The azomethine ylide strategy for β-lactam synthesis. An evaluation of alternative pathways for azomethine ylide generation

Article abstract of DOI:10.1039/b010050l

Following the generation of azomethine ylide 3 from the β-lactam-based oxazolidinone 1, a series of alternative entries to this and related 1,3-dipoles have been explored. The first approach is based on the use of monocyclic azetidinones 6-12 and 14 carrying a leaving group at C(4) and an activated (acidic) proton adjacent to the ring nitrogen, structural moieties which are both associated with 1. These monocyclic substrates show no tendency towards azomethine ylide formation, which points towards the ring strain present in 1 as an important prerequisite for azomethine ylide formation. The reactivity associated with the racemic Glaxo betaine 17, the structure of which has now been confirmed by X-ray crystallography, appears to involve an azomethine ylide 19, which is very similar to 3. However, attempts to trap 19 using an intermolecular cycloaddition failed; the intramolecular process involving an enolate as a trapping agent to give oxapenem 18 is more effective. Two novel thia-substituted bicyclic oxazolidinones 22 and 23, as well as the unsubstituted variant 33, have been prepared. In the case of 22 and 23, products derived from an alternative mode of iminium ion formation are observed. This pathway is a consequence of C-S bond cleavage, and this reactivity profile has been evaluated computationally. The data suggest that relief of strain within the four-membered ring-as opposed to 1 in which five-membered ring cleavage leads to an iminium ion-provides a driving force for C-S bond cleavage. As a result, the ability of 22 and 23 to give a synthetically useful azomethine ylide is compromised by the siting of an alternative leaving group adjacent to the azetidinone nitrogen. The unsubstituted bicyclic oxazolidinone 33 is thermally unstable, and no cycloadducts have been characterized from this system. Again, computational studies suggest that both direct and stepwise decarboxylation of 33 are energetically demanding processes.

Full text of DOI:10.1039/b010050l

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The azomethine ylide strategy for ꢀ-lactam synthesis. An
evaluation of alternative pathways for azomethine ylide generation
Giles A. Brown,a Sarah R. Martel,a Richard Wisedale,a Jonathan P. H. Charmant,a
Neil J. Hales,b Colin W. G. Fishwickc and Timothy Gallagher*a
1
a School of Chemistry, University of Bristol, Bristol, UK BS8 1TS
b AstraZeneca, Mereside, Alderley Park, Macclesfield, UK SK10 4TG
c School of Chemistry, University of Leeds, Leeds, UK LS2 9JT
Received (in Cambridge, UK) 18th December 2000, Accepted 1st March 2001
First published as an Advance Article on the web 16th May 2001
Following the generation of azomethine ylide 3 from the β-lactam-based oxazolidinone 1, a series of alternative
entries to this and related 1,3-dipoles have been explored. The first approach is based on the use of monocyclic
azetidinones 6–12 and 14 carrying a leaving group at C(4) and an activated (acidic) proton adjacent to the ring
nitrogen, structural moieties which are both associated with 1. These monocyclic substrates show no tendency
towards azomethine ylide formation, which points towards the ring strain present in 1 as an important prerequisite
for azomethine ylide formation. The reactivity associated with the racemic Glaxo betaine 17, the structure of which
has now been confirmed by X-ray crystallography, appears to involve an azomethine ylide 19, which is very similar to
3. However, attempts to trap 19 using an intermolecular cycloaddition failed; the intramolecular process involving an
enolate as a trapping agent to give oxapenem 18 is more effective. Two novel thia-substituted bicyclic oxazolidinones
22 and 23, as well as the unsubstituted variant 33, have been prepared. In the case of 22 and 23, products derived
from an alternative mode of iminium ion formation are observed. This pathway is a consequence of C–S bond
cleavage, and this reactivity profile has been evaluated computationally. The data suggest that relief of strain within
the four-membered ring—as opposed to 1 in which five-membered ring cleavage leads to an iminium ion—provides
a driving force for C–S bond cleavage. As a result, the ability of 22 and 23 to give a synthetically useful azomethine
ylide is compromised by the siting of an alternative leaving group adjacent to the azetidinone nitrogen. The
unsubstituted bicyclic oxazolidinone 33 is thermally unstable, and no cycloadducts have been characterized from
this system. Again, computational studies suggest that both direct and stepwise decarboxylation of 33 are
energetically demanding processes.
ylide 3 as the key dipolar species.1,4 As a result, and unlike
the simpler and more established oxazolidinone fragment-
Introduction
In the preceding paper,1 we described the application of the
β-lactam based oxazolidinone 1 as a source of azomethine ylide
reactivity providing an efficient and flexible entry to bicyclic
β-lactams, including carbapenams, carbapenems, penams and
penems.2 The generation of azomethine ylides by decarboxyl-
ation of oxazolidinones is well established for simpler systems,3
and the formation of cycloadducts 4 can be accounted for
in a formal sense in terms of the “parent” azomethine ylide
2, the product of a concerted decarboxylation of 1 (path a,
Scheme 1). However, evidence has now been presented
in support of an alternative and stepwise fragmentation of
1 (path b, Scheme 1) leading to the carboxylated azomethine
ations, the cycloaddition event in the β-lactam series takes
place before loss of carbon dioxide. Provided that path b
is available (see preceding paper which describes a 3,3-
disubstituted oxazolidinone which does not have access to this
path), then available evidence also disfavours the participation
of an alternative stepwise process as a means of gener-
ating azomethine ylide 2: fragmentation to form an iminium
ion, followed by decarboxylation (path c, Scheme 1). The
important mechanistic features of the azomethine ylide strategy
elucidated to date, which are based on the evidence presented
in the preceding paper1 and elsewhere,4 are summarized in
Scheme 1.
Scheme 1
DOI: 10.1039/b010050l
J. Chem. Soc., Perkin Trans. 1, 2001, 1281–1289
This journal is © The Royal Society of Chemistry 2001
1281

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Scheme 2 Reagents and conditions: i, R1SNa, EtOH, H2O (R1 = Ph 88%; R1 = Me 71%); ii, BrCH2CO2Me, NaH, DMF (R1 = Ph 87%; R1 = Me
71%); iii, heat, NPM, see text; iv, NaIO4, MeOH, H2O (78%); v, 2-pySNa, EtOH, H2O (72%), then BrCH2CO2Me, LHMDS (67%); vi, NaIO4,
MeOH, H2O (79%); vii, BrCH2COO(CH2)2CH᎐CH2, NaH, DMF (65%); viii, NaIO4, MeOH, H2O (60%); ix, Ac2O, NPM, reflux (done in both the
᎐
presence and absence of EtNi-Pr2); x, BrCH(CO2Me)2, NaH, THF, Ϫ50 ЊC (33%).
