The effect of vinyl esters on the enantioselectivity of the lipase-catalysed transesterification of alcohols

Article abstract of DOI:10.1016/S0957-4166(01)00083-0

The enantioselectivity of the lipase from Pseudomonas cepacia (PCL) in the transesterification of 2-phenyl-1-propanol 1 was studied using a series of vinyl 3-arylpropanoates as acyl donors. The most enantioselective transesterification reaction of the alcohol was attained by using vinyl 3-(p-iodophenyl)- or 3-(p-trifluoromethylphenyl)propanoates, with enantiomer ratios, E, of 116 and 138, respectively. Vinyl 3-phenylpropanoate was also effective for the resolution of 1 mediated by lipases from P. fluorescens and porcine pancreas and for the PCL-catalysed transesterification of several 2-phenyl-1-alkanols. The enantiomeric resolution of 1 was practically carried out by the first enantioselective transesterification using PCL and vinyl 3-(p-iodophenyl)propanoate to afford (R)-1 and then the enantioselective hydrolysis of the resultant ester to afford (S)-1.

Full text of DOI:10.1016/S0957-4166(01)00083-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 585–596
The effect of vinyl esters on the enantioselectivity of the
lipase-catalysed transesterification of alcohols
Masashi Kawasaki,a,* Michimasa Goto,b Shigeki Kawabataa and Tadashi Kometanib
aDepartment of Liberal Arts and Sciences, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa,
Kosugi-Machi, Toyama 939-0398, Japan
bDepartment of Chemical and Biochemical Engineering, Toyama National College of Technology, 13 Hongo,
Toyama 939-8630, Japan
Received 27 December 2000; accepted 1 February 2001
Abstract—The enantioselectivity of the lipase from Pseudomonas cepacia (PCL) in the transesterification of 2-phenyl-1-propanol
1 was studied using a series of vinyl 3-arylpropanoates as acyl donors. The most enantioselective transesterification reaction of the
alcohol was attained by using vinyl 3-(p-iodophenyl)- or 3-(p-trifluoromethylphenyl)propanoates, with enantiomer ratios, E, of
116 and 138, respectively. Vinyl 3-phenylpropanoate was also effective for the resolution of 1 mediated by lipases from P.
fluorescens and porcine pancreas and for the PCL-catalysed transesterification of several 2-phenyl-1-alkanols. The enantiomeric
resolution of 1 was practically carried out by the first enantioselective transesterification using PCL and vinyl 3-(p-
iodophenyl)propanoate to afford (R)-1 and then the enantioselective hydrolysis of the resultant ester to afford (S)-1. © 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
Several studies have previously showed that moderately
enantioselective transesterification reactions of racemic
alcohols with vinyl acetate were improved by using
other vinyl esters which have a longer chain length in
the acyl moiety, such as vinyl propanoate and vinyl
butanoate.5,7–10 However, few examples report improve-
ment of very low selectivity11 (E<10) reactions by
changing only the chain length of the vinyl ester.8,12
Although some examples of special acyl donors having
a phenyl group in the acyl moiety have been reported,
the effects of the acyl donor structure have not previ-
ously been systematically investigated.6,13–15
Among the various methods for synthesising optically
active alcohols, the resolution of alcohol racemates by
lipase-catalysed transesterification in organic solvents is
widely used today because of its convenience.1
Although lipases can accept a wide range of alcohols as
their substrates, the enantioselectivity of the transester-
ification of a racemic alcohol is not always high. There-
fore, much effort has been devoted to increasing the
enantioselectivity. As such, various solvents have been
used in the reaction2 and the effect of additives,3
temperature4 and microwave irradiation5 on the reac-
tion have also been examined.
Recently, we reported a preliminary result for the enan-
tioselective transesterification of 2-phenyl-1-propanol 1,
which had never been efficiently resolved by lipase-
catalysed reactions with the lipase from Pseudomonas
cepacia (PCL) and vinyl v-phenylalkanoates.16
Although the E value with vinyl acetate was 5, the
value was improved to 31 with vinyl 3-phenyl-
propanoate. This is the first example that shows the
utility of vinyl esters having a bulky substituent for the
lipase-catalysed transesterification. In this paper, we
report the results obtained by using vinyl 3-
(aryl)propanoates bearing a variety of substituents on
the phenyl group, to increase the enantioselectivity
toward 1, the validity of these compounds for different
lipases, and their use in the resolution of other alcohols.
During the transesterification reaction, the lipase is
initially acylated by an acyl donor, such as a vinyl ester,
and the acylated lipase then reacts enantioselectively
with an alcohol.6 As the lipase-catalysed transesterifica-
tion proceeds through a ping–pong mechanism, we
wished to ascertain which acylated lipase exerts the
highest enantioselectivity;6 thus, we became interested
in the effect of structural changes in the acyl moiety of
the vinyl ester on the observed enantioselectivity.
* Corresponding author. E-mail: kawasaki@pu-toyama.ac.jp
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00083-0

586
M. Kawasaki et al. / Tetrahedron: Asymmetry 12 (2001) 585–596
Scheme 1. PCL-catalysed transesterification of 1 with vinyl 3-(substituted phenyl)propanoates.
2. Results and discussion
tion of 1 compared to vinyl acetate (VA). Furthermore,
all the para-substituted phenyl derivatives except 3f are
more efficient for the resolution compared to 3a, the
non-substituted phenyl derivatives. The rates of the
reactions† performed using the vinyl 3-arylpropanoates
except for 3j and 3o are lower than that with VA.
2.1. PCL-catalysed transesterification of 1 with a
variety of vinyl 3-(para-substituted phenyl)propanoates
While the PCL-catalysed transesterification with vinyl
3-phenylpropanoate had an E value of 32, the reaction
took place with higher enantioselectivity in the presence
of vinyl 3-(4-methylphenyl)propanoate (E=62).16
Therefore, we focused on the PCL-catalysed transester-
ification between 1 and a variety of vinyl 3-(para-substi-
tuted phenyl)propanoates in cyclohexane (Scheme 1).
Fourteen p-substituted vinyl 3-arylpropanoates were
compared with 3a as shown in Table 1.
The enantioselectivity of the lipase-catalysed transester-
ification of alcohols with carboxylic acids (or their vinyl
esters) irregularly varies with the chain lengths of the
acids.5–10,12 In our case, the variation of the chain
length of their substituents have little influence on the E
value although 3b–d are more effective acyl donors than
3a. The reaction rates reduced with lengthening
alkyl chain. The tert-butyl derivative 3e is an effective
acylating reagent among the vinyl 3-(p-alkylphenyl)-
propanoates. The E values with the p-alkoxyphenyl
3f–h and biphenyl derivatives 3i are approximately
The enantiomer preferentially esterified by PCL had the
(S)-configuration in all reactions, which was established
by comparing the HPLC retention time of the unre-
acted alcohol in the reaction mixture with that of an
authentic sample.
† The reaction rates were calculated from the conversion and reaction
time values. Therefore, the rates are average reaction rates, which
mean ‘approximate reaction rates’. All the reaction rates in this
paper are the ‘approximate reaction rates’.
The vinyl 3-phenylpropanoates 3a–o are more effective
acylating agents for the enantioselective transesterifica-
Table 1. PCL-catalysed transesterification of 1 with vinyl 3-(para-substituted phenyl)propanoates
(p-RC6H4CH2CH2CO2CHꢀCH2) in cyclohexanea
b
b
Acyl donor
R
Time (h)
Conv. (%)b
%
e.e.P ((S)-2)
%
e.e.S ((R)-1)
Eb
VAc
3a
3b
2.5
5
4
25
32
20
30
24
22
37
41
34
32
25
23
38
37
26
43
60
91
96
94
95
97
88
92
92
92
95
96
95
97
98
95
20
43
24
41
30
27
52
64
47
43
32
29
57
56
34
73
5
H
32
62
48
52
85
26
46
38
37
53
65
69
116
138
86
CH3
C2H5
n-C3H7
t-C4H9
CH3O
n-C6H13
n-C8H17
C6H5
F
Cl
Br
I
CF3
CN
3cd
3de
3ee
3fd
3g
4
4.5
24
3
19
5
25
1.5
3
5
9
3
3
O
O
3he
3id
3j
3k
3l
3m
3ne
3o
a Conditions: PCL (5 mg /mL), 1 (30 mM), acyl donor (30 mM), 10°C.
b Transesterification with an acyl donor was repeated three times and the median E value calculated in each reaction is shown in Table 1. For the
reactions with E under 80, the differences between the median E values and the maxima or minima were within 5. On the other hand, for the
reactions with E over 80, the differences between the median E values and the maxima or minima were within 10. Values of an e.e.P and an
e.e.S were measured three times, respectively, and the averages were used to calculate an E.
c VA, vinyl acetate.
d PCL (15 mg/mL).
e PCL (25 mg/mL).

M. Kawasaki et al. / Tetrahedron: Asymmetry 12 (2001) 585–596
587
equal to the E observed for 3a. Thus, the alkoxy and
phenyl substituents have little influence on the enantio-
selectivity of the reaction.
tion of 1. As shown in Table 2, all the vinyl esters are
more effective acylating agents for the enantioselective
transesterification of 1 compared to VA. The fluoro-sub-
stituted derivatives 3j, 3p, and 3q exhibited moderate
results. The E values for the o-iodo and m-iodo deriva-
tives 3r and 3s were much lower than the p-iodo deri-
vative 3m. In contrast, the E with 3r is the smallest among
the vinyl 3-arylpropanoates examined in this study.
