Stereoselective synthesis of 4-substituted azetidine-2,3-diones by ring opening of 1,3-thiazolidine-derived spiro-β-lactams

Article abstract of DOI:10.1016/j.tetasy.2008.02.011

New 3-heterocycle substituted 1,3-thiazolidine-derived 4-spiro-β-lactams with a relative trans-configuration were stereoselectively synthesised by means of a Staudinger ketene-imine reaction between the ketene generated from the (2S,4R)-1,3-thiazolidine-2,3,4-tricarboxylic acid 3-(1,1-dimethylethyl) 4-methyl ester 1 and imines 2b-e. The 1,3-thiazolidine-derived 4-spiro-β-lactams were transformed into the corresponding enantiomerically pure 4-heterocycle substituted azetidine-2,3-diones by means of an oxidative cleavage of the 1,3-thiazolidine ring. The opening of the 1,3-thiazolidine ring was studied under different experimental conditions and a consistent mechanism is proposed.

Full text of DOI:10.1016/j.tetasy.2008.02.011

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 554–561
Stereoselective synthesis of 4-substituted azetidine-2,3-diones by
ring opening of 1,3-thiazolidine-derived spiro-b-lactams
Giuseppe Cremonesi,a Piero Dalla Croce,b Francesco Fontanab and Concetta La Rosaa,*
a
`
Istituto di Chimica Organica ‘A. Marchesini’, Facolta di Farmacia, V. Venezian 21, I-20133 Milano, Italy
bDipartimento di Chimica Organica e Industriale and C.N.R.-I.S.T.M., V. Venezian 21, I-20133 Milano, Italy
Received 13 December 2007; accepted 8 February 2008
Abstract—New 3-heterocycle substituted 1,3-thiazolidine-derived 4-spiro-b-lactams with a relative trans-configuration were stereoselec-
tively synthesised by means of a Staudinger ketene–imine reaction between the ketene generated from the (2S,4R)-1,3-thiazolidine-2,3,4-
tricarboxylic acid 3-(1,1-dimethylethyl) 4-methyl ester 1 and imines 2b–e. The 1,3-thiazolidine-derived 4-spiro-b-lactams were trans-
formed into the corresponding enantiomerically pure 4-heterocycle substituted azetidine-2,3-diones by means of an oxidative cleavage
of the 1,3-thiazolidine ring. The opening of the 1,3-thiazolidine ring was studied under different experimental conditions and a consistent
mechanism is proposed.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
new 1,3-thiazolidine-derived 4-spiro-b-lactams8a,b using a
Staudinger ketene–imine reaction between imines and the
non-symmetrical cyclic ketenes generated from N-acyl-
1,3-thiazolidine-2-carboxylic acids by means of Mukaiy-
ama’s reagent. Subsequently, we synthesised enantiomeri-
cally pure 1,3-thiazolidine-derived 4-spiro-b-lactams 3a
and 4a starting from the optically active (2S,4R)-1,3-thi-
azolidine-2,3,4-tricarboxylic acid 3-(1,1-dimethylethyl)
4-methyl ester 1 and benzyl-benzylidene-amine 2a as indi-
cated in Scheme 1.8c
The stereoselective synthesis of b-lactams has received con-
siderable attention over recent years because of their wide
variety of biological activities,1 in particular, asymmetric
synthesis by means of a Staudinger ketene–imine reaction
has been extensively studied.2 Spiro-b-lactams are interest-
ing compounds not only because of their antiviral3a and
antibacterial activities,3b but also because they inhibit cho-
lesterol absorption,3c indicating that they are potentially
useful drugs. They can also act as b-turn mimetics,4a while
the 4-spiro-b-lactams can be used as synthetic precursors
for cyclic a,a-disubstituted b-amino acids and peptide
derivatives.4b
Our studies led us to conclude that, when the imine-nitro-
gen atom is substituted with an electron-donor group (e.g.,
PhCH2), the main diastereoisomer obtained has a relative
trans configuration between the sulfur atom and the 3-C-
phenyl group.8b Moreover, with the enantiomerically pure
substrate 1, the reactions afford only two diastereoisomers
which have the same trans relative configuration but oppo-
site configurations to the C-3 and the spiranic carbon
atoms.
Some b-lactams, such as the azetidine-2,3-diones or a-keto-
b-lactams, are very interesting small heterocycles that could
be useful intermediates because of the various possible
transformations of the ketone and amide functional
groups. The most significant of these transformations in-
volves the synthesis of 3-hydroxy substituted b-lactams,
which are important key fragments of many natural
products.5
Our interest in compounds 3 and 4 was based on the pres-
ence of the spiro-fused 1,3-thiazolidine ring, whose selec-
tive opening made it possible to obtain a-keto-b-lactams
and recover the chiral auxiliary. This transformation was
accomplished in two steps: the spiro-b-lactams 3a and 4a
were deprotected at the thiazolidine-N-atom under anhy-
drous conditions with gaseous HCl in AcOEt, and then
heated in a CHCl3/DMSO 90:10 solution for 6 h. These
Continuing our studies of the synthesis6 and reactivity7 of
hetero-spirocyclic b-lactams, we have recently synthesised
*
Corresponding author. E-mail: concetta.larosa@unimi.it
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.02.011

G. Cremonesi et al. / Tetrahedron: Asymmetry 19 (2008) 554–561
555
COOtBu
I
N
CH3
COOtBu
Cl
CH3OOC
CH3OOC
R
CH N CH2 R1
N
N
COOH
C
O
CH2Cl2
TEA
2a-e
S
1
S
2,3,4 a : R = Ph
2,3,4 b : R = Ph
;
;
;
R1 = Ph
CH3OOC
CH3OOC
COOtBu
COOtBu
R1 = PMP
R1 = PMP
N
N
R
O
H
2,3,4 c : R =
+
S
S
R
S
N
N
2,3,4 d : R =
;
;
R1 = PMP
R1 = PMP
O
CH2R1
CH2R1
O
H
N
2,3,4 e : R =
3a-e
4a-e
S
Scheme 1.
