Azabicyclo[3.2.0]heptan-7-ones (carbapenams) from pyrrole

Article abstract of DOI:10.1039/a703170j

The azabicyclo[3.2.0]heptan-7-ones 4, 10, 16 and 24 have been prepared from pyrrole. The same general approach has been used for all these derivatives; namely, substitution of pyrrole at the 2- and 5-carbon atoms, catalytic hydrogenation to produce pyrrolidine-2-acetic acid derivatives, and cyclisation using tris(1,3-dihydro-2-oxobenzoxazol-3-yl)phosphine oxide 6. The catalytic hydrogenation of 2,5-disubstituted pyrroles gives only the corresponding cis-2,5-disubstituted pyrrolidines. The hydrogenation proceeds more easily when the nitrogen atom bears a tert-butoxycarbonyl substituent. The N-tert-butoxycarbonylpyrroles 8 and 21 bearing an α-substituent in the acetate side chain were hydrogenated with a high degree of facial stereoselectivity. This allowed the 6-phthalimidoazabicyclo-[3.2.0]heptan-7-one 24 to be isolated as a single diastereoisomer. The X-ray crystal structure of a precursor, the triester, 22a, has been obtained.

Full text of DOI:10.1039/a703170j

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Azabicyclo[3.2.0]heptan-7-ones (carbapenams) from pyrrole
Thomas L. Gilchrist,* Américo Lemos and Carol J. Ottaway
Chemistry Department, University of Liverpool, Liverpool, UK L69 2YZ
The azabicyclo[3.2.0]heptan-7-ones 4, 10, 16 and 24 have been prepared from pyrrole. The same general
approach has been used for all these derivatives; namely, substitution of pyrrole at the 2- and 5-carbon
atoms, catalytic hydrogenation to produce pyrrolidine-2-acetic acid derivatives, and cyclisation
using tris(1,3-dihydro-2-oxobenzoxazol-3-yl)phosphine oxide 6. The catalytic hydrogenation of
2
,5-disubstituted pyrroles gives only the corresponding cis-2,5-disubstituted pyrrolidines. The
hydrogenation proceeds more easily when the nitrogen atom bears a tert-butoxycarbonyl substituent.
The N-tert-butoxycarbonylpyrroles 8 and 21 bearing an á-substituent in the acetate side chain were
hydrogenated with a high degree of facial stereoselectivity. This allowed the 6-phthalimidoazabicyclo-
[
3.2.0]heptan-7-one 24 to be isolated as a single diastereoisomer. The X-ray crystal structure of a
precursor, the triester, 22a, has been obtained.
1
The aim of this work was to explore the possibility of preparing
new azabicyclo[3.2.0]heptan-7-one (carbapenam) derivatives
starting from pyrrole. Pyrrole is known to undergo a wide range
of high yielding and predictable electrophilic substitution reac-
tions and the intention was to exploit this reactivity to intro-
duce a range of substituents on to the five membered ring.
The carbapenam ring system could then be constructed by
reduction followed by a cyclodehydration of an appropriate
side chain carboxylic acid. This general approach is outlined
in Scheme 1.
ent at C-5 (R = H, CO Me) but unsubstituted at C-3 and C-4
2
2
3
(R = R = H). Pyrroles have been prepared in which hydrogen,
methyl and phthalimido groups have been present as the side
chain substituent R .
The carbapenam 4 was prepared by the route shown in
4
Scheme 2. Pyrrole was first converted into tert-butyl pyrrole-2-
i
CO2But
CO2But
76%
2
MeO C
N
H
N
H
R2
R3
R2
R3
1
2
CO2H
R1
CO2H
ii 65%
R1
N
H
N
H
N
H
R4
R4
H
iii
3%
CO2H
2
5
+
N
H2
MeO2C
MeO2C
CF3CO2–
N
6
2
R2
R3
O
4
3
H
R1
Scheme 2 Reagents and conditions: i, (CCl
MeOH, room temp.; ii, H (13.5 atm), Rh–Al O , TFA, room temp.; iii,
CO) CO, 110 ЊC, then
3 2
N
R4
2
2
3
6
, NEt , MeCN, 80 ЊC
3
O
Scheme 1
acetate 1. Three methods were investigated for carrying out this
reaction. tert-Butyl diazoacetate and pyrrole gave the ester 1 in
7
The sequence has been used once before, to prepare the
parent azabicyclo[3.2.0]heptan-7-one. Ethyl pyrrole-2-acetate
moderate yield (52%) when heated together at 80 ЊC in the pres-
ence of copper bronze. However, the reaction mixture became
dark and viscous and the ester 1 showed a tendency to
decompose when it was being isolated by vacuum distillation.
1
was prepared from pyrrole and ethyl diazoacetate. The ester
was converted into the corresponding pyrrolidine by catalytic
hydrogenation and the azetidinone was obtained from this in
unspecified yield. There are several other literature examples of
the preparation of the ring system by cyclisation of pyrrolidine-
8
The method of Baciocchi et al., involving the substitution of
pyrrole by alkoxycarbonylmethyl radicals generated from alkyl
iodoacetates, was also investigated. tert-Butyl iodoacetate (pre-
pared from tert-butyl bromoacetate and sodium iodide) was
stirred with a large excess of pyrrole in aqueous DMSO in the
presence of iron() sulfate and hydrogen peroxide. The pyrrole
had to be removed by distillation and, even when pyrrole was
used in large excess, some 2,5-disubstitution occurred. The best
method proved to be that recently described by Schloemer et al.
by which the ester 1 is produced from N-pyrrolylmagnesium
2
-acetic acids. These syntheses start from glutamic acid deriv-
2,3 4
atives or from proline and can thus be directed to producing
chiral non-racemic products.
The stereochemistry of products obtained by the route out-
lined in Scheme 1 will be determined in the reduction step.
Pyrroles can be catalytically hydrogenated to pyrrolidines and
literature precedents indicate that this leads to cis substituted
5,6
9
products. From the literature examples there was no indi-
cation whether any control could be exercised over substituents
chloride and tert-butyl bromoacetate. This gave the ester 1
cleanly and in good yield. The diester 2 was prepared from this
in 76% yield by reaction with triphosgene and methanol. A
minor by-product, the N-methoxycarbonylpyrrole 5, was
removed by column chromatography.
4
located in a side chain (e.g. R in Scheme 1). The experiments
reported here have been confined to pyrrole-2-acetic acid
derivatives bearing a hydrogen or a methoxycarbonyl substitu-
J. Chem. Soc., Perkin Trans. 1, 1997
3005

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O
i
CO2Et
CO2Et
N
N
O
N
P
O
80%
CO2But
t
Me
CO2But
Bu O2C
N
CO2Me
8
7
3
5
6
ii
70%
The catalytic hydrogenation of the diester 2 could be
achieved only in an acidic medium. The reaction was carried
6
out over a rhodium catalyst and under a pressure of hydrogen
H Me
H
of 13 atm. There was no reaction in ethanol containing a small
amount of acetic acid and the reduction took place slowly in
neat acetic acid as solvent. The hydrogenation was much more
rapid in trifluoroacetic acid and this had the advantage of
hydrolysing the tert-butyl ester at the same time. The pyrroli-
dine monoester was isolated as its trifluoroacetate salt 3 in 65%
yield after recrystallisation; there was no evidence (by NMR)
of the presence of another isomer in the crude reaction
mixture.
5
H
N
H
Me
N
6
CO2Et
t
Bu O2C
iii, iv
O
9a
10a
H H
H
5
+
Me
+
N
Me
N
6
CO2Et
H
t
Bu O2C
O
Tris (1,3-dihydro-2-oxobenzoxazolin-3-yl)phosphine oxide 6
was used to bring about the cyclisation of the amino acid 3.
