Synthesis of pure methyl [(2S,3R,αR)-1-(3-bromo-4-methoxyphenyl)-3-(α-acetoxy)ethyl-4- oxoazetidin-2-carboxylate] and its enantiomer

Article abstract of DOI:10.1016/S0957-4166(01)00003-9

Synthesis of key intermediates leading to 2-iso-oxacephems was carried out starting from L- and D-threonine. As predicted in our previous paper (Tetrahedron Lett. 1995, 36, 8303-8306) all diastereomers of 2-iso-oxacephems can be prepared from the appropriate enantiomers of the amino acid threonine. The absolute configuration of the 2,3- and α-carbon atoms in the β-lactam structure was determined by X-ray crystallographic studies.

Full text of DOI:10.1016/S0957-4166(01)00003-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 89–94
Synthesis of pure methyl
[(2S,3R,aR)-1-(3-bromo-4-methoxyphenyl)-3-(a-acetoxy)ethyl-4-
oxoazetidin-2-carboxylate] and its enantiomer
Zsuzsanna Sa´nta,a La´szlo´ Pa´rka´nyi,b Ildiko´ Ne´meth,a Jo´zsef Nagya and Jo´zsef Nyitraia,*
aInstitute for Organic Chemistry, Budapest University of Technology and Economics, H-1521 Budapest, Hungary
bCentral Chemical Research Institute of Hungarian Academy of Sciences, H-1525 Budapest, Hungary
Received 2 November 2000; accepted 21 December 2000
Abstract—Synthesis of key intermediates leading to 2-iso-oxacephems was carried out starting from
L- and D-threonine. As
predicted in our previous paper (Tetrahedron Lett. 1995, 36, 8303–8306) all diastereomers of 2-iso-oxacephems can be prepared
from the appropriate enantiomers of the amino acid threonine. The absolute configuration of the 2,3- and a-carbon atoms in the
b-lactam structure was determined by X-ray crystallographic studies. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Treatment of a benzene solution of 6a with DBU
effected ring closure at room temperature to form the
lactam 7a, which was then subjected to basic hydrolysis
and mono-decarboxylation of the malonate residue to
give the mono-ester 8a. Treatment of 8a with sodium
borohydride in tert-butanol led to chemoselective
reduction, allowing the cis-mono-ester 9a to be isolated
from the trans isomer. The above steps towards 9a were
carried out as was described in our preliminary paper1
(Scheme 1). (For detailed conditions see Section 4.) The
same methods were used in the synthesis of the enan-
Bicyclic b-lactams and their nuclear analogues2 are still
of great interest as a result of both their antibacterial
activity and the continuing need for novel b-lactamase
inhibitors. It is widely known that the configuration in
positions 6 and 7 in bicyclic b-lactams is a determining
factor in their biological activity. Our aim to synthesize
Thienamycin analogues in the 2-iso-oxacephem series
makes obtaining the correct configuration of the a-car-
bon atom in the hydroxyethyl side chain a key chal-
lenge in this synthesis.
tiomeric analogues from
D-threonine, to ultimately
form 9b.
2. Discussion
With the exceptions of a-hydroxy, a-amino or a-acyl-
amino esters,4,5 sodium borohydride does not usually
reduce esters. Use of this reducing agent was extended
to b-lactam esters6 where interesting chemoselectivity
was observed. Of the diastereomeric mixture of esters
8a only the trans isomer reacted with sodium borohy-
dride at ambient temperature; this is because the car-
bonyl group in the cis-ester is in a hindered position,
being crowded by the a-acetoxyethyl and 4-
methoxyphenyl groups. The reduction product, trans-
alcohol 11a, could then be easily isolated
chromatographically from the desired cis isomer 9a. It
is also notable that, at elevated reaction temperature,
the cis-ester 9a partially isomerized into the corre-
sponding trans-ester due to the basicity of sodium
borohydride. The reduction of b-lactam cis-esters has
previously been carried out via hydrolysis and subse-
Herein, we report the total synthesis of the monocyclic
b-lactam enantiomers 9a and 9b. The key intermediates
leading to the 2-iso-oxa- and 2-iso-cephems were syn-
thesized in four steps.3 At the start of the synthesis
bromide 3a was synthesized from
L-threonine using
literature procedures. Upon treatment with thionyl
chloride in dichloromethane at elevated temperature, 3a
was cleanly converted to the acid chloride 4a. The
b-lactam precursor 6a was then formed by amination of
acid chloride 4a with the malonate and 4-
methoxyphenyl functionalized secondary amine 5.