conditions allowed the corresponding a-keto-b-lactams to
be obtained in good yields together with the dimethyl cysti-
nate dihydrochloride.8c However, the mechanism of this
reaction has not been completely clarified, and should be
studied further.8b
methoxybenzylamine in dry CH2Cl2 over anhydrous
Na2SO4 as a single (E) geometrical isomer, as determined
by IR and 1H NMR. Their stability under the experimental
conditions of the Staudinger reaction (TEA in refluxing
CH2Cl2 for 24 h) was also confirmed by means of suitable
experiments insofar as the imines were stable under these
conditions (as established by 1H NMR analysis) but, when
heated in refluxing CH3OH in the presence of CH3ONa,
they equilibrated to afford a mixture of two tautomeric imi-
nes (Fig. 1).10
In this context, and in view of the growing interest in the
synthesis of enantiopure b-lactams, we herein report the
asymmetric synthesis of new 1,3-thiazolidine-derived 4-
spiro-b-lactams by means of a Staudinger ketene–imine
reaction between the optically active (2S,4R)-1,3-thiazoli-
dine-2,3,4-tricarboxylic acid 3-(1,1-dimethylethyl) 4-methyl
ester 1 and imines 2b–e, which, respectively, derive from
benzaldehyde, 2-thiophene-carbaldehyde, 2-furane-carbal-
dehyde, 2-thiazole-carbaldehyde and 4-methoxybenzyl-
amine. The aim was to obtain 4-spiro-b-lactams that are
substituted at the 3-position by a heterocycle and have a
removable group, such as the p-methoxy-phenyl group,
on the b-lactam-nitrogen, because the transformations of
these compounds would allow new azetidine-2,3-diones to
be obtained. At the same time, additional studies of 1,3-thi-
azolidine ring opening would enable us to propose a mech-
anism to explain the course of the reaction.
The reaction of amino acid 1, imines 2b–e and 2-chloro-1-
methylpyridinium iodide (Mukaiyama’s reagent) in the
presence of TEA in refluxing CH2Cl2 for 24 h gave the
spiro-b-lactams as a mixture of two diastereoisomers,
3b–e and 4b–e, which were easily separated and purified
by means of flash chromatography (Scheme 1).
The relative and absolute configurations of the new stereo-
centres of spiro-b-lactams 3b–e and 4b–e were assigned by
comparing the NMR spectra of the products with those of
the previously obtained compounds 3a (whose structure
was confirmed by means of X-ray analysis) and 4a.8c The
1H NMR spectra were complicated by the existence of
rotamers arising from the presence of the N-Boc group,
and hence were recorded at 80 °C in DMSO-d6. In this
way, it was possible to observe a complete correspondence
between the multiplicities and chemical shifts of, for exam-
ple, the H-7 proton (doublet, 4.30 d in 3a, doublet, 4.30–
4.54 d in 3b–e; triplet, 4.75 d in 4a, triplet, 4.70–4.86 d in
4b–e), the COOCH3 signal (3.65 d in 3a, 3.60–3.71 d in
3b–e; 3.39 d in 4a, 3.38–3.53 d in 4b–e), and the H-6 pro-
tons (3.31, 3.69 d in 3a, 3.27–3.38, 3.50–3.70 d in 3b–e;
2. Results and discussion
The starting material, (2S,4R)-1,3-thiazolidine-2,3,4-tricar-
boxylic acid 3-(1,1-dimethylethyl) 4-methyl ester 1, was
prepared from (R)-cysteine methyl ester hydrochloride
and glyoxylic acid followed by treatment with (BOC)2O,
as previously reported.8c Imines 2b,9 2c, 2d and 2e were
prepared from the corresponding aldehydes and 4-
CH3O Na
CH3OH
CH3O
CH2
N
CH
R
CH3O
CH
N
CH2
R
2b-e
2b : R = Ph
2d : R =
2e : R =
O
N
2c : R =
S
S
Figure 1.

556
G. Cremonesi et al. / Tetrahedron: Asymmetry 19 (2008) 554–561
Table 1.
presence of a stereocentre in the 1,3-thiazolidine ring differ-
entiates the two faces of the intermediate ketene, and so the
b-lactams 3 deriving from the attack on the less hindered
face should always be the more abundant adducts. Further-
more, the fact that the 2-thienyl and 2-furyl ring is smaller
than the phenyl ring does not explain the reversed ratio
because this does not happen in the case of the 2-thiazolyl
ring.
Total yield (%)
Ratio (%) (3):(4)
3–4a
3–4b
3–4c
3–4d
3–4e
638c
62
77
60
64:36
56:44
36:64
46:54
69:31
72
The mechanism of the 1,3-thiazolidine ring opening was
thoroughly studied on the more easily available spiro-b-
lactam 3f8b (Scheme 2) starting from the following observa-
tions: (i) the reaction took place only on the spiro-b-lactam
deprotected at the thiazolidine-N-atom and as an ammo-
nium salt; and (ii) an oxidant was necessary to complete
the reaction. Our first experiments verified that when
DMSO was used as a co-solvent, it acted as an oxidant
because Me2S was identified as a reduction product by
3.25, 3.44 d in 4a, 3.20–3.25, 3.44–3.48 d in 4b–e). Table 1
shows the yields and the ratios of the new products 3b–e
and 4b–e in comparison with 3a and 4a.
Also in this case, and with regard to the relative configura-
tion of C-3 and C-4 carbon, the Staudinger reaction pro-
ceeded with total stereoselectivity, giving both spiro-b-
lactams with a relative trans disposition. On the other
hand, as shown in Table 1, the ratios between the adducts
were generally lower than (and, in the case of the 2-thienyl
and 2-furyl derivatives 3/4c,d even opposite to) that ob-
served for 3a/4a. This result cannot be explained on the ba-
sis of the proposed mechanism of the ketene–imine
reaction,11,12 according to which the attack of nucleophilic
imines such as (E)-2b–e occurs from the less hindered side
of the ketene opposite to the N-Boc group (Fig. 2). The
1
means of H and 13C NMR analysis, and the cystamine
dihydrochloride was recovered as an oxidation product.
Moreover, the reaction did not run if DMF was used as
co-solvent instead of DMSO.
Further observations showed that the spiro-b-lactam has to
be present as an ammonium salt and not as a free base,
however the nature of its counter-ion does not influence
the course of the reaction as turning the chloride counter-
ion into the non-nucleophile perchlorate anion did not
change the result of the reaction, thus proving that the
counter-ion is not involved in the mechanism.
