Synthesis and NMR studies of key intermediates to a new class of β-lactam: The trinems

Article abstract of DOI:10.1039/a605081f

An efficient synthesis of the four isomeric epoxides 4a-d, key compounds to the trinem ring system, starting from (3R,4R,1′R)-(+)-4-acetoxy-3-[1′-(tert-butyldimethylsilyloxy)ethyl] azetidin-2-one 6a is described. All the intermediates have been characteri

Full text of DOI:10.1039/a605081f

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Synthesis and NMR studies of key intermediates to a new class of
â-lactam: the trinems
Carla Marchioro,* Giorgio Pentassuglia,* Alcide Perboni and Daniele Donati
Glaxo Wellcome S.p.A., Medicines Research Centre, via Fleming 4, 37135 Verona, Italy
An efficient synthesis of the four isomeric epoxides 4a–d, key compounds to the trinem ring system,
starting from (3R,4R,1ЈR)-(+)-4-acetoxy-3-[1Ј-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one 6a is
described. All the intermediates have been characterized by means of N M R techniques.
β-Lactam antibiotics are important antibacterial agents because
of their high potency and broad spectrum of activity usually
accompanied by low levels of toxicity.1 Because of this, research
over recent years has been focused on discovering novel β-
lactams from natural sources (e.g. cephalosporins, mono-
bactams, carbapenems), by semisynthesis of new derivatives
from naturally occurring sources (e.g. penicillins, cephalo-
sporins, carbapenems) and by design of novel classes of
compounds (e.g. penems, carbacephalosporins, oxacephalo-
sporins).2 Recently a new family of totally synthetic β-lactam
antibiotics, the trinems (formerly referred to as tribactams, Fig.
1, 1) has been discovered in our laboratories.3 These com-
Fig. 2
Fig. 1
pounds possessed both very broad antibacterial activity and
high stability to most clinically relevant β-lactamases. From the
structural point of view, the main feature of the members of
this class is the presence of a third ring, C, fused to the bicyclic
nucleus of carbapenems; this can be 5–7 membered, carbocyclic
or a heteroatom-containing ring. Our research activities have
been particularly focused on exploiting derivatives where C is a
6-membered carbocyclic ring substituted at C-4 (Fig. 1, 2). In
Scheme 1
particular sanfetrinem (GV104326) 3a and its metabolically
labile ester GV118819 ‘3b’ have shown a particularly good bio-
logical profile and have been selected for development studies.4
As both antibacterial activity and biological stability of
Results and discussion
trinems 2 were found to be dependent on the absolute configur-
ation at the stereogenic centres at C-4 and C-8, the identifi-
cation of efficient and stereoselective routes to these com-
pounds would allow us to synthesize more efficiently other
derivatives. On this basis, we identified the isomeric epoxides
4a–d (Fig. 2) as advanced key intermediates.
Compounds 4a–d can react with nucleophiles to give α-
substituted cyclohexanols 5 (where, for example, 5a and 5b rep-
resent the epoxide ring opening of 4a with methylamine and
methanol, respectively) which could be converted into 4-
substituted trinems 2 through well established procedures (for
example, see Scheme 1 for compound 3a).3a,5
Synthesis
In early studies we succeeded in the direct cyclohexenylation
of commercially available 4-acetoxyazetidinone 6a 6 with
cyclohexenyl bromide in the presence of zinc dust in anhydrous
tetrahydrofuran (THF), to obtain an inseparable mixture of
cyclohexenyl derivatives 7a,b7a (Scheme 2). A 4:1 mixture of
7a :7b was also obtained through an intramolecular Sakuraj-
type reaction.7b
In order to obtain pure isomers of 7a and 7b a less direct
route was thus preferred. It has previously been demonstrated 3c
that 1-(trimethylsilyloxy)cyclohexene reacts with the 4-acetoxy-
azetidinone 6a in the presence of a number of catalysts, but
J. Chem. Soc., Perkin Trans. 1, 1997
463

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same reaction conditions were used for 7b and, in this case, a
20:80 mixture of epoxides 4c and 4d was isolated (Scheme 4).
Scheme 2
most preferably zinc chloride, to give a 40:60 mixture of the
ketoazetidinones 8a,b in 90% overall yield from 6a. We were
able to change the diastereoisomer ratio by changing the
reaction conditions. Protection of 6a at the lactam nitrogen
with a trimethylsilyl group gave 6b that was reacted with 1-
(trimethylsilyloxy)cyclohexene in the presence of tin() chlor-
ide to give, after work-up and removal of the trimethylsilyl
group, an 80:20 mixture of isomers 8a,b in 95% overall yield
from 6a (Scheme 2). The ketoazetidinone 8a could be
obtained in 55% yield after crystallization of the crude reac-
tion mixture.
Scheme 4
In order to explain this stereochemical outcome we hypoth-
esized the formation of a hydrogen bond between the lactam
hydrogen and the peracid as reported by Roush 9 and by
Kocovský.10
This was indirectly supported through the epoxidation of the
N-tert-butyldimethylsilyl derivative 10a (Scheme 4). Thus, reac-
tion of 10a with 3-chloroperoxybenzoic acid gave a mixture of
the epoxides 11a and 11b in a 6:94 ratio and 60% yield. The
absolute configurations at the stereogenic centres for 11b were
established by conversion into 4b after removal of the silyl pro-
tecting group.
Compounds 8a and 8b were then separately transformed into
the tosylhydrazones 9a and 9b in good yield (Scheme 3). It is
All the epoxides were found to undergo regioselective ring
opening with a number of nucleophiles, such as methanol and
methylamine, allowing the introduction of a variety of sub-
stituents on the trinem structure. In the case of the epoxide 4a
the regiochemistry of the reaction is consistent 11 with a prefer-
ence for a ring-opening to give a trans-diaxial product such as 5;
for the epoxide 4b, however, the substituent at C-3Ј, for steric
reasons, directs nucleophile attack to C-1Ј.
Compound 4a has been most widely studied because its reac-
tion with methanol allowed the stereoselective introduction of a
methoxy group and gave an intermediate that could be easily
transformed into sanfetrinem and GV118819. In the same
way12,3c we were able to open regioselectively the epoxide 4a
with amines, alcohols and thiols in order to evaluate the micro-
biological profile of the corresponding 4-substituted trinems.
NMR Studies
The complete proton and carbon assignments for compounds
4a–d, 7a–b, 8a–b and 9a–b were relatively straightforward and
were made with the combined results of several experiments:
1H NMR, 13C NMR, 1H–13C NMR correlation (gHMQC,
gHSQC) and gCOSY; in addition, the structures have been
investigated by means of NOE techniques. The reference num-
bering is given in Fig. 3.