This and some closely related phosphine oxides were first
9
b
10b
Scheme 3 Reagents and conditions: i, KHMDS then MeI, Ϫ78 ЊC; ii,
H (13.5 atm), Rh–Al O , TFA, room temp.; iii, HCl, room temp.; iv, 6,
10
described by Kunieda and co-workers and were shown to be
effective reagents for the cyclisation of β-amino acids to β-
lactams. In particular, they were superior to some other com-
monly used dehydrating agents for the preparation of bicyclic
β-lactams. The reagent 6 is a crystalline solid that is easily pre-
pared from inexpensive starting materials. The azetidinone 4
was isolated in 23% yield as a colourless oil. The relative
2
2
3
NEt , MeCN, 80 ЊC
3
CO2Et
Me
N
H
t
CO2Bu
1
stereochemistry at C-2 and C-6 was established from the H
NMR spectrum, which is closely similar to that of the corres-
ponding p-nitrobenzoate ester reported by Bycroft et al. The
11
H2
signal for H-2† appears near δ 3.9 in these two esters but at δ
Fig. 1 A conformation of the diester 8 that will lead to preferential
formation of the pyrrolidine 9a
3
4
.42 in the epimeric ester in which H-2 and H-5 are trans. The
ester 4 was previously reported only as a mixture with its epi-
12
mer. This route produced the azetidinone ester 4 as a racem-
ate but the catalytic hydrogenation step is stereoselective. The
next objective was to determine whether the method could be
adapted to the preparation of azabicyclo[3.2.0]heptan-7-ones
bearing a substituent at C-6 with any degree of control of
stereochemistry. In order to explore this possibility the 6-
methyl derivatives 10a and 10b were prepared by the route
shown in Scheme 3. Ethyl pyrrole-2-acetate was first protected
on nitrogen by reaction with di-tert-butyl dicarbonate and 4-
dimethylaminopyridine (DMAP). The diester 7 was then
methylated in the side chain in good yield by reaction with
potassium hexamethyldisilazide (KHMDS) and iodomethane
and the resulting diester 8 was hydrogenated over rhodium in
ethanol containing acetic acid. The hydrogenation of the ester
1
mass spectrum and the H NMR spectrum of the mixture. A
decoupling experiment allowed the H-5 to H-6 coupling con-
stant of the major isomer to be determined. The value of 5.2
Hz indicates a cis arrangement of the two hydrogens and thus
the structure 10a for the major isomer. Hence, the major prod-
uct of hydrogenation of the pyrrole diester 8 is the pyrrolidine
a. The selectivity of the hydrogenation is consistent with a
reduction that takes place through a conformation of the ester
in which the methyl group of the side chain lies in the same
plane as the pyrrole ring. Hydrogenation would then take place
preferentially from the less hindered face (Fig. 1). Molecular
modelling calculations carried out on analogous indole
diesters, which show the same facial selectivity when hydrogen-
ated, indicate that this is likely to be a minimum energy
9
8
8
was easier than that of the ester 2 because of the activating
13
conformation.
effect of the 1-tert-butoxycarbonyl substituent, as Kaiser and
An analogous route to the azetidinone esters 16a and 16b was
devised, starting from the pyrrole diester 2. All our attempts to
introduce the Boc protecting group cleanly were unsuccessful.
There was a competitive substitution of the side chain methy-
lene group and, with one equivalent of di-tert-butyl dicarbo-
nate, a mixture of the starting ester 2, the required triester 12
and the tetraester 11 was produced. The triester 12 was
unchanged when treated with more di-tert-butyl dicarbonate
and so it is not an intermediate in the formation of the tetra-
ester 11. A mixture of 11 and 12 was methylated and from the
resulting reaction mixture the tetraester 13 was isolated in low
yield (Scheme 4). When this was treated with TFA at room
temperature the α-methylpyrrole-2-acetic acid 14 was formed;
this was isolated in good yield as a crystalline solid.
6
Muchowski found. The product of the hydrogenation was a
mixture of the pyrrolidine diesters 9a and 9b. The hydrogen-
ation proceeded with a surprisingly high degree of diastereo-
selectivity. The ratio of the two esters was estimated as 8:1 from
the NMR spectrum of the mixture, but it was not possible at
this stage to determine which was the major component. The
mixture was hydrolysed, and the protecting group removed, by
reaction with hydrochloric acid and the resulting mixture of
amino acids was cyclised to the azetidinones 10a and 10b by
using the phosphine oxide 6. The mixture of azetidinones
could not be isolated completely free from dihydrobenzoxa-
zolone, a contaminant derived from the cyclising agent, by col-
umn chromatography. The two isomers were identified from the
The ester 14 was hydrogenated in TFA and the trifluoro-
acetate salts 15a and 15b were isolated. In this case the hydro-
genation was unselective, the ratio of 15a to 15b being 1:1.
Evidently the tert-butoxycarbonyl substituent on nitrogen is
†
The numbering system is based on systematic nomenclature and dif-
fers from that often used in the literature for carbapenems and related
compounds.
3
006
J. Chem. Soc., Perkin Trans. 1, 1997

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CO2But
MeO2C
CO2But
N
H
N
ii
H
iii
O
2
32%
17
76%
i
CO2But
6
4%
N
N
i
H
H
NOH
1
8
CO2But
CO2But
CO2But
MeO2C
+
MeO2C
N
N
iv 85%
CO2But
CO2But
t
CO2But
1
1
2
CO Bu
1
2
MeO2C
N
H
N
v
H
N
65%
N
ii 30%
O
O
O
O
CO2But
CO2But
iii
CO2H
MeO2C
Bu O2C
MeO C
2
20
N
87%
N
H
19
t
Me
Me
1
3
14
vi 98%
O
iv 87%
H
N
H
CO2But
MeO2C
Bu O2C
N
O
MeO2C
t
N
O
t
CO2Bu
N
H Me
t
H
Bu O C
2
22a
5
+
H
MeO2C
MeO2C
O
vii
N
H
Me
N
H2
6
+
CO2H
86%
CF3CO2–
O
O
21
H H
v
1
5a
1
6a
N
MeO2C
N
Bu O2C
3
1%
t
+
+
2
CO Bu
t
O
H H
H
22b
5
Me
+
N
H2
MeO2C
MeO2C
CF3CO2–
N
Me
H
6
CO2H
viii 84%
O
1
6b
15b
H
O
t
2
5
ix
O
H
Scheme 4 Reagents and conditions: i, (Bu O C) O, DMAP, room
temp.; ii, KHMDS then MeI, Ϫ78 ЊC; iii, TFA, room temp.; iv, H (13.5
atm), Rh–Al O , TFA, room temp.; v, 6, NEt , MeCN, 80 ЊC
2
MeO C
2
2
H
N
N
6
32%
2
N
H
+
2
3
3
MeO C
2
N
O
O
H2
O
CO2H
important in enforcing a conformational preference on the pyr-
CF3CO2–
role for the hydrogenation step. The mixture of salts 15a and
2
4
2
3
1
1
5b was cyclised, as before, to give the corresponding β-lactams
6a and 16b (1:1) in 31% yield. The mixture was not separated
Scheme 5 Reagents and conditions: i, 25a, Na CO , room temp.; ii,
2
3
t
ϩ
Ϫ
(
8
COCl) , pyridine, Ϫ78 ЊC then Bu OH; iii, HONH Cl , pyridine,
2
3
but it was possible to assign signals corresponding to each iso-
mer in the NMR spectrum.