There are a number of issues associated with the reactivity
of the different azomethine ylides 2 vs. 3. The stabilization of
the 1,3-dipole intermediate inferred from the presence of the
additional carboxy function present in 3 may place limitations
on the scope of the cycloaddition process. Indeed, 3 reacts
poorly with electron-rich dipolarophiles and use of even
moderately hindered substrates can present problems. Access
to a less stabilized (and more reactive) 1,3-dipole, such as
the “parent” β-lactam-based azomethine ylide 2 could there-
fore enhance the potential of the basic azomethine ylide
strategy, and the generation of 2 has remained a goal of this
programme.
In this paper we outline a number of approaches to both the
azomethine ylide 2 and a series of structurally related 1,3-
dipoles, which were designed to explore and extend the range
of β-lactam cycloadducts that can be made available using
the basic cycloaddition strategy. All of these approaches have
led to reaction pathways other than 1,3-dipole formation, and
results obtained serve to underscore those key features associ-
ated with the success of the oxazolidinone-mediated pathway.
In particular, with respect to dipole generation, the scope of the
cycloaddition strategy has now been more fully defined and the
observations presented below reinforce the notion that the ring
strain and the 1,3-dicarbonyl (malonyl) component associated
with 1 play a critical role in the expression of azomethine ylide
reactivity, as in 1,3-dipole 3.
for the “carboxylated” azomethine ylide 3. This involved
positioning a suitable leaving group at C(4) of an N-alkylated
azetidinone, which carries an acidic C–H adjacent to nitrogen.
Substrates 6–12 and 14, all of which incorporate this com-
bination of structural features, were prepared starting from
the commercially available 4-acetoxyazetidin-2-one 5, and the
routes employed, some aspects of which are based on earlier
literature,5–8 are outlined in Scheme 2.
These substrates were then screened for their ability to gen-
erate a viable azomethine ylide under thermal conditions, in a
variety of solvents (MeCN, PhMe, 1,2-dichlorobenzene) and
using N-phenylmaleimide (NPM) as a trap. The 4-thiosubsti-
tuted azetidinones 6 and 7 were thermally stable (up to approx.
180 ЊC), and attempts to induce iminium ion formation
(using AgBF4 as a thiophile) resulted only in decomposition.
Enhancing the leaving group ability of sulfur via sulfoxide 8 was
also unsuccessful; 8 was stable in both MeCN (at reflux) and
PhMe (at reflux). Use of ZnI2 (in MeCN at 50 ЊC) as a Lewis
acid to promote ionization again led to decomposition of 8.
The azetidinyl 2-pyridyl sulfide 9, which incorporates an
internal base and the corresponding sulfoxide 10 (obtained
as a 1 : 1.5 mixture of diastereoisomers) were prepared using
similar methods. Again, these substrates proved to be remark-
ably stable and no evidence was obtained under a variety of
thermal conditions for azomethine ylide formation.
Substrates carrying an intramolecular alkenyl trap were
examined, but again, both sulfide 11 and sulfoxide 12 were
thermally stable. When 12 was heated in acetic anhydride (with
a view to promoting ionization via O-acylation of the sulfoxide
entity), only the corresponding acetate 13 was isolated (as
judged by 1H NMR). In summary, all efforts to drive the form-
ation of an azomethine ylide by initial N-acyl iminium ion
Studies directed towards the generation of the “parent”
azomethine ylide 2
Our initial approach to generating the parent azomethine ylide
2 was based on a similar process to that successfully exploited
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J. Chem. Soc., Perkin Trans. 1, 2001, 1281–1289

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Scheme 3 Reagents and conditions: i, Et3N, EtOAc (62%); ii, heat, EtOAc (78%); iii, NEt3, EtOAc (87%).
Table 1 Selected bond lengths (Å) and angles (Њ) for betaine 17
N(1)–C(4)
N(1)–C(5)
N(1)–C(2)
C(2)–N(18)
C(2)–C(3)
C(3)–C(4)
C(4)–O(4)
C(5)–C(6)
1.369(3)
1.441(2)
1.474(2)
1.527(3)
1.544(3)
1.518(3)
1.213(2)
1.393(3)
1.441(3)
129.7(2)
93.8(2)
132.0(2)
114.5(2)
87.89(15)
118.4(2)
85.40(15)
92.9(2)
C(5)–C(9)
C(4)–N(1)–C(5)
C(4)–N(1)–C(2)
C(5)–N(1)–C(2)
N(1)–C(2)–N(18)
N(1)–C(2)–C(3)
N(18)–C(2)–C(3)
C(4)–C(3)–C(2)
N(1)–C(4)–C(3)
C(6)–C(5)–C(9)
C(6)–C(5)–N(1)
C(9)–C(5)–N(1)
O(6)–C(6)–C(5)
Fig. 1 Solid state structure of 17. Hydrogen atoms and water mol-
ecules have been omitted for clarity.
124.8(2)
117.1(2)
118.1(2)
121.6(2)
formation from a simple but only monocyclic azetidinone
precursor have been unsuccessful.†
Enhancing the acidity of the proton adjacent to nitrogen
provided an alternative, but ultimately equally fruitless line of
investigation. The N-malonyl derivative 14 was prepared and
subjected to thermolysis (xylene at reflux, with and without
a catalytic quantity of trifluoroacetic acid) in the presence
of N-phenylmaleimide (NPM); no cycloadduct formation was
observed. Fragmentation of this substrate would have led to a
1,3-dipole 15 similar to 3, but 14 proved to be stable and was
recovered unchanged even after prolonged heating (xylene at
reflux for 3 hours). These same conditions would have resulted
in complete consumption of the bicyclic variant 1, and this
again raises the issue of the viability of a monocyclic vs. a (more
strained) bicyclic precursor to a β-lactam-based azomethine
ylide.
In addition, exposure of 18 to triethylamine resulted in
re-formation of betaine 17 (Scheme 3). The most likely inter-
mediate involved in the formation of betaine 17 (and its sub-
sequent conversion to 18) is the stablized azomethine ylide 19,
though participation of a C-protonated variant of 19 on the
pathway between 16 and 17 cannot be excluded. Azomethine
ylide 19 bears a striking similarity to azomethine ylide 3 and,
given the close relationship between the two processes involved
(1→3→4 and 16→18), it was felt that this process merited
further investigation as a potential source of azomethine ylide
reactivity.