Furthermore, the rate of the reaction performed with 3r
is much smaller than those of 3m and 3s. It is thought
that the acyl–enzyme intermediate from PCL and 3r,
which has a bulky group (iodine atom) on the o-position,
is too difficult to form. Even if the formation of the
intermediate occurs, it may be hard to react with 1.
In the case of the 3-(p-halogenated phenyl)propanoates,
although p-fluoro, p-chloro and p-bromo esters 3j–l are
more effective acyl donors than 3a, variation of their
substituents had little influence on the observed E values.
p-Iodo derivative 3m is an exceptionally efficient acylat-
ing agent. The other vinyl esters having electron-with-
drawing groups such as 3n and 3o with trifluoromethyl
and cyano groups also markedly increased the enantio-
selectivity. It appears that acyl donors containing elec-
tron-withdrawing groups are more efficient for the enan-
tioselective transesterification of 1 than those containing
electron-donating groups. Among these seven vinyl
esters, the p-iodo- and p-trifluoromethyl derivatives
exhibited more than a 100 E value of 116 and 138,
respectively. The E value with 3n is about 30 times larger
than that of VA. Although there are reports that poorly
selective (E<10) lipase-catalysed transesterifications were
improved when acyl donors other than vinyl acetate were
used,8,12 our results should be recorded as one of the most
successful studies.
2.3. Application of vinyl 3-(substituted phenyl)propanoates
in the transesterification of 1 by other lipases
We examined the vinyl 3-arylpropanoates as acyl donors
for lipases from Pseudomonas fluorecens (PFL), Candida
antarctica (CAL), C. Rugosa (CRL), and porcine pan-
creas (PPL). The vinyl 3-phenylpropanoate 3a and vinyl
3-(4-chlorophenyl)propanoate 3k were used as the acyl
donors. As shown in Table 3, both the enantioselectivity
of the PFL-catalysed transesterifications and that of PPL
were increased using the 3-arylpropanoates. Notably, the
E with 3k by PFL is about 24 times larger than that with
VA. CAL and CRL were influenced minimally by
changing the acylating agents, which shows that the
acylating agent does not always affect the enantioselec-
tivity of the lipase-catalysed transesterification.13
2.2. PCL-catalysed transesterification of 1 with vinyl
3-(ortho-substituted phenyl)propanoates or vinyl 3-(meta-
substituted phenyl)propanoates
We next tried 3-(ortho-substituted phenyl)- and 3-(meta-
substituted phenyl)propanoates for the transesterifica-
Table 2. PCL-catalysed transesterification of 1 with vinyl 3-(ortho-substituted phenyl)propanoates or vinyl 3-(meta-substi-
tuted phenyl)propanoates (o- or m-RC6H4CH2CH2CO2CHꢀCH2)a
Acyl donor
R
Time (h)
Conv. (%)
% e.e.P ((S)-2)
% e.e.S ((R)-1)
E
3p
3qb
3r
o-F
m-F
o-I
1.5
5
195
2
35
30
30
31
94
92
86
92
50
39
36
42
53
35
19
36
3s
m-I
a Conditions: PCL (25 mg/mL), 1 (30 mM), acyl donor (30 mM), 10°C.
b PCL (15 mg/mL).
Table 3. Transesterification of 1 with vinyl 3-arylpropanoates using various lipases in cyclohexanea
Lipase
PFL
Acyl donor
Time (h)
Conv. (%)
% e.e.P ((S)-2)
% e.e.S ((R)-1)
E
VA
3a
3k
VA
3a
3k
1.5
1.5
2
1
1.5
2
40
96
96
8
38.5
40
38
53
47
49
47
41
38
13
17
12
30
46
40
77
93
25
52
63
5
14
5
78
93
93
25
88
84
24
47
44
3
2
1
11
39
80
3
22
73
2
5
7
CAL
CRLb
PPLc
VA
3a
1.1
1.4
1.1
9
40
68
3k
VAd
3ad
3kd
a Conditions: lipase (5 mg/mL), 1 (30 mM), acyl donor (60 mM), 10°C.
b Lipase (50 mg/mL).
c Lipase (25 mg/mL).
d Acyl donor (30 mM).

588
M. Kawasaki et al. / Tetrahedron: Asymmetry 12 (2001) 585–596
2.4. Application of vinyl 3-(substituted phenyl)-
propanoates for transesterification of other alcohols
octan-2-ol 10, PCL favoured the (R)-enantiomer. An E
of 5 was obtained for the reaction with VA, while the
reaction with 3a had an E of 10. The reaction of 10 was
only slightly influenced by the acyl donor. These results
suggest that the optimal structure of the acyl donor
required for maximal enantioselectivity varies with the
alcohol.
We then investigated whether a combination of PCL
and vinyl 3-(substituted phenyl)propanoates effectively
resolved alcohols 4–8. We first examined the primary
alcohols 2-phenyl-1-alkanols 4–6, 3-chloro-2-phenyl-1-
propanol 7 and 2-methyl-1-hexanol 8. These results are
summarised in Table 4.
2.5. Preparative kinetic resolution of 1
All enantiomers preferentially esterified by PCL had
(S)-configuration, as established by HPLC, comparing
the retention time of the unreacted alcohol in the
reaction with those of the authentic samples prepared
by us (see Section 3). We observed that the change in
the acyl donor from VA to 3a induced an improvement
in the enantioselectivity for the transesterification of
4–7. Thus, it was concluded that 3a is an efficient
reagent for the PCL-catalysed transesterification of 2-
phenyl-1-alkanols. Replacing the phenyl group of 1
with an n-butyl group was unsuccessful, and 3a was
ineffective for the resolution of 8.
As a conclusion to the study we conducted the resolu-
tion of 1 on a preparative scale (Scheme 2). We first
carried out the PCL-catalysed asymmetric transesterifi-
cation of ( )-1 with 3m to obtain optically pure (R)-1
with >99% e.e. The product, ester (S)-11, was then
hydrolysed using PPL to obtain the optically active
(S)-1. Because we have succeeded in the highly enan-
tioselective hydrolysis (E=107) of 2-phenyl-1-propyl
3-phenylpropanoate,26 an analogue of 11, using PPL,
we employed the PPL-catalysed hydrolysis. Thus, ( )-1
(1.00 g) was first subjected to the PCL-catalysed trans-
esterification with 3m in cyclohexane at 30°C to give
(R)-1 (0.28 g, 28% with e.e. of >99%) and (S)-11 (1.34
g, 43% with e.e. of >84%). (S)-11 was then subjected to
PPL-catalysed hydrolysis in phosphate buffer (pH 7.0)
at 30°C to give (S)-1 (0.21 g, 21% with 97% e.e.).
During the transesterification of 3-phenyl-1-butanol 9
with VA, PCL showed an extremely low enantioselec-
tivity (E=2) with preference for the (S)-enantiomer.
Therefore, the vinyl 3-arylpropanoates 3a and 3k and
three
vinyl
v-phenylalkanoates
(C6H5(CH2)n−
Each enantiomer of a racemic alcohol may interact
with an acylated lipase to give different transition
states. The size of this activation energy difference
dictates the enantioselectivity of a given lipase.6 There-
fore, the acylated lipases, even if they are of the same
origin, will exert their inherent interaction with alco-
hols.6 It can also be postulated that the acyl group of
1CO2CHꢀCH2, n=4–6) were examined as acyl donors,
however, the E values were hardly changed by variation
of the acyl donors. There have been few reports on the
lipase-catalysed resolution of racemic alcohols in which
the stereogenic centre and the hydroxy function (the
site of enzymatic reaction) are separated by more than
two carbons.17–25 In the transesterification reaction of
Table 4. PCL-catalysed transesterification of primary alcohols with vinyl 3-arylpropanoatesa
Alcohol
Acyl donor
Time (h)
Conv. (%)
% e.e.P
% e.e.S
E
4
VA
3a
VA
3a
3.5
4
3
2
2
27
27
27
23
25
48
21
48
23
27
82
98
90
97
92
97
33
72
40
19
30
37
33
29
31
91
9
65
12
7
14
142
26
87
32
210
2
12
3
2
5b
6b
7b
8d
VA
3a
2
VAc
3a
1.5
1.5
0.5
2
VA
3a
a Conditions: PCL (25 mg/mL), alcohol (30 mM), acyl donor (60 mM), 10°C.
b Temperature: 30°C.
c Lipase (5 mg/mL).
d Lipase (5 mg/mL), acyl donor (30 mM).

M. Kawasaki et al. / Tetrahedron: Asymmetry 12 (2001) 585–596
589
Scheme 2. Preparative kinetic resolution of 1.
an acylated lipase is located in its alcohol-binding site,
where the steric and/or electronic interactions between
the acyl moiety and the alcohol can occur,6 thus caus-
ing variations in the active site environment.9 On the
basis of these assumptions, we considered two effects
(direct and indirect effects) of the acyl moieties of VA
and 3a on the enantioselectivity of PCL.16
Wako Chemicals and generally used without further
purification. H NMR spectra were recorded on a Jeol
1
JNM-LA 400 spectrometer for solutions in CDCl3 with
TMS as an internal standard and J values are given in
hertz (Hz). IR spectra were obtained using a Jasco
FT/IR-410 spectrometer. Optical rotations were mea-
sured with a Perkin–Elmer 241 polarimeter. Gas chro-
matograms were recorded on a Shimadzu GC-14B with
OV 101 bonded capillary column (Gaschro Industry),
17 m×0.25 mm or CP-Cyclodextrin-B-236-M-19 capil-
lary column (Chrompack), 25 m×0.25 mm. HPLC
analyses were carried out on a Hitachi L-6250 intelli-
gent pump with a Hitachi L-4000 UV detector using
CHIRALCEL OB-H (Daicel), 250×4.6 mm or CHI-
RALCEL OD-H (Daicel), 250×4.6 mm or CHIRAL-
CEL OJ (Daicel), 250×4.6 mm chiral columns.