0 ЊC; iv, Al–Hg then N-ethoxycarbonylphthalimide, NEt , room
3
temp.; v, (Cl CO) CO, 110 ЊC, then MeOH, room temp.; vi,
Bu O C) O, DMAP, room temp.; vii, H (13.5 atm), Pt᎐C, room temp.;
3
2
An alternative approach to 6-substituted azabicyclo-
t
(
2
2
2
[
3.2.0]heptan-7-ones of this type is to replace the acetate side
viii, TFA, room temp.; ix, 6, NEt, MeCN, 80 ЊC
chain with one containing an appropriate functional group in
the first step of the reaction sequence. This approach was
adopted in order to prepare derivatives bearing a protected
amino group (Scheme 5). Pyrrole was first converted into the
hydroxyimino ester 18. This reaction was achieved in one step
by using the chlorooxime 25a as an electrophile; we have pre-
viously reported an analogous reaction with the corresponding
Cl
CO2But
MeO C
2
NOH
O
N
N
RO2C
t
Bu O2C
O
5a R = But
2
2
5b R = Et
14
ethyl ester 25b. The chlorooxime 25a, which is a new com-
pound, was prepared from tert-butyl glycine. A method of
preparation of the oxime 18 that proved to be easier to scale up
was a two step sequence by way of the oxo ester 17. This ester
was prepared in modest yield from pyrrole, oxalyl chloride and
tert-butyl alcohol.
2
6
phthalimide 19. The remaining steps of the reaction sequence
are analogous to those in Scheme 3. The methoxycarbonyl
group was introduced at C-5 using triphosgene and the pyrrole
nitrogen of the diester 20 was protected (in this case without
complications) as its tert-butoxycarbonyl derivative 21. When
this compound was hydrogenated over rhodium the only prod-
The oxime 18 was reduced to the corresponding amine using
aluminium amalgam and this was directly converted into the
J. Chem. Soc., Perkin Trans. 1, 1997
3007

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uct detected was a tetrahydro derivative 26 in which the benzene
ring has been reduced in preference to the pyrrole ring. In con-
trast, hydrogenation over platinum took place selectively at the
pyrrole ring. A 4:1 mixture of isomers 22a and 22b was
obtained, from which the major component 22a was isolated in
quenched with saturated aqueous ammonium chloride. The
organic layer was separated and the aqueous layer was washed
with ether. The combined organic extracts were washed with
aqueous saturated ammonium chloride, dried (MgSO ) and
4
evaporated to a dark oil. The excess of pyrrole was removed by
distillation. The product was distilled at 125 ЊC and 0.05 mmHg
to yield tert-butyl pyrrole-2-acetate 1 as a yellow oil (1.24 g,
6
2% yield. An X-ray crystal structure of the triester 22a was
obtained and this clearly established the relative stereo-
chemistry at C-α, C-2 and C-5.‡ The hydrogenation of the
diester 21 thus shows the same facial stereoselectivity as that of
the diester 8. The presence of the tert-butoxycarbonyl substitu-
ent on nitrogen is apparently more important in determining
this selectivity than the nature of the substituent in the side
chain. The diester was hydrolysed with TFA to give the tri-
fluoroacetate salt 23. This was cyclised to the azetidinone 24,
which was isolated in 32% yield as a crystalline solid. Its struc-
ϩ
68%) (Found: M , 181.110. Calc. for C H NO : M, 181.110);
1
0
15
2
Ϫ1
νmax(film)/cm 3388, 1720, 1369, 1148 and 717; δ (400 MHz)
H
1.46 (9 H, s), 3.58 (2 H, s), 5.99 (1 H, m, H-3), 6.14 (1 H, m,
H-4), 6.74 (1 H, m, H-5) and 8.76 (1 H, br s, NH).
tert-Butyl 5-methoxycarbonylpyrrole-2-acetate 2
Triphosgene (1.64 g, 5.5 mmol) was added to a solution of tert-
butyl pyrrole-2-acetate 1 (1.00 g, 5.5 mmol) in dry toluene
(50 ml). The solution was heated under reflux for 1.5 h. The
solution was allowed to cool, then dry methanol (20 ml) was
added and the solution was stirred at room temp. for a further
1.5 h. After this time an excess of triethylamine (5.0 ml) was
added and the solution was stirred for 15 min. The solvent was
removed, ether was added and the solid residue was filtered off.
The ether fractions were decolourised with charcoal then evap-
orated to leave a red crystalline solid. Column chromatography
(1:2 ether–light petroleum, bp 40–60 ЊC) gave the diester 2 (1.0
g, 76%) as a colourless solid, mp 75 ЊC (Found: C, 60.6; H, 7.3;
N, 5.65. C H NO requires C, 60.2; H, 7.2; N, 5.85%);
1
ture was established from the H NMR spectrum. The coupling
constant of 5.2 Hz between H-5 and H-6 is consistent with a cis
relationship of the two hydrogens. The signal for H-6 is also
coupled to H-2 (J 1.0 Hz). This long range coupling and the
chemical shift of the signal for H-2 (4.1 ppm) are indicative of
the all cis structure 24.
In summary, the methodology is quite flexible in terms of the
types of substituent that can be incorporated into the final
products. It could probably be extended to pyrroles containing
additional substituents at the 3- and 4-positions of the pyrrole
ring. The predictable cis hydrogenation of pyrroles, together
with the unexpected diastereoselectivity observed in the hydro-
genation of the N-tert-butoxycarbonylpyrroles, allows some
degree of stereochemical control in the formation of the aze-
tidinones. The yields of azetidinones are moderate, probably
because of incomplete conversion of the amino acids, but
longer reaction times did not result in an increase in the yields.
12
17
Ϫ1
4
νmax(Nujol)/cm 3270, 1731, 1687, 1286, 1121, 1002 and 770;
δ (200 MHz) 1.48 (9 H, s), 3.60 (2 H, s, CH CO), 3.84 (3 H, s),
H
2
6.03 (1 H, dd, J2,3 2.7, J3,4 3.8, H-3), 6.83 (1 H, dd, J 2.7, J3,4
1,4
ϩ
3.8, H-4) and 9.54 (1 H, br s, NH); m/z 239 (M , 19%), 183 (37),
138 (100), 106 (51) and 57 (62).
A by-product that was isolated as an oil in low yield by col-
umn chromatography was tentatively identified as the diester 5,
Ϫ1
νmax(film)/cm 1742, 1442, 1333, 1156 and 721; δ (200 MHz)
H
Experimental
1
.45 (9 H, s, CMe ), 3.78 (2 H, s, CH CO), 3.90 (3 H, s, Me),
3
2
General
6.08–6.15 (2 H, m, H-3 and H-4) and 7.25 (1 H, m, H-5); m/z
239 (M , 7%), 138 (84) and 57 (100).
1
ϩ
H NMR spectra were recorded either on a Bruker AC 200
(
200 MHz) or on a Bruker AMX 400 (400 MHz) spectrometer.
5
-Methoxycarbonylpyrrolidinium-2-acetic acid trifluoroacetate 3
Multiplicities are recorded as broad peaks (br), singlets (s),
doublets (d), triplets (t), quartets (q) and multiplets (m). J
Values are in Hz. Infrared spectra were recorded either on a
Perkin-Elmer 298 or on a Perkin-Elmer 1720-X FTIR spec-
trometer. Solid samples were run as KBr discs unless indicated
otherwise, and liquids as thin films. Mass spectra were recorded
on a VG micromass 7070E as electron impact or chemical ion-
isation spectra. Microanalyses were performed in the Uni-
versity of Liverpool Microanalysis Laboratory. Melting points
The diester 2 (1.67 g, 7.0 mmol) was placed in a hydrogenation
bomb with rhodium on alumina (0.20 g) and trifluoroacetic
acid (4 ml). The bomb was pressurised to 13.5 atm and the
contents were stirred vigorously for 12 h. A further portion
(
0.10 g) of catalyst was added, the bomb was repressurised and
the contents stirred for 12 h. The catalyst was filtered off and
the filtrate was evaporated to leave the salt 3 as an oil which
crystallised on standing. Recrystallisation gave the salt 3 (1.37
g, 65%), mp 108 ЊC (from dichloromethane–ether) (Found: C,
(
mp) were determined on a Kofler block. Flash column chro-
3
4
7
2
9.3; H, 4.7; N, 4.4. C H F NO requires C, 39.7; H, 5.0; N,
10 14 3 6
Ϫ1
matography was carried out using Mackerey Nagel MN-
Kieselgel 60 and hand bellows or an air line to supply the
pressure to the column. Thin layer chromatography (TLC) was
carried out on Merck 10 × 2 cm aluminium-backed plates with
a 0.2 mm layer of Kieselgel 60 F254. Ether refers to diethyl
ether.