Scheme 3
worth noting that only the E isomer of the hydrazones could be
isolated, although traces of the Z isomers could be detected by
careful NMR analysis of the reaction mixtures.
Both hydrazones 9a and 9b were successfully transformed
into cyclohexenyl derivatives in 64 and 70% yield, respectively,
according to the well established Shapiro procedure.8 Epoxi-
dation of 7a (3-chloroperoxybenzoic acid, dichloromethane,
23 ЊC) gave an 80:20 mixture of isomers 4a and 4b that could be
easily separated by flash chromatography (for the structural
assignment of epoxides 4a and 4b see next paragraph). The
The description of the complete proton and carbon assign-
1
ments for compound 4a serves as an example. The H NMR
signal assignments were made first via the sequential correl-
ations observed from the gCOSY spectra. The protons H-3 and
H-4 (δ 3.77, dd, J 2.4, 6.8 Hz) showed a strong correlation in the
464
J. Chem. Soc., Perkin Trans. 1, 1997

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Fig. 4
Fig. 3
gCOSY spectrum, as expected. Proton H-4 was also coupled to
H-3Ј (δ 2.0) and this one was correlated to H-2Ј and both the
H-4Ј protons: from these all of the aliphatic protons were read-
ily identified. The axial and equatorial protons were assigned
through their coupling constants and chemical shifts.
Fig. 5
13C NMR signals were then ascribed through gHMQC
(gradient heteronuclear multiple quantum correlation) and
gHSQC (gradient heteronuclear single quantum correlation).
The stereochemistries in the series 4a–d were studied by
means of NOE experiments. All the observed NOEs, together
with a suggestion for the solution conformation are reported in
Fig. 4: in the case of compound 4a the configuration at C-3Ј
was confirmed from the presence of NOE enhancements
between H-3 and H-3Ј and between H-4 and H-2Ј; these find-
ings, together with the same enhancements after irradiation of
H-3, suggest a rotation around the C(4)᎐C(3Ј) bond and the
configurations at H-2Ј and H-1Ј were also based upon the com-
parison of NOE data of compounds 4a and 4b.
Fig. 6
In both isomers, saturation of H-8 results in a strong NOE
enhancement in the signal of H-9 in compound 2a and in the
case of the epimer, 2b, in a strong enhancement in the H-10
signal in addition to a small effect on the H-9 signal (Fig. 5).
The two isomers 8a and 8b also show significant differences
in their chemical shifts. Comparing the proton chemical shifts,
characteristic differences can be observed between the H-4 sig-
nals of the two isomeric compounds: in the case of 8a, the
signal is at about 4.1 ppm while in compound 8b the signal is at
about 3.6 ppm. This trend in the chemical shifts difference can
be observed also in compounds 9a and 9b: respectively, 4.0 and
3.6 for their H-4 chemical shifts. The configuration of the
double bond of both compounds is derived from the NOE
experiments: in the case of 9a saturation of the lower field aro-
matic protons results in enhancements in H-1 and H-4, satur-
ation of the upper field aromatic protons in an enhancement of
the Heq-6Ј signal, irradiation of H-4 results in an enhancement
of H-3, H-1, H-2Ј and in the lower field aromatic protons.
Irradiation of H-3 results in an enhancement of H-2Ј, Heq-3Ј,
H-5 and H-4 and a smaller effect on the aromatic region. The
most relevant result is from saturation of Heq-6Ј: an NOE
enhancement is evident on the NH of the Ts group, Heq-4Ј and
Heq-5Ј; irradiation of H-2Ј gives enhancement on H-3, H-4 and
Heq-5Ј and in the upper field aromatic region. From all these
results, the structure in Fig. 6 is derived.
The stereochemistries were also confirmed by the chemical
transformation of 4a to compound 3a, as reported in Scheme 1.
The relative configuration at C-2Ј in compounds 8a and
8b was unequivocally established through conversion into com-
Scheme 5
pounds related to the structure (2a and 2b, where X = H,
Scheme 5)†,3a and relative NOE studies while the stereo-
chemistries at C-3 and C-4 are derived from the coupling con-
stant value, i.e. J3,4 = 2.2 Hz.13
† 2a: δH 1.25 (3 H, d, 11-Me), 1.35 (1 H, m, 7-Hax), 1.84 (2 H, m, 2 × 6-
H), 1.92 (2 H, m, 2 × 5-H), 1.96 (1 H, m, 7-Heq), 2.05 (1 H, m, 4-Hax),
2.86 (1 H, m, 8-H), 3.15 (1 H, dd, J 3.0 and 6.5, 10-H), 3.45 (1 H, m, 4-
Heq), 4.15 (1 H, dd, J 3.0 and 10.0, 9-H), 4.20 (1 H, m, 11-H), 4.70 (2 H,
m, CH2CH᎐CH2), 5.30 (2 H, m, CH2CH᎐CH2) and 5.95 (1 H, m,
᎐
᎐
CH2CH᎐CH2). 2b: δH 1.25 (1 H, m, 7-Hax), 1.33 (3 H, d, 11-Me), 1.70 (1
᎐
H, m, 6-H), 1.75 (1 H, m, 5-Hax), 1.85 (1 H, m, 6-H), 2.10 (1 H, m, 5-
Heq), 1.96 (1 H, m, 7-Heq), 2.35 (1 H, m, 4-Hax), 2.89 (1 H, m, 8-H), 3.13
(1 H, dd, J 2.8 and 7.6, 10-H), 3.44 (1 H, m, 4-Heq), 3.71 (1 H, dd, J 2.8
Moving to the compounds 7a and 7b there are no significant
differences in the chemical-shift values, and the coupling con-
stant J4,3Ј value (7.4 Hz in 7a and 8.6 Hz in 7b), suggests a close
steric similarity between the two compounds.
and 6.6, 9-H), 4.20 (1 H, m, 11-H), 4.80 (2 H, m, CH2CH᎐CH2), 5.33 (2
᎐
H, m, CH2CH᎐CH2) and 5.95 (1 H, m, CH2CH᎐CH2).
᎐
᎐
J. Chem. Soc., Perkin Trans. 1, 1997
465

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(1 H, br s, NH); δC(75.43 MHz) Ϫ4.86, Ϫ4.51 [2 × (Me3C)-
Experimental
Me2Si], 17.79 [(Me3C)Me2Si], 22.78 (C-6), 24.60 (C-4Ј), 25.65
[(Me3C)Me2Si], 27.46 (C-5Ј), 31.07 (C-3Ј), 41.89 (C-6Ј), 50.77
(C-2Ј), 55.57 (C-4), 63.15 (C-3), 65.51 (C-5), 167.88 (C-2) and
212.05 (C-1Ј) [Found (HRMS): m/z 326.213 44. Calc. for
(MH+): 326.215 148]; m/z 326 (MH+, 10%), 310 (14), 268 (84)
and 126 (100).
