Catechuic acid and ethyl 2,4,5-trihydroxybenzoate from d-glucose

Article abstract of DOI:10.1016/j.carres.2009.02.002

Synthesis of catechuic acid (1) and ethyl 2,4,5-trihydroxybenzoate (2) from d-glucose-derived β-ketoester is described. The polyhydroxylated β-ketoester obtained from the hydrolysis of sugar β-ketoester 3 was subjected to an aldol-type condensation to get

Full text of DOI:10.1016/j.carres.2009.02.002

Carbohydrate Research 344 (2009) 734–738
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Carbohydrate Research
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Catechuic acid and ethyl 2,4,5-trihydroxybenzoate from D-glucose
*
Namdeo N. Bhujbal, Omprakash P. Bande, Dilip D. Dhavale
Garware Research Centre, Department of Chemistry, University of Pune, Pune 411007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 January 2009
Received in revised form 2 February 2009
Accepted 3 February 2009
Available online 8 February 2009
Synthesis of catechuic acid (1) and ethyl 2,4,5-trihydroxybenzoate (2) from D-glucose-derived b-ketoester
is described. The polyhydroxylated b-ketoester obtained from the hydrolysis of sugar b-ketoester 3 was
subjected to an aldol-type condensation to get 4 that on enolization, dehydration, and hydrogenation
afforded ethyl 2,4,5-trihydroxybenzoate (2). On the other hand, hydrogenation of aldol product 4 affor-
ded polyhydroxylated keto-carbasugar 6, which on mild acid treatment and ester hydrolysis in basic
media led to catechuic acid 1. Intermediate 4 is co-related to 3-dehydroshikimic acid, a biochemical inter-
Keywords:
Aldol reaction
b-Ketoester
mediate from D-glucose in the synthesis of pro-catechuic acid.
Ó 2009 Elsevier Ltd. All rights reserved.
Carbocycles
Carbohydrates
Phenolic acids
1. Introduction
thesis, wherein intramolecular ring closure of carbohydrates
afforded polyhydroxylated carbocyclic or polyhydroxylated cyclo-
hexenone derivatives that are converted to the phenolic com-
pounds.20,40–42 While working in the area of carbohydrate
chemistry, we have synthesized sugar b-ketoesters and demon-
strated their utility in the synthesis of griseolic acid and nojirimy-
cin analogues.43–49 We now demonstrate the transformation of
sugar b-ketoesters 3a/b to catechuic acid (1) and ethyl 2,4,5-
trihydroxybenzoate (2) by emulating the biochemical cascade
reactions (vide supra) of intramolecular aldol condensation and
enolization that are known from poly-b-ketoesters to phenolic
acids/esters.50 Our results are reported herein.
The phenolic acids and derivatives have significant importance
in food chemistry, nutritional science, drug chemistry, and plant
physiology.1–6 For example, the spermidine derivatives of catechu-
ic acid (1), namely agrobactin and parabactin (Fig. 1), are known to
be iron chelators7,8 and are used in the therapy of Cooley’s anemia
and as anticancer treatments.9–11 Other phenolic compounds such
as gallic acid, vanillic acid, ferulic acid, caffeic acid, chlorogenic
acid, rosmarinic acid, and cichoric acid are known to be natural
antioxidants12,13 and antimutagenics,14,15 while alkyl tri-
hydroxybenzoates are antimicrobials and antagonists of shikimic
acid.16
In general, synthesis of phenolic acids/esters involves both bio-
chemical and chemical synthetic pathways. Frost and co-workers
2. Results and discussion
reported the biochemical conversion of D-glucose to pro-catechuic
The required sugar b-ketoesters 3a and 3b were prepared on
acid, gallic acid, vanillin, and mono-, di-, and trihydroxy benzenes
via 3-dehydroshikimic acid.17–24 Koppisch et al. biosynthesized
3,4-dihydroxybenzoate from erythrose-4-phosphate and phospho-
enolpyruvate.25 In addition, bio-transformations of aromatic com-
pounds to the hydroxybenzoic acids using micro-organisms are
known.26–32 The chemical synthetic approaches to phenolic
acids/esters involve (i) functionalization of phenols either by pho-
tolytic oxidation33,34 or by the hydroxylation of salicylic acid and
b-resorcylic acid,35–37 (ii) carboxylation of procatechol followed
by lithiation,38 and (iii) TMSOTf-catalyzed [3+3] cyclization of
1,3-bis(silyl enol ether) with 1,1,3,3-tetramethoxypropane.39 As
an alternative, sugars are used as substrates in the chemical syn-
the 50-g scale from
a-D-glucose as reported earlier by us in
overall 35% and 28% yields, respectively.43 As shown in Scheme 1,
treatment of 3a with 9:1 TFA–water at 0 °C for 2 h, followed by
removal of solvent under reduced pressure and column chroma-
tography of the crude product afforded ethyl 4-O-benzyl-3,5-dihy-
droxy-6-oxocyclohex-1-ene carboxylate (4a) [Vasella et al.51
reported the synthesis of analogous cyclohexenone, namely tert-
butyl 3,4,5-tri-O-triethylsilyl-6-oxo-cyclohex-1-ene carboxylate,
from methyl 6-deoxy-6-iodo-a-D-glucopyranoside in 50% yield.
