Research on the pig liver esterase (PLE)-catalyzed kinetic resolution of half-esters derived from prochiral diesters

Article abstract of DOI:10.1016/j.tetasy.2013.01.019

The pig liver esterase (PLE)-catalyzed kinetic resolution of half-esters derived from prochiral diesters is described. Generally, the PLE-catalyzed enantioselective hydrolysis of prochiral diesters affords the corresponding half-esters in high yield, beca

Full text of DOI:10.1016/j.tetasy.2013.01.019

Tetrahedron: Asymmetry 24 (2013) 357–361
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Research on the pig liver esterase (PLE)-catalyzed kinetic resolution
of half-esters derived from prochiral diesters
⇑
Naoyoshi Noguchi, Kazuhiro Tsuna, Masahisa Nakada
Department of Chemistry and Biochemistry, Advanced School of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 December 2012
Accepted 21 January 2013
The pig liver esterase (PLE)-catalyzed kinetic resolution of half-esters derived from prochiral diesters is
described. Generally, the PLE-catalyzed enantioselective hydrolysis of prochiral diesters affords the cor-
responding half-esters in high yield, because further hydrolysis of the half-esters does not typically occur.
However, we found that some half-esters undergo PLE-catalyzed hydrolysis when they are gradually
added to a PLE suspension in a potassium phosphate buffer at pH 8.0 via a syringe pump, leading to
the kinetic resolution of the half-esters.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
ters, as well as in the kinetic resolution of racemic esters.5 In addi-
tion, PLE has been utilized for the conversion of diesters to half-
The preparation of new chiral compounds is important for
enantioselective synthesis, because it sometimes requires many
steps if a chiral compound suitable for the synthesis is not readily
available. Thus, the preparation of a new chiral compound involves
reducing the number of steps in enantioselective synthesis, there-
by improving its efficiency.
Various methods have been reported to prepare chiral com-
pounds; for example, preparation from the chiral pool, asymmetric
synthesis from prochiral compounds, and resolution of racemic
mixtures.1 Among these methods, asymmetric synthesis, in partic-
ular catalytic asymmetric synthesis from prochiral compounds, is
an area of growing interest because of its efficiency. However,
enzymatic transformations have the advantages of employing mild
reaction conditions that do not require anhydrous or toxic re-
agents, organic solvents, or an inert atmosphere. They also do not
produce toxic effluents and by-products.2 Thus, enzyme-catalyzed
transformations can be easily carried out on a large scale, have
been considered as environmentally benign processes, and have
also been utilized in industrial-scale syntheses.
esters in high yield.6
In addition to its wide applicability, another notable feature of
PLE is that it does not catalyze the hydrolysis of half-esters pro-
duced through PLE-mediated hydrolysis of prochiral diesters7 ex-
cept for one special case.8 That is, in general, the PLE-catalyzed
hydrolysis of prochiral diesters typically affords the corresponding
half-esters almost quantitatively, and does not yield di-carboxylic
acids. Therefore, chiral half-esters suitable for the total synthesis
of natural products have been prepared via PLE-catalyzed hydroly-
sis in high yield.
We investigated the PLE-catalyzed hydrolysis of dialkyl a,a-di-
substituted malonates and found that in some cases the corre-
sponding half-esters were obtained in high yield and enantiomeric
excess (ee).9 During our studies, the PLE-catalyzed kinetic resolu-
tion of a half-ester (89% ee) was observed, which resulted in the
half-ester being recovered in an enantioenriched form (96% ee)
(Scheme 1).10 To the best of our knowledge, this is the first exam-
ple of the PLE-catalyzed kinetic resolution of a half-ester.
This successful result encouraged us to conduct further stud-
ies on the PLE-catalyzed kinetic resolution of half-esters which
were derived from prochiral diesters, and we report the results
herein.
