Synthesis of 4-aryl-substituted β-lactam enantiomers by enzyme-catalyzed kinetic resolution

Article abstract of DOI:10.1016/S0957-4166(01)00388-3

Enantiopure 4-phenyl- and 4-(p-tolyl)-2-azetidinones 3a, 3b, 4a and 4b (with e.e.s of ≥96%) were prepared through lipase-catalyzed asymmetric butyrylation of the primary OH group of N-hydroxymethylated β-lactams (±)-5 and (±)-6 at the (R)-stereogenic centre or by lipase-catalyzed asymmetric debutyrylation of O-butyryloxymethyl-2-azetidinones (±)-7 and (±)-8 at the (R)-stereogenic centre. The ring-opening of lactams 5a, 5b, 6b and 8a with HCl/EtOH afforded the corresponding β-amino ester enantiomers 9a, 9b, 10a and 10b with e.e.s of ≥92%.

Full text of DOI:10.1016/S0957-4166(01)00388-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2351–2358
Synthesis of 4-aryl-substituted b-lactam enantiomers by
enzyme-catalyzed kinetic resolution
Eniko3 Forro´ and Ferenc Fu¨lo¨p*
Institute of Pharmaceutical Chemistry, University of Szeged, H-6701 Szeged, PO Box 121, Hungary
Received 15 August 2001; accepted 4 September 2001
Abstract—Enantiopure 4-phenyl- and 4-(p-tolyl)-2-azetidinones 3a, 3b, 4a and 4b (with e.e.s of ]96%) were prepared through
lipase-catalyzed asymmetric butyrylation of the primary OH group of N-hydroxymethylated b-lactams ( )-5 and ( )-6 at the
(R)-stereogenic centre or by lipase-catalyzed asymmetric debutyrylation of O-butyryloxymethyl-2-azetidinones ( )-7 and ( )-8 at
the (R)-stereogenic centre. The ring-opening of lactams 5a, 5b, 6b and 8a with HCl/EtOH afforded the corresponding b-amino
ester enantiomers 9a, 9b, 10a and 10b with e.e.s of ]92%. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
ses for racemic and enantiopure 2-azetidinones have
been reported. As an example, Bandini et al. synthe-
sized a-halo-b-lactams, which are versatile synthons for
a wide variety of functionalized lactams with potential
applications as b-lactamases or inhibitors of 3-hydroxy-
3-methyl glutarate coenzyme.13 Optically active 3,4-sub-
stituted 2-azetidinones were successfully synthesized by
the enzymatic resolution of N-acetyloxymethyl or N-
hydroxymethyl b-lactams.14 Achilles et al. presented a
new synthetic route to enantiopure (S)-4-phenyl-2-aze-
tidinone (e.e.=83%), which was obtained by enantiose-
lective synthesis from (S)-b-phenyl-b-alanine, while the
(R)-enantiomer (e.e.=84%) was obtained by enzymatic
resolution with a-chymotrypsin.1
N-Peptidyl-substituted 2-azetidinones, obtained from
either racemic or enantiopure 4-phenyl-2-azetidinone,
were recently evaluated as inhibitors of the serine
protease elastase and the cysteine protease papain.1 A
facile transformation of 3,4-disubstituted 2-azetidinones
to chiral 5,6-dihydro-2-pyridones, which can serve as
valuable chiral intermediates for different piperidine
and indolizidine alkaloids and azasugars, was reported
by Lee et al.2 b-Lactams can be transformed into
valuable b-amino acids, which are of immense interest
from both pharmacological and chemical viewpoints.3–6
The increasing importance of acyclic b-amino acid
derivatives is reflected by the large number of syntheses
published for their preparation in both racemic7,8 and
enantiopure9–11 form. A convenient method for the
preparation of optically active amino acids from a-
methylene b-lactams by lipase-catalyzed kinetic resolu-
tion was recently described by Adam et al.12 Because of
the importance of b-lactams, a large number of synthe-
Our aim was to prepare the enantiomerically pure
b-lactams 3a, 3b, 4a and 4b (Scheme 4). The previous
results on the enzymatic resolution of alicyclic b-
lactams15–18 suggested the possibility of enantioselective
O-acylation of the primary hydroxyl group of ( )-5 and
Scheme 1.
* Corresponding author. Tel.: 36 62 545564; fax: 36 62 545705; e-mail: fulop@pharma.szote.u-szeged.hu
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00388-3

2352
E. Forro´, F. Fu¨lo¨p / Tetrahedron: Asymmetry 12 (2001) 2351–2358
( )-6 (Scheme 2). Over and above the primary focus of
this work, we wished to search for the most efficient
conditions for lipase-catalyzed resolution of ( )-5 and
( )-6, the widespread investigations on b-amino acid
derivatives prompted us to study the possible transfor-
mations of b-lactam enantiomers into b-amino esters
(Scheme 4).
