The azomethine ylide strategy for β-lactam synthesis. Azapenams and 1-azacephams

Article abstract of DOI:10.1039/b203890k

Reaction of the β-lactam-based oxazolidinone 5 with N-sulfonylimines provides the exo and endo azapenams 8 in 22-54% yield. The reactivity of 2H-azirines as 1,3-dipolarophiles towards β-lactam-based azomethine ylides derived from oxazolidinones 5 and 15 h

Full text of DOI:10.1039/b203890k

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The azomethine ylide strategy for ꢀ-lactam synthesis.
Azapenams and 1-azacephams†
a
a
a
a
a
David Brown, Giles A. Brown, Mark Andrews, Jonathan M. Large, Dominique Urban,
a
b
a
1
Craig P. Butts, Neil J. Hales and Timothy Gallagher*
a
School of Chemistry, University of Bristol, Bristol, UK BS8 1TS.
E-mail: T.Gallagher@bristol.ac.uk; Fax: ϩ(44) 117 9298611; Tel: ϩ(44) 117 9288260
AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UK SK10 4TG
b
Received (in Cambridge, UK) 22nd April 2002, Accepted 6th June 2002
First published as an Advance Article on the web 31st July 2002
Reaction of the β-lactam-based oxazolidinone 5 with N-sulfonylimines provides the exo and endo azapenams 8 in
2–54% yield. The reactivity of 2H-azirines as 1,3-dipolarophiles towards β-lactam-based azomethine ylides derived
from oxazolidinones 5 and 15 has also been evaluated. Azirines 11 and 12a provide cycloadducts 13a,b and 16
2
2,4
respectively, which incorporate the novel 2,6-diazatricyclo[4.2.0.0 ]octan-7-one ring system. These adducts were
resistant towards C–N cleavage as the basis of an entry to 1-azacephams (1,5-diazabicyclo[4.2.0]octan-8-ones) 4.
The use of the 3-(4-methoxyphenyl)-2H-azirine 19 provides a labile initial cycloadduct, which undergoes in situ
ring-cleavage and further reaction to give the 2 : 1 adduct 1-azacepham 22. The initial product is stable when
3
-(4-nitrophenyl)-2H-azirine 23 is employed, and cycloadducts 24a and 24b are converted under mild reducing
conditions to the 1-azacepham derivatives 25 and 26.
Introduction
The azomethine ylide strategy for β-lactam synthesis is based
on the thermolysis of a β-lactam-based oxazolidinone 1, which
1
leads via a stepwise mechanism to azomethine ylide 2. This
intermediate reacts with a wide range of both conventional and
less conventional 1,3-dipolarophiles to give (after decarboxyl-
ation, which follows the cycloaddition event) bicyclic β-lactams
2
3
(Scheme 1). The synthetic flexibility associated with this
Results
Imines as 1,3-dipolarophiles
Imines represent a synthetically useful group of dipolarophiles,
and reactivity can be modulated via the N-substituent: N-alkyl
vs. N-aryl vs. N-sulfonyl (or a variant with another electron-
6
Scheme 1 Reagents and conditions: i, RCH(᎐X), MeCN, sealed tube
80 ЊC) or at reflux.
withdrawing N-substituent). In addition, increased reactivity is
(
associated with highly strained N-alkylimines, the most potent
of which are 2H-azirines. With a focus on the generation of
cycloaddition strategy is an important feature, and with
alkenes and alkynes this chemistry provides carbapenams and
2,3
azapenams and azapenems (the ∆ analogues), we have
evaluated the ability of a range of acyclic imines to trap
1
3a
∆
-carbapenems respectively.
When azomethine ylide 2 is trapped by heteroatom variants
aldehydes, ketones, thio- and selenocarbonyls), this cyclo-
7
the azomethine ylide 6 derived from oxazolidinone 5 (PNB =
p-nitrobenzyl) (Scheme 2).
Using benzaldehyde-based imines as representative sub-
strates, we were unable to isolate cycloadducts using imines
(
3b
addition strategy offers entries to oxapenams, penams (and
penems),
respectively.
3c,e
3d,e
and selenapenams,
where X = O, S, and Se
based on the general structure PhCH᎐NRЈ, where RЈ = Ph,
᎐
8a
8b
Boc or P(O)Ph . However, the N-sulfonyl variant 7a (Ar =
Ph; RЈ᎐SO Tol) did react under our standard conditions
2
8b
In this paper we describe the reactivity of azomethine ylide 2
towards two distinct classes of imines. With simple imines, the
process described below serves to extend the azomethine ylide
strategy to the synthesis of azapenams (the 1,4-diazabicyclo-
᎐
2
(
5
(
MeCN, 81 ЊC) to give the racemic azapenam derivative 8a in
4% yield, and as a 2 : 1 mixture of exo (major) and endo
minor) diastereomers at C(3)‡. The stereochemical assignment
[
3.2.0]heptan-7-one ring system) represented in general terms
1
of these adducts was based on H NMR and X-ray crystallo-
graphic analysis (see below).
4
by 3 (X = NRЈ).
However, the reactivity associated with one particular family
of imines—2H-azirines—has provided access to the 1-aza-
cepham skeleton 4 (i.e. the 1,5-diazabicyclo[4.2.0]octan-8-one
Two other aryl aldehyde-derived N-sulfonylimines 7b (Ar =
8b
8b
4
-MeC H ) and 7c (Ar = 2-naphthyl) were also successfully
6 4
employed as dipolarophiles to give adducts 8b (Ar = 4-MeC H )
6
4
5
ring system). The net transformation formally involves a 3ϩ3
and 8c (Ar = 2-naphthyl) in 22 and 49% yields respectively. In
both cases inseparable mixtures of exo and endo cycloadducts
annulation but a stepwise process via a novel tricyclic azapenam
intermediate is implicated.
‡
The aryl substituent at C(3) can occupy a position on the convex or
†
This paper is respectfully dedicated to the memory and many
concave face of the azabicycle and these are labelled as exo and endo
achievements of Professor Malcolm Campbell (1943–2001).
respectively.
2
014
J. Chem. Soc., Perkin Trans. 1, 2002, 2014–2021
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b203890k

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shift for H(5) in the exo series (δ 5.06–5.17) consistently appears
at higher field than is observed for H(5) in the endo series
δ 5.27–5.34).
(
2
H-Azirines as 1,3-dipolarophiles: synthetic access to the 1-
azacepham ring system
2
H-Azirines 9 represent an unusual group of imine-based 1,3-
10
dipolarophiles and our interest in these as substrates was
prompted by two considerations. Firstly, the ring strain present
within the azirine ring should provide compensation for the low
reactivity normally associated with N-alkylimines. Secondly,
cycloadducts 10 derived from azirines and an oxazolidinone
(
such as 5) incorporate a highly strained C–N bond within
2,4
the novel 2,6-diazatricyclo[4.2.0.0 ]octan-7-one ring system.
Subsequent (and selective) cleavage of the strained C(4)–N(2)
Scheme 2 Reagents and conditions: i, 7a–c (1.1. equiv.) (Tol = 4-
MeC H ), MeCN, sealed tube, 80 ЊC, 20 h (ratios correspond to the
exo–endo mixture obtained).