Generally, the enzyme catalyzes the reaction of a specific sub-
strate, that is, it exhibits substrate specificity. However, some en-
zymes catalyze a broad range of substrates and have, therefore,
been utilized to prepare many new chiral compounds. For example,
lipase and PLE have been extensively used in the preparation of
chiral compounds.3 Baker’s yeast is a whole cell and yet shows
broad applicability.4
2. Results and discussion
We found that the PLE-catalyzed hydrolysis of the prochiral di-
methyl malonate derivative 1a quantitatively afforded the corre-
sponding half-ester 2a in 89% ee (Scheme 1). The PLE-catalyzed
hydrolysis of isolated 2a was found to afford enantioenriched 2a
(96% ee, 88% recovery),10 which was successfully used in the total
synthesis of (+)-ophiobolin A.11
PLE is known to show low substrate specificity and has been
utilized in the catalytic asymmetric hydrolysis of prochiral dies-
⇑
Corresponding author. Tel./fax: +81 3 5286 3240.
E-mail address: mnakada@waseda.jp (M. Nakada).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.01.019

358
N. Noguchi et al. / Tetrahedron: Asymmetry 24 (2013) 357–361
Ph
Ph
Ph
PLE, KPB8
30 °C, 9 h
PLE, KPB8
30 °C, 7 d
MeO2C
CO2H
MeO2C
CO2H
MeO2C
CO2Me
2a
88% recovery, 96% ee
2a
100%, 89% ee
1a
Scheme 1. PLE-catalyzed asymmetric hydrolysis of 1a and kinetic resolution of 2a.
(R)
Ph
fast
slow
MeO2C
CO2H
Ph
Ph
2a major
(S)
MeO2C
(pro-R)
CO2Me
HO2C
CO2H
Ph
(pro-S)
fast
slow
1a
HO2C
CO2Me
ent-2a minor
Scheme 2. A rationale for the kinetic resolution of 2a.
The PLE-catalyzed hydrolysis of 2a in Scheme 1 suggests that
Ph
Ph
PLE, KPB8
the PLE-catalyzed kinetic resolution of a half-ester occurred as
shown in Scheme 2, that is, the PLE-catalyzed hydrolysis of the
pro-(S) methyl ester of 1a proceeded faster than that of the pro-
(R) methyl ester of 1a. Therefore, the PLE-catalyzed hydrolysis of
the half-ester ent-2a that affords the corresponding di-carboxylic
acid would be faster than that of the half-ester 2a, thus leading
to an increase of the ee of the half-ester 2a.
30 °C, 7 d
MeO2C
CO2H
MeO2C
CO2H
2b
59%, 36% ee
2b
PLE, KPB8
10% DMSO
30 °C, 7 d
MeO2C
CO2H
MeO2C
CO2H
90%, 0% ee
We were surprised to find the kinetic resolution of 2a since the
PLE-catalyzed kinetic resolution of half-esters has not been re-
ported. Therefore, we conducted the PLE-catalyzed hydrolysis of
2a repeatedly, and found that the hydrolysis of 3.7 mg of 2a using
15 units of PLE in a 0.1 M potassium phosphate buffer (pH 8.0,
KPB8) at room temperature for 7 d afforded 2a of 96% ee. On the
other hand, we also found that the hydrolysis of 791.0 mg of 2a
using 350 units of PLE in 0.1 M KPB8 for 7 d afforded 2a of 91%
ee (95% recovery). These results suggested that the ratio of the
amount of PLE to 2a might be important in its kinetic resolution.
Therefore, we investigated the use of a syringe pump to add 2a
gradually to the suspension of PLE in 0.1 M KPB8 over 3 d, and
found that the kinetic resolution of 2a occurred reproducibly, to af-
ford 2a of 96% ee.