* Corresponding author. Tel.: 36-1-463-2205; fax: 36-1-463-3297;
e-mail: nyitrai.szk@chem.bme.hu
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00003-9

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Z. Sa´nta et al. / Tetrahedron: Asymmetry 12 (2001) 89–94
quently using the mixed anhydride method,6 which was
unsuccessful in the case of compound 9a.
3. Conclusion
Two enantiomeric b-lactams 9a and 9b have been
For unambiguous determination of the absolute
configuration of all carbon atoms, a heavy atom was
needed in the enantiomers 9a and 9b. Bromination at
the aromatic center of 9a and 9b with bromine in acetic
acid was regioselective in both cases, with one isomer
resulting from bromination at the 3-position on the
aromatic ring to afford 10a and 10b, respectively, in
good yield (Scheme 2). Single-crystal X-ray analysis, as
shown on an ORTEP diagram (Fig. 1), proved that the
first reaction (step i in Scheme 1) proceeded with com-
plete retention of configuration, whilst in the ring clo-
sure step (step v in Scheme 1) complete inversion took
place on the C-2 stereocenter of threonine.
formed starting from L- and D-threonine. The introduc-
tion of a bromo-substituent into the aromatic ring had
no effect on the configuration in positions a, 2 and 3, as
could be expected. It was also unambiguously proven
that our method for the synthesis of enantiomerically
pure 3-(1-acetoxyethyl)-b-lactams is a general one; the
stereochemistry of the product depends only on the
stereogenicity of the starting threonine. The carbon
atom in position 2 in the chain of threonine reacts in
the amino-bromine exchange step with retention, and
the ring closure takes place with inversion (SN2i). This
study indicates that starting from
D-allo-threonine will
allow Thienamycin-like stereochemistry to be reached.
Scheme 1. Synthesis of one enantiomer 9a (aR,2S,3R) is shown only. i: NaNO2, KBr, 1.25 M H2SO4, 0“25°C; ii: AcCl, CH2Cl2,
Py, 5°C; iii: SOCl2, CH2Cl2, 60°C; iv: toluene, 80°C; v: DBU, benzene, rt; vi: (a) 1N NaOH, Py, 5°C; (b) a-picoline, 150°C, 80
min; vii: NaBH4, tert-BuOH, rt. Abbr.: PMP=4-methoxyphenyl.

Z. Sa´nta et al. / Tetrahedron: Asymmetry 12 (2001) 89–94
91
4.2. Dimethyl {N-[(2S,3R)-3-acetoxy-2-bromobutyryl]-
N-(4-methoxyphenyl)aminomalonate} 6a
A
mixture of (2S,3R)-3-acetoxy-2-bromobutyryl
chloride7 4a (7.3 g, 30.0 mmol) and dimethyl [N-(4-
methoxyphenyl)aminomalonate] (7.6 g, 30.0 mmol) was
stirred at 80°C in toluene (25 ml) for 2 days, filtered off,
and the filtrate was washed with water (3×10 ml) and
dried over MgSO4. The solution was concentrated to
dryness. The crude oil (13.2 g, 95%) was used for the
following step: 1.0 g was purified on 15 g of Kieselgel G
by using CH2Cl2“CH2Cl2:EtOAc 10:1 as eluent to give
the pure oily product. [h]D=+90. IR (neat): w 1720
(CO), 1640 (CON), 1200 and 1000 (COC) cm−1. 1H
NMR (CDCl3): l 1.30 (3H, d, J=6.25 Hz, CH3), 2.0
(3H, s, CH3CO), 3.64, 3.75, and 3.81 (9H, 3s, 3×
OCH3), 4.07 (1H, d, J=9.4 Hz, CHBr), 5.30–5.33 (1H,
m, CHOAc), 5.32 [1H, s, CH(COOMe)2], 6.91 (2H, d,
J=8.25 Hz, ArH), 7.42 (2H, brd, ArH) ppm.
Scheme 2. i: Bromine, acetic acid, rt.
