Resolution of 2-aryloxy-1-propanols via lipase-catalyzed enantioselective acylation in organic media

Article abstract of DOI:10.1016/S0957-4166(01)00258-0

2-Aryloxy-1-propanols, primary alcohols with an oxygen atom at the stereocenter, were resolved with good to high enantioselectivity by acylation with vinyl butanoate mediated by Pseudomonas sp. lipase in di-iso-propyl ether. Potential factors affecting the enantioselectivity of the enzymatic acylation were examined: solvents, acyl donors and temperature. Using this enantioselective acylation procedure, enantiomerically pure (R)-2-(4-chlorophenoxy)-1-propanol was prepared on a gram scale.

Full text of DOI:10.1016/S0957-4166(01)00258-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1595–1602
Resolution of 2-aryloxy-1-propanols via lipase-catalyzed
enantioselective acylation in organic media
Toshifumi Miyazawa,a,* Tomoyuki Yukawa,a Takashi Koshiba,b Hiroko Sakamoto,a Shinichi Ueji,b
Ryoji Yanagiharaa and Takashi Yamadaa
aDepartment of Chemistry, Faculty of Science and Engineering, Konan University, Higashinada-ku, Kobe 658-8501, Japan
bDivision of Natural Environment and Bioorganic Chemistry, Faculty of Human Development and Sciences, Kobe University,
Nada-ku, Kobe 657-8501, Japan
Received 14 May 2001; accepted 5 June 2001
Abstract—2-Aryloxy-1-propanols, primary alcohols with an oxygen atom at the stereocenter, were resolved with good to high
enantioselectivity by acylation with vinyl butanoate mediated by Pseudomonas sp. lipase in di-iso-propyl ether. Potential factors
affecting the enantioselectivity of the enzymatic acylation were examined: solvents, acyl donors and temperature. Using this
enantioselective acylation procedure, enantiomerically pure (R)-2-(4-chlorophenoxy)-1-propanol was prepared on a gram scale.
© 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
model has recently been proposed6 from molecular
modeling studies of transition state analogs bound to
the active site of the lipase, where primary alcohols are
bound in a different manner to secondary alcohols.
However, the rule is not reliable for primary alcohols
with an oxygen atom at the stereogenic center.5,6
Accordingly, it seemed challenging to explore the enzy-
matic resolution of this class of primary alcohols using
lipases. We report herein the detailed results of our
investigation concerning the resolution of 2-aryloxy-1-
propanol analogues via the lipase-catalyzed enantiose-
lective acylation.7 These 2-aryloxy-1-propanols are
useful chiral starting materials for the synthesis of a
sorbinil homolog8 and of juvenile hormone analogs
(juvenoids) of the 2-(4-hydroxybenzyl)-1-cyclohexanone
series.9
Homochiral alcohols are useful building blocks for the
synthesis of a wide variety of biologically active com-
pounds and functional materials such as liquid crystals.
Enzymatic methodologies have recently been recog-
nized as the most attractive approaches for obtaining
such compounds in enantiomerically pure form. Lipases
from different sources have been used for the resolution
of racemic alcohols via hydrolysis, transesterification or
esterification.1 However, compared to the high number
of reports on the resolution of secondary alcohols using
lipases, successful examples with primary alcohols have
been documented far less.2 It has been reported that
most lipases show low enantioselectivity toward pri-
mary alcohols and only lipases from Pseudomonas
cepacia and porcine pancreas resolve these substrates
with moderate to high enantioselectivity.3 In the lipase-
catalyzed resolution of secondary alcohols, a simple
rule based on the size of the substituents was proposed
which could predict the favored enantiomer.4 A similar
rule was later introduced for the P. cepacia lipase-cata-
lyzed reactions of primary alcohols,5,† and a revised
2. Results and discussion
Initially, lipases from microbial and pancreatic sources
were screened for the acylation of the parent 2-phen-
oxy-1-propanol 1a with vinyl butanoate as an acyl
donor in di-iso-propyl ether‡ (Scheme 1). Some of the
results are shown in Table 1.
* Corresponding author. Fax: +81-78-435-2539; e-mail: miyazawa@
base2.ipc.konan-u.ac.jp
† Other predictive active site models have also been reported for
lipases from Pseudomonas sp. and Alcaligenes sp. to identify which
enantiomer of an alcohol (primary or secondary) reacts faster in the
lipase-catalyzed acylation (see Refs. 2a and 2b).
‡ We have reported the lipase-catalyzed highly enantioselective deac-
ylation and acylation of mandelic acid derivatives in this solvent.10
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00258-0

1596
T. Miyazawa et al. / Tetrahedron: Asymmetry 12 (2001) 1595–1602
Scheme 1. Lipase-catalyzed enantioselective acylation of ( )-2-aryloxy-1-propanols [(RS)-1] with vinyl esters.