6
4
bond offers, in principle, an opportunity to generate the
5
1
-azacepham (1,5-diazabicyclo[4.2.0]octan-8-one) framework
exemplified by general structure 4 (Scheme 3).
were obtained. For each product, only the regioisomer shown
was detected, which is consistent with what we have observed
previously with other heteroatom-based dipolarophiles.
3
However, all attempts to achieve a cycloaddition between 6 and
an imine derived from either an alkyl aldehyde or a ketone
failed.
In the case of the β-naphthyl case 8c, partial separation of
the major (exo) isomer was achieved, and the structure (regio
and relative stereochemistry) was confirmed by X-ray crystallo-
graphic analysis (Fig. 1)§. It is also significant to note that, as
Scheme 3
A series of azirine substrates were identified that offer
different options for C(4)–N(2) bond cleavage. Three azirine-
3
-carboxylates derivatives have been utilised: the 2-(2,6-
1
1
1
2
dichlorophenyl) 11 and the 2-unsubstituted variants 12a,b
respectively. Thermolysis of 11 in the presence of oxazolidinone
gave a 1 : 2 mixture of cycloadducts 13a and 13b in 25%
5
combined yield (Scheme 4). Structural assignments of 13a and
Fig. 1 Solid state structure of exo-8c.
Scheme 4 Reagents and conditions: i, 11 (1.3 equiv.), MeCN, reflux, 25
h (25%).
1
anticipated from H NMR analysis, the stereochemical relation-
ship between C(2) (where the ester function is exo) and C(5)
1
3b were based on NOE experiments (see Experimental
corresponds to the thermodynamically more stable relative
9
section). In addition, the minor (and less polar) component 13a
provided crystals suitable for X-ray crystallographic analysis.
This served to confirm the structure of 13a, which contains
configuration. Again, this is a trend that has been observed
with all cycloadducts derived to date from oxazolidinone 5,
3
regardless of the nature of the 1,3-dipolarophile. Based on
2,4
the novel 2,6-diazatricyclo[4.2.0.0 ]octan-7-one ring system
Fig. 2).¶
confirmation of exo-8c, we have assigned the major com-
ponents of 8a and 8b as the exo isomer. Also, the chemical
(
§
Crystal data for exo-8c: C H N O S, M = 571.59, monoclinic,
¶ Crystal data for 13a: C H Cl N O ,
M
=
506.29, triclinic,
3
0
25
3
7
22 17
2
3
7
a = 43.767(8), b = 5.847(1), c = 22.777(5) Å, β = 113.78(1)Њ,
a = 8.007(1), b = 11.908(2), c = 12.814(2) Å, α = 65.448(2), β = 80.677(3),
3
Ϫ1
3
Ϫ1
V = 5333.9(18) Å , Z = 8, µ = 0.177 mm , T = 173 K, 26690 reflections
measured, 6143 unique (Rint = 0.0672) which were used in all
calculations. Final R = 0.0491. CCDC reference number 184386. See
http://www.rsc.org/suppdata/p1/b2/b203890k/ for crystallographic files
in .cif or other electronic format.
γ = 79.668(3)Њ, V = 1088.1(3) Å , Z = 2, µ = 0.350 mm , T = 173 K,
11461 reflections measured, 4958 unique (Rint 0.0296) which
=
were used in all calculations. Final R = 0.0382. CCDC reference
number 184387. See http://www.rsc.org/suppdata/p1/b2/b203890k/ for
crystallographic files in .cif or other electronic format.
J. Chem. Soc., Perkin Trans. 1, 2002, 2014–2021
2015

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isolated in a low 20% yield. In addition, adduct 17 derived from
vinyl azide 14a was also isolated in 17% yield as a single regio-
isomer. Note that the stereochemistry at C(3) of 17 has not
been established. Attempts to avoid this side reaction by forma-
tion of azirine 12b prior to exposure to oxazolidinone 15 led to
poor yields of the desired adducts. Diluting the cycloaddition
reaction mixture (to favour the unimolecular decomposition of
1
4a) did not lead to an improvement in product yield or
distribution.
The stereochemistry of cycloadduct 16 has not been
rigorously determined. We anticipate that the C(1)/C(5) stereo-
chemistry is as shown, which corresponds to the thermo-
dynamically more stable relative configuration and matches
that observed with the imine cycloadducts (see 8c above); the
Fig. 2 Solid state structure of 13a.
4
presence of a small (W) coupling ( J 1 Hz) between one of the
H(3) methylene protons and H(5) within this rigid framework
Initial attempts directed towards C(4)–N(2) cleavage of 13a
and 13b (both separately and also as the mixture of isomers)
focussed on exploiting the ring strain associated with this bond
within a constrained ring system. A variety of different acid-
and base-mediated reaction conditions were examined, with
5
together with the lack of a J coupling between H(5) and
15
H(8α) is consistent with the C(1)/C(5) stereochemistry shown.
The relative stereochemistry at C(4) has not, however, been
determined. Again, a wide variety of reaction conditions were
examined in order to achieve aziridine ring cleavage and pro-
vide the 1-azacepham framework, but cycloadduct 16 proved to
be stable towards acid- and base-mediated fragmentation.||
Based on the known propensity of α-amino esters to undergo
13,14c
and without N-activation (via acylation or sulfonylation).
However, no evidence for the desired C–N bond cleavage was
observed. Indeed, 13a and 13b proved to be relatively both
stable; 13b underwent essentially quantitative hydrogenolysis of
the PNB ester to give the corresponding carboxylic acid but
14f
reductive C–N cleavage [e.g. eqn. (1) ], the ability of cyclo-
14c,d
2,4
even under these conditions
the 2,6-diazatricyclo[4.2.0.0 ]-
octan-7-one ring system remained intact.||
(
1)
Studies then concentrated on the simpler C(2)-unsubstituted
azirine carboxylates 12a,b derived from the α-azidoacrylates
12
1
4a,b. It was feasible to prepare the azirine prior to the 1,3-
adducts 13a,b and 16 to react with a range of reducing agents
was also evaluated (Scheme 6). Our exploratory studies focused
dipolar cycloaddition step, but best results were obtained when
azirine 12a was generated and used in situ. Indeed, Gilchrist
and Alves have reported that the methyl ester 12b (derived from
vinyl azide 14b) is both volatile and unstable. Although oxazo-
lidinone 5 reacts with 12a, we focussed on cycloadducts derived
12
7
from the methyl ester-containing oxazolidinone 15 **. Azirine
generation and cycloaddition were achieved by heating 14a
with oxazolidinone 15 under standard conditions (Scheme 5).
Scheme 6
on the mixture of the simpler cycloadduct 16, but exposure
14b
to Riecke zinc, CrCl2, or SmI (in THF, with MeOH or
2
Me NCH CH OH, and in the presence of DMPU or
2
2
2
1
4e,f
HMPA)
failed to give the desired product, although starting
1
material was consumed. Some evidence ( H NMR) for the
desired C(4)–N(2) cleavage was obtained, but the correspond-
ing 1-azacepham 18, if formed, appeared to be unstable and
proved impossible to isolate cleanly.|| Furthermore, exposure of
1
6 to SmI2 in the presence of methanol proved to be an
exceptionally efficient method for methanolysis of the β-lactam
ring resulting in cleavage to give the corresponding β-amino
ester.