The lipase PS- and lipase AK-catalyzed butyrylations
of ( )-5 with vinyl butyrate (VB) in di-iso-propyl ether
at 25°C displayed relatively similar high E values and
reaction times (the times needed to reach 50% conver-
sion) (Table 1, rows 3 and 6). Besides lipase PS and
lipase AK, PPL (porcine pancreatic lipase) also proved
to be a promising catalyst for the asymmetric butyryla-
tion of ( )-1 (Table 1, row 8), while CAL-A (lipase
from Candida antarctica A) was insufficiently selective
(Table 1, row 7).
2. Results and discussion
2.1. Syntheses of ( )-5–( )-8
On the basis of our previous experience with lipase PS
catalysis,18,20,21 vinyl butyrate was chosen as the acyl
donor for further studies (for practical reasons, vinyl
acetate was not used, because the acetate and alcohol
peaks partially overlap in the chromatograms in the
case of 5).
The racemic b-lactams 3 (R=H) and 4 (R=Me) were
prepared from styrene 1 or 4-methylstyrene 2, respec-
tively, by chlorosulfonyl isocyanate (CSI) addition.19
The products were transformed with paraformaldehyde
under sonication into the N-hydroxymethylated b-lac-
tams ( )-5 (R=H) and ( )-6 (R=Me), starting sub-
stances for lipase-catalyzed asymmetric O-acylations
(Scheme 1). The O-acyl derivatives ( )-7 (R=H) and
( )-8 (R=Me), starting compounds for lipase-catalyzed
hydrolyses, were synthesized from ( )-5 and ( )-6 with
butyric anhydride, in the presence of triethylamine.
Since the nature of the solvent usually influences the
enantioselectivity of enzymatic reactions,18,21 several
solvents (mixture of solvents) were tested in the lipase
PS-catalyzed butyrylation of ( )-5. The reaction pro-
ceeded somewhat more slowly and less enantioselec-
tively in tetrahydrofuran (Table 1, row 1) than those
completed in acetone, di-iso-propyl ether and toluene
(Table 1, rows 2, 3 and 5), which all afforded very high
enantioselectivities (E]193). When a mixture of di-iso-
propyl ether:CHCl3 (1:1) was used (Table 1, row 4), a
longer reaction time and a lower enantioselectivity were
observed than in di-iso-propyl ether alone (Table 1, row
3). With regard to the reaction rates, toluene was
chosen as the solvent for the gram-scale resolution.
2.2. Lipase-catalyzed asymmetric acylations of ( )-5
and ( )-6
In earlier studies, lipase PS (Pseudomonas cepacia) and
lipase AK (Pseudomonas fluorescens) proved to be
applicable for the enantioselective acylation of N-
hydroxymethylated b-lactams.14–18 High enantioselec-
tivities (E usually >200) were observed, in spite of the
relatively large distance between the reaction site and
the asymmetric centre. The previous results on the
lipase-catalyzed kinetic resolutions of b-lactams sug-
gested the possibility of selective acylation of ( )-5
(R=H) and ( )-6 (R=Me) (Scheme 2).
It was observed that the butyrylation of ( )-5 in toluene
at 25°C did not stop at 50% conversion: the e.e. value
for the product ester started to decrease with time (Fig.
1).
Scheme 2.
Table 1. Lipase-catalyzed (30 mg mL−1) acylation of (9)-5 (0.1 M) with VB (0.2 M) at 25°C
a
Enzyme
Solvent
Time (h)
% Conv.
E.e.sa (%)
E.e.p (%)
E
Row
Lipase PSb
Lipase PSb
Lipase PSb
Lipase PSb
Lipase PSb
Lipase AKb
CAL-Ab
Tetrahydrofuran
Acetone
Di-iso-propyl ether
Di-iso-propyl ether:CHCl3 (1:1)
Toluene
Di-iso-propyl ether
Di-iso-propyl ether
Di-iso-propyl ether
24
7.5
2
17
1.5
2
50
49
50
52
49
50
51
50
90
94
96
97
94
95
42
91
91
98
96
91
97
95
41
92
65
1
2
3
4
5
6
7
8
\200
193
89
\200
145
4
2
18
PPL
76
a According to chiral GC.
b Contains 20% (w/w) of lipase adsorbed on Celite in the presence of sucrose.

E. Forro´, F. Fu¨lo¨p / Tetrahedron: Asymmetry 12 (2001) 2351–2358
2353
Figure 1. Experimental e.e. values versus conversion for the lipase PS-catalyzed butyrylation of ( )-5 in toluene at 25°C.
The gram-scale resolutions of ( )-5 and ( )-6 were
performed in toluene with lipase PS as catalyst and
vinyl butyrate as acyl donor at 25°C. The results are
presented in Table 2 and in Section 3.
debutyrylations of ( )-7 and ( )-8 were also investi-
gated (Scheme 3).