Method 2. To a solution of 4-acetoxyazetidinone 6a (45.2 g,
157.0 mmol) in CH2Cl2 (400 ml) were added at 0 ЊC triethyl-
amine (33 ml, 237 mmol) and trimethylsilyl chloride (25 ml, 197
mmol). The resulting reaction mixture was stirred at room tem-
perature for 1 h after which it was washed with pre-cooled water
and brine, dried (Na2SO4) and evaporated to give 6b (55 g, 97%)
which was used without further purification; δH 0.02 [6 H, s,
(Me3C)Me2Si], 0.22 (9 H, s, Me3Si), 0.8 [9 H, s, (Me3C)Me2Si],
1.18 (3 H, d, J 5.7, 5-Me), 2.04 (3 H, s, OCOMe), 3.08 (1 H, m,
3-H), 4.15 (1 H, m, 5-H) and 6.08 (1 H, d, J 1.0, 4-H).
All reactions were performed in oven-dried glassware under a
positive pressure of nitrogen. All reagents were purchased from
commercial sources and used as received, unless otherwise indi-
cated. Solvents were distilled under a nitrogen atmosphere from
sodium benzophenone ketyl (THF), CaH2 (triethylamine,
DMF) or P2O5 (CH2Cl2). Zinc chloride, ZnCl2, was fused in
vacuo before use. Analytical thin-layer chromatography (TLC)
was performed on E. Merck silica gel 60 F254 plates (0.25 mm).
Compounds were visualized by dipping in a phosphomolybdic
acid solution followed by heating. Flash chromatography was
performed on E. Merck silica gel (230–400 mesh).14 Melting
points are uncorrected and were determined with a capillary
melting point apparatus. IR spectra were recorded in CDCl3
solution unless otherwise indicated and are reported in wave-
numbers (cmϪ1). H NMR spectra were recorded at 500 MHz,
1
13C NMR were recorded at 100.57 or at 75.43 MHz: all the
To a vigorously stirred solution of tin() chloride (20.5 ml,
175 mmol) in dry acetonitrile (250 ml), cooled at Ϫ40 ЊC was
added dropwise a solution of 6b (55 g, 152 mmol) in dry
acetonitrile (150 ml). During the addition the temperature was
maintained <Ϫ25 ЊC; a solution of 1-(trimethylsilyloxy)cyclo-
hexene (41 ml, 210 mmol) was then rapidly added to the reac-
tion mixture which was then stirred for 1 h. After this it was
diluted with diethyl ether, washed with pre-cooled 10% aqueous
NaOH, dried (Na2SO4) and evaporated. The residue was dis-
solved in methanol (300 ml) and stirred for 30 min in the pres-
ence of silica gel (30 g) and triethylamine (1 ml). The silica gel
was filtered off and the filtrate evaporated to give 8a and 8b
(48 g, 95%) (ratio 8a :8b = 80:20). The mixture was recrystal-
lized from light petroleum to give pure 8a (28 g, 55%).
spectra were collected in CDCl3 at 25 ЊC; J values are given in
Hz. In the H NMR spectra, chemical shifts are reported in
1
ppm with respect to residual CHCl3 at 7.26 downfield from TMS
while in the carbon NMR spectra, the central signal (δ 77.0) 13
C
resonance of CDCl3 was used as internal reference. NMR
assignments are assisted by NOE and 2D- techniques. For the
numbering systems used in the NMR assignments, see Fig. 3.
Mass spectra were recorded in FAB (70 eV) mode using 3-
nitrobenzyl alcohol as matrix. All optical rotations [α] values
were obtained in CH2Cl2 solution, at the sodium D line, at
20 ЊC and are given in units of 10Ϫ1 deg cm2 gϪ1
.
(3S,4R)-3-[(1R)-1-(tert-Butyldimethylsilyloxy)ethyl]-4-[(2ЈR)-
1Ј-oxocyclohexan-2Ј-yl]azetidin-2-one 8a and (3S,4R)-3-[(1R)-1-
(tert-butyldimethylsilyloxy)ethyl]-4-[(2ЈS)-1Ј-oxocyclohexan-2Ј-
yl]azetidin-2-one 8b
(3S,4R)-3-[(1R)-1-(tert-Butyldimethylsilyloxy)ethyl]-4-{[(2ЈR)-
1Ј-(4-methylphenylsulfono)hydrazono]cyclohexan-2Ј- yl}-
azetidin-2-one 9a
Method 1. To a solution of 4-acetoxyazetidinone 6a (2.85 g,
9.91 mmol) and zinc chloride (2.50 g, 18.34 mmol) in dry
CH2Cl2 (20 ml) was added dropwise a solution of 1-
(trimethylsilyloxy)cyclohexene (2.12 ml, 10.90 mmol) in dry
CH2Cl2 (20 ml). The resulting reaction mixture was stirred for 3
h after which further 1-(trimethylsilyloxy)cyclohexene (0.25 ml,
1.28 mmol) in dry CH2Cl2 (2 ml) was added to it and stirring
was continued for 1 h. The solution was washed with brine,
dried (Na2SO4) and evaporated. The product was purified by
flash chromatography eluting with a 7:3 mixture of cyclo-
hexane and ethyl acetate to afford 8a (1.18 g) and 8b (1.77 g)
(ratio 8a :8b = 40:60, total yield 90%).
Compound 8a: white solid; mp 105–107 ЊC; [α] +33.9 (c 0.54)
(Found: C, 62.62; H, 9.54; N, 4.22. C17H31NO3Si requires C,
62.71; H, 9.62; N, 4.30%); νmax/cmϪ1 3418s, 1757s and 1707s; δH
0.06 [3 H, s, (Me3C)Me2Si], 0.08 [3 H, s, (Me3C)Me2Si], 0.87 [9
H, s, (Me3C)Me2Si], 1.24 (3 H, d, J 6.5, 5-Me), 1.69 (3 H, m, 3Ј-
Hax, 5Ј-Hax, 4Ј-Hax), 1.96 (1 H, m, 4Ј-Heq), 2.15 (2 H, m, 5Ј-Heq
and 3Ј-Heq), 2.36 (1 H, m, 6Ј-Hax), 2.43 (1 H, m, 6Ј-Heq), 2.56
(1 H, m, 2Ј-H), 2.88 (1 H, dd, J 2.3 and 5.5, 3-H), 4.10 (1 H, dd,
J 2.3 and 3.5, 4-H), 4.19 (1 H, m, 5-H) and 5.75 (1 H, br s,
NH); δC(100.57 MHz) Ϫ4.95, Ϫ4.20 [2 × (Me3C)Me2Si], 17.97
[(Me3C)Me2Si], 22.55 (C-6), 24.66 (C-4Ј), 25.77 [(Me3C)-
Me2Si], 27.64 (C-5Ј), 27.76 (C-3Ј), 42.37 (C-6Ј), 49.35 (C-2Ј),
52.59 (C-4), 60.58 (C-3), 65.97 (C-5), 168.58 (C-2) and 211.57
(C-1Ј) [Found (HRMS): m/z 326.215 980. Calc. for (MH+):
326.215 148]; m/z 326 (MH+, 28%), 310 (20) and 268 (100).