We have repeated the Glaxo work and isolated betaine inter-
mediate 17. The structure of 17 (recrystallized from water) has
now been confirmed by X-ray crystallographic analysis (Fig. 1
and Table 1).‡ Further, betaine 17 appears to be racemic,
based on the crystallographic analysis and a lack of an optical
rotation.§
Generation and reactivity of betaine 17
In the preceding paper, we discussed the ease with which the
bicyclic oxazolidinone 1 undergoes thermal racemization, but
not decarboxylation, when heated in the absence of a reactive
dipolarophile. While this was a critical observation in terms of
our mechanistic studies, it is not without precedent. Some years
ago, Cherry et al.9 reported that treatment of enantiomerically
Our aim was to attempt to intercept 19 using a reactive
dipolarophile (NPM), but under a range of thermolysis con-
ditions, betaine 17 gave only the conjugated oxapenem 18. It is
interesting to compare the reactivity of 1 to that of 17. The
pure deoxyclavulanic acid 16 with triethylamine resulted in C᎐C
᎐
‡ Single crystals of C21H29N3O6ؒ3H2O (17ؒ3H2O) were obtained from
water, coated in vacuum grease and mounted on a glass fibre. Crystal
data. C21H35N3O9, M = 473.5, triclinic, a = 8.014(4), b = 8.438(4),
migration to give the racemic oxapenem 18. Further, these
workers were able to isolate the betaine intermediate 17 and
showed that this species was converted to 18 on heating.
c = 18.463(10) Å, α = 89.99(2), β = 82.22(4), γ = 78.06(4)Њ, U =
3
¯
1209.8(10) Å , T = 173 K, space group P1 (no. 2), Z = 2, µ(Mo-
† The selenide and selenoxide corresponding to 6 and 8 respectively
were also prepared by analogous routes. The selenide was thermally
stable but the selenoxide proved to be too unstable to merit further
study. The sulfoxide-based substrates [8, 10, 12] were prepared with a
view to promoting a concerted rather than stepwise fragmentation
analogous to the well-known sulfoxide elimination process used in
alkene synthesis. The possibility of a base assisting an alternative
concerted pathway prompted incorporation of the pyridyl unit into 9
and 10.
Kα) = 0.102 mmϪ1
,
10221 reflections measured, 4224 unique
(Rint = 4.1%). Final residuals: wR2 = 10.1% (all data), R1 = 4.3% (2719
observed data). Selected bond lengths and angles are shown in Table 1.
CCDC 155747. See http://www.rsc.org/suppdata/p1/b0/b010050l/ for
crystallographic files in .cif format.
§ The Glaxo group9 verified the racemic nature of 18 by correlation
to an enantiomerically pure derivative. Oxapenem 18 is also opened by
other nucleophiles (e.g. thiols), chemistry which is especially significant
for providing an early entry to penems.
J. Chem. Soc., Perkin Trans. 1, 2001, 1281–1289
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presence of a good (carboxylate) leaving group in 1 may provide
a synthetically useful concentration of the reactive azomethine
ylide i.e. 3. However, in the case of 17, the internal nucleophile
(the oxygen of the ketone enolate) is an efficient trap for the
iminium component of 19, and an intermolecular cyclo-
addition pathway cannot effectively compete.
Alternative oxazolidinone precursors
A series of other β-lactam based oxazolidinones 22, 23 and 33
have also been prepared and evaluated as alternative sources of
azomethine ylide reactivity. In the first instance the motivation
to attempt to extend the scope of dipole precursors arose from
problems that we had encountered in the application of the
azomethine ylide strategy (based on 1) for the synthesis of
so-called ∆2-carbapenems. Thermolysis of oxazolidinone 1 in
the presence of an alkyne does provide a versatile synthesis of
the carbapenem isomers 20 (Scheme 4). However, the isomeriz-
ation of 20 (a ∆1-carbapenem—classical penam numbering) to
the biologically more important isomer 21 (a ∆2-carbapenem)
is neither an efficient nor general process,10 and a practical
solution to this problem demanded an alternative approach.
Use of the sulfide or sulfoxide-based oxazolidinones 22
and 23 respectively in principle offered access to a number of
interesting 1,3-dipoles. Decarboxylation of 22 or 23 would
provide novel, functionalized β-lactam-based azomethine
ylides (e.g. 1,3-dipole 35, see Scheme 6 below). Alternatively, a
stepwise fragmentation and proton shift would offer access to
azomethine ylide 24, which was anticipated to react with an
alkene to give cycloadduct 25. This cycloadduct could then
undergo thiol or sulfoxide elimination, rather than decarb-
oxylation, to provide the desired ∆2-carbapenem directly. In this
way we aimed to retain the carboxy function present in the
starting oxazolidinones 22 or 23 as the carboxylic acid of the
final target (Scheme 4).
The sulfide- and sulfoxide-containing oxazolidinones 22 and
23 respectively were both prepared starting from clavulanic acid
26 (Scheme 5). Using the procedures described by Hunt,11
clavulanic acid was converted to diene 27. Addition of PhSH to
27 gave a 2 : 1 mixture of regioisomeric adducts 28 (40% yield
as an inseparable 1 : 5 mixture of E and Z isomers) and 29 (19%
yield). Chromatographic separation followed by controlled
ozonolysis of 28 gave the sulfide-containing oxazolidinone
22 as an oil. Oxidation (MCPBA) of 28 followed again by
controlled ozonolysis provided the sulfoxide derivative 23 as a
mixture of diastereoisomers.¶
Thermolysis of 22 in the presence of NPM resulted in the
formation of the thiol adduct 31 in 43% yield. A related frag-
mentation process was observed when 23 was heated in the
presence of DMAD, and in this case the sulfenic acid adduct 32
was isolated in 35% yield. In each case, other sulfur-containing
by-products (e.g. PhSSPh, PhSSO2Ph) were also isolated and
characterized. In neither case could products retaining the
β-lactam component be characterized and the fate of this unit
remains unclear. Products 31 and 32 can be accounted for by
loss of PhSϪ or PhSOϪ from the oxazolidinone precursors
22 and 23 respectively and subsequent capture of these
nucleophiles by the electrophilic alkene/alkyne present. While
no direct evidence has been obtained for the intermediacy of
the N-acyl iminium component 30 (see also below, structure 36,
Scheme 6), it would appear that this pathway is preferred
to formation of the alternative (and desired) N-acyl iminium
species 24 (cf. Scheme 4) resulting from C–O bond scission.
Further, a possible reason for the preference of 22 (and by
᎐
Scheme 4 Reagents and conditions: i, R1C᎐CH; ii, DBU, CH2Cl2
᎐
(under these thermodynamic conditions, ca. 1 : 1 ratio of 20 to 21 is
observed when R1 = SPh).
extrapolation 23) to undergo C–S cleavage to give 30 rather
than C–O cleavage (which would lead to 24) has been identified,
which is discussed in more detail below.