.6%); νmax(Nujol)/cm 2923, 1729, 1706, 1332, 1197, 797 and
20; δ (TFA with C D capillary; 400 MHz) 2.00 (1 H, m, H-4),
H
6
6
.52 (2 H, m, H-3 and H-3Ј), 2.71 (1 H, m, H-4Ј), 3.24 (2 H, m,
CH CO), 4.04 (3 H, s, Me), 4.34 (1 H, unresolved m, H-2), 4.82
(1 H, m, H-5), 7.78 (2 H, br s, NH) and 8.47 (1 H, br s, OH); m/z
2
ϩ
(
FAB) 188 (M , 100%) and 128 (49).
8
tert-Butyl pyrrole-2-acetate 1
Methyl 7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxylate 4
A solution of the salt 3 (0.40 g, 1.3 mmol), the phosphine oxide
6
Methylmagnesium chloride (13.90 ml, 41.8 mmol; 3.0  in
THF) was added dropwise by means of a cannula over 15 min
to a stirred solution of pyrrole (2.97 g, 44.3 mmol) in dry THF
(0.59 g, 1.3 mmol) and triethylamine (0.63 ml, 0.46 g, 4.5
mmol) in dry acetonitrile (50 ml) was heated under reflux under
nitrogen for 6 h. The solution was evaporated to a solid, then
subjected to column chromatography (ether) under nitrogen.
The faster running fractions yielded benzoxazolinone, while the
(
66 ml) at Ϫ20 ЊC. The solution was stirred at Ϫ20 ЊC for 30
min, then at room temp. for 30 min. The pale green solution was
cooled to Ϫ10 ЊC then tert-butyl bromoacetate (1.95 g, 1.6 ml,
1
0 mmol) was added rapidly and the solution was stirred and
lower fractions gave the azetidinone 4 as a colourless oil (0.05 g,
allowed to reach room temp. over 2 h. The reaction mixture was
ϩ
2
3%) (Found: M , 169.074. C H NO requires M, 169.074);
8
11
3
δH(200 MHz) 1.71–1.91 (1 H, m, H-4Ј), 2.08–2.43 (3 H, m, H-3,
H-3Ј and H-4), 2.78 (1 H, dd, J6,6Ј 15.9, J5,6Ј 2.7, H-6Ј), 3.12 (1
‡
Atomic coordinates, thermal parameters and bond lengths and angles
have been deposited at the Cambridge Crystallographic Data Centre
CCDC). See Instructions for Authors, J. Chem. Soc., Perkin Trans. 1,
997, Issue 1. Any request to the CCDC for this material should quote
the full literature citation and the reference number 207/136.
H, ddd, J6,6Ј 15.9, J5,6 4.9, J2,6 1.6, H-6), 3.65–3.76 (1 H, m, H-5),
(
1
ϩ
3
.77 (3 H, s, Me) and 3.90 (1 H, m, H-2); m/z 169 (M , 37%),
141 (66), 110 (100) and 68 (38).
3
008
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
ϩ
Tris(2,3-dihydro-2-oxobenzoxazol-3-yl)phosphine oxide 6
Phosphorus oxychloride (1.15 ml, 1.89 g, 12.3 mmol) was
added under nitrogen to a solution of 2,3-dihydrobenzoxazol-
4.11 (2 H, 2 × q, J 7.1, CH CH ); m/z 271 (M , 0.5%), 170 (18),
114 (59), 70 (100) and 57 (67).
2
3
2
-one (5.0 g, 37 mmol) in dry dichloromethane (50 ml) at 0 ЊC.
6-Methyl-1-azabicyclo[3.2.0]heptan-7-ones 10a and 10b
Triethylamine (5.57 ml, 4.05 g, 40 mmol) was then added drop-
wise and the mixture was stirred at 0 ЊC for 1 h, then at room
temp. for 12 h. The solid was filtered off and washed well with
dichloromethane. The dichloromethane layers were combined
and evaporated to leave an off-white solid. This material was
purified by column chromatography (dichloromethane) under
nitrogen, and a colourless solid was isolated (4.0 g, 72%), mp
Conc. hydrochloric acid (10.0 ml) was added to the esters 9
(0.30 g, 1.1 mmol). The solution was stirred at room temp. for
1 h then diluted with water and stirred for a further 12 h. The
solution was evaporated to leave the corresponding carboxylic
acid hydrochlorides as a red oil (0.17 g, 86%); δ (200 MHz,
H
D O) 1.29 (0.3 H, d, J 7.3), 1.32 (2.7 H, d, J 7.3), 1.65–1.85
2
(1 H, m, H-3), 1.93–2.10 (2 H, m, H-4 and H-4Ј), 2.19–2.34
(1 H, m, H-3Ј), 2.90 (1 H, m), 3.5 (2 H, m, H-5 and H-5Ј) and
10
2
50 ЊC (lit., mp 252 ЊC) (Found: C, 56.15; H, 2.7; N, 9.3. Calc.
Ϫ1
ϩ
for C H N O P: C, 56.1; H, 2.7; N, 9.35%); νmax/cm 1804,
3.68–3.80 (1 H, m, H-2Ј); m/z (FAB) 144 (M , 100%), 98 (16)
21
12
3
7
1
478, 1251, 1132, 967 and 755; δ (200 MHz) 7.20–7.30 (9 H, m)
and 70 (53).
H
ϩ
and 7.68–7.73 (3 H, m); m/z 449 (M , 21%), 315 (100), 134
63.84) and 106 (48).
A solution of the hydrochlorides (0.30 g, 1.68 mmol) and
tris(1,3-dihydro-2-oxo-benzoxazol-3-yl)phosphine oxide 6 (0.76
g, 1.68 mmol) in dry acetonitrile (100 ml) was heated under
reflux with triethylamine (0.60 g, 0.80 ml, 6.00 mmol) for 6 h.
The solution was allowed to cool then evaporated to leave a
crystalline solid. Column chromatography under nitrogen (3:2
dichloromethane–ethyl acetate) yielded a solid which NMR
showed to be a mixture of the β-lactams 10a and 10b and dihyd-
(
Ethyl 1-tert-butoxycarbonylpyrrole-2-acetate 7
To a solution of ethyl pyrrole-2-acetate (2.00 g, 13 mmol) in
dichloromethane (100 ml) was added DMAP (1.59 g, 13 mmol)
followed by di-tert-butyl dicarbonate (4.19 g, 19.2 mmol). The
solution was stirred at room temp. for 3 h, when TLC showed
that all of the starting material had reacted. The solution was
evaporated to leave a yellow solid. After column chromatog-
raphy (dichloromethane) the diester 7 was isolated as a yellow
oil (3.20 g, 97%) (Found: C, 61.5; H, 7.7; N, 5.8. C H NO
ϩ
robenzoxazolone (Found: M , 125.084. C H NO requires M,
7
11
125.084); δ (200 MHz) 0.82 (1 H, m, H-4), 1.09 (2.6 H, d, J 7.4,
H
CHMe of 10a), 1.36 (0.4 H, d, J 7.4, CHMe of 10b), 1.78–1.90
(1 H, m, H-4Ј), 1.90–2.08 (2 H, m, H-3 and H-3Ј), 2.73–2.86 (1
H, m, H-2), 3.33–3.46 (1 H, m, H-6), 3.46–3.58 (1 H, m, H-2Ј)
1
3
19
4
Ϫ1
requires C, 61.6; H, 7.6; N, 5.5%); νmax(film)/cm 1740, 1319,
ϩ
1
180, 1128 and 728; δ (200 MHz) 1.30 (3 H, t, J 7.15, CH CH ),
and 3.69–3.79 (1 H, m, H-5); m/z 125 (M , 25%), 67 (100) and
H
2
3
1
.62 (9 H, s, CMe ), 3.91 (2 H, s), 4.16–4.33 (2 H, q, J 7.15,
41 (41).
