Synthesis of (3,4) β-methylenecepham and (3,4) β-methylene-carbacepham via intramolecular carbene addition to double bond

Article abstract of DOI:10.1016/S0968-0896(03)00084-1

A series of new (3,4) β-methylenecepham and carbacepham analogues were synthesised as potential antibacterial agents. The key step of the synthesis included presumed generation of the carbene species from the oxalimide substrate effected by triethylphosphite and its intramolecular addition to the double bond. The stereochemistry of the tricyclic system has been elucidated by NMR and X-ray crystallography. In preliminary screening, two of the synthesised compounds exhibited modest antibacterial activity at 1.5-2.0 mg/mL against a number of bacterial strains.

Full text of DOI:10.1016/S0968-0896(03)00084-1

Bioorganic & Medicinal Chemistry 11 (2003) 1957–1967
Synthesis of (3,4) ꢀ-Methylenecepham and (3,4) ꢀ-Methylene-
carbacepham Via Intramolecular Carbene Addition to
Double Bond
Anna Korda* and Jerzy Winiarski
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Received 11 November 2002; accepted 31 January 2003
Abstract—A series of new(3,4) b-methylenecepham and carbacepham analogues were synthesised as potential antibacterial agents.
The key step of the synthesis included presumed generation of the carbene species from the oxalimide substrate effected by tri-
ethylphosphite and its intramolecular addition to the double bond. The stereochemistry of the tricyclic system has been elucidated
by NMR and X-ray crystallography. In preliminary screening, two of the synthesised compounds exhibited modest antibacterial
activity at 1.5–2.0 mg/mL against a number of bacterial strains.
# 2003 Published by Elsevier Science Ltd.
Introduction
Much less attention has been given to (3,4)-methylenecep-
hams. Long9 has reported that cyclopropanecepham (I)
(Fig. 1) with 7-acylamido substituent and typical cis con-
figuration of b-lactam protons lacks antibacterial activity
nor do related oxacephams bearing a dichlorosubtituted
cyclopropane.10 On the other hand, (2,3) a- and b-methy-
lenecephams (II) in a standard disk assay tested active at
2.0 mg/mL against a number of typical bacterial strains.11
For nearly 50 years, b-lactam antibiotics have proven to
be of enormous importance for treatment of bacterial
diseases. Many structural modifications of the typical
nuclei were prepared, their therapeutic performance
elucidated and conclusions drawn about the factors
influencing the antibacterial action. As part of this
effort, we present a novel, simple method for the con-
struction of tricyclic compounds structurally related to
cephems, namely (3,4) b-methylenecepham and (3,4)
b-methylenecarbacepham.
Syntheses of the described cyclopropane structures have
comprised relatively long multistep procedures. The
penam analogues were prepared from penicillin sulfox-
ide via azetidinone disulfides, and 2b-halomethylpeni-
cillins through their intramolecular cyclisation.2,4
Carbapenam5ꢀ7 and cepham11 compounds were formed
upon thermolysis of appropriate tricyclic pyrazoline
esters prepared from available azetidinone starting
materials in at least 10 steps. Oxa and carbacephams
were obtained in a series of reactions involving palla-
dium catalysed ene-halogenocyclisation to form g-iodo-
ketones or esters and their 1,3 elimination to yield
cyclopropane ring.12,13 Similar iodine substituted sub-
strate obtained in laborious transformations of peni-
cillin G served for the synthesis of I.9
There have been a fewreports describing synthesis and
chemistry of (2,3) a- and b-methylenepenams.1,2
b-Methylene isomer was significantly less biologically
active than the penam analogue, while the a-isomer
exhibited much higher antibacterial potency and against
selected bacterial strains could be compared to penicillin
G. Thus it was argued that stereochemistry of the tri-
cyclic system is crucial for the antibacterial properties.
Similar conclusions have been drawn from the analysis
of b-lactamase inhibiting properties of (2,3)-methylene
analogues of sulbactam.3,4 In the study related to oli-
vanic acids, (2,3) a- and b-methylenecarbapenam com-
pounds have been synthesized and their cyclopropane
stereochemistry assigned, but no antibacterial or b-lac-
tamase inhibiting properties were assessed.5ꢀ8
In viewof these findings, we have developed synthetic
strategy to make target tricyclic molecules, which are
hybrids of thienamycin related antibiotics and cepha-
losporins, that is they have a hydroxyethyl group and
trans proton configuration of the b-lactam ring, which is
fused with the six-membered ring and the cyclopropane.
*Corresponding author. Fax +48-22-632-6681; e-mail: akorda@icho.
edu.pl
0968-0896/03/$ - see front matter # 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0968-0896(03)00084-1

1958
A. Korda, J. Winiarski / Bioorg. Med. Chem. 11 (2003) 1957–1967
Figure 1. Structures of compounds I–III.
Chemistry
ded the expected oxalimides (3a–d) in overall yield of
55–67% from (1). Compounds 3a–d were cyclised in the
presence of triethylphosphite in refluxing xylene. Under
these conditions oxalimide substrates bearing carbonyl
group at C-4 side chain of azetidinone form bicyclic
compounds with unsaturated ring (penem synthesis
being the most abundant example). In the mechanistic
considerations of oxalimide cyclisation, a carbene inter-
mediate has been postulated based, among other evi-
dence, on the isolation of cyclopropane compounds of
type III, which were formed by trapping of the carbene
To synthesise target compounds (3R,4R)-3-[(R)-1-tert-
butyldimethylsilyloxyethyl)-4-acetoxyazetidin-2-one (1)
was used as the starting material. Substitution of the
acetyl group using sodium hydride generated anions of
appropriate allyl derivatives (allyl mercaptan, 2-allyl-
malonic acid diethyl ester, 2-acetylpent-4-enoic acid
ethyl ester, 3-allylpentane-2,4-dione) provided more
stable trans substituted azetidinones (2a–d) (Schemes 1
and 2). Their reaction with allyl chloro-oxalate, affor-
Scheme 1. Reagents: (i) allyl mercaptan, NaH, EtOH, (0 ꢁC/2 h, rt/18 h); (ii) allyl chlorooxalate, Et3N, CH2Cl2 (ꢀ20 ꢁC/1 h); (iii) P(OEt)3, xylene
ꢁ
.
(reflux/9 h); (iv) (i-Pr)2EtN 3HF, AcOEt (50 C/10 h); (v) Pd(PPh3)4, PPh3, sodium 2-ethyl hexanoate, AcOEt,(rt/3 h) H2O, H3PO4.
Scheme 2. Reagents: (i) (b) 2-allylmalonic acid diethyl ester or (c) 2-acetyl-pent-4-enoic acid ethyl ester or (d) 3-allylpentane-2,4-dione, NaH, THF
(0 ꢁC!rt/2 h); (ii) allyl chlorooxalate, Et3N, CH2Cl2 (ꢀ20 ꢁC/1 h); (iii) P(OEt)3, xylene (reflux/9 h).

A. Korda, J. Winiarski / Bioorg. Med. Chem. 11 (2003) 1957–1967
1959
Scheme 3. Reagents: (i) P(OEt)3, xylene (reflux/9 h).
by the double bond of the allyl ester group.14ꢀ16 We
have successfully applied this process to the synthesis of
tricyclic cepham and carbacepham compounds and
obtained tricyclic compounds 4a–d from the oxalimides
(3a–d) in yields of 25–50%. Reaction of oxalimides
(3c,d) which had a suitable ketone group competitively
produced both possible cyclised products: tricyclic
compounds with cyklopropane ring (4c,d) and bicyclic
carbapenems (4e,f) (Scheme 3). Cyclised compounds
(4a–d) were subsequently deprotected: hydroxyl group
in the presence of di-isopropyl ethyl amine tri-
fluorohydride which afforded compounds 5a–d; and
carboxyl group in the presence of Pd(PPh3)4 (Scheme 4).
Thus, the desired acids (6a–d) were obtained from (1) in
five steps.
the plane of the six-membered ring. As other synthesised
molecules (6b–d) exhibit very similar pattern of cyclo-
propyl protons in 1H NMR spectra as 6a we think the X-
ray findings for the latter molecule are also valid for 6b–d
meaning they are all syn-fused tricyclic structures.
Antibacterial Activity
The b-lactam compounds synthesized were tested for in
vitro antibacterial activity against a panel of susceptible
and resistant Gram-positive and Gram-negative organ-
isms (Agar Diffusion Well Method). In a standard disk
assay test acids 6a and 6d at 1.5–2.0 mg/mL exhibited
activity against Escherichia coli (b-lactam susceptible,
cephalosporin susceptible ampicyllin resistant) Klebsiella
pneumoniae (cephalosporin susceptible, ampicyllin resis-
tant) Providencia rettgeri (b-lactam susceptible), Mor-
ganella morgani (ampicyllin and II generation
cephalosporin resistant), Staphylococcus aureus (methy-
cillin resistant). Of the two compouds 6d consistently
showed slightly better activity. Acids 6b and 6c that is
compounds having an ethyl ester group or groups at C-6
exhibited no activity against the panel of bacteria tested.