In order to explore the scope and limitations of the PLE-cata-
lyzed kinetic resolution via this protocol, we examined the PLE-cat-
alyzed hydrolysis of some racemic mono-esters (Scheme 3). In the
hydrolysis of 2b, a half-ester of a malonate derivative, 59% of 2b
was recovered and the ee was 36%. In the hydrolysis of 2c,12 also
a half-ester of a malonate derivative, the starting material re-
mained almost unchanged and the recovered half-ester was a race-
mic mixture. In the hydrolysis of the non-malonate half-ester 2d,13
virtually no hydrolysis occurred, and racemic 2d was recovered.
The hydrolysis of half-ester 2e14 afforded enantio-enriched 2e
(47% recovery, 98% ee). Considering that the maximum recovery
yield of kinetic resolution is 50%, 47% is an excellent recovery yield.
In the case of its saturated form 2f,14 the ee of the recovered 2f was
30% (49% recovery).
2c
2c
CO2Me
CO2H
CO2Me
PLE, KPB8
30 °C, 7 d
91%, 0 % ee
CO2H
2d
2d
MeO2C
CO2H
MeO2C
CO2H
H
H
PLE, KPB8
10% acetone
30 °C, 7 d
47%, 98% ee
Ph
Ph
2e
MeO2C
2e
CO2H
MeO2C
CO2H
H
H
PLE, KPB8
10% acetone
30 °C, 7 d
49%, 30% ee
Ph
Ph
2f
2f
Scheme 3. PLE-catalyzed kinetic resolution of racemic half-esters 2b–f.
the use of a syringe pump is also required for the efficient ki-
netic resolution on a large scale. The reason for the substrate/
PLE ratio problem and the necessity for use of a syringe pump
have not yet been explained. Therefore, further studies including
kinetic studies are under investigation and will be reported in
due course.
The results in Schemes 1 and 3 indicate that the PLE-catalyzed
hydrolysis of half-esters occurs depending on the structure of sub-
strate. It is premature to discuss the relationships between the
structures of half-esters and their hydrolysis before accumulating
further examples. However, among the substrates shown in
Schemes 1 and 3, half-esters containing a phenyl group 2a, 2b,
2e, and 2f were hydrolyzed by PLE, whereas other substrates, such
as 2c and 2d, remained almost unchanged.
3. Conclusion
In conclusion, we found in some cases that the PLE-catalyzed
hydrolysis of half-esters results in their kinetic resolution and is
dependent on the structure of substrates. The kinetic resolution
required a slow addition of the half-esters using a syringe pump,
As aforementioned, the PLE-catalyzed hydrolysis of half-esters
depends on the ratio of the amount of PLE to that of half-ester;

N. Noguchi et al. / Tetrahedron: Asymmetry 24 (2013) 357–361
359
and converted some racemic half-esters into enantioenriched
C
20H22NO3: 324.1600. Found: 324.1603;
½
a 2D7
ꢂ
¼ þ42:0 (c 0.3,
ones. Therefore, the developed protocol could be used to im-
prove the ee of half-esters prepared via PLE-catalyzed hydrolysis
of prochiral diesters, although it depends on the structure of
substrates.
CHCl3); 89% ee. Ee was determined by the HPLC analysis; DICEL
CHIRALPAK AS-H 0.46 cm / ꢀ 25 cm; hexane/isopropanol = 9/1;
flow rate = 0.5 mL/min; retention time: 16.8 min for ent-3a,
17.9 min for 3a.
4.3. PLE-catalyzed kinetic resolution of 2a
4. Experimental
To a suspension of PLE (350 units) in a pH 8 potassium phos-
phate buffer (250 mL) was added half-ester 2a (791 mg,
3.19 mmol, 89% ee) via a syringe pump over 72 h at 30 °C. One
week after the addition of 2a, 2 M HCl was added to the reaction
mixture to adjust the solution to pH 3. The aqueous layer was ex-
tracted with EtOAc (200 mL ꢀ 3), dried over Na2SO4, filtered and
evaporated. The residue was purified by flash chromatography
(hexane/ethyl acetate = 4/1) to recover 2a (508 mg, 88%, 96% ee)
as a colorless liquid. The ee of the recovered half-esters was deter-
mined by the HPLC analysis of the corresponding anilides, which
were prepared by a standard method (EDCꢃHCl, aniline).