Compound 8b: white solid; mp 107–109 ЊC; [α] +40.1 (c 0.57)
(Found: C, 62.54; H, 9.72; N, 4.24. C17H31NO3Si requires C,
62.71; H, 9.62; N, 4.30%); νmax/cmϪ1 3423s, 1755s and 1707s; δH
0.07 [3 H, s, (Me3C)Me2Si], 0.08 [3 H, s, (Me3C)Me2Si], 0.86 [9
H, s, (Me3C)Me2Si], 1.22 (3 H, d, J 6.5, 5-Me), 1.42 (1 H, m, 3Ј-
Hax), 1.65 (2 H, m, 4Ј-Hax and 5Ј-Hax), 1.95 (1 H, m, 4Ј-Heq),
2.10 (1 H, m, 5Ј-Heq), 2.16 (1 H, m, 3Ј-Heq), 2.33 (1 H, m, 2Ј-H),
2.40 (1 H, m, 6Ј-Hax), 2.42 (1 H, m, 6Ј-Heq), 2.70 (1 H, m, 3-H),
3.63 (1 H, dd, J 2.18 and 9.92, 4-H), 4.18 (1 H, m, 5-H) and 6.12
To a solution of 8a (1 g, 3.0 mmol) in glacial acetic acid (30 ml)
was added toluene-p-sulfonylhydrazine (0.63 g, 3.38 mmol).
The resulting reaction mixture was stirred for 3 h, diluted with
CH2Cl2 (80 ml), neutralized with 5% aqueous NaHCO3, dried
(Na2SO4) and evaporated. The product was purified by flash
chromatography eluting with a 7:3 mixture of diethyl ether and
light petroleum to afford 9a (1 g, 66%) as a white solid; mp
95–96 ЊC; [α] +78.90 (c 0.73) (Found: C, 58.17; H, 8.10; N, 8.24.
C24H39N3O4SSi requires C, 58.37; H, 7.98; N, 8.51%); νmax/cmϪ1
3306s and 1755s; δH 0.04 [3 H, s, (Me3C)Me2Si], 0.06 [3 H, s,
(Me3C)Me2Si], 0.87 [9 H, s, (Me3C)Me2Si], 1.04 (3 H, d, J 6.5, 5-
Me), 1.46 (1 H, m, 3Ј-Hax), 1.47 (2 H, m, 4Ј-Hax and 5Ј-Hax),
1.81 (1 H, m, 3Ј-Heq), 1.82 (1 H, m, 6Ј-Hax), 1.90 (1 H, m, 5Ј-
Heq), 1.92 (1 H, m, 4Ј-Heq), 2.35 (1 H, m, 2Ј-H), 2.45 (3 H, s,
5Љ-Me), 2.55 (1 H, m, 6Ј-Heq), 2.82 (1 H, dd, J 2.5 and 5.2, 3-
H), 4.00 (1 H, dd, J 2.5 and 6.5, 4-H), 4.10 (1 H, m, 5-H), 5.60 (1
H, br s, NH), 7.34 (2 H, m, 4Љ-H), 7.46 (1 H, br s, 1Љ-NH) and
7.81 (2 H, m, 3Љ-H); δC(100.57 MHz) Ϫ5.10, Ϫ4.39 [2 ×
(Me3C)Me2Si], 17.84 [(Me3C)Me2Si], 21.52 (C-6Љ), 22.33 (C-6),
23.81 (C-4Ј), 25.68 [(Me3C)Me2Si], 25.85 (C-5Ј), 26.31 (C-3Ј),
26.80 (C-6Ј), 46.14 (C-2Ј), 49.85 (C-4), 59.62 (C-3), 65.63 (C-5),
128.06 (C-3Љ), 129.65 (C-4Љ), 135.15 (C-2Љ), 144.35 (C-5Љ),
161.32 (C-1Ј) and 168.54 (C-2); m/z 494 (MH+, 29%), 436 (25)
and 319 (100).
(3S,4R)-3-[(1R)-1-(tert-Butyldimethylsilyloxy)ethyl]-4-{[(2ЈS)-
1Ј-(4-methylphenylsulfono)hydrazono]cyclohexan-2Ј-yl}azetidin-
2-one 9b
Following the same procedure as described for the synthesis of
9a, 9b (0.16 g, 72%) was obtained from 8b (0.15 g, 0.45 mmol);
mp 187–189 ЊC; [α] +67.6 (c 0.61) (Found: C, 58.51; H, 8.05; N,
8.52. C24H39N3O4SSi requires C, 58.37; H, 7.98; N, 8.51%); νmax
/
cmϪ1 3304s and 1753s; δH 0.085 [s, 3 H, (Me3C)Me2Si], 0.095 [s,
3 H, (Me3C)Me2Si], 0.93 [s, 9 H, (Me3C)Me2Si], 1.19 (1 H, m,
3Ј-Hax), 1.20 (3 H, d, J 6, 5-Me), 1.38 (1 H, m, 5Ј-Hax), 1.49 (1
466
J. Chem. Soc., Perkin Trans. 1, 1997

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H, m, 4Ј-Hax), 1.75 (1 H, m, 6Ј-Hax), 1.84 (1 H, m, 4Ј-Heq),
1.90 (1 H, m, 5Ј-Heq), 1.96 (1 H, m, 3Ј-Heq), 2.09 (1 H, m,
2Ј-H), 2.46 (3 H, s, 5Љ-Me), 2.63 (1 H, m, 3-H), 2.64 (1 H, m,
6Ј-Heq), 3.60 (1 H, dd, J 2.0 and 9.5, 4-H), 4.17 (1 H, m, 5-H),
5.68 (1 H, br s, NH), 7.22 (1 H, br s, 1Љ-NH), 7.35 (2 H, m, 4Љ-H)
and 7.82 (2 H, m, 3Љ-H); δC(100.57 MHz) Ϫ4.81, Ϫ4.47
[2 × (Me3C)Me2Si], 18.06 [(Me3C)Me2Si], 21.71 (C-6Љ), 22.69
(C-6), 24.47 (C-4Ј), 25.54 (C-5Ј), 25.85 [(Me3C)Me2Si], 26.57
(C-6Ј), 30.33 (C-3Ј), 49.65 (C-2Ј), 51.32 (C-4), 62.90 (C-3),
65.33 (C-5), 128.13 (C-3Љ), 129.81 (C-4Љ), 135.07 (C-2Љ), 144.74
(C-5Љ), 161.26 (C-1Ј) and 167.84 (C-2); m/z 494 (MH+, 100%),
436 (27) and 319 (18).