The present approach demonstrates a possible pathway
to various types of interesting novel tricyclic cephams
and carbacephams and provides additional evidence
that carbene species play significant role in the cyclisa-
tion processes effected by trialkylphosphites.
Stereochemical assignments of the final compounds
were made on the basis of 1-D and 2-D NMR spectro-
scopy and X-ray crystallography. The trans configur-
ation of b-lactam ring protons is confirmed by their
typical coupling constant of 2–2.5 Hz. The NOESY
spectra of compound 6a (Fig. 2) showcorrelation,
between the 3-CH proton and the 5-CH proton. How-
ever, there is no correlation between either of 3-CH
protons and the protons of the b-lactam ring (7-CH or
8-CH), which previously gave grounds for stereo-
chemical assignments made for similar carbapenam tri-
cyclic compounds.7 Thus, to unambiguously assign the
configuration of cyclopropane ring the X-ray crystal
structure of 6a was measured (Fig. 3).17 It provides
conclusive evidence for the syn-fusion of rings that is
both b-lactam and cyclopropyl rings are located above
In conclusion, we have synthesised a series of syn-fused
tricyclic b-lactam compounds related to cephams amd
carbacephams using novel synthetic methodology of
intramolecular carbene addition to double bond and
evaluated their structure, conformation and biological
activity.
Experimental
General
Solvents were reagent grade and were obtained from
POCH Gliwice Poland Company. 3-allylpentane-2,4-
dione, 2-acetyl-pent-4-enoic acid ethyl ester, allyl
chloro-oxalate, sodium 2-ethyl hexanoate, palladium
tetrakis triphenylphosphine and di-i-propylethyl amine
trifluorohydride were synthesized according to literature
procedures. Azetidinone (1) was purchased from
Kaneka Co., other reagents and chemicals were pur-
chased from Aldrich or Fluka Chemical Companies.
Melting points are uncorrected. NMR spectra were
recorded with Mercury 400 spectrometer. Chemical
shifts are expressed in ppm, coupling constants are
expressed in Hz, LSIMS and EI mass spectra were
ꢁ
.
Scheme 4. Reagents: (i) (i-Pr)2EtN 3HF, anisole (50 C/10 h); (ii)
Pd(PPh3)4, PPh3, sodium 2-ethyl hexanoate, AcOEt, (rt/3 h) H2O,
H3PO4.

1960
A. Korda, J. Winiarski / Bioorg. Med. Chem. 11 (2003) 1957–1967
Figure 2. 2-D NOESY of compound 6a.
obtained on MASPEC II system. Optical rotations were
measured on a Jasco DIP-360 digital polarimeter. Col-
umn chromatography was performed on Merck silica
gel 60 (230–400 mesh)
(3S,4R)-4-Allylsulfanyl-3-[(R)-1-tert-butyldimethylsily-
loxyethyl]-azetidin-2-one (2a). Sodium hydride (60%
suspension in mineral oil, 6.0 g 0.15 mol, washed with
hexane) was added in portions to ethanol (150 mL)
precooled to 0 ꢁC and allyl mercaptan (9.3 g, 0.12 mol)
was added dropwise to the mixture maintaining tem-
perature at 0 ꢁC. To the above the solution of (3R,4R)-3
- [(R) - 1 - tert - butyldimethylsilyloxyethyl) - 4 - acetox-
yazetidin-2-one (1) (28.7 g, 0.1 mol) in ethanol (50 mL)
was added dropwise and the mixture was stirred at 0 ꢁC
for 2 h, warmed up to ambient temperature and left
Figure 3. X-ray crystal structure of compound 6a.

A. Korda, J. Winiarski / Bioorg. Med. Chem. 11 (2003) 1957–1967
1961
overnight. The solvent was evaporated under reduced
pressure and the resultant oil was partitioned between
water (200 mL) and ethyl acetate (200 mL). The water
layer was twice extracted with ethyl acetate. (2Â30 mL)
The combined organic extracts were dried over MgSO4
and concentrated to give crude product 2a (29.2 g) as
oil, which was without purification subjected to acyla-
tion with allyl chloro-oxalate. A sample for analytical
purposes was purified by column chromatography on
silica gel (9:1 n-hexane–AcOEt).
(3S,4S)-4-(1-acetyl,1-etoxycarbonyl-but-3-enyl)-3-[(R)-1-
tert-butyldimethyl-silyloxy-ethyl]-azetidin-2-one (2c).
From 1, (11.5 g, 0.04 mol) and 2-acetyl-pent-4-enoic
acid ethyl ester (7.0 g, 0.045 mol). Crude product 2c
(15.8 g) was subjected without purification to acylation
with allyl chloro-oxalate.
A sample for analytical purposes was purified by chro-
matography on silica gel (3:1 n-hexane–AcOEt) giving
2c as two diastereoisomers:
1H NMR (CDCl3) d 0.065 (s, 3H, SiCH3), 0.076 (s, 3H,
SiCH3), 0.876 (s, 9H, t-Bu), 1.226 (d, J=6.2 Hz, 3H,
CH3), 3.138 (ddd, J=3.5, 2.4, 0.9 Hz; 1H, 3-CH), 3.258
(ddt, J=14.1, 6.4 Hz, 1.3 Hz; 1H, SCH2), 3.314 (ddt,
J=14.1, 7.5, 1.1 Hz; 1H, SCH2), 4.245 (dq, J=6.2, 3.5
Hz; 1H, OCHCH3) 4.827 (d, J=2.4 Hz; 1H, 4-CH),
5.138 (dq, J=10.1, 1.3 Hz; 1H, H2C¼), 5.220 (dq,
J=17.0, 1.3 Hz; 1H, H2C¼), 5.891 (ddt, J=17.0, 10.1,
6.6 Hz; 1H, H2C¼CH), 5.995 (br s, 1H, NH).
1H NMR (CDCl3) d 0.063 (s, 3H, SiCH3), 0.068 (s, 6H,
SiCH3), 0.072 (s, 3H, SiCH3), 0.876 (s, 9H, t-Bu), 0.882
(s, 9H, t-Bu), 1.152 (d, J=6.4 Hz, 3H, CH3), 1.200 (d,
J=6.4 Hz, 3H, CH3), 1.273 (t, J=7.2 Hz, 3H,
CH3CH2), 1.309 (t, J=7.2 Hz, 3H, CH3CH2), 2.169 (s,
3H, CH3C¼O), 2.186 (s, 3H, CH3C¼O), 2.566–2.685
(m, 4H, CCH2CH¼), 2.964–2.300 (m, 2H, 3-CH),
4.192–4.300 (m, 4H, OCHCH3, 4-CH), 5.113–5.193 (m,
4H, H2C¼) 5.640–5.777 (m, 2H, H2C¼CH) 5.855 (br s,
1H, NH), 5.964 (br s 1H, NH).
13C NMR (CDCl3) ꢀ5.12, ꢀ4.31, 17.92, 22.32, 25.68,
34.29, 54.13, 64.13, 66.20, 117.51, 134.92, 167.09.
13C NMR ꢀ4.81, ꢀ4.38, 13.95, 14.06, 17.93, 22.44, 22.85,
25.71, 25.78, 28.02, 29.56, 35.55, 51.20, 51.52, 60.29,
60.42, 61.91, 62.06, 64.48, 64.90. 65.18, 119.65, 131.44,
132.13, 167.46, 168.00, 169.82, 170.73, 204.06, 204.34.
MS HR (LSIMS) for C14H27O2NSiS (M+Na)+, found
324.14246, calcd 324.14295.
(3S,4S)-4-(1,l-Dietoxycarbonyl-but-3-enyl)-3-[(R)-1-tert-
butyldimethylsilyloxyethyl]-azetidin-2-one (2b). Sodium
hydride (60% suspension in mineral oil, 4.0 g, 0.10 mol,
washed with hexane) was suspended in tetra-
hydrofurane (200 mL) precooled to 0 ꢁC and 2-allyl-
malonic acid diethylester (17.9 g, 0.09 mol) was added
dropwise to the mixture maintaining temperature at
10 ꢁC. To the above, the solution of (1) (23.2 g, 0.08
mol) in THF (80 mL) was added dropwise and the mixture
was stirred at rt for 2 h. The solvent was evaporated under
reduced pressure and the resultant oil was partitioned
between water (100 mL) and ethyl acetate (100 mL). The
organic extract was dried over MgSO4 and concentrated in
vacuo. The crude product 2b (33.2 g) was subjected with-
out purification to acylation with allyl chloro-oxalate.
MS HR (LSIMS) C20H35O5NSi for (M+H)+, found
398.23481, calcd 398.23628.
