Enantioselective synthesis of 2-isocephem and 2-isooxacephem antibiotics

Article abstract of DOI:10.1039/a700650k

The azido lactone 8 was prepared in a highly stereoselective manner by introduction of an azide function to the lactone 6 derived from L-aspartic acid, and then was converted into (2S,3S)-3-amino-2-azido-4-hydroxybutanoic acid 4. Four-component condensation of the amino acid 4, p-nitrobenzyl isocyanide and formaldehyde or 2,2-diethoxyacetaldehyde furnished the corresponding 3,4-cis-azetidinone 16 or 26 in excellent yield. 3-Methoxy-2-isooxacephalosporin was prepared by the intramolecular acylation of imidazolide 23 derived from compound 16. 3-Unsubstituted 2-isocephem and 2-isooxacephem analogues were prepared from the azetidinone 26.

Full text of DOI:10.1039/a700650k

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Enantioselective synthesis of 2-isocephem and 2-isooxacephem
antibiotics
Hajime Nitta,a Ikuo Ueda a and Minoru Hatanaka *,b
a
The Institute of Scientific and Industrial Research, Osaka University, Mihogaoka, Ibaraki,
Osaka 567, Japan
b Department of Applied Chemistry and Biotechnology, Faculty of Engineering,
Fukui University, Bunkyo, Fukui 910, Japan
The azido lactone 8 was prepared in a highly stereoselective manner by introduction of an azide function
to the lactone 6 derived from L-aspartic acid, and then was converted into (2S,3S)-3-amino-2-azido-4-
hydroxybutanoic acid 4. Four-component condensation of the amino acid 4, p-nitrobenzyl isocyanide and
formaldehyde or 2,2-diethoxyacetaldehyde furnished the corresponding 3,4-cis-azetidinone 16 or 26 in
excellent yield. 3-M ethoxy-2-isooxacephalosporin was prepared by the intramolecular acylation of
imidazolide 23 derived from compound 16. 3-U nsubstituted 2-isocephem and 2-isooxacephem analogues
were prepared from the azetidinone 26.
sation on the amino acid can provide (3S,4S)-azetidinones
Introduction
having the functionality suitable to build up the fused 6-
membered heterocyclic ring. In this paper we report the details
of the enantioselective syntheses of 2-isocephem and 2-iso-
oxacephems.5
Synthesis of the nuclear analogues of β-lactam antibiotics has
attracted considerable interest. A wide range of structure types
have been made available by total synthesis, and led to testing
for antibacterial activity. 2-Isocephalosporin 1 and 2-iso-
oxacephalosporin 2 have been shown to have potent anti-
bacterial activity in their derivatives bearing hydrogen, methyl,
and substituted methyl as the C-3 substituents.1 Although one
of the enantiomers exhibits superior activity as is the case with
all β-lactam antibiotics, many previous syntheses led to racemic
mixtures.2 Several efforts have been directed to the synthesis of
the enantiomerically pure forms. The primary problem is the
construction of the cis-oriented chiral centres at the azetidinone
ring. The existing methods for the syntheses of these com-
Results and discussion
Synthesis of (2S,3S)-3-amino-2-azido-4-hydroxybutanoic acid
The (S)-lactones 6 and 7 were prepared by the reduction of N-
protected -aspartic anhydrides 3 and 5 with NaBH4 in good
yields (Scheme 2).6 Treatment of compound 6 with 2 mol equiv.
NHR
H
H
CO2H
HO2C
H
H
H
H
RCONH
RCONH
O
O
NH2
O
S
O
3 R = Boc
5 R = Cbz
N
N
R
R
O
O
CO2H
CO2H
i
1
2
NHBoc
NHR
H
H
pounds involve an asymmetric ketene–imine cycloaddition reac-
tion as a key step in which a chiral auxiliary was incorporated in
either imine or ketene form.1a,1b,3,4 Our solution of this problem
is to use -aspartic acid as a chiral starting material (Scheme 1).
We expected that the β-amino acid 4 having the desired two
H
N3
O
ii, iii
O
O
O
O
8
6 R = Boc
7 R = Cbz
iv, v
N3
NHBoc
N3
H
H
H
Boc = CO2But
Cbz = CO2CH2Ph
HO2C
OH
O
H
O
HO2C
OH
O
NH2
H
NH2
3
4
4
H
H
N
N3
Scheme 2 Reagents and conditions: i, NaBH4, THF; ii, LDA, THF; iii,
TsN3; iv, TFA; v, Amberlite IRA-45
OH
R
O
of lithium diisopropylamide (LDA) in tetrahydrofuran (THF)
at Ϫ67 ЊC followed by toluene-p-sulfonyl azide gave the desired
trans azide lactone 8 in 50% yield. Stereochemistry of com-
pound 8 was established on the basis of the observed coupling
constant (J2,3 7.9 Hz) and no observation of a nuclear Over-
CONHPNB
Scheme 1
contiguous chiral centres could be derived via introduction of
an azide group to the amino lactone 3, which was readily avail-
able from -aspartic acid. Subsequent four-component conden-
1
hauser enhancement (NOE) between H-2 and H-3 in the H
NMR spectrum. Although alkylation of the lactone 7 has been
J. Chem. Soc., Perkin Trans. 1, 1997
1793

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reported to be accompanied by significant amounts of the cis
isomer beside the trans isomer,7 the introduction of the azide
group to lactone 6 proceeded in a highly stereoselective fashion
and the formation of the cis azide was not detected. Attempted
hydrolysis of the lactone ring of compound 8 with aqueous
alkali failed and led to the elimination of tert-butoxy-
formamide. However, opening of the lactone ring occurred
simultaneously when the C-3 amino-protecting group was
removed. Thus, deprotection of 8 with trifluoroacetic acid
(TFA) and successive neutralization of the resulting trifluoro-
acetate with Amberlite IRA-45 in aq. methanol gave the crystal-
line amino acid 4 in 76% yield.
amino acid 10, formaldehyde and p-nitrobenzyl isocyanide
(CNPNB) was carried out in a very dilute methanol solution at
room temperature for 12 h, the azetidinone 11 was obtained in
78% yield. The p-nitrobenzylamide entity was then converted
into the p-nitrobenzyl ester via N-nitrosation and a thermal
rearrangement in refluxing CCl4. Subsequent acid treatment
gave the p-nitrobenzyl ester 12.