The isomeric thiol adduct 29 provided access to yet another
oxazolidinone substrate. Careful oxidative cleavage of 29 gave
the unsubstituted β-lactam-based oxazolidinone 33 (Scheme 5),
a compound that has previously been prepared by a very similar
procedure.12 However, oxazolidinone 33 was very sensitive and
could not be rigorously purified from the other ozone-derived
product. We have examined the ability of 33 to generate
an azomethine ylide, but without success: thermolysis of
crude 33 (MeCN, 81 ЊC) in the presence of an excess NPM
failed to generate an adduct and no characterizable products
were isolated. The reactivity of 33 has also been examined
computationally and compared to carboxylated variants (see
Scheme 7).
Computational studies
The fragmentation of sulfide 22 and the fate of “parent” oxazol-
idinone 33 have also both been explored computationally. By
analogy to the theoretical approach described in the preceding
paper,1 semi-empirical calculations were used to compare the
hypothetical stepwise and concerted decarboxylation of sulfide
22 to yield an azomethine ylide 35 vs. a fragmentation pathway
involving loss of PhSϪ (Scheme 6 and Tables 2 and 3).
These data confirm that fragmentation of oxazolidinone 22
via loss of phenylthiolate to yield cation 36 (activation energy
∆E7 = 26.13 kcal molϪ1) is considerably more favourable than
decarboxylation to yield azomethine ylide 35 by either the
stepwise pathway (involving transition states TS1 and TS2 with
activation energies ∆E1 = 38.73 and ∆E3 = 15.31 kcal molϪ1
respectively) or a concerted pathway (involving transition
state TS3 with an activation energy ∆E5 = 48.27 kcal molϪ1)
pathways. As with other calculations involving concerted
decarboxylation to yield β-lactam based azomethine ylides (see
preceding paper), the transition structure TS3 could not be
obtained using calculations which simulate the presence of
solvent, and all energies are derived from single-point estimates
on a transition structure obtained in the gas-phase. A partic-
ularly interesting aspect of these studies relates to the
mechanism of elimination of thiolate from oxazolidinone 22.
Repeated attempts to identify the transition state for the
cleavage of the C–S bond consistently produced structure TS4
in which the endocyclic N–C bond present within the four-
membered ring is partially cleaved. This bond is essentially
antiperiplanar to the breaking C–S bond (assuming the C(2)
¶ Though reported as such in the literature,11 the stereochemistry at
C(2) of 22 has not been rigorously determined. Placing the SPh residue
on the exo face does, however, represent the thermodynamically more
reasonable configuration. Nevertheless, and to avoid any confusion, it
should be made clear that we have assumed the configurations shown in
Scheme 5 and in the computational study associated with Scheme 6.
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Scheme 5 Reagents and conditions: i, N,N-dimethylformamide dimethyl acetal; ii, PhSH, AIBN, heat; iii, O3, EtOAc (99% for 22; 97% for 23);
iv, MCPBA, CH2Cl2 (78%); v, NPM, MeCN, reflux, 120 h; vi, DMAD, MeCN, reflux, 48 h.
Scheme 6
stereochemistry shown) such that this transition structure
results from an E2 type elimination pathway to yield an acyl
cation 36 (Scheme 6). The relative ease of this reaction com-
pared to the hypothetical decarboxylative entry to azomethine
ylide 35 may be due, in part, to the relief of ring strain associ-
ated with the formation of cation 36 via TS4. Clearly also,
cation 36 is, in a broad sense, structurally equivalent to cation
30 (see Scheme 5).
limited experimental observations concerning the behaviour
of this substrate (Scheme 7 and Tables 4 and 5). The stepwise
decarboxylation of oxazolidinone 33 via (i) cleavage of the ring
C–O bond (through TS5) to yield zwitterion 37 followed by (ii)
decarboxylation (through TS6) to yield parent β-lactam-based
azomethine ylide 38 is predicted to require 27.49 kcal molϪ1
(∆E9) and 33.99 kcal molϪ1 (∆E11) respectively. Although
the energy associated with the initial fragmentation (∆E9) is
similar to that calculated for the corresponding transformation
involving the ester-containing oxazolidinone 1 (R = Me), which
Similar calculations involving the hypothetical decarboxyl-
ation of parent oxazolidinone 33 also tend to support the
J. Chem. Soc., Perkin Trans. 1, 2001, 1281–1289
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Scheme 7
Table 2 Heats of formation and transition state imaginary frequencies Table 4 Heats of formation and transition state imaginary frequencies
for Scheme 6 for Scheme 7
Structure
Hf /kcal molϪ1 a
νi/cmϪ1 b
Structure
Hf /kcal molϪ1 a
Ϫ83.63
Ϫ66.10
Ϫ41.02
Ϫ56.14
Ϫ32.11
(Ϫ41.24)c
νi/cmϪ1 b
22
Ϫ71.82
—
—
—
—
33
—
—
—
34
Ϫ43.26
Ϫ49.18
Ϫ57.34
Ϫ33.09
Ϫ27.95
(Ϫ23.55)c
Ϫ45.69
37
35
38
36
TS5
TS6
TS7
Ϫ334.97
Ϫ669.64
(Ϫ511.26)c
TS1
TS2
TS3
TS4
Ϫ402.58
Ϫ455.41
(Ϫ490.98)c
Ϫ52.02
a Heats of formation obtained using PM3 Hamiltonian using the
COSMO model to simulate a solvent field equivalent to that of
acetonitrile. b All transition structures were characterized by having
a single negative vibrational frequency. c Transition state unable to be
located in acetonitrile and energy is a single-point estimate (COSMO)13
on a gas-phase derived transition structure.
a Heats of formation obtained using PM3 Hamiltonian using the
COSMO model to simulate a solvent field equivalent to that of
acetonitrile. b All transition structures were characterized by having
a single negative vibrational frequency. c Transition state unable to be
located in acetonitrile and energy is a single-point estimate (COSMO)13
on a gas-phase derived transition structure.
Table 5 Activation energies for Scheme 7
Table 3 Activation energies for Scheme 6
Energy
Value/kcal molϪ1
Energy
Value/kcal molϪ1
Energy
Value/kcal molϪ1
Energy
Value/kcal molϪ1
∆E9
∆E10
∆E11
27.49
Ϫ9.96
33.99
∆E12
∆E13
∆E14
Ϫ8.91
(42.39)a
(Ϫ0.22)a
∆E1
∆E2
∆E3
∆E4
38.73
Ϫ10.17
15.31
Ϫ21.23
∆E5
∆E6
∆E7
∆E8
(48.27)a
Ϫ25.63
26.13
a Transition state unable to be located in acetonitrile and energy is a
single-point estimate (COSMO)13 on a gas-phase derived transition
structure.
