Candida antarctica lipase B-mediated regioselective acylation of dihydroxybenzenes in organic solvents

Article abstract of DOI:10.1016/j.tet.2015.04.033

Candida antarctica lipase B proved to be a highly active biocatalyst for the direct acylation of phenolic hydroxy groups of substituted hydroquinones and resorcinols, which have rarely been reported so far. More importantly, the acylation reactions took place generally in a markedly regioselective manner: the hydroxy group remote from the substituent was preferentially acylated. In the case of substituted hydroquinones, the selectivity increased with the increase in the bulk of the substituent. Interestingly, the 1-O-monoacylated derivatives were obtained as the sole products in the case of 4-substituted resorcinols.

Full text of DOI:10.1016/j.tet.2015.04.033

Tetrahedron xxx (2015) 1e9
Contents lists available at ScienceDirect
Tetrahedron
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Candida antarctica lipase B-mediated regioselective acylation of
dihydroxybenzenes in organic solvents
*
Toshifumi Miyazawa , Manabu Hamada, Ryohei Morimoto, Yuki Maeda
Department of Chemistry, Faculty of Science and Engineering, Konan University, Higashinada-ku, Kobe 658-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Candida antarctica lipase B proved to be a highly active biocatalyst for the direct acylation of phenolic
hydroxy groups of substituted hydroquinones and resorcinols, which have rarely been reported so far.
More importantly, the acylation reactions took place generally in a markedly regioselective manner: the
hydroxy group remote from the substituent was preferentially acylated. In the case of substituted hy-
droquinones, the selectivity increased with the increase in the bulk of the substituent. Interestingly, the
1-O-monoacylated derivatives were obtained as the sole products in the case of 4-substituted
resorcinols.
Received 12 December 2014
Received in revised form 11 April 2015
Accepted 13 April 2015
Available online xxx
Keywords:
Candida antarctica lipase B
Hydroquinones
Ó 2015 Elsevier Ltd. All rights reserved.
Resorcinols
Regioselective acylation
Regioselectivity
1. Introduction
groups, there have been much less studies on phenolic hydroxy
groups. Several reports have dealt with the lipase-catalyzed
Enzymatic methodologies have now come to constitute impor-
tant alternatives or complements to chemical synthesis. Among
a number of enzymes exploited for synthetic purposes, lipases
(triacylglycerol hydrolases, EC 3.1.1.3) are recognized as a very at-
tractive group of catalysts because of their stability, usability and
broad substrate tolerance. Moreover, since they are easily available
from a variety of sources, especially bacteria and fungi, there must
be a fair chance of finding a suitable enzyme for a transformation of
interest in terms of catalytic activity and/or selectivity. Lipases have
been employed for the preparation of homochiral compounds
mainly related to pharmaceuticals and agrochemicals through
enantioselective hydrolysis in aqueous milieux or esterification/
transesterification in organic solvents.1 Besides the stereoselective
nature of lipases, their regioselective properties have also been
exploited for the preparation of compounds, which are not easily
obtainable by pure chemical methods. The synthesis of selectively
protected derivatives of compounds containing multiple hydroxy
groups such as carbohydrates has been undertaken through the
lipase-catalyzed acylation or deacylation procedure.2 These enzy-
matic acyl-transfer approaches are more straightforward than the
standard chemical methods, because they can protect or deprotect
a hydroxy group in the presence of several others under optimized
reaction conditions. Compared to such studies on alcoholic hydroxy
deacylation of peracetylated polyhydroxybenzenes,3,4 and fla-
vones and related compounds5 by transesterification with an al-
cohol such as n-butanol in organic media. On the other hand, only
a few reports have dealt with the lipase-catalyzed regioselective
direct acylation of phenolic hydroxy groups.6 This is probably be-
cause a phenolic hydroxy group is generally far less nucleophilic
than an alcoholic hydroxy group and/or because phenolic com-
pounds are known to inhibit some enzymes.7 Nicolosi and co-
workers reported that in the Burkholderia (Pseudomonas) cepacia
lipase-catalyzed acetylation of aromatic dihydroxy aldehydes and
ketones with vinyl acetate in cyclohexaneet-amyl alcohol, the hy-
droxy group other than the one at position ortho to the carbonyl
was selectively acylated. They attributed this high regioselectivity
to the chelation of the carbonyl with the o-hydroxy group.6a,8
Stimulated by this work, we set about examining the regiose-
lectivity in the lipase-catalyzed acylation of the simplest members
of polyphenols, i.e., dihydroxybenzenes (hydroquinones and res-
orcinols) carrying substituents other than the carbonyl. The prep-
aration of regioselectively protected derivatives of polyphenolic
compounds by direct acylation procedure should be an extremely
challenging task. We envisaged that if the substituent group was
sterically demanding enough regioselective reactions might occur
even in the absence of a carbonyl. In fact, we found that of the li-
pases examined Candida antarctica lipase B was a highly active
biocatalyst for the direct acylation of phenolic hydroxy groups and
the reactions took place generally in a very regioselective manner.9
The present paper reports the results of our investigation in detail.
* Corresponding author. Tel.: þ81 78 431 4341; fax: þ81 78 435 2539; e-mail
address: miyazawa@konan-u.ac.jp (T. Miyazawa).
http://dx.doi.org/10.1016/j.tet.2015.04.033
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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2
T. Miyazawa et al. / Tetrahedron xxx (2015) 1e9
Table 1
2. Results and discussion
Burkholderia cepacia lipase-catalyzed propanoylation of substituted hydroquinones
(1) with vinyl propanoatea
Initially, several hydroquinones (1) bearing different sub-
stituents including the acetyl group on the benzene ring were
subjected to enzymatic acylation under almost the same reaction
conditions as those of the earlier work by Nicolosi and co-work-
ers,6a employing vinyl propanoate (3 M equiv.) in the presence of
immobilized B. cepacia lipase (Amano lipase PS) on Celite in cyclo-
hexaneet-amyl alcohol (9:1, v/v) at 45 ꢀC. As depicted in Scheme 1,
the hydroquinone 1 can undergo acylation through two pathways
to form either the 4-O-propanoyl derivative (2) or the 1-O-prop-
anoyl derivative (3), and finally to afford the 1,4-di-O-propanoyl
derivative (4). The product distributions after 3 days of incubation
obtained through 1H NMR analysis are compiled in Table 1. The
phenolic hydroxy groups of all the hydroquinones (1) examined
managed to be acylated, though the reactions were rather slow. The
acylation of acetylhydroquinone (1g) was the slowest among those
of the substituted hydroquinones examined, and besides the ex-
pected 4-O-acyl derivative (2g) the isomeric 1-O-acyl derivative
(3g) was also produced in a fair amount, indicating the in-
completeness of the lipase’s regioselectivity even toward the aro-
matic dihydroxyketone. On the other hand, the reaction of t-
butylhydroquinone (1e) proceeded in a highly regioselective man-
ner beyond our expectations: the hydroxy group remote from the
substituent was preferentially acylated, affording mainly the 4-O-
acylted derivative (2e). This can be seen more clearly from the time-
course of the propanoylation of 1e followed through the quantifi-
cation of products by HPLC analysis (Fig.1). The yield of 2e increased
steadily with time and reached to ca. 90% after 7days. The reaction
profile was almost the same with 2,6-dimethylhydroquinone (1b),
though the 1,4-di-O-acylated product (4b) was not observed at all
even after 7 days in this case. These results imply that the steric
demand of the substituent(s) must be responsible for the observed
high regioselectivity. When the steric bulk of a substituent became
smaller, the reaction proceeded in a less regioselective manner, as
can be seen from Fig 2 indicating the reaction profile of methox-
yhydroquinone (1f). Although the 4-O-acyl derivative (2f) was still
the main product, the isomeric 1-O-acyl derivative (3f) and the 1,4-
di-O-acyl derivative (4f) were produced in fair amounts with time.
The situation was almost the same with methylhydroquinone (1a)
bearing the smallest substituent examined, though a larger amount
of the 1,4-di-O-acylated derivative (4a) was produced with time in
this case. Thus, we recognized a relationship between the steric
demand of the substituent(s) and the regioselectivity in the B.
cepacia lipase-catalyzed acylation.
Substrate
R
R0
Yield (%)
2
Convn. (%)
3
4
1a
1b
1e
1f
CH3
CH3
(CH3)3C
CH3O
CH3CO
H
CH3
H
H
H
41
79
73
41
22
27
4
2
16
6
30
0
1
13
0
98
83
76
70
28
1g
a
Reactions were conducted using 1 (0.1 mmol), vinyl propanoate (0.3 mmol) and
Burkholderia cepacia lipase immobilized on Celite (40 mg) in 240
hexaneet-amyl alcohol (9:1) at 45 ꢀC for 3 days.
ml of cyclo-
Fig. 1. Reaction profile of the B. cepacia lipase-catalyzed acylation of t-butylhy-
droquinone (1e) with vinyl propanoate in diisopropyl ether. Symbols: circle, 2e; tri-
angle, 3e; square, 4e.
OH
R
R'
OCOC2H5
OH
OCOC2H5
R
2
Fig. 2. Reaction profile of the B. cepacia lipase-catalyzed acylation of methoxyhy-
droquinone (1f) with vinyl propanoate in diisopropyl ether. Symbols: circle, 2f; tri-
angle, 3f; square, 4f.
R
R'
R'
OH
OCOC2H5
OCOC2H5
R
4
1
Since B. cepacia lipase showed only a limited regioselectivity
toward the hydroquinones bearing a smaller substituent, other
lipases from microbial and pancreatic sources were screened to
find out enzymes with better regioselectivity as well as better
catalytic activity by choosing as a model compound methylhy-
droquinone (1a), which showed the poorest regioselectivity in
the B. cepacia lipase-catalyzed acylation. The reaction was con-
ducted using vinyl propanoate in diisopropyl ether10 at 45 ꢀC, and
R'
OH
3
Scheme 1. Lipase-catalyzed regioselective propanoylation of substituted hydroquinones
(1). R: a, Me; b, Me; c, Et; d, i-Pr; e, t-Bu; f, MeO; g, Ac; h, F; i, Cl; j, Br. R0: a and cej, H; b, Me.