Intramolecular acylation of various carbamate derivatives
of alcohol 12 was next investigated. When the phenylthio-
carbamate of alcohol 12 was subjected to intramolecular
acylation by means of the procedure analogous to that
reported,9 only a low yield (10% or less) of compound 15 was
obtained. In addition, attempted intramolecular acylation of
the other carbamates, including the chlorocarbamate and
phenoxycarbamate of alcohol 12, resulted in no formation of
bicycle 15. The best results were accomplished with the N-
imidazolylcarbonyl entity as a carbamoyl group. Compound 12
was treated with 1,1Ј-carbonyldiimidazole (CDI) to give the car-
bamate 13 in 87% yield. Treatment of imidazolecarboxylate 13
with 2 mol equiv. of lithium hexamethyldisilazide (LHMDS) in
THF at Ϫ78 ЊC for 3 min and successive quenching with acetic
acid produced the crude 3-hydroxy-2-isooxacephem 14. Com-
pound 14 was labile and hence was treated without purification
with an excess of diazomethane to give the desired 3-methoxy-
2-isooxacephem 15 in 64% yield from azetidinone 13. Thus, an
efficient method for the construction of the 3-methoxy-2-iso-
oxacephem ring system was established.
Synthesis of 3-methoxy-2-isooxacephalosporin
There are few reports concerning the synthesis of 3-
heterosubstituted 2-isooxacephalosporins, although their bio-
logical activity is interesting because the corresponding 3-
methoxycephalosporins show potent activity.8 Previously we
described how 3-hydroxycarbacephem and 2-oxocarbapenem
ring systems could be prepared via an intermolecular acylation
reaction as a key step.9 This methodology was evaluated for our
present purposes.
A model experiment for the construction of the 3-methoxy-2-
iso-oxacephem ring system was examined with the O-protected
amino acid 10 (Scheme 3). The amino acid was prepared from
H
i, ii
The (2S,3S)-azido amino acid 4 was next subjected to the
four-component condensation with formaldehyde and CNPNB
to give the (3S,4S)-azidoazetidinone 16 in 96% yield (Scheme 4).
MeO2C
7
OH
NHCbz
9
iii—v
H
H
N
N3
i
OH
H
N
4
H
OTHP
vi
O
HO2C
OTHP
CONHPNB
O
NH2
16
CONHPNB
11
10
ii—iv
vii—ix
H
H
N
H
H
N
PhCH2CONH
N3
OR
OR
ix, x
H
N
H
N
OH
OCO
N
N
x
O
O
CO2PNB
CO2PNB
O
O
xi
21 R = TBDMS
22 R = H
23 R = CO-Im
17 R = TBDMS
18 R = H
19 R = CO-Im
CO2PNB
CO2PNB
13
v
v
vi
vi
12
H
N
vii, viii
vii, viii
O
H
H
N
H
H
N
OR
CO2PNB
O
PhCH2CONH
N3
O
O
14 R = H
15 R = Me
OMe
OMe
CO2PNB
ii
O
O
CO2PNB
24
20
Scheme 3 Reagents and conditions: i, K2CO3; ii, CH2N2; iii, 2,3-
dihydropyran, TsOH; iv, KOH; v, Pd–C, H2; vi, HCHO, CNPNB,
MeOH; vii, N2O4; viii, ClCH2CH2Cl, reflux; ix, HClO4, aq. 1,4-dioxane;
x, CDI; xi, LHDMS, THF, Ϫ78 ЊC. CNPNB = p-nitrobenzyl iso-
cyanide, CDI = 1,1Ј-carbonyldiimidazole, LHDMS = lithium hexa-
methyldisilazide
O
O
TBDMS = SiMe2But
Im = imidazol-l-yl
PhCH2CON
H
H
N
O
the (3S)-lactone 7 in 85% overall yield via straightforward
sequences consisting of hydrolysis with K2CO3, esterification
with diazomethane, protection of the resulting hydroxy group,
and removal of the other protective groups by alkali hydrolysis
and hydrogenolysis. When a four-component condensation of
CO2PNB
25
Scheme 4 Reagents and conditions: i, HCHO, CNPNB, MeOH; ii,
TBDMSCl; iii, N2O4; iv, ClCH2CH2Cl, reflux; v, HCl; vi, CDI; vii,
LHMDS, Ϫ78 ЊC; viii, CH2N2; ix, H2S, Et3N; x, PhCH2COCl
1794
J. Chem. Soc., Perkin Trans. 1, 1997

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The cis-orientation of the C-3 and C-4 hydrogens of compound
16 was confirmed by the observed coupling constant (J3,4 5.1
Hz) in the H NMR spectrum. After the hydroxy group of
into the 7-azido-2-isooxacephem 29 by hydrolysis (TFA) fol-
lowed by treatment of the resulting vinyl alcoholic intermediate
28 with triethylamine. Alternatively, methanesulfonylation
of intermediate 28 and subsequent treatment with hydrogen
sulfide furnished the 7-azido-2-isocephem 30.
1
compound 16 was protected with tert-butyldimethylsilyl chlor-
ide (TBDMSCl), the p-nitrobenzylamide was transformed via
N-nitrosation with N2O4 into the p-nitrobenzyl ester. Removal
of the TBDMS group with aq. HCl gave alcohol 18 in 90%
yield which was converted upon treatment with CDI into the
carbamate 19 in 71% yield. However, attempted cyclization of
19 with LHDMS led to the formation of a complex mixture
and not the expected 3-methoxy-2-isooxacephalosporin 20.
Therefore, we examined prior to cyclization, conversion of the
azide group of compound 17 into an amide because the forma-
tion of amide anion would be expected to retard the formation
of a carbanion at C-3 during the cyclization process. Reduction
of the azide group with H2S in the presence of triethylamine
and subsequent acylation with phenylacetyl chloride afforded
compound 21 in 75% yield, which was then converted into the
carbamate 23 in 84% yield. Cyclization of the carbamate 23 in
a manner similar to that described for compound 15 gave the
3-methoxy-2-isooxacephalosporin 24 in 53% yield without
epimerization at the 3 position. In addition, unfavourable
cyclization between the nitrogen and the carbamate leading to
bicycle 25 was not observed.
Conclusions
We have developed a convenient method for the preparation
of 2-isocephem and 2-isooxacephem in an enantioselective
fashion. The strategy involves the four-component condens-
ation of (2S,3S)-amino acid 4 leading to the excellent formation
of (3S,4S)-azetidinones 16 and 26. Intramolecular acylation
of imidazolecarboxylate 23 derived from azide 16 gave the
3-methoxy-2-isooxacephalosporin 24. 3-Unsubstituted 2-iso-
cephem 30 and 2-isooxacephem 29 were prepared from the
azetidinone 26 using the reported procedure.
Experimental
All mps were measured on a Gallenkamp micro melting point
apparatus and are uncorrected. IR spectra were recorded on a
Hitachi 260-10 spectrometer. UV spectra were recorded on a
Hitachi U-3210 spectrometer. 1H NMR spectra were measured
at 270 MHz on a JEOL 270EX spectrometer or at 360 MHz on
a Bruker AM-360 spectrometer, using SiMe4 as the internal
standard. J-Values are given in Hz. 13C NMR spectra were
recorded at 68 MHz on a JEOL 270EX spectrometer or at 90
MHz on a Bruker AM-260 spectrometer. Solvent peak (CDCl3:
δC 77.0) was used for the internal standard. Mass spectra were
recorded on a Hitachi M-80B spectrometer. Optical rotations
were measured on a Perkin-Elmer 240c polarimeter and [α]D -
values are given in units of 10Ϫ1 deg cm2 gϪ1. Column chrom-
atography was carried out on silica gel. Extracts were dried over
MgSO4 and evaporated under reduced pressure.