Table 1. Lipase-catalyzed acylation of (RS)-1a with vinyl
butanoate in di-iso-propyl ethera
mediated by Pseudomonas sp. lipase. The solvents
examined had little influence on the enantioselectivity
of the reaction, with the exception of benzene in which
it deteriorated compared with the reaction in di-iso-
propyl ether. Acylation in acetonitrile was found to
proceed very slowly.
b
Lipase source
% Convn.
51
Time (min)
110
% E.e.S
89
E
Pseudomonas
sp.c
35
P. cepaciad
Porcine
60
62
13
60
92
94
13
12
Table 2. Solvent effect on the Pseudomonas sp. lipase-cat-
alyzed acylation of (RS)-1a with vinyl butanoatea
pancrease
C. 6iscosumf
M. ja6anicusg
66
56
19
150
96
66
11
6.0
b
Solvent
% Convn.
Time
(min)
% E.e.S
E
a Reactions were conducted at 25°C as described in Section 4.
1,4-Dioxane
Acetonitrile
THF
52
51
51
49
55
50
48
110
95 h
100
60
100
60
89
88
88
47
94
83
78
34
32
30
b E.e. of the remaining alcohol, whose preferred absolute configura-
tion is R.
c Amano AK; 5 mg.
d Amano P; 25 mg.
e Sigma Type II; 25 mg.
f Asahi Kasei LP; 12 mg.
g Amano M; 25 mg.
Benzene
4.5
Tetrachloromethane
Cyclohexane
Hexane
27
27
27
300
a Reactions were conducted at 25°C as described in Section 4.
b E.e. of the remaining alcohol, whose preferred absolute configura-
tion is R.
The rate and enantioselectivity of the reaction varied
markedly depending on the enzyme employed, while the
stereochemical preference remained unchanged, the pre-
ferred absolute configuration of the remaining alcohol
being R (see below). Of the enzymes tested, Pseu-
domonas sp. lipase (Amano AK) showed the highest
enantioselectivity as judged from the values of enan-
tiomeric ratio, E.11 A large number of examples have
already been accumulated on the effect of organic
solvents on lipase-catalyzed reactions.12 However, it is
still difficult to predict the solvent effect, especially on
enantioselectivity, and the practical way is to select an
appropriate solvent through screening experiments.
Next, the resolution of a number of aryloxy-1-propanol
analogues 1 bearing different benzene ring substituents
was examined in the acylation with vinyl butanoate
mediated by the same lipase in di-iso-propyl ether. As
shown in Table 3, the substituent did not have a
significant effect on the reaction rate but had a consid-
erable effect on the enantioselectivity of the reaction.
The substitution of a chlorine atom reduced the enan-
tioselectivity without affecting the acylation rate. On
the other hand, the substitution of two chlorine atoms
at the o- and p-positions lowered the enantioselectivity
as well as that of the p-ethyl or p-iso-propyl group,
suggesting that the bulk of the substituent on the
Table 2 shows the effect of solvents other than di-iso-
propyl ether on the acylation of 1a with vinyl butanoate
Table 3. Pseudomonas sp. lipase-catalyzed acylation of 2-aryloxy-1-propanols [(RS)-1] with vinyl butanoate in di-iso-propyl
ethera
b
Compound
X
% Convn.
Time (min)
% E.e.S
E
1a
1b
1c
1d
1e
1f
H
4-F
51
50
48
51
50
52
53
50
110
100
100
130
120
110
90
89
86
89c
92
90
76c
84
73
35
34
48
55
58
19
18
15
2-Cl
3-Cl
4-Cl
2,4-Cl2
4-Et
4-Pri
1g
1h
110
a Reactions were conducted at 25°C as described in Section 4.
b E.e. of the remaining alcohol.
c E.e. of the ester formed.

T. Miyazawa et al. / Tetrahedron: Asymmetry 12 (2001) 1595–1602
1597
benzene ring has a deleterious effect on the enantiose-
lectivity. Even in these cases, however, the E values
were larger than 15, with which the recovered substrate
with a practically high enantiomeric excess (e.e.) can be
obtained when the reaction is allowed to proceed over
ca.60% conversion.11 In all of the cases examined, the
recovered alcohols were of (R)-configuration, as confi-
rmed by comparison with the authentic samples, i.e.