MHz) Ϫ5.0, Ϫ4.3 [2 × (Me3C)Me2Si], 17.90 [(Me3C)Me2Si],
19.9 (C-5Ј), 21.1 (C-4Ј), 22.6 (C-6), 23.3 (C-6Ј), 25.7 [(Me3C)-
Me2Si], 38.9 (C-3Ј), 51.8 (C-1Ј), 53.2 (C-2Ј), 53.3 (C-4), 62.4 (C-
3), 65.3 (C-5) and 168.5 (C-2); m/z 326 (MH+, 33), 310 (10), 268
(72) and 126 (100).
Compound 4b: white solid; mp 96–98 ЊC; [α] Ϫ20 (c 0.59)
(Found: C, 62.63; H, 9.64; N, 4.31. C17H31NO3Si requires C,
62.71; H, 9.62; N, 4.30%); νmax/cmϪ1 3414s and 1757vs; δH 0.08
[3 H, s, (Me3C)Me2Si], 0.09 [3 H, s, (Me3C)Me2Si], 0.88 [9 H, s,
(Me3C)Me2Si], 0.90 (1 H, m, 4Ј-Hax), 1.27 (3 H, d, J 6.5, 5-Me),
1.43 (2 H, m, 2 × 5Ј-H), 1.62 (1 H, m, 4Ј-Heq), 1.69 (1 H, m,
6Ј-Hax), 1.99 (1 H, m, 3Ј-H), 2.10 (1 H, m, 6Ј-Heq), 2.93 (1 H,
dd, J 2.2 and 6.4, 3-H), 3.08 (1 H, m, 2Ј-H), 3.16 (1 H, m, 1Ј-H),
3.55 (1 H, dd, J 2.2 and 8.4, 4-H), 4.13 (1 H, m, 5-H) and 6.00
(1 H, br s, NH); δC(100.57 MHz) Ϫ5.10, Ϫ4.64 [2 × (Me3C)-
Me2Si], 16.73 (C-5Ј), 17.72 [(Me3C)Me2Si], 22.84 (C-6), 24.50
(C-6Ј), 24.61 (C-4Ј), 25.62 [(Me3C)Me2Si], 38.49 (C-3Ј), 52.16
(C-2Ј), 52.58 (C-1Ј), 54.15 (C-4), 62.90 (C-3), 66.0 (C-5) and
168.12 (C-2); m/z 326 (MH+, 28%), 268 (61) and 126 (100).
(3S,4R)-3-[(1R)-1-(tert-Butyldimethylsilyloxy)ethyl]-4-[(3ЈS)-
cyclohex-1Ј-en-3Ј-yl]azetidin-2-one 7a15
To a stirred solution of LDA [prepared from dry diisopropyl-
amine (1.35 ml) and a 1.6  solution of butyllithium in hexanes
(5.7 ml)] was slowly added at Ϫ40 ЊC a solution of 9a (1.12 g,
2.27 mmol) in dry THF (20 ml). The reaction mixture was
slowly warmed to Ϫ20 ЊC and maintained at 0 ЊC for 1 h. After
this it was added to pre-cooled 5% aqueous HCl (20 ml) and
extracted with ethyl acetate (2 × 40 ml). The combined organic
phases were washed successively with 5% aqueous NaHCO3
and brine, dried (Na2SO4) and evaporated. The product was
purified by flash chromatography eluting with a 1:1 mixture of
diethyl ether and light petroleum to afford 7a (0.45 g, 64%) as a
white solid.
(3S,4R)-3-[(1R)-1-(tert-Butyldimethylsilyloxy)ethyl]-4-
[(1ЈR,2ЈS,3ЈS)-1Ј,2Ј-epoxycyclohexan-3Ј-yl]azetidin-2-one 4c
and (3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-
[(1ЈS,2ЈR,3ЈS)-1Ј,2Ј-epoxycyclohexan-3Ј-yl]azetidin-2-one 4d
Following the same procedure as described for the synthesis of
4a and 4b, from 7b (1.44 g, 4.62 mmol) was obtained 4c (0.28 g)
eluting with a 1:1 mixture of diethyl ether and light petroleum
and 4b (1.13 g) by continuing the elution with an 8:2 mixture of
the same solvents (ratio 4c:4d = 20:80, total yield 90%).
Compound 4c: mp 129–131 ЊC; [α] +3.90 (c 0.64) (Found: C,
62.40; H, 9.70; N, 4.20. C17H31NO3Si requires C, 62.71; H, 9.62;
N, 4.30%); νmax/cmϪ1 3414s and 1757vs; δH 0.07 [3 H, s,
(Me3C)Me2Si], 0.08 [3 H, s, (Me3C)Me2Si], 0.87 [9 H, s,
(Me3C)Me2Si], 0.91 (1 H, m, 4Ј-Hax), 1.20 (1 H, m, 4Ј-Heq),
1.22 (3 H, d, J 6.0, 5-Me), 1.38 (1 H, m, 2 × 5Ј-H), 1.68 (1 H, m,
6Ј-Hax), 1.99 (1 H, m, 3Ј-H), 2.10 (1 H, m, 6Ј-Heq), 2.88 (1 H,
dd, J 2.0 and 5.5, 3-H), 2.91 (1 H, m, 2Ј-H), 3.20 (1 H, m, 1Ј-H),
3.62 (1 H, dd, J 2.0 and 8.3, 4-H), 4.21 (1 H, m, 5-H) and 6.18
(1 H, br s, NH); δC(100.57 MHz) Ϫ4.85, Ϫ4.29 [2 × (Me3C)-
Me2Si], 17.10 (C-5Ј), 17.94 [(Me3C)Me2Si], 22.86 (C-6), 24.51
(C-4Ј), 24.83 (C-6Ј), 25.75 [(Me3C)Me2Si], 38.95 (C-3Ј), 52.58
(C-1Ј), 52.84 (C-2Ј), 53.15 (C-4), 62.94 (C-3), 65.30 (C-5) and
168.55 (C-2); m/z 326 (MH+, 33%), 310 (10), 268 (76) and 126
(100).