11.65
a Transition state unable to be located in acetonitrile and energy is a
single-point estimate (COSMO)13 on a gas-phase derived transition
structure.
To summarize, a combination of factors seem to predispose
the β-lactam based oxazolidinone 1 towards stepwise frag-
mentation to give the synthetically important azomethine ylide
3. Ring strain in the bicyclic framework plays an important role,
and this is evident from the monocyclic azetidinones shown
in Scheme 2 that do not give azomethine ylides despite the
presence of similar structural components to those present in 1
i.e. a leaving group at C(4) and an acidic C–H bond adjacent to
the ring nitrogen.
requires 26.18 kcal molϪ1, the energy barrier for the decarbox-
ylation step (via TS6) is over twice that calculated (33.99 vs.
16.16 kcal molϪ1) for the equivalent pathway involving
1 (R = Me).1 Similarly, the concerted decarboxylation of 33
(via TS7) is calculated to require nearly 10 kcal molϪ1 more
energy than is calculated for 1 (R = Me).
It would appear that for the simple, unsubstituted system 33,
the stepwise decarboxylative generation of the corresponding
azomethine ylide 38 is unfavourable due to the large barrier
(∆E11) to loss of carbon dioxide. This is presumed to reflect
the reduced ability of zwitterion 37 to stabilize the increasing
electron density at the exocyclic methylene as the reaction
enters into the transition state (TS6), when compared to the
corresponding pathway starting with 1 (R = Me).
The need for caution regarding the calculated energies for
the concerted decarboxylation pathway is underlined in the
case of TS7. The single point estimate in a simulated solvent
dielectric on the gas phase-derived structure yields an energy
which is 0.22 kcal molϪ1 lower than the solution phase
energy of the products (dipole 38 and CO2). However, com-
The Glaxo betaine 17 is interesting in this context because
this species appears to undergo reversible ring closure via an
azomethine ylide 19. However, we have not been able to capture
this dipolar intermediate in a cycloaddition reaction, and it
appears that the enolate oxygen associated with 19 is a highly
efficient trap. In relation to the fragmentation of 1 to give 3,
then the differences in reactivity seen with 17 (and by impli-
cation 19) may also involve differences in charge distribution—
a ketone enolate vs. a carboxy-based variant.
The sulfur-containing bicyclic oxazolidinones 22 and 23
again bear a close resemblance to 1, and were designed with a
complementary synthetic role in mind. However in these cases,
the preferred iminium species appears to be associated with
C–S rather than C–O cleavage, although the fate of the β-
lactam moiety remains unclear. In the case of 22, compu-
tational studies suggest that the ionization process involves
participation and cleavage of the β-lactam ring, and this likely
leads to even more relief of strain.
paring the gas phase energies for thiazolidinone 33 (Egas
=
Ϫ63.90 kcal molϪ1), TS7 (Egas = Ϫ8.65 kcal molϪ1) and
38 ϩ CO2 (Egas = Ϫ28.79 kcal molϪ1) yields more reasonable
relative energies.
1286
J. Chem. Soc., Perkin Trans. 1, 2001, 1281–1289

View Article Online
Fragmentation—either concerted or stepwise—of the simple,
unsubstituted derivative 33 failed to yield a cycloadduct,
apparently because this system lacks the electronic stabliz-
ation that is associated with the carboxy function found in 3.
Calculations indicate that both of these pathways are ener-
getically highly demanding, and we have been unable to isolate
any 1,3-dipolar cycloadducts arising from 33.
In conclusion, while the azomethine ylide strategy is of
proven and general utility for the synthesis of a wide range of
bicyclic β-lactams, oxazolidinones such as 1 remain the only
viable source of the β-lactam based azomethine ylide to under-
pin this synthetic strategy. Less stabilized and more reactive
variants, such as 2, remain elusive, but we now know much
more about those alternative reaction pathways that limit
the range of oxazolidinones that are capable of generating
synthetically useful β-lactam based azomethine ylides.
Methyl 4-(2-pyridylthio)-2-oxoazetidin-1-ylacetate 9
To a solution of LiHMDS [prepared from addition of n-
butyllithium (1.6 mol dmϪ3 in hexanes; 18.0 cm3, 28.8 mmol) to
a solution of 1,1,1,3,3,3-hexamethyldisilazane (6.1 cm3, 28.9
mmol) in THF (150 cm3) at Ϫ10 ЊC under nitrogen and
maintained at this temperature for 15 min before cooling
to Ϫ78 ЊC] at Ϫ78 ЊC was added a solution of 4-(2-pyridyl-
thio)azetidin-2-one (5.11 g, 28.4 mmol) in THF (15 cm3). The
mixture was stirred at Ϫ78 ЊC for 15 min, then methyl bromo-
acetate (3.0 cm3, 31.7 mmol) was added and the mixture was
then allowed to warm to 15 ЊC over 2.5 h. Filtration and
evaporation of the filtrate under reduced pressure followed by
purification of the residue by flash chromatography (50%
EtOAc–50% petroleum ether) gave azetidinone 9 (4.79 g, 67%)
as a colourless crystalline solid, mp 80–81 ЊC (iPr2O) (lit.,12
reported as an oil); δH (270 MHz) 3.07 (1 H, dd, J 15.0, 2.9,
3-H), 3.57 (1 H, dd, J 15.0, 5.3, 3-H), 3.78 (3 H, s, OMe), 3.81
(1 H, d, J 18.0), 4.32 (1 H, d, J 18.0), 5.79 (1 H, dd, J 5.3, 2.9,
4-H), 7.04 (1 H, m, Ar), 7.22 (1 H, m, Ar), 7.53 (1 H, m, Ar) and
8.30 (1 H, m, Ar).