3
CH CH ), 6.12–6.17 (2 H, m, H-3 and H-4 of pyrrole) and 7.28–
2
3
ϩ
7
2
.30 (1 H, m, H-5 of pyrrole); m/z (CI) 271 (M ϩ NH , 10%),
tert-Butyl 1-tert-butoxycarbonyl-5-methoxycarbonylpyrrole-2-
acetate 12 and di-tert-butyl 1-tert-butoxycarbonyl-5-methoxy-
carbonylpyrrole-2-malonate 11
4
54 (21), 168 (100), 154 (100), 136 (60) and 68 (77).
Ethyl 1-tert-butoxycarbonyl-á-methylpyrrole-2-acetate 8
To a solution of the pyrrole diester 2 (4.50 g, 18.8 mmol) in
dichloromethane (100 ml) at room temp. was added DMAP
(2.48 g, 20.3 mmol) and di-tert-butyl dicarbonate (6.50 g, 29.8
mmol). After 3 h the solvent was removed. Column chrom-
atography of the residue (ether–light petroleum 1:2) gave an oil
The ester 7 (1.00 g, 4 mmol) in dry THF (2 ml) was cooled to
Ϫ78 ЊC under nitrogen. A solution of potassium bis(trimethyl-
silyl)amide (12 ml, 6 mmol, 1.5 equiv.; 0.5  in toluene) and dry
THF (2 ml) was added dropwise. The solution became deep red.
After 1 h iodomethane (0.45 ml, 0.85 g, 8 mmol) in dry THF (3
ml) was added dropwise at Ϫ78 ЊC. An exothermic reaction
occurred. The mixture was stirred for 1.5 h then quenched with
saturated aqueous ammonium chloride. The solution was
extracted with ether (3 × 20 ml), then the combined ether layers
ϩ
(1.95 g) that crystallised on standing, m/z 339 (M of 12, 0.2%),
239 (5), 138 (51) and 57 (100). The solid was a mixture of the
esters 12 and 11 by NMR. 12: δ (200 MHz) 1.44 (9 H, s, CMe ),
H
3
1.55 (9 H, s, CMe ), 3.80 (2 H, s, CH CO), 3.82 (3 H, s, MeO),
3
2
6.02 (1 H, d, J 3.8, H-3) and 6.78 (1 H, m, H-4). 11: δ (200
H
were washed with brine and water, dried (MgSO ) and evapor-
MHz) 1.48 (18 H, s, 2 × CMe ), 1.57 (9 H, s, CMe ), 3.82 (3 H, s,
4
3
3
ated to a red oil. Column chromatography (dichloromethane)
MeO), 5.07 (1 H, s, α-CH), 6.19 (1 H, d, J 2.8, H-3) and 6.78
yielded the ester 8 as an oil (0.85 g, 80%) (Found: C, 63.0; H,
(1 H, m, H-4).
8
.0; N, 5.6. C H NO requires C, 62.9; H, 7.9; N, 5.2%);
14 21 4
Ϫ1
νmax(film)/cm 1738, 1331, 1178, 1132 and 724; δ (200 MHz)
Di-tert-butyl 1-tert-butoxycarbonyl-5-methoxycarbonyl-á-
methylpyrrole-2-malonate 13
H
1
.22 (3 H, t, J 7.1, CH CH ), 1.55 (12 H, br s, CMe and
2
3
3
CHMe), 4.14 (2 H, q, J 7.1, CH CH ), 4.24 (1 H, q, J 7.7,
CHMe), 6.10–6.13 (2 H, m, H-3 and H-4) and 7.21–7.26 (1 H,
m, H-5); m/z 267 (M , 0.3%), 167 (20), 94 (100) and 57 (91).
A solution of the esters 12 and 11 (1.63 g) in dry THF (50 ml)
was cooled to Ϫ78 ЊC under nitrogen. A solution of KHMDS
(14.4 ml of 0.5  solution in toluene, 7.2 mmol) in dry THF (10
ml) was added dropwise. The solution gradually became deep
red. After 30 min freshly distilled iodomethane (2 ml, 4.56 g, 32
mmol) was added dropwise. The solution was stirred at Ϫ78 ЊC
for 1 h then allowed to warm to room temp. during 1 h. Satur-
ated aqueous ammonium chloride was added and the product
was extracted with ether (3 × 40 ml). Column chromatography
(ether–light petroleum 2:1) yielded the ester 13 (0.50 g) as a pale
yellow crystalline solid, mp 124–126 ЊC (from hexane) (Found:
C, 60.8; H, 7.8; N, 3.1. C H NO requires C, 60.9; H, 7.8; N,
2
3
ϩ
Ethyl 1-tert-butoxycarbonyl-á-methylpyrrolidine-2-acetate 9a
and 9b
Rhodium on alumina catalyst (0.02 g; 5% by weight) was added
to a solution of pyrrole ester 8 (0.27 g, 1 mmol) in ethanol (5.0
ml) and acetic acid (1.0 ml) in a 25 ml pressure hydrogenation
apparatus. The bomb was pressurised to 13.5 atm and the con-
tents were stirred for 12 h. The catalyst was filtered off and the
filtrate was evaporated to a small volume. Ether (5.0 ml) was
added and the solution was stirred with solid sodium carbonate
for 1 h. The mixture was filtered and the filtrate was evaporated
23
35
8
Ϫ1
3.1%); νmax/cm 1764, 1732, 1368, 1230, 1160, 844 and 756;
δ (200 MHz) 1.48 (18 H, s, 2 × CMe ), 1.53 (9 H, s, CMe ), 1.89
H
3
3
ϩ
to leave 9a and 9b as a yellow oil (0.19 g, 70%) (Found: M ,
(3 H, s, Me), 3.81 (3 H, s, MeO), 5.94 (1 H, d, J 3.85, H-3) and
Ϫ1
ϩ
2
71.179. C H NO requires M, 271.178); νmax(film)/cm 1729,
6.72 (1 H, d, J 3.85, H-4); m/z 453 (M , 0.3%), 353 (6), 252 (52),
14
25
4
1
693, 1169 and 773; δ (200 MHz) 1.03 (0.3 H, d, J 7.15, CHMe
196 (100), 138 (48) and 57 (100).
H
of 9b), 1.13 (2.7 H, d, J 7.1, CHMe of 9a), 1.25 (3 H, 2 × t, J
7
.1, CH CH ), 1.48 (9 H), 1.70–2.0 (4 H, m, H-3, H-3Ј, H-4 and
5-Methoxycarbonyl-á-methylpyrrole-2-acetic acid 14
2
3
H-4Ј), 3.13–3.25 (2 H, m, H-5 and H-5Ј), 3.40–3.53 (1 H,
unresolved m, CHMe), 3.90–4.00 (1 H, unresolved m, H-2) and
TFA (3 ml) was added dropwise to a solution of the malonate
ester 13 (0.525 g, 1.16 mmol) in dichloromethane (3 ml) at room
J. Chem. Soc., Perkin Trans. 1, 1997
3009

View Article Online
temp. After 2 h the solution was evaporated to leave a pale pink
oil which crystallised on standing (0.20 g, 87%), mp 114–116 ЊC
oration and water (50 ml) was added to the cooled residue. The
flask was cooled in an ice bath and stirred until the product
crystallised. The solid was filtered off then dissolved in ether
and washed with dilute hydrochloric acid until the washings
(
colourless crystals from dichloromethane–hexane) (Found:
ϩ
Ϫ
1
M , 197.069. C H NO requires M, 197.069); νmax(Nujol)/cm
9
11
4
3
297, 1674, 1457, 1215 and 768; δ (200 MHz) 1.58 (3 H, d, J
were neutral. The ether layer was dried (MgSO ) and evapor-
H
4
7
.7, CHMe), 3.82–3.90 (1 H, q, J 7.7, CHMe), 3.84 (3 H, s,
ated to dryness leaving the oxime 18 (4.1 g, 76%), mp 124 ЊC
(from dichloromethane–hexane) (Found: C, 57.1; H, 6.7; N,
13.4. C H N O requires C, 57.1; H, 6.7; N, 13.3%);
MeO), 6.13 (1 H, dd, J3,4 3.8, J1,3 2.7, H-3), 6.86 (1 H, dd, J3,4
.8, J1,4 2.7, H-4), 9.00 (1 H, br s, NH) and 10.25 (1 H, br s,
3
10
14
2
Ϫ1
3
ϩ
OH); m/z 197 (M , 36%), 152 (97), 138 (55), 120 (100), 106 (61),
νmax(Nujol)/cm 3382, 3169, 1715, 1271, 1107 and 996; δ (200
H
6
9 (65) and 57 (59).