Synthesis of 2-isocephem and 2-iso-oxacephem nuclei
An azetidinone suitable for the construction of 3-unsubstituted
2-isocephem and 2-isooxacephem targets could be also pre-
pared from the amino acid 4 by a four-component conden-
sation (Scheme 5). When an equimolar mixture of the amino
H
H
N3
i
OH
4
H
N
CH(OEt)2
O
CONHPNB
(3S)-3-(tert-Butoxycarbonylamino)-4-butanolide 6
26
The procedure reported for the preparation of compound 76
was modified as follows. To a well stirred suspension of NaBH4
(12.4 g, 0.328 mol) in THF (100 cm3) was added a solution of -
N-(tert-butoxycarbonyl)aspartic acid anhydride 3 (70 g, 0.325
mol) in THF (350 cm3) at 0 ЊC over a period of 1.5 h. After
being stirred for an additional 2 h, the mixture was treated
carefully with 6 M aq. hydrochloric acid (90 cm3), and extracted
with ethyl acetate. The organic layer was washed successively
with water and brine, dried and evaporated. The remaining oil
was dissolved in benzene (500 cm3) and the solution was heated
under reflux using a Dean–Stark apparatus for 3 h. The ben-
zene solution was washed with saturated aq. NaHCO3, dried
and evaporated. The resulting solid was recrystallized from
ethyl acetate–hexane to give title compound 6 as crystals (50 g,
76%), mp 108 ЊC (Found: C, 53.47; H, 7.23; N, 6.96. C9H15NO4
requires C, 53.70; H, 7.52; N, 6.96%); [α]D25 Ϫ61 (c 1.0, EtOH);
νmax(KBr)/cmϪ1 1770 and 1680; δH (270 MHz; CDCl3) 1.45 (9 H,
s, CMe3), 2.47 (1 H, dd, J 3.6 and 17.8, 2-H), 2.84 (1 H, dd, J 7.9
and 17.8, 2-H), 4.22 (1 H, d, J 6.0, 4-H), 4.47–4.53 (2 H, m, 3-
and 4-H) and 5.24 (1 H, br s, NH); δC(68 MHz; CDCl3) 28.2,
34.8, 47.6, 73.7, 80.3, 155.1 and 157.3.
ii—iv
H
H
N
H
H
N
N3
N3
v
OMs
OMs
OH
H
CH(OEt)2
O
O
CO2PNB
CO2PNB
27
28
vi
ii, vii
H
H
H
H
N
N3
N3
O
S
N
O
O
CO2PNB
CO2PNB
29
30
Scheme
5
Reagents and conditions: i, (EtO)2CHCHO, CNPNB,
MeOH; ii, MsCl, Et3N; iii, N2O4, AcONa; iv, CCl4, reflux; v, TFA; vi,
Et3N; vii, H2S, Et3N
(2S,3S)-2-Azido-3-(tert-butoxycarbonylamino)-4-butanolide 8
A solution of compound 6 (5 g, 24.9 mmol) in THF (30 cm3)
was added at Ϫ78 ЊC to a solution of LDA prepared from
diisopropylamine (7.35 cm3, 52.5 mmol) and 1.5 M butyl-
lithium–hexane solution (35 cm3, 52.5 mmol). The mixture was
stirred for 2 h at Ϫ78 ЊC and treated with a solution of toluene-
p-sulfonyl azide (5.9 g, 30 mmol) in THF (30 cm3). After being
stirred for 1 h at Ϫ78 ЊC, the mixture was treated with trimeth-
ylsilyl chloride (9.5 mg, 75 mmol), warmed to 0 ЊC over a period
of 1 h and then concentrated. The remaining residue was
shaken with ice–water (100 cm3) and ethyl acetate (100 cm3).
The organic layer was dried and evaporated. Column chroma-
acid 4, 2,2-diethoxyacetaldehyde and CNPNB was stirred in
methanol at room temperature, the cis-azetidinone 26 was
obtained as a 1:1 mixture of the diastereomers at the C-1Ј
position in 93% yield.
Methanesulfonylation of the hydroxy group of compound 26
followed by conversion of the amide group into an ester via N-
nitrosation gave compound 27 in 57% yield, which corres-
ponded to the key intermediate in the synthesis of 2-isocephem
and 2-isooxacephem systems reported by Doyle et al.2a Finally,
according to Doyle’s procedure, compound 27 was converted
J. Chem. Soc., Perkin Trans. 1, 1997
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tography (benzene–ethyl acetate, 14:1, v/v) of the residue gave
title compound 8 as crystals (3 g, 50%), mp 110–111 ЊC (from
diisopropyl ether) (Found: C, 44.65; H, 5.76; N, 23.40.
C9H14N4O4 requires C, 44.63; H, 5.82; N, 23.14%); [α]D25 Ϫ69 (c
1.0, EtOH); νmax(KBr)/cmϪ1 2100, 1780 and 1680; δH (360
MHz; CDCl3) 1.46 (9 H, s, CMe3), 4.08–4.14 (4 H, m, OH, NH2
and 4-H), 4.15 (1 H, br d, J 7.9, 2-H), 4.45 (1 H, br s, 3-H), 4.55
(1 H, dd, J 7.4 and 7.4, 4-H) and 4.94 (1 H, br s, NH); δC(67.8
MHz) 28.2, 53.1, 60.4, 68.7, 81.1, 154.9 and 171.4.
methanol (400 cm3) was stirred at room temperature for 12 h.
The methanol was evaporated off and the residue was dissolved
in ethyl acetate. The solution was washed successively with aq.
NaHCO3 and brine, dried and evaporated to give title azetidi-
none 11 as an oil (5.8 g, 78%), νmax(CH2Cl2)/cmϪ1 1760, 1680
and 1520; m/z (FAB) 378 (Mϩ ϩ 1).
p-Nitrobenzyl (2S)-2-hydroxymethyl-4-oxoazetidine-1-acetate 12
A solution of amide 11 (4.6 g, 12.2 mmol) in CHCl3 (50 cm3)
was added dropwise to a suspension of N2O4 (37.4 mmol) and
sodium acetate (4.1 g, 50 mmol) in CHCl3 (20 cm3) at 0 ЊC and
the mixture was then stirred for 1 h at 0 ЊC. Saturated aq.
NaHCO3 (9 cm3) was added and the organic layer was dried
and evaporated. The residue was heated in refluxing 1,2-
dichloroethane (100 cm3) for 3 h. After evaporation of the mix-
ture, column chromatography of the residue gave an oil (3.0 g,
64%). The oil (2.9 g, 7.67 mmol) was dissolved in 1,4-dioxane
(24 cm3) and treated with 20% aq. HClO4 (8 ml) at 0 ЊC. The
solution was stirred for 30 min at 0 ЊC, poured into aq.