Experimental
For general details, see preceding paper.1 Literature procedures
were used to prepare intermediates 6,7 77 and 912 (however, see
below), 14,8 16,9 17,9 27–29.11
Methyl 4-(2-pyridylsulfinyl)-2-oxoazetidin-1-ylacetate 10
Using the same procedure as described for the preparation of
sulfoxide 8, oxidation of 9 gave 10 in 71% yield as a colourless
oil and as a 1 : 1.5 mixture of diastereoisomers (Found: C, 49.4;
H, 4.75; N, 10.22. C11H12N2O4S requires C, 49.25; H, 4.51; N,
10.44%) (Found: M ϩ Hϩ, 269.0606. C11H13N2O4S requires
M, 269.0596); νmax (film)/cmϪ1 1780 and 1750; δH (270 MHz)
3.35–3.45 (2 H, m, 3-H (both isomers)), 3.56 (1 H, d, J 18.0,
major isomer), 3.64 (3 H, s, OMe, minor isomer), 3.80 (3 H, s,
OMe, major isomer), 4.03 (1 H, d, J 18.0, minor isomer), 4.26
(1 H, d, J 18.0, minor isomer), 4.45 (1 H, d, J 18.0, major
isomer), 5.15 (1 H, m, 4-H, both isomers), 7.43 (1 H, m, Ar),
7.96–8.00 (2 H, m, Ar) and 8.65 (1 H, m, Ar); δC (75.5 MHz)
35.7 (CH2), 40.2 (CH2), 42.1 (CH2), 42.58 (CH2), 52.0 (CH3),
52.3 (CH3), 69.5 (CH), 70.7 (CH), 120.0 (CH), 120.1 (CH),
124.8 (CH), 124.9 (CH), 138.0 (CH), 138.2 (CH), 149.5 (CH),
Methyl 4-phenylthio-2-oxoazetidin-1-ylacetate 8
A solution of methyl 4-phenylthio-2-oxoazetidin-1-ylacetate
67 (1.79 g, 7.1 mmol) in MeOH (20 cm3) was treated with a
solution of NaIO4 (1.78 g, 8.3 mmol) in water (10 cm3) and
stirred for 17 h at room temperature. The mixture was filtered
and the filtrate was concentrated in vacuo. The residual oil was
partitioned between EtOAc (30 cm3) and water (10 cm3) and the
aqueous solution further extracted with EtOAc (20 cm3). The
combined organic extracts were dried (Na2SO4), concentrated
and purified by flash chromatography (60% EtOAc–40%
petroleum ether) to give 8 (1.48 g, 78%) as a 1 : 1 mixture of
diastereoisomers and as a colourless oil (Found: M ϩ Hϩ,
268.0643. C12H14NO4S requires M, 268.0644); νmax (film)/cmϪ1
1780 and 1750; δH (270 MHz—doubling of signals due to
diastereoisomers is indicated) 2.86 and 3.15 (1 H, dd, J 14.9,
4.9 and J 15.2, 3.0, 3-H), 3.23 and 3.46 (1 H, dd, J 15.2, 4.6
and J 14.9, 2.0, 3-H), 3.65 and 3.78 (3 H, s, OMe), 3.74 and
3.88 (1 H, d, J 18.5), 4.29 and 4.44 (1 H, d, J 18.5), 4.76 and
4.80 (1 H, dd, J 4.9, 2.0 and J 4.6, 3.0, 4-H) and 7.50–7.68
(5 H, m, Ar); δC (75.5 MHz) 35.8 and 39.8 (CH2), 42.0 and
43.0 (CH2), 52.4 and 52.6 (OCH3), 71.1 and 71.4 (CH), 124.0
and 124.2 (CH), 129.6 (CH), 131.7 and 131.8 (CH), 139.4 and
161.2 (C), 161.8 (C), 164.8 (C᎐O), 167.4 (C᎐O), 167.9
᎐
᎐
(C᎐O) (some doubling of signals due to diastereoisomers was
᎐
observed).
But-3-enyl 4-phenylthio-2-oxoazetidin-1-ylacetate 11
To a suspension of NaH (60% dispersion in mineral oil, 270
mg, 6.75 mmol) in DMF (20 cm3) under nitrogen at Ϫ50 ЊC was
added a solution of 4-phenylthioazetidin-2-one (1.13 g, 6.31
mmol) in THF (5 cm3). The temperature was allowed to rise
to Ϫ30 ЊC over 40 min before cooling to Ϫ60 ЊC, and then a
solution of but-3-enyl bromoacetate15 (1.26 g, 6.53 mmol) in
THF (5 cm3) was added. After allowing to warm to 0 ЊC over
1 h, the mixture was further stirred for 2 h. Ether (30 cm3) and
water (20 cm3) were added and the phases separated. The
aqueous solution was extracted with Et2O (20 cm3) and the
ethereal solutions combined, dried (Na2SO4) and concentrated
in vacuo. Purification of the residue by flash chromatography
(20% EtOAc–80% petroleum ether) gave 11 (1.19 g, 65%) as a
pale yellow oil (Found: Mϩ, 291.0922. C15H17NO3S requires M,
291.0929); νmax (film)/cmϪ1 1780–1750, 1642 and 1584; δH (270
MHz) 2.23–2.31 (2 H, m), 2.77 (1 H, dd, J 15.0, 2.4, 3-H), 3.31
(1 H, dd, J 15.0, 5.0, 3-H), 3.65 (1 H, d, J 18), 3.98–4.12 (2 H,
m), 4.20 (1 H, d, J 18), 4.97–5.05 (2 H, m), 5.12 (1 H, dd, J 5.0,
2.4, 4-H), 5.64 (1 H, m) and 7.17–7.36 (5 H, m, Ar); δC (75.5
MHz) 32.7 (CH2), 40.9 (CH2), 44.8 (CH2), 59.0 (CH2), 64.4
(CH), 117.5 (CH2), 128.7 (CH), 129.2 (CH), 130.0 (Cipso), 133.4
140.3 (Cipso), 164.7 and 165.2 (C᎐O), and 168.0 and 168.3
᎐
(C᎐O); m/z (C.I., NH ) 285 (M ϩ NH , 100%), 268 (M ϩ Hϩ,
ϩ
᎐
3
4
19).
4-(2-Pyridylthio)azetidin-2-one
An ice-cold solution of 2-mercaptopyridine (1.11 g, 10 mmol)
in 95% EtOH (15 cm3) was treated with a solution of NaOH
(0.40 g, 10 mmol) in 95% EtOH (10 cm3) and water (2 cm3). The
resultant solution was added to an ice-cold solution of
4-acetoxyazetidin-2-one 5 (1.29 g, 10 mmol) in 95% EtOH (20
cm3) dropwise over 15 min. After addition was complete, the
ice-bath was removed and the yellow solution was stirred at
room temperature overnight. After removal of solvents, the
residual oil was partitioned between EtOAc (100 cm3) and brine
(75 cm3). The aqueous solution was further extracted with
EtOAc (50 cm3) and the combined organic extracts were dried
(Na2SO4), concentrated under reduced pressure and purified by
flash chromatography (50% EtOAc–50% petroleum ether) to
give the title compound (1.29 g, 72%) as a colourless crystalline
solid, mp 82 ЊC (iPr2O) (lit.,14 reported as an oil); δH (270 MHz)
2.98 (1 H, dd, J 15.0, 2.6, 3-H), 3.45 (1 H, dd, J 15.0, 5.1, 3-H),
5.49 (1 H, dd, J 5.1, 2.6, 4-H), 7.02–7.21 (2 H, m, Ar), 7.53 (1 H,
m, Ar) and 8.41 (1 H, m, Ar).