(S)- or (R)-enriched 2-aryloxy-1-propanols prepared
through the reduction of the corresponding (S)- or
(R)-enriched 2-aryloxypropanoic acids, respectively,
obtained via the lipase-catalyzed transesterification of
their racemic vinyl esters or esterification of racemic
acids.13 This indicates that the (S)-alcohols react prefer-
entially to give the (S)-butanoates 2. The stereochemi-
cal preference observed here is contrary to that
predicted by the empirical rule mentioned above for the
P. cepacia lipase-catalyzed reactions of primary alco-
hols without an oxygen atom at the stereogenic center.5
Furthermore, gram-scale resolution of (RS)-2-(4-
chlorophenoxy)-1-propanol 1e was achieved. After
incubation for 8 h (56% conversion) with vinyl
butanoate in di-iso-propyl ether in the presence of
Pseudomonas sp. lipase, (R)-1e with >99% e.e. was
isolated as the unreacted substrate alcohol through
column chromatography on silica gel.
lipase’s enantioselectivity due to both steric and elec-
tronic factors.
Table 4. Effect of acyl donors on the Pseudomonas sp.
lipase-catalyzed acylation of (RS)-1a in di-iso-propyl
ethera
c
R of vinyl
esterb
% Convn.
Time (min)
% E.e.S
E
CH3
C2H5
52
52
51
51
55
46
47
40
50
80
110
120
40
50
10
120
93
90
89
87
94
74
63
11
42
35
35
36
28
28
11
n-C3H7
n-C5H11
n-C7H15
n-C11H23
ClCH2
CF3
1.5
a Reactions were conducted at 25°C as described in Section 4.
b See Scheme 1.
c E.e. of the remaining alcohol.
2.2. Effect of temperature
Temperature is another factor which can potentially
affect the rate and enantioselectivity of enzymatic reac-
tions, and there is a general belief that enzymes exhibit
their highest selectivity at low temperature. In the
Aspergillus oryzae protease-catalyzed hydrolysis of the
iso-butyl esters of some aliphatic amino acids, we
observed previously that the enantioselectivity was
improved greatly at 5°C compared with the reaction at
25°C.15 However, it has been pointed out that the
higher enantioselectivity at lower temperature is not
always the case; a temperature-dependent reversal of
stereochemistry has been reported in a few enzymatic
reactions.16 A rational understanding of this phe-
nomenon has also been proposed.17 Accordingly, the
acylations of 1a were investigated using vinyl butanoate
or vinyl chloroacetate as the acyl donor in di-iso-propyl
ether at different temperatures (0–40°C). The enantiose-
lectivity was found to improve with decreasing temper-
ature, though the reaction rate was diminished
considerably. The best compromises in terms of both
the acylation rate and the enantioselectivity were
obtained at 5°C in the acylation with vinyl butanoate
(45% conversion after 200 min; E=60) and at 0°C in
the acylation with vinyl chloroacetate (37% conversion
after 180 min; E=15). When −RT ln E, representing
the activation free energy difference (DDG‡) between
the enantiomers, was plotted against the absolute tem-
perature, T, approximately linear correlations were
obtained between them (Fig. 1), although the slope was
very small for the chloroacetylation.
2.1. Effect of acyl donors
The lipase-catalyzed enantioselective acylation of a
racemic alcohol with an achiral donor ester proceeds
via the acyl–enzyme intermediate and the enan-
tiodiscrimination of the alcohol should occur during the
subsequent alcoholysis of the intermediate. Accord-
ingly, it is reasonable to anticipate that the enantiose-
lectivity as well as the rate of the acylation reaction
must be significantly affected by the donor ester, partic-
ularly by its acid moiety. However, systematic investi-
gations have scarcely been carried out. We previously
examined the effect of a series of vinyl esters in the
Pseudomonas sp. lipase-catalyzed acylation of methyl
(RS)-mandelate and found that the chain length of the
fatty acid moiety of the vinyl esters had a marked effect
on the conversion rate, with those carrying a shorter
alkyl chain serving as better acyl donors. The enan-
tioselectivity was highest with vinyl butanoate.10a More
recently, Ema et al. also studied the effect of different
vinyl esters on the lipase-catalyzed acylation of
2-[(N,N-dimethylcarbamoyl)methyl]-3-cyclopenten-1-ol
and observed a similar change in enantioselectivity with
the chain length of the acyl moiety of the donor
esters.14
As shown in Table 4 for the Pseudomonas sp. lipase-cat-
alyzed acylation of 1a in di-iso-propyl ether, the enan-
tioselectivity was the highest with vinyl acetate and it
tends to become lower with the chain length of the fatty
acid moiety, though the difference between the acetate
and the butanoate, for example, was not very large.