H
CH3OOC
H
R
3
N
t BuOOC
S
N
C
CH2R1
As thiols can be transformed into disulfides by means of
various oxidising agents,13 we also changed the nature of
the oxidant from the nucleophile DMSO14 to the non-
O
H
nucleophile oxidant I2,15 but the reaction still took place.
CH3OOC
N
16
We attempted some other oxidants (PCC, Ca(OCl)2
)
and also atmospheric oxygen,17 obtaining the a-keto-b-lac-
tam 58b with variable experimental conditions and in vari-
able yields (Table 2).
t BuOOC
4
S
C
CH2R1
O
N
R
H
We finally verified the role of water, whose presence is fun-
damental and influences the reaction rate.16a We observed
that, if water is added to the reaction mixture as wet alu-
Figure 2.
Cl
H
N
COOtBu
Cl
H
H
N
H
N
N
N
Ph
N
HClg / AcOEt
Ph
H
Ph
Ph
H
S
S
S
SH
Cl
H
H
60°C, 4h
N
H
N
O
O
O
O
CH2Ph
CH2Ph
CH2Ph
CH2Ph
( )-3f
a
b
c
O
O
Ph
H
Cl
H
Cl
H
O
H
( )-5
H
H
N
+
H
S
O
Ox
N
N
CH2Ph
Ph
H
Ph
H
S
N
N
NH
3 Cl
O
O
CH2Ph
CH2Ph
S
2
2
S
d
e
Cl
NH3
Scheme 2.

G. Cremonesi et al. / Tetrahedron: Asymmetry 19 (2008) 554–561
557
Table 2.
Entry Oxidant
Surprisingly, in the case of the enantiopure 3e our protocol
failed since the N-Boc-deprotected spiro-b-lactam resulted
stable to the next oxidation step and it was recovered
unchanged as confirmed by means of its MS spectra
(M+ꢀHCl: 404). We ascribed this result to the presence of
the basic thiazole nitrogen which could be involved in an
intramolecular hydrogen bond with a proton of the thiazol-
idine ammonium group affording compound a0 (Fig. 3).
Experimental conditions
Yield
(%)
1
2
3
4
5
6
DMSO
I2
I2
CHCl3, 45 °C, 6 h
CH2Cl2, 40 °C, 97 h
CH2Cl2, wet Al2O3, 40 °C, 7 h
72
95
80
20
PCC/Al2O3 CH3COCH3, 50 °C, 100 h
Ca(OCl)2
O2
CH3COCH3, wet Al2O3, 50 °C, 100 h 10
CHCl3, 25 °C, 30 days
99
H
H
N
CH3OOC
S
N
mina, the transformation with I2 is complete in only 7 h in-
stead of 97 h (Table 2, entries 2 and 3): these experimental
conditions proved to be the best, also given the easy work-
up. On the basis of all these considerations, we now pro-
pose the mechanism shown in Scheme 2.
H
S
O
N
CH2PMP
a'
Figure 3.
We hypothesise initial prototropy of the ammonium ion
between the nitrogen (structure a) and the sulfur atoms
(structure b) of the thiazolidine ring.18 This equilibrium
allows the donation of the nitrogen electron pair and con-
sequently the opening of the thiazolidine ring (structure c).
At this point, the presence of an oxidant capable of oxidis-
ing the thiol group to the corresponding disulfide (structure
d) avoids ring closure and shifts the equilibrium to the
right. Finally, the nucleophilic addition of water (derived
from atmospheric moisture or deliberately introduced)
gives the corresponding hemiaminal (structure e) that
evolves to the a-keto-b-lactam and cysteamine dimer.
This possibility was confirmed by an examination of the
corresponding a0 Dreiding Molecular Model, which
pointed out the proximity of these two atoms and the pos-
sible formation of a stable six-membered ring. Under our
usual experimental conditions the deprotection of thiazo-
lidine-N-atom is carried out with an excess of gaseous
HCl in ethyl acetate. During this first step the thiazole
nitrogen atom is protonated but when, at the end of the
reaction, the solvent is evaporated off, this weakly basic
nitrogen20 could lose HCl. The concomitant formation of
the intramolecular hydrogen bond could prevent the
N–S prototropy and the consequent oxidative cleavage
(second step). To verify our hypothesis, we carried out
the reaction on 3e without the elimination of the excess
of gaseous HCl and with the addition of DMSO as oxidant
(see Section 4). Indeed, under these conditions, the corres-
ponding a-keto-b-lactam 5e was obtained (Scheme 3).
We subsequently applied this 1,3-thiazolidine ring oxida-
tive cleavage to the enantiopure spiro-b-lactams 4b–d using
I2 as an oxidant in the presence of wet Al2O3, and obtained
the corresponding new enantiopure a-keto-b-lactams 5b–d
(Scheme 3) in fair to good yields due to their instability.
For this reason it was not possible to determine their ee
by means of HPLC analysis, but they were measured by
1H NMR spectroscopy, using (+)-Eu(hfc)3 as a chiral shift
reagent. In this way, the ee of compounds 5b–d was calcu-
lated to be more than 98% ( 2) by comparison with the 1H
NMR spectra of the racemic a-keto-b-lactams obtained
from the equimolar mixtures of the diastereoisomeric
spiro-b-lactams 3–4b–d.
Finally we tried to deprotect the b-lactam-N-atom directly
during the oxidative cleavage of the spiro-b-lactams with
the aim of obtaining N-unsubstituted azetidin-2,3-diones,
a class of compounds rarely present in the literature.21,22
Unfortunately, starting from compounds 3b–c and using
CAN23 or Na2S2O824 as oxidant, we were unable to obtain
the desired product because in all cases we observed the
complete degradation of the spiro-b-lactam.
Additionally, the absence of racemisation19a through a
keto–enol tautomerism, which could be observed in certain
situations,19b was confirmed by means of 1H NMR spectra
of compound 5c recorded at temperature ranging from
T = ꢀ10 °C to room temperature in CCl4 solution.