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T. Miyazawa et al. / Tetrahedron xxx (2015) 1e9
3
Table 3
all the lipases were used in the immobilized form. Some of the
results obtained after 1 day of incubation are shown in Table 2. Of
the enzymes tested, Candida antractica lipase B (CAL-B)11 and
lipoprotein lipase from Pseudomonas sp. (Toyobo) were active
enough toward the acylation of the phenolic hydroxy groups of
1a. In terms of regioselectivity, the former lipase was the best,
while the latter enzyme showed poor selectivity. The screening of
lipases was also conducted with a substituted resorcinol, i.e., 4-
ethylresorcinol (5a), employing the same acyl donor
(Scheme 2). The acylations of 5a were slower than those of the
hydroquinone 1a. Some of the results obtained after 3 days of
incubation are shown in Table 3. Of the lipases with tolerable
activity toward 5a, B. cepacia lipase showed a very low regiose-
lectivity, while the acylations catalyzed by CAL-B and Chromo-
bacterium viscosum lipase proceeded regiospecifically: the 1-O-
acyl derivative (6a) was obtained as the sole product. In this case
also, the hydroxy group remote from the substituent was pref-
erentially acylated. These results indicate that CAL-B was an en-
zyme of choice for the direct acylation of phenolic hydroxy
groups in terms of both activity and regioselectivity. Accordingly,
further studies were conducted using this lipase. As far as we
know, this lipase has not so far been employed for such a purpose
with success.
Enzymatic propanoylation of 4-ethylresorcinol (5a) with vinyl propanoate using
various lipasesa
Lipase source
Yield (%)
6a
7a
8a
Candida antarctica Bb
Burkholderia cepaciac,d
Alcaligenes sp.e
37
24
8
7
27
0
20
0
0
0
0
7
0
0
0
Achromobacter sp.f
Chromobacterium viscosumg
a
Reactions were conducted using 5a (0.1 mmol), vinyl propanoate (0.3 mmol)
l) at 45 ꢀC for 3 days.
Boehringer Mannheim (BioCatalytics) Chirazyme
Amano lipase PS.
Convn.: 51%.
Meito lipase PL.
and an immobilized lipase (40 mg) in diisopropyl ether (240
m
b
L-2.
c
d
e
f
Meito lipase AL.
Asahikasei lipase.
g
Although a large number of experimental data have already
been accumulated on the effect of organic solvents on lipase-
catalyzed reactions,12 it is still difficult to predict the solvent ef-
fect, especially on regioselectivity. Therefore, the practical way is to
select an appropriate solvent through screening experiments. The
effect of solvents was investigated on the CAL-B-catalyzed acylation
of 1a with vinyl propanoate (see Supplementary data). Acylations
were reasonably fast in hydrocarbons and ethers, while they pro-
ceeded extremely slowly and less regioselectively in such polar
solvents as acetone and acetonitrile. The lipase was most active in
diisopropyl ether among the solvents examined with a tolerable
regioselectivity. Thus, the CAL-B-catalyzed acylation of a number of
hydroquinones (1) carrying different substituents on the benzene
ring was examined using vinyl propanoate in diisopropyl ether at
45 ꢀC. As is usual with this type of reaction, the product distribution
can be time-dependent. Fig. 3 shows the time-course of the prop-
anoylation of methoxyhydroquinone (1f) as a typical example. The
starting hydroquinone was consumed abruptly during the first 6 h,
then decreased gradually, and finally disappeared after 24 h. The
amount of the 4-O-acyl derivative (2f) increased steeply at first,
then reached a maximum after ca.12 h and then turned to a gradual
decrease, while that of 1-O-acyl derivative (3f) increased gradually
at first, then reached a maximum after ca. 6 h and then turned to
a slight but steady decrease. The initial rates of formation of 2f and
Table 2
Enzymatic propanoylation of methylhydroquinone (1a) with vinyl propanoate using
various lipasesa
Lipase source
Yield (%)
2a
Convn. (%)
3a
4a
Candida antarctica Bb
Burkholderia cepaciac
Alcaligenes sp.d
51
14
3
3
4
18
17
4
5
5
17
4
1
1
1
86
35
8
Achromobacter sp.e
Porcine pancreasf
9
10
24
96
Chromobacterium viscosumg
Pseudomonas sp.h
9
26
13
26
2
44
a
Reactions were conducted using 1a (0.1 mmol), vinyl propanoate (0.3 mmol)
and an immobilized lipase (40 mg) in diisopropyl ether (240
m
l) at 45 ꢀC for 1 day.
b
Boehringer Mannheim (BioCatalytics) Chirazyme
Amano lipase PS.
L-2.
c
d
e
f
Meito lipase PL.
Meito lipase AL.
Sima lipase Type II.
Asahikasei lipase.
3f determined after
1
h
of incubation were 6.1ꢁ10ꢂ7 and
g
h
8.5ꢁ10ꢂ8 mol hꢂ1 (mg of lipase)ꢂ1, respectively: the former was ca.
7 times faster than the latter. On the other hand, 1,4-di-O-acyl de-
rivative (4f) was not observed during the first 4 h, then increased
Toyobo lipoprotein lipase.
OCOC2H5
100
80
60
40
20
0
OH
R
OCOC2H5
OH
6
OCOC2H5
R
OH
R
OH
8
5
0
10
20
30
40
50
OCOC2H5
R
Time (h)
7
Fig. 3. Reaction profile of the CAL-B-catalyzed acylation of methoxyhydroquinone (1f)
with vinyl propanoate in diisopropyl ether. Symbols: diamond, 1f; circle, 2f; triangle,
3f; square, 4f.
Scheme 2. Lipase-catalyzed regioselective propanoylation of 4-substituted resorcinols
(5). R: a, Me; b, Et; c, (CH3)3CCH2C(CH3)2ꢂ; d, Bn; e, Cl; f, Br.
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4
T. Miyazawa et al. / Tetrahedron xxx (2015) 1e9
almost linearly, and finally it became the major product after 72 h.
Thus, the product distribution proved to be dependent largely on
the reaction time. Accordingly, the results obtained after 1 day of
incubation are taken up for discussion and compiled in Table 4. In
all the cases, the 4-O-acyl derivative (2) was obtained as the main
product, and the 1-O-acyl derivative (3) and/or the 1,4-di-O-acyl
derivative (4) were also produced in various amounts depending on
the substituent existed. When the substituent was changed from
methyl (in 1a) to ethyl (in 1c), the proportion of the 4-O-acyl de-
rivative in the reaction products increased to a considerable extent.
With isopropylhydroquinone (1d) the 1-O-acyl derivative (3d) was
not observed, and the 4-O-acyl derivative (2e) was produced as the
exclusive product with t-butylhydroquinone (1e). Thus, the selec-
tivity toward the hydroxy group remote from the substituent in-
creased with the increase in the bulk of the substituent, i.e., methyl
to isopropyl/t-butyl. This implies that the enhancement of steric
demand of the substituent must be one of the contributory factors
for the observed regioselectivity. The behavior of methoxyhy-
droquinone (1f) resembles that of 1c, which implies also the im-
portance of steric requirement in activity and regioselectivity. With
fluorohydroquinone (1h) the regioselectivity deteriorated to a great
extent, though its activity toward the acylation was as high as those
of the alkyl-substituted hydroquinones. The other halogen sub-
stituents (in 1i and 1j) reduced the activity of hydroquinone, with
a moderate regioselectivity. The effect of halogen substituents on
the activity and regioselectivity in the acylation of hydroquinones
seems rather complicated, indicating that besides the steric effect
other factors, such as the electronic effect, must be taken into
consideration.
Quite interestingly, however, the acylation proceeded regiospe-
cifically independent of the substituent, yielding the 1-O-acyl de-
rivative (6) as the exclusive product and none of the 3-O-acyl
derivative (7) nor the 1,4-di-O-acyl derivative (8). The steric factor of
substituents in the substituted resorcinols had a much larger effect
on its activity than that in the substituted hydroquninones. With 4-
methylresorcinol (5a) the acylation proceeded most ‘smoothly’
among the resorcinols examined. It was retarded in the presence of
bulkier substituents (in 5b and 5c), and no reaction took place with
4-t-butylresorcinol. This is probably because of the less accessibility
of the lipase even toward the hydroxy group at position 1, to say
nothing of the hydroxy group at position 3. The acylation of halogen-
substituted resorcinols (5e and 5f) proceeded at the rate between
those of 5a and the other alkyl-substituted resorcinols.
For the purpose of comparison, some typical non-enzymatic
procedures for the acylation of phenolic hydroxy groups were
also tried in the propanoylation of 4-ethylresorcinol (5b) (see
Supplementary data). These chemical acylations were much in-
ferior in terms of regioselectivity to the present enzymatic
procedure.
3. Conclusion
CAL-B proved to be a tolerably active biocatalyst, compared to
other lipases, for the direct acylation of the phenolic hydroxy
groups of substituted hydroquinones and resorcinols. More im-
portantly, the CAL-B-catalyzed acylation reactions take place gen-
erally in a highly regioselective manner: the hydroxy group remote
from the substituent is preferentially acylated. In particular, they
are regiospecific toward substituted resorcinols. In the case of
substituted hydroquinones, the selectivity toward the hydroxy
group remote from the substituent increases with the increase in
the bulk of the substituent. The main or, in some cases, exclusive
products obtained through the direct acylation of those dihydrox-
ybenzenes are the regioisomers of those produced through the
CAL-B-catalyzed deacylation of dihydroxybenzenes acylated at
both phenolic hydroxy groups.4 This should be of significant im-
portance from a synthetic standpoint, because either regioisomer
of monoacylated derivatives of dihydroxybenzenes can easily be
obtained by choosing either acylation or deacylation mediated by
the easily available single biocatalyst.