4.3. Dimethyl {N-[(2R,3S)-3-acetoxy-2-bromobutyryl]-
N-(4-methoxyphenyl)aminomalonate} 6b
D
-Threonine (11.9 g, 0.1 mol) and KBr (41.8 g, 0.35
4. Experimental
4.1. General
mol) were dissolved under cooling in 1.25 M sulfuric
acid (210 ml). Sodium nitrite (11.16 g, 0.16 mol) was
added in small portions to this solution at 0°C. After 1
h the solution was stirred for another 1 h at 25°C. The
reaction mixture was extracted with ether (5×50 ml).
The combined organic extract was washed with brine
then dried (MgSO4). After evaporation of the solvent,
the residue was distilled at 0.1 torr. The crude product
2b (11.9 g, 65%) was pure enough for use in the
following step. [h]D=+21.2. IR (neat): w 3600–3200 br
IR spectra were obtained on a Zeiss Specord IR 75
spectrometer. Optical rotations (T=22.0°C, unless
stated otherwise, c=1.0 g/100 cm3, CH2Cl2) were taken
on a Perkin–Elmer 241 polarimeter, that was calibrated
by measuring the optical rotations of both enantiomers
1
of menthol. H NMR (500 MHz) and 13C NMR (125
1
MHz) spectra were measured on a Bruker DRX-500
spectrometer. Elemental analyses were performed in the
Microanalytical Laboratory of the Department of
Organic Chemistry, L. Eo¨tvo¨s University, Budapest,
Hungary. Melting points were measured on a hot plate
melting point apparatus and are uncorrected. Chro-
matographic work up was carried out by using Merck
silica gel 60 (0.2–0.063) for column chromatography
and PF254 ready plates for TLC, unless otherwise
stated.
(OH), 1710 (CO) cm−1. H NMR (CDCl3): l 1.36 (3H,
d, J=6.25 Hz, CH3), 4.19 (1H, qd, J=6.25 Hz, J=4.3
Hz, CHOH), 4.31 (1H, d, J=4.3, CHBr), 6.08 (1H, brs,
OH) ppm. 13C NMR (CDCl3): l 20.34 (CH3), 52.91
(CHBr), 67.67 (CHOH), 172.89 (CO) ppm.
Freshly distilled acetyl chloride (8.0 ml, 0.11 mol) was
added to a stirred solution of (2R,3S)-2-bromo-3-
hydroxybutyric acid 2b (7.9 g, 43.2 mmol) in CH2Cl2
(50 ml) at 5°C. A mixture of pyridine (8.0 ml, 7.82 g, 99
Figure 1. The molecular diagram of 10a with the numbering of atoms. Atomic displacement ellipsoids represent 50% probabilities.

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Z. Sa´nta et al. / Tetrahedron: Asymmetry 12 (2001) 89–94
mmol) and CH2Cl2 (50 ml) was also added at the same
temperature. After stirring for 1.5 h water was added to
the mixture. The solution was acidified with HCl to pH
2–3, extracted with ether (3×30 ml) and the organic
solution was concentrated to an oily residue, which was
stirred with a mixture of THF and water (1:1; 100 ml)
for 4 h at ambient temperature in order to remove the
anhydride. After extraction with ether (3×30 ml) the
combined organic layers were dried (MgSO4) and con-
centrated to dryness. The solvent impurities were
removed in vacuo (0.1 torr) to give 9.52 g (98%) oily
product 3b. [h]D=+3.8. IR (neat): w 1720 (CO) cm−1.
1H NMR (CDCl3): l 1.42 (3H, d, J=6.35 Hz, CH3),
2.11 (3H, s, CH3CO), 4.36 (1H, d, J=6.35, CHBr),
5.31–5.37 (1H, m, CHOAc) ppm. 13C NMR (CDCl3): l
17.79 (CH3), 20.97 (CH3CO), 47.91 (CHBr), 69.42
(CHOAc), 170.19 and 171.87 (COO’s) ppm.
7.48 (4H, AA%BB%, J=8.8 Hz, ArH) ppm. Anal. calcd
for C18H21NO8 C, 56.99; H, 5.58; N, 3.69; found C,
56.89; H, 5.56; N, 3.77.