Our recent experience22 of the enzyme-catalyzed asym-
metric O-deacylation of N,O-diacetyl derivatives of
cyclic 1,3-amino alcohols, led us to investigate the
Novozym-catalyzed hydrolysis of ( )-7. Surprisingly,
Novozym 435 (lipase from Candida antarctica B), which
catalyzed the O-deacylation reactions of the above-
mentioned compounds with high enantioselectivity (E
usually >200), did not show any selectivity in the
debutyrylation of ( )-7 with ethanol in di-iso-propyl
ether (1:10) at 60°C (Table 3, row 1).
The esters 5a and 6a produced by (R)-selective butyry-
lation of the N-hydroxymethylated b-lactams ( )-5 and
( )-6 were hydrolyzed to the corresponding alcohols 7a
and 8a in K2CO3/MeOH at room temperature, without
loss of enantiopurity (Scheme 3).
2.3. Lipase-catalyzed asymmetric debutyrylations of
( )-7 and ( )-8
Nagai et al.14 described the enantioselective hydrolysis
of N-acetyloxymethyl b-lactams with lipase B and
Since the gram-scale resolution of ( )-6 did not result in
6a with the expected enantiopurity (e.e.=88%), the
Table 2. Lipase PSa (30 mg mL−1)-catalyzed resolution of (9)-5 and (9)-6 with VB (0.2 M) in toluene at 25°C
Time (h)
Conv. (%)
E
Alcohol recovered (5b and 6b)
Ester produced (5a and 6a)
Yieldb (%) Isomer
E.e.c (%)
[h]2D5
Yieldb (%) Isomer
E.e.c (%)
[h]2D5
5
6
1.5
1.5
50
52
\200
78
56
S
S
98
95
−166.7d
−168e
80
89
R
R
97
88
+61.4d
+43.5d
57
a Contains 20% (w/w) of lipase adsorbed on Celite in the presence of sucrose.
b Yield 100% at 50% conversion.
c According to chiral GC.
d c=1, EtOH.
e c=0.5, EtOH.
Scheme 3.
Scheme 4.

2354
E. Forro´, F. Fu¨lo¨p / Tetrahedron: Asymmetry 12 (2001) 2351–2358
Table 3. Lipase-catalyzed (30 mg mL−1) debutyrylation of (9)-7 (0.1 M) with EtOH (91 ml mL−1) in di-iso-propyl ether
a
Enzyme
Temp. (°C)
Time (h)
Conv. (%)
E.e.sa (%)
E.e.p (%)
E
Row
Novozym 435
Lipase PSb
Lipase PSb
Lipase PSb
Lipase AKb
60
50
40
25
40
1
4.5
6
22
6
95
50
49
49
49
69
96
94
88
89
4
96
98
91
93
1.7
194
\200
62
1
2
3
4
5
83
a According to chiral GC.
b Contains 20% (w/w) of lipase adsorbed on Celite in the presence of sucrose.
Table 4. Lipase PSa (30 mg mL−1)-catalyzed resolutions of (9)-7 and (9)-8 with EtOH in di-iso-propyl ether (1:10), at
40°C
Time (h)
Conv. (%)
E
Ester recovered (7b and 8b)
Alcohol produced (7a and 8a)
Yieldb (%) Isomer
E.e.c (%)
[h]2D5
Yieldb (%) Isomer
E.e.d (%)
[h]2D5
7
8
7
6
50
52
\200
95
80
S
S
97
97
−62.5d
−62f
93
90
R
R
96
91
+161e
89
+155.8g
a Contains 20% (w/w) of lipase adsorbed on Celite in the presence of sucrose.
b Yield 100% at 50% conversion.
c According to chiral GC.
d c=0.65, EtOH.
e c=0.35, EtOH.
f c=1, EtOH.
g c=0.3, EtOH.
lipase PS as suitable catalysts in di-iso-propyl ether
saturated with water. In order to enhance the enan-
tioselectivity, Novozym was replaced by lipase PS or
lipase AK. Both lipases catalyzed the debutyrylation of
( )-7 with high enantioselectivities (Table 3, rows 2 and
5).
2.4. Transformations of the enantiomers
Treatment of 5a, 5b, 6b and 8a with NH4OH/MeOH
afforded b-lactams 3a, 3b (R=H) and 4a, 4b (R=Me),
while transformations by ring opening with HCl/EtOH
resulted in enantiomers of b-amino esters 9a, 9b (R=
H) and 10a, 10b (R=Me) (Scheme 5). The physical
data on the enantiomers prepared are reported in Table
5.
On decreasing the reaction temperature from 50 to
40°C, the reaction rate for the lipase PS-catalyzed
debutyrylation of ( )-7 decreased but the E value was
slightly enhanced (Table 3, rows 2 and 3). When the
reaction was performed at 25°C, the reaction time
increased markedly and the enantioselectivity of the
reaction decreased to E=62 (Table 3, row 4).
