[2 + 2] Cycloaddition reactions of imines with cyclic ketenes: Synthesis of 1,3-thiazolidine derived spiro-β-lactams and their transformations

Article abstract of DOI:10.1002/hlca.200590125

Unsymmetric cyclic ketenes were generated from N-acyl-1,3-thiazolidine-2- carboxylic acids 1a-c by means of Mukaiyama's reagent, and then reacted with imines 2a-c to the new, isomeric spiro-β-lactams 3 and 4 via [2 + 2] cycloaddition (Staudinger ketene-imine reaction; Scheme 1). The reactions were stereoselective (Table 1) and mainly afforded the spiro-β-lactams with a relative trans configuration. The spiro-β-lactams could be transformed into the corresponding monocyclic β-lactams by means of thiazolidine ring opening or into substituted thiazolidines via hydrolysis of the β-lactam ring.

Full text of DOI:10.1002/hlca.200590125

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Helvetica Chimica Acta ± Vol. 88 (2005)
[2 ‡ 2] Cycloaddition Reactions of Imines with Cyclic Ketenes: Synthesis of
1,3-Thiazolidine Derived Spiro-b-lactams and Their Transformations
by Giuseppe Cremonesia), Piero Dalla Croceb), and Concetta La Rosa*a)
a
Á
) Istituto di Chimica Organica ꢀA. Marchesiniꢁ, Facolta di Farmacia, Via Venezian 21, I-20133 Milano
(e-mail: concetta.larosa@unimi.it)
b) Dipartimento di Chimica Organica e Industriale, C.N.R. ± I.S.T.M., Via Venezian 21, I-20133 Milano
On the occasion of the 85th birthday of Professor Rolf Huisgen
Unsymmetric cyclic ketenes were generated from N-acyl-1,3-thiazolidine-2-carboxylic acids 1a ± c by means
of Mukaiyamaꢁs reagent, and then reacted with imines 2a ± c to the new, isomeric spiro-b-lactams 3 and 4 via
[2 ‡ 2] cycloaddition (Staudinger ketene ± imine reaction; Scheme 1). The reactions were stereoselective
(Table 1) and mainly afforded the spiro-b-lactams with a relative trans configuration. The spiro-b-lactams could
be transformed into the corresponding monocyclic b-lactams by means of thiazolidine ring opening or into
substituted thiazolidines via hydrolysis of the b-lactam ring.
Introduction. ± The reaction of ketenes with imines to 2-azetidinones, known as
Staudinger ketene ± imine cycloaddition [1], is one of the most-versatile and useful
procedures for constructing b-lactam rings [2]. There is always great interest in these
small heterocycles [3] because of their usefulness as synthetic intermediates in organic
chemistry [4], and their antibacterial properties [5]. Recent discoveries have also
shown that they are active as cholesterol absorption inhibitors [6], thrombin inhibitors
[7], and anti-hyperglycemic agents [8].
Spiro-b-lactams are particularly interesting because their antiviral [9a] and
antibacterial activities [9b], as well as their inhibition of cholesterol absorption [9c],
make them potentially useful compounds for drug development. They can also act as b-
turn mimetics [10] and, particularly the 4-spiro-b-lactams, are synthetic precursors for
cyclic a,a-disubstituted b-amino acids and peptide derivatives [11]. The synthesis of
conformationally constrained amino acids is of special interest because the peptides
derived from these modified amino acids may have valuable biological properties. As a
consequence, the synthesis of 4-spiro-b-lactams has recently received particular
attention [12].
Further to our previous studies on the synthesis [13] and reactivity [14] of spiro-b-
lactams, we now report the Staudinger ketene ± imine reaction between unsymmetrical
cyclic ketenes generated from N-acyl-1,3-thiazolidine-2-carboxylic acids 1 and imines 2
for the synthesis of the new 1,3-thiazolidine derived 4-spiro-b-lactams 3 and 4
(Scheme 1). Our interest in these compounds is based on the spiro-fused thiazolidine
ring, which could be opened to obtain a-keto-b-lactams.
In our early work on cycloaddition reactions between mesoionic compounds
(generated from cyclic N-acyl-a-amino acids via Ac2O) and N-(phenylmethylidene)-
benzenesulfonamide (2d) [13a,b], we obtained both the [3 ‡ 2] and [2 ‡ 2] adducts
ꢂ 2005 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta ± Vol. 88 (2005)
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Scheme 1
derived from the equilibrium between the two valence tautomer intermediates (ketene
vs. mesoionic compound) already observed by Huisgen in his pioneering work on
mesoionic compounds [15].