However, further conversion to catechuate derivative is not
Our attempts to improve the yield of 4a/b under variety of reaction conditions of
acid catalyst (CSA/PTSA/H2SO4/HCl/HClO4), solvent (CH2Cl2, benzene, EtOH, 1,4-
dioxane), and temperatures (0 °C–reflux temperature) were unsuccessful.
* Corresponding author. Tel.: +91 020 25691727; fax: +91 020 25691728.
E-mail address: ddd@chem.unipune.ernet.in (D.D. Dhavale).
0008-6215/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2009.02.002

N. N. Bhujbal et al. / Carbohydrate Research 344 (2009) 734–738
735
We believe that formation of 5 from cyclohexenone derivatives
4a/b involves an enolization as the first step leading to formation
of either X or Y, wherein loss of a water molecule from the proton-
ated species Y afforded 5, an immediate precursor to 2 (Eq. 1).à
R
OH
OH
OH
O
OH
OH
N
H
N
O
H
O
OH
O
OH
O
HO
HO
OEt
HN
OEt
N
O
4
H
BnO
BnO
R = H Agrobactin
R = OH Parabactin
H
H
OH
OH
Y
X
Figure 1.
eq. 1
H
H
HO
OH
O
O
O
OEt
O
-H2O
Ref.15a
EtO
5
R
glucose
-
D
BnO
H
O
OH
R1
O
1
Targeting toward the synthesis of catechuic acid (1), hydroge-
nation of 4a with 10% Pd/C in methanol under balloon pressure
for 30 min afforded 6a, wherein reduction of the double bond
and removal of the –OBn protection took place simultaneously.
Similarly, hydrogenation of 4b at 80 psi pressure for 3 h afforded
6b. In order to confirm the conformations of 6a and 6b, the assign-
ment of proton signals in the 1H NMR spectrum of 6a/6b was made
by decoupling experiments.§ Thus, in the case of 6a, appearance of
H-3 at d 4.34 as a doublet with J = 9.8 Hz and of H-4 at d 3.45 as a
triplet with J = 9.8 Hz indicates the axial orientation of H-3, H-4,
and H-5. Furthermore, H-1 appeared at d 3.90 as a doublet of dou-
blets with J = 13.2 Hz and 5.0 Hz, indicating the axial orientation
of H-1. This confirmed the conformation of 6a with all the substitu-
ents in the equatorial orientation as shown in Figure 2.
3a
3b
R = OBn, R = H
1
R = H, R = OBn
TFA/H2O
O
O
OH
O
HO
OEt
OEt
1
HCl, EtOH
R
2
R1
RO
OH
OH
4a R = OBn, R1 = H, 52%
5 R = OBn, 68%
2 R = H, 97%
H2,Pd/C
1
4b
R = H, R = OBn, 54%
H
H
H
H
3
H
H
1
H2, Pd/C
3
HO
5
H
5
4
OH
2
4
OH
2
HO
HO
OH
H
H
O
O
H
1
R
6
OH
O
6
R
O
O
HO
R
H
H
OEt
HO
6a
6b
HCl, EtOH
OR
R = COOEt
Figure 2. Conformations of 6a/6b.
R1
OH
6a R =OH, R1 = H, 95%
7 R = Et, 78%
LiOH
6b R = H ,R1 = OH, 89%
In case of 6b, H-3 appeared at d 4.35 as a doublet with J = 3.0 Hz,
indicating an axial–equatorial orientation of H-3 and H-4, while H-
1, H-4, and H-5 appeared as a multiplet in the range of d 4.30–4.38,
making it difficult to assign the conformation. However, we have
tentatively assigned the conformation for 6b (Fig. 2), based on
the addition of the hydrogen from the b-face, making the –CO2Et
substituent equatorial as found in 6a. In the next step, reaction
of 6a with a catalytic amount of HCl (12 N, 0.2 equiv) in ethanol
at 60 °C for 30 min afforded ethyl catechuate (7). While performing
an analogous reaction with 6b, it was anticipated that the axial ori-
entation of the C-4 hydroxy substituent (in 6a C-4 hydroxy is equa-
torial) will lead to a different product. However, reaction of 6b with
ethanolic HCl at 60 °C for 1 h afforded an identical product 7 as evi-
1
R = OH, 71%
Scheme 1. Synthesis of 1 and 2 from the b-ketoester.