When a series of vinyl 3-(substituted phenyl)propan-
oates were employed in the PCL-catalysed transesteri-
fication of 1, the enantioselectivities were increased, with
several exceptions, compared to the enantioselectivity
with 3a. The complicated factor(s) composed of steric
and/or electronic effects induced by the substituents of
the benzene ring may contribute to the variation in the
active site environment to increase the enantioselectivity
of the lipase. We are now trying to clarify the mecha-
nism of the enantioselectivity enhancement induced by
the acyl donors using the X-ray crystal structures of
covalent complexes of PCL27 with transition-state ana-
logues for the transesterification of 1 with 3a.
3.2. Lipase-catalysed transesterification of alcohols
In a typical run as in the transesterification of 1, 4–7, 9
and 10, PCL (10 mg) was placed in a vial to which was
added a cyclohexane solution (2 mL) containing the
alcohol (60 mmol) and the acyl donor (60 mmol). The
resulting suspension was then magnetically stirred at
10°C. The reaction was quenched by filtration and the
filtrate was concentrated under reduced pressure. The
residue was chromatographed on a silica gel column
using hexane–ethyl acetate as the eluent. An aliquot of
the combined fractions containing the unreacted alco-
hol was analysed by HPLC or GC to determine the e.e.
of the alcohol. The produced ester was hydrolysed (1 M
NaOH, MeOH) to the corresponding alcohol, the e.e.
of which was determined as mentioned above. The E
value and the conversion of the reaction were calcu-
lated from the e.e.s of the unreacted alcohol and the
produced ester.11
In conclusion, we have synthesised a variety of vinyl
3-arylpropanoates and demonstrated their validity for
the lipase-catalysed transesterification of 2-phenyl-1-
alkanols. Vinyl 3-arylpropanoates appear to be useful
in the optical resolution of 2-phenyl-1-alkanols. We are
currently investigating the development of other acyl
donors for effective enantiomeric resolution of other
alcohols.
3. Experimental
3.1. General
PCL, PFL and CRL were supplied by Amano Pharma-
ceutical. CAL and PPL were supplied by Novo Nordisk
and Sigma, respectively. All commercially available
reagent chemicals were obtained from Acros Organics,
Aldrich, Lancaster, Nacalai Tesque, Tokyo Kasei and
Conditions for the determination of the e.e.s of the
alcohols are as follows. 1: HPLC (Chiralcel OB-H),
hexane:2-propanol=30:1 (v/v); 4: GC (CP-Cyclodex-
trin-B-236-M-19), 99°C; 5: HPLC (Chiralcel OJ), hex-

590
M. Kawasaki et al. / Tetrahedron: Asymmetry 12 (2001) 585–596
ane:2-propanol=15:1 (v/v); 6: HPLC (Chiralcel OJ),
hexane:2-propanol=50:1 (v/v); 7: GC (CP-Cyclodex-
trin-B-236-M-19), 117°C; 9: HPLC (Chiralcel OD-H),
hexane:2-propanol=15:1 (v/v); 10: the e.e.s were deter-
mined after conversion to the corresponding acetate
ester with acetyl chloride and pyridine in benzene. GC
(CP-Cyclodextrin-B-236-M-19), 105°C.
anhydrous magnesium sulfate and removal of the sol-
vent, was used without further purification in the next
step (white solid, 8.90 g, 75%); H NMR: l 7.11 (4H, s,
1
ArH), 3.74 (1H, t, J=7.2, ArCH2CH
6
), 3.25 (2H, d,
J=7.3, ArCH2CH), 2.32 (3H, s, ArCH3
6
6 ).
A solution of crude 4-methylbenzylmalonic acid (6.90
g, 33.1 mmol) in xylene (50 mL) was stirred under
reflux for 5 h and cooled. After standing overnight in a
refrigerator, a white solid was collected on a Bu¨chner
funnel and washed with hexane to give 3-(4-
In the transesterification of 8, decane or heptadecane
was also added to the reaction mixture as an internal
standard for gas chromatography to measure the con-
version of the reaction. The e.e. of the unreacted alco-
hol was determined by GC (CP-Cyclodextrin-B-236-
M-19, 115°C) after oxidation (Jones reagent, acetone)
of the alcohol to the corresponding carboxylic acid.
The E value and the e.e. of the produced ester were
calculated from the conversion and the e.e. of the
unreacted alcohol.11
1
methylphenyl)propanoic acid (3.52 g, 65%); H NMR:
l 7.11 (4H, s, ArH), 2.93 (2H, t, J=7.8, ArCH2
6
CH2),
).
2.66 (2H, t, J=7.8, ArCH2CH2), 2.32 (3H, s, ArCH3
6
6
Vinylation of 3-(4-methylphenyl)propanoic acid was
carried out according to the procedure for the prepara-
tion of 3a. Chromatography (silica gel, hexane–ethyl
acetate 36:1 (v/v)) of the crude product provided 3b as
a colourless oil (65%); 1H NMR: l 7.28 (1H, dd,
3.3. Vinyl 3-phenylpropanoate 3a
J=6.4, J=13.9, CH
(1H, dd, J=1.7, J=13.9, CHꢀCH2
J=1.7, J=6.3, CHꢀCH2 (trans)), 2.95 (2H, t, J=7.7,
ArCH2CH2), 2.69 (2H, t, J=7.7, ArCH2CH2), 2.32
6
ꢀCH2), 7.10 (4H, s, ArH), 4.88
Vinyl ester 3a was prepared from 3-phenylpropanoic
acid (1.50 g, 10.0 mmol) and freshly distilled vinyl
acetate (90 mL, 970 mmol) in the presence of Pd(OAc)2
(0.32 g, 1.4 mmol) according to the procedure to vinyl-
ate hydroxycarboxylic acids.28 Chromatography (silica
gel, hexane–ethyl acetate 5:1 (v/v)) of the crude product
6
(cis)), 4.57 (1H, dd,
6
6
6
(3H, s, ArCH3); IR (neat): 1755 (wCꢀO), 1647 (wCꢀC
)
cm−1. Found: C, 75.62; H, 7.42. Calcd for C12H14O2: C,
75.76; H, 7.42%.
1
provided 3a as a colourless oil (1.00 g, 57%); H NMR:
l 7.32–7.20 (6H, m, ArH and CH
6
ꢀCH2), 4.88 (1H, dd,
(cis)), 4.57 (1H, dd, J=1.7,
(trans)), 2.99 (2H, t, J=7.8,
3.5. Vinyl 3-(4-ethylphenyl)propanoate 3c
J=1.7, J=13.9, CHꢀCH2
6
J=6.3, CHꢀCH2
6
In a three-necked flask, sodium (0.47 g, 20.4 mmol) was
added gradually to absolute ethanol (15 mL). The
solution was stirred at about 40°C, after which diethyl
malonate (3.36 g, 21.0 mmol) was added slowly via a
syringe. To the solution was added gradually 4-ethyl-
benzyl bromide (4.04 g, 20.3 mmol) through a dropping
funnel. The reaction mixture was refluxed for 5 h and
cooled to room temperature. As much ethanol as possi-
ble was evaporated in vacuo. The residue was treated
with water at 0°C and then extracted with ether. The
organic layer was washed with brine, and dried over
anhydrous sodium sulfate. After removal of the solvent,
the residue was distilled under reduced pressure (120–
210°C/1.0 mmHg) to give diethyl 4-ethylbenzyl-
ArCH6 2CH2), 2.72 (2H, t, J=7.7, ArCH2CH6 2); IR
(neat): 1754 (wCꢀO), 1646 (wCꢀC) cm−1. Found: C, 74.49;
H, 6.87. Calcd for C11H12O2: C, 74.97; H, 6.86%.
3.4. Vinyl 3-(4-methylphenyl)propanoate 3b
THF (210 mL) and sodium hydride (60%, 5.33 g, 133.3
mmol) were stirred under an inert gas atmosphere.
Diethyl malonate (16.00 g, 99.9 mmol) was added
slowly via a syringe. To the solution was added gradu-
ally 4-methylbenzyl chloride (16.86 g, 119.9 mmol) via a
syringe. The reaction mixture was stirred for 1 h at
room temperature under N2. The mixture was acidified
with HCl (2 M) and extracted three times with ethyl
acetate. The organic layer was washed with brine, dried
over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was chro-
matographed (silica gel, hexane–ethyl acetate 7:1 (v/v))
to give diethyl 4-methylbenzylmalonate as a colourless
1
malonate (2.03 g, 36%) as a colourless oil; H NMR: l
7.11 (4H, s, ArH), 4.16 (1H, q, J=7.3, CO2CH2
3.62 (1H, t, J=8.0, ArCH2CH), 3.18 (2H, d, J=7.8,
ArCH2CH), 2.60 (2H, q, J=5.7, ArCH2CH3), 1.22 (3H,
t, J=11.0, ArCH2CH3), 1.22 (3H, t, J=11.0,
CO2CH2CH3).