NaHCO3 and extracted with ethyl acetate. The organic layer
was washed with brine, dried and evaporated to give title ester
12 as crystals (2.2 g, 98%), mp 117–118 ЊC (from benzene–
hexane) (Found: C, 52.98; H, 4.89; N, 9.47. C13H14N2O6
requires C, 53.06; H, 4.80; N, 9.52%); νmax(CH2Cl2)/cmϪ1 3520,
1765 and 1750; δH (360 MHz; CDCl3) 2.98 (1 H, dd, J 4.8 and
14.6, 3-H), 3.04 (1 H, dd, J 2.7 and 14.6, 3-H), 3.24 (1 H, m,
2-CHHOH), 3.67 (1 H, m, 2-H), 3.86 (2 H, m, 2-CHHOH),
3.86 and 4.47 (2 H, ABq, J 18.4, NCH2CO2), 5.29 (2 H, s,
CH2Ar), 7.53 (2 H, d, J 8.7, ArH) and 8.25 (2 H, d, J 8.7, ArH);
δC(90 MHz; CDCl3) 38.6, 42.4, 54.6, 61.4, 66.0, 123.8, 128.6,
141.8, 147.9, 167.6 and 169.9.
(2S,3S)-3-Amino-2-azido-4-hydroxybutanoic acid 4
Compound 8 (5 g, 20.7 mmol) was treated with TFA (10 cm3)
and anisole (2 cm3) at 0 ЊC for 30 min. The mixture was con-
densed to remove the TFA and the residue was taken into water
(50 cm3). The solution was washed with diethyl ether, adjusted
to pH 6.0 with Amberlite IRA-45, and stirred for 6 h while the
pH was kept at 6.0 by addition of Amberlite IRA-45. After
filtration, the filtrate was evaporated to give compound 4 as
crystals (2.5 g, 76%), mp 135–137 ЊC (from aq. acetone)
(Found: C, 30.23; H, 4.98; N, 35.03. C4H8N4O3 requires C,
30.00; H, 5.03; N, 34.99%); [α]D25 Ϫ149 (c 1.0, water); δH [270
MHz; CD3OD–(CD3)2SO] 3.45 (1 H, ddd, J 5.0, 5.0 and 7.6, 3-
H), 3.63 (1 H, dd, J 7.6 and 11.5, 4-H), 3.76 (1 H, dd, J 5.0 and
11.5, 4-H) and 4.14 (1 H, d, J 5.0, 2-H); δC[67.8 MHz; CD3OD–
(CD3)2SO] 54.9, 60.5, 62.9 and 172.8.
Methyl 3-(N-benzyloxycarbonylamino)-4-hydroxybutanoate 9
A solution of compound 7 (10 g, 42.5 mmol) in 50% aq. acet-
one (100 cm3) containing K2CO3 (7 g, 50 mmol) was heated at
50 ЊC for 3 h. The cooled mixture was adjusted to pH 2.0 with
hydrochloric acid and extracted with ethyl acetate. The extract
was treated with an excess of diazomethane–diethyl ether solu-
tion. The mixture was treated with several drops of AcOH,
washed successively with aq. NaHCO3 and brine, dried and
evaporated to give ester 9 as an oil (11 g), which was used in the
next step without further purification; νmax(neat)/cmϪ1 3400,
2950, 1730, 1710 and 1690; δH (270 MHz; CDCl3) 2.60 (2 H, br
d, J 6.3, 2-H2), 3.23 (1 H, t, J 5.6, OH), 3.63 (3 H, s, OMe), 3.65
(2 H, m, 4-H2), 4.05 (1 H, m, 3-H), 5.05 (2 H, s, CH2Ph), 5.70 (1
H, d, J 8.2, NH) and 7.32 (5 H, br s, Ph); δC(67.8 MHz; CDCl3)
35.5, 49.7, 51.7, 63.8, 66.7, 127.96, 128.03, 128.4, 136.2, 156.2
and 172.1; m/z 267 (Mϩ).
p-Nitrobenzyl (2S)-2-(imidazol-1-ylcarbonyloxymethyl)-4-
oxoazetidine-1-acetate 13
A solution of the alcohol 12 (0.2 g, 0.68 mmol) and CDI (0.12
g, 0.75 mmol) in CH2Cl2 (5 cm3) was stirred at room temper-
ature overnight. The mixture was washed successively with aq.
NaHCO3 and brine, dried and evaporated to give title diester
13 as an oil (0.226 g, 87%), νmax(CH2Cl2)/cmϪ1 1770 and 1750;
δH (270 MHz; CDCl3) 2.29 (1 H, dd, J 3.0 and 15.0, 3-H), 3.25 (1
H, dd, J 5.4 and 15.0, 3-H), 4.07 and 4.23 (2 H, ABq, J 18.0,
NCH2CO2), 4.22 (1 H, m, 2-H), 4.48 (1 H, dd, J 6.4 and 11.8, 2-
CHHO), 4.80 (1 H, dd, J 3.0 and 11.8, 2-CHHO), 5.19 (2 H, s,
CH2Ar), 7.07 (1 H, br s, imidazole H), 7.37 (1 H, br s, imidazole
H), 7.49 (2 H, d, J 8.7, ArH), 8.08 (1 H, s, imidazole H) and 8.22
(2 H, d, J 8.7, ArH); δC(67.8 MHz; CDCl3) 40.0, 42.4, 50.3,
65.8, 67.6, 116.9, 123.8, 128.7, 131.0, 136.9, 148.1, 166.0 and
167.8; m/z (FAB) 389 (Mϩ ϩ 1).
(3S)-3-Amino-4-(tetrahydropyran-2-yloxy)butyric acid 10
Compound 9 (11.4 g, 42.7 mmol) was treated with 2,3-
dihydropyran (4.7 cm3, 51.6 mmol) and toluene-p-sulfonic acid
hydrate (TsOH) (0.08 g, 0.42 mmol) in CH2Cl2 (50 cm3) for 1 h
at room temperature. The mixture was washed successively with
aq. NaHCO3 and brine, dried and evaporated. The remaining
oil was dissolved in methanol (50 cm3) and 2 M aq. KOH (20
cm3) was added dropwise. The mixture was stirred overnight at
room temperature and evaporated. The residue was taken into
water (30 cm3) and the aqueous solution was washed with
diethyl ether, adjusted to pH 2.0, and extracted with ethyl acet-
ate. The oily residue was dissolved in EtOH (130 cm3) and
hydrogenated at room temperature under atmospheric pressure
in the presence of 5% Pd–C (1.3 g). The oily product was tritur-
ated in acetone to give title amino acid 10 (7.5 g, 85%) as crys-
tals, mp 158–160 ЊC (from aq. acetone) (Found: C, 50.18; H,
9.01; N, 7.28. C8H17NO4 requires C, 50.25; H, 8.96; N, 7.32%);
[α]D25 Ϫ31 (c 1.0, MeOH); δH [270 MHz; CD3OD–(CD3)2SO]
1.51–1.85 (6 H, m, CH2CH2CH2), 2.40 (2 H, m, 2-H2), 3.25–
3.61 (3 H, m, 3-H and OCH2CH2), 3.73–3.88 (2 H, m, 4-H2) and
4.62 (1 H, m, OCHO); δC[67.8 MHz; CD3OD–(CD3)2SO] 20.4,
20.5, 26.4, 31.4, 36.71, 36.75, 50.4, 50.5, 63.3, 63.4, 68.1, 68.6,
100.1, 100.7 and 176.7.