4.1. General procedures
1H and 13C NMR spectra were recorded on JEOL AL-400 spec-
trometers. 1H and 13C chemical shifts are reported in ppm down-
field from tetramethylsilane (TMS, d scale) with the solvent
resonances as internal standards. The following abbreviations were
used to explain the multiplicities: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; band, several overlapping signals; br, broad.
IR spectra were recorded on a JASCO FT/IR-8300. Optical rotations
were measured using a 2 ml cell with a 1 dm path length on a JAS-
CO DIP-1000. Chiral HPLC analysis was performed on a JASCO PU-
980 and UV-970. Mass spectra and elemental analyses were pro-
vided at the Materials Characterization Central Laboratory, Waseda
University. All reactions were monitored by thin-layer chromatog-
raphy carried out on 0.25 mm E. Merck silica gel plates (60F-254)
using UV light as visualizing agent and phosphomolybdic acid
and heat as developing agents. E. Merck silica gel (60, particle size
0.040–0.063 mm) was used for flash chromatography. Preparative
thin-layer chromatography (PTLC) separations were carried out
on self-made 0.3 mm E. Merck silica gel plates (60F-254). Pig liver
esterase was purchased from Sigma–Aldrich, and all the other re-
agents were purchased from Aldrich, TCI, or Kanto Chemical Co.
Ltd.
4.3.1. Racemic 2-methoxycarbonyl-2-methyl-5-phenylpentan-
oic acid 2b
To a stirred solution of (E)-2-methoxycarbonyl-2-methyl-5-
phenylpent-4-enoic acid (13.8 mg, 0.056 mmol) in EtOH (1.0 mL)
was added a catalytic amount of 10% Pd/C under an atmosphere
of Ar, and the reaction mixture was stirred under an atmosphere
of hydrogen. After the reaction was complete, the mixture was fil-
tered and concentrated under reduced pressure. The residue was
purified by preparative thin-layer chromatography (dichlorometh-
ane/methanol = 10/1) to afford racemic 2b (8.3 mg, 60%): Rf = 0.33
(dichloromethane/methanol = 10/1); 1H NMR (400 MHz, CDCl3) d
7.29–7.26 (2H, m), 7.20–7.16 (3H, m), 3.73 (3H, s), 2.63 (2H, t,
J=7.3 Hz), 2.00–1.86 (2H, m), 1.68–1.55 (2H, m), 1.44 (3H, s); 13C
NMR (100 MHz, CDCl3) d 177.5, 172.6, 141.5, 128.3, 125.8, 53.6,
52.7, 36.0, 35.5, 26.3, 20.2; IR (neat) mmax 3028, 2996, 2956, 1736,
1718, 1454, 1268 cmꢁ1; FAB-MS [M+H]+ Calcd for C14H19O4:
251.1283. Found: 251.1288.
4.2. Preparation of (R,E)-2-methoxycarbonyl-2-methyl-5-phen-
ylpent-4-enoic acid 2a by the PLE-catalyzed hydrolysis
To a suspension of diester 1a (30.0 mg, 0.114 mmol) in a pH 8
phosphate buffer (3 mL) was added PLE (15 units), and the reaction
mixture was stirred at 30 °C. After 1a had disappeared, 2 M HCl
was added to the reaction mixture to adjust the solution to pH 3.