6 CH3),
6
6
6
6
1
6
oil (15.20 g, 58%); H NMR: l 7.09 (4H, s, ArH), 4.16
(4H, q, J=7.0, CO2CH2
ArCH2CH), 3.21 (2H, d, J=7.9, ArCH2
s, ArCH3), 1.23 (6H, t, J=7.2, CO2CH2CH3
6
CH3), 3.63 (1H, t, J=7.7,
CH), 2.13 (3H,
).
Diethyl 4-ethylbenzylmalonate was converted to vinyl
3-(4-ethylphenyl)propanoate 3c through three steps
described for the preparation of vinyl 3-(4-
methylphenyl)propanoate 3b; 4-ethylbenzylmalonic acid
6
6
6
To a solution of diethyl 4-methylbenzylmalonate (15.20
g, 57.5 mmol) in EtOH (150 mL) was added NaOH (2.5
M, 150 mL, 380 mmol). After stirring under reflux for
7 h, ethanol was evaporated under reduced pressure.
The residue was washed three times with ether. The
aqueous layer was acidified with HCl (2 M) and
extracted three times with ethyl acetate. Crude 4-
methylbenzylmalonic acid, isolated after drying over
1
as a white solid (crude, 84%); H NMR: l 7.14 (4H, s,
ArH), 3.75 (1H, t, J=7.2, ArCH2CH
J=7.6, ArCH2CH), 2.62 (2H, q, J=7.6, ArCH2
1.22 (3H, t, J=7.6, ArCH2CH3);
6 ), 3.25 (2H, d,
6
6
CH3),
6
3-(4-
1
ethylphenyl)propanoic acid (54%) as a white solid; H
NMR: l 7.14 (4H, s, ArH), 2.94 (2H, t, J=7.8,
ArCH6 2CH2CO2), 2.68 (2H, t, J=7.7, ArCH2CH6 2CO2),

M. Kawasaki et al. / Tetrahedron: Asymmetry 12 (2001) 585–596
591
2.62 (2H, q, J=7.6, ArCH2
ArCH2CH3); vinyl 3-(4-ethylphenyl)propanoate 3c
(94%) as a colourless oil; H NMR: l 7.28 (1H, dd,
J=6.4, J=13.9, CHꢀCH2), 7.13 (4H, s, ArH), 4.88
(1H, dd, J=1.6, J=14.0, CHꢀCH2 (cis)), 4.57 (1H, dd,
J=1.7, J=6.4, CHꢀCH2 (trans)), 2.95 (2H, t, J=7.8,
ArCH2CH2CO2), 2.70 (2H, t, J=7.8, ArCH2CH2CO2),
2.62 (2H, q, J=7.6, ArCH2CH3), 1.22 (3H, t, J=7.7,
ArCH2CH3
); IR (neat): 1756 (wCꢀO), 1647 (wCꢀC) cm−1.
6
CH3)), 1.22 (3H, t, J=7.6,
for
the
preparation
of
vinyl
3-(4-propyl-
6
phenyl)propanoate 3d; 3-(4-t-butylphenyl)propanoic
acid (83%) as a white powder; H NMR: l 7.32 (2H, d,
J=8.3, ArH (2, 6)), 7.15 (2H, d, J=8.1, ArH (3, 5)),
1
1
6
6
2.94 (2H, t, J=7.8, ArCH2
ArCH2CH2), 1.31 (9H, s, C(CH3)3); vinyl 3-(4-t-
butylphenyl)propanoate 3e (63%) as a colourless oil; H
NMR: l 7.31 (1H, dd, J=7.8, J=14.2, CHꢀCH2), 7.29
(2H, d, J=20.3, ArH (2, 6)), 7.15 (2H, d, J=8.3, ArH
(3, 5)), 4.88 (1H, dd, J=1.6, J=14.0, CHꢀCH2 (cis)),
4.58 (1H, dd, J=1.6, J=6.2, CHꢀCH2 (trans)), 2.96
(2H, t, J=7.8, ArCH2CH2), 2.71 (2H, t, J=7.9,
6 CH2), 2.68 (2H, t, J=7.8,
6
6
1
6
6
6
6
6
Found: C, 76.14; H, 7.99. Calcd for C13H16O2: C, 76.44;
H, 7.90%.
6
6
6
ArCH2CH6 2), 1.31 (9H, s, C(CH3)3); IR (neat): 1757
3.6. Vinyl 3-(4-propylphenyl)propanoate 3d
(wCꢀO), 1647 (wCꢀC) cm−1. Found: C, 77.34; H, 8.82.
Calcd for C15H20O2: C, 77.55; H, 8.68%.
A mixture of 4-propylbenzaldehyde diethyl acetal (4.45
g, 20.0 mmol), acetic acid (20 mL), and water (10 mL)
was stirred under reflux for 17 h. The mixture was
cooled to 0°C and cold NaOH (6 M, 50 mL) was
added. The mixture was extracted with ether. The
organic layer was washed with brine, then dried over
anhydrous sodium sulfate, and concentrated under
reduced pressure. The residue was distilled (150–195°C/
20 mmHg) to give 4-propylbenzaldehyde (2.68 g, 91%)
3.8. Vinyl 3-(4-methoxyphenyl)propanoate 3f
A mixture of 3-(4-hydroxyphenyl)propanoic acid (1.67
g, 10.0 mmol), aqueous NaOH (6 M, 4 mL 24 mmol),
iodomethane (1.56 g, 11.0 mmol) and methanol (40
mL) was stirred at 50°C for 10 h. After evapora-
tion, aqueous NaOH (1 M) was added to the resi-
due, and the aqueous layer washed with ether. The
aqueous layer was acidified with aqueous HCl (1 M) at
0°C. The white solid produced was filtered and recrys-
tallised from hexane to give 3-(4-methoxyphenyl)-
1
as a colourless oil; H NMR: l 9.97 (1H, s, CHO), 7.80
(2H, d, J=8.0, ArH (2, 6)), 7.34 (2H, d, J=8.3, ArH
(3, 5)), 2.67 (2H, t, J=7.7, ArCH
m, ArCH2CH2CH3), 0.96 (3H, t, J=7.3, ArCH2-
CH2CH3).
6 2CH2CH3), 1.68 (2H,
6
6
1
propanoic acid as a white powder (1.25 g, 70%); H
NMR: l 7.13 (2H, d, J=8.3, ArH (2, 6)), 6.84 (2H,
d, J=8.5, ArH (3, 5)), 3.79 (3H, s, OCH3), 2.91 (2H,
t, J=7.7, ArCH2CH2), 2.65 (2H, t, J=7.7, ArCH2-
CH2).
3-(4-Propylphenyl)propanoic acid was prepared from
the 4-propylbenzaldehyde (2.68 g, 18.1 mmol) and 2,2-
dimethyl-1,3-dioxane-4,6-dione (2.56 g, 17.8 mmol) in
triethylammonium formate (TEAF) with the composi-
tion of (Et3N)2·(HCO2H)5 (20 mL) according to the
method for the preparation of 3-arylpropanoic acids.29
Recrystallisation (2,2,4-trimethylpentane) of the crude
product provided 3-(4-propylphenyl)propanoic acid
Vinylation of the 3-(4-methoxyphenyl)propanoic acid
was carried out according to the procedure for the
preparation of 3a. Chromatography (silica gel, hexane–
ethyl acetate 5:1 (v/v)) of the crude product afforded 3f
1
(2.15 g, 63%) as a white powder; H NMR: l 7.11 (4H,
1
as a colourless oil (68%); H NMR: l 7.26 (1H, dd,
s, ArH), 2.94 (2H, t, J=7.8, ArCH2
t, J=7.8, ArCH2CH2CO2), 2.55 (2H, t, J=7.7,
ArCH2CH2CH3), 1.60 (2H, m, ArCH2CH2CH3), 0.93
(3H, t, J=7.3, ArCH2CH2CH3).
6 CH2CO2), 2.67 (2H,
J=5.8, J=14.5, CH
(2, 6)), 6.84 (2H, d, J=8.0, ArH (3, 5)), 4.88 (1H, dd,
J=1.4, J=14.3, CHꢀCH2 (cis)), 4.57 (1H, dd, J=1.6,
J=6.2, CHꢀCH2 (trans)), 3.79 (3H, s, OCH3), 2.93
(2H, t, J=7.8, ArCH2CH2), 2.68 (2H, t, J=7.7,
6 ꢀCH2), 7.13 (2H, d, J=8.8, ArH
6
6
6
6
6
6
6
Vinylation of the 3-(4-propylphenyl)propanoic acid was
carried out according to the procedure for the prepara-
tion of 3a. Chromatography (silica gel, hexane–ethyl
acetate 5:1 (v/v)) of the crude product provided 3d
ArCH2CH6 2); IR (neat): 1753 (wCꢀO), 1646 (wCꢀC), 1248
(was CꢁOꢁC), 1036 (ws CꢁOꢁC) cm−1. Found: C, 70.16; H,
7.09. Calcd for C12H14O3: C, 69.88; H, 6.84%.
1
(80%) as a colourless oil; H NMR: l 7.28 (1H, dd,
J=6.2, J=13.9, CH
(1H, dd, J=1.3, J=14.0, CHꢀCH2
J=1.5, J=6.1, CHꢀCH2 (trans)), 2.95 (2H, t, J=7.8,
ArCH2CH2CO2), 2.70 (2H, t, J=7.8, ArCH2CH2CO2),
2.55 (2H, t, J=7.6, ArCH2CH2CH3), 1.62 (2H, m,
6
ꢀCH2), 7.11 (4H, s, ArH), 4.88
6
(cis)), 4.57 (1H, dd,
3.9. Vinyl 3-(4-n-hexyloxyphenyl)propanoate 3g
6
6
6
Compound 3g was prepared from 1-bromohexane and
3-(4-hydroxyphenyl)propanoic acid as the starting
materials according to the procedure for the prepara-
tion of vinyl 3-(4-methoxyphenyl)propanoate 3f; 3-(4-n-
hexyloxyphenyl)propanoic acid as a white solid (71%);
1H NMR: l 7.12 (2H, d, J=8.6, ArH (2, 6)), 6.83 (2H,
d, J=8.8, ArH (3, 5)), 3.93 (2H, t, J=6.6,
6
ArCH2CH6 2CH3), 0.93 (3H, t, J=7.3, ArCH2CH2CH6 3);
IR (neat): 1756 (wCꢀO), 1647 (wCꢀC) cm−1. Found: C,
77.44; H, 8.47. Calcd for C14H18O2: C, 77.03; H, 8.31%.