Scheme 5 Reagents and conditions: i, 14a (1.1 equiv.), MeCN, reflux,
1
5 h (16: 20%; 17: 17%).
Given the difficulties encountered with reductive cleavage of
the α-amino ester moiety embodied within 16, an alternative
mode of C–N bond cleavage has been pursued. This is based
on positioning an electron-rich arene at C(4) of the 2,6-
Two azirine-derived cycloadducts were detected in the crude
reaction mixture, but only the major cycloadduct 16 could be
2,4
|
| Use of both basic and acidic conditions to mediate the cleavage of
diazatricyclo[4.2.0.0 ]octan-7-one scaffold. Reaction of the
1
3,14c
aziridines has precedent in the literature.
We also evaluated reduc-
16
known azirine 19 (Ar = 4-MeOC H ) with oxazolidinone 5
6
4
tive cleavage methods for cycloadducts 13a,b and 16 based on literature
did not afford the expected cycloadduct 20. Rather, the major
product, which was isolated in 41% yield when two equivalents
of 19 were used, has been assigned as the 2 : 1 cycloadduct 22
14
precedents, although we did not examine the use of Li in liquid
14a
ammonia because of the lability of the β-lactam ring. A number of
these reactions did consume the starting material but the products
appeared to be unstable and decomposed on attempted isolation.
Efforts to avoid this by N-acetylation or N-sulfonylation also failed.
1
(Scheme 7). This assignment is based primarily on H (COSY
13
and NOE) and C NMR spectroscopy, and a key feature is the
5b
There is a report that the N-unsubstituted 1-azacephams are unstable,
but this may be substrate specific.
NOE observed between H(2) (δ 5.10) and H(11) (δ 4.44). In
4
addition a small W-coupling ( J 2 Hz) between H(6) (δ 4.74)
*
* The use of the methyl ester oxazolidinone variant 15 was dictated by
and H(11Ј) (δ 2.95) was also observed (see 22A). A plausible
mechanism to account for 22 is shown in Scheme 7. Ring cleav-
age of the initial cycloadduct 20 must take place under the
the lability of the PNB moiety in the presence of strong reductants.
Oxazolidinone 5 did react with azirines 12a and 12b, and cycloadducts
analogous to 16 and 17 were isolated and characterised.
2
016
J. Chem. Soc., Perkin Trans. 1, 2002, 2014–2021

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Scheme 8 Reagents and conditions: i, NaN , ICl, MeCN; ii, t-BuOK,
3
Et O; iii, PhMe, reflux (36% overall yield); iv, 5 or 15, MeCN, sealed
2
tube, 80 ЊC, 18 h (24a; 40%; 24b: 66%); v, (from 24a) H , Pd/C, EtOAc,
2
8
h, then TsCl, py, CH Cl (34% overall yield); vi, (from 24b) H , Pd/C,
2
2
2
EtOAc, 18 h, then TsCl, py, CH Cl (29% overall yield).
2
2
NMR spectra, the six-membered ring of both 25 and 26
appears to adopt a chair conformation, which is expected to be
flattened slightly adjacent to the β-lactam ring.
Scheme 7 Reagents and conditions: i, 5, 19 (2.3 equiv.), MeCN, 100 ЊC,
sealed tube, 15 h.
In summary, activated imines may be trapped by β-lactam-
based azomethine ylide 6 to provide racemic azapenams as mix-
tures of C(3) epimers. Azirines also provide a versatile and
effective group of 1,3-dipolarophiles. The ester-based cyclo-
adducts 13a,b and 16 are stable with respect to C–N bond
reaction conditions and the resulting zwitterion 21 can capture
another equivalent of azirine 19. A second methoxy-assisted
17
C–N cleavage followed by proton transfer would account for
the formation of the observed product 22. Interestingly,
reducing the amount of azirine 19 to one equivalent still led to
the 2 : 1 adduct 22, but in lower yield.
This was a significant observation, and this facile fragmen-
tation pathway can be controlled by appropriate choice of the
aryl moiety, and a nitro-substituted arene would provide a
suitable ‘safety catch’ unit. The nitro group would render the
cycloadduct stable towards further fragmentation under the
initial cycloaddition conditions, but this is then easily converted
to a potent electron-donating residue which then would be
anticipated to trigger C–N bond cleavage (Scheme 8).††
2,4
cleavage within the 2,6-diazatricyclo[4.2.0.0 ]octan-7-one
framework, even under strongly reducing conditions. Cyclo-
addition with the electron-rich aryl-substituted azirine 19 leads
to an adduct which does result in C–N bond cleavage, but this
takes place spontaneously under the cycloaddition conditions,
and is followed by further reaction to give the 2 : 1 adduct 22.
By using a nitroaryl moiety, the initial cycloadduct 24a,b is
prevented from undergoing further fragmentation. Subsequent
release (by nitro group reduction) of the corresponding aniline
then triggers the desired C–N bond cleavage. Depending on the
nature of the ester-protecting group (24a vs. 24b), these condi-
tions lead to either 25 or 26, both of which are novel azacepham
derivatives.
3
-(4-Nitrophenyl)-2H-azirine 23 was prepared in 36% overall
yield starting from 4-nitrostyrene. Thermolysis of 23 in the
presence of oxazolidinone 15 gave a single cycloadduct 24a in
The results described in this paper extend the scope of viable
dipolarophiles associated with the azomethine ylide strategy
to include imines, but more significantly, use of azirines pro-
vides a novel entry to azacephams. At this time the range of
4
0% isolated yield. Using oxazolidinone 5, the correspond-
ing PNB ester 24b was isolated in 66% yield, as a single
diastereomer. Again, the structure of cycloadducts 24a and 24b
has not been completely assigned, but the C(4) stereochemistry
is lost in the next step in any event.
1
-azacephams available is limited, but the chemistry reported in
this paper represents the first entry to the 2-carboxy derivatives
of this class of bicyclic β-lactam.
Hydrogenation of 24a, followed by double N-sulfonylation
to aid isolation) gave the 2,3-disubstituted azacepham 25 in
4% overall yield for two steps. Reduction of 24b led to a more
(
3
extensive reaction and resulted in PNB ester cleavage, nitro
group reduction as well as decarboxylation (and alkene reduc-
tion) to give, after N-sulfonylation, 26 in 29% overall yield
Experimental
General experimental procedures have recently been
1b
(
Scheme 8).‡‡ In neither case were we able to obtain crystals
described. All solvents were dried and deoxygenated prior
to use. All compounds reported are racemic. Where shown,
proton and carbon assignments were made using a combin-
suitable for crystallographic analysis and the stereochemical
assignments of both 25 and 26 are based primarily on extensive
NOE studies. These data are presented in the Experimental
1
1
1
13
ation of H– H and H– C correlation spectroscopy, and any
1
section. Based on the coupling constants observed in the H
‡
‡ The timing of the different steps leading to 26 is open to further
†
† A competition experiment was also carried out to compare the
investigation and the possibility that a decarboxylative fragmentation
may be involved in the crucial C–N bond cleavage cannot be ruled out.