reported.]. Reaction of 4a with HCl (12 N, 1.0 equiv) in EtOH at
reflux for 30 min afforded ethyl 4-O-benzyl 2,5-dihydroxybenzoate
(5) as the only isolable product. The structure of 5 was confirmed
by the 1H–1H COSY spectrum, wherein no cross-peaks were
obtained in the aromatic region, suggesting that the aromatic pro-
tons at d 6.52 and 7.34 are not mutually coupled and therefore are
placed in the para position with respect to each other. In order to
know the effect of orientation of the –OBn substituent, a similar
reaction sequence was repeated with D-allose-derived b-ketoester
3b. Thus, reaction of 3b with TFA–water afforded 4b, which on
treatment with ethanolic HCl gave the identical product 5 as evi-
dent from the mixed mp and spectral data. In the final step,
hydrogenolysis of 5 with 10% Pd/C in MeOH at 80 psi pressure
afforded ethyl 2,4,5-trihydroxybenzoate (2) in overall 12% yield
from D-glucose.
à
Elimination of water molecule from protonated species
formation of ethyl 4-O-benzyl-2,3-dihydroxybenzoate, and not to product 5 that was
X will lead to the
obtained.
The 1H and 13C NMR spetra of 6a and 6b showed additional signals (<10%) due to
the corresponding enol form.
§

736
N. N. Bhujbal et al. / Carbohydrate Research 344 (2009) 734–738
dent from the spectral and analytical data. The formation of prod-
uct 7 can be explained by assuming that the keto-compounds 6a/
6b under mild acidic reaction conditions remain in equilibrium
with the enol form Z, wherein the quasi-axial orientation of the
C4-OH group undergoes facile loss of two molecules of water to
give ethyl catechuate (7) as the only product (Eq. 2).
proach (Path B), one molecule of acetyl-CoA and three molecules
of malonyl-CoA form the eight-carbon poly-b-ketoester III that
undergoes an intramolecular aldol-type condensation and dehy-
dration to give cyclohexenone derivative IV, which by enolization,
dehydration, and hydrolysis cascade leads to the formation of ors-
ellinic acid/6-methylsalicylic acid and related natural products.50
In the present chemical synthesis of 1 and 2 from
have synthesized analogous hydroxylated seven-carbon b-ketoes-
ter V from -glucose and converted it to catechuic acid (1) and
ethyl 2,4,5-trihydroxybenzoate (2), mimicking the steps involved
in the poly-b-ketoester biogenetic pathway (Path B).
In conclusion, catechuic acid (1) and ethyl 2,3,4-trihydroxyben-
zoate (2) were synthesized from D-glucose-derived b-ketoester 3,
which on opening of the 1,2-acetonide functionality follows an
analogous path of aldol condensation, enolization and dehydration
as known for the poly-b-ketoester biosynthetic pathway. A notable
feature of our nonenzymatic approach is that all the carbon atoms
D-glucose, we
OH
O
OH
O
H
D
HO
HO
O
OEt
-H2O
OEt
-H2O
6
H
7
H
H
+
O
H
OH
eq. 2
+
H
H
Z
In the final step, treatment of 7 with LiOH in ethanol–water at
room temperature afforded catechuic acid (1) in overall 11% yield
from D-glucose. The physical constants and analytical data of 1
of the D-glucose-derived b-ketoester are retained in the target mol-
ecules as in the biogenetic pathway, and the reaction sequence led
to exclusive formation of the products (no other regioisomer).
are found to be in accordance with those reported.38 An interesting
resemblance between the present chemical synthesis and bioge-
netic pathways to phenolic acids was noticed by us. The biogenesis
of phenolic acids/esters mainly involves two different pathways:
one involving shikimate and the other involving a poly-b-ketoes-
ter. In the shikimate pathway (Scheme 2, Path A), phosphoenolpyr-
3. Experimental
3.1. General
Melting points were recorded with a Thomas–Hoover capillary
melting point apparatus, and are uncorrected. IR spectra were re-
corded with an FTIR instrument as a thin film or using KBr pellets,
uvate and erythrose phosphate first form the a-ketoester I that is
converted to the 3-dehydroshikimic acid (II) and then to isochoris-
mic acid, leading to 2,3-dihydroxybenzoic acid. In the latter ap-
and are expressed in cmÀ1 1H (300 MHz) and 13C (75 MHz) NMR
.