We have recently reported [13d] a procedure for the exclusive synthesis of the
ketene intermediate A by means of Mukaiyamaꢁs reagent (ˆ2-chloro-1-methylpyr-
idinium iodide): the reaction of 1a,b with 2d afforded a mixture of the diastereoiso-
meric N-phenylsulphonyl-spiro-b-lactams 3f,g and 4f,g in good yields, with a ratio of
97:3 in favor of the cis-configured isomers 4 (Scheme 1). We would now like to
optimize and extend this protocol to differently N-substituted imines and 1,3-
thiazolidine-2-carboxylic acids, with the aim of obtaining spiro-b-lactams susceptible
to further transformations. The hydrolytic opening of the thiazolidine ring of 3f,g and
4f,g showed that these compounds are more reactive at the b-lactam than at the
thiazolidine ring because of the presence of the strong electron-withdrawing sulfonyl
group.
Results and Discussion. ± We first decided to substitute the phenylsulphonyl group
(R1) at the imine N-atom of 2 with a benzyl (Bn) group, which has an opposite
electronic effect and, when necessary, could be easily eliminated. Subsequently, a tert-
butoxycarbonyl (Boc) protecting group (R) was introduced on the thiazolidine-2-
carboxylic acid 1 in order to be able to remove it more easily. We then investigated the
reaction between the acetyl- (Ac), benzoyl- (Bz), and Boc-protected substrates 1a ± c,
resp., and imine 2a (Scheme 1). We found that our previous experimental conditions
[13d] could be improved: an equimolar mixture of 1 and 2a, Mukaiyamaꢁs reagent, and
Et3N was heated at reflux in CH2Cl2 for 6 ± 8 h, which afforded a mixture of the
diastereoisomeric spiro-b-lactams 3a±c and 4a± c in good yields (Table 1, Entries 1± 3).

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The mixtures were separated by means of column chromatography, and the relative
configurations at C(3) and C(4) of the azetidinone ring were established by means of
1H-NMR spectra, and compared with those of previously obtained compounds [13a,d].
The chemical shift of HÀC(3) changed from d(H) 4.51 À 4.60 in 3a ± c to 5.01 ± 5.22 in
4a ± c, thus showing a deshielding effect of the N-acyl group in compounds 4.
Table 1. Yields and Diastereoisomer Ratios 3/4 in the Reactions of 1 and 2 (see Scheme 1 and Exper. Part)
Entry
3 and 4
R
R1
Total yield [%]
3/4
1
2
3
4
a
b
c
d
e
f
Me
Ph
t-BuO
Me
Ph
Bn
Bn
Bn
Ph
7268 : 32
87
91
20
39
70
80
75 : 25
93 : 7
91 : 9
88 : 12
3 : 97
3 : 97
5
4-MeO-C6H4
PhSO2
PhSO2
6a)
7a)
Me
Ph
g
a) According to [13d].
When looking at the isomer distribution (Table 1), it should be noted that the
observed cis/trans ratio (in favor of the trans-isomer) is inverted in comparison with
that previously obtained in the reactions between 1a,b and 2d, in which, under the same
experimental conditions, this ratio was in favor of the cis-isomer (Entries 6 and 7).
Two other imines, 2b and 2c, were also tested in the reaction with 1a and 1b,
respectively, to determine the diastereoisomeric ratio for a different substituent at the
imine N-atom. Under the same experimental conditions, 2b was more reactive, but
afforded 3d and 4d in modest total yields. Imine 2c led to a better yield, and a favorable
trans-selectivity was observed (Entries 4 and 5).