2.5. Absolute configurations
The analyzed chromatograms indicated that the corre-
sponding enantiomers of 5 and 6, and 7 and 8 react
preferentially on lipase PS-catalyzed O-acylation and
O-deacylation, respectively. The absolute configura-
tions were proved by comparing the [h] values with the
literature data. The value of [h]2D5=−136.3 (c=0.5,
EtOH) for 3b and the literature value1 for (S)-4-phenyl-
The gram-scale resolutions of ( )-7 and ( )-8 were
carried out with ethanol in di-iso-propyl ether (1:10) at
40°C. The results are presented in Table 4 and in
Section 3.
Scheme 5.

E. Forro´, F. Fu¨lo¨p / Tetrahedron: Asymmetry 12 (2001) 2351–2358
2355
Table 5. Physical data on enantiomers prepared
Optical rotations were measured with a Perkin-Elmer
341 polarimeter. H NMR spectra were recorded on a
Bruker Avance DRX 400 spectrometer. Melting points
1
Compound
Abs. config.
E.e. (%)
[h]2D5
were determined on a Kofler apparatus.
3a
3b
4a
4b
9a
9b
10a
10b
(R)
(S)
(R)
(S)
(R)
(S)
(R)
(S)
97
99
96
99
95
96
92
97
+132.4 (c=0.5, EtOH)
−136.3 (c=0.5, EtOH)
+122 (c=0.5, EtOH)
−125.5 (c=0.5, EtOH)
−11.4 (c=0.35, EtOH)
+11.8 (c=0.5, EtOH)
−11.8 (c=0.5, EtOH)
+12.9 (c=1.9, EtOH)
3.2. Preparation of racemic 4-phenyl-2-azetidinone
( )-3
A solution of styrene 1 (2 g, 19.2 mmol) in CH2Cl2 (20
mL) was added dropwise to a stirred solution of chloro-
sulfonyl isocyanate (1.66 mL, 19.2 mmol) in CH2Cl2 (20
mL). The reaction mixture was stirred at room temper-
ature for 8 h and left to stand overnight. The resulting
liquid was added dropwise to a vigorously stirred solu-
tion of Na2SO3 (0.24 g) and K2CO3 (5.56 g) in H2O (50
mL). The organic layer was separated and the aqueous
phase was extracted with diethyl ether. The combined
organic layers were dried (Na2SO4) and, after filtration,
concentrated. The resulting white solid, racemic 3 (2.34
g, 83%), was recrystallized from di-iso-propyl ether (mp
2-azetidinone, [h]2D5=−130.2 (c=1.12, EtOH), indicate
the (R)-selectivity of acylation and deacylation. The
value of [h]2D5=+5.9 (c=0.7, MeOH) for 9b and the
literature value23 for ethyl (S)-3-amino-3-phenylpropi-
onate hydrochloride, [h]2D5=+5.8 (c=1, MeOH), again
indicate the R-selectivity of hydrolysis and acylation.
1
104–105°C, lit.14 mp 108–109°C). H NMR (400 MHz,
In conclusion, an efficient method was developed for
the synthesis of 4-aryl-2-azetidinones and the corre-
sponding b-amino ester enantiomers via lipase-cata-
lyzed (R)-selective butyrylation or debutyrylation. It is
interesting that both butyrylation and debutyrylation
had high selectivity rates in the case of phenyl-substi-
tuted compounds, while the 4-(p-tolyl) derivatives
reacted with much lower selectivities.
CDCl3) l (ppm): 2.85–2.89 (1H, dd, J=2, 14.8, CHAH)
3.41–3.46 (1H, ddd, J=2.4; 5.2; 7.6, CHBH), 4.71–4.73
(1H, dd, J=2.5; 5.3, CH), 6.34 (1H, bs, NH) 7.26–7.40
(5H, m, Ph). Anal. calcd for C9H9NO: C, 73.45; H,
6.16; N, 9.52; found: C, 73.12; H, 6.31; N, 9.50%.
3.3. Preparation of racemic 4-(p-tolyl)-2-azetidinone
( )-4
3. Experimental
With the procedure described above, 4-methylstyrene 2
(2 g, 16.93 mmol) afforded racemic 4 (1.1 g, 40%; mp
85–86°C) as white crystals. 1H NMR (400 MHz,
CDCl3) l (ppm): 2.35 (3H, s, CH3) 2.83–2.87 (1H, dd,
J=1.7; 14.8, CHAH) 3.39–3.44 (1H, ddd, J=2.4; 5.2;
7.6, CHBH), 4.67–4.69 (1H, dd, J=2.3; 5.2, CH), 6.13
(1H, bs, NH) 7.17–7.27 (4H, m, Ph). Anal. calcd for
C10H11NO: C, 74.51; H, 6.88; N, 8.69; found: C, 74.71;
H, 6.91; N, 8.70%.
3.1. Materials and methods
Vinyl acetate was purchased from Fluka, vinyl butyrate
from Aldrich Co., lipase PS and lipase AK from
Amano Pharmaceuticals, PPL (type II) from Sigma,
and CAL-A and Novozym 435 (as an immobilized
preparation) from Novo Nordisk. Before use, lipase PS,
lipase AK and CAL-A (5 g) were dissolved in Tris–HCl
buffer (0.02 M; pH 7.8) in the presence of sucrose (3 g),
followed by adsorption on Celite (17 g) (Sigma). The
lipase preparations thus obtained contained 20% (w/w)
of lipase.