3. Conclusions
We have stereoselectively synthesised new enantiomerically
pure 1,3-thiazolidine-derived 4-spiro-b-lactams substituted
CH3OOC
COOtBu
O
R
O
1) HClg/AcOEt, rt, 24h
N
O
N
2) 4b-d : I2,wet Al2O3, CH2Cl2, rt, 20h
3e : DMSO, T= 50 °C, 16h
S
R
CH2PMP
N
CH2PMP
(S)-5b : R=Ph
(R)-5c : R=2-Thienyl
(S)-5d : R=2-Furyl
(S)-5e : R=2-Thiazolyl
4b-d
3e
Scheme 3.

558
G. Cremonesi et al. / Tetrahedron: Asymmetry 19 (2008) 554–561
with a heterocycle at the 3-position by reacting a non-sym-
metrical, optically active cyclic ketene with C-heterocyclic
substituted imines. The reaction was stereoselective as only
trans-diastereoisomers were obtained. The pairs of adducts
were separated and transformed into the corresponding
4-heterocycle substituted azetidine-2,3-diones by means of
a new oxidative cleavage of the 1,3-thiazolidine ring. The
mechanism of this transformation was studied and com-
pletely clarified. In this way, by starting from the diastereo-
isomeric spiro-b-lactam 3 and/or 4, it is possible to obtain
both of the enantiomers of the corresponding a-keto-b-lac-
tam 5.
128.85, 129.19, 130.43, 131.03, 142.48, 154.68, 158.65.
MS-EI (m/z): 231 (M+), 121. IR (Nujol): 1626 (mC@N).
4.5. Furan-2-ylmethylene-(4-methoxybenzyl)-amine 2d
1
Oil (70%); bp 175 °C/0.6 mmHg. H NMR: d 3.79 (3H, s,
OCH3); 4.72 (2H, s, CH2); 6.46 (1H, dd, J = 3.4, 1.6, H4-
Fur); 6.76 (1H, d, J = 3.4, H3-Fur); 6.88 (2H, d, J = 8.6,
Ho-Bz); 7.24 (2H, d, J = 8.6, Hm-Bz); 7.5 (1H, d, J = 1.6,
H5-Fur); 8.13 (1H, s, CH). 13C NMR: d 54.94 (OCH3);
64.18 (CH2); 111.32, 113.66, 129.15, 130.62, 144.38,
149.72, 151.4, 158.49. MS-EI (m/z): 215 (M+), 121. IR (Nu-
jol): 1646 (mC@N).
4. Experimental
4.1. General
4.6. (4-Methoxybenzyl)-thiazol-2-ylmethyleneamine 2e
1
Oil (98%). H NMR: d 3.81 (3H, s, OCH3); 4.82 (2H, s,
Melting points were measured using a Bu¨chi apparatus and
CH2); 6.7 (2H, d, J = 8.7, Ho-Bz); 7.23 (2H, d, J = 8.7,
Hm-Bz); 7.41 (1H, dd, J = 3.2, 1.0, H4-Thiaz); 7.92 (1H,
d, J = 3.2, H5-Thiaz); 8.49 (1H, d, J = 1.0, CH). 13C
NMR: d 55.06 (OCH3); 63.57 (CH2); 113.59, 121.43,
129.3, 129.82, 143.76, 155.27, 158.74, 166.98. MS-EI
(m/z): 232 (M+), 121. IR (Nujol): 1640 (mC@N).
1
are uncorrected. H and 13C NMR spectra were recorded
in CDCl3 (unless otherwise specified) on a Bruker AMX
300 spectrometer; chemical shifts (d) are given in ppm rel-
ative to TMS and all of the coupling constants are in Hertz.
Optical rotations were measured at 25 °C on a Jasco P-
1030 polarimeter. The MS spectra were determined using
a VG Analytical 7070 EQ mass spectrometer with an at-
tached VG analytical 11/250 data system. The IR spectra
were determined using a Jasco FT-IR-4100 spectrometer,
4.7. General procedure for the reactions of 1 with 2b–e and
Mukaiyama’s reagent
in cmꢀ1
.
A mixture of 1 (1.1 mmol), imine 2b–e (1.0 mmol), 2-
chloro-N-methylpyridium iodide (1.2 mmol) and Et3N
(3.0 mmol) in dry CH2Cl2 (15 mL) was heated at reflux
temperature for 12–20 h under a nitrogen atmosphere.
After cooling, the solution was washed with 5% aq HCl,
5% aq NaHCO3 and then with H2O. The organic layer
was dried over Na2SO4 and the solvent was removed under
reduced pressure. The crude products were purified by flash
chromatography (SiO2, n-hexane/AcOEt = 50:50).
Compound (2S,4R)-1,3-thiazolidine-2,3,4-tricarboxylic acid
3-(1,1-dimethylethyl) 4-methyl ester 18c was prepared
according to the reported method.
4.2. General procedure for the synthesis of imines 2b–e
A mixture of carboxaldehyde (10 mmol), 4-methoxybenzyl-
amine (10 mmol), dry dichloromethane (20 mL) and anhy-
drous sodium sulfate was stirred for 24 h at room
temperature. The mixture was filtered and the filtrate evap-
orated to give the crude imines 2b–e, which were judged
4.8. (3R,4R,7R)-2-(4-Methoxybenzyl)-1-oxo-3-phenyl-5-
thia-2,8-diazaspiro[3.4]octane-7,8-dicarboxylic acid 8-tert-
butyl ester 7-methyl ester 3b
1
>95% pure by H NMR.