However, it should be noted that in the case of 13b, hydrogenolysis of
the PNB ester is not complicated by decarboxylation or C–N bond
rupture.
reactivity of the methoxyphenylazirine 19 and the nitrophenyl analogue
2
3 towards azomethine ylide 6 derived from oxazolidinone 5. Only
cycloadduct 24b derived from the electron-deficient azirine 23 was
observed.
J. Chem. Soc., Perkin Trans. 1, 2002, 2014–2021
2017

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ambiguities associated with assignments are indicated. Details
of NOE experiments are provided with the other spectroscopic
data.
173.0, 168.0, 167.0 (2 × NCO, 2 × CO PNB), 148.0, 147.7,
144.0, 143.0, 141.7, 141.5, 138.5, 138.4, 137.0, 136.2, 135.3 (11
× C-quat.), 131.0, 129.9, 129.7, 129.0, 128.7, 128.6, 128.1,
2
1
27.9, 127.5, 126.9, 123.7, 123.2 (12 × Ar), 71.5 (C-5 minor),
4
-Nitrobenzyl (2R*,3R*,5R*)- and (2R*,3S*,5R*)-4-N-(4-
71.4 (C-2 minor or C-3 minor), 70.5 (C-5 major), 69.1 (C-2
major or C-3 major), 67.2 (C-2 minor or C-3 minor), 66.0
(CH Ar minor), 65.4 (CH Ar major), 63.9 (C-2 major or C-3
methylphenylsulfonyl)-3-phenyl-7-oxo-1,4-diazabicyclo[3.2.0]-
heptane-2-carboxylate 8a
2
2
major), 47.5 (C-6 minor), 46.4 (C-6 major), 21.4, 21.3, 21.2,
A solution of oxazolidinone 5 (70 mg, 0.23 mmol) and N-tosyl-
imine 7a (65 mg, 0.25 mmol) in MeCN (3 cm ) was heated at
ϩ
2
1.1 (4 × CH ); m/z (EI) 535 (M , 7%).
3
3
8
0 ЊC for 20 h in a sealed tube. Removal of solvent in vacuo
4
-Nitrobenzyl (2R*,3R*,5R*)- and (2R*,3S*,5R*)-4-N-(4-
and purification by flash chromatography (petrol–EtOAc, 4 : 1)
gave azapenam 8a (64 mg, 54%) as a colourless solid and
as an inseparable 2 : 1 mixture of exo and endo isomers (Found:
methylphenylsulfonyl)-3-(2-naphthyl)-7-oxo-1,4-diazabicyclo-
3.2.0]heptane-2-carboxylate 8c
[
ϩ
Ϫ1
M ϩ H , 522.1330. C H N O S requires 522.1335); νmax/cm
Using the same procedure as described for 7a, reaction of
oxazolidinone 5 with imine 7c gave azapenam 8c in 49% yield as
a colourless solid and as a 3 : 1 mixture of isomers. The major
isomer has been assigned as exo-8c (see below) (Found: M ,
571.1427. C H N O S requires 571.1413). νmax/cm (CH Cl )
26
24
3
7
(
CH Cl ) 1793, 1753; δ (300 MHz, C D , signals correspond-
2 2 H 6 6
ing to the major and minor isomers are indicated) 7.79–7.30
16 H, m, 9 × Ar major, 7 × Ar minor), 7.06–6.29 (10 H, m,
× Ar major, 6 × Ar minor), 5.41 (1 H, d, J 3.5, H-2 minor or
ϩ
(
4
Ϫ1
30
25
3
7
2
2
H-3 minor), 5.30 (1 H, m, H-5 minor), 5.26 (1 H, d, J 8.5, H-2
major or H-3 major), 5.11 (1 H, dd, J 3.5, 1.0, H-5 major), 4.96
1795, 1754; δH (300 MHz, C D ) 7.72–7.17 (8 H, m, 4 × Ar
6 6
major and 4 × Ar minor), 7.13–6.47 (18 H, m, 7 × Ar major and
11 × Ar minor), 6.05 (2 H, d, part of AAЈBBЈ, J 8.5, Ar major),
5.95 (2 H, d, part of AAЈBBЈ, J 8.5, Ar major), 5.54 (1 H, d,
J 4.5, H-2 minor or H-3 minor), 5.34 (1 H, m, H-5 minor), 5.33
(1 H, d, J 8.5, H-2 major or H-3 major), 5.17 (1 H, dd, J 3.5,
1.5, H-5 major), 4.98 (1 H, d, J 8.5, H-2 major or H-3 major),
4.80 (1 H, d, J 4.5, H-2 minor or H-3 minor), 4.56 (1 H, d,
J 13.5, CH H Ar minor), 4.43 (1 H, d, J 13.5, CH H Ar
(
1 H, d, J 8.5, H-2 major or H-3 major), 4.72 (1 H, d, J 3.5, H-2
minor or H-3 minor), 4.54 (1 H, d, J 13.5, CH H Ar minor),
A
B
4
.46 (1 H, d, J 13.5, CH H Ar minor), 4.18 (1 H, d, J 13.0,
A B
CH H Ar major), 4.08 (1 H, d, J 13.0, CH H Ar major), 3.64
A
B
A
B
(
1 H, dd, J 17.0, 1.0, H-6β major), 3.15 (1 H, dd, J 17.0, 3.5,
H-6α major), 3.11 (1 H, dd, J 16.5, 1.0, H-6β minor), 3.07
(
(
1 H, dd, J 16.5, 3.0, H-6α minor), 1.86 (3 H, s, CH minor) 1.84
3
A
B
A
B
3 H, s, CH3 major); δC (75.5 MHz, C D , signals for the
minor), 4.24 (1 H, d, J 13.0, CH H Ar major), 3.81 (1 H, d,
6
6
A B
aromatic carbons were not completely resolved) 174.9, 173.1,
J 13.0, CH H Ar major), 3.69 (1 H, dd, J 17.0, 1.5, H-6β
A B
1
1
68.0, 167.0 (2 × NCO, 2 × CO PNB), 148.0, 147.8, 144.3,
43.3, 141.9, 141.5, 139.3, 136.9, 135.2, 134.1 (5 × C-quat.
major), 3.15 (1 H, d, J 16.5, H-6β minor), 3.12 (1 H, dd, J 17.0,
3.5, H-6α major), 3.02 (1 H, dd, J 16.5, 3.0, H-6α minor), 1.72
(3H, s, CH minor), 1.55 (3 H, s, CH major); δ (75.5 MHz,
2
major, 5 × C-quat. minor), 129.9, 129.7, 129.3, 129.2, 128.8,
3
3
C
1
7
27.5, 127.0, 126.8, 123.8, 123.4 (5 × Ar major, 5 × Ar minor),
1.4 (C-5 minor), 71.2 (C-2 minor or C-3 minor), 70.4 (C-5
C D , signals due to two aromatic C-quat. were not observed
and the aromatic carbons were not completely resolved) 174.7,
6 6
major), 69.1 (C-2 major or C-3 major), 66.8 (C-2 minor or C-3
minor), 65.8 (CH Ar minor), 65.3 (CH Ar major), 63.7 (C-2
173.2, 168.0, 167.0 (2 × NCO, 2 × CO PNB), 147.7, 147.4,
2
144.1, 143.1, 141.6, 140.7, 136.7, 135.7, 133.6, 133.4, 133.1,
132.5 (12 × C-quat.), 131.0, 129.5, 128.8, 128.7, 128.6, 128.5,
128.4, 128.2, 127.6, 127.3, 127.2, 126.9, 126.8, 126.4, 123.7,
2
2
major or C-3 major), 47.2 (C-6 minor), 46.4 (C-6 major), 21.2,
ϩ
2
1.1 (2 × CH ); m/z (CI, NH ) 522 (M ϩ H , 25%).