3.4. Preparation of racemic 1-hydroxymethyl-4-phenyl-
2-azetidinone ( )-5
4-Phenyl-2-azetidinone ( )-3 (2 g, 13.59 mmol) was
dissolved in THF (20 mL). Paraformaldehyde (0.41 g,
13.75 mol equiv.), K2CO3 (0.11 g) and H2O (0.78 mL)
were added. The solution was sonicated for 5 h. The
solvent was evaporated off and the residue was dis-
solved in ethyl acetate (50 mL). The solution was dried
(Na2SO4) and then concentrated. The residue was
recrystallized from di-iso-propyl ether to afford a white
crystalline product, ( )-5 (1.6 g, 66%; mp 83–85°C, lit.
In a typical small-scale experiment, racemic 2-azetidi-
none (0.1 M solution) in an organic solvent (2 mL) was
added to the lipase tested (30 mg mL−1). In the case of
acylation, VB (0.2 M in the reaction mixture), and in
the case of hydrolysis, EtOH (91 ml mL−1) was added.
The mixture was shaken at 25°C for acylation and at
40°C for hydrolysis. The progress of the reaction was
followed by taking samples from the reaction mixture
at intervals and analyzing them by gas chromatogra-
phy. The e.e. values for the produced enantiomers were
determined by gas chromatography on a Chrompack
CP-Chirasil-DEX CB column (25 m). Amino esters 9a,
9b, 10a and 10b were derivatized with hexanoic anhy-
dride in the presence of 4-dimethylaminopyridine and
pyridine before gas chromatographic analysis on a Chi-
rasil-L-Val column (25 m).
1
mp14 84–85°C). H NMR (400 MHz, CDCl3) l (ppm):
2.88–2.93 (1H, dd, J=2.4; 15.2, CHAH) 3.17 (1H, bs,
OH), 3.37–3.42 (1H, dd, J=5.6; 15.2, CHBH), 4.22–
4.25 (1H, d, J=11.6, NCHAHOH) 4.82–4.84 (1H, dd
J=2.4; 5.4. CH), 5.03–5.06 (1H, d, J=11.6,
NCHBHOH) 7.32–7.39 (5H, m, Ph). Anal. calcd for
C10H11NO2: C, 67.78; H, 6.26; N, 7.90; found: C, 67.63;
H, 6.41; N, 7.90%.

2356
E. Forro´, F. Fu¨lo¨p / Tetrahedron: Asymmetry 12 (2001) 2351–2358
3.5. Preparation of racemic 1-hydroxymethyl-4-(p-tolyl)-
2-azetidinone ( )-6
di-iso-propyl ether); e.e.=97%] and the ester (R)-5a
[0.56 g, 40%; [h]2D5=+61.4 (c=1, EtOH); e.e.=97%] as
a pale-yellow oil.
With the procedure described above, 4-(p-tolyl)-2-aze-
tidinone 4 (1 g, 6.2 mmol) afforded ( )-6 (1.01 g, 85%;
1H NMR (400 MHz, CDCl3) l (ppm) for 5a: similar to
that for ( )-7. Anal. calcd for C14H17NO3: C, 68.00; H,
6.93; N, 5.66; found: C, 68.09; H, 6.66; N, 5.68%.
1
mp 67–71°C) as white crystals. H NMR (400 MHz,
CDCl3) l (ppm): 2.35 (3H, s, CH3) 2.80–2.84 (1H, bs,
OH) 2.87–2.91 (1H, dd, J=2.4; 14.8, CHAH) 3.35–3.40
(1H, dd, J=5.2; 14.8, CHBH), 4.20–4.26 (1H, dd, J=
9.6; 11.6 NCHAHOH) 4.78–4.80 (1H, dd J=2.8; 5.2,
CH), 5.00–5.04 (1H, dd J=5.2; 11.6, NCHBHOH),
7.18–7.25(4H, m, Ph). Anal. calcd for C11H13NO2: C,
69.09; H, 6.85; N, 7.32; found: C, 68.89; H, 6.81; N,
7.27%.
1H NMR (400 MHz, CDCl3) l (ppm) for 5b: similar to
that for ( )-5. Anal. calcd for C10H11NO2: C, 67.78; H,
6.26; N, 7.90; found: C, 67.61; H, 6.34; N, 7.79%.
A mixture of 5a (0.1 g, 0.4 mmol) and K2CO3 (0.14 g,
0.96 mmol) in MeOH (15 mL) was stirred for 6 h at
room temperature. After evaporation, the residue was
dissolved in H2O (20 mL) and extracted with diethyl
ether. The organic phase was dried (Na2SO4), filtered
and evaporated. The product (R)-7a [0.06 g, 84%;
[h]2D5=+159.8 (c=1, EtOH); e.e.=95%] was recrystal-
lized from di-iso-propyl ether (mp 86–88°C).
