitani, M.; Morita, T.; Ozaki, S. J . Chem. Soc.,
Chem. Commun. 1989, 482-483.
(7) Shamsuddin, A. M. Anticancer Res. 1999, 19, 3733-3736.
(8) (a) Kroon, P. A.; Williamson, G. J . Sci. Food Agric. 1999, 79,
355-361. (b) Clifford, M. N. J . Sci. Food Agric. 1999, 79, 362-372. (c)
Saulnier, L.; Thibault, J . F. J . Sci. Food Agric. 1999, 79, 396-402.
10.1021/jo015629e CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/14/2001

7200 J . Org. Chem., Vol. 66, No. 21, 2001
Notes
Sch em e 1
Sch em e 2a
F igu r e 2. 1H NMR spectra (400 MHz) of 4 in CD2Cl2 at
various concentrations.
3450 cm-1 can be assigned to the intermolecularly
hydrogen-bonded OH group, because the absorbance of
the band increased with increases in the concentration
of 4.
a
The formation of intermolecular hydrogen bonding was
Reagents and conditions: Et3N, DMAP, and CH2Cl2, room
1
temperature, 12 h.
also confirmed by measuring the H NMR spectrum of 4
in CD2Cl2 at various concentrations (Figure 2). The OH
proton signals appeared at 2.4-2.7 ppm in the 2.5 mM
solution, and these signals shifted downfield with in-
creases in the concentration of 4. These results strongly
suggest that the OH groups of 4 form intermolecular
hydrogen bonds in the real reaction mixture, and this
intermolecular hydrogen bonding results in the poor
reactivity in the esterification reaction of 4 with 5 in CH2-
Cl2 solution.
In general, intermolecular hydrogen bonding can be
dissociated by raising the temperature or by the addition
of a cosolvent such as DMF, THF, or pyridine; in fact, it
is well-known that the esterification of an acid chloride
by an alcohol proceeds efficiently in pyridine.18
We also found that the reaction of 4 with 5 in pyridine
proceeded smoothly, and the ester compounds 6a -d were
obtained in moderate yields. When the reaction was
carried out in pyridine in the presence of DMAP at 70
°C using 4 and 5 in a molar ratio of 1:5, 6c was selectively
obtained in an 81% yield. This regioselectivity is also
compatible with the facts that (1) the hydroxyl group at
the 2-position of 4 has a poor reactivity due to a hindered
axial bond19 and (2) the hydroxyl group at the 5-position
of 4 is protected by bulky silyl substituents.14,20
F igu r e 1. IR absorption spectra of 4 in CH2Cl2: (a) 2.5 mM,
(b) 10 mM, and (c) 50 mM.
Ferulic acid was converted into 3-(4′-acetoxy-3′-meth-
oxyphenyl)-2-propenoyl chloride (5) via two steps. The
reaction of 4 with 5 was carried out in the presence of a
mixture of triethylamine and 4-(dimethylamino)pyridine
(DMAP) in CH2Cl2 (Scheme 2). However, the yield of the
desired ester was very low.
The acid chloride 5 usually has sufficient reactivity in
the ester formation with an alcohol.9 Therefore, we
studied the reason for the poor reactivity of 4 in this
reaction. The solubility experiment revealed the unex-
pected fact that 4 was soluble in hydrophobic solvents.
This fact implies that intramolecular and/or intermo-
lecular hydrogen bonding exists in 4 in hydrophobic
solvents such as CH2Cl2.
The FT-IR spectra of 4 in a 50 mM CH2Cl2 solution
showed three peaks at 3688, 3585, and 3450 cm-1 in the
OH-stretching region (Figure 1). The absorption peaks
at 3688 and 3585 cm-1 can be assigned to the free OH
group and the intramolecularly hydrogen-bonded OH
group, respectively.15-17 The absorption band centered at
Exp er im en ta l Section
Gen er a l Meth od s. The 1H (400 MHz) and 13C (100 MHz)
NMR spectra were recorded on a Varian unity-plus 400 spec-
trometer. FT-IR spectra were recorded on a Shimazu FTIR
8200D instrument. The solutions were measured between NaCl
windows. Solid samples were measured as KBr pellets using a
J ASCO IR-810 instrument. Melting points were measured in
capillary tubes with a Yanagimoto micro melting point ap-
paratus and are uncorrected. Elemental analyses were per-
formed on a Perkin-Elmer 2400II instrument. Compound purity
(15) Chung, S. K.; Ryu, Y. Carbohydr. Res. 1994, 258, 145-167.