(3S,4S)-4-(1,1-Diacetyl-but-3-enyl)-3-[(R)-1-tert-butyldi-
methylsilyloxyethyl]-azetidin-2-one (2d). From (1) (16.7
g, 0.058 mol) and 3-allylpentane-2,4-dione (9.1 g, 0.065
mol) The crude product was purified by column chro-
matography on silica gel (3:1 n-hexane–AcOEt) giving
(2d) (9.8 g, 0.029 mol, 44%).
1H NMR (CDCl3) d 0.050 (s, 3H, SiCH3), 0.056 (s, 3H,
SiCH3), 0.866 (s, 9H, t-Bu), 1.163 (d, J=6.4 Hz, 3H,
CH3), 2.176 (s, 3H, CH3C¼O), 2.181 (s, 3H, CH3C¼O),
2.787 (dd, J=3.5, 2.4 Hz, 1H, 3-CH), 2.624 (ddt,
J=15.6, 6.4, 1.5 Hz, 1H, CCH2CH¼), 2.729 (ddt,
J=15.6, 8.0, 1.1 Hz, 1H, CCH2CH¼), 4.215 (dq,
J=6.4, 3.5 Hz; 1H, OCHCH3), 4.218 (d, J=2.4 Hz; 1H,
4-CH), 5.138 (dq, J=10.1, 1.3 Hz, 1H, H2C¼), 5.181
(dq, J=16.8, 1.3 Hz, 1H, H2C¼), 5.623 (ddt, J=16.8,
10.1, 6.6 Hz; 1H, H2C¼CH), 6.028 (br s, 1H, NH).
A sample for analytical purposes was purified by col-
umn chromatography on silica gel (3:1 n-hexane–
AcOEt).
1H NMR (CDCl3) d 0.070 (s, 3H, SiCH3), 0.073 (s, 3H,
SiCH3), 0.880 (s, 9H, t-Bu), 1.188 (d, J=6.4 Hz, 3H,
CH3), 1.253 (t, J=7.1 Hz, 3H, CH3CH2), 1.257 (t,
J=7.1 Hz, 3H, CH3CH2), 2.612 (ddt, J=14.5, 6.6, 1.3
Hz; 1H, CCH2CH¼), 2.736 (ddt, J=14.5, 7.9, 1.1 Hz;
1H, CCH2CH¼), 3.071 (ddd, J=3.3, 2.2, 1.3 Hz; 1H, 3-
CH), 4.186–4.261 (m, 6H, CH3CH2, OCHCH3, 4-CH),
5.130 (dq, J=8.6, 1.5 Hz; 1H, H2C¼), 5.151 (dq,
J=13.7, 1.5 Hz; 1H, H2C¼), 5.779 (ddt, J=17.0, 10.1,
6.8 Hz; 1H, H2C¼CH), 6.002 (br s, 1H, NH).
13C NMR (CDCl3) ꢀ4.82, ꢀ4.40, 17.94, 22.81, 25.67,
25.75, 25.83, 28.42, 30.30, 34.70, 51.28, 60.37, 64.87,
71.15, 119.87, 131.64, 167.80, 205.16, 206.03.
MS HR (LSIMS) for C19H33O4NSi (M+Na)+, found
390.20905, calcd 390.20766.
(3S,4R)-4-Allylsulfanyl-3-[(R)-1-tert-butyldimethylsily-
loxyethyl]-1-[(1-allyloxy)-2-methyl-1-oxo]-azetidin-2-one
(3a). Crude (2a) (29.2 g) was dissolved in dichloro-
methane (300 mL) and the solution was cooled to
ꢀ20 ꢁC. Triethylamine (21.8 mL, 15.8 g, 0.16 mol) was
added and allyl chloro-oxalate (21.8 g, 0.15 mol) was
added dropwise maintaining temperature at ꢀ20 ꢁC.
The mixture was stirred for 1 h and warmed up to
MS HR (LSIMS) C21H37O6NSi for (M+H)+ found
428.24712 calcd 428.24683.
According to the same procedure, compounds 2c and d
were prepared.

1962
A. Korda, J. Winiarski / Bioorg. Med. Chem. 11 (2003) 1957–1967
ambient temperature. Water (100 mL) was added and
the layers were separated. Water layer was extracted
with additional methylene chloride (30 mL), organic
layer was dried over MgSO4 and concentrated under
reduced pressure. The crude product was purified by
column chromatography on silica gel (10:1 n-hexane–
AcOEt) giving 3a as an oil (22.7 g, 0.055 mol, 55% yield
from 1).
silica gel (5:1 n-hexane–AcOEt) giving (3c) as two dia-
stereoisomers (14.0 g, 0.028 mol, 67% yield from 1).
1H NMR (CDCl3) d ꢀ0.024 (s, 3H, SiCH3), 0.014 (s, 3H,
SiCH3), 0.054(s, 6H, SiCH3), 0.064 (s, 3H, SiCH3), 0.823 (s,
9H, t-Bu), 0.834 (s, 9H, t-Bu), 1.261 (d, J=6.4 Hz, 3H,
CH3), 1.283 (t, J=7.1 Hz, 3H, CH3CH2), 1.292 (t, J=7.1
Hz, 3H, CH3CH2), 1.306 (d, J=6.4 Hz, 3H, CH3), 2.202 (s,
3H, CH3C¼O), 2.234 (s, 3H, CH3C¼O), 2.466 (dd,
J=13.7, 8.4 Hz;1H, CCH2CH¼), 2.733 (ddt, J=14.5, 7.0,
1.1 Hz; 1H, CCH2CH¼), 2.783 (ddt, J=13.7, 6.0, 1.4
Hz; 1H, CCH2CH¼), 3.078 (ddt, J=14.4, 7.7, 1.0 Hz;
1H, CCH2CH¼), 3.386 (t, J=3.3 Hz; 1H, 3-CH), 3.466
(t, J=2.6 1H, 3-CH Hz), 4.212–4.250 (m, 6H, CH3CH2,
OCHCH3), 4.803 (d, J=3.1 Hz, 1H, 4-CH), 4.869 (d,
J=3.3 Hz, 1H, 4-CH), 4.739–4.773 (m, 4H, OCH2CH¼),
5.110–5.290 (m, 4H, H2C¼CHCH2C), 5.286 (dq, J=10.2,
1.0 Hz, 1H, H2C¼CHCH2O), 5.373 (dq, J=17.2, 1.0 Hz,
1H NMR (CDCl3) d 0.012 (s, 3H, SiCH3), 0.064 (s, 3H,
SiCH3), 0.833 (s, 9H, t-Bu), 1.210 (d, J=6.4 Hz, 3H,
CH3), 3.233 (dd, J=3.8, 2.5 Hz; 1H, 3-CH), 3.351 (ddt,
J=13.7, 5.3, 1.5 Hz; 1H, SCH2CH¼), 3.820 (dd,
J=13.7, 9.3 Hz; 1H, SCH2CH¼), 4.339 (dq, J=6.4, 2.4
Hz; 1H, OCHCH3), 4.811 (ddt, J=6.2, 4.7 1.3 Hz; 2H,
OCH2CH¼), 5.234 (dq, J=10.0, 1.1 Hz, 1H,
H2C¼CHCH2S), 5.315 (dq, J=17.0, 1.0 Hz; 1H,
H2C¼CHCH2S), 5.331–5.472 (m, 2H, H2C¼CHCH2O),
5.407 (d, J=3.8 Hz, 1H, 4-CH), 5.845 (ddt, J=17.0,
10.0, 5.3 Hz; 1H, H2C¼CHCH2S), 5.973 (ddt, J=17.2,
10.4, 6.0 Hz, 1H, H2C¼CHCH2O).
1H,
H2C¼CHCH2O),
5.589–5.693
(m,
1H,
H2C¼CHCH2C), 5.703–5.808 (m, 1H, H2C¼CHCH2C),
5.872–5.975 (m, 2H, H2C¼CHCH2O).
13C NMR (CDCl3) d ꢀ4.39, ꢀ3.66, 8.56, 17.71, 17.94,
21.75, 25.59, 35.95, 46.00, 64.01, 64.45, 67.35, 67.50, 67.85,
120.31, 120.49, 130.25, 130.37, 157.33, 158.15, 158.31.
13C NMR (CDCl3) ꢀ5.22, ꢀ5.12, ꢀ4.52, ꢀ4.46, 13.81,
13.84, 17.69, 17.72, 22.13, 22.44, 25.60, 25.62, 28.14,
29.41, 37.34, 38.17, 54.95, 56.41, 61.24, 61.97, 62.32,
62.44, 63.98, 65.46, 67.19, 120.05, 120.34, 130.46,
131.48, 155.98, 159.86, 165.30, 169.57, 202.88, 203.36.
According to the same procedure, compounds 3b–d
were prepared.
MS HR (LSIMS) C25H39O8NSi for (M+H)+, found
510.25221, calcd 510.25232.