p-Nitrobenzyl (6S)-3-methoxy-8-oxo-4-oxa-1-azabicyclo[4.2.0]-
oct-2-ene-2-carboxylate 15
The carbamate 13 (100 mg, 0.26 mmol) was dissolved in THF
(5 cm3) and treated at Ϫ78 ЊC with a 1 M LHMDS–hexane solu-
tion (0.78 cm3). The solution was stirred for 3 min at Ϫ78 ЊC
and then treated with AcOH (0.044 cm3). The mixture was
poured into 5% aq. citric acid (2 cm3) and extracted with ethyl
acetate. The extract of intermediate 14 was washed with water,
dried and treated, while cooled in ice, with an excess of dia-
zomethane in diethyl ether. The mixture was then set aside at
room temperature for 3 h, and then evaporated. Flash chroma-
tography of the residue on silica gel (benzene–ethyl acetate, 2:1,
v/v) gave title compound 15 as crystals (50 mg, 58%), mp 146–
147 ЊC (from ethyl acetate–isopropyl ether) (Found: C, 48.13;
H, 4.61; N, 6.98. C8H9NO5 requires C, 48.25; H, 4.55; N,
7.03%); [α]D25 ϩ188.8 (c 0.5, CHCl3); νmax(CH2Cl2)/cmϪ1 1775,
1770 and 1600; δH (360 MHz; CDCl3) 2.64 (1 H, dd, J 1.8 and
15.0, 7-H), 3.47 (1 H, dd, J 5.0 and 15.0, 7-H), 3.65 (1 H, m, 6-
H), 3.90 (3 H, s, OMe), 3.99 (1 H, dd, J 9.7 and 10.7, 5-H), 4.86
(1 H, dd, J 3.7 and 10.7, 5-H), 5.22 and 5.44 (2 H, ABq, J 13.9,
CH2Ar), 7.64 (2 H, d, J 8.7, ArH) and 8.21 (2 H, d, J 8.7, ArH);
(4S)-1-(p-Nitrobenzylcarbamoylmethyl)-4-(tetrahydropyran-2-
yloxymethyl)azetidin-2-one 11
A solution of amino acid 10 (4.0 g, 19.7 mmol), CNPNB (3.3 g,
20.4 mmol) and 35% aq. formaldehyde (1.8 g, 21.7 mmol) in
1796
J. Chem. Soc., Perkin Trans. 1, 1997

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δC(67.8 MHz; CDCl3) 41.0, 41.2, 55.8, 64.5, 72.6, 89.7, 123.5,
128.0, 144.0, 147.2, 159.3, 161.8 and 166.4; λmax(MeOH)/nm
274 (ε/dm3 molϪ1 cmϪ1 18 100).
was treated with conc. hydrochloric acid (0.2 cm3) and the mix-
ture was stirred for 1 h at room temperature. The solution was
poured into ice–water and extracted with CH2Cl2. The extract
was washed successively with aq. NaHCO3 and brine, dried and
evaporated to give the free alcohol 22 as crystals (0.35 g, 95%),
mp 149–150 ЊC (from ethyl acetate–diisopropyl ether) (Found:
C, 58.97; H, 5.03; N, 9.78. C21H21N3O7 requires C, 59.01; H,
4.95; N, 9.83%); νmax(CH2Cl2)/cmϪ1 1770, 1740 and 1680;
δH (360 MHz; CDCl3) 3.48 (1 H, dd, J 11.0 and 12.7, 2-
CHHOH), 3.58 and 3.64 (2 H, ABq, J 15.5, CH2Ph), 3.72 and
4.55 (2 H, ABq, J 18.6, NCH2CO2), 3.87 (3 H, m, 2-H and 2-
CHHOH), 5.25 and 5.30 (2 H, ABq, J 13.0, CH2Ar), 5.62 (1 H,
dd, J 5.15 and 9.5, 3-H), 6.88 (1 H, d, J 9.5, NH), 7.32 (5 H, m,
Ph), 7.51 (2 H, d, J 8.7, ArH) and 8.25 (2 H, d, J 8.7, ArH);
δC(67.8 MHz; CDCl3) 42.1, 43.6, 57.5, 58.2, 60.3, 66.5, 124.0,
127.3, 128.86, 128.89, 129.3, 134.1, 141.2, 148.0, 168.0, 170.4
and 171.2.
(3S,4S)-3-Azido-4-hydroxymethyl-1-(p-nitrobenzylcarbamoyl-
methyl)azetidin-2-one 16
By means of the procedure described for the preparation of
compound 11, the amino acid 4 (0.5 g, 3.1 mmol) was treated
with CNPNB (0.53 g, 3.2 mmol) and 35% aq. formaldehyde
(0.28 g, 3.3 mmol) in methanol (120 cm3) to give title compound
16 as crystals (1.0 g, 96%). Recrystallization from ethyl acetate–
diisopropyl ether gave a pure sample, mp 91–92 ЊC (Found: C,
46.52; H, 4.38; N, 24.9. C13H14N6O5 requires C, 46.71; H, 4.22;
N, 25.14%); νmax(CH2Cl2)/cmϪ1 2100, 1780 and 1680; δH [360
MHz; (CD3)2SO] 3.84 (2 H, m, 4-CH2OH), 3.88 and 4.22 (2 H,
ABq, J 16.8, NCH2CO), 3.96 (1 H, m, 4-H), 4.50 (2 H, br s,
CH2Ar), 4.78 (1 H, d, J 5.1, 3-H), 4.91 (1 H, t, J 5.5, OH), 7.78
(2 H, d, J 8.4, ArH), 8.18 (2 H, d, J 8.4, ArH) and 8.66 (1 H, m,
NH); δC[67.8 MHz; (CD3)2SO] 41.6, 43.3, 58.4, 58.5, 64.1,
122.7, 127.3, 145.3, 146.0, 164.3 and 167.3.