3
3
1
22.9, 122.8 (17 × Ar), 71.6 (C-5 minor), 71.3 (C-2 minor or C-3
4
-Nitrobenzyl (2R*,3R*,5R*)- and (2R*,3S*,5R*)-4-N-(4-
minor), 70.6 (C-5 major), 69.0 (C-2 major or C-3 major), 66.7
(C-2 minor or C-3 minor), 65.8 (CH Ar minor), 65.0 (CH Ar
methylphenylsulfonyl)-3-(4-methylphenyl)-7-oxo-1,4-diaza-
2
2
bicyclo[3.2.0]heptane-2-carboxylate 8b
major), 63.6 (C-2 major or C-3 major), 47.0 (C-6 minor), 46.7
ϩ
(
C-6 major), 21.6, 21.3, 21.1, 21.0 (4 × CH ); m/z (EI) 571 (M ,
3
Using the same procedure as described for 7a, reaction of
oxazolidinone 5 with imine 7b gave azapenam 8b in 22% yield
as a colourless oil and as an inseparable 3 : 1 mixture of iso-
2
9%).
Although the minor isomer could not be obtained in pure
form, partial separation of the major component (exo-8c) was
achieved by flash chromatography and crystallisation from
ϩ
mers (Found: M , 535.1409. C H N O S requires 535.1413);
2
7
25
3
7
Ϫ1
νmax/cm (CH Cl ) 1793, 1751; δ (300 MHz, C D , signals
2
2
H
6
6
CH Cl2 (slow evaporation) gave crystals suitable for X-ray
2
corresponding to the major and minor isomers are indicated)
.75 (2 H, d, part of AAЈBBЈ, J 9.0, Ar minor), 7.64 (2 H, d,
crystallographic analysis.
7
part of AAЈBBЈ, J 9.0, Ar major), 7.50 (2 H, d, part of
AAЈBBЈ, J 8.0, Ar minor), 7.22 (2 H, d, part of AAЈBBЈ, J 8.0,
Ar minor), 7.04 (2 H, d, part of AAЈBBЈ, J 8.0, Ar major), 6.85
4
-Nitrobenzyl (1S*,3R*,4S*,5R*)-4-methoxycarbonyl-3-(2,6-
2,4
dichlorophenyl)-7-oxo-2,6-diazatricyclo[4.2.0.0 ]octane-5-
carboxylate 13a and 4-nitrobenzyl (1S*,3S*,4R*,5R*)-4-
methoxycarbonyl-3-(2,6-dichlorophenyl)-7-oxo-2,6-diazatricyclo-
(
2 H, d, part of AAЈBBЈ, J 8.0, Ar minor), 6.66 (2 H, d, part of
AAЈBBЈ, J 9.0, Ar minor), 6.65 (2 H, d, part of AAЈBBЈ, J 8.0,
Ar minor), 6.51 (2 H, d, part of AAЈBBЈ, J 8.0, Ar major), 6.43
2
,4
[
4.2.0.0 ]octane-5-carboxylate 13b
(
2 H, d, part of AAЈBBЈ, J 8.0, Ar major), 6.31 (2 H, d, part of
A solution of oxazolidinone 5 (215 mg, 0.70 mmol) and azirine
11 (220 mg, 0.90 mmol) in MeCN (6 cm ) was heated at reflux
3
AAЈBBЈ, J 8.0, Ar major), 6.29 (2 H, d, part of AAЈBBЈ, J 9.0,
Ar major), 5.39 (1 H, d, J 4.0, H-2 minor or H-3 minor), 5.27
for 25 h. Removal of solvent in vacuo and purification by flash
chromatography (CH Cl –Et O, 49 : 1) gave cycloadduct 13a
(
1 H, dd, J 3.0, 1.0, H-5 minor), 5.19 (1 H, d, J 8.5, H-2 major
2
2
2
or H-3 major), 5.06 (1 H, dd, J 3.5, 1.5, H-5 major), 4.89 (1 H,
d, J 8.5, H-2 major or H-3 major), 4.72 (1 H, d, J 4.0, H-2
minor or H-3 minor), 4.50 (1 H, d, J 13.5, CH H Ar minor),
(31 mg, 8%) as a colourless solid. Continued elution gave 13b
(59 mg, 17%) as a colourless solid.
A
B
ϩ
4
.42 (1 H, d, J 13.5, CH H Ar minor), 4.23 (1 H, d, J 13.0,
Data for 13a. R 0.20 (CH Cl –Et O, 49 : 1) (Found: M ϩ H ,
A
B
f
2
2
2
35
Ϫ1
CH H Ar major), 4.09 (1 H, d, J 13.0, CH H Ar major), 3.60
506.0530. C H Cl N O requires 506.0522); νmax/cm (CH2-
A
B
A
B
22 18
2
3
7
(
1 H, dd, J 17.0, 1.5, H-6β major), 3.11–3.04 (2 H, m, H-6α
major and H-6β minor), 2.99 (1 H, dd, J 16.5, 3.0, H-6α minor),
.00 (3 H, s, CH minor), 1.85 (3 H, s, CH major), 1.84 (3 H, s,
Cl ) 2960, 1785; δH (400 MHz, CDCl ) 8.24 (2 H, d, part of
AAЈBBЈ, J 8.5, Ar), 7.56 (2 H, d, part of AAЈBBЈ, J 8.5, Ar),
7.19–7.33 (3 H, m, Ar), 5.38 (1 H, dd, J 4.0, 1.0, H-1), 5.29 (2 H,
2
3
2
3
3
CH minor), 1.81 (3 H, s, CH major); δ (75.5 MHz, C D , a
s, CH Ar), 5.17 (1 H, s, H-5), 3.44 (1 H, dd, J 16.5, 4.0, H-8α),
3
3
C
6
6
2
signal due to one aromatic C-quat. was not observed) 174.7,
3.39 (3 H, s, CO CH ), 3.28 (1 H, dd, J 16.5, 1.0, H-8β), 3.03
2
3
2
018 J. Chem. Soc., Perkin Trans. 1, 2002, 2014–2021

View Article Online
(
1 H, s, H-3); δ (100 MHz, CDCl ) 172.3, 166.8, 166.4 (NCO,
Ar), 7.02 (2 H, d, part of AAЈBBЈ, J 8.0, Ar), 6.82 (2 H, d, part
C
3
2
× CO ), 147.9, 142.0, 135.7 (3 × C-quat.), 129.8 (Ar), 129.1
of AAЈBBЈ, J 8.0, Ar), 6.75 (2 H, d, part of AAЈBBЈ, J 8.0, Ar),
6.71 (1 H, d, J 5.3, H-9), 5.10 (1 H, dd, J 4.5, 1.5, H-2), 4.88
(1 H, d, J 13.0, CH H Ar), 4.74 (1 H, d, J 2.0, H-6), 4.72 (1 H,
2
(
(
C-quat.), 128.8, 128.6, 123.9 (3 × Ar), 73.5 (C-5), 65.9
CH Ar), 64.3 (C-4), 61.9 (C-1), 52.7 (CO CH ), 41.2 (C-8),
2
2
3
A
B
ϩ
4
0.7 (C-3); m/z (CI) 510, 508, 506 (M ϩ H , 68%).