Table 4
CAL-B-catalyzed propanoylation of substituted hydroquinones (1) with vinyl
propanoatea
Substrate
R
R0
Yield (%)
2
Convn. (%)
3
4
1a
1c
1d
1e
1f
1h
1i
1j
CH3
H
H
H
H
H
H
H
H
51
73
75
93
71
39
41
47
18
8
0
17
12
16
0
19
19
5
86
93
91
93
100
91
CH3CH2
(CH3)2CH
(CH3)3C
CH3O
F
0
10
33
16
22
Cl
Br
62
77
8
4. Experimental
4.1. General
a
Reactions were conducted using 1 (0.1 mmol), vinyl propanoate (0.3 mmol) and
l) at 45 ꢀC for 1 day.
CAL-B (40 mg) in diisopropyl ether (240
m
Next, the CAL-B-catalyzed propanoylation of a number of res-
orcinols (5) carrying alkyl, aralkyl or halogen substituents on the
benzene ring was examined under the same reaction conditions as
above. In general, the reactions were retarded largely compared
with those of hydroquinones having the similar substituents. Thus,
the results obtained after 3 days of incubation are compiled in
Table 5.
1H NMR (500 MHz) and 13C NMR (125 MHz) spectra were col-
lected on a Varian Unity 500 spectrometer using DMSO-d6 as
a solvent with TMS as an internal standard. UV spectra were
recorded on a Shimadzu UV-1600PC spectrometer. Melting points
were determined on a Yamato MP-21 apparatus and are un-
corrected. The liquid chromatograph employed was a Shimadzu LC-
10AD instrument, equipped with a Rheodyne 7125 sample injector
and a Shimadzu SPD-10A variable wavelength UV monitor. A Shi-
madzu C-R8A data processor was used for data acquisition and
processing. TLC was run on precoated silica gel plates (Merck).
All the hydroquinones and resorcinols used in this study, except
ethyl-, isopropyl- and fluorohydroquinoes, were purchased from
Tokyo Chemical Industry Co. or Aldrich. All organic solvents were
distilled following standard protocols and dried over molecular
sieves prior to use.
Table 5
CAL-B-catalyzed propanoylation of substituted resorcinols (5) with vinyl
propanoatea
Substrate
R
Yield (%) of 6b
5a
5b
5c
5d
5e
5f
CH3
CH3CH2
(CH3)3CCH2C(CH3)2
C6H5CH2
Cl
Br
82
37
23
37
74
69
4.2. Enzymes
a
Reactions were conducted using 5 (0.1 mmol), vinyl propanoate (0.3 mmol) and
l) at 45 ꢀC for 3 days.
The 3-O-propanoate (7) and 1,3-di-O-propanoate (8) were not detected in all
the cases.
CAL-B (40 mg) in diisopropyl ether (240
m
b
Lipase B from Candida antarctica (CAL-B) was supplied by
Boehringer Mannheim (BioCatalytics) as an immobilized form
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T. Miyazawa et al. / Tetrahedron xxx (2015) 1e9
5
(Chirazyme
L
-2), which had a specific activity of 3.2 U/mg lyophi-
123.6 (C-3), 124.9 (C-2), 142.6 (C-4), 153.1 (C-1), 173.1 (C]O). Anal.
lized powder with tributyrin at 25 ꢀC. The following lipases were
obtained from Amano Pharmaceutical Co., Meito Sangyo Co., Asahi
Chemical Industry Co., or Sigma: ex B. cepacia (Amano PS), Alcali-
genes sp. (Meito PL), Achromobacter sp. (Meito AL), porcine pancreas
(Sigma Type II), Chromobacterium viscosum (Asahikasei LP). Lipo-
protein lipase from Pseudomonas sp. was supplied by Asahi
Chemical Industry Co. All the enzymes were employed as immo-
bilized forms on Celite. The preparation of immobilized B. cepacia
lipase is described as a typical example. B. cepacia lipase (Amano
PS; 400 mg) was dissolved in 10 ml of 0.1 M phosphate buffer (pH
7.0) and mixed with Celite No. 535 (Johns-Mansville Co.; 1 g), and
the mixture was lyophilized using an Eyela FDU-830 freeze-dryer
overnight.
Calcd for C10H12O3: C, 66.65; H, 6.71. Found: C, 66.88; H, 6.46.
4.4.2. 4-O-Propanoyl-2,6-dimethylhydroquinone (2b). Oil; １H NMR
d
1.25 (3H, t, J¼7.5 Hz, CH2CH3), 2.14 (6H, s, ArCH3), 2.55 (2H, q,
J¼7.5 Hz, CH2), 4.68 (1H, s, OH), 6.68 (2H, s, Ar); 13C NMR
d 9.1
(CH2CH3), 16.0 (ArCH3), 27.7 (CH2), 121.1 (C-3, C-5), 124.1 (C-2, C-6),
143.3 (C-4), 149.8 (C-1), 173.8 (C]O). Anal. Calcd for C11H14O3: C,
68.02; H, 7.27. Found: C, 68.15; H, 7.46.
4.4.3. 4-O-Propanoylethylhydroquinone (2c). Oil; 1H NMR
d 1.105
(3H, t, J¼7.5 Hz, COCH2CH3),1.11 (3H, t, J¼7.5 Hz, ArCH2CH3), 2.51
(2H, q, J¼7.5 Hz, ArCH2CH3), 2.53 (2H, q, J¼7.5 Hz, COCH2CH3),
6.70e6.73 (1H, distorted dd, J¼8.5 and 2.5 Hz, H-5), 6.74e6.76 (1H,
distorted d, J¼8.5 Hz, H-6), 6.79 (1H, d, J¼2.5 Hz, H-3), 9.30 (1H, s,
4.3. Preparation of hydroquinones
OH); 13C NMR
d 9.6 (COCH2CH3), 14.6 (ArCH2CH3), 23.2 (ArCH2CH3),
27.5 (COCH2CH3), 115.5 (C-6), 120.0 (C-3), 122.4 (C-5), 131.4 (C-2),
143.3 (C-4), 153.1 (C-1), 173.6 (C]O). Anal. Calcd for C11H14O3: C,
68.02; H, 7.27. Found: C, 67.81; H, 7.38.
4.3.1. Ethylhydroquinone (1c). This hydroquinone was prepared
through the Clemmensen reduction of acetylhydroquinone
according to the literature method;13 mp 112e113 ꢀC (CHCl3) [lit.13
,
mp 113e114 ꢀC]; 1H NMR
d
1.08 (3H, t, J¼7.5 Hz, CH3), 2.44 (2H, q,
4.4.4. 4-O-Propanoylisopropylhydroquinone (2d). Oil; 1H NMR
J¼7.5 Hz, CH2), 6.37 (1H, dd, J¼8.5 and 3.0 Hz, H-5), 6.47 (1H, d,
J¼3.0 Hz, H-3), 6.54 (1H, d, J¼8.5 Hz, H-6), 8.46 (1H, s, OH), 8.51 (1H,
s, OH).
d
1.11 (3H, t, J¼7.5 Hz, CH2CH3), 1.13 (6H, d, J¼7.0 Hz, CH(CH3)2), 2.53
(2H, q, J¼7.5 Hz, CH2), 3.18 (1H, septet, J¼7.0 Hz, CH(CH3)2),
6.70e6.72 (1H, distorted dd, J¼8.5 and 2.5 Hz, H-5), 6.75e6.76 (1H,
distorted d, J¼8.5 Hz, H-6), 6.80 (1H, d, J¼2.5 Hz, H-3), 9.33 (1H, s,
4.3.2. Isopropylhydroquinone (1d). Coupling of 2-isopropylphenol
with diazotized sulfanilic acid followed by reduction yielded 2-
isopropyl-4-aminophenol, which was then converted through di-
azotization to 2-isopropyl-1,4-quinone followed by reduction to the
hydroquinone according to the literature method;13 mp
129.5e131 ꢀC (CHCl3epertoleum ether) [lit.13, mp 129e131 ꢀC]; 1H
OH); 13C NMR
d 9.1 (CH2CH3), 22.5 (CH(CH3)2), 26.6 (CH(CH3)2), 27.0
(CH2), 115.2 (C-6), 119.2 (C-3), 119.4 (C-5), 135.3 (C-2), 143.1 (C-4),
152.0 (C-1), 173.1 (C]O). Anal. Calcd for C12H16O3: C, 69.21; H, 7.74.
Found: C, 68.93; H, 7.55.
4.4.5. 4-O-Propanoyl-t-butylhydroquinone (2e). Oil; 1H NMR
d 1.11
NMR
d
1.10 (6H, d, J¼7.0 Hz, (CH3)2CH), 3.12 (1H, septet, J¼7.0 Hz,
(3H, t, J¼7.5 Hz, CH3), 1.32 (9H, s, C(CH3)3), 2.53 (2H, q, J¼7.5 Hz,
CH2), 6.73e6.75 (1H, distorted dd, J¼8.5 and 2.0 Hz, H-5),
6.75e6.77 (1H, distorted d, J¼8.5 Hz, H-6), 6.80 (1H, d, J¼2.0 Hz, H-
CH), 6.36 (1H, dd, J¼9.0 and 3.0 Hz, H-5), 6.51 (1H, d, J¼3.0 Hz, H-3),
6.54 (1H, d, J¼9.0 Hz, H-6), 8.47 (1H, s, OH), 8.50 (1H, s, OH).