p-Nitrobenzyl (2S,3S)-2-(imidazol-1-ylcarbonyloxymethyl)-4-
oxo-3-(phenylacetamido)azetidine-1-acetate 23
By means of the procedure described for the preparation of
compound 14, compound 22 (0.26 g, 0.6 mmol) was treated
with a solution of CDI (0.12 g, 0.74 mmol) in CH2Cl2 (5 cm3) to
give title diester 23 as crystals (0.28 g, 88%), mp 153–154 ЊC
(from ethyl acetate–diisopropyl ether) (Found: C, 57.47; H,
4.41; N, 13.38. C25H23N5O8 requires C, 57.58; H, 4.45; N,
13.43%); νmax(CH2Cl2)/cmϪ1 1770, 1760, 1750 and 1680; δH [360
MHz; CDCl3–(CD3)2SO] 3.56 and 3.62 (2 H, ABq, J 14.5,
CH2Ph), 4.08 and 4.20 (2 H, ABq, J 18, NCH2CO2), 4.26 (1 H,
m, 2-H), 4.48 (2 H, d, J 5.1, 2-CH2O), 5.15 and 5.20 (2 H, ABq,
J 13.0, CH2Ar), 5.42 (1 H, dd, J 5.1 and 7.6, 3-H), 7.01 (1 H, br
s, imidazole H), 7.26 (5 H, m, Ph), 7.35 (1 H, br s, imidazole H),
7.48 (2 H, d, J 8.5, ArH), 7.97 (1 H, s, imidazole H), 8.05 (1 H,
d, J 7.6, NH) and 8.21 (2 H, d, J 8.5, ArH); δC[67.8 MHz;
CDCl3–(CD3)2SO] 42.0, 42.6, 56.2, 57.6, 65.1, 65.8, 117.3,
123.4, 126.3, 128.0, 128.6, 128.8, 130.0, 135.5, 137.1, 142.9,
147.2, 147.7, 166.3, 168.2 and 170.9.
p-Nitrobenzyl (2S,3S)-3-azido-2-(tert-butyldimethylsiloxy-
methyl)-4-oxoazetidine-1-acetate 17
A solution of amide 16 (1.0 g, 2.99 mmol), imidazole (0.5 g, 7.3
mmol) and TBDMSCl (0.45 g, 2.99 mmol) in dimethylform-
amide (DMF) (5 cm3) was stirred at room temperature over-
night. The mixture was poured into ice–water and extracted
with ethyl acetate. The organic layer was washed with brine,
dried and evaporated. Column chromatography of the residue
gave an oil (1.2 g, 89%).
In the same manner as described for the preparation of com-
pound 12, the oil (1.0 g, 2.23 mmol) was treated with N2O4 (6.7
mmol) to give title ester 17 as an oil (0.67 g, 67%), νmax(CH2Cl2)/
cmϪ1 2100, 1775 and 1750; δH (360 MHz; CDCl3) 0.05 (6 H, s,
SiMe2), 0.85 (9 H, s, CMe3), 3.84 (2 H, m, 2-CH2O), 4.02 and
4.34 (2 H, ABq, J 18.0, NCH2CO2), 4.05 (1 H, m, 2-H), 4.80 (1
H, d, J 5.15, 3-H), 5.25 (2 H, s, CH2Ar), 7.50 (2 H, d, J 8.7,
ArH) and 8.23 (2 H, d, J 8.7, ArH); δC(67.8 MHz; CDCl3) Ϫ5.7,
18.0, 25.6, 42.6, 58.1, 62.8, 65.0, 65.7, 123.8, 128.2, 128.6, 142.0,
147.8, 164.5 and 167.3; m/z (FAB) 450 (Mϩ ϩ 1).
p-Nitrobenzyl (6S,7S)-3-methoxy-8-oxo-7-phenylacetamido-4-
oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 24
By means of the procedure described for the preparation of
compound 15, the carbamate 23 (30 mg, 0.057 mmol) was
treated with a 1 M LHMDS–THF solution (0.18 cm3) and then
with an excess of diazomethane to give title isooxacephem 24
as crystals (14 mg, 53%), mp 142–143 ЊC (from ethyl acetate–
diisopropyl ether) (Found: C, 59.35; H, 4.32; N, 9.08.
C23H21N3O8 requires C, 59.11; H, 4.53; N, 8.99%); [α]D25 ϩ133 (c
0.3, CHCl3); νmax(CH2Cl2)/cmϪ1 1770, 1760 and 1680; δH (360
MHz; CDCl3) 3.56 (2 H, br s, CH2Ph), 3.86 (3 H, s, OMe), 3.89
(1 H, m, 6-H), 4.00 (1 H, dd, J 9.8 and 10.8, 5-H), 4.58 (1 H, dd,
J 3.9 and 10.8, 5-H), 5.17 and 5.38 (2 H, Abq, J 13.7, CH2Ar),
5.33 (1 H, dd, J 4.9 and 5.3, 7-H), 6.67 (1 H, d, J 5.3, NH), 7.22–
7.35 (5 H, m, Ph), 7.57 (2 H, d, J 8.7, ArH) and 8.17 (2 H, d, J
8.7, ArH); δC(90 MHz; CDCl3) 43.2, 47.4, 55.8, 59.0, 64.5, 69.5,
88.6, 123.6, 127.7, 128.1, 129.0, 129.2, 129.3, 133.9, 143.8,
147.6, 160.2, 161.4, 165.8 and 171.9; λmax(CHCl3)/nm 271 (ε
32 600).
p-Nitrobenzyl (2S,3S)-2-(tert-butyldimethylsiloxymethyl)-4-oxo-
3-(phenylacetamido)azetidine-1-acetate 21
Hydrogen sulfide gas was bubbled into a solution of azide 17
(1.0 g, 2.23 mmol) in CH2Cl2 (20 cm3) at 0 ЊC for 3 min. Tri-
ethylamine (0.31 g, 2.23 mmol) was added and the mixture was
stirred for 1 h at 0 ЊC. The mixture was poured into ice–water
and the aqueous layer was extracted with CH2Cl2. After being
dried, the organic layers were treated with pyridine (0.3 cm3, 3.7
mmol) and phenylacetyl chloride (0.38 g, 2.46 mmol) for 30 min
at room temperature. The mixture was washed with ice–water,
dried and evaporated. Column chromatography of the residue
gave title compound 21 as crystals (0.9 g, 75%), mp 98–99 ЊC
(from benzene–hexane) (Found: C, 59.78; H, 6.22; N, 7.85.
C27H35N3O7Si requires C, 59.88; H, 6.46; N, 7.76);
νmax(CH2Cl2)/cmϪ1 1770, 1750 and 1680; δH (360 MHz; CDCl3)
0.014 (6 H, s, SiMe2), 0.85 (9 H, s, CMe3), 3.54 and 3.62 (2 H,
ABq, J 15.5, CH2Ar), 3.56 (1 H, dd, J 4.7 and 11.0, 2-CHHO),
3.77 and 4.64 (2 H, ABq, J 18.0, NCH2CO2), 3.81 (1 H, dd,
J 2.4 and 11.0, 2-CHHO), 4.06 (1 H, m, 2-H), 5.25 (2 H, s,
CH2Ar), 5.49 (1 H, dd, J 5.15 and 9.0, 3-H), 6.27 (1 H, d, J 9.0,
NH), 7.31 (5 H, m, Ph), 7.51 (2 H, d, J 9.0, ArH) and 8.25 (2 H,
d, J 9.0, ArH); δC(67.8, MHz; CDCl3) Ϫ5.7, 17.8, 25.6, 42.0,
43.3, 57.1, 58.7, 60.8, 65.6, 123.8, 127.2, 128.2, 128.5, 128.8,
128.9, 134.3, 141.9, 147.8, 167.3 and 171.1.