With vinyl chloroacetate the enantioselectivity
decreased and with vinyl trifluoroacetate it deteriorated
greatly. The results obtained here and those mentioned
above10,14 indicate that acyl donors strongly affect the
The linear plots depicted in Fig. 1 indicate that there
should have been no change in the reaction mechanism,
i.e. in the lipase’s active conformation in the tempera-
ture range examined.§ In these acylations the racemic
§ If the differences in the activation enthalpy and activation entropy
(DDH‡ and DDS‡) remain constant in a certain temperature range,
the temperature dependence of enantioselectivity can be given by the
equation DDG‡=−RT ln E=DDH‡−TDDS‡. Thus, in such a case
−RT ln E should be linearly correlated with T.17

1598
T. Miyazawa et al. / Tetrahedron: Asymmetry 12 (2001) 1595–1602
following lipases were screened as transesterification
catalysts, which were obtained from Amano Pharma-
ceutical Co., Meito Sangyo Co., Asahi Chemical Indus-
try Co., or Sigma: ex Pseudomonas sp. (Amano AK),
Achromobacter sp. (Meito AL), P. cepacia (Amano P),
Chromobacterium viscosum (Asahi Kasei LP), Mucor
javanicus (Amano M), Rhizopus delemar (Amano D)
and porcine pancreas (Sigma Type II).
TLC was run on precoated silica gel plates (Merck). IR
spectra were recorded on a Nicolet N-750B FT-IR
spectrometer using attenuated total reflectance (ATR).
1H NMR spectra (300 MHz) were recorded on a Varian
Unity 300 spectrometer using CDCl3 as a solvent with
TMS as an internal standard. Melting points were
determined on a Yamato MP-21 apparatus and are
uncorrected. Optical rotations were measured with a
JASCO DIP-4 digital polarimeter. Elemental analyses
of new compounds are compiled in Table 5.
Figure 1. Influence of temperature on the difference in the
activation free energy (DDG‡=−RT ln E) between the enan-
tiomers for the Pseudomonas sp. lipase-catalyzed acylation of
(RS)-1a with vinyl butanoate (ꢀ) or vinyl chloroacetate (ꢁ)
in di-iso-propyl ether.
4.1. Preparation of racemic ( )-2-aryloxy-1-propanols
1a–1h
These compounds were prepared by the reduction of
the corresponding 2-aryloxypropanoic acids using
borane–THF complex. The preparation of 1a is
described as a typical example. To a stirred solution of
2-phenoxypropanoic acid (10.0 g, 60 mmol) in dry THF
(20 mL) was added BH3 in THF (1 M, 84 mL, 84
mmol; Aldrich) dropwise over a period of 80 min with
ice-cooling and the atmosphere of nitrogen, and the
mixture was stirred at ambient temperature overnight.
A 1:1 (v/v) mixture of THF and water (24 mL) was
added and the resulting mixture was stirred for 90 min.
After THF had been removed in vacuo, the residue was
diluted by adding water (30 mL), brought to pH 9 by
adding solid K2CO3, and extracted with ether (3×100
mL). The ethereal extracts were combined, washed with
water (3×30 mL), and dried over Na2SO4. After evapo-
ration of the solvent in vacuo the residual oil was
distilled under reduced pressure to give a colorless oil
(7.4 g, 81%). The 2-aryloxy-1-propanols 1b–1h were
likewise prepared and purified by distillation under
reduced pressure to give oils in 77–85% yield. The
physical and 1H NMR data of 1 thus prepared are
compiled in Table 6.
temperatures defined as Tr=DDH‡/DDS‡, at which
there occurs no enantiomeric discrimination, lie far
above the ordinary temperature and thus the reversion
of enantioselectivity was never observed. Such a situa-
tion must often be the case and the enantioselectivity
increases with decreasing temperature, as is usually
believed.18 Thus, lower temperature can often cause the
enhancement of enzyme’s enantioselectivity.
3. Conclusion
In summary, 2-aryloxy-1-propanols, which belong to
primary alcohols with an oxygen atom at the stereocen-
ter, were resolved with good to high enantioselectivity
via the Pseudomonas sp. lipase-catalyzed acylation pro-
cedure. The acyl donor and temperature affected the
enantioselectivity of the present enzymatic transesterifi-
cation considerably. The results obtained here, together
with those reported earlier, demonstrate that Pseu-
domonas lipases are useful enzymes for the resolution of
primary alcohols.
4.2. Preparation of alkanoates of ( )-2-aryloxy-1-
propanols
4. Experimental
Authentic samples of the butanoates of ( )-2-aryloxy-
1-propanols were prepared by the reaction of each
( )-2-aryloxy-1-propanol with butanoyl chloride. The
butanoylation of 1a is described as a typical example.