The mechanism of the Staudinger ketene ± imine cycloaddition is still a subject of
discussion [12a][16]. According to experimental and theoretical studies, this [2 ‡ 2]
cycloaddition is a two-step reaction, with the formation of a solvent-stabilized
zwitterionic intermediate. In our case, it would involve the attack of the imine lone pair
from the least-hindered side of the ketene opposite to the N-acyl group to provide the
zwitterionic intermediate B (Scheme 2). Conrotatory ring-closure of the latter then
leads to b-lactams 3, with a relative trans-configuration. Assuming that the (E)-
configuration of the starting imines (confirmed by NMR spectra) does not change
during the course of the reaction, the cis-diastereoisomers 4 could derive from double-
bond isomerization of B to B', a process that should be favored by the stabilization of
Scheme 2

Helvetica Chimica Acta ± Vol. 88 (2005)
1583
the positive charge by the phenyl group on the imine C-atom [16f,g], thus leading to the
thermodynamically more-stable b-lactams 4, with the more-encumbering N-acyl and 3-
Ph groups on opposite sides. Note that the cis-isomers 4a ± e are not due to a secondary
isomerization, because no cis-isomers were found when the trans-b-lactams 3a ± e were
subjected to the reaction conditions for 8 h.
In order to rationalize the reversed diastereoselectivity of the reaction with imine
2d, it is worth considering a possible change in reaction mechanism from a stepwise
process (involving a zwitterionic intermediate) to a concerted process. An asynchro-
nous concerted reaction pathway cannot be excluded for ketene ± imine cycloaddition
reactions in which the imine N-atom is substituted with an electron-withdrawing group
[16b,d]. The reduced nucleophilicity of 2d may cause the reaction to follow a concerted
[2 ‡ 2] cycloaddition rather than a two-step mechanism affording the cis-isomer: in this
case, the preferred approach between the ketene and the imine is that in which the N-
acyl and the CÀPh groups are on opposite sides (Scheme 3).
Scheme 3
In an attempt to support the anticipated change in mechanism when passing from
imines 2a,c to 2d, solvent effects on the ratio of diasteroisomers were investigated. The
reactions between 1b and 2a,d were performed in solvents with different polarities, and
the results are summarized in Table 2. The 3g/4g ratio remained almost the same in the
case of 2d, but a change in 3b/4b was observed with 2a: in this case, the trans/cis ratio
decreased, when passing from a less polar (1,4-dioxane) to a very polar solvent (1,3-
dimethylimidazolidin-2-one; DMI). This clearly illustrates the influence of the solvent
on the zwitterionic intermediate and, therefore, on the products ratio.
Table 2. Solvent-Dependent Product Ratios 3/4 in the Reaction of 1b with either 2a or 2d (see Scheme 1)
Solvent
3b/4b
3g/4g
1,4-Dioxane
Toluene
CH2Cl2
DMF
80 : 20
79 : 21
75 : 2 5
66 : 33
58 : 424 : 96
7: 93
5 : 95
7: 93
7: 93
DMIa)
a) 1,3-Dimethylimidazolidin-2-one
Next, we studied the hydrogenolysis, acid hydrolysis, and desulfurization of spiro-b-
lactams 3 and 4. Compounds of type a, b, f, and g were hydrogenated in the presence of
different catalysts (Pd, Pt, Raney-Ni) and solvents (AcOEt, EtOH, AcOH), at

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temperatures ranging from room temperature to 1008, and pressures from 1 to 30 atm.
These compounds turned out to be highly resistant at room temperature and
atmospheric pressure (no reaction), but were degraded when the temperature and/or
pressure was increased. The results were different from those of our previous
experiments obtained with N-(phenylsulphonyl) substituted spiro-b-lactams derived
from 1,3-thiazolidine-4-carboxylic acids, where the S-atom was not adjacent to the
spiro-C-atom [14]. In the latter case, the thiazolidine ring was desulfurized with Raney-
Ni as catalyst, and the azetidinone ring was opened at the C(3)ÀN bond. One possible
explanation for the different behaviors of the new compounds 3 or 4 could be that, in
this case, the S-atom is more-encumbered, thus preventing the attack.
A different behavior was observed when the benzyl (3a,b) or phenylsulfonyl
substituted spiro-b-lactams (4f,g) were subjected to acid hydrolysis. The derivatives
4f,g were selectively hydrolyzed at the azetidinone ring, and afforded the 2-substituted
1,3-thiazolidine-2-carboxylic acids 5f,g, i.e., cyclic a,b-diamino acids (Scheme 4). In
contrast, the corresponding N-benzyl derivatives 3a,b were stable in 10% aq. HCl at
room temperature, but completely decomposed when heated. A better result was
obtained with the N-Boc derivative 3c. In this case, the compound was deprotected at
the thiazolidine N-atom under anhydrous conditions, and afforded the spiro-b-lactam
6c, but was decomposed when heated with aq. HCl (Scheme 4).