3.6. Preparation of racemic 1-butyryloxymethyl-4-
phenyl-2-azetidinone ( )-7
Racemic 1-hydroxymethyl-4-phenyl-2-azetidinone
5
(0.3 g, 1.69 mmol) was dissolved in CH2Cl2 (45 mL).
Butyric anhydride (0.53 mL, 3.38 mmol) was added.
The solution was stirred at room temperature for one
night. After evaporation, the residue was chro-
matographed on silica. Elution with ethyl ace-
tate:hexane (3:1) afforded an oil of ( )-3 (0.4 g, 95%).
1H NMR (400 MHz, CDCl3) l (ppm): 0.89–0.92 (3H, t,
J=7.4, CH2CH3) 1.55–1.61 (2H, m, CH2CH3) 2.20–
2.24 (2H, m, CH2CH2CH3) 2.92–2.96 (1H, dd, J=2.8;
15.2, CHAH) 3.41–3.46 (1H, dd, J=5.2; 15.2, CHBH
4.71–4.73 (1H, dd, J=2.8; 5.6 CH), 4.94–4.87 (1H, d,
J=11.6, NCHAHOOCOPr) 5.29–5.32 (1H, d J=11.6,
NCHBHOCOPr) 7.34–7.39 (5H, m, Ph). Anal. calcd for
C14H17NO3: C, 68.00; H, 6.93; N, 5.66; found: C, 68.13;
H, 6.90; N, 5.66%.
3.9. Gram-scale resolution of ( )-6
With the procedure described above, the reaction of
racemic 6 (0.5 g, 2.61 mmol) and vinyl butyrate (0.42
mL, 5.22 mmol) in toluene (30 mL) in the presence of
lipase PS (0.9 g, 30 mg mL−1) at 25°C for 1.5 h afforded
the unreacted (S)-6b [0.14 g, 28%; [h]2D5=−168 (c=0.5,
EtOH); mp 98–100°C (recrystallized from di-iso-propyl
ether); e.e.=95%] and the ester (R)-6a [0.3 g, 44%;
[h]2D5=+43.5 (c=1, EtOH); e.e.=88%] as a pale-yellow
oil.
1H NMR (400 MHz, CDCl3) l (ppm) for 6a: similar to
that for ( )-8. Anal. calcd for C15H19NO3: C, 68.94; H,
7.33; N, 5.36; found: C, 69.02; H, 7.30; N, 5.22%.
3.7. Preparation of racemic 1-butyryloxymethyl-4-
(p-tolyl)-2-azetidinone ( )-8
1H NMR (400 MHz, CDCl3) l (ppm) for 6b: similar to
that for ( )-6. Anal. calcd for C11H13NO2: C, 69.09; H,
6.85; N, 7.32; found: C, 69.14; H, 6.83; N, 7.34%.
With the procedure described above, 1-hydroxymethyl-
4-(p-tolyl)-2-azetidinone 6 (0.4 g, 2.09 mmol) afforded
( )-8 (0.41 g, 75%). 1H NMR (400 MHz, CDCl3) l
(ppm): 0.89–0.92 (3H, t, J=7.4, CH2CH3) 1.55–1.61
(2H, m, CH2CH3) 2.20–2.24 (2H, m, CH2CH2CH3) 2.35
(3H, s, CH3) 2.90–2.94 (1H, dd, J=2.4; 15.2, CHAH)
3.38–3.43 (1H, dd, J=5.6; 15.2, CHBH) 4.67–4.09 (1H,
dd, J=2.8; 5.2 CH) 4.81–4.84 (1H, d, J=11.2,
3.10. Methanolysis of 5a and 6a to the corresponding
alcohols 7a and 8a
A mixture of 5a (0.1 g, 0.4 mmol) and K2CO3 (0.14 g,
0.96 mmol) in MeOH (15 mL) was stirred for 6 h at
room temperature. After evaporation, the residue was
dissolved in H2O (20 mL) and extracted with diethyl
ether. The organic phase was dried (Na2SO4), filtered
and evaporated. The product (R)-7a [0.06 g, 84%;
[h]2D5=+159.8 (c=1, EtOH); e.e.=95%] was recrystal-
lized from di-iso-propyl ether (mp 86–88°C).
NCHAHOOCOPr) 5.27–5.30 (1H,
d
J=11.2,
NCHBHOCOPr) 7.18–7.26 (4H, m, Ph). Anal. calcd for
C15H19NO3: C, 68.94; H, 7.33; N, 5.36; found: C, 69.11;
H, 7.25; N, 5.29%.