MHz) 1.62 (9 H, s), 6.31–6.35 (1 H, m, H-4), 6.98–6.99 (1 H, m,
H-3), 7.29–7.31 (1 H, m, H-5) and 10.65 (1 H, br s, NH); m/z
ϩ
5
-Methoxycarbonyl-á-methylpyrrolidinium-2-acetic acid
210 (M , 6%), 154 (57), 106 (45), 93 (61), 92 (100) and 57 (54).
trifluoroacetates 15a and 15b
(ii) From the chlorooxime 25a. Pyrrole (14.70 ml, 212.0 mmol)
in dichloromethane (120 ml) with sodium carbonate (17.0 g,
170.0 mmol) and the chlorooxime 25a [(3.81 g, 21.2 mmol)
added in one portion] gave, after distillation of the excess of
pyrrole and recrystallisation of the solid residue, the oxime 18
(3.03 g, 64%).
A solution of the acid 14 (0.20 g, 1.02 mmol) in TFA (5 ml) was
placed in a hydrogenation bomb with rhodium on alumina cata-
lyst (0.20 g; 10% by weight). The bomb was pressurised to 13.5
atm and the contents were stirred vigorously for 12 h. A further
portion of catalyst (0.01 g) was added, the bomb was repressur-
ised and the contents were stirred for a further 12 h. The cata-
lyst was filtered off and the filtrate was evaporated to leave a
tert-Butyl á-phthalimidopyrrole-2-acetate 19
ϩ
colourless oil (0.28 g, 87%) (Found: M , 202.108. C H NO
The hydroxyimino ester 18 (5.1 g, 15.6 mmol) in aqueous tetra-
hydrofuran (1:10; 120 ml) was reduced by reaction with alu-
9
16
4
Ϫ1
requires M, 202.108); νmax/cm 3381, 1682, 1459, 1203 and 724;
δ (200 MHz; TFA with C D capilliary) 1.90 (3 H, 2 × d, J
14
minium amalgam prepared from aluminium foil. The reaction
was monitored by TLC until the starting material had been
consumed (1.5 h). The mixture was then filtered through Celite,
the filter pad washed well with tetrahydrofuran, and the com-
bined filtrate and washings were reduced in volume (to ca. 40–
50 ml). To the solution was added triethylamine (2.4 ml, 17.3
mmol) followed by N-ethoxycarbonylphthalimide (3.80 g, 17.3
mmol) and the mixture was stirred for 2.5 h. Then the solvent
was removed and the crude product was dissolved in dichloro-
methane. The solution was washed with water and brine, dried
over magnesium sulfate and concentrated. Flash chrom-
atography [dichloromethane–hexane (7.5:1)] of the residue
gave the ester 19 as a colourless solid (6.75 g, 85%), mp 128–
130 ЊC (from dichloromethane–hexane) (Found: C, 66.3; H, 5.6;
H
6
6
7
.15, CHMe of 15a and 15b), 2.20–2.52 (1 H, m, H-3Ј), 2.75–
2
.95 (2 H, m, H-4 and H-4Ј), 3.00–3.15 (1 H, m, H-3), 3.59–3.93
(
1 H, m, CHMe), 4.40 (3 H, s, MeO), 4.55–4.65 (1 H, m, H-2)
ϩ
and 5.10–5.25 (1 H, m, H-5); m/z (FAB) 202 (M , 100%), 128
72), 68 (35) and 57 (27).
(
Methyl 6-methyl-7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxy-
lates 16a and 16b
A solution of the salts 15a and 15b (0.28 g, 0.89 mmol), the
phosphine oxide 6 (0.39 g, 0.89 mmol) and triethylamine (0.43
ml, 0.31 g, 3.07 mmol) in dry acetonitrile (35 ml) was heated
under reflux under nitrogen for 6 h. The solvent was removed
and column chromatography (ether) of the residue gave a 1:1
ϩ
mixture (by NMR) of 16a and 16b as a colourless oil (0.05 g,
N, 8.6; M , 326.126. C H N O requires C, 66.25; H, 5.6; N,
18
18
2
Ϫ1
4
ϩ
3
1
1%) (Found: M , 183.090. C H NO requires M, 183.090); m/z
8.6%; M, 326.127); νmax/cm 1771, 1736, 1392, 1250, 1158,
9
13
3
ϩ
83 (M , 16%), 124 (36), 115 (41) and 40 (100). 15a: δ (200
1109 and 731; δ (400 MHz) 1.41 (9 H, s), 6.00 (1 H, s), 6.13 (1
H
H
MHz) 1.22 (3 H, d, J 7.7, CHMe), 1.75–2.39 (4 H, m, H-3, H-3Ј,
H-4 and H-4Ј), 3.30 (1 H, m, H-6), 3.74 (3 H, s, MeO), 3.75–3.84
H, dd, J 6.0 and 2.7, H-3), 6.26–6.28 (1 H, m, H-4), 6.79–6.81 (1
H, m, H-5), 7.70–7.75 (2 H, m), 7.84–7.88 (2 H, m) and 9.29 (1
ϩ
(
1 H, m, H-5) and 3.86–3.94 (1 H, m, H-2). 15b: δ (200 MHz)
H, br, NH); m/z 326 (M , 2%), 270 (10), 225 (100), 198 (13), 104
H
1
.34 (3 H, d, J 7.2, CHMe), 1.75–2.39 (4 H, m, H-3, H-3Ј, H-4
(13), 76 (14) and 57 (25).
and H-4Ј), 3.00 (1 H, dq, J5,6 2.2, J6-Me 7.2, H-6), 3.34–3.45 (1 H,
m, H-5), 3.75 (3 H, s, MeO) and 3.84–3.94 (1 H, m, H-2).
tert-Butyl 5-methoxycarbonyl-á-phthalimidopyrrole-2-acetate 20
To a solution of the pyrrole 19 (1.0 g, 3.06 mmol) in dry toluene
(25 ml) under nitrogen was added triphosgene (0.91 g, 3.06
mmol) and the solution was heated under reflux. The reaction
was monitored by direct phase HPLC [silica column, mobile
phase: dichloromethane–isopropyl alcohol (98:2), flux 1.25 ml
tert-Butyl á-oxopyrrole-2-acetate 17
Oxalyl chloride (3.6 ml, 5.24 g, 41 mmol) was added dropwise
under nitrogen to dichloromethane (200 ml) at Ϫ78 ЊC contain-
ing pyridine (3.00 ml, 2.94 g, 37 mmol), freshly distilled pyrrole
Ϫ1
(
2.95 ml, 3.05 g, 45.5 mmol) and sodium carbonate (10 g). The
min ] which showed the gradual disappearance of the starting
dark green reaction mixture was stored at Ϫ20 ЊC overnight.
tert-Butyl alcohol was added and the mixture was allowed to
reach room temperature, then heated under reflux for 1 h. The
sodium carbonate was filtered off and the solution was evap-
material. After 1.5 h the solution was cooled to room tempera-
ture and methanol (10 ml) was added. The mixture was stirred
for a further 1.5 h then triethylamine was added in slight excess.