Path A
Shikimate pathway to 2,3-dihydroxybenzoic acid
COOH
NADPH
ATP,
PO
HO
COOH
OH
COOH
OH
H
aldol-
aldol-
O
PEP
O-P
COOH
PEP
reaction
reaction
isomerisation
O
H+
-HOP
NAD+
HO
OH
hydrolysis
OH
OH
OH
O
of enolether
NAD+
OH
2,3-dihyroxy-
D-erythrose 4-P
benzoic acid
(II)
(I)
Path B
Poly-β-ketoester pathway to orsellinic acid
SCoA
OH
O
O
enolisation
hydrolysis
O
O
O
O
COOH
aldol
O
reaction
SEnz
acetyl-CoA
EnzS
HO
+
poly-β-ketoester
COOH
SCoA
O
orsellinic acid
(IV)
(III)
7
malonyl-CoA
O
Path C
1 2
/
Synthetic pathway to
OH
O
O
enolisation
CO2Et
dehydration
aldol HO
reaction
O
O
OH
O
OEt
D
-glucose
EtO
H
HO
HO
n
n = 1, 2
OH OH
(V)
OH
1
or 2
4a/b
Scheme 2. Biogenetic pathways.

N. N. Bhujbal et al. / Carbohydrate Research 344 (2009) 734–738
737
spectra were recorded using CDCl3 or D2O as a solvent. Chemical
shifts were reported in d units (ppm) with reference to TMS as
an internal standard, and J values are given in Hertz. Elemental
analyses were carried out with a C, H-analyzer. Optical rotations
were measured using a polarimeter at 25 °C. Thin-layer chroma-
tography (TLC) was performed on pre-coated plates (0.25 mm, Sil-
ica Gel 60 F254). Column chromatography was carried out with
silica gel (100–200 mesh). The reactions were carried out in
oven-dried glassware under dry N2. MeOH and CH2Cl2 were puri-
fied and dried before use. Distilled n-hexane and EtOAc were used
for column chromatography. Pd–C (10%) was purchased from
CDCl3): d 14.3 CH3, 61.1 OCH2CH3, 71.1 OCH2Ph, 100.4 C-3, 104.6
C-1, 113.4 C-6, 127.8, 128.6, 128.7, 135.0 Ar-C, 138.2 C-5, 151.8
C-2, 157.0 C-4, 169.85 COOEt. Anal. Calcd for C16H16O5: C, 66.66;
H, 5.59. Found: C, 66.42; H, 5.83. Reaction of 4b (0.300 g, 1.04
mmol) with EtOH–HCl under identical conditions as described
for 4a afforded 5 as a white solid (0.186 g, 66%).
3.1.4. Ethyl 2,4,5-trihydroxybenzoate (2)
To a solution of 5 (0.100 g, 0.34 mmol) in MeOH (10 mL) was
added 10% Pd/C (0.020 g) [Caution! Extreme fire hazard!]. The
reaction mixture was hydrogenated at 80 psi pressure at room
temperature for 3 h. The reaction mixture was filtered through Cel-
ite, and Celite was washed with MeOH. The solvent was evaporated
under reduced pressure to give a solid. Purification by column
chromatography (9:1 n-hexane–EtOAc) afforded 2 as a white solid
(0.068 g, 97%); mp 165 °C; Rf 0.413 (7:3 n-hexane–EtOAc); IR (KBr):
r
–Aldrich and/or Fluka. After quenching the reaction with water,
the workup involved washing of combined organic layers with
water and brine, drying over anhydrous sodium sulfate, and evap-
oration of the solvent under reduced pressure.
3.1.1. (3S,4R,5S) Ethyl 4-O-benzyl-3,5-dihydroxy-6-
3500–3333, 1751, 1641 cmÀ1 1H NMR (300 MHz, CDCl3 + DMSO-
,
oxocyclohex-1-ene carboxylate (4a)
d6): d 1.28 (t, J = 7.2 Hz, 3H, CH3), 4.22 (q, J = 7.2 Hz, 2H, OCH2CH3),
6.27 (s, 1H, Ar-Ha), 7.10 (s, 1H, Ar-Hb), 7.70-9.50 (br s, exchanges
with D2O, 2H, 2 Â OH), 10.40 (s, exchange with D2O, 1H, OH); 13C
NMR (75 MHz, CDCl3, DMSO-d6): d 13.4 CH3, 59.6 OCH2CH3,
102.1 C-1, 104.0 C-3, 113.4 C-6, 137.1 C-2, 152.2 C-4, 155.7 C-5,
168.7 COOEt. Anal. Calcd for C9H10O5: C, 54.55; H, 5.09. Found: C,
54.50; H, 5.20.