3.7. Vinyl 3-(4-t-butylphenyl)propanoate 3e
ArOCH2
ArCH2CH2CO2), 2.65 (2H, t, J=7.6, ArCH2CH2
1.78–1.71 (2H, m, ArOCH2CH2(CH2)3CH3), 1.46–1.41
(2H, m, ArO(CH2)2CH2(CH2)2CH3), 1.35–1.33 (4H, m,
6
(CH2)4CH3),
2.90
(2H,
t,
J=7.8,
6 CO2),
6
Compound 3e was prepared from 4-tert-butylbenzalde-
hyde as the starting material according to the procedure
6
6

592
M. Kawasaki et al. / Tetrahedron: Asymmetry 12 (2001) 585–596
ArO(CH2)3CH2
ArO(CH2)5CH3); vinyl 3-(4-n-hexyloxyphenyl)prop-
anoate 3g as a colourless oil (70%); H NMR: l 7.27
(1H, dd, J=6.4, J=13.9, CHꢀCH2), 7.11 (2H, d, J=
8.8, ArH (2, 6)), 6.82 (2H, d, J=8.8, ArH (3, 5)), 4.87
(1H, dd, J=1.6, J=14.0, CHꢀCH2 (cis)), 4.56 (1H, dd,
J=1.5, J=6.3, CHꢀCH2 (trans)), 3.92 (2H, t, J=6.6,
ArOCH2(CH2)4CH3), 2.92 (2H, t, J=7.7,
ArCH2CH2CO2), 2.67 (2H, t, J=7.8, ArCH2CH2CO2),
1.80–1.72 (2H, m, ArOCH2CH2(CH2)3CH3), 1.48–1.41
(2H, m, ArO(CH2)2CH2(CH2)2CH3), 1.36–1.31 (4H, m,
ArO(CH2)3CH2CH2CH3), 0.90 (3H, t, J=7.1,
6
CH2
6
CH3), 0.90 (3H, t, J=7.0,
ing to the literature procedure.30 Chromatography (sil-
ica gel, hexane–ethyl acetate 5:1 (v/v)) of the crude
product followed by distillation (162–210°C/0.35
mmHg) provided 1-bromo-2-(4-biphenyl)ethane as a
6
1
6
1
white solid (2.10 g, 77%); H NMR: l 7.59–7.28 (9H,
6
m, ArH), 3.61 (2H, t, J=7.7, ArCH2CH2
6 ), 3.21 (2H, t,
6
J=7.6, ArCH2CH2).
6
6
6
6
In a three-necked flask was placed magnesium shavings
(0.25 g, 10.3 mmol). The shavings were covered with
6
6
about
1
mL of
a
solution of 1-bromo-2-(4-
6
6
biphenyl)ethane (2.08 g, 8.0 mmol) in anhydrous THF
(10 mL) under Ar. When the reaction started, the
remainder of the halide solution in THF was added.
The reaction mixture was warmed with mantle heater
for 1 h. After cooling to room temperature, the mixture
was poured on crushed dry ice. 6 M HCl was added to
the mixture at 0°C after the dry ice was evaporated.
The mixture was extracted with ether and the organic
extract washed twice with 1 M NaOH. The aqueous
layer was acidified with 6 M HCl and left to crystallise
at 0°C. After filtration, the solid collected was recrys-
tallised from benzene–hexane to give 3-(4-
biphenyl)propanoic acid as a white solid (0.59 g, 33%);
1H NMR: l 7.59–7.28 (9H, m, ArH), 3.02 (2H, t,
ArO(CH2)5CH6 3); IR (neat): 1756 (wCꢀO), 1647 (wCꢀC),
1245 (was CꢁOꢁC), 1032 (ws CꢁOꢁC) cm−1. Found: C, 73.58;
H, 8.73. Calcd for C17H24O3: C, 73.88; H, 8.75%.
3.10. Vinyl 3-(4-n-octyloxyphenyl)propanoate 3h
Compound 3h was prepared from 1-bromooctane and
3-(4-hydroxyphenyl)propanoic acid according to the
procedure for the preparation of vinyl 3-(4-
methoxyphenyl)propanoate 3f; 3-(4-n-octyloxyphenyl)-
1
propanoic acid (65%) as a white powder; H NMR: l
7.11 (2H, d, J=8.3, ArH (2, 6)), 6.83 (2H, d, J=8.5,
ArH (3, 5)), 3.92 (2H, t, J=6.6, ArOCH2
2.90 (2H, t, J=7.7, ArCH2CH2CO2), 2.65 (2H, t, J=
7.7, ArCH2CH2CO2), 1.80–1.73 (2H, m, ArOCH2-
CH2(CH2)5CH3), 1.58–1.28 (10H, m, ArO(CH2)2-
(CH2)5CH3), 0.88 (3H, t, J=7.0, ArO(CH2)7CH3); vinyl
6 (CH2)6CH3),
J=7.8, ArCH6 2CH2), 2.73 (2H, t, J=7.8, ArCH2CH6 2).
6
6
Vinylation of the 3-(4-biphenyl)propanoic acid was car-
ried out according to the procedure for the preparation
of 3a. Chromatography (silica gel, hexane–ethyl acetate
5:1 (v/v)) of the crude product provided 3i as a colour-
less oil (70%); 1H NMR: l 7.59–7.28 (10H, m, ArH and
6
6
6
3-(4-n-octyloxyphenyl)propanoate 3h as a colourless oil
(78%); 1H NMR: l 7.27 (1H, dd, J=6.3, J=12.0,
CH
J=7.6, ArH (3, 5)), 4.88 (1H, dd, J=1.6, J=14.0,
CHꢀCH2 (cis)), 4.57 (1H, dd, J=1.7, J=6.3, CHꢀCH2
(trans)), 3.92 (2H, t, J=6.1, ArOCH2(CH2)6CH3), 2.92
(2H, t, J=7.7, ArCH2CH2CO2), 2.68 (2H, t, J=7.7,
ArCH2CH2CO2), 1.80–1.73 (2H, m, ArOCH2CH2
(CH2)5CH3), 1.48–1.41 (2H, m, ArO(CH2)2CH2
(CH2)4CH3), 1.32–1.28 (8H, m, ArO(CH2)3(CH2 4
0.88 (3H, t, J=6.3, ArO(CH2)7CH3); IR (neat): 1758
6 ꢀCH2), 7.11 (2H, d, J=8.5, ArH (2, 6)), 6.82 (2H, d,
CH
(cis)), 4.57 (1H, dd, J=1.6, J=6.2, CHꢀCH2
3.02 (2H, t, J=7.7, ArCH2CH2), 2.75 (2H, t, J=7.7,
ArCH2CH2
); IR (neat): 1753 (wCꢀO), 1646 (wCꢀC) cm−1.
6
ꢀCH2), 4.89 (1H, dd, J=1.6, J=14.0, CHꢀCH2
6
6
(trans)),
6
6
6
6
6
6
Found: C, 80.96; H, 6.44. Calcd for C17H16O2: C, 80.92;
H, 6.39%.
6
6
-
-
6
6
) CH3),
6
3.12. Vinyl 3-(4-fluorophenyl)propanoate 3j
(wCꢀO), 1647 (wCꢀC), 1246 (was CꢁOꢁC), 1032 (ws
)
CꢁOꢁC
cm−1. Found: C, 74.67; H, 9.43. Calcd for C19H28O3: C,
74.96; H, 9.27%.