To a stirred solution of 1a (200 mg, 1.3 mmol) and
pyridine (120 mL, 1.5 mmol) in dry CH2Cl2 (2 mL) was
added dropwise from a syringe a solution of butanoyl
chloride (140 mL, 1.3 mmol) in CH2Cl2 (0.4 mL) under
ice-cooling, and the mixture was stirred at ambient
temperature overnight. Ether (30 mL) was added and
the white precipitates were filtered off, and then the
( )-2-Phenoxypropanoic,
( )-2-(2-chlorophenoxy)-
propanoic, ( )-2-(3-chlorophenoxy)propanoic and ( )-
2-(2,4-dichlorophenoxy)propanoic acids were purchased
from Tokyo Chemical Industry, ( )-2-(4-chlorophe-
noxy)propanoic acid from Aldrich, and ( )-2-(4-
fluorophenoxy)propanoic acid from Lancaster. ( )-2-(4-
Ethylphenoxy)propanoic and ( )-2-(4-iso-propylphe-
noxy)propanoic acids were prepared from 4-ethyl- and
4-iso-propylphenols, respectively, according to the liter-
ature method.13,19 All the organic solvents were distilled
and dried over molecular sieves prior to use. The

T. Miyazawa et al. / Tetrahedron: Asymmetry 12 (2001) 1595–1602
Table 5. Elemental analyses of new compounds
1599
Compound
Molecular formula
C (%) found (required)
H (%) found (required)
1a
1b
1c
1d
1e
1f
1g
1h
C9H12O2
70.92 (71.03)
63.78 (63.52)
57.76 (57.92)
57.83 (57.92)
58.21 (57.92)
48.85 (48.90)
73.65 (73.30)
73.96 (74.19)
68.27 (68.02)
68.95 (69.21)
69.87 (70.25)
72.04 (71.97)
72.99 (73.35)
75.66 (75.41)
57.91 (57.78)
65.14 (64.99)
60.80 (60.82)
61.14 (60.82)
60.69 (60.82)
53.32 (53.63)
69.87 (70.07)
72.97 (72.69)
8.00 (7.95)
6.58 (6.51)
5.93 (5.94)
5.99 (5.94)
5.75 (5.94)
4.82 (4.56)
9.06 (8.95)
9.07 (9.34)
7.21 (7.26)
8.02 (7.74)
8.28 (8.16)
8.70 (8.86)
9.56 (9.41)
10.47 (10.24)
5.53 (5.73)
7.16 (7.13)
6.56 (6.67)
6.39 (6.67)
6.88 (6.67)
5.57 (5.54)
8.28 (8.13)
9.04 (9.15)
C9H11FO2
C9H11ClO2
C9H11ClO2
C9H11ClO2
C9H10Cl2O2
C11H16O2
C12H18O2
C11H14O3
Acetate of 1a
Propanoate of 1a
Butanoate of 1a
Hexanoate of 1a
Octanoate of 1a
Dodecanoate of 1a
Chloroacetate of 1a
Butanoate of 1b
Butanoate of 1c
Butanoate of 1d
Butanoate of 1e
Butanoate of 1f
Butanoate of 1g
Butanoate of 1h
C
12H16O3
C13H18O3
15H22O3
C
C17H26O3
C21H34O3
C11H13ClO3
C13H17FO3
C13H17ClO3
C13H17ClO3
C
13H17ClO3
C13H16Cl2O3
C15H22O3
C16H24O3
1
Table 6. Physical and H NMR data of 2-aryloxy-1-propanols 1
Compound
Bp/°C
n2D0
Rfa
IR (ATR)
wmax/cm−1
(OH)
1H NMR lH (CDCl3)
1a
1b
1c
1d
1e
1f
65–68 (0.25
mmHg)
64–71 (0.07
mmHg)
78–84 (0.04
mmHg)
96–102 (0.2
mmHg)
93–99 (0.03–0.04 1.5379
mmHg)
106–111 (0.07
mmHg)
1.5244
1.5012
1.5380
1.5403
0.38
0.38
0.42
0.39
0.37
0.40
0.41
0.41
3379
3411
3398
3416
3381
3360
3388
3385
1.27 (3H, d, J 6.3), 2.05 (1H, br s), 3.68–3.79 (2H, d of ABq, J 11.4,
6.3 and 3.9), 4.50 (1H, d of quint., J 6.3 and 3.9), 6.91–7.32 (5H, m)
1.24 (3H, d, J 6.3), 2.11 (1H, dd, J 5.4 and 5.1), 3.65–3.78 (2H, m),
4.40 (1H, d of quint., J 6.3 and 3.9), 6.84–7.01 (4H, m)
1.32 (3H, d, J 6.3), 2.37 (1H, br s), 3.76 (2H, d-like, J 5.1), 4.48 (1H, d
of quint., J 6.3 and 5.1), 6.89–7.38 (4H, m)
1.27 (3H, d, J 6.3), 2.07 (1H, t-like, J 6.0), 3.66–3.79 (2H, m), 4.48
(2H, d of quint., J 6.3 and 4.2), 6.79–7.22 (4H, m)
1.24 (3H, d, J 6.3), 2.20 (1H, br s), 3.66–3.76 (2H, d of ABq, J 11.7,
6.3 and 4.2), 4.43 (1H, d of quint., J 6.3 and 4.2), 6.82–7.26 (4H, m)
1.30 (3H, d, J 6.3), 2.28–2.32 (1H, m), 3.74–3.78 (2H, m), 4.45 (1H, d
of quint., J 6.3 and 5.4), 6.92–7.37 (3H, m)
1.18–1.26 (6H, m), 2.24 (1H, br s), 2.59 (2H, q, J 7.5), 3.64–3.77 (2H,
m), 4.44 (1H, d of quint., J 6.3 and 3.9), 6.84–7.12 (4H, m)
1.21–1.26 (9H, m), 2.15 (1H, br s), 2.86 (1H, sept., J 6.9), 3.65–3.76
(2H, d of ABq, J 11.7, 6.3 and 3.6), 4.45 (1H, d of quint., J 6.3 and
3.6), 6.84–7.16 (4H, m)
1.5505
1g
1h
69–80 (0.05–0.06 1.5159
mmHg)
64–75 (0.04–0.05 1.5119
mmHg)
a Solvent: benzene–EtOAc (4:1, v/v).