(CH), 133.9 (CH), 165.2 (C᎐O) and 167.7 (C᎐O); m/z (E.I.) 291
᎐
᎐
(Mϩ, 1%).
But-3-enyl 4-phenylsulfinyl-2-oxoazetidin-1-ylacetate 12
To a solution of the 4-phenylthioazetidinone 11 (250 mg, 0.86
J. Chem. Soc., Perkin Trans. 1, 2001, 1281–1289
1287

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mmol) in MeOH (6 cm3) was added water (3 cm3) and NaIO4
(240 mg, 1.13 mmol). The reaction mixture was stirred at room
temperature for 19 h. The precipitate was removed by filtration,
washed with Et2O, and the combined filtrate and washings were
dried (Na2SO4) and then concentrated in vacuo. Purification
of the residue by flash chromatography (50% EtOAc–50%
petroleum ether) gave sulfoxide 12 (158 mg, 60%) as a 1 : 1
mixture of diastereoisomers and as a colourless oil (Found: C,
58.29; H, 5.42; N, 4.63. C15H17NO4S requires C, 58.62; H, 5.57;
N, 4.57%); νmax (CH2Cl2)/cmϪ1 1780 and 1750; δH (270 MHz)
2.31–2.47 (2 H, m), 2.86 and 3.15 (1 H, dd, J 15.0, 4.8 and
J 15.2, 3.0, 3-H), 3.22 and 3.46 (1 H, dd, J 15.2, 4.6 and J 15.0,
2.0, 3-H), 3.65 and 3.84 (1 H, d, J 18.5), 4.02–4.16 (1 H, m),
4.19–4.28 (1 H, m), 4.29 and 4.44 (1 H, d, J 18.5), 4.76 and 4.81
(1 H, dd, J 4.8, 2.0 and J 4.6, 3.0, 4-H), 5.07–5.17 (2 H, m),
5.65–5.85 (1 H, m) and 7.54–7.68 (5 H, m, Ar); δC (75.5 MHz)
32.6 and 32.7 (CH2), 35.7 and 39.7 (CH2), 42.1 and 43.0
(CH2), 64.5 and 64.7 (CH2), 71.0 and 71.4 (CH), 117.5 and
117.6 (CH2), 124.0 and 124.2 (CH), 129.5 (CH), 131.6 and
131.8 (CH), 133.3 (CH), 139.3 and 140.2 (Cipso), 164.7 and 165.1
[60 H silica gel, 15% EtOAc–85% petroleum ether] to give
(Z)-(2S,5R)-3-ethylidene-2-phenylsulfinyl-4-oxa-1-azabicyclo-
[3.2.0]heptan-7-one and (E)-(2S,5R)-3-ethylidene-2-phenyl-
sulfinyl-4-oxa-1-azabicyclo[3.2.0]heptan-7-one (169 mg, 78%),
an inseparable mixture of 4 diastereoisomers, as a colour-
less oil (Found: M ϩ Hϩ, 264.0693. C13H14NO3S requires M,
264.0694); νmax (CH2Cl2)/cmϪ1 1806; δH (300 MHz) 1.63–1.78
(12 H, m, 4 × CH3), 2.97–3.07 (4 H, m, 4 × 6β-H), 3.31–3.43
(4 H, m, 4 × 6α-H), 4.37 (1H, qd, J 7.0, 1.0), 4.76–4.91 (6 H, m),
5.20–5.28 (4 H, m), 5.32 (1 H, qd, J 7.5, 1.5), 7.30–7.74 (20 H,
m, Ar); m/z (E.I.) 264 (M ϩ Hϩ, 0.5%).
A solution of the above sulfoxides (0.131 g, 0.43 mmol) in
EtOAc (35 cm3) was cooled to Ϫ78 ЊC under a stream of O2 gas.
An O2–O3 stream was passed through the solution for 20
min, after which time TLC analysis of the sky blue solution
indicated the disappearance of starting material. The O2–O3
flow was interrupted and the mixture was slowly warmed
to room temperature under a stream of nitrogen to provide a
colourless solution, which was washed with H2O (2 × 30 cm3)
and then sat. NaCl (30 cm3). After drying (MgSO4), the solvent
was removed in vacuo to provide sulfoxides 23 (0.1042 g, 97%),
a 1 : 1 mixture of 2 diastereoisomers, as a colourless oil (Found:
M ϩ Hϩ, 252.0328. C11H10NO4S requires M, 252.0331); νmax
(CH2Cl2)/cmϪ1 1806 (br); δH (300 MHz: CD3CN—based on
COSY analysis, signals due to one isomer are indicated by Ј)
3.24 (1 H, dd, J 17.5, 1.0, 6β-H), 3.28 (1 H, dd, J 17.5, 1.0,
6Јβ-H), 3.54 (1H, dd, J 17.5, 3.5, 6α-H), 3.55 (1 H, dd, J 17.5,
3.5, 6Јα-H), 4.96 (1 H, ddd, J 3.5, 1.0, 0.5, 5-H), 5.19 (1 H, d,
J 0.5, 2Ј-H), 5.42 (1H, d, J 0.5, 2-H), 5.51 (1 H, ddd, J 3.5, 1.0,
0.5, 5Ј-H) and 7.52–7.67 (10 H, m, Ar); δC (75.5 MHz, CD3CN)
48.8 (CH2), 49.2 (CH2), 76.7 (CH), 77.3 (CH), 85.9 (CH), 87.2
(CH), 125.3 (CH), 125.5 (CH), 129.8 (CH), 129.9 (CH), 132.8
(C᎐O) and 167.5 and 167.7 (C᎐O); m/z (C.I., NH ) 325
᎐
᎐
3
ϩ
(M ϩ NH4 , 100%), 308 (M ϩ Hϩ, 25).
Thermolysis of sulfoxide 12 in acetic anhydride and NPM
A solution of sulfoxide 12 (23 mg, 0.8 mmol) in acetic
anhydride (1 cm3) was heated at reflux for 1 h. Removal of
1
solvent and analysis by H NMR showed one major β-lactam
product. This was not rigorously characterized, but tentatively
assigned as the 4-acetoxyazetidinone 13 [δH (270 MHz) 2.16
(3 H, s), 2.25–2.35 (2 H, m), 3.04 (1 H, dd, J 15.0, 2.0, 3-H), 3.38
(1 H, dd, J 15.0, 5.0, 3-H), 3.75 (1 H, d, J 18), 3.95–4.10 (2 H,
m), 4.20 (1 H, d, J 18), 4.97–5.05 (2 H, m), 5.65 (1 H, m) and
6.04 (1 H, dd, J 5.0, 2.0, 4-H)].