Compound 4d: mp 76–78 ЊC; [α] +18.7 (c 0.71) (Found: C,
63.11; 9.63; N, 4.35. C17H31NO3Si requires C, 62.71; H, 9.62; N,
4.30%); νmax/cmϪ1 3414s and 1757vs; δH 0.04 [6 H, s, (Me3C)-
Me2Si], 0.86 [9 H, s, (Me3C)Me2Si], 1.22 (3 H, d, J 6.5, 5-Me),
1.25 (1 H, m, 4Ј-Hax), 1.26 (1 H, m, 5Ј-Hax), 1.34 (1 H, m, 5Ј-
Heq), 1.51 (1 H, m, 4Ј-Heq), 1.85 (2 H, m, 2 × 6Ј-H), 1.88 (1 H,
m, 3Ј-H), 2.80 (1 H, m, 3-H), 3.12 (1 H, m, 2Ј-H), 3.21 (1 H,
m, 1Ј-H), 3.63 (1 H, dd, J 2.2 and 9.2, 4-H), 4.16 (1 H, m, 5-H)
and 6.51 (1 H, br s, NH); δC(100.57 MHz) Ϫ4.83, Ϫ4.33 [2 ×
(Me3C)Me2Si], 17.91 [(Me3C)Me2Si], 19.17 (C-5Ј), 21.73 (C-4Ј),
22.78 (C-6), 23.38 (C-6Ј), 25.75 [(Me3C)Me2Si], 39.77 (C-3Ј),
52.59 (C-1Ј), 52.71 (C-2Ј), 52.75 (C-4), 63.72 (C-3), 65.49 (C-5)
and 168.91 (C-2); m/z 326 (MH+, 15%), 310 (7), 268 (61) and
126 (100).
(3S,4R)-3-[(1R)-1-(tert-Butyldimethylsilyloxy)ethyl]-4-[(3ЈR)-
cyclohex-1Ј-en-3Ј-yl]azetidin-2-one 7b
Following the same procedure as described for the synthesis of
7a, 7b (0.17 g, 70%) was obtained from 9b (0.50 g, 1 mmol); mp
98–100 ЊC; [α] +62.8 (c 0.67) (Found: C, 66.07; H, 10.20; N,
4.52. C17H31NO2Si requires C, 65.95; H, 10.11; N, 4.53%); νmax
/
cmϪ1 3418s and 1755vs; δH 0.10 [3 H, s, (Me3C)Me2Si], 0.11 [3
H, s, (Me3C)Me2Si], 0.90 [9 H, s, (Me3C)Me2Si], 1.26 (3 H, d, J
6.4, 5-Me), 1.34 (1 H, m, 4Ј-Hax), 1.54 (1 H, m, 5Ј-Hax), 1.77 (1
H, m, 5Ј-Heq), 1.83 (1 H, m, 4Ј-Heq), 2.00 (2 H, m, 2 × 6Ј-H),
2.23 (1 H, m, 3Ј-H), 2.83 (1 H, m, 3-H), 3.46 (1 H, dd, J 2.1 and
8.6, 4-H), 4.20 (1 H, m, 5-H), 5.58 (1 H, dd, J 9.9 and 2.0, 2Ј-
H), 5.85 (1 H, m, 1Ј-H) and 5.91 (1 H, br s, NH); δC(75.43
MHz) Ϫ4.34, Ϫ3.34 [2 × (Me3C)Me2Si], 18.07 [(Me3C)-
Me2Si], 20.97 (C-5Ј), 22.87 (C-6), 24.99 (C-6Ј), 25.37 [(Me3C)-
Me2Si], 25.87 (C-4Ј), 39.61 (C-3Ј), 55.12 (C-4), 62.93 (C-3),
65.33 (C-5), 126.54 (C-1Ј), 129.76 (C-2Ј) and 169.02 (C-2); m/z
310 (MH+, 20%), 294 (8) and 110 (100).
(3S,4R)-3-[(1R)-1-(tert-Butyldimethylsilyloxy)ethyl]-4-
[(1ЈR,2ЈS,3ЈR)-1Ј,2Ј-epoxycyclohexan-3Ј-yl]azetidin-2-one 4a
and (3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-
[(1ЈS,2ЈR,3ЈR)-1Ј,2Ј-epoxycyclohexan-3Ј-yl]azetidin-2-one 4b
To a solution of 7a (0.24 g, 0.77 mmol) in CH2Cl2 (10 ml) was
added dropwise at 0 ЊC a solution of 3-chloroperoxybenzoic
acid (assay 55%; 0.3 g, 0.96 mmol) in CH2Cl2 (10 ml). The
solution was warmed to room temperature, stirred for 3 h and
then washed with 10% aqueous Na2SO3, 5% aqueous NaHCO3
and brine, dried (Na2SO4) and evaporated. The product was
purified by flash chromatography eluting with a 1:1 mixture of
diethyl ether and light petroleum to afford 4b (0.05 g) followed
by an 8:2 mixture of the same solvents to afford 4a (0.13 g) (ratio
4a :4b = 80:20, total yield 76%).
Compound 4a: white solid; mp 134–136 ЊC; [α] Ϫ35.1 (c 0.61)
(Found: C, 62.99; H, 9.61; N, 4.19. C17H31NO3Si requires C,
62.71; H, 9.62; N, 4.30%); νmax/cmϪ1 3413s and 1757vs; δH 0.07
[6 H, s, (Me3C)Me2Si], 0.87 [9 H, s, (Me3C)Me2Si], 1.22 (2 H, m,
5Ј-Hax and 4Ј-Hax), 1.26 (3 H, d, J 6.0, 5-Me), 1.40 (1 H, m, 5Ј-
Heq), 1.55 (1 H, m, 4Ј-Heq), 1.86 (1 H, m, 6Ј-Hax), 1.96 (1 H, m,
6Ј-Heq), 2.00 (1 H, m, 3Ј-H), 3.01 (1 H, m, 3-H), 3.12 (1 H, m,
2Ј-H), 3.16 (1 H, t, J 4.1, 1Ј-H), 3.77 (1 H, dd, J 2.4 and 6.8, 4-
H), 4.22 (1 H, m, 5-H) and 5.97 (1 H, br s, NH); δC(100.57
(3S,4R)-3-[(1R)-1-(tert-Butyldimethylsilyloxy)ethyl]-4-
[(1ЈS,2ЈS,3ЈR)-(1Ј-methoxy-2Ј-hydroxycyclohexan-3Ј-yl]-
azetidin-2-one 5b
To a solution of 4a (0.1 g, 0.3 mmol) in methanol (10 ml) was
added at 0 ЊC toluene-p-sulfonic acid monohydrate (0.01 g, 0.05
mmol). The solution was warmed to room temperature and
stirred for 2 h, after which it was diluted with diethyl ether (60
ml), washed with 5% aqueous NaHCO3 and brine, dried
(Na2SO4) and evaporated. The product was purified by flash
chromatography eluting with an 8:2 mixture of diethyl ether
and light petroleum to afford 5b as a white foam (0.07 g,
J. Chem. Soc., Perkin Trans. 1, 1997
467

View Article Online
65%); [α] Ϫ4.6 (c 0.54) (Found: C, 60.14; H, 10.00; N, 3.90.