3.8. Gram-scale resolution of ( )-5
Racemic 5 (1 g, 5.65 mmol) and vinyl butyrate (0.91
mL, 11.3 mmol) in toluene (60 mL) were added to
lipase PS (1.8 g, 30 mg mL−1) and the mixture was
shaken at 25°C for 1.5 h. The reaction was stopped by
filtering the enzyme off at 50% conversion (e.e. 5a=
97%, e.e. 5b=98%). After the solvent had been evapo-
rated off, the residue was chromatographed on silica,
with elution with ethyl acetate:hexane (3:1); this
afforded the unreacted (S)-5b [0.39 g, 39%; [h]2D5=
−166.7 (c=1, EtOH); mp 90–91°C (recrystallized from
Similarly, 6a (0.1 g, 0.38 mmol) afforded (R)-8a [0.05 g,
68%; [h]2D5=+118.4 (c=1.9, EtOH); e.e.=76%].
3.11. Gram-scale resolution of ( )-7
Racemic 7 (0.4 g, 1.62 mmol) was dissolved in di-iso-
propyl ether (20 mL). Lipase PS (0.6 g, 30 mg mL−1)
and ethanol (1 mL) were added and the mixture was
shaken at 40°C for 7 h. The enzyme was filtered off at
50% conversion, and the solvent was evaporated off.

E. Forro´, F. Fu¨lo¨p / Tetrahedron: Asymmetry 12 (2001) 2351–2358
2357
The residue was chromatographed on silica, elution
with ethyl acetate:hexane (3:1) affording the unreacted
ester (S)-7b [0.19 g, 47%; [h]2D5=−62.5 (c=0.65, EtOH);
e.e.=97%] as a pale-yellow oil and the alcohol (R)-7a
[0.13 g, 46%; [h]2D5=+161 (c=0.35, EtOH); e.e.=96%)
as a white crystalline product (mp 82–84°C, lit. mp14
84–85°C).
EtOH); mp 50–54°C (recrystallized from di-iso-propyl
ether); e.e.=96%].
1H NMR (400 MHz, CDCl3) l (ppm) for 4a: similar
to that for ( )-4. Anal. calcd for C10H11NO: C, 74.51;
H, 6.88; N, 8.69; found: C, 74.38; H, 6.69; N, 8.75%.
Similarly, (S)-6b (0.2 g, 1.05 mmol) afforded white
crystals of (S)-4b [0.11 g, 65%; [h]2D5=−125.5 (c=0.5,
EtOH); mp 57–60°C (recrystallized from di-iso-propyl
ether); e.e.=99%].
1H NMR (400 MHz, CDCl3) l (ppm) for 7a: similar to
that for ( )-5. Anal. calcd for C10H11NO2: C, 67.78; H,
6.26; N, 7.90; found: C, 67.69; H, 6.42; N, 7.98%.
1H NMR (400 MHz, CDCl3) l (ppm) for 7b: similar to
that for ( )-7. Anal. calcd for C14H17NO3: C, 68.00; H,
6.93; N, 5.66; found: C, 67.79; H, 6.92; N, 5.65%.
1H NMR (400 MHz, CDCl3) l (ppm) for 4b: similar
to that for ( )-4. Anal. calcd for C10H11NO: C, 74.51;
H, 6.88; N, 8.69; found: C, 74.66; H, 6.70; N, 8.69%.
3.12. Gram-scale resolution of ( )-8
3.14. Preparation of enantiomerically pure b-amino
ester hydrochlorides 9a, 9a, 10a and 10b
With the procedure described above, the reaction of
racemic 8 (0.4 g, 1.53 mmol) and ethanol (1 mL) in
di-iso-propyl ether (20 mL) in the presence of lipase
PS (0.6 g, 30 mg mL−1) at 40°C for 6 h afforded the
unreacted (S)-8b [0.16 g, 40%; [h]2D5=−62 (c=1,
EtOH); e.e.=97%] and the alcohol (R)-8a (0.12 g,
45%; [h]2D5=+155.8 (c=0.3, EtOH); mp 100–102°C
(recrystallized from di-iso-propyl ether); e.e.=91%).
The ester (R)-5a (0.1 g, 0.4 mmol) was dissolved in
22% HCl/EtOH (10 mL) and refluxed for 5 h. The
solvent was evaporated off and the product, (R)-9a
[0.03 g, 32%; [h]2D5=−11.4 (c=0.35, EtOH); e.e.=95%]
was recrystallized from EtOH/di-iso-propyl ether (mp
117–119°C).
1H NMR (400 MHz, CDCl3) l (ppm) for 9a: 1.13–
1.16 (3H, t, J=4, CH3) 3.00–3.03 (1H, d, J=15,
CHAH) 3.23–3.27 (1H, d, J=15, CHBH) 4.03–4.05
(2H, m, CH2CH3) 4.70 (1H, m, CH) 7.26–7.50 (5H, m,
Ph) 8.74 (2H, bs, NH2). Anal. calcd for C11H16NO2:
C, 57.52; H, 7.02; N, 6.10; found: C, 57.71; H, 6.05;
N, 6.10%.