d, J 13.0, CH H Ar), 4.44 (1 H, d, J 12.5, H-11), 4.05 (1 H, d,
A B
NOE experiments: irradiation of H-3 (δ 3.03) showed
J 5.5, NH), 3.78 (3 H, s, OCH ), 3.71 (3 H, s, OCH ), 2.95 (1 H,
3 3
enhancements of H-5 (δ 5.17) and H-8β (δ 3.28). Irradiation of
H-8β showed enhancements of H-3 and H-8α (δ 3.44). Irradi-
ation of H-5 showed enhancement of H-3. Crystallisation
from CH Cl –pentane gave crystals of 13a suitable for X-ray
dd, J 12.5, 2.0, H-11Ј), 2.80 (1 H, dd, J 15.5, 4.5, H-3α), 2.77
(1 H, dd, J 15.5, 1.5, H-3β); δC (67.9 MHz, CDCl ) 168.4,
3
167.1 (NCO, CO PNB), 159.4, 157.4, 147.5, 141.6, 132.2, 132.1
2
(6 × C-quat.), 128.7, 125.8 (2 × Ar), 123.7 (C-9), 123.5, 114.2,
114.0 (3 × Ar), 66.3 (C-2), 65.0 (CO CH Ar), 61.9 (C-6), 55.2
2
2
crystallographic analysis.
2
2
(
OCH ), 55.0 (OCH ), 51.5 (C-7), 48.8 (C-11), 40.8 (C-3); m/z
3 3
ϩ
ϩ
Data for 13b. R 0.14 (CH Cl –Et O, 49 : 1) (Found: M ϩ H ,
(EI) 556 (M , 21%).
f
2
2
2
3
5
Ϫ1
5
06.0516. C H Cl N O requires 506.0522); νmax/cm (CH2-
NOE experiments: irradiation of H-2 (δ 5.10) showed
enhancement of H-11 (δ 4.44).
22
18
2
3
7
Cl ) 2955, 1750; δ (300 MHz, CDCl ) 8.25 (2 H, d, part of
2
H
3
AAЈBBЈ, J 8.5, Ar), 7.59 (2 H, d, part of AAЈBBЈ, J 8.5, Ar),
.30–7.16 (3 H, m, Ar), 5.69 (1 H, s, H-5), 5.41 (1 H, d, J 13.5,
CH H Ar), 5.30 (1 H, d, J 13.5, CH H Ar), 5.17 (1 H, dd,
7
3-(4-Nitrophenyl)-2H-azirine 23
A
B
A
B
(
i) 1-Azido-1-(4-nitrophenyl)ethene. A stirred suspension of
3
J 4.5, 2.0, H-1), 3.63 (3 H, s, CO CH ), 3.62 (1 H, s, H-3), 3.56
2
3
sodium azide (236 mg, 3.69 mmol,) in dry MeCN (6 cm ) at
ЊC was treated over 15 minutes with iodine monochloride
0.18 cm , 3.69 mmol) and then stirred for 20 minutes. A solu-
(
1 H, dd, J 17.0, 4.5, H-8α), 3.34 (1 H, dd, J 17.0, 2.0, H-8β);
0
(
δC (75.5 MHz, CDCl ) 175.7, 168.2, 167.1 (NCO, 2 × CO ),
3
2
3
1
41.8, 135.5, 130.1 (3 × C-quat.), 129.8, 128.4, 128.3, 123.9
3
tion of 4-nitrostyrene (500 mg, 3.35 mmol) in MeCN (2 cm )
was added dropwise and the reaction mixture was allowed to
warm to room temperature and stirred for 2 h [TLC analysis
(
4 × Ar), 80.3 (C-5), 66.2 (C-4), 66.0 (CH Ar), 60.9 (C-1),
2
5
3.3 (CO CH ), 51.3 (C-3), 45.4 (C-8); m/z (CI) 510, 508, 506
2 3
ϩ
(
M ϩ H , 3%).
(
petrol–EtOAc, 4 : 1) indicated that two products had been
NOE experiments: irradiation of H-1 (δ 5.17) showed
enhancements of H-8a (δ 3.56) and H-3 (δ 3.62). Irradiation
of H-3 showed enhancement of H-1. Irradiation of H-5
3
formed]. The reaction mixture was poured into water (20 cm )
3
and extracted with Et O (3 × 20 cm ). The combined extracts
2
3
were washed with 5% aqueous Na S O (20 cm ) followed by
2
2
3
(
δ 5.69) showed no enhancements to any of the tricyclic ring
3
water (20 cm ), then dried (MgSO ) and concentrated in vacuo
4
protons.
to give a mixture of the diazide and the desired vinyl azide. This
3
mixture was redissolved in Et O (10 cm ) at 0 ЊC and treated
2
Methyl (1S*,5R*)-4-tert-butoxycarbonyl-7-oxo-2,6-diaza-
t
with BuOK (452 mg, 4.02 mmol) and stirred for 30 minutes,
2,4
tricyclo[4.2.0.0 ]octane-5-carboxylate 16 and methyl
after which time TLC analysis indicated complete conversion to
(
[
1S*,5R*)-3-azido-3-tert-butoxycarbonyl-7-oxo-1-azabicyclo-
3.2.0]heptane-2-carboxylate 17
3
the vinyl azide. The mixture was washed with water (10 cm ),
3
brine (10 cm ), dried (MgSO ) and concentrated in vacuo to give
4
A solution of oxazolidinone 15 (494 mg, 2.67 mmol) and vinyl
azide (945 mg, 5.59 mmol) in MeCN (50 cm ) was heated under
1-azido-1-(4-nitrophenyl)ethene as a colourless oil, which was
3
not purified further. δ (270 MHz, CDCl ) 8.21 (2 H, d, part of
H
3
reflux for 15 h. Removal of solvent in vacuo and purification
AAЈBBЈ, J 8.0, Ar), 7.73 (2 H, d, part of AAЈBBЈ, J 8.0, Ar),
5.64 (1 H, d, J 3.0, C᎐CH H ), 5.16 (1 H, d, J 3.0, C᎐CH H ).