Evaporation of the solvent followed by flash chromatography
[dichloromethane–ethyl acetate (20:1)] afforded the diester
20 (0.76 g, 65%), mp 127–128 ЊC (colourless prisms from
dichloromethane–hexane) (Found: C, 62.6; H, 5.2; N, 7.3; m/z
384.132. C H N O requires C, 62.5; H, 5.2; N, 7.3%; M,
orated to leave
dichloromethane–ethyl acetate (3:1)] gave a red crystalline
solid. Recrystallisation gave the pyrrole 17 (2.56 g, 32%), mp
a black oil. Column chromatography
[
7
6
4–78 ЊC (from dichloromethane–hexane) (Found: C, 61.9; H,
20
20
2
6
Ϫ1
.9; N, 7.1. C H NO requires C, 61.5; H, 6.7; N, 7.1%);
384.132); νmax(Nujol)/cm 3341, 1751, 1698, 1392, 1221 and
1
0
13
3
Ϫ1
νmax(Nujol)/cm 3391, 1731, 1632, 1250, 1056 and 777; δ (200
767; δ (400 MHz) 1.49 (9 H, s), 3.85 (3 H, s), 5.99 (1 H, s), 6.26
H
H
MHz) 1.66 (9 H, s), 6.31–6.38 (1 H, m, H-4), 7.14–7.21 (1 H, m,
(1 H, dd, J3,4 3.7, J3,1 2.5, H-3), 6.83 (1 H, d, J3,4 3.7, H-4), 7.74–
7.78 (2 H, m), 7.87–7.92 (2 H, m) and 9.96 (1 H, br s); m/z 384
(M , 1%), 328 (8), 310 (8), 283 (100), 251 (44), 104 (23) and 57
H-3), 7.29–7.35 (1 H, m, H-5) and 10.17 (1 H, br s, NH); m/z
ϩ
ϩ
1
95 (M , 3%), 94 (83) and 57 (100).
(
30).
tert-Butyl á-hydroxyiminopyrrole-2-acetate 18
i) From the oxo ester 17. A solution of the keto ester 17 (5.0
g, 25.6 mmol), hydroxylamine hydrochloride (5.0 g, 72 mmol)
and pyridine (5.0 ml, 4.9 g, 62 mmol) in ethanol (50 ml) was
heated under reflux for 1 h. The ethanol was removed by evap-
(
tert-Butyl 1-tert-butoxycarbonyl-5-methoxycarbonyl-á-phthal-
imidopyrrole-2-acetate 21
To a stirred solution of the diester 20 (1.72 g, 4.48 mmol) in dry
dichloromethane (30 ml) was added DMAP (0.55 g, 4.48
3
010
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
mmol) followed by di-tert-butyl dicarbonate (1.46 g, 6.72
mmol). After 45 min the reaction was complete (TLC). Evap-
oration of the solvent followed by flash chromatography
tert-Butyl chloro(hydroxyimino)acetate 25a
Glycine tert-butyl ester phosphite was prepared in two steps
from tert-butyl chloroacetate by the method described by
15
[
dichloromethane–hexane (20:1)] gave the triester 21 (2.13 g,
8%), mp 111–112 ЊC (colourless crystals from dichloro-
methane–hexane) (Found: C, 62.1; H, 5.8; N, 5.8. C H N O
Moore and Rydon. Glycine tert-butyl ester phosphite (26.2 g,
9
122 mmol) was dissolved in water (100 ml) and hydrochloric
Ϫ3
acid (density 1.19 g cm ; 10.2 ml, 122 mmol) was added. The
2
3
24
2
8
Ϫ1
requires C, 62.0; H, 5.8; N, 5.8%); νmax(Nujol)/cm 1777, 1751,
mixture was cooled to 5 ЊC and sodium nitrite (8.42 g, 122
mmol) in water (30 ml) was added dropwise, but rapidly. A
second equivalent of hydrochloric acid and a second equivalent
of sodium nitrite were added rapidly in the same manner and
then the reaction mixture was extracted with ether. The extracts
were dried over magnesium sulfate and concentrated to give a
pale-green oil which solidified on standing. Recrystallisation
gave the chlorooxime 25a as colourless crystals (9.62 g, 54%),
mp 90–91 ЊC (from dichloromethane–hexane) (Found: C, 40.3;
H, 5.6; N, 7.8. C H NO requires C, 40.5; H, 5.6; N. 7.8%);
1
1
6
7
3
387, 1328, 1230 and 1153; δ (400 MHz) 1.41 (9 H, s, 2-CMe ),
H
3
.57 (9 H, s, 1-CMe ), 3.81 (3 H, s), 6.13 (1 H, d, J 4.1, H-3),
3
.57 (1 H, s), 6.75 (1 H, d, J 4.1, H-4), 7.73–7.78 (2 H, m) and
ϩ
.87–7.91 (2 H, m); m/z (CI) 502 (M ϩ NH ) (85), 402 (100),
4
46 (100) and 283 (100).
tert-Butyl 1-tert-butoxycarbonyl-5-methoxycarbonyl-á-phthal-
imidopyrrolidine-2-acetates 22a and 22b
A solution of the triester 21 (2.35 g, 4.85 mmol) in acetic acid–
methanol (4:1) (35 ml) containing a suspension of 5% platinum
on carbon (0.47 g; 20%) was stirred under hydrogen at atmos-
pheric pressure and room temperature. After 32 h more catalyst
6
10
3
Ϫ1
νmax(Nujol)/cm 3317, 1698, 1423, 1074 and 1023; δ (400
H
MHz) 1.57 (9 H, s) and 9.65 (1 H, br s, OH); m/z (CI) 199 (13%)
ϩ
and 197 [(M ϩ NH ) , 42%], 163 (21), 147 (24), 74 (38) and 52
4
(
0.23 g, 10%) was added and after 16 h the reaction was com-
(100).
plete. The mixture was filtered, first through filter paper and
then through a Celite pad, both filter paper and Celite pad
being well washed with methanol. Evaporation of the solvent
gave a colourless oil (2.03 g, 86%) which crystallised on stand-
ing, δ (200 MHz) 0.99 (9 H, br s), 1.26 (approx. 2 H, s, CMe of
tert-Butyl 1-tert-butoxycarbonyl-á-(hexahydrophthalimido)-5-
methoxycarbonylpyrrole-2-acetate 26
The pyrrole 21 (3.29 g, 68 mmol) in methanol (20 ml) was stirred
under hydrogen at atmospheric pressure and room temperature
with 5% rhodium on alumina (0.03 g, 10%). After 18 h, TLC
showed the presence of the starting pyrrole and a new compon-
ent. Filtration and evaporation of the solvent gave a colourless
oil which upon flash chromatography [dichloromethane–ethyl
acetate (7.5:1)] gave the pyrrole ester 26 (0.17 g, 52%), mp 147–
H
3
2
3
2
2
2b), 1.36 (approx. 7 H, s, CMe of 22a), 2.10–2.34 (4 H, m, H-
3
, H-3Ј, H-4 and H-4Ј of 22a and 22b), 3.69 (0.75 H, s, MeO of
2b), 3.71 (2.25 H, s, MeO of 22a), 4.21 (1 H, unresolved m, H-
of 22a and 22b), 4.42 (0.25 H, d, J 10.3, α-CH of 22b), 4.65
(
0.75 H, d, J 10.1, α-CH of 22a), 4.78 (1 H, unresolved m, H-5
1
49 ЊC (from dichloromethane–hexane) (Found: C, 61.4; H, 7.0;
of 22a and 22b), 7.67 (2 H, unresolved m) and 7.81–7.85 (2 H,
m). Recrystallisation gave the ester 22a (1.46 g, 62%), mp 131–
Ϫ1
N, 5.7. C H N O requires C, 61.2; H, 7.0; N, 5.7%); νmax/cm
25 34
2
8
1
757 and 1741; δ (400 MHz) 1.42 (9 H, s), 1.47 (4 H, unresolved
1
32 ЊC (from dichloromethane–hexane) (Found: C, 61.7; H, 6.6;
H
Ϫ1
m), 1.58 (9 H, s), 1.88 (4 H, unresolved m), 2.91–2.98 (2 H, m),
.82 (3 H, s), 6.05 (1 H, dd, J 3.8 and 0.7, H-3), 6.38 (1 H, s, α-
CH) and 6.74 (1 H, dd, J 3.3 and 0.4, H-4); m/z (CI) 508
N, 5.7. C H N O requires C, 61.5; H, 6.6; N, 5.7%); νmax/cm
25
32
2
8
3
1
746 and 1708; δ (400 MHz) 1.01 (9 H, br s), 1.42 (9 H, s),
H
2
.11–2.32 (4 H, m, H-3, H-3Ј, H-4 and H-4Ј), 3.76 (3 H, s), 4.21
ϩ
[
(M ϩ NH ) , 16%], 408 (100) and 352 (100).