To an ice-cold solution of b-ketoester 3a (1 g, 2.77 mmol) in
CH2Cl2 (5 mL) was added 9:1 TFA–water (4 mL) at 0 °C. The reac-
tion mixture was stirred at 0 °C for 2 h, and was brought to room
temperature. The solvent was evaporated under reduced pressure
to give a viscous oil. The oil was dissolved in CH2Cl2, adsorbed on
silica gel, and loaded on a silica gel column. Purification by column
chromatography (4:1 n-hexane–EtOAc) afforded 4a as a white so-
lid (0.452 g, 52%); mp 123–125 °C; Rf 0.593 (3:2 n-hexane–EtOAc);
3.1.5. Ethyl (3S,4R,5S)-trihydroxy-2-oxocyclohexane
carboxylate (6a)
[
a]
D
À18.18 (c 0.110, CH2Cl2); IR (KBr): 3400–3200 (br), 1726,
1712, 1662 cmÀ1
;
1H NMR (300 MHz, CDCl3): d 1.35 (t, J = 7.2 Hz,
A solution of 4a (0.400 g, 1.3 mmol) and 10% Pd/C (0.080 g) in
MeOH (7 mL) [Caution! Extreme fire hazard!] was hydrogenated
at 20 psi pressure at room temperature for 1 h. The reaction mix-
ture was filtered through Celite, and Celite was washed with
MeOH. The filtrate was then concentrated, and the residue was
purified by column chromatography (2:3 n-hexane–EtOAc) to af-
ford 6a as a white solid (0.287 g, 95%); mp 148 °C; Rf 0.428 (EtOAc);
3H, CH3), 1.42 (br s, exchanges with D2O, 2H, OH), 3.68 (dd, J =
10.5, 8.7 Hz, 1H, 4-H), 4.31 (d, J = 10.5 Hz, 1H, H-5), 4.34 (q, J =
7.2 Hz, 2H, OCH2CH3), 4.66 (dd, J = 8.7, 2.2 Hz, 1H, H-3), 4.76 (d,
J = 11.4 Hz, 1H, OCH2Ph), 5.17 (d, J = 11.4 Hz, 1H, OCH2Ph), 7.32–
7.49 (m, 5H, Ar-H), 7.69 (d, J = 2.2 Hz, 1H, H-2); 13C NMR (75
MHz, CDCl3): d 14.0 CH3, 61.8 OCH2CH3, 70.0 C-3, 74.8 OCH2Ph,
78.2 C-5, 85.4 C-4, 128.2, 128.3, 128.5 Ar-C, 129.2 C-1, 137.6 Ar-
C, 156.2 C-2, 162.4 COOEt, 193.9 CO. Anal. Calcd for C16H18O6: C,
62.74; H, 5.92. Found: C, 62.98; H, 6.02.
[a
]
D
+4.66 (c 0.120, water); IR (KBr): 3427, 3337, 3246, 1743,
1718 cmÀ1 1H NMR (300 MHz, D2O): d 1.26 (t, J = 7.2 Hz, 3H,
;
CH3); 1.93 (apparent quartet, J = 13.2 Hz, 5.0 Hz, 1H, H-6a); 2.38
(dt, J = 13.2, 5.0 Hz, 1H, H-6b), 3.45 (t, J = 9.8 Hz, 1H, H-4), 3. 90
(dd, J = 13.2, 5.0 Hz, 1H, H-1), 4.00 (ddd, J = 13.2, 9.8, 5.0 Hz, 1H,
H-5), 4.22 (q, J = 7.2 Hz, 2H, OCH2CH3), 4.34 (d, J = 9.8 Hz, 1H, H-
3); 13C NMR (75 MHz, D2O): d 13.6 CH3, 30.9 C-6, 51.8 C-1, 62.9
OCH2CH3, 69.5 C-5, 77.9 C-4, 78.6 C-3, 173.7 COOEt, 204.6 CO. Anal.
Calcd for C9H14O6: C, 49.50; H, 6.47. Found: C, 49.77; H, 6.73.
3.1.2. (3S,4S,5S) Ethyl 4-O-benzyl-3,5-dihydroxy-6-oxocyclohex-
1-ene carboxylate (4b)
Reaction of sugar b-ketoester 3b as reported for 4a afforded 4b
as a white solid (0.47 g, 54%); mp 122–124 °C; Rf 0.56 (1:1 n-hex-
ane–EtOAc); [a] +91.50 (c 0.113, CH2Cl2); IR (KBr): 3500–3000
D
(br), 1740, 1697, 1627 cmÀ1 1H NMR (300 MHz, CDCl3): d 1.32 (t,
;
J = 7.2 Hz, 3H, CH3), 2.6–4.05 (br s, exchanges with D2O, 2H,
2 Â OH), 4.27 (q, J = 7.2 Hz, 2H, OCH2CH3), 4.38 (d, J = 2.4 Hz, 1H,
H-5); 4.40–5.00 (m, 1H, H-4), 4.62 (d, J = 11.0 Hz, 1H, OCH2Ph),
4.64 (br s, 1H, H-3), 4.98 (d, J = 11.0 Hz, 1H, OCH2Ph), 7.22–7.46
(m, 5H, Ar-H), 7.47 (d, J = 2.1 Hz, 1H, H-2); 13C NMR (75 MHz,
CDCl3): d 14.1 CH3, 61.6 OCH2CH3, 67.2 OCH2Ph, 75.6, 76.5, 82.5
C-3,4,5, 128.0, 128.1, 128.4, 128.6, 137.2 Ar-C, 155.8 C-2, 162.2
COOEt, 193.2 CO. Anal. Calcd for C16H18O6: C, 62.74; H, 5.92. Found:
C, 62.81; H, 5.86.