(16) Kuhn, L. P. J . Am. Chem. Soc. 1952, 74, 2492-2499.
(17) Kuhn, L. P. J . Am. Chem. Soc. 1954, 76, 4323-4326.
(18) Kabalka, G. W.; Varma, M.; Varma, R. S.; Srivastava, P. C.;
Knapp, F. F., J r. J . Org. Chem. 1986, 51, 2386-2388.
(19) Watanabe, Y.; Shinohara, T.; Fujimoto, T.; Ozaki, S. Chem.
Pharm. Bull. 1990, 38, 562-563.
(20) Watanabe, Y.; Yamamoto, T.; Ozaki, S. J . Org. Chem. 1996,
61, 14-15.

Notes
J . Org. Chem., Vol. 66, No. 21, 2001 7201
was checked by TLC on Silica Gel 60 F254 (E. Merck) with
detection by charring with phosphomolybdic acid (10% in EtOH
solution). Column chromatography was performed on Silica Gel,
Wakogel C-200 (Wako Pure Chemical Industry).
6a : TLC (1:1 n-hexane/ethyl acetate) Rf ) 0.35; mp 163-165
°C; 1H NMR (CDCl3) δ 7.72 (d, 1H, J ) 16.0 Hz), 7.04-7.13 (m,
3H), 6.54 (d, 1H, J ) 16.0 Hz), 4.97 (dd, 1H, J ) 2.8, 10.0 Hz),
4.25 (t, 1H, J ) 2.8 Hz), 4.18 (m, 1H), 3.95 (t, 1H, J ) 8.8 Hz),
3.86 (s, 3H), 3.79 (dd, 1H, J ) 2.8, 8.8 Hz), 3.45 (m, 1H), 2.59-
2.62 (m, 2H), 2.51 (d, 1H, J ) 3.2 Hz), 2.33 (s, 3H), 1.00-1.11
(m, 28H); 13C NMR (CDCl3) δ 168.76, 166.51, 151.36, 145.23,
141.57, 133.17, 123.24, 121.61, 117.60, 111.08, 76.15, 75.06,
74.76, 73.06, 71.00, 69.59, 55.88, 20.65, 17.44, 17.30, 17.20, 17.12,
12.81, 12.76, 12.06, 12.03. Anal. Calcd for C30H48O11Si2: C, 56.22;
H, 7.55. Found: C, 56.19; H, 7.60.
Ma ter ia ls. Ferulic acid and myo-inositol were provided by
Tsuno Food Industrial Co., Ltd. Ferulic acid was recrystallized
from ethanol. myo-Inositol was dried under reduced pressure
in a drying oven. (()-1,2-O-Cyclohexylidene-3,4-O-(1,1,3,3-tet-
raisopropyldisiloxanedi-1,3-yl)-myo-inositol (3) was prepared
according to literature.13,14 Other chemicals were commercial
products and were used without further purification. Solvents
were reagent grade and, in most cases, dried prior to use.
6b: TLC (1:1 n-hexane/ethyl acetate) Rf ) 0.49; mp 102-104
°C; 1H NMR (CDCl3) δ 7.71 (d, 1H, J ) 16.0 Hz), 7.04-7.13 (m,
3H), 6.47 (d, 1H, J ) 16.0 Hz), 5.40 (t, 1H, J ) 10.0 Hz), 4.14 (t,
1H, J ) 2.8 Hz), 3.98 (t, 1H, J ) 8.8 Hz), 3.86 (s, 3H), 3.53-
3.73 (m, 3H), 2.70-2.78 (m, 2H), 2.45 (d, 1H, J ) 3.2 Hz), 2.33
(s, 3H), 1.00-1.11 (m, 28H); 13C NMR (CDCl3) δ 168.76, 167.18,
151.32, 144.92, 141.42, 133.35, 123.21, 121.36, 117.80, 111.23,
74.67, 74.10, 73.06, 72.77, 70.92, 55.88, 20.66, 17.41, 17.32, 17.27,
17.20, 17.11, 12.78, 12.05, 12.02. Anal. Calcd for C30H48O11Si2:
C, 56.22; H, 7.55. Found: C, 56.17; H, 7.63.