The aqueous layer was extracted with EtOAc (1.5 mL ꢀ 2), dried
over Na2SO4, filtered and evaporated. The residue was purified by
flash chromatography (hexane/ethyl acetate = 4:1) to afford 2a
(28.3 mg, 100%, 89% ee. Ee was determined by the HPLC analysis
of 3a) as a colorless liquid: Rf = 0.33 (dichloromethane/metha-
nol = 10/1); 1H NMR (400 MHz, CDCl3) d 7.34–7.20 (5H, m), 6.47
(1H, d, J = 15.6 Hz), 6.10 (1H, dt, J = 15.6, 7.6 Hz), 3.75 (3H, s),
2.82 (1H, dd, J = 13.9, 7.6 Hz), 2.76 (1H, dd, J = 13.9, 7.6 Hz), 1.49
(3H, s); 13C NMR (100 MHz, CDCl3) d 177.3, 172.1, 136.9, 134.4,
128.4, 127.4, 126.2, 123.6, 54.0, 52.8, 39.5, 20.1; IR (neat) mmax
2956, 2360, 1736, 1112 cmꢁ1; HRMS (FAB) [M+H]+ Calcd for
4.3.2. (R)-2-Methoxycarbonyl-2-methyl-5-phenylpentanoic acid
2b
Compound 2b (36% ee. Ee was determined by HPLC of 3b) was
obtained in 59% yield according to the procedure for the PLE-cata-
lyzed kinetic resolution of 2a: Rf = 0.33 (dichloromethane/metha-
nol = 10/1); 1H NMR (400 MHz, CDCl3) d 7.29–7.26 (2H, m), 7.20–
7.16 (3H, m), 3.73 (3H, s), 2.63 (2H, t, J = 7.3 Hz), 2.00–1.86 (2H,
m), 1.68–1.55 (2H, m), 1.44 (3H, s); 13C NMR (100 MHz, CDCl3) d
177.5, 172.6, 141.5, 128.3, 125.8, 53.6, 52.7, 36.0, 35.5, 26.3, 20.2;
IR (neat) mmax 3028, 2996, 2956, 1736, 1718, 1454, 1268 cmꢁ1
;
HRMS (FAB) [M+H]+ Calcd for C14H19O4: 251.1283. Found:
251.1288; ½a 2D6
¼ þ0:7 (c 0.8, CHCl3).
ꢂ
C14H17NO4: 249.1127. Found: 249.1127;
½
a 2D8
ꢂ
¼ þ4:9 (c 0.9,
4.3.3. (R)-Methyl 2-methyl-2-phenylcarbamoyl-5-phenylpent-
anoate (3b)
MeOH).
½
a 3D6
ꢂ
¼ þ11:9 (c 0.5, CHCl3); 36% ee. Ee was determined by HPLC
4.2.1. (R)-Methyl 2-methyl-5-phenyl-2-phenylcarbamoyl-4-
pentenoate 3a
analysis; DICEL CHIRALCEL OD-H 0.46 cm / ꢀ 25 cm; hexane/iso-
propanol = 9/1; flow rate = 0.3 mL/min; retention time: 27.2 min
for ent-3b, 29.1 min for 3b. The absolute configuration of the prod-
uct was determined by the comparison of the sign of the specific
Compound 3a was prepared from 2a in 54% yield by a standard
procedure (EDCꢃHCl and aniline were used.): Rf = 0.48 (hexane/
ethyl acetate = 2/1); 1H NMR (400 MHz, CDCl3) d 8.99 (1H, s),
7.54 (2H, d, J = 8.5 Hz), 7.34–7.18 (7H, m), 7.11 (1H, t, J = 7.6 Hz),
6.48 (1H, d, J = 15.9 Hz), 6.10 (1H, dt, J = 15.9, 7.6 Hz), 3.79 (3H,
s), 2.96 (1H, ddd, J = 13.9, 7.3, 1.2 Hz), 2.79 (1H, ddd, J = 13.9, 7.6,
1.2 Hz), 1.58 (3H, s); 13C NMR (100 MHz, CDCl3) d 175.2, 168.6,
137.5, 136.8, 134.2, 128.9, 128.4, 127.4, 126.2, 124.4, 124.0,
120.1, 54.6, 52.9, 41.8, 21.1; IR (neat) mmax 3352, 2956, 1738,
rotation with that of compound 3b {½a D28
¼ þ23:3 (c 0.4, CHCl3),
ꢂ
89% ee}, which was prepared by the hydrogenation of 3a.