A solution of sulfoxide 12 (23 mg, 0.8 mmol), NPM (42 mg,
0.69 mmol) in acetic anhydride (1 cm3) was heated at reflux for
1 h. After this time, the solution was concentrated in vacuo, and
1H NMR of the crude product showed no evidence of cyclo-
addition. The major β-lactam product evident in the crude
product corresponded to 13 described above.
(CH), 132.9 (CH), 139.2 (Cipso), 140.4 (Cipso), 169.2 (C᎐O), 173.7
᎐
(C᎐O) and 173.8 (C᎐O) (a signal due to one C᎐O carbon atom
᎐
᎐
᎐
was not observed); m/z (E.I.) 250 (M Ϫ Hϩ, 1.5%).
Thermolysis of 22 in the presence of NPM
A solution of oxazolidinone 22 (50 mg, 0.213 mmol) and NPM
(40 mg, 0.234 mmol) in MeCN (2 cm3) [distilled and deoxy-
genated] was heated at 81 ЊC for 120 h in a sealed tube. The
solvent was removed in vacuo and the residue was purified by
flash column chromatography [60 H silica gel, 10% EtOAc–90%
petroleum ether] to give 31 (23 mg, 43%) as a colourless solid,
mp 143–145 ЊC (hexane) (lit.16 141–143 ЊC); δH (300 MHz) 2.90
(1 H, dd, J 19.0, 4.0, 4-H), 3.33 (1 H, dd, J 19.0, 9.5, 4-H), 4.15
(1 H, dd, J 9.5, 4.0, 3-H), 7.04–7.10 (2 H, m, Ar), 7.32–7.50
(6 H, m, Ar) and 7.56–7.62 (2 H, m, Ar).
(2S,5R)-2-Phenylthio-4-oxa-1-azabicyclo[3.2.0]heptane-3,7-
dione 22
A solution of (E) and (Z)-(2S,5R)-3-ethylidene-2-phenylthio-4-
oxa-1-azabicylo[3.2.0]heptan-7-ones 2811 (100 mg, 0.40 mmol)
in EtOAc (10 cm3) was cooled to Ϫ78 ЊC under a stream of O2
gas. An O2–O3 stream was passed through the solution in short
bursts until the starting materials were consumed, as judged by
TLC. Dimethyl sulfide (slight excess) was introduced and the
solution allowed to warm to room temperature. The colourless
solution was then washed with H2O (2 × 10 cm3) and saturated
NaCl (10 cm3), dried (Na2SO4) and the solvent evaporated in
vacuo to provide oxazolidinone 22 (90 mg, 95%) as a colourless
oil, which was essentially pure by 1H NMR and was used with-
out further purification (Found: Mϩ, 235.0306. C11H9NO3S
requires M, 235.0303); νmax (film)/cmϪ1 1800; δH (270 MHz) 3.16
(1 H, dd, J 17.2, 1.1, 6β-H), 3.50 (1 H, dd, J 17.2, 3.3, 6α-H),
4.81 (1 H, m, 5-H), 5.38 (1 H, s, 2-H), 7.34–7.48 (3 H, m, Ar),
7.63 (2 H, m, Ar); m/z (C.I.) 236 (M ϩ Hϩ, 42%).
Diphenyl disulfide (11 mg, 48%) was isolated as a colourless
solid, mp 60–61 ЊC (hexane) and identified by direct com-
parison to an authentic sample.
Thermolysis of 23 in the presence of DMAD
A solution of oxazolidinone 23 (60 mg, 0.24 mmol) and
DMAD (36 mg, 31.0 µl, 0.25 mmol) in MeCN (2 cm3) [distilled
and deoxygenated] was heated at 81 ЊC for 48 h in a sealed tube.
The solvent was removed in vacuo and the residue was purified
by flash column chromatography [60 H silica gel, 1 : 9→1 : 4
EtOAc–hexane] to give 3217 (22 mg, 35%) as a colourless oil: δH
(300 MHz) 3.65 (3 H, s, CH3), 3.81 (3 H, s, CH3), 7.00 (1 H, s,
CH) and 7.48–7.70 (5 H, m, Ar). Diphenyl disulfide (8 mg,
32%) was isolated as a colourless solid, mp 59–60 ЊC (hexane),
and (S)-phenyl benzenethiosulfonate (9 mg, 30%) was isolated
as a colourless solid, mp 41–43 ЊC (hexane), and identified by
direct comparison to an authentic sample.
(2S,5R)-2-Phenylsulfinyl-4-oxa-1-azabicyclo[3.2.0]heptan-3,7-
dione 23
A solution of 28 (204 mg, 0.826 mmol) in CH2Cl2 (20 cm3) was
cooled to 0 ЊC under nitrogen and a solution of MCPBA (85%
purity, 214 mg, 1.24 mmol) in CH2Cl2 (20 cm3) was added
dropwise over 30 min. The solution was warmed to room tem-
perature over 1 h, then washed with 10% NaHCO3 (2 × 20 cm3),
H2O (30 cm3) and sat. NaCl (30 cm3). The organic solution
was dried (MgSO4), the solvent was removed in vacuo and
the residue was purified by flash column chromatography
Acknowledgements
We thank Dr Nigel Watson (GlaxoWellcome Research and
Development) for experimental details relating to the prepar-
1288
J. Chem. Soc., Perkin Trans. 1, 2001, 1281–1289

View Article Online
7 S. Oida, A. Yoshida and E. Ohki, Heterocycles, 1980, 14,
ation of betaine 17, AstraZeneca and EPSRC for financial sup-
port, and SB Pharmaceuticals for a generous and continuing
supply of clavulanic acid.
1999.
8 T. Kametani, S. Hirata, H. Nemoto, M. Ihara and K. Fukumoto,
Heterocycles, 1979, 12, 523.
9 (a) P. C. Cherry, C. E. Newall, N. S. Watson and G. I. Gregory,
German Pat., 1978, 2 740 526; (b) P. C. Cherry, C. E. Newall and
N. S. Watson, J. Chem. Soc., Chem. Commun., 1978, 469; (c) P. C.
Cherry, C. E. Newall and N. S. Watson, J. Chem. Soc., Chem.
Commun., 1979, 663.
10 (a) J. H. Bateson, R. I. Hickling, P. M. Roberts, T. C. Smale and
R. Southgate, J. Chem. Soc., Chem. Commun., 1980, 1084; (b) S. M.
Schmitt, D. B. R. Johnston and B. G. Christensen, J. Org. Chem.,
1980, 45, 1135; (c) H. Ona, S. Uyeo, K. Motokawa and T. Yoshida,
Chem. Pharm. Bull., 1985, 33, 4346; (d) R. Sharva, R. J. Stoodley
and A. Whiting, J. Chem. Soc., Perkin Trans. 1, 1987, 2361; (e) J. H.
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