(()-3,4-O-(1,1,3,3-Tetr aisopr opyldisiloxan edi-1,3-yl)-myo-
in ositol (4). A mixture of a catalytic amount of p-toluenesulfonic
acid and ethylene glycol (0.74 g, 12.0 mmol) was added to a
solution of 3 (5.48 g, 10.9 mmol) in CHCl3 (50 mL). The mixture
was stirred at room temperature for 1 h. The organic layer was
washed with saturated aqueous NaHCO3 and water, and dried
over Na2SO4. The solvent was evaporated to dryness under
reduced pressure by an aspirator. The residue was chromato-
graphed (silica gel, CHCl3) to give 4 as a white solid (3.97 g,
86%): mp 118-121 °C; 1H NMR (DMSO-d6) δ 4.45-4.65 (m, 4H),
3.68-3.75 (m, 2H), 3.51 (dd, 1H, J ) 2.4, 9.2 Hz), 3.39 (m, 1H),
3.19 (m, 1H), 3.02 (m, 1H), 0.86-1.10 (m, 28H); 13C NMR
(DMSO-d6) δ 77.00, 75.61, 75.08, 72.97, 72.38, 71.51, 17.61,
17.57, 17.50, 17.39, 17.22, 12.54, 12.00, 11.87. Anal. Calcd for
C18H38O7Si2: C, 51.15; H, 9.06. Found: C, 51.12; H, 9.21.
(()-1,6-O-Bis[3-(4′-a cetyloxy-3′-m eth oxyp h en yl)-2-p r op e-
n oyl]-3,4-O-(1,1,3,3-tetr a isop r op yld isiloxa n ed i-1,3-yl)-m yo-
in ositol (6c) a n d (()-1,5,6-O-Tr is[3-(4′-a cetyloxy-3′-m eth -
oxyp h e n yl)-2-p r op e n oyl]-3,4-O-(1,1,3,3-t e t r a isop r op yl-
d isiloxa n ed i-1,3-yl)-m yo-in ositol (6d ). A mixture of a catalytic
amount of 4-(dimethylamino)pyridine and 5 (318 mg, 1.25 mmol)
was added to a solution of 4 (106 mg, 0.25 mmol) in anhydrous
pyridine (10 mL). The mixture was stirred at 70 °C for 1.5 h,
and the reaction was quenched by adding water. Ethyl acetate
was added, and the mixture was washed successively with
saturated aqueous KHSO4, saturated aqueous NaHCO3, and
brine. After the organic layer was dried over Na2SO4, the solvent
was removed under reduced pressure. The residue was chro-
matographed (silica gel, 3:2 n-hexane/ethyl acetate) to give 6c
as a white solid (174 mg, 81%): TLC (1:1 n-hexane/ethyl acetate)
Rf ) 0.57; mp 198-200 °C; 1H NMR (CDCl3) δ 7.57-7.63 (m,
2H), 6.97-7.04 (m, 6H), 6.30-6.40 (m, 2H), 5.72 (t, 1H, J ) 10.0
Hz), 5.35-5.38 (m, 2H), 4.99 (dd, 1H, J ) 2.4, 10.0 Hz), 4.06 (m,
1H), 3.91 (m, 1H), 3.77-3.84 (m, 7H), 3.55 (m, 1H), 2.24 (s, 6H),
0.85-1.10 (m, 28H); 13C NMR (CDCl3) δ 168.69, 166.18, 166.12,
151.37, 151.31, 145.48, 144.95, 141.64, 141.48, 133.20, 133.02,
123.17, 123.20, 121.76, 121.45, 117.59, 117.21, 111.17, 111.06,
74.61, 73.41, 71.10, 70.97, 70.80, 55.92, 55.87, 20.61, 17.46, 17.35,
3-(4′-Acetyloxy-3′-m eth oxyph en yl)-2-pr open oic Acid Ch lo-
r id e (5). Ferulic acid (1) (38.8 g, 0.2 mol) was added to a solution
of NaOH (25.4 g, 0.52 mol) in water (200 mL), and the mixture
was cooled to below 10 °C. Acetic anhydride (25.4 g, 0.25 mol)
was then added to the cold solution. The solution was stirred at
20 °C for 10 min and then at room temperature for 20 min. Then,
the pH of the solution was adjusted to 4-5 by adding dilute
sulfuric acid. The resulting white precipitate was filtered and
washed with water. Recrystallization from EtOH gave colorless
1
needles (37.7 g, 77%): mp 197-200 °C; H NMR (DMSO-d6) δ
12.45 (s, 1H), 7.61 (d, 1H, J ) 15.6 Hz), 7.12-7.49 (m, 3H), 6.61
(d, 1H, J ) 15.6 Hz), 3.84 (s, 3H), 2.28 (s, 3H); 13C NMR (DMSO-
d6) δ 168.6, 167.8, 151.3, 143.5, 141.0, 133.4, 123.4, 121.5, 119.7,
112.0, 56.2, 20.6.