3.1.6. Ethyl (3S,4S,5S)-trihydroxy-2-oxocyclohexane
carboxylate (6b)
[Caution! Extreme fire hazard!] Hydrogenation of 4b (0.300 g,
0.98 mmol) with 10% Pd/C (0.060 g) in MeOH (10 mL) at 80 psi
pressure at room temperature for 3 h and workup as for 4a gave
a crude solid. Purification by column chromatography (3:7 n-hex-
ane–EtOAc) afforded 6b as a white solid (0.191g, 89%); mp 173–
175 °C; Rf 0.346 (EtOAc); [
a]
À26.77 (c 0.200, water); IR (KBr):
D
3500–3400 (br), 3271, 1722 cmÀ1
;
1H NMR (300 MHz, D2O): d
1.27 (t, J = 7.2 Hz, 3H, CH3), 2.21–2.36 (m, 2H, H-6a,b), 4.23 (q, J
= 7.2 Hz, 2H, OCH2CH3), 4.29–4.36 (m, 3H, H-1,4,5), 4.35 (d, J =
3.0 Hz, 1H, H-3); 13C NMR (75 MHz, D2O): d 11.4 CH3, 27.8 C-6,
49.0 C-1, 60.6 OCH2Ph, 65.0 C-5, 73.4 C-4, 74.3 C-3, 168.6 COOEt,
204.6 CO. Anal. Calcd for C9H14O6: C, 49.50; H, 6.47. Found: C,
49.73; H, 6.66.
3.1.3. Ethyl 4-O-benzyl-2,5-dihydroxybenzoate (5)
A solution of 4a (0.300 g, 1.04 mmol) and HCl (0.034 g, 1.04
mmol) in EtOH (5 mL) was refluxed for 1 h. The solution was
cooled to room temperature, and the EtOH was removed under re-
duced pressure to give crude solid. Purification by column chroma-
tography (9:1 n-hexane–EtOAc) afforded 5 as a white solid (0.192
g, 68%); mp 138 °C; Rf 0.90 (7.5:2.5 n-hexane–EtOAc); IR (KBr):
3.1.7. Ethyl catechuate (7)
3500–3458 (br), 1728, 1664, 1633 cmÀ1
;
1H NMR (300 MHz,
A solution of 6a (0.050 g, 0.229 mmol) and concd HCl (0.016 g,
0.0458 mmol) in EtOH (2 mL) was stirred at 60 °C for 30 min and
was cooled to 0 °C. Neutralization by 10% NaHCO3 (0.5 mL) and
evaporation of the solvent under reduced pressure gave a crude so-
lid. Purification by column chromatography (9.5:0.5 n-hexane–
CDCl3): d 1.38 (t, J = 7.2 Hz, 3H, CH3), 4.34 (q, J = 7.2 Hz, 2H,
OCH2CH3), 5.10 (s, 2H, OCH2Ph), 5.25 (br s, exchanges with D2O,
1H, OH), 6.52 (s, 1H, Ar-Ha), 7.34 (s, 1H, Ar-Hb), 7.38 (s, 5H, Ar-
H), 10.27 (br s, exchanges with D2O, 1H, OH); 13C NMR (75 MHz,

738
N. N. Bhujbal et al. / Carbohydrate Research 344 (2009) 734–738
11. Jacobs, A.; White, G. P.; Tait, G. H. Biochem. Biophys. Res. Commun. 1977, 74,
1626–1630.
12. Nakamura, Y.; Torikai, K.; Ohigashi, H. J. Agric. Food Chem. 2001, 49, 5674–5678.
13. Ueda, J.; Saito, N.; Shimazu, Y.; Ozawa, T. Arch. Biochem. Biophys. 1996, 333,
377–384.
14. Birosova, L.; Mikulasova, M.; Vaverkova, S. Biomed. Pap. Med. Fac. Univ. Palacky
Olomoc Czech Repub. 2005, 149, 489–491.
15. Belicova, A.; Kriskova, L.; Nayg, M.; Krajcovic, J.; Ebringer, L. Folia Microbiol.
2001, 47, 511–514.
16. Carajal, G.; Penna, S.; Carbojal, E. J. J. Revista Latiinoamericana. de. Microbiol.
1962, 5, 45–53.
17. Draths, K. M.; Frost, J. W. J. Am. Chem. Soc. 1995, 117, 2395–2400.
18. Li, K.; Frost, J. W. J. Am. Chem. Soc. 1998, 120, 10545–10546.
19. Hansen, C. A.; Dean, A. B.; Draths, K. M.; Frost, J. W. J. Am. Chem. Soc. 1999, 121,
3799–3800.