Prepared from 4-fluorophenylacetic acid according to
the procedure for the preparation of vinyl 3-(4-
biphenyl)propanoate 3i; 2-(4-fluorophenyl)ethanol was
isolated as a colourless oil (86%); 1H NMR: l 7.21–7.17
(2H, m, ArH (3, 5)), 7.00 (2H, t, J=8.5, ArH (2, 5),
3.11. Vinyl 3-(4-biphenyl)propanoate 3i
To a solution of 4-biphenylacetic acid (3.20 g, 15.1
mmol) in dry THF (35 mL) at 0°C was slowly added
LiAlH4 (0.46 g, 12 mmol). After stirring at room tem-
perature for 5 h, the mixture was quenched at 0°C with
HCl (3 M, 30 mL). The resulting mixture was extracted
with ether. The organic phase was washed with 1 M
sodium hydroxide solution, saturated sodium chloride
solution and dried over sodium sulfate, followed by
recrystallisation from benzene–hexane to give 2-(4-
biphenyl)ethanol as a white solid (2.10 g, 71%); 1H
NMR: l 7.59–7.31 (9H, m, ArH), 3.92 (2H, m,
3.84 (2H, m, ArCH2CH2
6 ), 2.84 (2H, t, J=6.6,
ArCH2CH2); 1-bromo-2-(4-fluorophenyl)ethane (96%)
6
1
was isolated as a colourless oil; H NMR: l 7.19–7.16
(2H, m, ArH (3, 5)), 7.01 (2H, t, J=8.7, ArH (2, 6)),
3.54 (2H, t, J=7.4, ArCH2CH6 2), 3.14 (2H, t, J=7.1,
ArCH6 2CH2); 3-(4-fluorophenyl)propanoic acid (crude,
28%) was obtained as a white solid; 1H NMR: l
7.19–7.15 (2H, m, ArH (3, 5)), 6.98 (2H, t, J=8.7, ArH
(2, 6)), 2.93 (2H, t, J=7.7, ArCH2
6
CH2), 2.66 (2H, t,
J=7.7, ArCH2CH2); vinyl
6
3-(4-fluorophenyl)-
1
propanoate 3j (82%) was isolated as a colourless oil; H
ArCH2CH2
6
), 2.93 (2H, t, J=6.5, ArCH2
6
CH2).
NMR: l 7.27 (1H, dd, J=6.3, J=14.2, CH
7.18–7.15 (2H, m, ArH (3, 5)), 6.98 (2H, t, J=8.8, ArH
(2, 6)), 4.88 (1H, dd, J=1.6, J=14.0, CHꢀCH2 (cis)),
4.58 (1H, dd, J=1.7, J=6.3, CHꢀCH2 (trans)), 2.96
(2H, t, J=7.7, ArCH2CH2), 2.69 (2H, t, J=7.7,
6 ꢀCH2),
Bromination of the 2-(4-biphenyl)ethanol (2.08 g, 10.5
mmol) with CBr4 (3.92 g, 11.8 mmol) and Ph3P (3.03 g,
11.6 mmol) in CH2Cl2 (30 mL) was carried out accord-
6
6
6

M. Kawasaki et al. / Tetrahedron: Asymmetry 12 (2001) 585–596
593
ArCH2CH2
6
); IR (neat): 1754 (wCꢀO), 1647 (wCꢀC), 1148
dihydrate (0.98 g, 4.3 mmol), and iodine (2.03 g, 8.0
mmol) according to the method for the iodination of
aromatic compounds.31 Recrystallisation (heptane) of
the crude product provided 3-(4-iodophenyl)propanoic
(wCꢁF) cm−1. Found: C, 67.97; H, 5.94. Calcd for
C11H11FO2: C, 68.03; H, 5.71%.
1
3.13. Vinyl 3-(4-chlorophenyl)propanoate 3k
acid (2.41 g, 44%) as a white powder; H NMR: l 7.62
(2H, d, J=8.3, ArH (3, 5)), 6.97 (2H, d, J=8.1, ArH (2,
Prepared from 4-chlorobenzyl bromide according to the
procedure for the preparation of vinyl 3-(4-
ethylphenyl)propanoate 3c; diethyl 4-chlorobenzyl-
6)), 2.91 (2H, t, J=7.7, ArCH
6 2CH2), 2.66 (2H, t, J=7.6,
ArCH2CH2).
6
1
malonate (35%) was obtained as a colourless oil; H
Vinylation of the 3-(4-iodophenyl)propanoic acid was
carried out according to the procedure for the prepara-
tion of 3a. Chromatography (silica gel, hexane–ethyl
acetate 5:1 (v/v)) of the crude product provided 3m
(53%) as a colourless oil; 1H NMR: l 7.61 (2H, d,
J=8.3, ArH (3, 5)), 7.26 (1H, dd, J=6.3, J=13.9,
NMR: l 7.25 (2H, d, J=9.6, ArH (3, 5)), 7.14 (2H, d,
J=8.3, ArH (2, 6)), 4.20–4.12 (4H, m, CO2CH2
3.60 (1H, t, J=7.8, ArCH2CH), 3.18 (2H, d, J=7.8,
ArCH2CH), 1.22 (6H, t, J=7.2, CO2CH2CH3); 4-
6 CH3),
6
6
6
chlorobenzylmalonic acid (crude, 96%) was obtained as
1
a white solid; H NMR: l 7.27 (2H, d, J=6.1, ArH (3,
CH
dd, J=1.7, J=13.9, CHꢀCH2
J=1.7, J=6.4, CHꢀCH2 (trans)), 2.92 (2H, t, J=7.7,
6
ꢀCH2), 6.96 (2H, d, J=8.0, ArH (2, 6)), 4.88 (1H,
5)), 7.17 (2H, d, J=8.6, ArH (2, 6)), 3.71 (1H, t, J=7.3,
6
(cis)), 4.58 (1H, dd,
ArCH2CH6 ), 3.26 (2H, d, J=7.3, ArCH6 2CH); 3-(4-
6
1
chlorophenyl)propanoic acid as a white solid (62%); H
ArCH6 2CH2), 2.68 (2H, t, J=7.7, ArCH2CH6 2); IR
(neat): 1753 (wCꢀO), 1645 (wCꢀC) cm−1. Found: C, 43.69;
NMR: l 7.27 (2H, d, J=5.4, ArH (3, 5)), 7.15 (2H, t,
J=8.1, ArH (2, 6)), 2.93 (2H, t, J=7.6, ArCH2
6 CH2),
H, 3.68. Calcd for C11H11IO2: C, 43.73%; H, 3.67%.
2.67 (2H, t, J=7.7, ArCH2CH2); vinyl 3-(4-
6
chlorophenyl)propanoate 3k (66%) as a colourless oil;
3.16. Vinyl 3-(4-trifluoromethylphenyl)propanoate (3n)
1H NMR: l 7.29–7.24 (3H, m, ArH (3, 5) and
CH
dd, J=1.6, J=14.0, CHꢀCH2
J=1.7, J=6.4, CHꢀCH2 (trans)), 2.95 (2H, t, J=7.7,
6
ꢀCH2), 7.14 (2H, d, J=8.3, ArH (2, 6)), 4.88 (1H,
Vinylation of 3-(4-trifluoromethylphenyl)propanoic acid
was carried out according to the procedure for the
preparation of 3a. Chromatography (silica gel, hexane–
ethyl acetate 5:1 (v/v)) of the crude product provided 3n
as a colourless oil (82%); 1H NMR: l 7.56 (2H, d,
J=8.1, ArH (3, 5)), 7.33 (2H, d, J=8.1, ArH (2, 6)),
6
(cis)), 4.58 (1H, dd,
6
ArCH6 2CH2), 2.69 (2H, t, J=7.7, ArCH2CH6 2); IR
(neat): 1754 (wCꢀO), 1647 (wCꢀC), 1092 (wCꢁCl) cm−1.
Found: C, 62.98; H, 5.16. Calcd for C11H11ClO2: C,
62.72; H, 5.26%.
7.27 (1H, dd, J=6.3, J=13.9, CH
J=1.7, J=14.2, CHꢀCH2 (cis)), 4.59 (1H, dd, J=1.7,
J=6.4, CHꢀCH2 (trans)), 3.05 (2H, t, J=7.7,
ArCH2
6 ꢀCH2), 4.89 (1H, dd,
6
3.14. Vinyl 3-(4-bromophenyl)propanoate 3l
6
6
CH2), 2.74 (2H, t, J=7.6, ArCH2CH6 2); IR
Compound 3l was prepared from 4-bromobenzyl bro-
mide according to the procedure for the preparation of
vinyl 3-(4-ethylphenyl)propanoate 3c; diethyl 4-bro-
mobenzylmalonate (44%) was isolated as a colourless
(neat): 1756 (wCꢀO), 1648 (wCꢀC), 1326 (wCꢁF) cm−1.
Found: C, 59.24; H, 4.73. Calcd for C12H11F3O2: C,
59.02; H, 4.54%.