C18H35NO4Si requires C, 60.45; H; 9.88; N, 3.92%); νmax/cmϪ1
3418s and 1753s; δH 0.10 [6 H, s, (Me3C)Me2Si], 0.90 [9 H, s,
(Me3C)Me2Si], 1.29 (3 H, d, J 6.0, 5-Me), 1.45 (1 H, m, 4Ј-Hax),
1.52 (2 H, m, 2 × 5Ј-H), 1.66 (2 H, m, 4Ј-Heq and 6Ј-Hax), 1.74
(1 H, m, 6Ј-Heq), 1.85 (1 H, m, 3Ј-H), 2.96 (1 H, dd, J 2.5 and
6.0, 3-H), 3.34 (1 H, m, 1Ј-H), 3.35 (3 H, s, OMe), 3.66 (1 H, dd,
J 2.25 and 7.04, 4-H), 3.89 (1 H, m, 2Ј-H), 4.20 (1 H, m, 5-H)
and 5.83 (1 H, br s, NH); δC(100.57 MHz) Ϫ4.53, Ϫ4.23
[2 × (Me3C)Me2Si], 18.09 [(Me3C)Me2Si], 19.04 (C-5Ј), 21.73
(C-4Ј), 22.83 (C-6), 23.74 (C-6Ј), 25.82 [(Me3C)Me2Si], 40.11
(C-3Ј), 53.71 (C-4), 56.33 (OMe), 61.91 (C-3), 66.45 (C-5), 70.01
(C-1Ј), 79.05 (C-2Ј) and 168.52 (C-2); m/z 358 (MH+, 51%), 300
(91) and 158 (100).
Acknowledgements
The authors gratefully thank Dr Tino Rossi for useful discus-
sions, Mrs Maria Passarini for the IR spectra, Dr Mahmoud
Hamdan for the MS data, Mr Francesco Siliotto for the optical
rotations and Mr Massimo Pasquato for the elemental analyses.
References
1 (a) O. A. Mascaretti, C. E. Boschetti, G. O. Danelon, E. G. Mata
and O. A. Roveri, Curr. Med. Chem., 1995, 441; (b) R. Southgate
and N. F. Osborne, in Chemotherapeutics and Disease Control,
ed. Mary Howe-Grant, Wiley, New York, 1993, pp. 232–258; (c)
J. Roberts, ref. 1(b), pp. 259–313; K. R. Lindner, D. P. Bonner and
W. H. Koster, ref. 1(b), pp. 338–360; (d) R. J. Ponsford, ref 1(b),
pp. 360–389.
2 (a) R. Wise, Antimicrob. Newsl., 1990, 7, 73; (b) G. Franceschi,
E. Perrone, M. Alpegiani, A. Bedeschi, C. Della Bruna and
F. Zarini, in Recent Advances in the Chemistry of β-Lactam
Antibiotics, eds., P. H. Bentley and R. Southgate, RSC, London,
1989, pp. 222–246; (c) G. Pentassuglia, G. Tarzia, D. Andreotti,
C. Bismara, R. Carlesso, D. Donati, G. Gaviraghi, A. Perboni,
A. Pezzoli, T. Rossi, B. Tamburini and A. Ursini, J. Antibiot., 1995,
48, 399; (d) T. N. Salzmann, F. P. DiNinno, M. L. Greenlee,
R. N. Guthikonda, M. L. Quesada, S. M. Schmitt, J. J. Herrmann
and M. F. Woods, in Recent Advances in the Chemistry of β-Lactam
Antibiotics, ed. P. H. Bentley and R. Southgate, The Royal Society
of Chemistry, London, 1989, pp. 171–189; (e) R. D. G. Cooper, in
The Chemistry of β-Lactams, ed. M. I. Page, Chapman and
Hall, 1992, p. 272; ( f ) E. W. Colvin, in The Chemistry of β-Lactams,
ed. M. I. Page, 1992, pp. 325–347; (g) C. E. Newall, Spec.
Publ.-R. Soc. Chem., 1989, 70 (Recent Adv. Chem. β-Lactam
Antibiot.), 365–380; (h) J. H. C. Nayler, Trends Biochem. Sci., 1991,
16, 234; (i) J. E. Baldwin and E. Abraham, Nat. Prod. Rep., 1988, 5,
129; (l) R. Herranz, Farm. Clin., 1986, 3, 548; (m) D. P. Bonner and
R. B. Sykes, Med. Microbiol., 1984, 171; (n) T. Okonogi,
S. Shibahara, Y. Murai, S. Inouye, S. Kondo and B. G. Christensen,
Heterocycles, 1990, 31, 797.
3 (a) B. Tamburini, A. Perboni, T. Rossi, D. Donati, D. Andreotti,
G. Gaviraghi, R. Carlesso and C. Bismara, EP 0416953 A2/1991
(Chem. Abstr., 1992, 116, 235337t); (b) A. Perboni, T. Rossi,
G. Gaviraghi, A. Ursini and G. Tarzia, WO 9203437/1992 (Chem.
Abstr., 1992, 117, 7735m); (c) A. Perboni, B. Tamburini, T. Rossi,
D. Donati, G. Tarzia and G. Gaviraghi, in Recent Advances in
the Chemistry of Anti-Infective Agents, ed. P. H. Bentley and
R. Ponsford, The Royal Society of Chemistry, Cambridge, 1992,
pp. 21–35.
(3S,4R)-1-tert-Butyldimethylsilyl-3-[(1R)-1-(tert-butyldimethyl-
silyloxy)ethyl]-4-[(3ЈS)-cyclohexan-3Ј-yl]azetidin-2-one 10a
To a solution of 7a (0.5 g, 1.62 mmol) in DMF (3 ml) were
added triethylamine (0.21 ml, 2.1 mmol) and tert-butyl-
dimethylchlorosilane (0.29 g, 1.95 mmol). The resulting reac-
tion mixture was stirred for 4 h and then diluted with diethyl
ether, washed with water, dried (Na2SO4) and evaporated. The
product was purified by flash chromatography eluting with a
9:1 mixture of hexane and ethyl acetate to afford 10a (0.46 g,
65%) as a white solid; νmax/cmϪ1 1732vs ; δH 0.06 [3 H, s, (Me3C)-
Me2Si], 0.07 [3 H, s, (Me3C)Me2Si], 0.20 [3 H, s, (Me3C)Me2Si],
0.26 [3 H, s, (Me3C)Me2Si], 0.88 [9 H, s, (Me3C)Me2Si], 0.96
[9 H, s, (Me3C)Me2Si], 1.22 (3 H, d, J 6.3, 5-Me), 1.22 (1 H,
m), 1.5 (1 H, m), 1.8 (2 H, m), 2.00 (2 H, m), 2.5 (1 H, m),
2.79 (1 H, dd, J 2.4 and 2.6, 3-H), 3.51 (1 H, dd, J 2.7 and
2.4, 4-H), 4.02 (1 H, m, 5-H), 5.7 (1 H, m) and 5.83 (1 H, m).