Scheme 4
In addition to hydrolysis and hydrogenolysis, other procedures for opening the
thiazolidine ring were tested (with the aim of obtaining a-keto-b-lactams), namely a)
oxidative cleavage with ꢀmetachloroperbenzoic acidꢁ (MCPBA) [17], H2O, or KIO4
[18]; and b) metal-catalyzed hydrolysis with HgCl2 [19] or CuO/CuCl2 [20].
Unfortunately, none of these experiments were fruitful. However, finally, we managed
to cleave the thiazolidine ring under very mild conditions by simply heating a CHCl3/
DMSO 9 :1 solution of 6c to 458 for 6 h (Scheme 5). Under these conditions, the a-
keto-b-lactam 7 was obtained in a yield of 72%, together with a 71% yield of the
cystamine bis(hydrochloride) 8. DMSO is a well-known oxidant [21], which, in our

Helvetica Chimica Acta ± Vol. 88 (2005)
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case, might attack the electrophilic spiro-C-atom, which carries a good leaving group.
Such a mechanism is supported by the observation that the reaction does take place
neither when the free base (and not an ammonium salt) is reacted, nor if DMF is used
as a co-solvent instead of DMSO. Nevertheless, the mechanism of this reaction has not
been completely understood, even though the oxidation product 8 was isolated, and the
corresponding reduction product (Me2S) was identified by means of 1H-NMR analysis.
Scheme 5
Conclusions. ± The results of this study confirm the generality of the reported 1,3-
thiazolidine-derived spiro-b-lactam synthesis. Opposite trans or cis diastereoselectivity
can be obtained using different imines with electron-donating or electron-withdrawing
substituents at the N-atom. Finally, simple and mild chemical transformations of the
differently substituted compounds 3 and 4 made it possible to obtain thiazolidine
derivatives or a-keto-b-lactams. This new approach to a-keto-b-lactams will be a
subject of future development.
Experimental Part
General. Compounds 1a,b [22], 2b [23], and 2c [24] were prepared according to reported methods. Imines
2a,d and 2-chloro-1-methylpyridinium iodide (Mukaiyamaꢁs reagent) were obtained from commercial sources.
Melting points (m.p.) were measured on a Büchi apparatus, and are uncorrected. IR Spectra were determined
.
on a Perkin-Elmer 1725X FT-IR spectrometer; in cmÀ1 1H- and 13C-NMR Spectra were recorded in CDCl3
(unless specified otherwise) on a Bruker AC-300 spectrometer; chemical shifts d in ppm rel. to Me4Si, coupling
constants J in Hz. Mass spectra were determined on a VG Analytical 7070 EQ mass spectrometer, with an
attached VG analytical 11/250 data system.
3-(tert-Butoxycarbonyl)-1,3-thiazolidine-2-carboxylic Acid (1c). A mixture of 1,3-thiazolidine-2-carboxylic
acid [22] (2.0 g, 15.0 mmol), (Boc)2O (6.55g, 30 mmol), and Et3N (4.2ml, 30 mmol) in MeOH (36 ml) was
heated at 508 for 6 h. After evaporation of the solvent, the residue was treated with cold 5% aq. HCl soln.
(50 ml), and extracted with toluene. The org. layer was dried (Na2SO4), and the solvent was evaporated under
reduced pressure. The product was treated with hexane, and filtered to afford 1c (6.14g, 88%). Colorless solid.
M.p. 96 ± 978 (hexane). IR (nujol): 1677, 1721. 1H-NMR: 1.39 (s, Me3C); 2.94 (m, 1 H of CH2(5)); 3.19 (m, 1 H of
CH2(5)); 3.77 (m, 1 H of CH2(4)); 3.91 (m, 1 H of CH2(4)); 5.09 (s, HÀC(2)). 13C-NMR: 28.2 (Me3C); 29.6
‡
(C(5)); 49.8 (C(4)); 55.9 (C(2)); 81.7 (Me3C); 168.0 (CO); 177.0 (CˆO). EI-MS: 188 ([M À COOH] ), 132, 88.
Anal. calc. for C9H15NO4S (233.07): C 46.34, H 6.48, N 6.00; found C 46.27, H 6.53, N 5.86.