1
oil; H NMR: l 7.40 (2H, d, J=7.8, ArH (3, 5)), 7.09
3.17. Vinyl 3-(4-cyanophenyl)propanoate 3o
(2H, d, J=8.3, ArH (2, 6)), 4.24–4.09 (4H, m,
CO2CH2
(2H, d, J=7.8, ArCH2
6
CH3), 3.60 (1H, t, J=7.8, ArCH2CH
6 ), 3.16
Compound 3o was prepared from 4-cyanobenzaldehyde
as the starting material according to the procedure for
the preparation of vinyl 3-(4-propylphenyl)propanoate
3d; the product 3-(4-cyanophenyl)propanoic acid was
6
CH), 1.22 (6H, t, J=7.2,
CO2CH2CH6 3); 4-bromobenzylmalonic acid (93%) was
isolated as a white solid; 1H NMR: l 7.45 (2H, d,
J=6.6, ArH (3, 5)), 7.17 (2H, d, J=8.3, ArH (2, 6)),
1
obtained as a white powder (53%); H NMR: l 7.60
3.63 (1H, t, J=7.8, ArCH2CH
6 ), 3.09 (2H, d, J=7.8,
(2H, d, J=7.3, ArH (3, 5)), 7.33 (2H, d, J=7.3, ArH (2,
ArCH2CH); 3-(4-bromophenyl)propanoic acid (67%)
6
6)), 3.02 (2H, t, J=7.4, ArCH6 2CH2), 2.71 (2H, t, J=7.1,
1
was isolated as a white solid; H NMR: l 7.42 (2H, d,
J=7.8, ArH (3, 5)), 7.09 (2H, d, J=8.3, ArH (2, 6)),
ArCH2CH6 2); Vinyl 3-(4-cyanophenyl)propanoate 3o
(83%) as a colourless oil; 1H NMR: l 7.60 (2H, d,
J=8.0, ArH (3, 5)), 7.33 (2H, d, J=8.0, ArH (2, 6)),
2.92 (2H, t, J=7.6, ArCH2
ArCH2CH2); vinyl 3-(4-bromophenyl)propanoate (50%)
was isolated as a colourless oil; H NMR: l 7.41 (2H,
d, J=8.3, ArH (3, 5)), 7.25 (1H, dd, J=6.0, J=19.9,
6 CH2), 2.67 (2H, t, J=7.7,
6
7.25 (1H, dd, J=6.4, J=13.9, CH
J=1.7, J=13.9, CHꢀCH2 (cis)), 4.60 (1H, dd, J=1.7,
J=6.4, CHꢀCH2 (trans)), 3.05 (2H, t, J=7.4,
ArCH2
6 ꢀCH2), 4.89 (1H, dd,
1
6
6
CH
dd, J=1.6, J=14.0, CHꢀCH2
J=1.7, J=6.3, CHꢀCH2 (trans)), 2.93 (2H, t, J=7.6,
6
ꢀCH2), 7.08 (2H, d, J=8.1, ArH (2, 6)), 4.87 (1H,
6
CH2), 2.74 (2H, t, J=7.4, ArCH2CH6 2); IR
6
(cis)), 4.57 (1H, dd,
(neat): 2228 (wCꢀN), 1753 (wCꢀO), 1646 (wCꢀC) cm−1.
Found: C, 71.77; H, 5.54; N, 6.91. Calcd for
C12H11NO2: C, 71.62; H, 5.51; N, 6.96%.
6
ArCH6 2CH2), 2.69 (2H, t, J=7.7, ArCH2CH6 2); IR
(neat): 1754 (wCꢀO), 1646 (wCꢀC) cm−1. Found: C, 51.91;
H, 4.34. Calcd for C11H11BrO2: C, 51.79; H, 4.35%.
3.18. Vinyl 3-(2-fluorophenyl)propanoate 3p
3.15. Vinyl 3-(4-iodophenyl)propanoate 3m
Compound 3p was prepared from 2-fluorophenylacetic
acid as the starting material according to the procedure
for the preparation of vinyl 3-(4-biphenyl)propanoate
3-(4-Iodophenyl)propanoic acid was prepared from 3-
phenylpropanoic acid (3.00 g, 20.0 mmol), periodic acid

594
M. Kawasaki et al. / Tetrahedron: Asymmetry 12 (2001) 585–596
3i; 2-(2-fluorophenyl)ethanol (88%) was isolated as a
for the preparation of vinyl 3-(4-propylphenyl)-
1
colourless oil; H NMR: l 7.29–7.10 (2H, m, ArH (3,
propanoate 3d; 3-(2-iodophenyl)propanoic acid (60%)
1
5)), 7.10–7.01 (2H, m, ArH (4, 6)), 3.87 (2H, t, J=6.6,
was isolated as a white powder; H NMR: l 7.83 (1H,
ArCH2CH2
6
), 2.93 (2H, t, J=6.7, ArCH2
6
CH2); 1-
d, J=8.3, ArH (3)), 7.31–7.25 (2H, m, ArH (4, 5)),
6.94–6.90 (1H, m, ArH (6)), 3.06 (2H, t, J=7.9,
bromo-2-(2-fluorophenyl)ethane (58%) was isolated as a
colourless oil; H NMR: l 7.29–7.21 (2H, m, ArH (3,
5)), 7.12–7.02 (2H, m, ArH (4, 6)), 3.58 (2H, t, J=7.6,
1
ArCH6 2CH2), 2.69 (2H, t, J=7.9, ArCH2CH6 2); vinyl
3-(2-iodophenyl)propanoate 3r was isolated as a colour-
ArCH2CH6 2), 3.21 (2H, t, J=7.4, ArCH6 2CH2); 3-(2-
less oil (82%); 1H NMR: l 7.83 (1H, d, J=7.8,
fluorophenyl)propanoic acid (50%) was isolated as a
ArH(3)), 7.32–7.24 (3H, m, ArH (4, 5) and CH
6.94–6.90 (1H, m, ArH (6)), 4.90 (1H, dd, J=1.6,
J=13.8, CHꢀCH2 (cis)), 4.59 (1H, dd, J=1.7, J=6.3,
CHꢀCH2 (trans)), 3.09 (2H, t, J=7.8, ArCH2CH2),
6 ꢀCH2),
1
colourless oil; H NMR: l 7.30–7.18 (2H, m, ArH (3,
5)), 7.09–7.00 (2H, m, ArH (4, 6)), 3.00 (2H, t, J=7.7,
6
ArCH2
6
CH2), 2.70 (2H, t, J=7.7, ArCH2CH2
6
); vinyl
6
6
3-(2-fluorophenyl)propanoate 3p (83%) as a colourless
2.72 (2H, t, J=7.8, ArCH2CH6 2); IR (neat): 1753 (wCꢀO),
oil; 1H NMR: l 7.30–7.18 (3H, m, ArH (3, 5) and
1646 (wCꢀC) cm−1. Found: C, 43.97; H, 3.63. Calcd for
CH
J=1.7, J=13.9, CHꢀCH2
J=6.3, CHꢀCH2 (trans)), 3.01 (2H, t, J=7.7,
ArCH2
6
ꢀCH2), 7.08–7.00 (2H, m, ArH (4, 6)), 4.88 (1H, dd,
C11H11IO2: C, 43.73; H, 3.67.
6
(cis)), 4.58 (1H, dd, J=1.7,
6
6
CH2), 2.73 (2H, t, J=7.8, ArCH2CH2
6
); IR
3.21. Vinyl 3-(3-iodophenyl)propanoate 3s
(neat): 1755 (wCꢀO), 1647 (wCꢀC), 1149 (wCꢁF) cm−1.
Found: C, 68.18; H, 5.74. Calcd for C11H11FO2: C,
68.03; H, 5.71.
This compound was prepared from 3-iodobenzyl alco-
hol according to the procedure for the preparation of
vinyl 3-(2-iodophenyl)propanoate 3r; 3-iodobenzalde-
1
3.19. Vinyl 3-(3-fluorophenyl)propanoate 3q
hyde (91%) was isolated as a colourless oil; H NMR: l
9.93 (1H, s, CHO), 8.21 (1H, s, ArH (2)), 7.96 (1H, d,
J=7.8, ArH (6)), 7.85 (1H, d, J=7.8, ArH (4)), 7.29
(1H, t, J=7.8, ArH (5)); 3-(3-iodophenyl)propanoic
This compound was prepared from 3-fluoropheny-
lacetic acid according to the procedure for the prepara-
1
tion
of
vinyl
3-(4-biphenyl)propanoate
3i;
acid (65%) was isolated as a white solid; H NMR: l
2-(3-fluorophenyl)ethanol was isolated as a colourless
oil (84%); 1H NMR: l 7.30–7.25 (1H, m, ArH (4)),
7.02–6.91 (3H, m, ArH (2, 5, 6)), 3.87 (2H, t, J=6.3,
7.58–7.55 (2H, m, ArH (2, 4)), 7.18 (1H, d, J=7.6, ArH
(6)), 7.03 (1H, t, J=7.7, ArH (5)), 2.91 (2H, t, J=7.7,
ArCH6 2CH2), 2.67 (2H, t, J=7.8, ArCH2CH6 2); vinyl
ArCH2CH2
6
), 2.87 (2H, t, J=6.6, ArCH2
6
CH2); 1-
3-(3-iodophenyl)propanoate 3s was isolated as a colour-
1
bromo-2-(3-fluorophenyl)ethane was isolated as
a
less oil (77%); H NMR: l 7.58–7.55 (2H, m, ArH (2,
colourless oil (66%); 1H NMR: l 7.31–7.28 (1H, m,
4)), 7.27 (1H, dd, J=6.3, J=13.9, CH
d, J=7.6, ArH (6)), 7.03 (1H, t, J=7.8, ArH (5)), 4.89
(1H, dd, J=1.7, J=13.9, CHꢀCH2 (cis)), 4.59 (1H, dd,
J=1.7, J=6.3, CHꢀCH2 (trans)), 2.93 (2H, t, J=7.7,
6 ꢀCH2), 7.18 (1H,
ArH (4)), 7.00–6.92 (3H, m, ArH (2, 5, 6)), 3.57 (2H, t,
J=7.4, ArCH2CH2
6
), 3.17 (2H, t, J=7.4, ArCH2
6
CH2);
6
3-(3-fluorophenyl)propanoic acid was obtained as a
colourless oil (55%); 1H NMR: l 7.30–7.23 (1H, m,
ArH (4)), 7.00–6.89 (3H, m, ArH (2, 5, 6)), 2.96 (2H, t,
6
ArCH6 2CH2), 2.70 (2H, t, J=7.8, ArCH2CH6 2); IR
(neat): 1754 (wCꢀO), 1646 (wCꢀC) cm−1. Found: C, 43.90;
J=7.7, ArCH2
vinyl 3-(3-fluorophenyl)propanoate (3q) was isolated as
a colourless oil (71%); H NMR: l 7.30–7.23 (2H, m,
6
CH2), 2.69 (2H, t, J=7.7, ArCH2CH2
6
);
H, 3.66. Calcd for C11H11IO2: C, 43.73; H, 3.67%.