filtrate was washed successively with 1 M HCl (2×7
mL), water (7 mL), aq. NaHCO3 (1 M, 2×7 mL), and
brine (2×7 mL), and dried over Na2SO4. After evapora-
tion of the solvent in vacuo, the residual oil was
purified by preparative TLC on silica gel (Wakogel
B-5F) using ether–hexane (3:20, v/v) as an eluent to
give the butanoate of 1a as a colorless oil (180 mg,
61%). The butanoates of 1b–1h were likewise prepared
and purified by preparative TLC on silica gel to give
oils in 57–70% yield.
Other alkanoates of 1a were prepared by the reaction of
1a with the corresponding alkanoyl chloride (or ethyl
trifluoroacetate in the case of trifluoroacetylation) in
the presence of pyridine in the same manner as above
and purified by preparative TLC on silica gel to give
oils in 47–77% yield. The trifluoroacetate of 1a was
obtained as an oil through purification by Kugelrohr
distillation (bp 105°C/1.8 mmHg) in 60% yield. The
1
physical and H NMR data of the alkanoates of 1 thus
prepared are compiled in Table 7.

1600
T. Miyazawa et al. / Tetrahedron: Asymmetry 12 (2001) 1595–1602
1
Table 7. Physical and H NMR data of alkanoates of 1
Compound
n2D0
Rfa
IR (ATR)
1H NMR lH (CDCl3)
wmax/cm−1 (CꢀO)
b
Acetate of 1a
–
0.31
0.35
0.39
1732
1740
1738
1.33 (3H, d, J 6.3), 2.06 (3H, s), 4.14–4.29 (2H, d of ABq, J 11.4, 6.3 and 4.2),
4.61 (1H, d of quint., J 6.3 and 4.2), 6.91–7.31 (5H, m)
Propanoate of 1a 1.4904
Butanoate of 1a 1.4858
1.12 (3H, t, J 7.5), 1.34 (3H, d, J 6.3), 2.33 (2H, q, J 7.5), 4.14–4.31 (2H, d of
ABq, J 11.7, 6.3 and 4.5), 4.61 (1H, d of quint., J 6.3 and 4.5), 6.92–7.31 (5H, m)
0.93 (3H, t, J 7.2), 1.34 (3H, d, J 6.3), 1.64 (2H, sext., J 7.2), 2.29 (2H, t, J 7.2),
4.14–4.30 (2H, d of ABq, J 11.4, 6.3 and 4.5), 4.61 (1H, d of quint., J 6.3 and
4.5), 6.91–7.31 (5H, m)
Hexanoate of 1a 1.4832
Octanoate of 1a 1.4808
0.43
0.43
0.45
1739
1739
1740
0.87 (3H, t, J 6.6), 1.24–1.30 (4H, m), 1.33 (3H, d, J 6.3), 1.56–1.63 (2H, m), 2.30
(2H, t, J 7.5), 4.14–4.30 (2H, d of ABq, J 11.4, 6.3 and 4.5), 4.61 (1H, d of
quint., J 6.3 and 4.5), 6.91–7.31 (5H, m)
0.87 (3H, t, J 6.9), 1.21–1.31 (8H, m), 1.33 (3H, d, J 6.3), 1.55–1.64 (2H, m), 2.30
(2H, t, J 7.5), 4.13–4.30 (2H, d of ABq, J 11.7, 6.3 and 4.2), 4.61 (1H, d of
quint., J 6.3 and 4.2), 6.91–7.30 (5H, m)
0.88 (3H, t, J 6.6), 1.25–1.30 (16H, m), 1.33 (3H, d, J 6.3), 1.56–1.61 (2H, m),
2.30 (2H, t, J 7.5), 4.13–4.30 (2H, d of ABq, J 11.7, 6.3 and 4.5), 4.61 (1H, d of
quint., J 6.3 and 4.5), 6.91–7.30 (5H, m)