4.5. Dimethyl [(aS,3S)-3-(1-acetoxyethyl)-1-(4-methoxy-
phenyl)-4-oxoazetidine-2,2-dicarboxylate] 7b
Prepared analogously to 7a in 86% yield. Oil. [h]D=+
95. IR (neat): w 1750 (CON), 1720 (CO), 1200 and 1000
1
(COC) cm−1. H NMR (CDCl3): l 1.51 (3H, d, J=6.6
Hz, CH3), 1.98 (3H, s, CH3CO), 3.78–3.80 (9H, s,
3×OCH3), 3.99 (1H, d, J=2.3 Hz, 3-H), 5.28–5.32 (1H,
m, CHOAc), 6.85 and 7.46 (4H, dd, Jortho=7.15 Hz,
J
meta=1.8 Hz, ArH) ppm. 13C NMR (CDCl3): l 18.49
(CH3), 21.00 (CH3CO), 53.09 and 53.93 (2×CH3O),
55.59 (CH3OAr), 62.28 (CHOAc), 66.58 (C-3), 67.36
(C-2), 114.30, 120.7, 130.17, and 157.18 (Ar-Cs),
163.17 (C-4), 166.33 and 167.63 (COOMe), 170.26
(CH3CO) ppm. Anal. calcd for C18H21NO8 C, 56.99; H,
5.58; N, 3.69; found N, 3.82.
(2R,3S)-3-Acetoxy-2-bromobutyryl chloride 4b was
prepared analogously to its (2S,3R)-enantiomer.8 Thio-
nyl chloride (11.15 ml, 0.15 mol) was added dropwise to
a solution of (2R,3S)-3-acetoxy-2-bromobutyric acid 3b
(9.4 g, 41.9 mmol) in CH2Cl2 (40 ml) at 0°C. The
mixture was stirred at 60°C for 8 h. The solution was
concentrated to dryness. Benzene (2×50 ml) was added
and distilled from the crude oil to give 4b (8.05 g, 79%).
The residue was pure enough to use directly in the
following step.
4.6. (aR,3R)-3-(1-Acetoxyethyl)-2-methoxycarbonyl-1-
(4-methoxyphenyl)-4-oxoazetidine-2-carboxylic acid
1N NaOH (20 ml) was added to a stirred solution of
the diester 7a (8.0 g, 21 mmol) in pyridine (10 ml) at
5°C. The mixture was maintained at this temperature
overnight, then diluted with saturated NaHCO3 (12 ml)
and extracted with ethyl acetate (2×20 ml). The
aqueous solution was saturated with NaCl, acidified
with concentrated HCl and extracted with ethyl acetate.
The combined organic layers were washed with brine,
dried (MgSO4) and evaporated. The crude product (4.5
g, 59%) was purified for analysis by TLC using
CH2Cl2:EtOAc 10:3 as eluent. Mp: 103°C. [h]D=−20.9.
IR (KBr): w 3700–3400 (OH), 1750 (CON), 1720 (CO),
Analogously to 6a, 8.05 g (33.0 mmol) of 4b and
dimethyl [N-(4-methoxyphenyl)aminomalonate] (8.37 g,
33.0 mmol) gave 13.4 g (88%) of 6b. [h]2D3.5=−78.3. IR
1
(neat): w 1720 (CO) cm−1. H NMR (CDCl3): l 1.29
(3H, d, J=6.25 Hz, CH3), 1.99 (3H, s, CH3CO), 3.66,
3.76, and 3.82 (3×3H, 3s, 3×CH3O), 4.09 (1H, d, J=9.4
Hz, CHBr), 5.30–5.33 (1H, m, CHOAc), 5.32 [1H, s,
CH(COOMe)2], 6.91 (2H, d, J=8.25 Hz, ArH), 7.42
(2H, brd, ArH) ppm. 13C NMR (CDCl3): l 17.70
(CH3), 21.04 (CH3CO), 45.05 (CHBr), 53.12 and 53.18
(2×CH3O), 55.64 (CH3OAr), 65.08 [CH(COOMe)2],
71.13 (CHOAc), 114.96, 115.25, 130.14, 130.32, 131.62,
and 160.36 (Ar-Cs), 165.56, 165.88, 168.05, and 169.70
(COs) ppm.
1
1700 (COOH), 1220 and 1000 (COC) cm−1. H NMR
(CDCl3): l 1.45 (3H, d, J=6.6 Hz, CH3), 1.93 (3H, s,
CH3CO), 3.72 (6H, s, 2×OCH3), 3.90 (1H, d, J=3.0
Hz, 3-H), 5.0–5.4 (1H, m, CHOAc), 6.65 and 7.45 (4H,
AA%BB%, J=9 Hz, ArH), 9.67 (1H, brs, OH) ppm.
Anal. calcd for C17H19NO8 (365.34) C, 55.88; H, 5.24;
N, 3.83; found C, 55.62; H, 4.98; N, 3.53.