(3S,4R)-1-tert-Butyldimethylsilyl-3-[(1R)-1-(tert-butyl-
dimethylsilyloxy)ethyl]-4-[(1ЈR,2ЈS,3ЈR)-1Ј,2Ј-epoxycyclohexan-
3Ј-yl]azetidin-2-one 11a and (3S,4R)-1-tert-butyldimethylsilyl-3-
[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1ЈS,2ЈR,3ЈR)-
1Ј,2Ј-epoxycyclohexan-3Ј-yl]azetidin-2-one 11b
To a solution of 10a (0.42 g, 1.0 mmol) in CH2Cl2 (5 ml) was
added dropwise at 0 ЊC a solution of 3-chloroperoxybenzoic
acid (assay 55%; 0.37 g, 0.97 mmol) in CH2Cl2 (5 ml). The
solution was warmed to room temperature and stirred for 3 h,
after which it was washed with 10% aqueous Na2SO3, 5% aque-
ous NaHCO3 and brine, dried (Na2SO4) and evaporated. The
product was purified by flash chromatography eluting with a
95:5 mixture of hexane and ethyl acetate to afford 11a (0.015 g)
and 11b (0.25 g) (ratio 11b:11a = 94:6, total yield 60%).
Compound 11a: colourless oil; δH 0.07 [3 H, s, (Me3C)Me2Si],
0.08 [3 H, s, (Me3C)Me2Si], 0.17 [3 H, s, (Me3C)Me2Si], 0.29 [3
H, s, (Me3C)Me2Si], 0.86 [9 H, s, (Me3C)Me2Si], 0.96 [9 H, s,
(Me3C)Me2Si], 0.96 (1 H, m), 1.28 (3 H, d, J 6.2, 5-Me), 1.72–
1.2 (4 H, m), 2.11 (1 H, m), 2.23 (1 H, m), 2.88 (1 H, dd, J 2.1
and 8.4, 3-H), 3.02 (1 H, m), 3.14 (1 H, m), 3.74 (1 H, dd, J 2.1
and 4.8, 4-H) and 4.02 (1 H, m, 5-H).
4 E. Di Modugno, I. Erbetti, L. Ferrari, G. L. Galassi, S. M.
Hammond and L. Xerri, Antimicrob. Agents Chemother., 1994, 38,
2362.
5 I. Yuji and H. Koichi, Bull. Chem. Soc. Jpn., 1986, 59, 1363.
6 (3R,4R,1ЈR)-(+)-4-Acetoxy-3-[1Ј-(tert-butyldimethylsilyloxy)ethyl-
azetidin-2-one 6a is commercially available from the Aldrich
Chemical Company Inc., Milwaukee, WI.
7 (a) A. Perboni and C. Bismara, unpublished results; (b) C. Bismara,
R. Di Fabio, D. Donati, T. Rossi and R. J. Thomas, Tetrahedron
Lett., 1995, 36, 4283.
8 (a) R. H. Shapiro, Org. React., 1976, 23, 405; (b) P. A. Grieco and
M. Nishizawa, J. Org. Chem., 1977, 42, 1717.
9 W. R. Roush, J. A. Straub and R. J. Brown, J. Org. Chem., 1987, 52,
5127.
Compound 11b: colourless oil; δH 0.06 [3 H, s, (Me3C)Me2Si],
0.09 [3 H, s, (Me3C)Me2Si], 0.27 [3 H, s, (Me3C)Me2Si], 0.30 [3
H, s, (Me3C)Me2Si], 0.88 [9 H, s, (Me3C)Me2Si], 0.95 [9 H, s,
(Me3C)Me2Si], 1.27 (3 H, d, J 6.25, 5-Me), 1.45 (3 H, m), 1.69
(2 H, m), 2.22–2.08 (2 H, m), 2.80 (dd, J 7.0 and 2.5, 3-H), 3.12
(1 H, m), 3.20 (1 H, m), 3.56 (1 H, t, J 2.5 and 3.0, 4-H) and 4.04
(1 H, m, 5-H).
10 P. Kocovský and I. Starý, J. Org. Chem., 1990, 55, 3236.
11 M. D. Threadgill and P. Webb, J. Chem. Soc., Chem. Commun.,
1991, 269.
12 (a) G. Pentassuglia, A. Perboni, G. L. Araldi, D. Donati, A. Ursini,
G. Tarzia, A. Pezzoli, R. Carlesso, E. De Magistris and
G. Gaviraghi, Proceedings of the 1st Int. Symposium: Recent
Advances in the Chemistry of Anti-Infective Agents, Cambridge,
1992, p. 14; (b) M. E. Tranquillini, G. L. Araldi, D. Donati,
G. Pentassuglia, A. Pezzoli and A. Ursini, Bioorg. Med. Chem. Lett.,
1996, 6, 1683.
(3S,4R)-3-[(1R)-1-(tert-Butyldimethylsilyloxy)ethyl]-4-
[(1ЈS,2ЈR,3ЈR)-1Ј,2Ј-epoxycyclohexan-3Ј-yl]azetidin-2-one 4b
To a solution of 11b (0.145 g, 0.28 mmol) in methanol (2 ml)
was added at 0 ЊC potassium fluoride (0.05 g, 0.86 mmol). The
solution was warmed to room temperature and stirred for 15
min, after which it was diluted with diethyl ether, washed with
saturated NH4OH and brine, dried (Na2SO4) and evaporated to
give 4b (0.092 g, 100%).
13 F. A. Bouffard and B. G. Christensen, J. Org. Chem., 1981, 46, 2208.
14 W. C. Still, M. Kahn and A. Mitra, J. Org. Chem., 1978, 43, 2923.
15 T. Rossi, S. Biondi, S. Contini, R. J. Thomas and C. Marchioro,
J. Am. Chem. Soc., 1995, 117, 9604.
Paper 6/05081F
Received 22nd July 1996
Accepted 30th September 1996
468
J. Chem. Soc., Perkin Trans. 1, 1997