(3S,4S)-4-(1,l-Dietoxycarbonyl-but-3-enyl)-3-[(R)-1-tert-
butyldimethylsilyloxyethyl]-1-[(1-allyloxy)-2-methyl-1-
oxo]-azetidin-2-one (3b). From crude 2b (33.2 g). Pro-
duct was purified by column chromatography on silica
gel (5:1 n-hexane–AcOEt) giving (3b) (27.6 g, 0.051 mol,
64% yield from 1).
(3S,4S)-4-(1,1-Diacetyl-but-3-enyl)-3-[(R)-1-tert-butyldi-
methylsilyloxyethyl]-1-[(1-allyloxy)-2-methyl-1-oxo]-aze-
tidin-2-one (3d). From crude 2d (9.6 g). Product was
purified by column chromatography on silica gel (4:1
n-hexane–AcOEt) giving 3d (7.47 g, 0.016 mol, 60%
yield from 1).
1H NMR (CDCl3) d 0.075 (s, 6H, SiCH3), 0.849 (s, 9H,
t-Bu), 1.290 (d, J=6.4 Hz, 3H, CH3), 1.271 (t, J=7.1
Hz; 3H, CH3CH2), 1.275 (t, J=7.1 Hz; 3H, CH3CH2),
2.756 (ddt, J=14.1, 7.3, 1.1 Hz; 1H, CCH2CH¼), 2.960
(ddt, J=14.1, 7.3, 1.1 Hz; 1H, CCH2CH¼), 3.540 (t,
J=3.0 Hz; 1H, 3-CH), 4.189–4.252 (m, 4H, CH3CH2)
4.357 (dq, J=6.4, 2.9 Hz; 1H, OCHCH3), 4.760–4.788
(m, 2H OCH2CH¼), 4.837 (d, J=2.9 Hz, 1H, 4-CH),
5.168 (dq, J=10.0, 1.8 Hz; 1H, H2C¼CHCH2S), 5.257
(dq, J=17.0, 1.8 Hz; 1H, H2C¼CHCH2S), 5.303 (dq,
J=10.3, 1.3 Hz; 1H, H2C¼CHCH2O), 5.393 (dq,
J=17.1, 1.3 Hz; 1H, H2C¼CHCH2O), 5.812 (ddt,
J=17.0, 10.0, 7.3 Hz; 1H, H2C¼CHCH2S), 5.945 (ddt,
J=17.1, 10.3, 6.2 Hz, 1H, H2C¼CHCH2O).
1H NMR (CDCl3) d 0.006 (s, 3H, SiCH3), 0.084 (s, 3H,
SiCH3), 0.852 (s, 9H, t-Bu), 1.345 (d, J=6.4 Hz, 3H,
CH3), 2.227 (s, 3H, CH3C¼O), 2.296 (s, 3H, CH3C¼O),
2.619 (ddt, J=14.6, 8.3, 1.0 Hz; 1H, CCH2CH¼), 3.138
(ddt, J=14.6, 6.1, 1.6 Hz; 1H, CCH2CH¼), 3.366 (dd,
J=3.2, 2.5 Hz; 1H, 3-CH), 4.372 (dq, J=6.4, 2.4 Hz; 1H,
OCHCH3), 4.883 (d, J=3.2 Hz, 1H, 4-CH), 4.786 (dq,
J=6.0, 1.5 Hz; 1H, OCH2CH¼), 5.172 (dq, J=10.1, 1.0
Hz; 1H, H2C¼CHCH2C), 5.283 (dq, J=17.1, 1.2 Hz;
1H, H2C¼CHCH2C), 5.316 (dq, J=10.4, 1.2 Hz; 1H,
H2C¼CHCH2O), 5.395 (dq, J=17.2, 1.3 Hz;
1H, H2C¼CHCH2O), 5.623 (ddt, J=17.1, 10.1, 6.1
Hz; 1H, H2C¼CHCH2C), 5.942 (ddt, J=17.2, 10.4,
6.0 Hz, 1H, H2C¼CHCH2O).
13C NMR (CDCl3) ꢀ5.20, ꢀ4.53, 13.83, 13.92, 17.69,
22.69, 25.59, 38.19, 55.25, 59.52,61.88, 61.92, 62.14,
65.67, 67.58, 119.99, 120.10, 130.51, 132.00, 156.05,
159.88, 166.16, 168.10, 168.45.
13C NMR ꢀ4.91, ꢀ4.50, 17.96, 22.83, 25.76, 28.44,
30.31, 34.70, 51.29, 60.39, 64.89, 71.18, 119.89, 131.65,
167.80, 205.18, 206.05.
MS HR (LSIMS) C26H41O9NSi for (M+H)+, found
540.26077, calcd 540.26289.
MS HR (LSIMS) for C24H37O7NSi dla (M+H)+,
found 480.24212, calcd 480.24176.
(3S,4S)-4-(1-acetyl,1-etoxycarbonyl-but-3-enyl)-3-[(R)-1-
tert - butyldimethyl - silyloxyethyl] - 1 - [(1 - allyloxy) - 2 -
methyl-1-oxo]-azetidin-2-one (3c). From crude 2c (15.8
g). Product was purified by column chromatography on
(2R,7R,8S)-9-oxo-8t-[(R)-1-tert-Butyldimethylsilyloxye-
thyl]-6-thia-1-azatricyclo-[5.2.0.02,4]-nonane-2-carboxylic
acid allyl ester (4a). To the solution of 3a (11.50 g, 27.8

A. Korda, J. Winiarski / Bioorg. Med. Chem. 11 (2003) 1957–1967
1963
mmol) in xylene (250 mL) was added triethylphosphite
(9.23 g, 0.056 mol) and the mixture was heated at reflux
for 9 h. The mixture was concentrated at reduced pres-
sure and the residue was purified by column chromato-
graphy on silica gel (6:1 n-hexane–AcOEt) to give 4a as
an oil (4.58 g, 11.5 mmol, 41% yield).
IR (film from CHCl3) 2980, 2957, 2931, 2857, 1170,
1732, 1447, 1399, 1375, 1283, 1268, 1256, 1186, 1148,
838, 778.
(2R,7S,8S)-9-oxo-8t-[(R)-1-tert-Butyldimethylsilyloxy-
ethyl]-6-acetyl-1-azatricyclo-[5.2.0.02,4]nonane-2,6-dicar-
boxylic acid, 2-allyl ester, 6-ethyl ester (4c). (3.44 g, 7.0
mmol, 25% yield) from 3c (14.0 g, 27.5 mmol), also
penem, 4e is formed in this reaction. The products were
separated by means of column chromatography on
silica gel (6:1 n-hexane–AcOEt) Rf being 0.4 for 4c and
0.6 for 4e (TLC, Merck silica gel 60 F254aluminum
plates, 3:1 n-hexane–AcOEt).
1H NMR (CDCl3) d 0.089 s (s, 3H, SiCH3), 0.094 (s,
3H, SiCH3), 0.895 (s, 9H, t-Bu), 1.240 (d, J=6.1 Hz,
3H, CH3), 1.483 (dd, J=7.1 Hz, J=5.5 Hz, 1H, 3-CH),
1.824 (dd, J=9.0, 5.7 Hz, 1H, 3-CH), 2.041 (tt, J=9.0,
5.7 Hz, 1H, 4-CH), 2.497 (dd, J=14.6, 5.8 Hz; 1H, 5-
CH), 3.022 (dd, J=4.7, 2.0 Hz; 1H, 8-CH), 3.211 (dd,
J=14.6, 5.3 Hz; 1H, 5-CH), 4.217 (dq, J=6.1, 4.7 Hz;
1H, OCHCH3), 4.578 (d, J=1.8 Hz; 1H, 7-CH), 4.635
(dq, J=5.7, 1.1 Hz; 2H, OCH2CH¼), 5.235 (dq,
J=10.4, 2.5 Hz; 1H, H2C¼CH), 5.320 (dq, J=17.2, 1.5
Hz; 1H, H2C¼CH), 5.891 (ddt, J=17.2, 10.6, 5.7 Hz,
1H, H2C¼CH).
1H NMR (CDCl3) d 0.101 (s, 3H, SiCH3), 0.115 (s, 3H,
SiCH3), 0.914 (s, 9H, t-Bu), 1.110 (dd, J=14.8, 8.8 Hz,
1H, 5-CH), 1.149 (d, J=6.3 Hz, 3H, CH3), 1.277 (t,
J=7.1 Hz, 3H, CH3CH2), 1.449 (t, J=5.9 Hz, 1H, 3-
CH), 1.612 (tt, J=8.8, 6.2 Hz, 1H, 4-CH), 1.806 (dd,
J=8.7, 5.8 Hz, 1H, 3-CH) 2.203 (s, 3H, CH3C¼O),
2.576 (dd, J=5.6, 2.3 Hz; 1H, 8-CH), 2.653 (dd,
J=14.9, 6.6 Hz, 1H, 5-CH), 4.200 (quintet, J=7.0 Hz,
1H, OCHCH3), 4.236 (q, J=7.1 Hz, 1H, CH3CH2),
4.286 (q, J=7.1 Hz, 1H, CH3CH2), 4.578 (ddt, J=13.2,
5.6, 1.5 Hz; 1H, OCH2CH¼), 4.612 (d, J=2.2 Hz; 1H,
7-CH), 4.677 (ddt, J=13.2, 5.6, 1.5 Hz; 1H,
OCH2CH¼), 5.251 (dq, J=10.4, 1.4 Hz; 1H,
H2C¼CH), 5.357 (dq, J=17.2, 1.5 Hz; 1H, H2C¼CH),
5.927 (ddt, J=17.2, 10.4, 5.7 Hz, 1H, H2C¼CH).