EtOAc) afforded 7 as a white solid (0.033 g, 80%); mp 67 °C; Rf 0.80
(9:1 n-hexane–EtOAc); IR (KBr): 3500–3000 (br), 1734, 1674 cmÀ1
;
1H NMR (300 MHz, CDCl3): d 1.41 (t, J = 7.2 Hz, 3H, CH3), 4.40 (q, J =
7.2 Hz, 2H, OCH2CH3), 5.65 (s, exchange with D2O, 1H, OH), 6.77 (t,
J = 7.9 Hz, 1H, Ar-Hb), 7.08 (dd, J = 7.9, 1.5 Hz, 1H, Ar-Hc), 7.36 (dd, J
= 7.9, 1.5 Hz, 1H, Ar-Ha), 10.97 (br s, exchanges with D2O, 1H, OH);
13C NMR (75 MHz, CDCl3): d 14.2 CH3, 61.6 OCH2CH3, 112.5 C-1,
119.0 C-5, 119.6 C-6, 120.4 C-4, 144.8 C-3, 148.7 C-2, 170.2 COOEt.
Anal. Calcd for C9H10O4: C, 59.54; H, 5.53. Found: C, 59.49; H, 5.61.
The reaction of 6b (0.050 g, 0.229 mmol) with EtOH–HCl as de-
scribed for 6a afforded 7 as a white solid (0.029 g, 78%).
20. Kambourakis, S.; Frost, J. W. J. Org. Chem. 2000, 65, 6904–6909.
21. Gibson, J. M.; Thomas, P. S.; Thomas, J. D.; Barker, J. L.; Chandran, S. S.; Harrup,
M. K.; Draths, K. M.; Frost, J. W. Angew .Chem., Int. Ed. 2001, 40, 1945–1946.
22. Ran, N.; Knop, D. R.; Draths, K. M.; Frost, J. W. J. Am. Chem. Soc. 2001, 123,
10927–10934.
23. Li, W.; Xie, D.; Frost, J. W. J. Am. Chem. Soc. 2005, 127, 2874–2882. and
references cited therein.
24. Achkar, J.; Xian, M.; Zhao, H.; Frost, J. W. J. Am. Chem. Soc. 2005, 127, 5332–
5333.
25. Koppisch, A. T.; Hotta, K.; Fox, D. T.; Ruggiero, C. E.; Kim, C.; Sanchez, T.; Iyer, S.;
Browder, C. C.; Unkefer, P. J.; Unkefer, C. J. J. Org. Chem. 2008, 73, 5759–5765.
26. Sainsbury, M.; Dyke, S. F.; Moon, B. J. J. Chem. Soc. C 1970, 1797–1800.
27. Groseclose, E. E.; Ribbons, D. W. Biochem. Biophys. Res. Commun. 1973, 55, 897–
903.
3.1.8. Preparation of catechuic acid (1)
A solution of 7 (0.050 g, 0.324 mmol) and LiOH (0.040 g, 0.972
mmol) in 4:1 water–EtOH (1 mL) was stirred at 25 °C for 2 h and
was acidified by HCl. The solvent was evaporated under reduced
pressure, and the residue was extracted with Et2O (10 mL Â 3).
The combined extracts were dried over anhyd Na2SO4, and evapo-
ration of the solvent afforded 1 as a white solid (0.030 g, 71%); mp
207 °C; reported mp 207–210 °C.38 The spectral and analytical data
were identical with those reported.38
Acknowledgments
28. Fetzner, S.; Muller, R.; Lingens, F. Biol. Chem. Hoppe-Seyler 1989, 370, 1173–
1182.
29. Daumy, G. O.; Mccoll, A. S.; Andrews, G. C. J. Chem. Soc., Chem. Commun. 1979,
1073a.
We are grateful to Professor M.S. Wadia for helpful discussion.
We are thankful to DST, New Delhi (Grant No. SR/S1/OC-21/
2005), for the financial support. NNB is thankful to the UGC, New
Delhi, for teacher fellowship.
30. Shindo, K.; Nakamura, R.; Osawa, A.; Kagami, O.; Kanob, K.; Furukawa, K.;
Misawa, N. J. Mol. Catal. B: Enzym. 2005, 35, 134–141.
31. Gramer, C. J.; Raymond, K. N. Org. Lett. 2001, 3, 2827–2830.
32. De Voss, J. J.; Rutter, K.; Schroeder, B. G.; Su, H.; Zhu, Y.; Barry, C. E., 3rd Proc.
Natl. Acad. Sci. U.S.A. 2000, 97, 1252–1257.