4.7. (aS,3S)-3-(1-Acetoxyethyl)-2-methoxycarbonyl-1-
(4-methoxyphenyl)-4-oxoazetidine-2-carboxylic acid
4.4. Dimethyl [(aR,3R)-3-(1-acetoxyethyl)-1-(4-methoxy-
phenyl)-4-oxoazetidine-2,2-dicarboxylate] 7a
Prepared analogously to Section 4.6 in 58% yield.
The bromoester 6a (4.61 g, 10 mmol) was dissolved in
benzene (30 ml). DBU (1.57 ml, 10.5 mmol) in benzene
(4.2 ml) was dropped to this solution under cooling
(15–20°C). The mixture was stirred overnight, and the
DBU salt was filtered off and washed with ethyl ace-
tate. The combined organic filtrates were washed subse-
quently with 10% HCl, saturated NaHCO3 solution,
water and then with brine. It was evaporated after
drying (MgSO4) to give crude product (3.49 g, 92%)
which was used without purification for the following
step. The analytically pure product was obtained simi-
larly as mentioned above. Oil. [h]D=−97. IR (neat): w
1750 (CON), 1720 (CO), 1200 and 1000 (COC) cm−1.
1H NMR (CDCl3): l 1.47 (3H, d, J=6.6 Hz, CH3),
1.95 (3H, s, CH3CO), 3.72 (9H, s, 3×OCH3), 3.92 (1H,
d, J=2.7 Hz, 3-H), 5.0–5.4 (1H, m, CHOAc), 6.80 and
4.8. Methyl [(aR,2RS,3R)-3-(1-acetoxyethyl)-1-(4-
methoxyphenyl)-4-oxoazetidine-2-carboxylate] 8a
The compound from Section 4.6 (3.6 g, 10.0 mmol) was
stirred under reflux with 2-picoline (10 ml) for 80 min.
The solution was concentrated to dryness and dissolved
in EtOAc. The organic solution was washed subse-
quently with 10% HCl, saturated NaHCO3 and brine,
dried (MgSO4) and evaporated to give 2.32 g (72%)
crude mixture of esters 8a.
4.9. Methyl [(aS,2RS,3S)-3-(1-acetoxyethyl)-1-(4-
methoxyphenyl)-4-oxoazetidine-2-carboxylate] 8b
Prepared analogously to 8a in 67% yield.

Z. Sa´nta et al. / Tetrahedron: Asymmetry 12 (2001) 89–94
93
1
4.10. Methyl [(aR,2S,3R)-3-(1-acetoxyethyl)-1-(4-meth-
1230 and 1010 (COC) cm−1. H NMR (CDCl3): l 1.43
(3H, d, J=6.5 Hz, CH3), 1.9 (1H, brs, OH), 2.03 (3H,
s, CH3CO), 3.46 (1H, m, Jvic=4.6 Hz, Jtrans=2.5 Hz, 3-H),
3.79 (3H, s, OCH3), 3.98 (3H, m, 4-CH2+4-H), 5.31 (1H,
m, J=6.5 Hz, J=4.6 Hz, a-H), 6.89 (2H, m, Jortho=9 Hz,
ArH), 7.35 (2H, m, Jortho=9 Hz, ArH) ppm. Anal. calcd
for C15H19NO5 (293.32) C, 61.42; H, 6.53; N, 4.48; found
C, 61.23; H, 6.50; N, 4.67.
oxyphenyl)-4-oxoazetidine-2-carboxylate] 9a
A solution of 8a (15 g, 46 mmol) in tert-butyl alcohol
was treated with NaBH4 (8.75 g, 230 mmol) at ambient
temperature. The reaction mixture was concentrated to
dryness in vacuo. The residue was triturated with EtOAc,
the insoluble inorganic compounds were filtered off, and
washed thoroughly with EtOAc. The combined organic
filtrates were washed three times with brine, and the
aqueous layers were extracted with EtOAc. The organic
solution was dried (MgSO4) and evaporated. The residue
was separated from a single product by column chromato-
graphy to give the title compound (10.5 g, 68%). Rf=0.7
(TLC, CH2Cl2:EtOAc 10:2). Mp: 179°C. [h]D=−141.5.