General Procedure for the Reactions of 1a ± c with 2a ± c. A mixture of 1 (1.0 mmol), 2 (1.0 mmol), 2-chloro-
N-methylpyridium iodide (1.16 mmol), and Et3N (3.0 mmol) in anh. CH2Cl2 (15 ml) was heated at reflux for 6 ±
8 h under an N2 atmosphere. After cooling, the soln. was washed with H2O, 5% aq. HCl soln., and H2O. The
combined org. layers were dried (Na2SO4), and the solvent was removed under reduced pressure to afford the
crude products 3 and 4, which were purified by column chromatography (CC) (SiO2; toluene/AcOEt) and
recrystallization. For rel. yields, see Table 1.
(3S*,4S*)-8-Acetyl-3-phenyl-2-(phenylmethyl)-5-thia-2,8-diazaspiro[3.4]octan-1-one (3a). M.p. 165 ± 1668
(toluene). IR (nujol): 1664, 1763. 1H-NMR: 1.70 (s, Me); 3.06 (m, CH2S); 3.22 (m, 1 H of CH2N); 3.70 (m, 1 H

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Helvetica Chimica Acta ± Vol. 88 (2005)
of CH2N); 4.15 (d, J ˆ 15.0, 1 H of PhCH2); 4.53 (s, CH); 5.10 (d, J ˆ 15.0, 1 H of PhCH2); 7.12± 7.24 ( m, 10
arom. H). 13C-NMR: 23.2 (Me); 29.9 (C(6)); 45.1 (PhCH2); 51.6 (C(7)); 75.0 (C(3)); 83.2 (C(4)); 127.9 ± 129.3
‡
(Ph); 134.3 (Ph); 136.2(Ph); 165.0 (C ˆO); 167.5 (CˆO). EI-MS: 352( M ), 309, 219, 157. Anal. calc. for
C20H20N2O2S (352.12): C 68.16, H 5.72, N 7.95; found C 68.09, H 5.79, N 7.87.
(3R*,4S*)-8-Acetyl-3-phenyl-2-(phenylmethyl)-5-thia-2,8-diazaspiro[3.4]octan-1-one (4a). M.p. 200 ± 2018
(i-PrOH). IR (nujol): 1655, 1767. 1H-NMR: 2.14 (s, Me); 2 .52 (m, 1 H of CH2S); 2.88 (m, 1 H of CH2S); 3.63 (m,
1 H of CH2N); 3.83 (m, 1 H of CH2N); 4.12( d, J ˆ 14.8, 1 H of PhCH2); 4.72( d, J ˆ 14.8, 1 H of PhCH2); 5.08
(s, CH); 7.02 (m, 2arom. H); 7.14 ± 7.27 ( m, 8 arom. H). 13C-NMR: 24.3 (Me); 29.2 (C(6)); 45.6 (PhCH2); 52.4
(C(7)); 66.4 (C(3)); 85.0 (C(4)); 127.6 ± 129.2 (Ph); 134.4 (Ph); 134.7 (Ph); 167.7 (CˆO); 168.7 (CˆO). EI-MS:
‡
352( M ), 309, 219, 157. Anal. calc. for C20H20N2O2S (352.12): C 68.16, H 5.72, N 7.95; found C 68.06, H 5.68, N
7.83.
(3S*,4S*)-8-Benzoyl-3-phenyl-2-(phenylmethyl)-5-thia-2,8-diazaspiro[3.4]octan-1-one (3b). M.p. 204 ±
1
2068 (toluene). IR (nujol): 1657, 1767. H-NMR: 2.83 (m, 1 H of CH2S); 3.00 (m, 1 H of CH2S); 3.19 (m, 1 H
of CH2N); 3.61 (m, 1 H of CH2N); 4.14 (d, J ˆ 15.0, 1 H of PhCH2); 4.60 (s, CH); 5.04 (d, J ˆ 15.0, 1 H of
PhCH2); 6.70 (dd, 2arom. H); 7.14 ± 7.29 ( m, 13 arom. H). 13C-NMR ((D6)DMSO): 30.7 (C(6)); 45.4 (PhCH2);
53.8 (C(7)); 73.9 (C(3)); 82.6 (C(4)); 126.3 ± 129.7 (Ph); 134.0 (Ph); 136.0 (Ph); 136.8 (Ph); 165.7 (CˆO); 167.9
‡
(CˆO). EI-MS: 414 (M ), 354, 323, 309, 281, 219, 105. Anal. calc. for C25H22N2O2S (414.14): C 72.44, H 5.35, N
6.76; found C 71.83, H 5.22, N 6.53.