33. Nakanishi, I.; Nishizawa, C.; Ohkubo, K.; Takeshita, K.; Suzuki, K. T.; Ozawa, T.;
Hecht, S. M.; Tanno, M.; Sueyoshi, S.; Miyata, N.; Okuda, H.; Fukuzumi, S.; Ikota,
N.; Fukuhara, K. Org. Biomol. Chem. 2005, 3, 3263–3265.
34. Saito, S.; Kawabata, J. Helv. Chim. Acta 2006, 89, 1395–1406.
35. Forrest, J.; Petrow, V. J. Chem. Soc. 1950, 2340–2342.
36. Rajgopalan, S.; Varadrajan, S. Proc. Indian Acad. Sci. Sect. A 1949, 30, 265–269.
37. Aghoramurthy, K.; Seshadri, T. R. Proc. Indian Acad. Sci. Sect. A 1952, 35, 327–
331.
Supplementary data
Copies of 1H and 13C NMR spectra of compounds 4a, 4b, 5, 2, 6a,
6b, 7 and of 1H–1H COSY spectrum of 5 are provided. Supplemen-
tary data associated with this article can be found, in the online
version, at doi:10.1016/j.carres.2009.02.002.
38. Huang, D.-S.; Ting, S.-H. J. Chem. Res. (S) 1994, 500–501.
39. Sher, M.; Tam Dang, T. H.; Ahmed, Z.; Rashid, M. A.; Fischer, C.; Langer, P. J. Org.
Chem. 2007, 72, 6284–6286.
References
40. Ferrier, R. J. J. Chem. Soc., Perkin Trans. 1 1979, 1455–1458.
41. Ferrier, R. J. Chem. Rev. 1993, 93, 2779. and references cited therein.
42. Chida, N.; Othuuka, M.; Ogura, K.; Ogawa, S. Bull. Chem. Soc. Jpn. 1991, 64,
2118–2121.
43. Dhavale, D. D.; Bhujbal, N. N.; Joshi, P.; Desai, S. G. Carbohydr. Res. 1994, 263,
303–307.
44. Vyavahare, V. P.; Chakraborty, C.; Maity, B.; Chattopadhyay, S.; Puranik, V. G.;
Dhavale, D. D. J. Med. Chem. 2007, 50, 5519–5523.
45. Vyavahare, V. P.; Chattopadhyay, S.; Puranic, V. G.; Dhavale, D. D. Synlett 2007,
559–562.
1. Bunzel, M.; Ralph, J.; Steinhart, H. Czech J. Food Sci. 2004, 22, 64–69.
2. Ralph, J.; Bunzel, M.; Marita, J. M.; Hatfield, R. D.; Lu, F.; Kim, H.; Schatz, P. F.;
Grabber, J. H.; Steinhart, H. Phytochem. Rev. 2004, 3, 79–96.
3. Waldron, K. W.; Smith, A. C.; Parr, A. J.; Na, A.; Parker, M. L. Trends Food Sci.
Technol. 1997, 8, 213–221.
4. Birosova, L.; Mikulasova, M.; Vaverkova, S. J. Agric. Food Chem. 2007, 55, 10183–
10186.
5. Gomes, C. A.; Girao da Cruz, T.; Andrade, J. L.; Milhazes, N.; Borges, F.; Marques,
M. P. M. J. Med .Chem. 2003, 46, 5395–5401.
6. Saulnier, L.; Cre´peau, M.; Lahaye, M.; Thibault, J.; Garcia-Conesa, M. T.; Kroon,
46. Dhavale, D. D.; Saha, N. N.; Desai, V. N. J. Org. Chem. 1997, 62, 7482–
7484.
P. A.; Williamson, G. Carbohydr. Res. 1999, 320, 82–92.
7. Corey, E. J.; Battacharyya, S. Tetrahedron Lett. 1979, 3919–3922.
8. Bluhm, M. E.; Kim, S. S.; Dertz, E. A.; Raymond, K. N. J. Am. Chem. Soc. 2002, 124,
2436–2437.
9. Jacobs, A. Br. J. Haematol. 1979, 43, 1.
10. Neilands, J. B. In Development of Iron Chelators for Clinical Use; Martell, A. E.,
Anderson, W. F., Badman, D. G., Eds.; Elsevier: Amsterdam, 1981.
47. Saha, N. N.; Desai, V. N.; Dhavale, D. D. J. Org. Chem. 1994, 64, 1715–1719.
48. Karche, N. P.; Jachak, S. M.; Dhavale, D. D. J. Org. Chem. 2003, 68, 4531–4534.
49. Karche, N. P.; Jachak, S. M.; Dhavale, D. D. J. Org. Chem. 2001, 66, 6323–6332.
50. Paul, M. D. Medicinal Natural Products, A Biosynthetic Approach, 2nd ed.; John
Wiley and Sons: New York, 2001. pp 61, 124.
51. Mirza, S.; Molleyres, L.; Vasella, A. Helv. Chim. Acta 1985, 68, 988–996.