(
1 H, unresolved m, H-2), 4.70 (1 H, d, J 10.1, α-CH), 4.85 (1 H,
4
unresolved m, H-5), 7.68 (2 H, unresolved m) and 7.86–7.89 (2
H, m); m/z (CI) 489 [(M ϩ H) , 89%], 390 (64), 389 (100), 333
Crystal data for 22a
ϩ
C H N O , M = 488.54. Monoclinic, a = 12.862(8),3 b =
25
32
2
8
(
58) and 128 (49).
9
.629(7), c = 22.560(7) Å, β = 102.37(3)Њ, V = 1625(2) Å (by
least-squares refinement on diffractometer angles for 20 centred
5
-Methoxycarbonyl-á-phthalimidopyrrolidinium-2-acetic acid
reflections with 6.96 < 2θ < 11.26Њ, λ = 0.710 69 Å, T = 297 K),
trifluoroacetate 23
Ϫ3
space group P2 /c (#14), Z = 4, D = 1.189 g cm , clear
1
c
The ester 22a (0.60 g, 1.23 mmol) in dichloromethane–
trifluoroacetic acid (1:1) (4 ml) was stirred at room temperature
for 2 h. Evaporation of the solvent left an oil which was dis-
solved in dichloromethane (1 ml) and upon the addition of
ether gave the trifluoroacetate salt 23 as a colourless solid (0.46
g, 84%), mp 151–153 ЊC (Found: C, 48.3; H, 3.9; N, 6.1.
C H F N O requires C, 48.4; H, 3.8; N, 6.3%); νmax/cm 1778
and 1718; δ (400 MHz, D O) 1.68–1.78 (1 H, m), 2.12–2.34 (3
H, m), 3.62 (3 H, s), 4.35–4.40 (1 H, m, H-2), 4.44 (1 H, approx.
dd, J 9.3 and 4.7, H-5), 5.16 (1 H, d, J 5.0, α-CH), 7.76–7.79 (2
Ϫ1
prism, 0.300 × 0.200 × 0.350 mm, µ(Mo-Kα) = 0.83 cm .
Data collection and processing
Rigaku AF6S diffractometer, graphite-monochromated Mo-
Kα radiation, ω–2θ scans to a maximum 2θ value of 50.0Њ with
ω scan width (1.1 ϩ 0.30 tan θ)Њ; 5376 reflections collected of
which 5132 were unique (Rint = 0.034). The intensities of three
representative reflections which were measured after every 150
reflections remained constant throughout data collection; no
decay correction was applied. An empirical absorption correc-
tion, based on azimuthal scans of several reflections, was
applied which resulted in transmission factors ranging from
Ϫ1
18
17
3
2
8
H
2
ϩ
H, m) and 7.84–7.87 (2 H, m); m/z (FAB) 333 (M , 67%), 128
(
59), 43 (89) and 41 (100).
0
.97 to 1.00. The data were corrected for Lorenz and polaris-
Methyl 6-phthalimido-7-oxo-1-azabicyclo[3.2.0]heptane-2-carb-
oxylate 24
ation effects.
A solution of the salt 23 (37 mg, 0.08 mmol), the phosphine
oxide 6 (37 mg, 0.08 mmol) and triethylamine (0.04 ml, 0.03 g,
Structure solution and refinement
16
Automatic direct methods (all non-H atoms). Non-H atoms
were refined either anisotropically or isotropically. The final
cycle of full-matrix least-squares refinement was based on 1887
observed reflections [I > 3.00 σ(I)] and 191 variable parameters
and converged (largest parameter shift was 0.06 times its esd)
with weighted and unweighted agreement factors as shown in
eqns. (1) and (2).
0
.28 mmol) in dry acetonitrile (30 ml) was heated under reflux
under nitrogen for 6 h. The solution was allowed to cool then
evaporated to dryness. Column chromatography (ether) yielded
the bicyclic β-lactam 24 (8 mg, 32%), mp 122–124 ЊC (from
ϩ
ether) (Found: M , 314.090. C H N O requires M, 314.090);
1
6
14
2
5
Ϫ1
νmax/cm 1786, 1769 and 1723; δ (400 MHz) 1.85–2.32 (4 H, m,
H
H-3, H-3Ј, H-4 and H-4Ј), 3.90 (3 H, s), 4.10 (2 H, m, H-2 and
H-5), 5.55 (1 H, dd, J5,6 5.2, J2,6 1.0, H-6), 7.74–7.78 (2 H, m)
and 7.85–7.91 (2 H, m); m/z 314 (M , 46%), 200 (53), 128 (100),
R = Σ||F | Ϫ |F ||/Σ|F | = 0.101
(1)
o
c
o
ϩ
2
2
1/2
1
04 (68) and 80 (37).
R = {[Σw(|F | Ϫ |F |) /ΣwF ]} = 0.099
(2)
w
o
c
o
J. Chem. Soc., Perkin Trans. 1, 1997
3011

View Article Online
The standard deviation of an observation of unit weight was
Tetrahedron, 1987, 43, 281; D. R. Artis, I.-S. Cho, S. Jaime-Figueroa
and J. M. Muchowski, J. Org. Chem., 1994, 59, 2456; C. W. Jefford,
K. Sienkiewicz and S. R. Thornton, Tetrahedron Lett., 1994, 35,
7
.73. The maximum and minimum peaks on the final differ-
Ϫ3
ence Fourier map corresponded to 0.52 and Ϫ0.40 e Å ,
respectively. All calculations were performed using the TEX-
SAN crystallographic structure package of the Molecular
4
759; C. W. Jefford, K. Sienkiewicz and S. R. Thornton, Helv. Chim.
Acta, 1995, 78, 1511.
6
H.-P. Kaiser and J. M. Muchowski, J. Org. Chem., 1984, 49, 4203.
17
Structure Corporation.
7 M. Regitz, J. Hocker and A. Liedhegener, Org. Synth., Coll. Vol. V,
1
973, 179.
8
9
E. Baciocchi, E. Muraglia and G. Sleiter, J. Org. Chem., 1992, 57,
Acknowledgements
6817.
G. C. Schloemer, R. Greenhouse and J. M. Muchowski, J. Org.
Chem., 1994, 59, 5230.
We thank Mr J. V. Barkley (University of Liverpool) for deter-
mining the X-ray crystal structure of 22a. We also thank
CIPAN and JNICT (Portugal) for support (to A. L.) and the
EPSRC for a Studentship (to C. J. O.).
1
0 T. Nagamatsu and T. Kunieda, Chem. Pharm. Bull., 1988, 36, 1249;
T. Kunieda, T. Nagamatsu, T. Higuchi and M. Hirobe, Tetrahedron
Lett., 1988, 29, 2203.
1
1 B. W. Bycroft, C. Maslen, S. J. Box, A. G. Brown and J. W. Tyler,
J. Chem. Soc., Chem. Commun., 1987, 1623.
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Received 8th May 1997
Accepted 11th June 1997
5
1
991, p. 603; M. Tokuda, Y. Yamada, T. Takagi and H. Suginome,
3
012
J. Chem. Soc., Perkin Trans. 1, 1997