(3R*,4S*)-8-Benzoyl-3-phenyl-2-(phenylmethyl)-5-thia-2,8-diazaspiro[3.4]octan-1-one (4b). M.p. 194 ±
1958 (toluene). IR (nujol): 1634, 1765. 1H-NMR: 2.52 (m, 1 H of CH2S); 3.00 (m, 1 H of CH2S); 3.63 (m,
1 H of CH2N); 3.84 (m, 1 H of CH2N); 4.21 (d, J ˆ 14.8, 1 H of PhCH2); 4.75 (d, J ˆ 14.8, 1 H of PhCH2); 5.22 (s,
CH); 7.06 ± 7.54 (m, 15 arom. H). 13C-NMR ((D6)DMSO): 30.1 (C(6)); 45.2(Ph CH2); 54.7 (C(7)); 65.8 (C(3));
84.9 (C(4)); 127.6 ± 129.0 (Ph); 130.9 (Ph); 135.5 (Ph); 136.8 (Ph); 167.9 (CˆO); 168.7 (CˆO). EI-MS: 414
‡
(M ), 309, 281, 219, 105. Anal. calc. for C25H22N2O2S (414.14): C 72.44, H 5.35, N 6.76; found C 72.23, H 5.48, N
6.60.
(3S*,4S*)-8-(tert-Butoxycarbonyl)-3-phenyl-2-(phenylmethyl)-5-thia-2,8-diazaspiro[3.4]octan-1-one (3c).
M.p. 136 ± 1378 (i-PrOH). IR (nujol): 1673, 1769. 1H-NMR: 1.27 (s, Me3C); 2.90 ± 3.13 (m, NCH2CH2S); 4.02( d,
J ˆ 15.3, 1 H of PhCH2); 4.51 (s, CH); 5.04 (d, J ˆ 15.6, 1 H of PhCH2); 7.11 ± 7.25 (m, 10 arom. H). 13C-NMR:
27.9 ( Me3C); 29.9 (C(6)); 45.2 (PhCH2); 50.7 (C(7)); 74.1 (C(3)); 80.2(Me 3C); 82.3 (C(4)); 127.2 ± 128.8 (Ph);
‡
133.7 (Ph); 134.8 (Ph); 151.6 (CˆO); 165.9 (CˆO). EI-MS: 410 (M ), 309, 277, 177, 132. Anal. calc. for
C23H26N2O3S (410.17): C 67.29, H 6.38, N 6.82; found C 67.17, H 6.22, N 6.65.
(3R*,4S*)-8-(tert-Butoxycarbonyl)-3-phenyl-2-(phenylmethyl)-5-thia-2,8-diazaspiro[3.4]octan-1-one (4c).
Oil. IR (nujol): 1662, 1767. 1H-NMR: 1.42( s, Me3C); 2.43 (m, 1 H of CH2S); 2.79 (m, 1 H of CH2S); 3.51 (m, 1 H
of CH2N); 3.87 (m, 1 H of CH2N); 4.25 (br. s, PhCH2); 5.01 (s, CH); 6.98 (m, 2arom. H); 7.15 ± 7.23 ( m, 8 arom.
‡
H). EI-MS: 410 (M ), 309, 277, 177, 132. Anal. calc. for C23H26N2O3S (410.17): C 67.29, H 6.38, N 6.82; found C
67.19, H 6.25, N 6.71.
(3S*,4S*)-8-Acetyl-2,3-diphenyl-5-thia-2,8-diazaspiro[3.4]octan-1-one (3d). M.p. 216 ± 2178 (i-PrOH). IR
(nujol): 1667, 1763. 1H-NMR: 1.67 (s, Me); 3.16 (m, CH2S); 3.36 (m, 1 H of CH2N); 3.79 (m, 1 H of CH2N); 5.18
(s, CH); 7.17 ± 7.33 (m, 10 arom. H). 13C-NMR: 23.4 (Me); 31.0 (C(6)); 52.1 (C(7)); 75.2 (C(3)); 82.3 (C(4));
118.0 ± 129.5 (Ph); 133.0 (Ph); 138.0 (Ph); 163.0 (CˆO); 168.0 (CˆO). Anal. calc. for C19H18N2O2S (338.11): C
67.43, H 5.36, N 8.28; found: C 67.22, H 5.33, N 8.08.