4.3. Benzylidene-(4-methoxybenzyl)-amine 2b9
20
(Yield: 35%). Amorphous solid. ½aꢁD ¼ ꢀ154:8 (c 0.64,
1
CHCl3). H NMR (DMSO-d6, T = 80 °C): d 1.19 (s, 9H,
1
Oil (95%); bp 150 °C/0.1 mmHg. H NMR: d 3.79 (3H, s,
(CH3)3C), 3.30 (dd, 1H, H-6, Jgem = 12.6, Jvic = 1.2); 3.67
(s, 3H, COOCH3); 3.69 (dd, 1H, H-6, Jgem = 12.6,
Jvic = 7.8); 3.78 (s, 3H, OCH3); 4.24 (d, 1H, CH2Ph,
J = 15.0); 4.32 (d, 1H, H-7, J = 6.8); 4.74 (s, 1H, H-3);
4.83 (d, 1H, CH2Ph, J = 15.0); 6.91 (d, 2H, CH2Ph,
J = 8.6); 7.17 (d, 2H, CH2Ph, J = 8.6); 7.28–7.34 (m, 5H,
Ph). 13C NMR show the presence of rotamers about the
carbamate bond: d 27.7 (q, (CH3)3C); 31.8, 32.7 (t, C-6);
44.6, 44.9 (t, CH2Ph); 52.5 (q, COOCH3); 55.1 (q,
OCH3); 63.1, 64.0 (d, C-7); 75.0 (d, C-3); 81.3 (s,
(CH3)3C); 83.2, 83.8 (s, C-4); 113.0–151.0 (Ph); 159.2,
164.0, 170.3 (s, CO). IR (Nujol): 1711 (mCO, NCOOtBu,
OCH3); 4.77 (2H, s, CH2); 6.89 (2H, d, J = 8.6, Ho-Bz);
7.26 (2H, d, J = 8.6, Hm-Bz); 7.41 (3H, m, Ph); 7.78 (2H,
m, Ph); 8.37 (1H, s, CH). 13C NMR: d 55.11 (OCH3);
64.31 (CH2); 113.83, 128.13, 128.30, 128.89, 130.54,
131.31, 136.15, 158.61, 161.39. MS-EI (m/z): 225 (M+),
139. IR (Nujol): 1643 (mC@N).
4.4. (4-Methoxybenzyl)-thiophen-2-ylmethyleneamine 2c
Colourless solid (84%); mp 58–60 °C (n-hexane). 1H NMR:
d 3.84 (3H, s, OCH3); 4.78 (2H, s, CH2); 6.93 (2H, d,
J = 8.6, Ho-Bz); 7.11 (1H, dd, J = 4.9, 3.6, H4-Thio); 7.28
(2H, d, J = 8.6, Hm-Bz); 7.36 (1H, d, J = 3.6, H3-Thio);
7.44 (1H, d, J = 4.9, H5-Thio); 8.46 (1H, s, CH). 13C
NMR: d 55.19 (OCH3); 63.75 (CH2); 113.86; 127.25,
N–CO), 1774 (mCO
,
COOCH3). Anal. Calcd for
C26H30N2O6S: C, 62.65; H, 6.02; N, 5.62. Found: C,
62.51; H 5.95; N, 5.55. MS-FAB+ (m/z): 498 (M+), 443,
335, 277, 235.

G. Cremonesi et al. / Tetrahedron: Asymmetry 19 (2008) 554–561
559
4.9. (3S,4S,7R)-2-(4-Methoxybenzyl)-1-oxo-3-phenyl-5-
thia-2,8-diazaspiro[3.4]octane-7,8-dicarboxylic acid 8-tert-
butyl ester 7-methyl ester 4b
C-3); 82.2 (s, (CH3)3C); 83.7 (s, C-4); 113.0–151.1
(Ph + Thioph); 159.2, 164.1, 170.0 (s, CO). IR (Nujol):
1712 (mCO, NCOOtBu, N–CO), 1769 (mCO, COOCH3).
Anal. Calcd for C24H28N2O6S2: C, 57.14; H, 5.55; N,
5.55. Found: C, 57.08; H 5.47; N, 5.52. MS-FAB+ (m/z):
504 (M+), 449, 405, 283, 242.
20
(Yield: 27%) Amorphous solid. ½aꢁD ¼ þ46:9 (c 0.71,
1
CHCl3). H NMR (DMSO-d6, T = 80 °C): d 1.31 (s, 9H,
(CH3)3C), 3.26 (dd, 1H, H-6, Jgem = 11.6, Jvic = 7.1); 3.41
(s, 3H, COOCH3); 3.45 (dd, 1H, H-6, Jgem = 11.7,
Jvic = 6.6); 3.78 (s, 3H, OCH3); 4.13 (d, 1H, CH2Ph,
J = 15.0); 4.67 (s, 1H, H-3); 4.7 (t, 1H, H-7, J = 6.9);
4.79 (d, 1H, CH2Ph, J = 15.0); 6.89 (d, 2H, CH2Ph,
J = 8.6); 7.12 (d, 2H, CH2Ph, J = 8.6); 7.31–7.41 (m, 5H,
Ph). 13C NMR show the presence of rotamers about the
carbamate bond: d 27.7 (q, (CH3)3C); 31.5, 32.3 (t, C-6);
44.2 (t, CH2Ph); 52.1 (q, COOCH3); 55.1 (q, OCH3);
65.1, 65.6 (d, C-7); 73.6, 74.2 (d, C-3); 82.0 (s, (CH3)3C);
83.7 (s, C-4); 112.4–151.2 (Ph); 159.2, 164.9, 170.0 (s,
CO). IR (Nujol): 1712 (mCO, NCOOtBu, N–CO), 1770
(mCO, COOCH3). Anal. Calcd for C26H30N2O6S: C, 62.65;
H, 6.02; N, 5.62. Found: C, 62.55; H 5.93; N, 5.60. MS-
FAB+ (m/z): 498 (M+), 443, 399, 335, 277, 235.
4.12. (1R,4R,7R)-1-Furan-2-yl-2-(4-methoxybenzyl)-3-oxo-
5-thia-2,8-diazaspiro[3.4]octane-7,8-dicarboxylic acid 8-tert-
butyl ester 7-methyl ester 3d
20
1
(Yield: 28%). Oil. ½aꢁ ¼ ꢀ80:1 (c 0.14, CHCl3). H NMR
(DMSO-d6, T = 80 °DC): d 1.27 (s, 9H, (CH3)3C), 3.28 (d,
1H, H-6, Jgem = 12.5); 3.50 (dd, 1H, H-6, Jgem = 12.5,
Jvic = 7.5); 3.66 (s, 3H, COOCH3); 3.75 (s, 3H, OCH3);
4.19 (d, 1H, CH2Ph, J = 15.1); 4.41 (d, 1H, H-7, J = 7.5);
4.64 (s, 1H, H-3); 4.71 (d, 1H, CH2Ph, J = 15.1); 6.29 (d,
1H, H-3 Fur, J = 3.3); 6.39 (dd, 1H, H-4 Fur, J = 3.3,
1.9); 6.88 (d, 2H, CH2Ph, J = 8.6); 7.14 (d, 2H, CH2Ph,
J = 8.6); 7.54 (d, 1H, H-5 Fur, J = 1.9). 13C NMR show
the presence of rotamers about the carbamate bond: d
28.1 (q, (CH3)3C); 32.1, 32.9 (t, C-6); 44.6, 44.8 (t, CH2Ph);
52.9 (q, COOCH3); 55.6 (q, OCH3); 63.6, 64.3 (d, C-7);
68.9, 69.1 (d, C-3); 81.3 (s, (CH3)3C); 83.1 (s, C-4);
110.1–145.0 (Ph + Fur); 159.8, 163.2, 170.8 (s, CO). IR
4.10. (3S,4R,7R)-2-(4-Methoxybenzyl)-1-oxo-3-thiophen-2-
yl-5-thia-2,8-diazaspiro[3.4]octane-7,8-dicarboxylic acid 8-
tert-butyl ester 7-methyl ester 3c
(Nujol): 1711 (mCO, NCOOtBu, N–CO), 1772 (mCO
,
20
(Yield: 28%). Amorphous solid. ½aꢁD ¼ ꢀ176:6 (c 0.56,
COOCH3). Anal. Calcd for C24H28N2O7S: C, 59.02; H,
5.74; N, 5.74. Found: C, 58.89; H 5.65; N, 5.70. MS-
FAB+ (m/z): 488 (M+), 410, 387, 354, 325, 267.