Dodecanoate of 1.4787
1a
Chloroacetate of 1.5126
0.28
0.41
0.37
1760
1788
1738
1.35 (3H, d, J 6.3), 4.05 (2H, s), 4.25–4.42 (2H, d of ABq, J 11.4, 6.6 and 4.2),
4.64 (1H, d of quint., J 6.6 and 4.2), 6.91–7.31 (5H, m)
1.38 (3H, d, J 6.3), 4.38–4.57 (2H, d of ABq, J 11.4, 6.3 and 3.9), 4.67 (1H, d of
quint., J 6.3 and 3.9), 6.89–7.33 (5H, m)
0.93 (3H, t, J 7.5), 1.32 (3H, d, J 6.3), 1.59 (2H, sext., J 7.5), 2.29 (2H, t, J 7.5),
4.12–4.28 (2H, d of ABq, J 11.7, 6.3 and 4.2), 4.50 (1H, d of quint., J 6.3 and
4.2), 6.84–7.01 (4H, m)
1a
Trifluoroacetate
of 1a
1.4562c
Butanoate of 1b 1.4731
Butanoate of 1c 1.5007
0.38
1737
0.93 (3H, t, J 7.5), 1.39 (3H, d, J 6.3), 1.63 (2H, sext., J 7.5), 2.29 (2H, t, J 7.5),
4.18–4.33 (2H, d of ABq, J 11.7, 6.3 and 4.5), 4.60 (1H, d of quint., J 6.3 and
4.5), 6.89–7.38 (4H, m)
Butanoate of 1d 1.5017
Butanoate of 1e 1.4978
0.40
0.38
1739
1737
0.93 (3H, t, J 7.5), 1.33 (3H, d, J 6.3), 1.64 (2H, sext., J 7.5), 2.29 (2H, t, J 7.5),
4.14–4.28 (2H, d of ABq, J 11.7, 6.3 and 4.2), 6.79–7.22 (4H, m)
0.93 (3H, t, J 7.5), 1.32 (3H, d, J 6.3), 1.63 (2H, sext., J 7.5), 2.29 (2H, t, J 7.5),
4.12–4.28 (2H, d of ABq, J 11.7, 6.3 and 4.2), 4.55 (1H, d of quint., J 6.3 and
4.2), 6.83–7.25 (4H, m)
Butanoate of 1f 1.5114
Butanoate of 1g 1.4864
Butanoate of 1h 1.4860
0.36
0.43
0.42
1739
1739
1739
0.93 (3H, t, J 7.5), 1.37 (3H, d, J 6.3), 1.63 (2H, sext., J 7.5), 2.29 (2H, t, J 7.5),
4.17–4.31 (2H, d of ABq, J 11.7, 6.3 and 4.2), 4.56 (1H, d of quint., J 6.3 and
4.2), 6.94 (1H, d, J 9.0), 7.17 (1H, dd, J 9.0 and 2.7), 7.37 (1H, d, J 2.7)
0.93 (3H, t, J 7.5), 1.21 (3H, t, J 7.5), 1.32 (3H, d, J 6.0), 1.64 (2H, sext., J 7.5),
2.29 (2H, t, J 7.5), 2.58 (2H, q, J 7.5), 4.12–4.29 (2H, d of ABq, J 11.7, 6.3 and
4.2), 4.56 (1H, d of quint., J 6.3 and 4.2), 6.83–7.13 (4H, m)
0.93 (3H, t, J 7.5), 1.22 (6H, d, J 7.2), 1.32 (3H, d, J 6.3), 1.63 (2H, sext., J 7.5),
2.29 (2H, t, J 7.5), 2.86 (1H, sept., J 7.2), 4.12–4.29 (2H, d of ABq, J 11.7, 6.3
and 4.2), 4.56 (1H, d of quint., J 6.3 and 4.2), 6.83–7.15 (4H, m)
a Solvent: hexane–EtOAc (9:1, v/v).
b Semisolid.
c At 17°C.
nation of the ee value,¶ while the corresponding alco-
hols were separated well on either of the columns by
4.3. HPLC analyses
choosing an appropriate proportion of hexane/propan-
2-ol for each compound. The void time (t0) was esti-
mated using 1,3,5-tri-tert-butylbenzene. The separation
of the enantiomers of 1a–1h is compiled in Table 8.