13C NMR (CDCl3) 17.95, 20.35, 22.56, 23.08, 24.91,
25.75, 34.63, 51.02, 64.90, 66.11, 68.35, 118.41, 131.75,
167.75, 170.30.
MS HR (LSIMS) for C19H31O4NSiS (M+Na)+, found
420.16661, calcd 420.16408.
IR (film from CHCl3) 2955, 2930, 2886, 1769, 1732,
1399, 1375, 1279, 1252, 1185, 1144, 837, 778.
According to the same procedure compounds 4b–f were
prepared.
13C NMR (CDCl3) d ꢀ4.70, ꢀ4.51, 14.00, 18.04, 22.91,
23.02, 23.46, 25.86, 28.10, 28.70, 34.56, 51.69, 59.66,
60.88, 62.34, 65.60, 65.99, 118.22, 131.94, 168.83,
170.60, 170.83, 202.20.
(2R,7S,8S)-9-oxo-8t-[(R)-1-tert-Butyldimethylsilyloxy-
ethyl]-1-azatricyclo-[5.2.0.02,4]nonane-2,6,6-tricarboxylic
acid, 2-allyl ester, 6,6-diethyl ester (4b). (5.2 g, 9.9
mmol, 52% yield) from (3b) (10.2 g, 18.9 mmol) (col-
umn chromatography conditions: silica gel, 2:1 n-hex-
ane–AcOEt).
MS HR (LSIMS) for C25H39NO7Si (M+Na)+, found
516.2388, calcd 516.2380.
IR (film from CHCl3) 2983, 2957, 2933, 2859, 1810,
1755, 1738, 1712, 1371, 1343, 1253, 1204, 1150, 839,
810.
1H NMR (CDCl3) d 0.082 (s, 3H, SiCH3), 0.101 (s, 3H,
SiCH3), 0.925 (s, 9H, t-Bu), 1.051 (d, J=6.2 Hz, 3H,
CH3), 1.160 (dd, J=14.8, 8.8 Hz, 1H, 5-CH), 1.248 (t,
J=7.1 Hz, 3H, CH3CH2), 1.259 (t, J=7.1 Hz, 3H,
CH3CH2), 1.424 (t, J=5.9 Hz, 1H, 3-CH), 1.613 (tt,
J=8.8, 6.2 Hz, 1H, 4-CH), 1.795 (dd, J=8.8, 5.7 Hz,
1H, 3-CH), 2.770 (t, J=5.7 Hz; 1H, 8-CH), 2.793 (dd,
J=14.9, 6.8 Hz, 1H, 5-CH), 3.971 (dq, J=11.0, 7.1 Hz,
1H, CH3CH2), 4.20–4.26 (m, 1H, OCHCH3), 4.236 (q,
J=7.1 Hz, 2H, CH3CH2), 4.330 (dq, J=11.0, 7.1 Hz,
1H, CH3CH2), 4.575 (ddt, J=13.2, 5.8, 1.3 Hz; 1H,
OCH2CH¼), 4.633 (d, J=2.4 Hz; 1H, 7-CH), 4.686
(ddt, J=13.2, 5.7, 1.5 Hz; 1H, OCH2CH¼), 5.231 (dq,
J=10.4, 1.3 Hz; 1H, H2C¼CH), 5.346 (dq, J=17.2, 1.5;
1H, H2C¼CH), 5.87–5.98 (m, 1H, H2C¼CH).
(2R,7S,8S)-9-oxo-8t-[(R)-1-tert-Butyldimethylsilyloxy-
ethyl]-6,6-diacetyl-1-azatricyclo-[5.2.0.02,4]nonane-2-car-
boxylic acid allyl ester (4d). (3.30 g, 7.1 mmol, 49%
yield) from 3c (6.90g, 14.4 mmol). Also penem 4f is
formed in this reaction. The products were separated by
means of column chromatography on silica gel (5:1 n-
hexane–AcOEt) Rf being 0.07 for 4d and 0.5 for 4f
(TLC, Merck silica gel 60 F254aluminum plates, 3:1
n-hexane–AcOEt).
1H NMR (CDCl3) d 0.110 (s, 3H, SiCH3), 0.116 (s, 3H,
SiCH3), 0.908 (s, 9H, t-Bu), 1.149 (dd, J=15.6, 8.8 Hz,
1H, 5-H), 1.205 (d, J=6.4 Hz, 3H, CH3), 1.453 (dd,
J=11.5, 6.0 Hz, 1H, 3-H), 1.493 (tt, J=8.8, 6.2 Hz, 1H,
4-CH), 1.794 (dd, J=8.2, 5.5 Hz, 1H, 3-CH) 2.174 (s,
3H, CH3C¼O), 2.207 (s, 3H, CH3C¼O) 2.491 (dd,
J=6.6, 2.4 Hz; 1H, 8-CH), 2.755 (ddd, J=15.5, 6.4, 0.7
Hz, 1H, 5-CH), 4.125 (ddt, J=13.2, 5.5, 1.4 Hz; 1H,
OCH2CH¼), 4.209 (quintet, J=6.4 Hz, 1H, OCHCH3),
4.558 (ddt, J=13.2, 5.5, 1.4 Hz; 1H, OCH2CH¼), 4.661
(d, J=2.0 Hz; 1H, 7-CH), 5.277 (dq, J=10.4, 1.3 Hz;
13C NMR (CDCl3) d ꢀ5.05, ꢀ4.58, 13.82, 14.02, 18.01,
21.94, 22.98, 23.22, 25.79, 28.67, 34.67, 50.56, 54.01,
55.80, 61.98, 62.08, 63.70, 66.06, 118.21, 132.06, 169.23,
169.29, 169.71, 170.79.
MS HR (LSIMS) C26H41NO8Si for (M+Na)+, found
546.25049, calcd 546.24992.

1964
A. Korda, J. Winiarski / Bioorg. Med. Chem. 11 (2003) 1957–1967
1H, H2C¼CH), 5.392 (dq, J=17.2, 1.5 Hz; 1H,
H2C¼CH), 5.957 (ddt, J=17.2, 10.4, 5.7 Hz, 1H,
H2C¼CH).
13C NMR (CDCl3) ꢀ4.72, ꢀ4.38, 18.06, 22.84, 22.87,
23.06, 25.88, 26.89, 27.27, 29.22, 34.56, 50.83, 59.76,
66.11, 66.49, 67.99, 118.26, 131.87, 168.68, 170.43,
203.33, 203.50.
(5S,6S)-4-allyl-4-acetyl-7-oxo-8t-[(R)-1-tert-Butyldime-
thylsilyloxyethyl]-3-methyl-1-azabicyclo[3.2.0]hept-2-ene-
2-carboxylic acid allyl ester (4f). (1.92 g, 4.3 mmol, 30%
1
yield) from 3d (6.9g, 14.0 mmol). H NMR (CDCl3) d
0.057 (s, 3H, SiCH3), 0.070 (s, 3H, SiCH3), 0.868 (s,
9H, t-Bu), 1.212 (d, J=6.2 Hz, 3H, CH3), 2.015 (s,
3H, 3-CCH3), 2 252 (s, 3H, CH3C¼O), 2.564 (ddt,
J=15.5, 6.4, 1.6 Hz; 1H, CCH2CH¼), 2.697 (ddt,
J=15.6, 6.6, 1.4 Hz; 1H, CCH2CH¼), 3.485 (dd,
J=6.9, 3.0 Hz, 1H, 6-CH), 4.80 (m, 1H, OCHCH3),
4.303 (d, J=3.0 Hz, 1H, 5-CH), 4.715 (ddt, J=13.5,
5.6, 1.4 Hz; 1H, OCH2CH¼), 4.798 (ddt, J=13.5, 5.5,
1.4 Hz; 1H, OCH2CH¼), 5.272 (dq, J=10.5, 1.4 Hz;
1H, H2C¼CHCH2O), 5.451 (dq, J=17.2, 1.5 Hz; 1H,
H2C¼CHCH2O), 5.618 (ddt, J=17.0, 10.1, 6.5 Hz,
1H, H2C¼CHCH2O).
MS HR (LSIMS) for C24H37N O6Si (M+Na)+, found
486.22770, calcd 486.22879.