This material was not characterised further but was used
directly in the next step.
by flash chromatography (CH Cl –Et O, 9 : 1) gave the bicyclic
2
2
2
᎐
A
B
A
B
Ϫ1
cycloadduct 17 (132 mg, 17%) as pale yellow oil. νmax/cm
(
CH Cl ) 2127; δ (270 MHz, CDCl ) 4.94 (1 H, s, H-2), 4.25
2 2 H 3
(
1 H, m, H-5), 3.78 (3 H, s, CO CH ), 3.37 (1 H, dd, J 5.0 and
2 3
1
6.0, H-6α), 2.80 (1 H, dd, J 2.0 and 16.0, H-6β), 2.55 (1 H, dd,
(ii) 3-(4-Nitrophenyl)-2H-azirine 23. Crude 1-azido-1-(4-nitro-
J 5.5 and 13.5, H-4), 2.09 (1 H, dd, J 9.0 and 13.5, H-4), 1.55
phenyl)ethene prepared above was redissolved in toluene
(50 cm ) and heated at reflux for 6 h. Removal of solvent
3
(
9 H, s, C(CH ) ); δ (67.5 MHz, CDCl ) 175.1, 167.4, 167.0,
3
3
C
3
8
5.1, 79.9, 66.3, 53.1, 42.6, 42.1, 27.7. We were unable to obtain
in vacuo and purification by flash chromatography (petrol–
satisfactory high resolution or microanalytical data for this
compound.
Et O, 4 : 1) gave 23 (196 mg, 36% over 3 steps) as a colourless
2
ϩ
solid (Found: M , 162.0429. C H N O requires 162.0429).
8
6
2
2
Ϫ1
Continued elution gave cycloadduct 16 (149 mg, 20%) as a
νmax/cm (CHCl ) 1605; δH (400 MHz, CDCl ) 8.44 (2 H, d,
3
3
ϩ
colourless oil (Found: M , 282.1219. C H N O requires
part of AAЈBBЈ, J 8.0, Ar), 8.11 (2 H, d, part of AAЈBBЈ, J 8.0,
Ar), 1.94 (2 H, s, CH ); δ (100 MHz, CDCl ) 165.5 (C-NO ),
1
3
8
4
5
Ϫ1
2
82.1216); νmax/cm (CH Cl ) 1750; δ (270 MHz, CDCl ) 5.38
2 2 H 3
2
C
3
2
(
1 H, d, J 1.0, H-5), 4.62 (1 H, dd, J 2.0 and 4.5, H-1), 3.78 (3 H,
131.4 (C-quat.), 130.4, 124.4 (Ar), 20.9 (NCH ); m/z (EI) 162
(M , 9%).
2
ϩ
s, CO CH ), 3.39 (1 H, dd, J 4.5 and 16.5, H-8α), 3.21 (1 H, dd,
2
3
J 2.0 and 16.5, H-8β), 2.74 (1 H, d, J 1.0, H-3), 2.20 (1 H, s,
H-3), 1.50 (9 H, s, C(CH ) ); δ (67.5 MHz, CDCl ) 176.1,
Methyl (1S*,5R*)-4-(4-nitrophenyl)-7-oxo-2,6-diazatricyclo-
[4.2.0.0 ]octane-5-carboxylate 24a
3
3
C
3
2
,4
1
69.2, 166.6, 83.5, 79.2, 60.2, 59.7, 52.8, 45.4, 41.5, 27.8; m/z
ϩ
(
EI) 282 (M , 20%).
A solution of oxazolidinone 15 (75 mg, 0.40 mmol) and azirine
3
2
3 (72 mg, 0.45 mmol) in MeCN (3 cm ) was heated at 80 ЊC in
4
1
-Nitrobenzyl (2S*,6R*,7R*)-7,10-bis(4-methoxyphenyl)-4-oxo-
2,5
a sealed tube for 18 h. Removal of solvent in vacuo and purifi-
cation by flash chromatography (CH Cl –Et O, 2 : 1) gave
,5,8-triazatricyclo[5.3.1.0 ]undec-9-ene-6-carboxylate 22
2
2
2
A solution of the oxazolidinone 5 (70 mg, 0.23 mmol) and
cycloadduct 24a (49 mg, 40%) as a single diastereoisomer
16
3
ϩ
azirine 19 (77 mg, 0.53 mmol) in MeCN (3 cm ) was heated at
00 ЊC in a sealed tube for 15 h. Removal of solvent in vacuo
and purification by flash chromatography (CH Cl –Et O, 49 : 1)
and as a foam (Found: M , 303.0855. C H N O requires
1
4
13
3
5
Ϫ1
1
303.0855); νmax/cm (CHCl ) 1779, 1751, 1605; δH (270 MHz,
3
CDCl ) 8.18 (2 H, d, part of AAЈBBЈ, J 8.5, Ar), 7.56 (2 H, d,
2
2
2
3
gave the title compound 22 (52 mg, 41%) as a pale yellow
part of AAЈBBЈ, J 8.5, Ar), 5.31 (1 H, s, H-5), 5.10 (1 H, s, H-1),
3.42 (3 H, s, CO CH ), 3.35 (1 H, dd, J 16.5, 4.0, H-8α), 2.86
ϩ
oil (Found: M , 556.1950. C H N O requires 556.1958).
3
0
28
4
7
2
3
Ϫ1
νmax/cm (CHCl ) 3426, 1753, 1644, 1609; δH (400 MHz,
(1 H, dd, J 16.5, 1.5, H-8β), 2.04–2.01 (2 H, m, 2 × H-3);
δ (100 MHz, CDCl ) 173.1, 167.6 (NCO, CO Me), 147.7, 142.5
3
CDCl ) 8.06 (2 H, d, part of AAЈBBЈ, J 8.0, Ar), 7.35 (2 H, d,
3
C
3
2
part of AAЈBBЈ, J 8.0, Ar), 7.19 (2 H, d, part of AAЈBBЈ, J 8.0,
(2 × C-quat.), 128.5, 123.7 (2 × Ar), 76.8 (C-5), 63.8 (C-1), 61.6
J. Chem. Soc., Perkin Trans. 1, 2002, 2014–2021 2019

View Article Online
ϩ
3
(
6
C-4), 52.4 (CO CH ), 41.1 (C-8), 32.3 (C-3); m/z (EI) 303 (M ,
2%).
pyridine (0.08 cm , 0.98 mmol) and toluenesulfonyl chloride
(266 mg, 1.40 mmol) and stirred at 0 ЊC for 2 h. Removal of
solvent in vacuo and purification by flash chromatography
2
3
(
EtOAc–petrol, 2 : 1) gave 26 (36 mg, 29%) as a colourless
4
-Nitrobenzyl (1S*,5R*)-4-(4-nitrophenyl)-7-oxo-2,6-diaza-
ϩ
2,4
foam (Found: M , 525.1381. C H N O S requires 525.1392).