3), 9.39 (1H, s, OH); 13C NMR
d 9.1 (CH3), 27.0 (CH2), 29.3 (C(CH3)3),
4.3.3. Fluorohydroquinone (1h). This hydroquinone was prepared
through the oxidation of 2-fluorophenol with potassium persulfate
34.5 (C(CH3)3), 116.3 (C-6), 119.65 (C-3), 119.7 (C-5), 136.3 (C-2),
142.7 (C-4), 153.5 (C-1), 173.2 (C]O). Anal. Calcd for C13H18O3: C,
70.24; H, 8.16. Found: C, 70.33; H, 8.42.
according to the literature method;13 mp 123e124 ꢀC (CHCl3) [lit.13
,
mp 122e123 ꢀC]; 1H NMR
d
6.39 (1H, ddd, J¼9.0, 3.0 and 1.5 Hz, H-
5), 6.51 (1H, dd, J¼13.0 and 3.0 Hz, H-3), 6.73 (1H, dd, J¼10.0 and
4.4.6. 4-O-Propanoylmethoxyhydroquinone (2f). Oil; 1H NMR
d 1.12
9.0 Hz, H-6), 8.94 (1H, s, OH), 9.06 (1H, s, OH).
(3H, t, J¼7.5 Hz, CH2CH3), 2.54 (2H, q, J¼7.5 Hz, CH2), 3.73 (3H, s,
OCH3), 6.49 (1H, dd, J¼8.5 and 2.5 Hz, H-5), 6.70 (1H, d, J¼2.5 Hz, H-
4.4. Preparation of authentic 4-O-momopropanoyl de-
rivatives of hydroquinones
3), 6.75 (1H, d, J¼8.5 Hz, H-6), 8.97 (1H, s, OH); 13C NMR
d 9.1
(CH2CH3), 27.0 (CH2), 55.9 (OCH3), 106.7 (C-3), 113.5 (C-5), 115.2 (C-
6), 143.0 (C-4), 144.3 (C-1), 148.0 (C-2), 173.1 (C]O). Anal. Calcd for
The 4-O-monopropanoates of hydroquinones were obtained as
the major products of the CAL-B-catalyzed acylation of each hy-
droquinone. The preparation of the 4-O-propanoyl derivative (2c)
of ethylhydroquinone (1c) is described as a typical example. To
C
10H12O4: C, 61.22; H, 6.17. Found: C, 61.40; H, 6.21.
4.4.7. 4-O-Propanoylacetylhydroquinone (2g). Oil; 1H NMR
d
1.14
(3H, t, J¼7.5 Hz, CH2CH3), 2.59 (2H, q, J¼7.5 Hz, CH2), 2.62 (3H, s,
COCH3), 6.99 (1H, d, J¼9.5 Hz, H-6), 7.31 (1H, dd, J¼9.5 and 2.5 Hz,
H-5), 7.60 (1H, d, J¼2.5 Hz, H-3), 11.73 (1H, s, OH). Anal. Calcd for
a solution of 1c (204 mg, 1.5 mmol) and vinyl propanoate (490 ml,
4.5 mmol) in dry diisopropyl ether (3.6 ml) was added CAL-B
(300 mg), and the mixture was stirred at 45 ꢀC for 3 days. TLC
showed the disappearance of the parent hydroquinone in the re-
action mixture. The enzyme was filtered off and the filtrate was
evaporated in vacuo. From the residual oil the monopropanoate 2c
was isolated as the major product by preparative TLC using hex-
aneeEtOAc (2:1, v/v) as a developing solvent to give an oil (261 mg,
90%). The structure of 2c was unambiguously determined by 2D
NMR (HMQC, HMBC): cross-peaks of the proton of 1-OH with the
carbons at C-1, C-2 and C-6 appeared in the HMBC spectrum.
C11H12O4: C, 63.45; H, 5.81. Found: C, 63.40; H, 6.03.
4.4.8. 4-O-Propanoylfluorohydroquinone (2h). Oil; 1H NMR
d 1.11
(3H, t, J¼7.5 Hz, CH3), 2.55 (2H, q, J¼7.5 Hz, CH2), 6.76 (1H, ddd,
J¼8.5, 2.5 and 1.5 Hz, H-5), 6.94 (1H, dd, J¼9.5 and 8.5 Hz, H-6), 7.02
(1H, dd, J¼11.5 and 2.5 Hz, H-3), 9.88 (1H, s, OH); 13C NMR
d 9.0
(CH3), 27.0 (CH2), 110.7 (C-3), 117.5 (C-5), 117.9 (C-6), 142.8 (C-1),
149.5 (C-4), 151.5 (C-2), 172.9 (C]O). Anal. Calcd for C9H9FO3: C,
58.70; H, 4.93. Found: C, 58.96; H, 5.09.
4.4.1. 4-O-Propanoylmethylhydroquinone (2a). Mp 62e64 ꢀC; 1H
4.4.9. 4-O-Propanoylchlorohydroquinone (2i). Mp 77e79 ꢀC; 1H
NMR
d
1.11 (3H, t, J¼7.5 Hz, CH2CH3), 2.09 (3H, s, ArCH3), 2.53 (2H, q,
NMR
d
1.11 (3H, t, J¼7.5 Hz, CH3), 2.54 (2H, q, J¼7.5 Hz, CH2),
J¼7.5 Hz, CH2), 6.70 (1H, dd, J¼8.5 and 2.5 Hz, H-5), 6.74 (1H, d,
6.87e6.91 (1H, distorted dd, J¼8.5 and 2.5 Hz, H-5), 6.92e6.95
J¼8.5 Hz, H-6), 6.79 (1H, d, J¼2.5 Hz, H-3), 9.30 (1H, s, OH); 13C NMR
(1H, distorted d, J¼8.5 Hz, H-6), 7.15 (1H, J¼2.5 Hz, H-3), 10.18 (1H,
d
9.1 (CH2CH3), 16.1 (ArCH3), 27.0 (CH2), 114.8 (C-6), 119.5 (C-5),
s, OH); 13C NMR
d 9.5 (CH3), 27.5 (CH2), 117.1 (C-6), 120.0 (C-2),
Please cite this article in press as: Miyazawa, T.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.033

6
T. Miyazawa et al. / Tetrahedron xxx (2015) 1e9
122.0 (C-3), 123.9 (C-5), 143.3 (C-4), 151.6 (C-1), 173.4 (C]O). Anal.
125.1 (C-5), 141.3 (C-2), 141.6 (C-4), 154.7 (C-1), 173.1 (C]O). Anal.
Calcd for C9H9ClO3: C, 53.88; H, 4.52. Found: C, 53.83; H, 4.77.
Calcd for C13H18O3: C, 70.24; H, 8.16. Found: C, 70.45; H, 8.01.
4.4.10. 4-O-Propanoylbromohydroquinone (2j). Mp 76e79 ꢀC; 1H
4.5.6. 1-O-Propanoylmethoxyhydroquinone (3f). Oil; 1H NMR
d 1.11
NMR
d
1.11 (3H, t, J¼7.5 Hz, CH3), 2.54 (2H, q, J¼7.5 Hz, CH2),
(3H, t, J¼7.5 Hz, CH2CH3), 2.52 (2H, q, J¼7.5 Hz, CH2), 3.69 (3H, s,
6.93e6.95 (1H, distorted dd, J¼8.5 and 2.0 Hz, H-5), 6.97e6.95
OCH3), 6.29 (1H, dd, J¼8.5 and 2.5 Hz, H-5), 6.48 (1H, d, J¼2.5 Hz, H-
(1H, distorted d, J¼8.5 Hz, H-6), 7.30 (1H, dd, J¼2.5 and 0.5 Hz, H-
3), 6.82 (1H, d, J¼8.5 Hz, H-6), 9.45 (1H, s, OH); 13C NMR
d 9.2
3), 10.3 (1H, s, OH); 13C NMR
d
9.0 (CH3), 26.9 (CH2), 108.8 (C-2),
(CH2CH3), 26.7 (CH2), 55.7 (OCH3), 100.6 (C-3), 106.4 (C-5), 123.0 (C-
6), 131.9 (C-1), 151.6 (C-4), 156.3 (C-2), 172.5 (C]O). Anal. Calcd for
116.3 (C-6), 122.1 (C-5), 126.2 (C-3), 143.0 (C-4), 152.1 (C-1), 173.0
(C]O). Anal. Calcd for C9H9BrO3: C, 44.11; H, 3.70. Found: C, 44.32;
H, 3.77.
C10H12O4: C, 61.22; H, 6.17. Found: C, 61.28; H, 6.25.
4.5.7. 1-O-Propanoylacetylhydroquinone (3g). Oil; 1H NMR
d
1.17
(3H, t, J¼7.5 Hz, CH2CH3), 2.56 (2H, q, J¼7.5 Hz, CH2), 2.60 (3H, s,
COCH3), 6.91 (1H, d, J¼9.5 Hz, H-6), 7.17 (1H, dd, J¼9.5 and 2.5 Hz,
H-5), 7.32 (1H, d, J¼2.5 Hz, H-3), 9.17 (1H, s, OH). Anal. Calcd for
4.5. Preparation of authentic 1-O-momopropanoyl de-
rivatives of hydroquinones
C
11H12O4: C, 63.45; H, 5.81. Found: C, 63.34; H, 5.77.