IR (film from CHCl3) 2956, 2931, 2858, 1764, 1727,
1702, 1402, 1362, 1296, 1283, 1258, 1195, 1175, 1149,
836, 778.
(5S,6S)-4-allyl-7-oxo-8t-[(R)-1-tert-Butyldimethylsilyloxy-
ethyl]-3-methyl-1-azabicyclo[3.2.0]hept-2-ene-2,4-dicar-
boxylic acid, 2-allyl ester, 4-ethyl ester (4e). (4.45 g, 9.3
mmol, 33% yield) as two diastereoisomers from 3c (14.0
g, 27.5 mmol).
13C NMR (CDCl3) d ꢀ4.93, ꢀ4.32, 12.71, 17.85, 22.64,
26.68, 35.25, 58.24, 61.69, 65.75, 66.21, 68.27, 118.48,
119.66, 129.91, 131.42, 132.79, 144.06, 160.92, 173.49,
205.97.
1H NMR (CDCl3) d 0.065 (s, 3H, SiCH3), 0.070 (s, 3H,
SiCH3), 0.072 (s, 3H, SiCH3), 0.076 (s, 3H, SiCH3),
0.870 (s, 9H, t-Bu), 0.888 (s, 9H, t-Bu), 1.186 (d, J=6.2
Hz, 3H, CH3), 1.243 (d, J=6.2 Hz, 3H, CH3), 1.268 (t,
J=7.1 Hz, 3H, CH3CH2), 1.298 (t, J=7.0 Hz, 3H,
CH3CH2), 2.060 (s, 3H, 3-CCH3), 2.107 (s, 3H, 3-
CCH3), 2.470 (ddt, J=15.3, 6.0, 1.6 Hz; 1H, CCH2CH¼),
2.610 (ddt, J=14.7, 6.5, 1.5 Hz, 1H, CCH2CH¼), 2.750
(dd, J=14.6, 7.7 Hz, 1H, CCH2CH¼), 2.764 (ddt,
J=15.3, 7.3, 1.2 Hz; 1H, CCH2CH¼), 3.013 (dd,
J=5.2, 3.0 Hz, 1H, 6-CH), 3.358 (dd, J=6.3, 2.9 Hz,
1H, 6-CH), 4.095 (d, J=3.0 Hz, 1H, 5-CH), 4.205 (q,
J=7.1 Hz, 1H, CH3CH2), 4.211 (q, J=7.1 Hz, 1H,
CH3CH2), 4.234 (q, J=7.1 Hz, 1H, CH3CH2), 4.239 (q,
J=7.1 Hz, 1H, CH3CH2), 4.611 (d, J=2.9 Hz; 1H, 5-
CH), 4.700 (ddt, J=13.5, 5.6, 1.4 Hz; 1H. OCH2CH¼),
4.703 (ddt, J=13.6, 5.5, 1.5 Hz, 1H, OCH2CH¼), 4.774
(dd, J=9.5, 5.4 Hz; 1H, OCH2CH¼), 4.783 (ddt,
J=13.7, 5.4, 1.5 Hz, 1H, OCH2CH¼), 4.80 (m, 2H,
OCHCH3), 5.22 (m, 2H, H2C¼CHCH2C), 5.142 (dq,
J=10.2, 1.5 Hz; 1H, H2C¼CHCH2C), 5.165 (dq, J=17.2,
1.6 Hz; 1H, H2C¼CHCH2C), 5.250 (dq, J=10.5, 1.4
Hz, 1H, H2C¼CHCH2O), 5.259 (dq, J=10.4, 1.4 Hz;
1H, H2C¼CHCH2O), 5.440 (dq, J=17.2, 1.5 Hz;
1H, H2C¼CHCH2O), 5.445 (dq, J=17.2, 1.5 Hz, 1H,
H2C¼CHCH2O), 5.664 (ddt, J=17.7, 10.2, 6.6 Hz,
1H, H2C¼CHCH2C), 5.670 (ddt J=17.2, 10.2, 6.2 Hz;
1H, H2C¼CHCH2C), 5.961 (ddt J=17.2, 10.4, 6.2
Hz; 1H, H2C¼CHCH2O), 5.967 (ddt, J=17.2, 10.6,
5.5 Hz, 1H, H2C¼CHCH2O).
MS HR (LSIMS) for C24H37NO5Si (M+Na)+, found
470.23237, calcd 470.23387.
IR (film from CHCl3) 3376, 2955, 2931, 1737, 1714,
1380, 1361, 1255, 1192, 1093, 836, 778.
(2R,7R,8S)-9-oxo-8t-[(R)-1-Hydroxyethyl]-6-thia-1-aza-
tricyclo[5.2.0.02,4]nonane-2-carboxylic acid allyl ester
(5a). Compound 4a (4.0 g, 10.0 mmol) was dissolved in
ethyl acetate (50 mL) and di-i-propylethyl amine tri-
fluorohydride (7.7 g, 40.0 mmol) was added at rt .The mix-
ture was stirred with heating at 50 ꢁC for 5–10 h (TLC
monitoring). After the reaction was completed, the mixture
was washed with water, organic layer was dried over
MgSO4, filtered and evaporated under reduced pressure.
The residue was chromatographed on silica gel (1:1 n-hex-
ane–AcOEt) giving (5a) (2.2 g, 7.8 mmol, 78% yield).
1H NMR (CDCl3) d 1.319 (d, J=6.4 Hz, 3H, CH3),
1.503 (dd, J=7.3, 5.5 Hz, 1H, 3-CH), 1.815 (dd, J=9.1,
5.3 Hz, 1H, 3-CH), 1.990 (tt, J=7.3, 4.8 Hz, 1H, 4-CH),
2.674 (dd, J=14.5, 4.6 Hz; 1H, 5-CH), 3.055 (dd,
J=5.7, 1.6 Hz; 1H, 8-CH), 3.257 (dd, J=14.6, 4.9 Hz;
1H, 5-CH), 4.258 (qvintet, J=6.0 Hz, 1H, OCHCH3),
4.508 (d, J=1.7 Hz; 1H, 7-CH), 4.620 (dq, J=3.3, 1.0
Hz; 2H, OCH2CH¼), 5.232 (dq, J=10.4, 1.5 Hz; 1H,
H2C¼CH), 5.332 (dq, J=17.2, 1.6 Hz; 1H, H2C¼CH),
5.882 (ddt, J=17.2, 10.4, 5.5 Hz, 1H, H2C¼CH).
13C NMR (CDCl3) d 19.65, 21.70, 21.97, 23.74, 33.85,
51.03, 63.79, 65.19, 67.11, 117.22, 132.15, 167.70,
169.91.
13C NMR (CDCl3) d ꢀ5.01, ꢀ4.34, 12.35, 14.14, 17.87,
22.58, 25.66, 25.70, 36.40, 58.67, 60.89, 61.86, 62.65,
65.65, 66.40, 118.39, 119.65, 128.41, 131.51, 132.23,
144.75, 161.04, 171.74, 173.05.
MS HR (LSIMS) for C13H17NO4S (M+H)+, found
284.09541, calcd 284.09566.
MS HR (LSIMS) for C25H39O6NSi (M+H)+, found
478.26306, calcd 478.262449.
IR (film from CHCl3) 3453, 2971, 1761, 1734,
1402,1377, 1282, 1185.
IR (film from CHCl3) 3452, 2956, 2932, 2858, 1736,
1446, 1368, 1254, 1215, 1100, 1051, 836, 778.
The same procedure except that anisole was used as a
solvent was applied to obtain compounds 5b–d.

A. Korda, J. Winiarski / Bioorg. Med. Chem. 11 (2003) 1957–1967
1965
(2R,7S,8S)-9-oxo-8t-[(R)-1-Hydroxyethyl]-1-azatricy-
clo[5.2.0.02,4]nonane-2,6,6-tricarboxylic acid, 2-allyl es-
ter, 6,6-diethyl ester (5b). (6.2 g, 15.1 mmol, 83% yield)
from 4b (9.5 g, 18.2 mmol).
1H NMR (CDCl3) d 1.143 (dd, J=15.6, 8.9 Hz; 1H, 5-
CH), 1.354 (d, J=6.2 Hz, 3H, CH3), 1.418 (t, J=6.0
Hz, 1H, 3-CH), 1.544 (tt, J=8.8, 6.2 Hz, 1H, 4-CH),
1.809 (dd, J=8.8, 6.2 Hz, 1H, 3-CH), 2.206 (s, 3H,
CH3C¼O), 2.213 (s, 3H, CH3C¼O), 2.521 (dd, J=8.8,
2.4 Hz; 1H, 8-CH), 2.779 (ddd, J=15.4, 6.6, 0.7 Hz; 1H,
5-CH), 4.112 (quintet, J=7.0 Hz, 1H, OCHCH3), 4.585
(ddt, J=13.4, 5.7, 1.5 Hz; 1H, OCH2CH¼), 4.602 (d,
J=2.7 Hz; 1H, 7-CH), 4.683 (ddt, J=13.4, 5.5, 1.5 Hz,
1H, OCH2CH¼) 5.277 (dq, J=10.6, 1.5 Hz; 1H,
H2C¼CH), 5.373 (dq, J=17.4, 1.6 Hz; 1H, H2C¼CH),
5.942 (ddt, J=17.3, 10.4, 5.5 Hz, 1H, H2C¼CH).