1
CHCl3). H NMR (DMSO-d6, T = 80 °C): d 1.27 (s, 9H,
(CH3)3C), 3.32 (d, 1H, H-6, Jgem = 12.6); 3.60 (dd, 1H,
H-6, Jgem = 12.6, Jvic = 7.7); 3.69 (s, 3H, COOCH3); 3.78
(s, 3H, OCH3); 4.22 (d, 1H, CH2Ph, J = 15.1); 4.45 (d,
1H, H-7, J = 7.7); 4.81 (d, 1H, CH2Ph, J = 15.1); 4.88 (s,
1H, H-3); 6.92 (d, 2H, CH2Ph, J = 8.6); 7.0–7.04 (m, 2H,
H-3, H-4 Thioph); 7.18 (d, 2H, CH2Ph, J = 8.6); 7.5 (dd,
1H, H-5 Thioph, J = 4.3, 2.0). 13C NMR show the pres-
ence of rotamers about the carbamate bond: d 27.8 (q,
(CH3)3C); 31.8, 32.6 (t, C-6); 44.3 (t, CH2Ph); 52.5 (q,
COOCH3); 55.1 (q, OCH3); 63.1, 63.9 (d, C-7); 70.6 (d,
C-3); 81.3 (s, (CH3)3C); 81.5, 83.1 (s, C-4); 113.0–151.3
(Ph + Thioph); 159.1, 163.3, 170.3 (s, CO). IR (Nujol):
1713 (mCO, NCOOtBu, N–CO), 1775 (mCO, COOCH3).
Anal. Calcd for C24H28N2O6S2: C, 57.14; H, 5.55; N,
5.55. Found: C, 57.06; H 5.37; N, 5.45. MS-FAB+ (m/z):
504 (M+), 449, 405, 283, 242.
4.13. (1S,4S,7R)-1-Furan-2-yl-2-(4-methoxybenzyl)-3-oxo-
5-thia-2,8-diazaspiro[3.4]octane-7,8-dicarboxylic acid 8-tert-
butyl ester 7-methyl ester 4d
20
1
(Yield: 32%). Oil. ½aꢁD ¼ þ15:0 (c 1.02, CHCl3). H NMR
(DMSO-d6, T = 80 °C): d 1.40 (s, 9H, (CH3)3C), 3.22 (dd,
1H, H-6, Jgem = 11.6, Jvic = 6.6); 3.45 (dd, 1H, H-6, Jgem
=
11.6, Jvic = 6.4); 3.53 (s, 3H, COOCH3); 3.79 (s, 3H,
OCH3); 4.11 (d, 1H, CH2Ph, J = 15.2); 4.66 (s, 1H, H-3);
4.68 (d, 1H, CH2Ph, J = 15.2); 4.86 (t, 1H, H-7, J = 6.6);
6.44 (dd, 1H, H-4 Fur, J = 3.3, 1.7); 6.50 (d, 1H, H-3
Fur, J = 3.3); 6.90 (d, 2H, CH2Ph, J = 8.6); 7.14 (d, 2H,
CH2Ph, J = 8.6); 7.56 (d, 1H, H-5 Fur, J = 1.7). 13C
NMR show the presence of rotamers about the carbamate
bond: d 27.8, 28.1 (q, (CH3)3C); 32.1, 32.7 (t, C-6); 44.1,
44.4 (t, CH2Ph); 52.9 (q, COOCH3); 55.5 (q, OCH3);
65.1, 65.5 (d, C-7); 66.3, 67.8 (d, C-3); 82.6 (s, (CH3)3C);
83.5 (s, C-4); 109.3–149.1 (Ph + Fur); 160.2, 163.1, 171.0
(s, CO). IR (Nujol): 1709 (mCO, NCOOtBu, N–CO), 1772
(mCO, COOCH3). Anal. Calcd for C24H28N2O7S: C, 59.02;
H, 5.74; N, 5.74. Found: C, 58.95; H 5.68; N, 5.71. MS-
FAB+ (m/z): 488 (M+), 387, 325, 267.