As they were the minor products of the lipase-catalyzed direct
propanoylation of hydroquinones, the authentic samples of the 1-
O-monopropanoates of hydroquinones were prepared in much
higher yields through the lipase-catalyzed deacylation of each 1,4-
O-dipropanoylhydroquinone.4 The preparation of the 1-O-prop-
anoyl derivative (3c) of ethylhydroquinone (1c) is described as
a typical example. To a solution of 1,4-di-O-propanoylethylhy-
4.5.8. 1-O-Propanoylfluorohydroquinone (3h). Oil; 1H NMR
d 1.12
(3H, t, J¼7.5 Hz, CH3), 2.59 (2H, q, J¼7.5 Hz, CH2), 6.59 (1H, ddd,
J¼8.5, 2.5 and 1.0 Hz, H-5), 6.69 (1H, dd, J¼12.5 and 2.5 Hz, H-3),
7.04 (1H, dd, J¼9.0 and 8.5, H-6), 9.92 (1H, s, OH); 13C NMR
d 9.1
(CH3), 26.6 (CH2), 103.6 (C-3), 111.4 (C-5), 124.4 (C-6), 129.8 (C-1),
153.9 (C-2), 156.4 (C-4), 172.3 (C]O). Anal. Calcd for C9H9FO3: C,
58.70; H, 4.93. Found: C, 58.41; H, 4.84.
droquinone (4c) (125 mg, 0.5 mmol) and 1-propanol (113
ml,
1.5 mmol) in dry diisopropyl ether (1.1 ml) was added CAL-B
(100 mg), and the mixture was stirred at 45 ꢀC for 1 h. The en-
zyme was filtered off and the filtrate was evaporated in vacuo. From
the residual oil the monopropanoate 3c was isolated as the major
product by preparative TLC using hexaneeEtOAc (2:1, v/v) as a de-
veloping solvent to give an oil (56 mg, 68%). The structure of 3c was
unambiguously determined by 2D NMR (HMQC, HMBC): cross-
peaks of the proton of 4-OH with the carbons at C-3, C-4 and C-5
appeared in the HMBC spectrum.
4.5.9. 1-O-Propanoylchlorohydroquinone (3i). Oil; 1H NMR
d 1.15
(3H, t, J¼7.5 Hz, CH3), 2.60 (2H, q, J¼7.5 Hz, CH2), 6.75 (1H, dd, J¼9.0
and 2.5 Hz, H-5), 6.89 (1H, d, J¼2.5 Hz, H-3), 7.07 (1H, d, J¼9.0 Hz,
H-6), 9.92 (1H, s, OH). Anal. Calcd for C9H9ClO3: C, 53.88; H, 4.52.
Found: C, 53.99; H, 4.61.
4.5.10. 1-O-Propanoylbromohydroquinone (3j). Oil; 1H NMR
d 1.15
(3H, t, J¼7.5 Hz, CH3), 2.59 (2H, q, J¼7.5 Hz, CH2), 6.79 (1H, dd, J¼8.5
and 3.0 Hz, H-5), 7.04 (1H, d, J¼3.0 Hz, H-3), 7.06 (1H, d, J¼8.5 Hz, H-
6), 9.92 (1H, s, OH). Anal. Calcd for C9H9BrO3: C, 44.11; H, 3.70.
Found: C, 43.94; H, 3.72.
4.5.1. 1-O-Propanoylmethylhydroquinone (3a). Oil; 1H NMR
d 1.14
(3H, t, J¼7.5 Hz, CH2CH3), 2.00 (3H, s, ArCH3), 2.57 (2H, q, J¼7.5 Hz,
CH2), 6.57 (1H, dd, J¼8.5 and 3.0 Hz, H-5), 6.63 (1H, d, J¼3.0 Hz, H-
3), 6.80 (1H, d, J¼8.5 Hz, H-6), 9.30 (1H, s, OH); 13C NMR
d
9.3
4.6. Preparation of authentic 1,4-di-O-propanoyl derivatives
of hydroquinones
(CH2CH3), 16.0 (ArCH3), 26.9 (CH2), 113.3 (C-5), 117.2 (C-3), 122.7 (C-
6), 130.7 (C-2), 141.5 (C-1), 155.0 (C-4), 172.8 (C]O). Anal. Calcd for
C
10H12O3: C, 66.65; H, 6.71. Found: C, 66.41; H, 6.75.
Authentic samples of the 1,4-di-O-propanoates of hydroqui-
nones were prepared by the reaction of each hydroquinone with
propanoyl chloride in pyridine. The dipropanoylation of methyl-
hydroquinone (1a) is described as a typical example. To a stirred
solution of 1a (420 mg, 3.0 mmol) in dry pyridine (20 ml) was
added dropwise from a syringe propanoyl chloride (564 mg,
6.3 mmol), and the mixture was stirred at 100 ꢀC for 3 days. 1-(2-
Aminoethyl)piperazine (81 mg, 0.63 mmol) was added and the
mixture was stirred for 30 min. Then 0.5 M HCl (60 ml) was added
and the mixture was extracted with EtOAc (3ꢁ20 ml), the organic
extracts were washed successively with 1 M NaOH (3ꢁ30 ml),
water (30 ml), and brine (30 ml), and dried over Na2SO4. After
evaporation of the solvent in vacuo, the residual oil was purified by
column chromatography using hexaneeEtOAc (2:1, v/v) as an elu-
ent to give the dipropanoate 4a as white crystals (415 mg, 59%).
4.5.2. 1-O-Propanoyl-2,6-dimethylhydroquinone (3b). Oil; 1H NMR
d
1.15 (3H, t, J¼7.0 Hz, CH2CH3), 1.97 (6H, s, ArCH3), 2.60 (2H, q,
J¼7.0 Hz, CH2), 6.46 (2H, s, Ar), 9.17 (1H, s, OH). Anal. Calcd for
11H14O3: C, 68.02; H, 7.27. Found: C, 67.81; H, 7.19.
C
4.5.3. 1-O-Propanoylethylhydroquinone (3c). Oil; 1H NMR
d 1.07
(3H, t, J¼7.5 Hz, COCH2CH3), 1.14 (3H, t, J¼7.5 Hz, ArCH2CH3), 2.35
(2H, q, J¼7.5 Hz, ArCH2), 2.58 (2H, q, J¼7.5 Hz, COCH2), 6.57 (1H, dd,
J¼8.5 and 2.5 Hz, H-5), 6.64 (1H, d, J¼2.5 Hz, H-3), 6.80 (1H, d,
J¼8.5 Hz, H-6), 9.31 (1H, s, OH). Anal. Calcd for C11H14O3: C, 68.02;
H, 7.27. Found: C, 67.83; H, 7.11.
4.5.4. 1-O-Propanoylisopropylhydroquinone (3d). Oil; 1H NMR
d 1.10
(6H, d, J¼7.0 Hz, CH(CH3)2), 1.14 (3H, t, J¼7.5 Hz, CH2CH3), 2.57 (2H,
q, J¼7.5 Hz, CH2), 2.84 (1H, septet, J¼7.0 Hz, CH(CH3)2), 6.57 (1H, dd,
J¼8.5 and 3.0 Hz, H-5), 6.68 (1H, d, J¼3.0 Hz, H-3), 6.79 (1H, d,
J¼8.5 Hz, H-6), 9.30 (1H, s, OH). Anal. Calcd for C12H16O3: C, 69.21;
H, 7.74. Found: C, 69.48; H, 7.61.
4.6.1. 1,4-di-O-Propanoylmethylhydroquinone (4a). Mp 47e50 ꢀC;
1H NMR
d
1.13 (3H, t, J¼7.5 Hz, CH2CH3), 1.16 (3H, t, J¼7.5 Hz,
CH2CH3), 2.10 (3H, s, ArCH3), 2.59 (2H, q, J¼7.5 Hz, CH2), 2.63 (2H, q,
J¼7.5 Hz, CH2), 6.98 (1H, dd, J¼8.5 and 3.0 Hz, H-5), 7.06 (1H, d,
J¼3.0 Hz, H-3), 7.08 (1H, d, J¼8.5 Hz, H-6). Anal. Calcd for C13H16O4:
C, 66.09; H, 6.83. Found: C, 65.89; H, 6.72.
4.5.5. 1-O-Propanoyl-t-butylhydroquinone (3e). Oil; 1H NMR
d 1.14
(3H, t, J¼7.5 Hz, CH3), 1.24 (9H, s, C(CH3)3), 2.58 (2H, q, J¼7.5 Hz,
CH2), 6.58 (1H, dd, J¼8.5 and 3.0 Hz, H-5), 6.74 (1H, d, J¼3.0 Hz, H-
4.6.2. 1,4-di-O-Propanoyl-2,6-dimethylhydroquinone (4b). Oil; 1H
3), 6.77 (1H, d, J¼8.5 Hz, H-6), 9.29 (1H, s, OH); 13C NMR
d
9.0 (CH3),
NMR
d
1.13 (3H, t, J¼7.5 Hz, CH2CH3), 1.18 (3H, t, J¼7.5 Hz, CH2CH3),
27.7 (CH2), 30.0 (C(CH3)3), 34.2 (C(CH3)3), 113.1 (C-6), 113.6 (C-3),
2.07 (6H, s, ArCH3), 2.57 (2H, q, J¼7.5 Hz, CH2), 2.67 (2H, q, J¼7.5 Hz,
Please cite this article in press as: Miyazawa, T.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.033

T. Miyazawa et al. / Tetrahedron xxx (2015) 1e9
7
CH2), 6.88 (2H, s, Ar). Anal. Calcd for C14H18O4: C, 67.18; H, 7.25.
Found: C, 67.30; H, 7.44.
described above for the preparation of 4-O-monopropanoates of
hydroquinones.
4.6.3. 1,4-di-O-Propanoylethylhydroquinone (4c). Oil; 1H NMR
d
1.10
4.7.1. 1-O-Propanoyl-4-methylresorcinol (6a). Mp 68e70 ꢀC; １H
(3H, t, J¼7.5 Hz, COCH2CH3), 1.13 (3H, t, J¼7.5 Hz, COCH2CH3), 1.16
(3H, t, J¼7.5 Hz, ArCH2CH3), 2.46 (2H, q, J¼7.5 Hz, ArCH2), 2.59 (2H,
q, J¼7.5 Hz, COCH2), 2.63 (2H, q, J¼7.5 Hz, COCH2), 6.99 (1H, dd,
J¼8.5 and 3.0 Hz, H-5), 7.07 (1H, d, J¼3.0 Hz, H-3), 7.09 (1H, d,
J¼8.5 Hz, H-6). Anal. Calcd for C14H18O4: C, 67.18; H, 7.25. Found: C,
67.12; H, 7.48.