(3R*,4S*)-8-Acetyl-2,3-diphenyl-5-thia-2,8-diazaspiro[3.4]octan-1-one (4d). M.p. 210 ± 2118 (i-PrOH). IR
(nujol): 1646, 1762. 1H-NMR: 1.19 (s, Me); 2 .65 (m, 1 H of CH2S); 2.98 (m, 1 H of CH2S); 3.73 (m, 1 H of
CH2N); 3.91 (m, 1 H of CH2N); 5.66 (s, CH); 7.12± 7.32( m, 10 arom. H). Anal. calc. for C19H18N2O2S (338.11):
C 67.43, H 5.36, N 8.28; found: C 67.23, H 5.16, N 8.08.
(3S*,4S*)-8-Benzoyl-2-(4-methoxyphenyl)-3-phenyl-5-thia-2,8-diazaspiro[3.4]octan-1-one (3e). M.p. 188 ±
1898 (toluene). IR (nujol): 1636, 1753. 1H-NMR: 2.92 (ddd, J ˆ 2.4, 5.6, 10.7, 1 H of CH2S); 3.09 (m, 1 H of
CH2S); 3.33 (m, 1 H of CH2N); 3.70 (ddd, J ˆ 2.3, 5.9, 11.0, 1 H of CH2N); 3.71 (s, MeO); 5.21 (s, CH); 6.71 (d, 2
arom. H); 6.78 (d, 2arom. H); 7.12± 7.37 ( m, 10 arom. H). 13C-NMR: 31.8 (C(6)); 54.5 (C(7)); 55.9 (MeO); 74.1
(C(3)); 81.9 (C(4)); 114.8 (Ph); 119.3 (Ph); 126.9 ± 130.6 (Ph); 131.6 (Ph); 132.8 (Ph); 136.6 (Ph); 156.7 (CˆO);
‡
163.2(C ˆO); 169.2(C ˆO). EI-MS: 430 (M ), 325, 281, 219. Anal. calc. for C25H22N2O3S (430.14): C 69.75, H
5.15, N 6.51; found: C 69.60, H 5.04, N 6.24.
(3R*,4S*)-8-Benzoyl-2-(4-methoxyphenyl)-3-phenyl-5-thia-2,8-diazaspiro[3.4]octan-1-one (4e). M.p.
178 ± 1808 (toluene). IR (nujol): 1636, 1755. 1H-NMR: 2.63 (m, 1 H of CH2S); 3.09 (m, 1 H of CH2S), 3.67
(s, MeO); 3.75 (m, 1 H of CH2N); 3.81 (m, 1 H of CH2N); 5.75 (s, CH); 6.73 (d, 2arom. H); 7.34 ± 7.54 ( m, 12
arom. H). 13C-NMR: 30.4 (C(6)); 54.9 (C(7)); 55.4 (MeO); 65.5 (C(3)); 84.8 (C(4)); 114.3 (Ph), 119.2(Ph),

Helvetica Chimica Acta ± Vol. 88 (2005)
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127.3 ± 131.0 (Ph), 131.6 (Ph), 134.9 (Ph), 135.9 (Ph), 154.3 (CˆO), 165.3 (CˆO), 169.6 (CˆO). EI-MS: 430
‡
(M ), 325, 281, 219. Anal. calc. for C25H22N2O3S (430.14): C 69.75, H 5.15, N 6.51; found: C 69.62, H 5.01, N 6.28.
General Procedure for the Hydrolysis of Compounds 4f and 4g. A suspension of the spiro-b-lactam
(0.25 mmol) in a mixture of 1,4-dioxane (10 ml) and 5% aq. HCl soln. (10 ml) was heated at reflux for 3 h. After
evaporation of the dioxane and cooling, the products were collected by filtration.
3-Acetyl-2-{phenyl[(phenylsulfonyl)amino]methyl}-1,3-thiazolidine-2-carboxylic acid (5f). Yield: 56%.