1H NMR (400 MHz, CDCl3) l (ppm) for 8a: similar
to that for ( )-6. Anal. calcd for C11H13NO2: C, 69.09;
H, 6.85; N, 7.32; found: C, 68.99; H, 6.80; N, 7.19%.
1H NMR (400 MHz, CDCl3) l (ppm) for 8b: similar
to that for ( )-8. Anal. calcd for C15H19NO3: C, 68.94;
H, 7.33; N, 5.36; found: C, 69.01; H, 7.34; N, 5.42%.
Similarly, the alcohol (S)-5b (0.1 g, 0.56 mmol)
afforded (S)-9b [0.07 g, 54%; [h]2D5=+11.8 (c=0.5,
EtOH), [h]2D5=+5.9 (c=0.7, MeOH); lit.24 [h]2D5=+5.8
(c=1, MeOH); e.e.=96%; as a slowly crystallizing oil.
3.13. Preparation of enantiomerically pure b-lactams
3a, 3b, 4a and 4b
The ester (R)-5a (0.2 g, 0.81 mmol) was dissolved in
MeOH (10 mL), NH4OH (1 mL) was added and the
mixture was stirred at room temperature for 24 h. The
solvent was evaporated off, the residue was chro-
matographed on silica, and elution with ethyl ace-
tate:hexane (3:1) afforded white crystals of (R)-3a
[0.08 g, 67%; [h]2D5=+132.4 (c=0.5, EtOH); mp 107–
110°C (recrystallized from di-iso-propyl ether); e.e.=
97%].
1H NMR (400 MHz, CDCl3) l (ppm) for 9b: similar
to that for 9a. Anal. calcd for C11H16NO2: C, 57.41;
H, 7.11; N, 6.18; found: C, 57.71; H, 6.05; N, 6.10%.
Similarly, the alcohol (R)-8a (0.1 g, 0.52 mmol)
afforded (R)-10a [0.08 g, 63%; [h]2D5=−11.8 (c=0.5,
EtOH); e.e.=92%] as a slowly crystallizing oil.
1H NMR (400 MHz, CDCl3) l (ppm) for 10a: 1.15
(3H, s, CH2CH3) 2.31 (3H, s, CH3) 3.03 (1H, bs,
CHAH) 3.24 (1H, bs, CHBH) 4.04 (2H, bs, CH2CH3)
4.67 (1H, m, CH) 7.14–7.41 (4H, m, Ph) 8.64 (2H, bs,
NH2). Anal. calcd for C12H18NO2: C, 59.13; H, 7.44;
N, 5.75; found: C, 59.01; H, 7.33; N, 5.69%.
1H NMR (400 MHz, CDCl3) l (ppm) for 3a: similar
to that for ( )-7. Anal. calcd for C9H9NO: C, 73.45;
H, 6.16; N, 9.52; found: C, 73.12; H, 6.22; N, 9.51%.
Similarly, (S)-5b (0.2 g, 1.13 mmol) afforded white
crystals of (S)-3b [0.13 g, 78%; [h]2D5=−136.3 (c=0.5,
EtOH); mp 116–117°C (recrystallized from di-iso-pro-
pyl ether), lit. mp24 115.5–116°C; e.e.=99%].
Similarly, the alcohol (S)-6b (0.1 g, 0.52 mmol)
afforded (S)-10b [0.07 g, 54%; [h]2D5=+12.9 (c=1.9,
EtOH); e.e.=97%] as a slowly crystallizing oil.
1H NMR (400 MHz, CDCl3) l (ppm) for 3b: similar
to that for ( )-3. Anal. calcd for C9H9NO: C, 73.45;
H, 6.16; N, 9.52; found: C, 73.81; H, 6.13; N, 9.47%.
1H NMR (400 MHz, CDCl3) l (ppm) for 10b: similar
to that for 10a. Anal. calcd for C12H18NO2: C, 59.13;
H, 7.44; N, 5.75; found: C, 59.09; H, 7.21; N, 5.51%.
Similarly, (S)-8a (0.15 g, 1.78 mmol) afforded white
crystals of (R)-4a [0.09 g, 71%; [h]2D5=+122 (c=0.5,

2358
E. Forro´, F. Fu¨lo¨p / Tetrahedron: Asymmetry 12 (2001) 2351–2358
10. Mokhallalati, M. K.; Wu, M.-J.; Pridgen, L. N. Tetra-
Acknowledgements
hedron Lett. 1993, 34, 47.
11. Roche, D.; Prasad, K.; Repic, O. Tetrahedron Lett. 1999,
40, 3665.
12. Adam, W.; Groer, P.; Humpf, H.-U.; Saha-Mo¨ller, C. R.
The authors’ thanks are due to OTKA (grants No. T
030452 and T 034901) and FKFP (grant 0115/2001) for
financial support.
J. Org. Chem. 2000, 65, 4919.
13. Bandini, E.; Favi, G.; Martelli, G.; Panunzio, M.; Piersnti,
G. Org. Lett. 2000, 2, 1077.
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