NMR
d
1.11 (3H, t, J¼7.5 Hz, CH2CH3), 2.09 (3H, s, ArCH3), 2.55 (2H,
q, J¼7.5 Hz, CH2), 6.43 (1H, dd, J¼9.0 and 2.5 Hz, H-6), 6.51 (1H, d,
J¼2.5 Hz, H-2), 7.04 (1H, d, J¼9.0 Hz, H-5), 9.56 (1H, s, OH); 13C
NMR d 9.1 (CH2CH3), 15.6 (CH3Ar), 27.0 (CH2), 108.3 (C-2), 111.9 (C-
6), 121.5 (C-4), 130.7 (C-5), 149.3 (C-1), 155.9 (C-3), 172.7 (C]O).
Anal. Calcd for C10H12O3: C, 66.65; H, 6.71. Found: C, 66.82; H,
6.82.
4.6.4. 1,4-di-O-Propanoylisopropylhydroquinone (4d). Oil; 1H NMR
d
1.125 (6H, d, J¼7.0 Hz, CH(CH3)2), 1.13 (3H, t, J¼7.5 Hz, CH2CH3),
4.7.2. 1-O-Propanoyl-4-ethylresorcinol (6b). Oil; １H NMR
d 1.11
1.16 (3H, t, J¼7.5 Hz, CH2CH3), 2.60 (2H, q, J¼7.5 Hz, CH2), 2.65 (2H,
q, J¼7.5 Hz, CH2), 2.95 (1H, septet, J¼7.0 Hz, CH(CH3)2), 6.98 (1H, dd,
J¼8.5 and 3.0 Hz, H-5), 7.07 (1H, d, J¼3.0 Hz, H-3), 7.09 (1H, d,
J¼8.5 Hz, H-6). Anal. Calcd for C15H20O4: C, 68.16; H, 7.63. Found: C,
68.35; H, 7.82.
(3H, t, J¼7.5 Hz, COCH2CH3), 1.12 (3H, t, J¼7.5 Hz, ArCH2CH3), 2.51
(2H, q, J¼7.5 Hz, COCH2), 2.55 (2H, q, J¼7.5 Hz, ArCH2), 6.46 (1H,
dd, J¼8.5 and 2.5 Hz, H-6), 6.52 (1H, d, J¼2.5 Hz, H-2), 7.05 (1H, d,
J¼8.5 Hz, H-5), 9.55 (1H, s, OH); 13C NMR
d 9.6 (COCH2CH3), 14.8
(ArCH2CH3), 23.0 (ArCH2CH3), 27.6 (COCH2CH3), 109.0 (C-2), 112.5
(C-6), 128.1 (C-4), 129.7 (C-5), 149.7 (C-1), 156.1 (C-3), 173.2 (C]
O). Anal. Calcd for C11H14O3: C, 68.02; H, 7.27. Found: C, 67.75; H,
7.24.
4.6.5. 1,4-di-O-Propanoyl-t-butylhydroquinone (4e). Oil; 1H NMR
d
1.13 (3H, t, J¼7.5 Hz, CH2CH3), 1.17 (3H, t, J¼7.5 Hz, CH2CH3), 1.28
(9H, s, C(CH3)3), 2.59 (2H, q, J¼7.5 Hz, CH2), 2.65 (2H, q, J¼7.5 Hz,
CH2), 7.01 (1H, dd, J¼9.0 and 2.5 Hz, H-5), 7.06 (1H, d, J¼2.5 Hz, H-
3), 7.07 (1H, d, J¼9.0 Hz, H-6). Anal. Calcd for C16H22O4: C, 69.04; H,
7.97. Found: C, 68.76; H, 8.02.
4.7.3. 1-O-Propanoyl-4-t-octylresorcinol (6c). Oil; １H NMR
d 0.70
(9H, s, C(CH3)3), 1.11 (3H, t, J¼7.5 Hz, CH2CH3), 1.36 (6H, s,
C(CH3)2), 1.91 (2H, s, CH2C(CH3)3), 2.53 (2H, q, J¼7.5 Hz, CH2CH3),
6.46 (1H, d, J¼2.5 Hz, H-2), 6.48 (1H, dd, J¼7.5 and 2.5 Hz, H-6),
4.6.6. 1,4-di-O-Propanoylmethoxyhydroquinone (4f). Oil; 1H NMR
7.12 (1H, d, J¼7.5 Hz, H-5), 9.57 (1H, s, OH); 13C NMR
d 9.1
d
1.13 (3H, t, J¼7.5 Hz, CH2CH3), 1.14 (3H, t, J¼7.5 Hz, CH2CH3), 2.58
(CH2CH3), 27.1 (CH2CH3), 30.9 (C(CH3)2), 31.4 (C(CH3)3), 32.2
(C(CH3)3), 38.3 (C(CH3)2), 51.5 (CH2C(CH3)3), 109.3 (C-2), 111.6 (C-
6), 127.7 (C-5), 131.9 (C-4), 149.3 (C-1), 156.9 (C-3), 172.6 (C]O).
Anal. Calcd for C17H26O3: C, 73.35; H, 9.41. Found: C, 73.17; H,
9.47.
(2H, q, J¼7.5 Hz, CH2), 2.60 (2H, q, J¼7.5 Hz, CH2), 3.74 (3H, s, OCH3),
6.70 (1H, dd, J¼8.5 and 2.5 Hz, H-5), 6.94 (1H, d, J¼2.5 Hz, H-3), 7.10
(1H, d, J¼8.5 Hz, H-6). Anal. Calcd for C13H16O5: C, 61.90; H, 6.39.
Found: C, 61.66; H, 6.57.
4.6.7. 1,4-di-O-Propanoylacetylhydroquinone (4g). Oil; 1H NMR
4.7.4. 1-O-Propanoyl-4-benzylresorcinol (6d). Oil; 1H NMR
d 1.10
d
1.14 (3H, t, J¼7.5 Hz, CH2CH3), 1.15 (3H, t, J¼7.5 Hz, CH2CH3), 2.50
(3H, t, J¼8.0 Hz, CH3), 2.55 (2H, q, J¼8.0 Hz, CH2CH3), 3.85 (2H, s,
CH2Ph), 6.47 (1H, dd, J¼8.0 and 2.5 Hz, H-6), 6.56 (1H, d, J¼2.5 Hz,
H-2), 7.02 (1H, d, J¼8.0 Hz, H-5), 7.14e7.27 (5H, m, Ph), 9.73 (1H, s,
(3H, s, COCH3), 2.62 (2H, q, J¼7.5 Hz, CH2), 2.63 (2H, q, J¼7.5 Hz,
CH2), 7.27 (1H, d, J¼8.5 Hz, H-6), 7.41 (1H, dd, J¼8.5 and 3.0 Hz, H-
5), 7.67 (1H, d, J¼3.0 Hz, H-3). Anal. Calcd for C14H16O5: C, 63.63; H,
6.10. Found: C, 63.79; H, 6.33.
OH); 13C NMR
d 9.6 (CH3), 27.6 (CH2CH3), 35.4 (CH2Ph), 109.2 (C-2),
112.6 (C-6), 125.7 (C-4), 126.4 (C-40), 128.9 (C-20), 129.3 (C-30), 131.1
(C-5), 141.7 (C-10), 150.1 (C-1), 156.1 (C-3), 173.2 (C]O). Anal. Calcd
for C16H16O3: C, 74.98; H, 6.29. Found: C, 75.24; H, 6.24.
4.6.8. 1,4-di-O-Propanoylfluorohydroquinone (4h). Mp 78e79 ꢀC;
１H NMR
d
1.13 (3H, t, J¼7.5 Hz, CH3) 1.15 (3H, t, J¼7.5 Hz, CH3), 2.60
(2H, q, J¼7.5 Hz, CH2), 2.65 (2H, q, J¼7.5 Hz, CH2), 7.04 (1H, ddd,
J¼8.5, 2.5 and 1.5 Hz, H-5), 7.31 (1H, dd, J¼11.0 and 2.5 Hz, H-3), 7.34
(1H, dd, J¼9.0 and 8.5 Hz, H-6). Anal. Calcd for C12H13FO4: C, 60.00;
H, 5.45. Found: C, 60.13; H, 5.50.
4.7.5. 1-O-Propanoyl-4-chlororesorcinol (6e). Oil; １H NMR
d 1.10
(3H, t, J¼7.5 Hz, CH3), 2.56 (2H, q, J¼7.5 Hz, CH2), 6.57 (1H, dd, J¼8.5
and 2.5 Hz, H-6), 6.70 (1H, d, J¼2.5 Hz, H-2), 7.32 (1H, d, J¼8.5 Hz,
H-5), 10.32 (1H, s, OH). Anal. Calcd for C9H9ClO3: C, 53.88; H, 4.52.
Found: C, 54.03; H, 4.43.
4.6.9. 1,4-di-O-Propanoylchlorohydroquinone (4i). Oil; 1H NMR
d
1.13 (3H, t, J¼7.5 Hz, CH3), 1.17 (3H, t, J¼7.5 Hz, CH3), 2.60 (2H, q,
4.7.6. 1-O-Propanoyl-4-bromoresorcinol (6f). Oil; １H NMR
d 1.12
J¼7.5 Hz, CH2), 2.66 (2H, q, J¼7.5 Hz, CH2), 7.19 (1H, dd, J¼8.5 and
2.5 Hz, H-5), 7.36 (1H, d, J¼8.5 Hz, H-6), 7.47 (1H, d, J¼2.5 Hz, H-3).
Anal. Calcd for C12H13ClO4: C, 56.15; H, 5.11. Found: C, 56.22; H, 4.88.