Transesterification reactions were monitored by chiral
HPLC on a Chiralcel OB column (4.6 mm id×250 mm)
or a Chiralpak AS column (4.6 mm id×250 mm)
(Daicel Chemical Industries) using hexane–propan-2-ol
as an eluent. The liquid chromatograph employed was
a Shimadzu LC-5A instrument, equipped with a Rheo-
dyne 7125 sample injector and a Shimadzu SPD-2A
variable wavelength UV monitor. A Shimadzu C-R1A
data processor was used for data acquisition and pro-
cessing. In general the enantiomers of alkanoates of
2-aryloxy-1-propanols were not separated on either
column satisfactorily enough for the accurate determi-
¶ The enantiomers of butanoates of 1c and 1f were separated better
than those of their parent alcohols: k% =0.77 and k% =1.18 for the
S
R
butanoate of 1c on Chiralcel OB using hexane–propan-2-ol (95:5,
v/v); k% =1.46 and k% =2.27 for the butanoate of 1f on Chiralcel OB
S
R
using hexane–propan-2-ol (99:1, v/v).

T. Miyazawa et al. / Tetrahedron: Asymmetry 12 (2001) 1595–1602
Table 8. HPLC separation of the enantiomers of 2-aryloxy-1-propanols 1a
1601
Columnb
Mobile phasec
k%
k%
he
d
d
Compound
S
R
1a
1b
1c
1d
1e
1f
A
A
B
A
B
B
A
A
95:5
95:5
95:5
99:1
95:5
99:1
299:1
299:1
1.74
1.73
1.41
4.89
1.69
4.19
6.74
5.16
2.68
3.15
1.99
5.64
2.27
4.82
8.80
6.44
1.54
1.82
1.41
1.15
1.34
1.15
1.31
1.25
1g
1h
a HPLC conditions: flow rate, 1.0 mL min−1; column temperature, 30°C; detection, UV at 254 nm.
b A, Chiralpak AS; B, Chiralcel OB.
c The proportion of hexane/propan-2-ol.
d Capacity factor: k%=(tR−t0)/t0, where t0=void time.
e Separation factor: h=k% /k% .
R
S
4.4. Preparation of enantiomerically enriched samples
of 2-aryloxy-1-propanols
vinyl butanoate (6 mL, 47.4 mmol) and then Pseu-
domonas sp. lipase (300 mg). The reaction mixture was
stirred at 25°C. The reaction was terminated after 8 h
(56% conversion) by removing the enzyme powder by
filtration. The enzyme was washed with ether. Evapora-
tion of the solvent in vacuo from the combined filtrate
and the washing afforded a pale yellow oil, from which
the products were isolated by column chromatography
on silica gel (Wakogel C-300) using ether–hexane (1:20,
v/v) as an eluent, to give initially the butanoate of (S)-1e
as a colorless oil (2.01 g, 48% yield). Further elution
afforded (R)-1e as a colorless oil (1.11 g, 36% yield);
[h]2D5=−35.1 (c 1.0, CHCl3); >99% e.e. by HPLC.
(S)- or (R)-Enriched 2-aryloxy-1-propanols were pre-
pared by reduction with borane–THF complex on a
small scale (ca.0.2 mmol) of the corresponding (S)- or
(R)-enriched 2-aryloxypropanoic acids, respectively,
which were obtained via the Aspergillus niger lipase
(Amano lipase A)-catalyzed transesterification of the
racemic vinyl esters with methanol [(S)-preference] or
the Candida rugosa lipase (Meito lipase MY or Amano
lipase AY)-catalyzed esterification of the racemic acids
with butanol [(R)-preference] in organic solvents.13 With
all the 2-aryloxy-1-propanols the (S)-enantiomer eluted
before the (R)-counterpart on both Chiralcel OB and
Chiralpak AS columns using hexane–propan-2-ol as an
eluent. In the case of (S)-1e reduction was conducted on
a semi-preparative scale as follows: (S)-2-(4-chlorophe-
noxy)propanoic acid (380 mg, 1.9 mmol; 83% e.e.) was
treated with BH3 in THF (1 M, 5 mL) in the same
manner as above. After a usual work-up, the crude
material was purified by preparative TLC using EtOAc–
benzene (1:4, v/v) to give a colorless oil (208 mg, 59%):
[h]2D5=+27.9 (c 1.0, CHCl3); 83% e.e. by HPLC.
Acknowledgements
The authors are thankful to Amano Pharmaceutical
Co., Meito Sangyo Co. and Asahi Kasei Co. for the
donation of lipases used in this study. This work was
supported in part by grants from the Ministry of Educa-
tion, Science, Sports and Culture, Japan (to T.M.) and
from the Hirao Taro Foundation of the Konan Univer-
sity Association for Academic Research.
4.5. General procedure for the lipase-catalyzed enan-
tioselective acylation of 2-aryloxy-1-propanols
References
A solution of the 2-aryloxy-1-propanol (0.3 mmol) and
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formed in some cases was conducted simultaneously by
HPLC analysis on the chiral columns mentioned above.
Aliquots (ca. 10 mL) of the reaction mixture were
withdrawn at frequent intervals, diluted with di-iso-pro-
pyl ether (100 mL), filtered through a PTFE membrane
filter, and then injected (1–5 mL) onto the column.
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