1H NMR (CDCl3) d 1.251 (t, J=7.1 Hz, 3H, CH3CH2),
1.256 (t, J=7.1 Hz, 3H, CH3CH2), 1.267 (dd, J=14.6,
6.0 Hz; 1H, 5-CH), 1.285 (d, J=6.0 Hz, 3H, CH3),
1.424 (t, J=6.0 Hz, 1H, 3-CH), 1.653 (tt, J=8.4, 6.4
Hz, 1H, 4-CH), 1.830 (dd, J=8.8, 5.7 Hz, 1H, 3-CH),
2.806 (dd, J=6.6, 2.6 Hz; 1H, 8-CH), 2.811 (ddd,
J=15.0 Hz, 6.6, 0.7; 1H, 5-CH), 4.057–4.322 (m, 5H,
CH3CH2, OCHCH3), 4.422 (d, J=2.4 Hz; 1H, 7-CH),
4.596 (ddt, J=13.5, 5.7, 1.6 Hz, 1H, OCH2CH¼), 4.659
(ddt, J=13.4, 5.5, 1.5 Hz, 1H, OCH2CH¼) 5.248 (dq,
J=10.6, 1.5 Hz; 1H, H2C¼CH), 5.367 (dq, J=17.2, 1.6,
Hz; 1H, H2C¼CH), 5.922 (ddt, J=17.2, 10.4, 5.6 Hz,
1H, H2C¼CH).
13C NMR (CDCl3) d 16.02, 16.09, 22.18, 22.99, 23.01,
26.73, 26.86, 28.86, 34.52, 52.54, 59.41, 63.60, 63.66,
66.12, 66.70, 68.04, 118.26, 131.71, 168.20, 170.29,
203.53, 203.67.
MS HR (LSIMS) for C18H23O6N (M+Na)+, found
372.14324, calcd 372.14231.
13C NMR (CDCl3) d 13.84, 13.98, 14.15, 20.98, 22.76,
23.10, 28.28, 34.71, 52.80, 54.00, 60.11, 60.37, 62.31,
65.42, 66.04, 118.09, 131.73, 168.19, 169.00, 169.56,
170.39.
IR (film from CHCl3) 3473, 2973, 1760, 1700, 1363,
1299, 1284, 1197, 1175, 1151.
MS HR (LSIMS) for C20H27NO8 (M+H)+, found
410.18040, calcd 410.18149.
(2R,7R,8S)-9-oxo-8t-[(R)-1-Hydroxyethyl]-6-thia-1-aza-
tricyclo[5.2.0.02,4]nonane-2-carboxylic acid (6a). To the
solution of sodium 2-ethylhexanoate (1.5 g, 9.0 mmol),
triphenylphosphine (0.08 g, 0.3 mmol) and Pd(PPh3)4
(0.08 g, 0.07 mmol) in ethyl acetate (10 mL) was added
dropwise a solution of 5a (2.1 g, 7.4 mmol) in ethyl
acetate (10 mL) at rt. The mixture was stirred for 1–3 h
with TLC monitoring. After the reaction was completed
the mixture was extracted with water (2Â10 mL). The
water layer was acidified with H3PO4 (pH=3.0) while a
jelly-like precipitate was formed which was extracted
with ethyl acetate (2Â20 mL). The organic layer was
dried with MgSO4 and evaporated under reduced pres-
sure. The resultant solid was treated with diethyl ether
(15 mL) filtered and dried giving 6a (0.84 g, 3.1 mmol,
42% yield); mp 154 ꢁC, [a]D25=154.8 (c 1%, CH3Cl).
IR (film from CHCl3) 3475, 2978, 1764, 1742, 1713,
1396, 1367, 1300, 1280, 1265, 1186.
(2R,7S,8S)-9-oxo-8t-[(R)-1-Hydroxyethyl]-6-acetyl-1-
azatricyclo[5.2.0.02,4]nonane-2,6-dicarboxylic acid, 2-
allyl ester, 6-ethyl ester (5c). (1.8 g, 4.7 mmol, 94%
1
yield) from 4c (2.5 g, 5.1 mmol). H NMR (CDCl3) d
1.124 (dd, J=15.0, 8.6 Hz; 1H, 5-CH), 1.276 (t, J=7.1
Hz, 3H, CH3CH2), 1.329 (d, J=6.2 Hz, 3H, CH3), 1.428
(t, J=5.8 Hz, 1H, 3-CH), 1.648 (tt, J=8.8, 6.2 Hz, 1H,
4-CH), 1.826 (dd, J=7.8, 5.9 Hz, 1H, 3-CH), 2.230 (s,
3H, CH3C¼O), 2.572 (dd, J=8.6, 2.4 Hz; 1H, 8-CH),
2.685 (ddd, J=14.8, 6.6, 0.7 Hz; 1H, 5-CH), 4.130
(qvintet, J=7.1 Hz, 1H, OCHCH3), 4.244 (q, J=7.1
Hz, 1H, CH3CH2), 4.274 (q, J=7.1 Hz, 1H, CH3CH2),
4.536 (d, J=2.4 Hz; 1H, 7-CH), 4.600 (ddt, J=13.4, 5.7,
1.5 Hz; 1H, OCH2CH¼), 4.651 (ddt, J=13.4, 5.5, 1.5
Hz, 1H, OCH2CH¼) 5.258 (dq, J=10.7, 1.5 Hz; 1H,
H2C¼CH), 5.337 (dq, J=17.2, 1.6 Hz; 1H, H2C¼CH),
5.923 (ddt, J=17.2, 10.4, 5.5 Hz, 1H, H2C¼CH).
1H NMR (DMSO-d6) d 1.142 (d, J=6.2 Hz, 3H, CH3),
1.219 (dd, J=7.1, 5.1 Hz, 1H, 3-CH), 1.622 (dd, J=9.1,
5.1 Hz, 1H, 3-CH), 1.924 (tt, J=9.0, 5.3 Hz, 1H, 4-CH),
2.630 (dd, J=14.6, 5.3 Hz; 1H, 5-CH), 2.924 (dd,
J=7.1, 1.6 Hz; 1H, 8-CH), 3.279 (dd, J=14.5, 5.1 Hz;
1H, 5-CH), 3.900 (quintet, J=6.6 Hz, 1H, OCHCH3),
4.464 (d, J=1.7 Hz; 1H, 7-CH), 5.61 (brs, 1H, OH),
12.63 (brs, 1H, COOH).
13C NMR (CDCl3) ꢀ4.58, 13.95, 22.11, 23.06, 23.43,
25.60, 27.72, 28.32, 34.58, 53.50, 59.42, 60.67, 62.40,
65.98, 66.31, 118.17, 131.72, 168.28, 170.41, 170.63,
202.39.
13C NMR (CDCl3) d 19.07, 21.47, 21.74, 23.91, 33.70,
51.14, 63.90, 67.20, 167.53, 171.96.
MS HR (LSIMS) for C19H25O7N (M+H)+, found
380.17108, calcd 380.17093.
MS HR (EI) for C10H13NO4S for M+, found
243.05666, calcd 243.05653 Elemental analysis: calcd
%C 49.37, %H 5.38, %N 5.76, %S 13.18, found %C
49.14, %H 5.36, %N 5.62, %S 13.17.
IR (film from CHCl3) 3483, 2978, 1762, 1712, 1400,
1369, 1298, 1283, 1263, 1179.
IR (KBr) 3312, 2979.2920, 1744, 1720, 1393, 1381, 1255,
1196, 1185.
(2R,7S,8S)-9-oxo-8t-[(R)-1-Hydroxyethyl]-6,6-diacetyl-1
- azatricyclo[5.2.0.02,4]nonane-2-carboxylic acid allyl es-
ter (5d). (1.31 g, 3.8 mmol, 65% yield) from (4d) (2.66
g, 5.7 mmol).
According to the same procedure compounds 6b–d were
prepared.