(3H, t, J¼7.5 Hz, CH3), 2.58 (2H, q, J¼7.5 Hz, CH2), 6.54 (1H, dd, J¼8.5
and 2.5 Hz, H-6), 6.73 (1H, d, J¼2.5 Hz, H-2), 7.49 (1H, d, J¼8.5 Hz,
H-5), 10.56 (1H, s, OH). Anal. Calcd for C9H9BrO3: C, 44.11; H, 3.70.
Found: C, 44.37; H, 3.59.
4.6.10. 1,4-di-O-Propanoylbromohydroquinone (4j). Mp 58e60 ꢀC;
1H NMR
d
1.13 (3H, t, J¼7.5 Hz, CH3), 1.17 (3H, t, J¼7.5 Hz, CH3), 2.60
4.8. Preparation of authentic 3-O-momopropanoyl de-
rivatives of 4-substituted resorcinols
(2H, q, J¼7.5 Hz, CH2), 2.66 (2H, q, J¼7.5 Hz, CH2), 7.22 (1H, dd, J¼8.5
and 2.5 Hz, H-5), 7.34 (1H, d, J¼8.5 Hz, H-6), 7.59 (1H, d, J¼2.5 Hz, H-
3). Anal. Calcd for C12H13BrO4: C, 47.86; H, 4.35. Found: C, 48.06; H,
4.26.
Authentic samples of the 3-O-monopropanoates of 4-
substituted resorcinols were prepared through the lipase-
catalyzed deacylation of each 1,4-O-dipropanoylresorcinol. They
were prepared in the same manner as described above for the
preparation of 1-O-monopropanoates of hydroquinones.
4.7. Preparation of authentic 1-O-momopropanoyl de-
rivatives of 4-substituted resorcinols
The 1-O-monopropanoates of 4-substituted resorcinols were
obtained as the major products of the CAL-B-catalyzed acylation of
each resorcinol. They were prepared in the same manner as
4.8.1. 3-O-Propanoyl-4-methylresorcinol (7a). Oil; 1H NMR
d 1.14
(3H, t, J¼7.5 Hz, CH2CH3), 1.97 (3H, s, ArCH3), 2.59 (2H, q, J¼7.5 Hz,
CH2), 6.44 (1H, d, J¼2.0 Hz, H-2), 6.57 (1H, dd, J¼8.5 and 2.0 Hz, H-
Please cite this article in press as: Miyazawa, T.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.033

8
T. Miyazawa et al. / Tetrahedron xxx (2015) 1e9
6), 7.03 (1H, d, J¼8.5 Hz, H-5), 9.43 (1H, s, OH). Anal. Calcd for
10H12O3: C, 66.65; H, 6.71. Found: C, 66.76; H, 6.67.
(1H, d, J¼2.5 Hz, H-2), 6.96 (1H, dd, J¼8.5 and 8.5 Hz, H-6), 7.41 (1H,
d, J¼8.5 Hz, H-5). Anal. Calcd for C20H30O4: C, 71.82; H, 9.04. Found:
C, 71.73; H, 9.31.
C
4.8.2. 3-O-Propanoyl-4-ethylresorcinol (7b). Oil; 1H NMR
d 1.05 (3H,
t, J¼7.5 Hz, ArCH2CH3), 1.14 (3H, t, J¼7.5 Hz, COCH2CH3), 2.34 (2H, q,
J¼7.5 Hz, ArCH2CH3), 2.59 (2H, q, J¼7.5 Hz, COCH2CH3), 6.43 (1H, d,
J¼2.5 Hz, H-2), 6.61 (1H, dd, J¼8.5 and 2.5 Hz,H-6), 7.06 (1H, d,
4.9.4. 1,3-di-O-Propanoyl-4-benzylresorcinol (8d). Oil; 1H NMR
d
1.08 (3H, t, J¼7.5 Hz, CH3), 1.16 (3H, t, J¼7.5 Hz, CH3), 2.52 (2H, q,
J¼7.5 Hz, CH2CH3), 2.59 (2H, q, J¼7.5 Hz, CH2CH3), 3.86 (2H, s,
CH2Ph), 6.96 (1H, d, J¼2.5 Hz, H-2), 6.99 (1H, dd, J¼7.5 and 2.5 Hz,
H-6), 7.17 (1H, d, J¼7.5 Hz, H-5), 7.18e7.31 (5H, m, Ph). Calcd for
J¼8.5 Hz, H-5), 9.45 (1H, s, OH); 13C NMR
d 9.2 (COCH2CH3), 14.8
(ArCH2CH3), 22.1 (ArCH2CH3), 27.1 (COCH2CH3), 109.6 (C-2), 113.3
(C-6), 125.7 (C-4), 129.8 (C-5), 149.2 (C-3), 156.3 (C-1), 172.6 (C]O).
Anal. Calcd for C11H14O3: C, 68.02; H, 7.27. Found: C, 67.79; H, 7.05.
C
19H20O4: C, 73.06; H, 6.45. Found: C, 72.94; H, 6.49.
4.9.5. 1,3-di-O-Propanoyl-4-chlororesorcinol (8e). Oil; 1H NMR
4.8.3. 3-O-Propanoyl-4-t-octylresorcinol (7c). Oil; 1H NMR
d
0.69
d
1.13 (3H, t, J¼7.5 Hz, CH3), 1.17 (3H, t, J¼7.5 Hz, CH3), 2.60 (2H, q,
(9H, s, C(CH3)3), 1.16 (3H, t, J¼7.5 Hz, CH2CH3), 1.28 (6H, s, C(CH3)2),
1.71 (2H, s, CH2C(CH3)3), 2.60 (2H, q, J¼7.5 Hz, CH2CH3), 6.40 (1H, d,
J¼2.5 Hz, H-2), 6.57 (1H, dd, J¼9.0 and 2.5 Hz, H-6), 7.14 (1H, d,
J¼9.0 Hz, H-5), 9.41 (1H, s, OH). Anal. Calcd for C17H26O3: C, 73.35;
H, 9.41. Found: C, 73.54; H, 9.39.
J¼7.5 Hz, CH2), 2.66 (2H, q, J¼7.5 Hz, CH2), 7.13 (1H, dd, J¼8.0 and
2.5 Hz, H-6), 7.23 (1H, d, J¼2.5 Hz, H-2), 7.62 (1H, d, J¼8.0 Hz, H-5).
Anal. Calcd for C12H13ClO4: C, 56.15; H, 5.11. Found: C, 55.98; H, 5.29.
4.9.6. 1,3-di-O-Propanoyl-4-bromoresorcinol (8f). Oil; 1H NMR
d
1.11 (3H, t, J¼7.5 Hz, CH3), 1.16 (3H, t, J¼7.5 Hz, CH3), 2.59 (2H, q,
4.8.4. 3-O-Propanoyl-4-benzylresorcinol (7d). Oil; 1H NMR
d
1.05
J¼7.5 Hz, CH2), 2.64 (2H, q, J¼7.5 Hz, CH2), 7.05 (1H, dd, J¼8.5 and
2.5 Hz, H-6), 7.20 (1H, d, J¼2.5 Hz, H-2), 7.73 (1H, d, J¼8.5 Hz, H-5).
Anal. Calcd for C12H13BrO4: C, 47.86; H, 4.35. Found: C, 47.78; H, 4.17.
(3H, t, J¼7.5 Hz, CH3), 2.50 (2H, q, J¼7.5 Hz, CH2CH3), 3.69 (2H, s,
CH2Ph), 6.46 (1H, d, J¼2.5 Hz, H-2), 6.60 (1H, dd, J¼8.5 and 2.5 Hz,
H-6), 7.03 (1H, d, J¼8.5 Hz, H-5), 7.10e7.25 (5H, m, Ph), 9.53 (1H, s,
OH). Anal. Calcd for C16H16O3: C, 74.98; H, 6.29. Found: C, 74.81; H,
6.45.
4.10. General procedure for the lipase-catalyzed acylation of
hydroquinones and resorcinols in an analytical scale
4.8.5. 3-O-Propanoyl-4-chlororesorcinol (7e). Oil; 1H NMR
d
1.01
A solution of a dihydric phenol (0.1 mmol) and vinyl propanoate
(3H, t, J¼7.5 Hz, CH3), 2.55 (2H, q, J¼7.5 Hz, CH2), 6.69 (1H, dd, J¼8.5
and 2.5 Hz, H-6), 6.70 (1H, d, J¼2.5 Hz, H-2), 7.02 (1H, d, J¼8.5 Hz,
H-5), 10.17 (1H, s, OH). Anal. Calcd for C9H9ClO3: C, 53.88; H, 4.52.
Found: C, 53.74; H, 4.46.
(32.7 ml, 0.3 mmol) in anhydrous diisopropyl ether (240 ml) was
stirred with an immobilized lipase preparation (40 mg) in an in-
cubator. After filtering off the enzyme and evaporation of the fil-
trate, the residue was subjected to NMR analysis to determine the
conversion and product distribution, as the 1H NMR spectra of the
starting diol and its authentic propanoates (two isomeric monop-
ropanoates and dipropanoate) are available with each hydroqui-
none or resorcinol. In the reactions of substituted hydroquinones
(1aej), the proton signals used for the purpose were different from
compound to compound. The ArCH3 proton signals together with
the COCH2CH3 signals were utilized with 1a. The proton signals
appearing as a singlet were employed in the following cases: 1b,
ArCH3; 1e, C(CH3)3; 1f, OCH3; 1g, COCH3. The proton signals (H-5,
H-2 or H-6) in the aromatic region were used with 1c, 1d and 1hej.