νmax/cm (CHCl ) 3374, 1763; δ (300 MHz, CDCl ) 7.66 (2 H,
tricyclo[4.2.0.0 ]octane-5-carboxylate 24b
26 27
3
5 2
Ϫ1
3
H
3
A solution of oxazolidinone 5 (77 mg, 0.25 mmol) and azirine
d, part of AAЈBBЈ, J 8.5, Ar), 7.65 (2 H, d, part of AAЈBBЈ,
J 8.5, Ar), 7.39 (2 H, d, part of AAЈBBЈ, J 8.5, Ar), 7.25 (2 H, d,
part of AAЈBBЈ, J 8.5, Ar), 7.11 (1 H, br, NH ), 7.04 (2 H, d,
part of AAЈBBЈ, J 6.5, Ar), 6.97 (2 H, d, part of AAЈBBЈ, J 6.5,
Ar), 4.22 (1 H, dd, J 3.3, 1.0, H-6), 3.90 (1 H, dd, J 13.5, 4.5,
either H-2β or H-4β), 3.80 (1 H, dd, J 12.0, 2.5, either of H-2β
or H-4β), 3.50 (1 H, dd, J 15.5, 1.0, H-7β), 3.39 (1 H, ddd,
J 15.6, 3.3, 1.5, H-7α), 3.05 (1 H, m, H-3), 2.61 (1 H, t, J 12.0,
either H-2α or H-4α), 2.47 (3 H, s, Ar-CH ), 2.41 (1 H, t, J 12.0,
either H-2α or H-4α), 2.40 (3 H, s, Ar-CH ); δC (75.5 MHz,
CDCl ) 171.2 (NCO), 144.9, 144.1 (2 × SO -C-quat.), 136.3,
1
1
4
5
3
2
3 (45 mg, 0.28 mmol) in MeCN (3 cm ) was heated at 80 ЊC in
a sealed tube for 18 h. Removal of solvent in vacuo and purifi-
cation by flash chromatography (CH Cl –Et O, 3 : 1) gave
cycloadduct 24b (70 mg, 66%) as a single diastereoisomer and
as a colourless solid (Found: M , 424.1020. C H N O
requires 424.1019); νmax/cm (CHCl ) 1781, 1753; δH (270
2
2
2
ϩ
20
16
4
7
Ϫ1
3
MHz, CDCl ) 8.13 (2 H, d, part of AAЈBBЈ, J 8.0, Ar), 8.05
3
(
2 H, d, part of AAЈBBЈ, J 8.0, Ar), 7.49 (2 H, d, part of
AAЈBBЈ, J 9.0, Ar), 7.24 (2 H, d, part of AAЈBBЈ, J 9.0, Ar),
.30 (1 H, s, H-5), 5.15 (1 H, s, H-1), 4.94 (1 H, d, J 13.0,
CH H Ar), 4.87 (1 H, d, J 13.0, CH H Ar), 3.38 (1 H, dd,
3
3
5
3
2
A
B
A
B
36.1, 134.6, 131.9 (4 × C-quat.), 130.1, 129.7, 128.1, 128.0,
27.1, 121.7 (6 × Ar), 61.8 (C-6), 50.4 (C-2 or C-4), 46.6 (C-7),
J 16.5, 4.5, H-8α), 2.89 (1 H, dd, J 16.5, 1.0, H-8β), 2.05 (1 H, br
s, H-3), 2.01 (1 H, br s, H-3Ј); δ (100 MHz, CDCl ) 173.3, 167.2
C
3
3.4 (C-2 or C-4), 41.5 (C-3), 21.7, 21.6 (2 × Ar-CH ); m/z (EI)
3
(
NCO, CO PNB), 142.2, 141.7 (2 × C-quat.), 129.1, 128.4,
ϩ
2
25 (M , 25%).
1
23.8, 123.6 (4 × Ar), 72.5 (C-5), 65.8 (CH Ar), 63.9 (C-1), 61.8
2
ϩ
NOE experiments: irradiation of H-3 (δ 3.05) showed
(
C-4), 41.2 (C-8), 32.4 (C-3); m/z (EI) 424 (M , 4%).
enhancements of the signals at δ 3.90 and δ 3.80 (which have
been assigned as H-2β and H-4β, but we cannot distinguish
between these signals), but no enhancement of H-6 (δ 4.22)
was observed. Irradiation of H-6 showed an enhancement of
H-7α (δ 3.39) only.
Methyl (2R*,3S*,6R*)-3-{4-[N-(4-methylphenylsulfonyl)amino]-
phenyl}-5-(4-methylphenylsulfonyl)-8-oxo-1,5-diazabicyclo-
[
4.2.0]octane-2-carboxylate 25
A solution of cycloadduct 24a (80 mg, 0.26 mmol) in EtOAc
3
(
4 cm ) containing 10% Pd on carbon (30 mg) was stirred vigor-
Acknowledgements
ously under one atmosphere of hydrogen for 8 h. The catalyst
was removed by filtration through Celite and the solution was
concentrated in vacuo. The residue was immediately redissolved
We thank Drs Martin Murray and Ian Fairlamb for extensive
NMR (NOE and NOESY) work, and EPSRC and AstraZeneca
for generous financial support.
3
in dry CH Cl (2 cm ), cooled to 0 ЊC and treated with dry
2
2
3
pyridine (0.07 cm , 0.84 mmol) and toluenesulfonyl chloride
301 mg, 1.58 mmol). The mixture was stirred for 30 minutes at
ЊC, then warmed to room temperature and stirred for a
(
0
References
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7 2
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.89 (2 H, d, part of AAЈBBЈ, J 8.5, Ar), 6.52 (1 H, br, NH),
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(
3
(
1 H, dd, J 11.6, 3.3, H-4β), 3.58 (1 H, dd, J 15.8, 1.1, H-7β),
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3
Ar-CH ), 2.40 (3 H, s, Ar-CH ); δ (100 MHz, CDCl ) 168.9,
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3
C
3
1
1
1
4
65.4 (NCO, CO Me), 145.0, 144.2 (2 × SO -C-quat.), 136.6,
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2
4
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ϩ
(
EI) 583 (M , 14%).
NOE experiments: irradiation of H-2 (δ 4.60) gave an
enhancement of H-3β (δ 3.41). Irradiation of H-3β gave
enhancements of H-2 (δ 4.60) and H-4β (δ 3.74). Irradiation of
H-4α (δ 3.18) gave enhancements of H-4β, H-6 (δ 4.64) and the
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(
(
3S*,6R*)-3-{4-[N-(4-Methylphenylsulfonyl)amino]phenyl}-5-
4-methylphenylsulfonyl)-8-oxo-1,5-diazabicyclo[4.2.0]octane 26
A solution of cycloadduct 24b (99 mg, 0.23 mmol) in EtOAc
3
(
4 cm ) containing 10% Pd on carbon (35 mg) was stirred vigor-
ously under an atmosphere of hydrogen for 18 h. The catalyst
was removed by filtration through Celite and the solvent
removed in vacuo to give a solid which was immediately redis-
6
(a) J.-P. Anselme, in The chemistry of the carbon–nitrogen double
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(
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3
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2
2
2
020
J. Chem. Soc., Perkin Trans. 1, 2002, 2014–2021

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9
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1
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5
1
0 F. W. Fowler, Adv. Heterocycl. Chem., 1971, 13, 45 . For reactions
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1
2 M. J. Alves and T. L. Gilchrist, Tetrahedron Lett., 1998, 39, 7579.
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J. Chem. Soc., Perkin Trans. 1, 2002, 2014–2021
2021