1966
A. Korda, J. Winiarski / Bioorg. Med. Chem. 11 (2003) 1957–1967
(2R,7S,8S)-9-oxo-8t-[(R)-1-Hydroxyethyl]-1-azatricy-
clo[5.2.0.02,4]nonane-2,6,6-tricarboxylic acid, 6,6-diethyl
ester (6b). (1.8 g, 4.9 mmol 51% yield) from (5b) (3.9 g,
9.5 mmol); mp 182 ꢁC, [a] D25=ꢀ88.2 (c 1%, CH3Cl). 1H
NMR (CDCl3) d 1.258 (t, J=7.0 Hz, 3H, CH3CH2),
1.259 (d, J=6.4 Hz, 3H, CH3), 1.280 (t, J=7.0 Hz, 3H,
CH3CH2), 1.295 (dd, J=14.6, 8.2 Hz, 1H, 5-CH), 1.449
(t, J=6.0 Hz, 1H, 3-CH), 1.720 (tt, J=8.2, 6.4 Hz, 1H, 4-
CH), 1.865 (dd, J=8.8, 5.7 Hz, 1H, 3-CH), 2.818 (dd,
J=14.6, 6.4 Hz, 1H, 5-CH), 2.855 (dd, J=5.8, 2.6 Hz, 1H,
8-CH), 4.077 (dq, J=10.8, 7.1 Hz, 1H, OCHCH3), 4.21-
4.35 (m, 4H, CH3CH2), 4.443 (d, J=2.6 Hz, 1H, 7-CH).
(tt, J=8.6, 5.5 Hz, 1H, 4-CH), 2.552 (dd, J=8.6, 2.4
Hz; 1H, 8-CH), 2.803 (dd J=15.5, 6.2 Hz; 1H, 5-CH),
4.215 (dq, J=8.6, 6.2 Hz, 1H, OCHCH3), 4.631 (d,
J=2.2 Hz; 1H, 7-CH).
13C NMR (CDCl3) d 22.27, 23.59, 26.85, 28.92, 35.24,
52.49, 59.50, 66.65, 68.00, 168.50, 174.15, 203.59,
203.89.
MS HR (EI) C15H20O6N for M+ found 310.12848,
calcd 310.12906.
Elemental analysis: calcd %C 58.05, %H 6.50, %N
4.51, found %C 58.06, %H 6.34, %N 4.59.
13C NMR (CDCl3) d 13.86, 13.96, 20.91, 23.24, 23.72,
28.36, 34.55, 52.37, 53.92, 60.04, 62.40, 62.59, 64.92,
168.94, 169.03, 169.72, 174.42.
IR (KBr) 3340, 2973, 2926, 17726, 1698, 1420, 1365,
1305, 1256, 1203, 1182.
MS HR (LSIMS) for C17H23NO8 for (M+Na)+, found
392.11428, calcd 392.11428.
Acknowledgements
Elemental analysis: calcd %C 55.28, %H 6.27, %N
3.79, found %C 55.23, %H 6.34, %N 3.85.
We thank Dr. Z. Urbanczyk-Lipkowska of Institut of
Organic Chemistry Polish Academy of Sciences for the
X-ray crystal structure and Dr. W.Kaminska of Centrum
Zdrowia Dziecka for conducting antibacterial screening.
IR (KBr) 3407, 2995, 2974, 1770, 1730, 1716, 1451,
1390, 1372, 1285, 1260, 1201, 1168, 1147, 1096, 1029.
(2R,7S,8S)-9-oxo-8t-[(R)-1-Hydroxyethyl]-6-acetyl-1-aza-
tricyclo[5.2.0.02,4]nonane-2,6-dicarboxylic acid, 6-ethyl
ester (6c). (0.57 g, 1.7 mmol, 34% yield) from 5c (1.9 g,
References and Notes
5.0 mmol); mp 98 ꢁC, [a] 25=ꢀ162.4 (c 1%, CH3Cl).
D
1. Keith, D. D.; Tengi, J.; Rossman, P.; Todaro, L.; Weigele,
M. Tetrahedron 1983, 39, 2445.
1H NMR (CDCl3) d 1.157 (dd, J=15.2, 8.8 Hz, 1H, 5-
CH), 1.303 (t, J=7.1 Hz, 3H, CH3CH2), 1.318 (d,
J=6.2 Hz, 3H, CH3), 1.472 (t, J=6.0 Hz, 3H, 3-CH),
1.712 (tt, J=8.8, 6.4 Hz, 1H, 4-CH), 1.866 (dd, J=8.8,
5.8 Hz, 1H, 3-CH), 2.235 (s, 3H, CH3C¼O), 2.618 (dd,
J=8.1, 2.4 Hz, 1H, 8-CH), 2.699 (dd, J=14.5, 6.7 Hz,
1H, 5-CH), 4.197 (dq, J=8.1, 6.4 Hz, 1H, OCHCH3),
4.296 (dq, J=7.1, 5.7 Hz, 4H, CH3CH2), 4.550 (d,
J=2.4 Hz, 1H, 7-CH).
2. Christensen, J.; Georgopapadakou, N.; Keith, D.; Luk, K.-
C.; Madison, V.; Mook, R.; Pruess, D.; Roberts, J.; Rossman,
P.; Wei, C.-C.; Weigele, M.; West, K. In Recent Advances in
the Chemistry of ꢀ-Lactam Antibiotics; Bentley, P. H., South-
gate, R., Eds.; Special Publication No. 70; Royal Society of
Chemistry: London, 1989; p 33.
3. Wei, C. C.; Christenson, J. G.; Corraz, A. J.; Keith, D. D.
Bioorg. Med. Chem. 1991, 1, 43.
4. Kamiya, T.; Teraji, T.; Hashimoto, M.; Nakaguchi, O.;
Oku, T. J. Am. Chem. Soc. 1975, 97, 5020.
5. Bateson, J. H.; Corbett, D. F.; Southgate, R. In Recent
Advances in the Chemistry of ꢀ-Lactam Antibiotics; Brown,
A.G., Roberts, S.M., Eds.; Special Publications No. 52: Royal
Society of Chemistry: London, 1984; p 116.
13C NMR (CDCl3) 13.99, 22.02, 23.71, 24.07, 27.94,
28.47, 34.44, 53.21, 59.49, 60.58, 62.74, 66.01, 168.93,
170.84, 175.36, 202.55.
6. Bateson, J. H.; Kaura, A. C.; Southgate, R. Tetrahedron
Lett. 1991, 32, 2065.
7. Bateson, J. H.; Southgate, R.; Tyler, J. W.; Fell, S. C. M. J.
Chem. Soc., Perkin Trans. 1 1986, 973.
MS HR (EI) C16H21NO7 for M+, found 339.13146,
calcd 339.13180.
8. Bateson, J. H.; Fell, S. M.; Kaura, A. C.; Arun, C.; South-
gate, R. J. Chem. Soc. Perkin Trans. 1 1992, 13, 1577.
9. Long, A.G. In Recent Advances in the Chemistry of ꢀ-Lac-
tam Antibiotics; Elks, J., Ed.; Special Publications No. 28; The
Chemical Society: London, 1977; p 214.
Elemental analysis: calcd %C 56.63, %H 6.24, %N
4.13, found %C 56.54, %H 6.22, %N 4.06.
IR (KBr) 3417, 2979, 1770, 1741, 1714, 1450, 1370,
1298, 1271, 1189.
10. Branch, L. C.; Pearson, M. J. J. Chem. Soc., Perkin Trans.
1 1979, 2268.
11. Lammert, S. R.; Kukolja, S. J. Am. Chem. Soc. 1975, 97,
5583.
12. Mori, M.; Kanda, N.; Ban, Y. J. Chem. Soc., Chem.
Commun. 1986, 1375.
13. Mori, M.; Kanda, N.; Ban, Y.; Aoe, K. J. Chem. Soc.,
Chem. Commun. 1988, 12.
14. Afonso, A.; Hon, F.; Weinstein, J.; Ganguly, A. K.;
McPhail, A. T. J. Am. Chem. Soc. 1982, 104, 6138.
15. Yoshida, A.; Hayashi, T.; Takeda, N.; Oida, S.; Okhi, E.
Chem. Pharm. Bull. 1983, 768.
(2R,7S,8S)-9-oxo-8t-[(R)-1-Hydroxyethyl]-6,6-diacetyl-
1-azatricyclo[5.2.0.02,4]nonane-2-carboxylic acid (6d).
(0.40 g, 1.3 mmol, 35%) from 5d (1.3 g, 3.7 mmol); mp
163–165 ꢁC, [a] 2D5=ꢀ238.2 (c 1%, CH3Cl).
1H NMR (CDCl3) d 1.165 (dd, J=15.6, 8.9 Hz; 1H, 5-
CH), 1.361 (d, J=6.2 Hz, 3H, CH3), 1.465 (t, J=6.0
Hz, 1H, 3-CH), 1.859 (dd, J=8.6, 5.9 Hz, 1H, 3-CH),
2.211 (s, 3H, CH3C¼O), 2.246 (s, 3H, CH3C¼O), 2.288

A. Korda, J. Winiarski / Bioorg. Med. Chem. 11 (2003) 1957–1967
1967
16. Kawamoto, I.; Endo, R.; Suzuki, K.; Hata, T. Hetero-
cycles 1987, 25, 123.
17. Crystallographic data (excluding structure factors) for
structure 6a have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication No. CCDC
196221. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK (fax: +44-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).