IR (KBr): w 2936, 2880, 2840 (CH), 1750 (CON), 1720
(CO), 1248 and 1032 (COC) cm−1. 1H NMR (CDCl3): l
1.49 (3H, d, J=6.5 Hz, CH3), 1.99 (3H, s, CH3CO), 3.70
(1H, dd, Jh-H=3.0 Hz, Jcis=6.4 Hz, 3-H), 3.73 (3H, s,
OCH3), 3.78 (3H, s, OCH3), 4.59 (1H, d, Jcis=6.4 Hz,
2-H), 5.26 (1H, qd, J=6.5 Hz, J3-H=3.0 Hz, a-H), 6.87
(2H, d, Jortho=8.8 Hz, ArH), 7.31 (2H, d, Jortho=8.8 Hz,
ArH) ppm. 13C NMR (CDCl3): l 18.88 (CH3), 21.17
(CH3CO), 52.60 (CH3OOC), 53.92 (C-2), 55.72 (CH3-
OAr), 56.98 (C-3), 66.23 (C-a), 114.53, 118.55, 131.10 and
156.68 (Ar-Cs), 162.60 (C-4), 168.40 (COOMe), 170.58
(CH3CO) ppm. Anal. calcd for C16H19NO6 (321.33) C,
59.81; H, 5.96; N, 4.36; found C, 59.85; H, 5.86; N, 4.43.
4.13. (aS,2S,3S)-3-(1-Acetoxyethyl)-4-hydroxymethyl-1-
(4-methoxyphenyl)azetidine-2-one 11b
Prepared by the reduction of 8b in 12% yield as described
above. Oil. Rf=0.15 (TLC, CH2Cl2:EtOAc 10:2). [h]D24.5
=
−49.0. IR (neat): w 3600–3200 (OH), 1740 (CON), 1710
(CO), 1230 and 1010 (COC) cm−1. 1H NMR (CDCl3): l
1.44 (3H, d, J=6.45 Hz, CH3), 1.83 (1H, brs, OH), 2.04
(3H, s, CH3CO), 3.46 (1H, dd, Jvic=4.5 Hz, Jtrans=2.4
Hz, 3-H), 3.79 (3H, s, OCH3), 3.92 (1H, dd, JCH ,4H=3.5
Hz, Jgem=12 Hz, CH2), 3.99 (1H, ddd, JCH ,4H=3.5 Hz,
2
2
J
J
J
CH ,4H=3.7 Hz, J3H,4H=2.4 Hz, 4H), 4.06 (1H, dd,
CH ,4H=3.7 Hz, Jgem=12 Hz, CH2), 5.32 (1H, qd,
2
2
CH ,hH=6.6 Hz, J4H,hH=4.6 Hz, a-H), 6.89 and 7.37 (4H,
3
AA%BB%, J=9 Hz, ArH) ppm. 13C NMR (CDCl3)
l 17.93 (CH3), 21.40 (CH3CO), 55.39 (C-3), 55.67 (C-4),
55.75 (CH3OAr), 61.13 (CH2OH), 67.64 (C-a), 114.76,
118.85 (C-2% and C-3%), 130.95 (C-1%), 156.58 (C-4%),
163.95 (C-2), 170.80 (MeCO) ppm.
The side product proved to be the corresponding alcohol
11a.
4.14. Methyl [(aR,2S,3R)-3-(1-acetoxyethyl)-1-(3-
bromo-4-methoxyphenyl)-4-oxoazetidine-2-carboxylate]
10a
4.11. Methyl [(aS,2R,3S)-3-(1-acetoxyethyl)-1-(4-meth-
oxyphenyl)-4-oxoazetidine-2-carboxylate] 9b
A solution of bromine (0.1 ml; 2 mmol) in acetic acid (3
ml) was added to a solution of 9a (0.20 g; 0.6 mmol) in
acetic acid (7 ml), and the mixture was stirred for 1 day
at ambient temperature. The solution was poured onto
a mixture of crushed ice (100 g) and Na2S2O5 (0.20 g; 1
mmol). The product which crystallized immediately as a
white powder, collected by filtration and dissolved in
CH2Cl2. The resultant dichloromethane solution was
washed with cold water and 5% Na2CO3 solution, then
dried (Mg2SO4), and evaporated to provide pure product
(0.17 g, 71%). Using a stoichiometric amount of bromine
give a mixture of unreacted starting material (Rf 0.6) and
product (Rf 0.65) using CH2Cl2:EtOAc 10:2 as eluent.