M.p. 212 ± 2148 (dec.; H2O). IR (nujol): 1628, 1704, 3257. 1H-NMR ((D6)acetone): 1.70 (s, Me); 2 .50 (m, 1 H of
CH2S); 2.68 (ddd, J ˆ 2.3, 5.2, 10.9, 1 H of CH2S); 2.99 (m, 1 H of CH2N); 3.83 (ddd, J ˆ 2.3, 5.2, 10.9, 1 H of
CH2N); 5.45 (br. s, CH); 6.60 (br. s, NH); 7.00 ± 7.50 (m, 10 arom. H); with D2O, the signal at d(H) 6.60
disappeared, and that at 5.45 became a singlet. Anal. calc. for C19H20N2O5S2 (420.08): C 54.27, H 4.79, N 6.66,
found: C 54.39, H 4.72, N 6.35.
3-Benzoyl-2-{phenyl[(phenylsulfonyl)amino]methyl}-1,3-thiazolidine-2-carboxylic Acid (5g). Yield: 84%.
M.p. 235 ± 2378 (dec.; H2O). IR (nujol): 1629, 1712, 3261. 1H-NMR ((D6)DMSO): 2.80 (m, CH2S); 3.00 (m, 1 H
of CH2N); 3.54 (m, 1 H of CH2N); 5.62( d, J ˆ 9.11, CH); 6.70 (d, 2arom. H); 7.11 ± 7.57 ( m, 11 arom. H); 7.59
(d, 2arom. H); 7.85 ( d, J ˆ 9.11, NH); 12.30 (br. s, COOH); with D2O, the signals at d(H) 7.85 and 12.30
disappeared, and that at 5.62became a singlet. Anal. calc. for C24H22N2O5S2 (482.10): C 59.73, H 4.60, N 5.81;
found: C 59.52, H 4.55, N 5.70.
(3S*,4S*)-3-Phenyl-2-(phenylmethyl)-5-thia-2,8-diazaspiro[3.4]octan-1-one Hydrochloride (6c). A soln. of
3c (0.7 g, 1.7mmol) in 1m HCl in AcOEt (10 ml) was heated at 608 for 3 h. After cooling, the product was
collected by filtration, and recrystallized (i-PrOH). Yield: 0.47 g (80%). M.p. 180 ± 1818 (i-PrOH). IR (nujol):
1773, 1749, 3271. 1H-NMR: 2.98 (m, 1 H of CH2S); 3.18 (m, 1 H of CH2S); 3.48 (m, 1 H of CH2N); 3.66 (m, 1 H
of CH2N); 4.18 (d, J ˆ 14.8, 1 H of PhCH2); 4.70 (d, J ˆ 14.8, 1 H of PhCH2); 5.36 (s, CH); 7.13 ± 7.32( m, 10
arom. H). 13C-NMR ((D6)DMSO): 30.9 (C(6)); 44.5 (PhCH2); 48.7 (C(7)); 63.8 (C(3)); 90.3 (C(4)); 127.4 ±
‡
128.9 (Ph); 134.0 (Ph); 134.3 (Ph); 165.7 (CˆO); 177.8 (CˆO). EI-MS: 310 ([M À HCl] ), 219, 195, 177. Anal.
calc. for C18H19ClN2OS (346.09): C 62.33, H 5.52, N 8.08; found: C 62.14, H 5.22, N 7.92.
4-Phenyl-1-(phenylmethyl)azetidine-2,3-dione (7). A soln. of 3c (50 mg, 0.14 mmol) in CHCl3 (4 ml) and
DMSO (0.4 ml) was heated at 458 for 6 h. The resulting solid was filtered off to afford 8 (23 mg, 71%)1). The
filtrate was evaporated to dryness, and the residue was purified by flash chromatography (SiO2; hexane/AcOEt
1
3 :1) to afford 7 (52mg, 72%). M.p. 80 ± 81 8 ((i-Pr)2O; lit. oil [26]). IR (nujol): 1743, 1825. H-NMR: 4.11 (d,
J ˆ 14.6, 1 H of PhCH2); 4.83 (s, HÀC(4)); 5.13 (d, J ˆ 14.6, 1 H of PhCH2); 7.10 ± 7.34 (m, 10 arom. H).
13C-NMR: 45.9 (PhCH2); 73.9 (CH); 126.4 ± 131.0 (Ph); 131.9 (Ph); 133.5(Ph); 164.0 (CˆO); 202.0 (CˆO).
‡
FAB-MS: 252 ([M ‡ H] ), 194, 91. Anal. calc. for C16H13NO2 (251.09): C 76.48, H 5.21, N 5.57; found: C 76.36,
H 5.04, N 5.45.
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Received March 2, 2005