(3S,4S)-3-Azido-1-[2Ј,2Ј-diethoxy-1Ј-(p-nitrobenzylcarbamoyl)-
ethyl]-4-(hydroxymethyl)azetidin-2-one 26
A solution of amino acid 4 (0.67 g, 4.2 mmol), CNPNB (0.7 g,
4.3 mmol) and diethoxyacetaldehyde (0.66 g, 5 mmol) in
methanol (15 cm3) was stirred at room temperature overnight
and was then evaporated. Column chromatography of the resi-
due (benzene–ethyl acetate, 5:1, v/v) gave title azetidinone 26
(1.7 g, 93%) as a 1:1 diastereomeric mixture, which could be
separated by repeated flash chromatography. One isomer:
νmax(CH2Cl2)/cmϪ1 2100, 1760 and 1670; δH (270 MHz; CDCl3)
1.13 (3 H, t, J 7,6, CH2CH3), 1.19 (3 H, t, J 7.6, CH2CH3),
3.43 (2 H, m, 4-CH2O), 3.75–4.03 (5 H, m, OCH2CH3 and OH),
p-Nitrobenzyl (2S,3S)-2-hydroxymethyl-4-oxo-3-(phenyl-
acetamido)azetidine-1-acetate 22
A solution of silyl ether 21 (0.47 g, 0.87 mmol) in THF (5 cm3)
J. Chem. Soc., Perkin Trans. 1, 1997
1797

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4.32 (1 H, m, 4-H), 4.43 (1 H, dd, J 6.0 and 16.0, NHCHHAr),
4.60 (1 H, dd, J 6.0 and 16.0, NHCHHAr), 4.62 (1 H, d, J 4.0,
1Ј-H), 4.86 (1 H, d, J 5.3, 3-H), 5.02 (1 H, d, J 4.0, OCHO, 7.45
(2 H, d, J 8.9, ArH), 8.17 (2 H, d, J 8.9, ArH) and 8.60 (1 H, t,
J 6.0, NH); δC(67.8 MHz; CDCl3) 15.1, 15.2, 42.5, 57.8, 58.8,
59.9, 64.4, 64.6, 65.2, 101.2, 123.6, 128.0, 145.6, 147.0, 166.1
and 168.1; m/z(FAB) 437 (Mϩ ϩ 1).
MHz; CDCl3) 46.1, 65.2, 65.9, 68.2, 123.7, 128.3, 142.7, 145.8,
147.6, 161.5 and 163.5; λmax(MeOH)/nm 269 (ε 16 650).
p-Nitrobenzyl (6S,7S)-7-azido-8-oxo-4-thia-1-azabicyclo[4.2.0]-
oct-2-ene-2-carboxylate 30
Methanesulfonyl chloride (0.049 g, 0.42 mmol) was added to a
solution of mesyl ester 28 (0.17 g, 0.385 mmol) and triethyl-
amine (0.062 cm3, 0.385 mmol) in THF (10 cm3). The mixture
was stirred for 1 h at room temperature, poured into ice–water
and extracted with ethyl acetate. The organic layer was washed
in turn with 5% hydrochloric acid, aq. NaHCO3 and brine,
dried and evaporated. The remaining oil was dissolved in
CH2Cl2 (5 cm3) and H2S gas was bubbled in for 3 min at 0 ЊC.
Triethylamine (0.11 cm3, 0.81 mmol) was added slowly and the
mixture was stirred for 1 h at 5 ЊC. Nitrogen gas was bubbled
through to remove the H2S and the mixture was poured into
ice–water. The organic layer was washed in turn with 5% hydro-
chloric acid, aq. NaHCO3 and brine, dried and evaporated. The
residue was triturated in diethyl ether to give title isocephem 30
as crystals (70 mg, 50%), mp 147–148 ЊC (from ethyl acetate–
diisopropyl ether) (Found: C, 46.46; H, 3.19; N, 19.33; S, 8.86.
C14H11N5O5S requires C, 46.54; H, 3.07; N, 19.38; S, 8.87%); [α]D25
Ϫ46.6 (c 0.5, 1,4 dioxane); νmax(KBr)/cmϪ1 2100, 1760 and 1700;
δH (360 MHz; CDCl3) 3.06 (1 H, dd, J 3.8 and 13, 5-H), 3.13
(1 H, dd, J 9.4 and 13, 5-H), 3.94 (1 H, m, 6-H), 5.22 (1 H, d, J
5.1, 7-H), 5.29 and 5.41 (2 H, ABq, J 13.0, CH2Ar), 7.13 (1 H, s,
3-H), 7.60 (2 H, d, J 8.8, ArH) and 8.24 (2 H, d, J 8.8, ArH);
δC(90 MHz; CDCl3) 25.5, 49.2, 65.9, 68.6, 120.8, 123.3, 123.8,
142.5, 148.0, 159.6 and 161.2; λmax(EtOH)/nm 302 (ε 13 200).
Another isomer: νmax(CH2Cl2)/cmϪ1 2100, 1760 and 1670;
δH (270 MHz; CDCl3) 1.20 (3 H, t, J 7.6, CH2CH3), 1.23 (3 H, t,
J 7.6, CH2CH3), 3.52 (2 H, m, 4-CH2O), 3.75–4.03 (5 H, m,
OCH2CH3 and OH), 4.27 (1 H, m, 4-H), 4.43 (1 H, dd, J 5.6 and
16.0, NHCHHAr), 4.56 (1 H, d, J 5.6, 1Ј-H), 4.68 (1 H, dd, J
6.6 and 16.0, NHCHHAr), 4.75 (1 H, d, J 5.3, 3-H), 4.94 (1 H,
d, J 5.6, OCHO), 7.45 (2 H, d, J 8.9, ArH), 7.52 (1 H, br s, NH)
and 8.17 (2 H, d, J 8.9, ArH); δC(67.8 MHz; CDCl3) 14.9, 15.1,
42.7, 57.2, 59.6, 60.0, 62.8, 64.5, 65.0, 100.4, 123.7, 127.9, 145.3,
147.2 and 166.7; m/z (FAB) 437 (Mϩ ϩ 1).
p-Nitrobenzyl 2Ј-[(2S,3S)-3-azido-2-methylsulfonyloxymethyl-
4-oxoazetidin-1-yl]-2Ј-2Ј-diethoxypropionate 27
A solution of methanesulfonyl chloride (0.5 g, 4.3 mmol) in
THF (5 cm3) was added dropwise to a solution of alcohol 26
(1.7 g, 3.9 mmol), in the form of the 1:1 isomeric mixture, and
triethylamine (0.7 cm3, 5 mmol) in THF (20 cm3) at 0 ЊC. After
being stirred for 1 h at room temperature, the solution was
poured into ice–water (20 cm3) and extracted with ethyl acetate.