In the reactions of 4-substituted resorcinols (5aef), the proton
signals (H-5, H-2 or H-6) in the aromatic region were mainly
employed for the purpose. The whole content of the reaction
mixture was used up for one analysis, and several discrete reaction
mixtures were used at different reaction times.
4.8.6. 3-O-Propanoyl-4-bromoresorcinol (7f). Oil; 1H NMR
d 1.10
(3H, t, J¼7.5 Hz, CH3), 2.57 (2H, q, J¼7.5 Hz, CH2), 6.65 (1H, dd, J¼8.5
and 2.5 Hz, H-6), 6.65 (1H, d, J¼2.5 Hz, H-2), 7.42 (1H, d, J¼8.5 Hz,
H-5), 10.36 (1H, s, OH). Anal. Calcd for C9H9BrO3: C, 44.11; H, 3.70.
Found: C, 44.22; H, 3.96.
4.9. Preparation of authentic 1,3-di-O-propanoyl derivatives
of 4-substituted resorcinols
Authentic samples of the 1,3-di-O-propanoates of 4-substituted
resorcinols were prepared by the reaction of each resorcinol with
propanoyl chloride in pyridine. They were prepared in the same
manner as described above for the preparation of 1,4-di-O-prop-
anoates of hydroquinones.
4.9.1. 1,3-di-O-Propanoyl-4-methylresorcinol (8a). Oil; 1H NMR
4.11. HPLC monitoring of the propanoylation of methoxyhy-
droquinone (1f)
d
1.12 (3H, t, J¼7.5 Hz, CH2CH3), 1.15 (3H, t, J¼7.5 Hz, CH2CH3), 2.09
(3H, s, ArCH3), 2.57 (2H, q, J¼7.5 Hz, CH2), 2.62 (2H, q, J¼7.5 Hz,
CH2), 6.94 (1H, dd, J¼8.5 and 2.5 Hz, H-6), 6.96 (1H, d, J¼2.5 Hz, H-
2), 7.30 (1H, d, J¼8.5 Hz, H-5). Anal. Calcd for C13H16O4: C, 66.09; H,
6.83. Found: C, 66.17; H, 7.07.
A solution of 1f (42 mg, 0.3 mmol) and vinyl propanoate (98
0.9 mmol) in diisopropyl ether (720 l) was stirred with CAL-B
(120 mg) at 45 ꢀC in a 1-ml vial. Aliquots (ca. 10
l) of the re-
ml,
m
m
action mixture were withdrawn at frequent intervals, diluted with
ether, and filtered through a PTFE membrane filter. After evapora-
tion of ether, the residue was dissolved in acetonitrile (1 ml), and
subjected to HPLC analysis under the following conditions: column,
Ascentis RP-Amide (4.6 mm i.d.ꢁ250 mm); mobile phase, 34% aq
4.9.2. 1,3-di-O-Propanoyl-4-ethylresorcinol (8b). Oil; 1H NMR
d 1.11
(3H, t, J¼7.5 Hz, COCH2CH3), 1.12 (3H, t, J¼7.5 Hz, COCH2CH3), 1.16
(3H, t, J¼7.5 Hz, ArCH2CH3), 2.47 (2H, q, J¼7.5 Hz, ArCH2), 2.58 (2H,
q, J¼7.5 Hz, COCH2), 2.63 (2H, q, J¼7.5 Hz, COCH2), 6.92 (1H, d,
J¼2.5 Hz, H-2), 6.98 (1H, dd, J¼8.5 and 2.5 Hz, H-6), 7.33 (1H, d,
J¼8.5 Hz, H-5). Anal. Calcd for C14H18O4: C, 67.18; H, 7.25. Found: C,
67.32; H, 7.07.
acetonitrile containing H3PO4 (0.01 M); flow rate, 1.0 ml minꢂ1
;
column temperature, 30 ꢀC; detection, UV at 280 nm. The tR’s of
relevant compounds are as follows: 1f, 2.7 min; 3f, 7.8 min; 2f,
8.7 min; 4f, 31.9 min. The absorbances of these compounds at
280 nm were obtained separately by usual UV measurements using
their methanolic solutions and the factors were determined based
on the absorbance of 1f as follows: 2f, 1.13; 3f, 1.25; 4f, 0.79. The
peak areas obtained on HPLC were corrected using these factors.
4.9.3. 1,3-di-O-Propanoyl-4-t-octylresorcinol (8c). Oil; 1H NMR
d
0.70 (9H, s, C(CH3)3), 1.12 (3H, t, J¼7.5 Hz, CH2CH3), 1.17 (3H, t,
J¼7.5 Hz, CH2CH3), 1.34 (6H, s, C(CH3)2), 1.77 (2H, s, CH2C(CH3)3),
2.58 (2H, q, J¼7.5 Hz, CH2CH3), 2.63 (2H, q, J¼7.5 Hz, CH2CH3), 6.89
Please cite this article in press as: Miyazawa, T.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.033

T. Miyazawa et al. / Tetrahedron xxx (2015) 1e9
5. Natoli, M.; Nicolosi, G.; Piattelli, M. J. Org. Chem. 1992, 57, 5776.
9
Supplementary data
6. (a) Nicolosi, G.; Piattelli, M.; Sanfilippo, C. Tetrahedron 1993, 49, 3143; (b)
Chebil, L.; Anthoni, J.; Humeau, C.; Gerardin, C.; Engasser, J.-M.; Ghoul, M. J.
Agric. Food Chem. 2007, 55, 9496; (c) Torres, P.; Poveda, A.; Jimenez-Barbero, J.;
Ballesteros, A.; Plou, F. J. J. Agric. Food Chem. 2010, 58, 807.
7. For example, see: (a) Parmar, V. S.; Prasad, A. K.; Sharma, N. K.; Bisht, K. S.;
Sinha, R.; Taneja, P. Pure Appl. Chem. 1992, 64, 1135; (b) Rohn, S.; Rawel, H. M.;
Kroll, J. J. Agric. Food Chem. 2002, 50, 3566; (c) Nakai, M.; Fukui, Y.; Asami, S.;
Toyoda-Ono, Y.; Iwashita, T.; Shibata, H.; Mitsunaga, T.; Hashimoto, F.; Kiso, Y. J.
Agric. Food Chem. 2005, 53, 4593.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.04.033.
References and notes
€
€
1. For reviews, see: (a) Paravidino, M.; Bohm, P.; Groger, H.; Hanefeld, U. In Enzyme
€
Catalysis in Organic Synthesis, 3rd ed.; Drauz, K., Groger, H., May, O., Eds.; Wiley-
8. They also reported that in the reaction of (þ)ꢂcatechin [(2R, 3S)-2-(3,4-
dihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3,5,7-triol] with vinyl ace-
tate in the presence of supported B. cepacia lipase in acetonitrile two de-
rivatives acylated only at the A ring were formed, i.e., 5-O-acetylcatechin and 7-
O-acetylcatechin: Lambusta, D.; Nicolosi, G.; Patti, A.; Piattelli, M. Synthesis
1993, 1155.
VHC: Weinheim, Germany, 2012; p 251; (b) Faber, K. Biotransformations in Organic
Chemistry, 6th ed.; Springer: Berlin, Germany, 2011; p 87; 324; (c) Bornscheuer, U.
T.; Kazlauskas, R. J. Hydrolases in Organic Synthesis: Regio- and Stereoselective
Biotransformations, 2nd ed.; Wiley-VHC: Weinheim, Germany, 2006; p 61.
2. For reviews, see: Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolases in Organic
Synthesis: Regio- and Stereoselective Biotransformations, 2nd ed.; Wiley-VHC:
Weinheim, Germany, 2006; p 141.
3. (a) Parmar, V. S.; Prasad, A. K.; Sharma, N. K.; Singh, S. K.; Pati, H. N.; Gupta, S.
Tetrahedron1992, 48, 6495; (b) Parmar, V. S.; Prasad, A. K.; Sharma, N. K.; Vardhan,
A.; Pati, H. N.; Sharma, S. K.; Bisht, K. S. J. Chem. Soc., Chem. Commun. 1993, 27; (c)
Bisht, K. S.; Tyagi, O. D.; Prasad, A. K.; Sharma, N. K.; Gupta, S.; Parmar, V. S. Bioorg.
Med. Chem. 1994, 2, 1015; (d) Parmar, V. S.; Kumar, A.; Bisht, K. S.; Mukherjee, S.;
Prasad, A. K.; Sharma, S. K.; Wengel, J.; Olsen, C. E. Tetrahedron 1997, 53, 2163.
4. We also reported the preliminary results concerning the highly regioselective
deacylation of resorcinols and hydroquinones acylated at both phenolic hy-
droxy groups mediated by Candida antarctica lipase B: Miyazawa, T.; Hamada,
M.; Morimoto, R.; Murashima, T.; Yamada, T. Tetrahedron Lett. 2007, 48, 8334.
9. For
a preliminary report, see: Miyazawa, T.; Hamada, M.; Morimoto, R.;
Murashima, T.; Yamada, T. Tetrahedron Lett. 2008, 49, 175.
10. This solvent was employed in the lipase-catalyzed highly enantioselective ac-
ylation of 2-aryloxy-1-propanols: Miyazawa, T.; Yukawa, T.; Koshiba, T.; Saka-
moto, H.; Ueji, S.; Yanagihara, R.; Yamada, T. Tetrahedron: Asymmetry 2001, 12,
1595.
11. Anderson, E. M.; Larsson, K. M.; Kirk, O. Biocat. Biotrans. 1998, 16, 181.
12. Enzymatic Reactions in Organic Media; Koskinen, A. M. P., Klibanov, A. M., Eds.;
Blackie A & P: Glasgow, UK, 1996.
13. Johnson, T. B.; Hodge, W. W. J. Am. Chem. Soc. 1913, 35, 1014.
Please cite this article in press as: Miyazawa, T.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.033