1
ArH (4) and CH
6)), 4.89 (1H, dd, J=1.7, J=13.9, CHꢀCH2
(1H, dd, J=1.7, J=6.4, CHꢀCH2 (trans)), 2.98 (2H, t,
);
6
ꢀCH2), 7.00–6.89 (3H, m, ArH (2, 5,
3.22. 3-Chloro-2-phenyl-1-propanol 7
6
(cis)), 4.58
6
Monochlorination of 2-phenyl-1,3-propanediol (3.49 g,
22.9 mmol) with CCl4 (20 mL) and Ph3P (3.05 g, 11.6
mmol) in CH2Cl2 (60 mmol) was carried out as
described for the preparation of 1-bromo-2-(4-
biphenyl)ethane. Chromatography (silica gel, hexane–
ethyl acetate 5:1 (v/v)) of the crude product followed by
distillation (122–164°C/0.7 mmHg) gave 7 as a colour-
J=7.6, ArCH6 2CH2), 2.71 (2H, t, J=7.7, ArCH2CH6 2
IR (neat): 1755 (wCꢀO), 1647 (wCꢀC), 1150 (wCꢁF) cm−1.
Found: C, 67.91; H, 5.77. Calcd for C11H11FO2: C,
68.03; H, 5.71%.
3.20. Vinyl 3-(2-iodophenyl)propanoate 3r
1
less oil (0.79 g, 40%); H NMR: l 7.39–7.25 (5H, m,
2-Iodobenzaldehyde was prepared from 2-iodobenzyl
alcohol (4.62 g, 19.7 mmol) and PCC (6.49 g, 30.1
mmol) according to the method for the oxidation of
alcohols to aldehydes.32 Chromatography (silica gel,
hexane–ethyl acetate 5:1 (v/v)) of the crude product
provided 2-iodobenzaldehyde (4.11 g, 90%) as a pale
brown solid; 1H NMR: l 10.08 (1H, s, CHO), 7.96 (1H,
d, J=7.8, ArH (6)), 7.89 (1H, d, J=7.8, ArH (3)), 7.47
(1H, t, J=7.6, ArH (4)), 7.29 (1H, t, J=7.8, ArH (5)).
ArH), 3.98 (1H, t, J=5.5, ArCHCH6 2OH), 3.91–3.78
(2H, m, ArCHCH6 2Cl), 3.25–3.16 (1H, m, ArCH); IR
(neat): 3353 (wOꢁH), 700 (wCꢁCl) cm−1. Found: C, 63.05;
H, 6.49. Calcd for C9H11ClO: C, 63.35; H, 6.50%.
3.23. Preparation of optically active alcohols as
authentic samples
We prepared the optically active isomers of 4–9 for the
authentic samples used to determine the absolute
configurations of the enantiomers preferentially
2-Iodobenzaldehyde was converted to vinyl 3-(2-
iodophenyl)propanoate 3r through two steps described

M. Kawasaki et al. / Tetrahedron: Asymmetry 12 (2001) 585–596
595
esterified in their transesterification mediated by the
lipases studied in the present study. Since optically
active (S)-1 and (S)-10 are commercially available, we
used these as the authentic samples.
7. Nakamura, K.; Takenaka, K.; Ohno, A. Tetrahedron:
Asymmetry 1998, 9, 4429–4439.
8. Pe´ter, M.; Van der Eycken, J.; Berna´th, G.; Fu¨lo¨p, F.
Tetrahedron: Asymmetry 1998, 9, 2339–2347.
9. Ema, T.; Maeno, S.; Takaya, Y.; Sakai, T.; Utaka, M. J.
Org. Chem. 1996, 61, 8610–8616 and references cited
therein.
10. Ema, T.; Maeno, S.; Takaya, Y.; Sakai, T.; Utaka, M.
Tetrahedron: Asymmetry 1996, 7, 625–628.
11. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J.
Am. Chem. Soc. 1982, 104, 7294–7299.
Racemic 4–6, 8, and 9 (0.1–0.2 g) were esterified with
vinyl acetate (2–4 equiv.) by PCL in cyclohexane
according to the procedure described in Section 3.2. In
the reaction of 7 (0.2 g), vinyl 3-phenylpropanoate 3a
(1.5 equiv.) was employed.
In the reaction of 5–8, the unreacted alcohols were
recovered and their e.e. and optical rotations were
measured, which are as follows. (R)-5: e.e.=78%, [h]D23
−7.8 (c 1.16, CHCl3) (lit.33 [h]D25 −9.0 (c 2.33, CHCl3),
56% e.e. (R)); (R)-6: e.e.=80%, [h]2D2 −26.0 (c 0.93,
MeOH) (lit.34 [h]D23 −16.3 (c 1.21, MeOH), 63% e.e.
(R)); (R)-7: e.e.=61%, treatment of (R)-7 with Jones
reagent in acetone gave the corresponding carboxylic
acid of (R)-configuration, [h]1D9 −45.1 (c 1.13, EtOH)
(lit.35 [h]2D0 −115 (c 0.3, EtOH), (R)); (R)-8: e.e.=96%
(measured after oxidation to the corresponding car-
boxylic acid), [h]D21 +12.8 (c 1.51, CHCl3) (lit.36 [h]D25 +11
(c 2.5, CHCl3), e.e. >98% (R)).
12. For carboxylic acids as acyl donors in a lipase-catalysed
esterification, see: Guo, Z.-W.; Wu, S.-H.; Chen, C.-S.;
Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1990, 112,
4942–4945.
13. Hirose, K.; Naka, H.; Yano, M.; Ohashi, S.; Naemura,
K.; Tobe, Y. Tetrahedron: Asymmetry 2000, 11, 1199–
1210.
14. Pozo, M.; Gotor, V. Tetrahedron: Asymmetry 1995, 6,
2797–2802.
15. Koshiro, S.; Sonomoto, K.; Tanaka, A.; Fukui, S. J.
Biotechnol. 1985, 2, 47–57.
16. Kawasaki, M.; Goto, M.; Kawabata, S.; Kodama, T.;
Kometani, T. Tetrahedron Lett. 1999, 40, 5223–5226.
17. Kawasaki, M.; Nakamura, K.; Kawabata, S. J. Mol.
Catal. B: Enzym. 1999, 6, 447–451.
18. Im, D. S.; Cheong, C. S.; Lee, S. H.; Park, H.; Youn, B.
H. Tetrahedron: Asymmetry 1999, 10, 3759–3767.
19. Kitano, K.; Matsubara, J.; Ohtani, T.; Otsubo, K.;
Kawano, Y.; Morita, S.; Uchida, M. Tetrahedron Lett.
1999, 40, 5235–5238.
20. Gamalevich, G. D.; Serebryakov, E. P. Russ. Chem. Bull.
1997, 46, 171–183.
21. Morita, S.; Matsubara, J.; Otsubo, K.; Kitano, K.;
Ohtani, T.; Kawano, Y.; Uchida, M. Tetrahedron: Asym-
metry 1997, 8, 3707–3710.
In the reaction of 4 and 9, the produced acetate esters
were recovered and their optical rotations were mea-
sured. After the measurement, the esters were
hydrolysed (NaOH, MeOH) to the corresponding alco-
hols and their e.e. determined, these are as follows.
Acetate ester of (S)-4: e.e.=62%, [h]2D1 +10.4 (c 2.17,
CHCl3) (lit.34 [h]D24 +10.3 (c 1.08, CHCl3), e.e.=62%
(S)). Acetic acid ester of (S)-9: e.e.=29%, [h]2D2 +15.9 (c
2.13, benzene) (lit.37 [h]2D0 −35.2 (c 3.36, benzene), e.e.=
64% (R)).
22. Serebryakov, E. P.; Gamalevich, G. D. Mendeleev Com-
mun. 1996, 221–224.
Acknowledgements
23. Nagai, H.; Shiozawa, T.; Achiwa, K.; Terao, Y. Chem.
Pharm. Bull. 1993, 41, 1933–1938.
24. Ikushima, Y.; Saito, N.; Yokoyama, T.; Hatakeda, K.;
Ito, S.; Arai, M.; Blanch, H. W. Chem. Lett. 1993,
109–112.
The authors thank Amano Pharmaceutical Co., Ltd
and Novo Nordisk Co., Ltd for kindly providing the
lipases. The authors also thank the researchers at the
Biotechnology Research Centre, Toyama Prefectural
University, for their generous support with NMR spec-
troscopic and specific rotation measurements.
25. Nagai, H.; Shiozawa, T.; Achiwa, K.; Terao, Y. Chem.
Pharm. Bull. 1992, 40, 2227–2229.
26. Goto, M.; Kawasaki, M.; Kometani, T. J. Mol. Catal. B:
Enzym. 2000, 9, 245–250.
27. Cygler, M.; Grochulski, P.; Kazlauskas, R. J.; Schrag, J.
D.; Bouthillier, F.; Rubin, B.; Serreqi, A. N.; Gupta, A.
K. J. Am. Chem. Soc. 1994, 116, 3180–3186.
28. Lobell, M.; Schneider, M. P. Synthesis 1994, 375–377.
29. To´th, G.; Ko¨ve´r, K. E. Synth. Commun. 1995, 25, 3067–
3074.
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