[h]2D4.5=−127.3. Mp: 166°C. IR (KBr): w 1744 (CON),
1720 (CO), 1240 and 1048 (COC) cm−1. 1H NMR
(CDCl3): l 1.47 (3H, d, J=7.0 Hz, CH3), 1.98 (3H, s,
CH3CO), 3.71 (1H, m, J3H,2H=6.5 Hz, J3H,hH=2.8 Hz,
3-H), 3.73 (3H, s, OCH3), 3.85 (3H, s, ArOCH3), 4.59 (1H,
Compound 9b was similarly prepared as 9a, starting with
the corresponding diester 7b via the diastereomeric
monoester 8b, without purification of the intermediate
aS,3S-2-methoxycarbonyl-2-carboxylic acid. This was
immediately reduced with sodium borohydride in tert-
butyl alcohol to 11b in 11.5% yield, and separated by
column chromatography from the unreacted 9b in 65%
yield. Rf=0.7 (TLC, CH2Cl2:EtOAc 10:2). Mp: 178°C.
[h]D=+143.1. IR (KBr): w 2990, 2956, 2936 (CH),1750,
1
1736 (CO), 1516 (Ar), 1248 and 1050 (COC) cm−1. H
NMR (CDCl3): l 1.50 (3H, d, J=6.4 Hz, CH3), 2.01
(3H, s, CH3CO), 3.71 (1H, dd, Jh-H=2.9 Hz, Jcis=6.4
Hz, 3-H), 3.75 (3H, s, OCH3), 3.80 (3H, s, OCH3), 4.60
(1H, d, Jcis=6.4 Hz, 2-H), 5.26 (1H, qd, J=6.4 Hz,
J
3-H=2.9 Hz, a-H), 6.89 (2H, d, Jortho=8.9 Hz, ArH),
7.32 (2H, d, Jortho=8.9 Hz, ArH) ppm. 13C NMR
(CDCl3): 18.91 (CH3), 21.19 (CH3CO), 52.63
l
(CH3OOC), 53.94 (C-3), 55.74 (CH3OAr), 57.01 (C-2),
66.25 (C-a), 114.56, 118.57, 131.12, and 156.71 (Ar-Cs),
162.61 (C-4), 168.40 (COOMe), 170.61 (CH3CO) ppm.
Anal. calcd for C16H19NO6 (321.33) C, 59.81; H, 5.96;
N, 4.36; found C, 59.75; H, 5.53; N, 4.46.
J3H,2H=6.5 Hz, 2-H), 5.23 (1H, qd, JCH ,hH=7 Hz,
J3-H,hH=2.8 Hz, a-H), 6.84 (1H, d, Jortho=8.39 Hz, Ar-5%-
H), 7.29 (1H, dd, Jortho=8.9 Hz, Jmeta=2.5 Hz, Ar-6%-H),
7.58 (1H, d, Jmeta=2.5 Hz, Ar-2%-H) ppm. 13C NMR
(CDCl3):
l 18.76 (CH3), 21.08 (CH3CO), 52.65
(CH3OOC), 53.98 (C-2), 56.69 (CH3OAr), 57.14 (C-3),
66.16 (C-a), 112.07 (C-3%), 112.34 (C-5%), 117.34 (C-6%),
122.33 (C-2%), 131.62 (C-1%), 153.05 (C-4%), 162.69 (C-4),
168.10 (COOMe), 170.44 (C-4) ppm. Anal. calcd for
C15H18BrNO5 (400.23) C, 48.02; H, 4.53; Br, 19.96; N,
3.50; found C, 48.30; H, 4.68; Br, 19.87; N, 3.74.
4.12. (aR,2R,3R)-3-(1-Acetoxyethyl)-4-hydroxymethyl-
1-(4-methoxyphenyl)azetidine-2-one 11a
Oil. Rf=0.15 (TLC, CH2Cl2:EtOAc 10:2). [h]D=+43.7.
IR (neat): w 3600–3200 (OH), 1740 (CON), 1710 (CO),

94
Z. Sa´nta et al. / Tetrahedron: Asymmetry 12 (2001) 89–94
4.15. Methyl [(aS,2R,3S)-3-(1-acetoxyethyl)-1-(3-
bromo-4-methoxyphenyl)-4-oxoazetidine-2-carboxylate]
10b
diagram10 of 10a with the numbering of atoms is
depicted in Fig. 1.