4.3.4. Methyl 2-(4-methoxyphenylcarbamoyl)-2-methyloct-
anoate 3c
The ee of 2c was determined by HPLC of 3c: Rf = 0.57 (hexane/
ethyl acetate = 2/1); 1H NMR (400 MHz, CDCl3) d 9.06 (1H, s),
7.45 (2H, AA0XX0 pattern, J = 9.0 Hz), 6.85 (2H, AA0XX0 pattern,
1674, 1542, 1248 cmꢁ1
;
HRMS (FAB) [M+H]+ Calcd for

360
N. Noguchi et al. / Tetrahedron: Asymmetry 24 (2013) 357–361
J = 9.0 Hz), 3.78 (6H, s), 2.03 (1H, dt, J = 15.4, 7.6 Hz), 1.86 (1H, dt,
J = 15.4, 7.6 Hz), 1.51 (3H, s), 1.26–1.19 (8H, m), 0.86 (3H, t,
J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) d 176.2, 169.0, 156.2,
130.9, 121.6, 114.0, 55.4, 54.1, 52.7, 38.9, 31.5, 29.4, 25.1, 22.5,
21.1, 14.0; IR (neat) mmax 3336, 2932, 1714, 1666, 1602, 1516,
1246 cmꢁ1; HRMS (FAB) [M+H]+ Calcd for C18H28NO4: 322.2018.
Found: 322.2005; racemic mixture; ee was determined by HPLC;
DICEL CHIRALCEL OD-H 0.46 cm / ꢀ 25 cm; hexane/isopropa-
nol = 19/1; flow rate = 0.4 mL/min; retention time: 20.0, 22.0 min.
4.3.7. (S,E)-Methyl 3-phenylcarbamoylmethyl-5-phenylpenta-
noate 3f
The ee of 2f was determined by HPLC of 3f: Rf = 0.16 (hexane/
ethyl acetate = 4/1); 1H NMR (400 MHz, CDCl3) d 7.81 (1H, s),
7.52 (2H, d, J = 7.8 Hz), 7.33–7.17 (7H, m), 7.09 (1H, t, J = 7.6 Hz),
3.71 (3H, s), 2.71 (2H, t, J = 7.3 Hz), 2.56–2.38 (5H, m), 1.84–1.64
(2H, m); 13C NMR (100 MHz, CDCl3) d 173.5, 169.9, 141.5, 137.9,
128.9, 128.4, 128.3, 125.9, 124.1, 119.6, 51.8, 41.9, 37.7, 36.2,
33.3, 33.1; IR (KBr) mmax 3312, 3023, 2944, 2856, 1730, 1659,
1598, 1523, 1441, 1207, 1153 cmꢁ1; HRMS (FAB) [M+H]+ Calcd
for C20H24NO3: 326.1756. Found: 326.1751; ½a D28
¼ þ4:0 (c 0.5,
ꢂ
4.3.5. Methyl 6-phenylcarbamoyl-3-cyclohexenecarboxylate 3d
The ee of 2d was determined by HPLC of 3d: Rf = 0.14 (hexane/
ethyl acetate = 4/1); 1H NMR (400 MHz, CDCl3) d 8.01 (1H, s), 7.50
(2H, d, J = 8.3 Hz), 7.29 (2H, dd, J = 8.3, 7.3 Hz), 7.08 (1H, t,
J = 7.3 Hz), 5.77 (2H, s), 3.72 (3H, s), 3.14–3.05 (2H, m), 2.76–2.27
(4H, m); 13C NMR (100 MHz, CDCl3) d 174.7, 170.9, 137.9, 128.8,
125.6, 124.8, 124.0, 119.8, 52.1, 41.6, 40.6, 26.9, 26.0; IR (neat) mmax
CHCl3); 30% ee; ee was determined by HPLC; DICEL CHIRALCEL
OD-H 0.46 cm / ꢀ 25 cm; hexane/isopropanol = 3/1; flow
rate = 0.3 mL/min; retention time: 26.2 min for 3f, 29.4 min for
ent-3f. The absolute configuration of the product was determined
to be the same as that of compound 3f {½a D21
¼ þ8:1 (c 4.7, CHCl3),
ꢂ
93% ee}, which was prepared by the hydrogenation of 3e (93% ee),
by comparison of their specific rotation.