The extract was washed with brine, dried and evaporated to
give the crude mesyl ester as an oil. The oil was dissolved and
dry CHCl3 (10 cm3) and the solution was added to a 0.7 M
N2O4–CHCl3 solution (15 cm3) containing sodium acetate (1.15
g, 14 mmol) at 0 ЊC. The mixture was stirred for 1 h at 0 ЊC,
washed successively with aq. NaHCO3 and brine, dried and
evaporated. The residue was then heated in refluxing CCl4 for 3
h. After cooling and evaporation of the solvents column chro-
matography of the residue (benzene–ethyl acetate, 2:1, v/v)
gave title mesyl ester 27 as an oil (1.02 g, 57%), νmax(CH2Cl2)/
cmϪ1 2120, 1775 and 1755; m/z (FAB) 516 (Mϩ ϩ 1).
Acknowledgements
We are grateful to the Material Analytical Center of ISIR,
Osaka University, for mass and NMR spectra and
microanalyses.
References
1 (a) T. W. Doyle, J. L. Douglas, B. Belleau, T. T. Conway, C. F. Ferrari,
D. E. Horning, G. Lim, B.-Y. Luh, A. Martel, M. Menard and L. R.
Morris, Can. J. Chem., 1980, 58, 2508; (b) H. Mastalerz, M. Menard,
V. Vinet, J. Desiderio, J. Fung-Tomc, R. Kessler and Y. Tsai, J. Med.
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N. Tada, S. Nishitani, J. Minamikawa and J. Ishikawa, Tetrahedron:
Asymmetry, 1994, 5, 441.
2 (a) T. W. Doyle, B. Belleau, B.-Y. Luh, T. T. Conway, M. Menard,
D. J. Douglas, D. T.-W. Chu, G. Lim, L. R. Morris, P. Rivest
and M. Casey, Can. J. Chem., 1977, 55, 484; (b) T. W. Doyle,
J. L. Douglas, B. Belleau, J. Meunier and B.-Y. Luh, Can. J. Chem.,
1977, 55, 2873; T. T. Conway, G. Lim, J. L. Douglas, M. Menard,
T. W. Doyle, P. Rivest, D. Horning, L. R. Morris and D. Cimon,
Can. J. Chem., 1978, 56, 1335; D. B. Bryan, R. F. Hall, K. G. Holden,
W. F. Huffman and J. G. Gleason, J. Am. Chem. Soc., 1977, 99, 2354.
3 S. M. Tenneson and B. Belleau, Can. J. Chem., 1980, 58, 1605.
4 An alternative approach has been reported: D. A. Evans and E. B.
Sjorgen, Tetrahedron Lett., 1985, 26, 3783.
5 Preliminary reports: H. Nitta, M. Hatanaka and T. Ishimaru,
J. Chem. Soc., Chem. Commun., 1987, 51; H. Nitta, M. Hatanaka and
I. Ueda, J. Chem. Soc., Perkin Trans. 1, 1990, 432.
6 G. J. McGarver, R. N. Hiner, Y. Matsubara and T. Oh, Tetrahedron
Lett., 1983, 24, 2733.
7 S. W. McCombie, W. A. Metz and A. Afonso, Tetrahedron Lett.,
1986, 27, 305.
8 S. Kukolja and R. R. Chauvette, in Chemistry and Biology of
β-Lactam Antibiotics, ed. R. B. Morin and M. Gorman, Academic
Press, New York, 1982, vol. 1, p. 93.
p-Nitrobenzyl 2Ј-[(2S,3S)-3-azido-2-methylsulfonyloxymethyl-
4-oxoazetidin-1-yl]-3Ј-hydroxypropenoate 28
Compound 27 (1.0 g, 1.9 mmol) was treated with 95% aq. TFA
(5 ml) at 50 ЊC for 1 h. The mixture was evaporated and the
residue was dissolved in ethyl acetate. The solution was washed
successively with aq. NaHCO3 and brine, dried and evaporated
to give title compound 28 as an oil (0.68 g, 81%), which was
used in the next step without further purification, νmax(neat)/
cmϪ1 2120, 1760 and 1710; δH [360 MHz; (CD3)2SO] 3.01 (3 H, s,
OMe), 4.2–4.5 (2 H, m, 2-H and 2-CHHOH), 4.48 (1 H, m, 2-
CHHOH), 5.10 (1 H, d, J 5.1, 3-H), 5.35 (2 H, s, CH2Ar), 7.62
(2 H, d, J 8.8, ArH), 7.75 (¹H, s, vinyl H), 7.90 (¹H, s, vinyl H)
¯
²
¯
²
and 8.28 (2 H, d, J 8.8, ArH); m/z (FAB) 413 (Mϩ ϩ 1 Ϫ CHO).
p-Nitrobenzyl (6S,7S)-7-azido-8-oxo-4-oxa-1-azabicyclo[4.2.0]-
oct-2-ene-2-carboxylate 29
Triethylamine (0.26 ml, 0.9 mmol) was added to a solution of
mesyl ester 28 (0.4 g, 0.9 mmol) in CH2Cl2 (10 cm3) and the
solution was heated under reflux for 3 h. The solution was
washed successively with ice–water, 5% hydrochloric acid, aq.
NaHCO3 and brine, dried and evaporated to give the iso-
oxacephem 29 as crystals (0.3 g, 94%), which was recrystallized
from ethyl acetate–diisopropyl ether to afford a pure sample,
mp 149–150 ЊC (Found: C, 48.72; H, 3.40; N, 20.07.
C14H11N5O6 requires C, 48.70; H, 3.21; N, 20.28%); [α]D25 Ϫ32.2
(c 1.0, EtOH); νmax(KBr)/cmϪ1 2100, 1770 and 1700; δH (360
MHz; CDCl3) 3.79 (1 H, m, 6-H), 3.94 (1 H, dd, J 9.5 and 11.3,
5-H), 4.60 (1 H, dd, J 3.7 and 11.3, 5-H), 5.27 (1 H, d, J 5.2, 7-
H), 5.28 and 5.43 (2 H, ABq, J 13.5, CH2Ar), 7.04 (1 H, s, 3-H),
7.60 (2 H, d, J 8.9, ArH) and 8.23 (2 H, d, J 8.9, ArH); δC(67.8
9 M. Hatanaka, Y. Yamamoto, H. Nitta and T. Ishimasu, Tetrahedron
Lett., 1981, 22, 3883; M. Hatanaka and T. Ishimaru, Tetrahedron
Lett., 1983, 24, 4837.
Paper 7/00650K
Received 28th January 1997
Accepted 28th February 1997
1798
J. Chem. Soc., Perkin Trans. 1, 1997