4.11. (3R,4S,7R)-2-(4-Methoxybenzyl)-1-oxo-3-thiophen-2-
yl-5-thia-2,8-diazaspiro[3.4]octane-7,8-dicarboxylic acid 8-
tert-butyl ester 7-methyl ester 4c
20
(Yield: 49%) Amorphous solid. ½aꢁD ¼ þ50:5 (c 0.92,
1
CHCl3). H NMR (DMSO-d6, T = 80 °C): d 1.39 (s, 9H,
(CH3)3C), 3.22 (dd, 1H, H-6, Jgem = 11.6, Jvic = 7.3); 3.42
(s, 3H, COOCH3); 3.44 (dd, 1H, H-6, Jgem = 11.6,
Jvic = 6.6); 3.78 (s, 3H, OCH3); 4.09 (d, 1H, CH2Ph,
J = 15.1); 4.71 (d, 1H, CH2Ph, J = 15.1); 4.8 (t, 1H, H-7,
J = 6.9); 4.88 (s, 1H, H-3); 6.91 (d, 2H, CH2Ph, J = 8.6);
7.04 (dd, 1H, H-4 Thioph, J = 5.0, 3.8); 7.12 (d, 2H,
CH2Ph, J = 8.6); 7.2 (d, 1H, H-3 Thioph, J = 3.8); 7.53
(d, 1H, H-5 Thioph, J = 5.0). 13C NMR show the presence
of rotamers about the carbamate bond: d 27.6, 27.9 (q,
(CH3)3C); 32.3, 33.0 (t, C-6); 43.9 (t, CH2Ph); 52.3 (q,
COOCH3); 55.1 (q, OCH3); 64.9 (d, C-7); 69.1, 69.6 (d,
4.14. (3S,4R,7R)-2-(4-Methoxy-benzyl)-1-oxo-3-thiazol-2-
yl-5-thia-2,8-diazaspiro[3.4]octane-7,8-dicarboxylic acid 8-
tert-butyl ester 7-methyl ester 3e
20
(Yield: 50%). Amorphous solid. ½aꢁD ¼ ꢀ149:1 (c 0.83,
1
CHCl3). H NMR (DMSO-d6, T = 80 °C): d 1.21 (s, 9H,
(CH3)3C), 3.38 (dd, 1H, H-6, Jgem = 12.4, Jvic = 1.0); 3.66
(dd, 1H, H-6, Jgem = 12.4, Jvic = 7.6); 3.70 (s, 3H,
COOCH3); 3.79 (s, 3H, OCH3); 4.45 (d, 1H, CH2Ph,

560
G. Cremonesi et al. / Tetrahedron: Asymmetry 19 (2008) 554–561
J = 15.0); 4.54 (d, 1H, H-7, J = 7.6); 4.88 (d, 1H, CH2Ph,
J = 15.0); 4.93 (s, 1H, H-3); 6.93 (d, 2H, CH2Ph,
J = 8.6); 7.24 (d, 2H, CH2Ph, J = 8.6); 7.69 (d, 1H, H-4
Thiaz, J = 3.2); 7.83 (d, 1H, H-5 Thiaz, J = 3.2). 13C
NMR shows the presence of rotamers about the carbamate
bond: d 27.1, 27.5 (q, (CH3)3C); 31.8, 32.5 (t, C-6); 44.7 (t,
CH2Ph); 52.3 (q, COOCH3); 54.9 (q, OCH3); 62.9, 63.6 (d,
C-7); 70.5, 71.0 (d, C-3); 81.3 (s, (CH3)3C); 82.6 (s, C-4);
112.3–150.9 (Ph + Thiaz); 159.0, 163.6, 169.6 (s, CO). IR
and the solvent was removed under reduced pressure.
Monobactam 5e was purified as indicated below.
4.18. (S)-1-(4-Methoxybenzyl)-4-phenyl-azetidine-2,3-dione
5b
Colourless solid (75%); mp 58–60 °C (CCl4/(isoPr)2O).
20
1
½aꢁD ¼ þ17:5 (c 0.64, CH2Cl2). H NMR: d 3.79 (s, 3H,
OCH3); 4.11 (d, 1H, CH2Ph, J = 14.6); 4.87 (s, 1H, H-4);
5.14 (d, 1H, CH2Ph, J = 14.6); 6.85 (d, 2H, CH2Ph,
J = 8.7); 7.09 (d, 2H, CH2Ph, J = 8.7); 7.3–7.5 (m, 5H,
Ph). 13C NMR: d 45.1 (t, CH2Ph); 55.5 (q, OCH3); 73.8
(d, C-4); 113.8–131.6 (Ph); 160.2, 193.8 (s, CO). IR (Nujol):
1745, 1822 (mCO). Anal. Calcd for C17H15NO3: C, 72.60; H,
5.34; N, 4.98. Found: C, 72.55; H 5.23; N, 4.88. MS-FAB+
(m/z): 281 (M+), 221.
(Nujol): 1708 (mCO, NCOOtBu, N–CO), 1775 (mCO
,
COOCH3). Anal. Calcd for C23H27N3O6S2: C, 54.65; H,
5.35; N, 8.32. Found: C, 54.44; H 5.27; N, 8.15. MS-
FAB+ (m/z): 505 (M+), 450, 406, 284, 242.
4.15. (3R,4S,7R)-2-(4-Methoxy-benzyl)-1-oxo-3-thiazol-2-
yl-5-thia-2,8-diazaspiro[3.4]octane-7,8-dicarboxylic acid 8-
tert-butyl ester 7-methyl ester 4e
4.19. (R)-1-(4-Methoxybenzyl)-4-thiophen-2-yl-azetidine-
2,3-dione 5c
20
(Yield: 22%). Amorphous solid. ½aꢁD ¼ þ35:1 (c 0.79,
1
CHCl3). H NMR (DMSO-d6, T = 80 °C): d 1.38 (s, 9H,
(CH3)3C), 3.25 (dd, 1H, H-6, Jgem = 11.6, Jvic = 6.9); 3.49
(dd, 1H, H-6, Jgem = 11.6, Jvic = 6.6); 3.50 (s, 3H,
COOCH3); 3.78 (s, 3H, OCH3); 4.27 (d, 1H, CH2Ph,
J = 15.0); 4.75 (d, 1H, CH2Ph, J = 15.0); 4.85 (t, 1H, H-
7, J = 6.7); 4.99 (s, 1H, H-3); 6.90 (d, 2H, CH2Ph, J =
8.7); 7.14 (d, 2H, CH2Ph, J = 8.7); 7.72 (d, 1H, H-4 Thiaz,
J = 3.2); 7.82 (d, 1H, H-5 Thiaz, J = 3.2). 13C NMR shows
the presence of rotamers about the carbamate bond: d 27.4,
27.8 (q, (CH3)3C); 31.9, 32.4 (t, C-6); 44.6 (t, CH2Ph); 52.4
(q, COOCH3); 55.1 (q, OCH3); 64.7, 65.1 (d, C-7); 69.8,
71.4 (d, C-3); 82.4 (s, (CH3)3C); 83.67(s, C-4); 113.6–
151.9 (Ph + Thiaz); 159.2, 164.1, 169.6 (s, CO). IR (Nujol):
1708 (mCO, NCOOtBu, N–CO), 1775 (mCO, COOCH3).