3324, 3032, 2952, 1730, 1666, 1602, 1538, 1442, 1250, 1206 cmꢁ1
;
HRMS (FAB) [M+H]+ Calcd for C15H18NO3: 260.1287. Found:
260.1279; Ee was determined by the HPLC analysis and found to
be 0% ee: DICEL CHIRALPAK AS-H 0.46 cm / ꢀ 25 cm; hexane/iso-
propanol = 3/1; flow rate = 0.3 mL/min; retention time: 31.5,
36.6 min.
Acknowledgments
This work was financially supported in part by The Grant-in-Aid
for Scientific Research on Innovative Areas ‘Organic Synthesis
based on Reaction Integration. Development of New Methods and
Creation of New Substances’ (No. 2105).
4.3.6. (S,E)-Methyl 3-phenylcarbamoylmethyl-5-phenylpent-4-
enoate 3e
References
The ee of 2e was determined by HPLC of 3e: Rf = 0.22 (hexane/
ethyl acetate = 2/1); 1H NMR (400 MHz, CDCl3) d 7.68 (1H, s), 7.49
(2H, d, J = 7.8 Hz), 7.33–7.19 (7H, m), 7.08 (1H, t, J = 7.3 Hz), 6.50
(1H, d, J = 15.9 Hz), 6.18 (1H, dd, J = 15.9, 8.1 Hz), 3.67 (3H, s),
3.28 (1H, dtt, J = 8.1, 7.1, 6.8 Hz), 2.67–2.51 (4H, m); 13C NMR
(100 MHz, CDCl3) d 172.5, 169.2, 137.7, 136.7, 131.1, 130.5,
128.9, 128.4, 127.4, 126.2, 124.2, 119.8, 51.8, 42.3, 38.8, 36.7; IR
(KBr) mmax 3345, 1736, 1655, 1600, 1527, 1256 cmꢁ1; mp 98.1–
98.6 °C; HRMS (FAB) [M+H]+ Calcd for C20H22NO3: 324.1600.
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¼ ꢁ27:4 (c 0.3, CHCl3); 98% ee. Ee was
ꢂ
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determined by the HPLC analysis; DICEL CHIRALPAK AS-H
0.46 cm / ꢀ 25 cm; hexane/isopropanol = 3/1; flow rate = 0.4 mL/
min; retention time: 42.8 min for ent-3e, 47.2 min for 3e. The abso-
lute configuration of the product was determined to be the same as
that of compound 3e {½a D20
¼ ꢁ40:8 (c 1.3, CHCl3), 93% ee}, which
ꢂ
was prepared from 2e14 (93% ee), by the comparison of their spe-
cific rotation.
The absolute configuration of 2e was determined by compari-
son of the specific rotation of its derivative 4e with the reported
data.15 Compound 2e was converted into 4e as follows:
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MeO2C
CO2H
MeO2C
CO2H
H
H
H2, Pd/C (cat.)
EtOH, rt
Ph
Ph
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1713–1714.
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2e (93% ee)
O
O
1) (COCl)2, DMF (cat.)
CH2Cl2, rt
H
2) NaBH4, MeOH, THF
–30 °C to rt
then, 5 M HCl, rt
58% (3 steps)
Ph
4e
[α]D17 = –29.1 (c 2.4, CHCl3)
lit.15 [α]D25 = +14.5 (c 0.48, CHCl3) 85% ee
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4e:
ent-

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