Prepared analogously to its enantiomer 10a starting
from 9b. [h]2D4.5=+127.2. Mp: 166°C. IR (KBr): w 1756
(CON), 1728 (CO), 1244 and 1048 (COC) cm−1. 1H
Acknowledgements
NMR (CDCl3): l 1.49 (3H, d, JCH ,h=6.5 Hz, CH3),
´
3
The authors are grateful to Miss K. Ofalvi for record-
1.99 (3H, s, CH3CO), 3.72 (1H, m, J3H,2H=6.5 Hz,
J3H,hH=2.8 Hz, 3-H), 3.75 (3H, s, OCH3), 3.87 (3H, s,
ArOCH3), 4.59 (1H, J3H,2H=6.5 Hz, 2-H), 5.25 (1H,
´
ing IR spectra. We gratefully acknowledge Dr. Aron
Szollossy for his contributions by measuring a 2D-
COSY NMR spectrum of 9a. Thanks are also due to
Mrs. H. Medzihradszky-Schweiger and staff for the
micro-analysis and to OTKA (Hungarian Scientific
Research Fund; grant T 14200 and T 14978) for finan-
cial assistance.
3
3
qd, JCH
,
hH=6.5 Hz, J3-H,hH=2.8 Hz, a-H), 6.86 (1H, d,
3
Jortho=8.9 Hz, Ar-5%-H), 7.32 (1H, dd, Jortho=8.9 Hz,
meta=2.5 Hz, Ar-6%-H), 7.59 (1H, Jmeta=2.5 Hz, Ar-2%-
J
H) ppm. 13C NMR (CDCl3): l 18.82 (CH3), 21.13
(CH3CO), 52.71 (CH3O), 54.03 (C-2), 56.75 (CH3OAr),
57.21 (C-3), 66.20 (C-a), 112.17 (C-3%), 112.38 (C-5%),
117.42 (C-6%), 122.40 (C-2%), 131.66 (C-1%), 153.14 (C-4%),
162.70 (C-4), 168.12 (COOMe), 170.52 (CH3CO) ppm.
Anal. calcd for C15H18BrNO5 (400.23) C, 48.02; H,
4.53; Br, 19.96; N, 3.50; found C, 48.00; H, 4.79; Br,
19.92; N, 3.61.
References
1. Madara´sz, Z.; Ne´meth, I.; Toscano, P.; Welch, J.; Nyi-
trai, J. Tetrahedron Lett. 1995, 36, 8303–8306.
2. (a) Morin, R. B.; Gorman, M. Chemistry and Biology of
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4.16. Crystallography
The two enantiomers were recrystallized from CH2Cl2–
hexane to furnish suitable single crystals for X-ray
analyses. Intensity data were collected on an Enraf–
Nonius CAD4 diffractometer (graphite-monochro-
,
mated Mo Ka radiation, u=0.710730 A). The
structures were solved by direct methods and refined9
against F2. Crystal data for 10a, 10b. C16H18BrNO6,
Fwt=400.22, T=293(2) K, F(000)=408, monoclinic,
space group P21, Z=2, 10a: a=7.940(1), b=5.566(1),
7. Shiozaki, M.; Hiraoka, T. Tetrahedron 1982, 38, 3457–
3463.
8. Shimaghigashi, Y.; Waki, M.; Izumiya, N. Bull. Chem.
3
,
,
c=19.977(2) A, i=97.38(1)°, V=875.6(2) A , Dcalcd
=
1.518 Mg/m3, v=2.378 mm−1, number of independent
reflections=8275, R1=0.0339, wR2=0.0797, goodness-
of-fit=0.845, absolute structure parameter=−0.001(6).
Soc. Jpn. 1979, 52, 949–950.
9. (a) Sheldrick, G. M. SHELXS-97, Program for Crystal
Structure Solution (1997), University of Go¨ttingen, Ger-
many; (b) Sheldrick, G. M. SHELXL-97, Program for
Crystal Structure Refinement (1997), University of Go¨t-
tingen, Germany.
,
10b: a=7.940(1), b=5.565(1), c=19.966(2) A, i=
3
97.40(1)°, V=874.9(2) A , Dcalcd=1.519 Mg/m3, v=
,
2.380 mm−1, number of independent reflections=5436,
R1=0.0341, wR2=0.0761, goodness-of-fit=0.855, abso-
lute structure parameter=−0.013(8).
A
molecular
10. Spek, L. Acta Crystallogr., Sect. A 1990, 46, C34.
.
.