Anal. Calcd for C23H27N3O6S2: C, 54.65; H, 5.35; N,
8.32. Found: C, 54.52; H 5.19; N, 8.23. MS-FAB+ (m/z):
505 (M+), 450, 406, 284, 242.
Purified by means of column chromatography (SiO2,
hexane/AcOEt = 7:3). Colourless solid (55%); mp 128–
20
1
130 °C (CCl4). [aꢁD ¼ þ84:9 (c 0.17, CHCl3). H NMR: d
3.82 (s, 3H, OCH3); 4.19 (d, 1H, CH2Ph, J = 14.3); 5.16
(s, 1H, H-4); 5.25 (d, 1H, CH2Ph, J = 14.3); 6.99 (d, 2H,
CH2Ph, J = 8.5); 7.16 (d, 1H, H-3 Thioph, J = 3.4); 7.22
(t, 1H, H-4 Thioph, J = 4.8); 7.31 (d, 2H, CH2Ph,
J = 8.5); 7.52 (d, 1H, H-5 Thioph, J = 5.0). 13C NMR: d
45.2 (t, CH2Ph); 55.7 (q, OCH3); 69.2 (d, C-4); 114.6–
130.6 (Ph + Thioph); 162.5, 189.8 (s, CO). IR (Nujol):
1756, 1820 (mCO). Anal. Calcd for C15H13NO3S: C, 62.72;
H, 4.53; N, 4.88. Found: C, 62.58; H 4.44; N, 4.76. MS-
FAB+ (m/z): 287 (M+), 230, 219.
4.20. (S)-4-Furan-2-yl-1-(4-methoxybenzyl)-azetidine-
2,3-dione 5d
4.16. General procedure for the oxidative thiazolidine ring
opening of spiro-b-lactams 4b–d
Purified by means of column chromatography (SiO2, hex-
ane/AcOEt = 1:1). (Yield: 34%). Amorphous solid.
20
1
½aꢁD ¼ þ38:4 (c 0.42, CH2Cl2). H NMR: d 3.85 (s, 3H,
OCH3); 4.24 (d, 1H, CH2Ph, J = 14.7); 5.0 (s, 1H, H-4);
5.1 (d, 1H, CH2Ph, J = 14.7); 6.39 (d, 1H, H-3 Fur,
J = 3.3); 6.43 (t, 1H, H-4 Fur, J = 3.2); 6.91 (d, 2H,
CH2Ph, J = 8.6); 7.18 (d, 2H, CH2Ph, J = 8.6); 7.46 (br
s, 1H, H-5 Fur). 13C NMR: d 46.3 (t, CH2Ph); 55.3 (q,
OCH3); 67.3 (d, C-4); 109.8–131.1 (Ph + Fur); 159.5,
195.5 (s, CO). IR (Nujol): 1749, 1821 (mCO). Anal. Calcd
for C15H13NO4: C, 66.42; H, 4.80; N, 5.17. Found: C,
66.28; H 4.64; N, 4.97. MS-FAB+ (m/z): 271 (M+), 213.
A solution of spiro-b-lactams 4b–d (1 mmol) in 10 mL of
1 M HClg in AcOEt was stirred at room temperature for
24 h under a nitrogen atmosphere. After the evaporation
of the solvent, the residue was treated with 10 mL of
CH2Cl2, I2 (2 mmol) and wet Al2O3 (1.0 g) at room temper-
ature for 20 h. The alumina was filtered off and the organic
solvent was washed with 10% aq Na2S2O3 and then with
H2O. The organic layer was dried over Na2SO4 and the sol-
vent was removed under reduced pressure. Monobactams
5b–d were purified as indicated below.
4.21. (S)-1-(4-Methoxybenzyl)-4-thiazol-2-yl-azetidine-
2,3-dione 5e
4.17. Procedure for the oxidative thiazolidine ring opening of
spiro-b-lactam 3e
Purified by means of column chromatography (SiO2, tolu-
ene/AcOEt = 75:25). (Yield: 30%). Amorphous solid.
A solution of spiro-b-lactams 3e (0.15 mmol) in 5 ml of
1 M HClg in AcOEt was stirred at room temperature for
24 h under a nitrogen atmosphere. DMSO (0.2 mL) was
added and the mixture was heated at T = 50 °C for 16 h.
After the evaporation of the solvent, the residue was trea-
ted with CH2Cl2 and washed with a saturated aqueous
NaCl solution. The organic layer was dried over Na2SO4
20
1
½aꢁD ¼ ꢀ20:7 (c 0.52, CH2Cl2). H NMR: d 3.80 (s, 3H,
OCH3); 4.39 (d, 1H, CH2Ph, J = 15.0); 4.77 (s, 1H, H-4);
4.93 (d, 1H, CH2Ph, J = 15.0); 6.80 (d, 2H, CH2Ph,
J = 8.6); 7.21 (d, 2H, CH2Ph, J = 8.6); 7.46 (d, 1H, H-4
Thiaz, J = 3.2); 7.83 (d, 1H, H-5 Thiaz, J = 3.2). IR (Nu-
jol): 1741, 1820 (mCO). Anal. Calcd for C14H12N2O3S: C,

G. Cremonesi et al. / Tetrahedron: Asymmetry 19 (2008) 554–561
561
9. Arrowsmith, J. E.; Cook, M. J. J. Chem. Soc., Perkin Trans. 1
1979, 2364–2368.
10. Smith, P. A. S.; Dang, C. V. J. Org. Chem. 1976, 41, 2013–
2015.
58.33; H, 4.17; N, 9.72. Found: C, 58.24; H 4.04; N, 9.56.
MS-FAB+ (m/z): 288 (M+), 230.
11. (a) Alonso, E.; del Pozo, C.; Gonzalez, J. J. Chem. Soc.,
Perkin Trans. 1 2002, 571–576; (b) Khasanov, A. B.;
Ramirez-Weinhouse, M. M.; Webb, T. R.; Thiruvazhi, M.
J. Org. Chem. 2004, 69, 5766–5769; (c) Macias, A.; Alonso,
E.; del Pozo, C.; Venturini, A.; Gonzales, J. J. Org. Chem.
2004, 69, 7004–7012.
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