Thionyl chloride (8.5 mL, 0.12 mol) was added to a suspension
of 3-(4′-acetyloxy-3′-methoxyphenyl)-2-propenoic acid (23.6 g, 0.1
mol) in CHCl3 (100 mL) containing a catalytic amount of DMF.
The mixture was stirred for 4 h at the reflux temperature. After
the solvent and excess thionyl chloride were removed under
reduced pressure, the acid chloride 5 was obtained as pale yellow
crystals (25.0 g, 98%). This material was used without further
purification: mp 129-131 °C; 1H NMR (CDCl3) δ 7.79 (d, 1H, J
) 15.6 Hz), 7.09-7.12 (m, 3H), 6.59 (d, 1H, J ) 15.6 Hz), 3.88
(s, 3H), 2.35 (s, 3H); 13C NMR (CDCl3) δ 168.5, 165.9, 151.7,
149.8, 142.8, 131.8, 123.6, 122.5, 122.4, 111.9, 56.0, 20.6. Anal.
Calcd for C12H11ClO4: C, 56.60; H, 4.35. Found: C, 56.56; H,
4.28.
17.32, 17.26, 17.21, 17.13, 12.79, 12.06. Anal. Calcd for C42H58O15
Si2: C, 58.72; H, 6.81. Found: C, 58.67; H, 6.94.
-
Further elution gave 6d as a white solid (29.6 mg, 11%): TLC
(1:1 n-hexane/ethyl acetate) Rf ) 0.47; mp 191-194 °C; 1H NMR
(CDCl3) δ 7.52-7.67 (m, 3H), 7.00-7.08 (m, 9H), 6.24-6.43 (m,
3H), 5.91 (t, 1H, J ) 10.4 Hz), 5.37 (t, 1H, J ) 10.0 Hz), 5.27
(dd, 1H, J ) 2.4, 10.0 Hz), 4.33 (t, 1H, J ) 2.8 Hz), 4.26 (t, 1H,
J ) 9.2 Hz), 3.95 (dd, 1H, J ) 2.8, 8.4 Hz), 3.84 (s, 6H), 3.81 (s,
3H), 2.31 (s, 6H), 2.29 (s, 3H), 0.90-1.12 (m, 28H); 13C NMR
(CDCl3) δ 168.77, 168.68, 166.00, 165.77, 165.53, 151.36, 151.30,
145.61, 145.19, 144.93, 141.67, 141.54, 141.49, 133.21, 133.03,
123.21, 123.15, 121.80, 121.64, 121.39, 117.36, 117.12, 111.17,
111.09, 75.12, 74.27, 72.74, 71.00, 70.89, 69.22, 55.94, 55.91,
20.64, 17.45, 17.34, 17.24, 17.14, 17.08, 12.79, 12.09, 12.03. Anal.
Calcd for C54H68O19Si2: C, 60.21; H, 6.36. Found: C, 60.18; H,
6.44.
(()-1-O-[3-(4′-Acetyloxy-3′-m eth oxyph en yl)-2-pr open oyl]-
3,4-O-(1,1,3,3-tetr a isop r op yld isiloxa n ed i-1,3-yl)-m yo-in osi-
tol (6a ) a n d (()-6-O-[3-(4′-Acetyloxy-3′-m eth oxyp h en yl)-2-
p r op en oyl]-3,4-O-(1,1,3,3-t et r a isop r op yld isiloxa n ed i-1,3-
yl)-m yo-in ositol (6b). The acid chloride 5 (159 mg, 0.625 mmol)
was added to a solution of 4 (106 mg, 0.25 mmol) in anhydrous
pyridine (10 mL). The mixture was stirred for 14 h at room
temperature, and the reaction was quenched by adding water.
Ethyl acetate was added, and the mixture was washed succes-
sively with saturated aqueous KHSO4, saturated aqueous
NaHCO3, and brine. After the organic layer was dried over Na2-
SO4, the solvent was removed under reduced pressure. The
residue was chromatographed on preparative TLC (1 mm
thickness of silica gel, 3:2 n-hexane/ethyl acetate) to give 6a (52.8
mg, 33%) and 6b (10.5 mg, 6.6%) as white solids, respectively.
Ack n ow led gm en t. This study was performed with
support from the Special Coordination Funds for Pro-
moting Science and Technology (Leading Research
Utilizing Potential of Regional Science and Technology)
of the Ministry of Education, Culture, Sports, Science
and Technology of the J apanese Government.
J O015629E