Asymmetric synthesis of 1,3-thiazolidine-derived spiro-β-lactams via a Staudinger reaction between chiral ketenes and imines

Article abstract of DOI:10.1016/j.tetasy.2005.08.054

Enantiomerically pure 1,3-thiazolidine-derived spiro-β-lactams were stereoselectively synthesised by means of a Staudinger ketene-imine reaction starting from optically active N-Boc-1,3-thiazolidine-2-carboxylic acid derivatives and imines. The reactions were stereoselective and afforded spiro-β-lactams with a relative trans-configuration. The absolute configuration of the new stereocentres was assigned on the basis of the well-accepted mechanism and confirmed by means of the X-ray crystal structure analysis. The spiro-β-lactams were transformed into enantiomerically pure chiral monocyclic β-lactams by opening the thiazolidine ring and recovering the chiral auxiliary.

Full text of DOI:10.1016/j.tetasy.2005.08.054

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3371–3379
Asymmetric synthesis of 1,3-thiazolidine-derived
spiro-b-lactams via a Staudinger reaction between
chiral ketenes and imines
Giuseppe Cremonesi,a Piero Dalla Croce,b Francesco Fontana,a
Alessandra Fornic 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
cC.N.R.-I.S.T.M., V. Golgi, 19, I-20133 Milano, Italy
Received 27 July 2005; accepted 30 August 2005
Available online 20 October 2005
Abstract—Enantiomerically pure 1,3-thiazolidine-derived spiro-b-lactams were stereoselectively synthesised by means of a Stau-
dinger ketene–imine reaction starting from optically active N-Boc-1,3-thiazolidine-2-carboxylic acid derivatives and imines. The
reactions were stereoselective and afforded spiro-b-lactams with a relative trans-configuration. The absolute configuration of the
new stereocentres was assigned on the basis of the well-accepted mechanism and confirmed by means of the X-ray crystal structure
analysis. The spiro-b-lactams were transformed into enantiomerically pure chiral monocyclic b-lactams by opening the thiazolidine
ring and recovering the chiral auxiliary.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
acids and derived peptides may have valuable biological
properties.
The stereoselective synthesis of b-lactams has received
considerable attention over recent years and, in particu-
lar, asymmetric synthesis through a Staudinger reaction
between a ketene and an imine has been extensively and
successfully studied.1 This is related to the renewed and
growing interest in such heterocycles2 because of their
use in organic chemistry and recent discoveries of their
biological activities as, for example, cholesterol absorp-
tion inhibitors,3 thrombin inhibitors4 and anti-hypergly-
cemic agents.5
Continuing our studies of the synthesis12 and reactiv-
ity13 of spiro-b-lactams, we have recently reported the
synthesis of new 1,3-thiazolidine-derived 4-spiro-b-lac-
tams 3 and 4a–g obtained by means of a Staudinger
ketene–imine reaction between imines 2a–d and the
non-symmetrical cyclic ketenes
a generated from
N-acyl-1,3-thiazolidine-2-carboxylic acids 1a–c by
means of MukaiyamaÕs reagent (Scheme 1).14
Our interest in compounds 3 and 4 is based on the pres-
ence of the 2-spiro fused thiazolidine ring, which can be
opened to obtain a-keto-b-lactams.14b The reactions
afforded mixtures of diastereoisomeric 4-spiro-b-lactams
3 and 4 in a ratio depending on imine-nitrogen nucleo-
philicity and, therefore, the nature of the R1 substituent.
When the nitrogen atom was substituted with an elec-
tron-withdrawing group (R1 = PhSO2) the ratio was in
favour of products 4 with a relative cis-configuration
between the sulfur atom and C-phenyl group (3/4 = 3/97).
However when R1 was an electron-donor group (e.g.,
PhCH2), the principal products were compounds 3 with
a relative trans-configuration (3/4 = 68–93/32–7). This
More specifically, spiro-b-lactams are interesting
because they can act as antiviral,6 antibacterial agents7
and also inhibit cholesterol absorption.8 They are also
b-turn mimetics,9 with 4-spiro-b-lactams in particular
being synthetic precursors of cyclic a,a-disubstituted b-
amino acids and peptide derivatives.10 The synthesis of
4-spiro-b-lactams has therefore received particular
attention11 because conformationally constrained amino
*
Corresponding author. E-mail: concetta.larosa@unimi.it
0957-4166/$ - see front matter ꢀ 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.08.054

3372
G. Cremonesi et al. / Tetrahedron: Asymmetry 16 (2005) 3371–3379
COR
COR
O
COR
COR
C
Cl
N
N
N
I
O
N
N
Me
+
S
S
H
+
Ph CH N R1
Et3N
CH2Cl2
COOH
S
N
N
S
O
Ph
R1
R1
H
Ph
∆
α
3a-g
4a-g
1a : R = Me
1b : R = Ph
1c : R = OtBu
2a : R1 = CH2Ph
2b : R1 = Ph
2c : R1 = 4-MeOPh
2d : R1 = SO2Ph
3a, 4a : R = Me, R1 = CH2Ph
3b, 4b : R = Ph, R1 = CH2Ph
3c, 4c : R = OtBu, R1 = CH2Ph
3d, 4d : R = Me, R1 = Ph
3e, 4e : R = Ph,
R1 = 4-MeOPh
3f, 4f : R = Me, R1 = SO2Ph
3g, 4g : R = Ph, R1 = SO2Ph
Scheme 1.
suggested that a different mechanism operates in the two
cases.14b
using optically active N-Boc-1,3-thiazolidine-2-carbox-
ylic acid derivatives 1d and 1e as the precursors of
non-symmetrical chiral cyclic ketenes (Fig. 1).
In this context, and in view of the growing interest in the
synthesis of enantiopure b-lactams, we planned the
asymmetric synthesis of chiral, non-racemic 1,3-thiazol-
idine-derived spiro-b-lactams using the Staudinger reac-
tion. Chiral ketenes or chiral imines are viable options
for achieving asymmetric induction, although some cat-
alytic approaches have recently been developed.15
2. Results and discussion
As amino acids 1a–c have been synthesised by condens-
ing the glyoxylic acid with cysteamine followed by
N-acylation,17 we decided to put a stereocentre at the
4-position of the thiazolidine ring. This meant using a
2-substituted-cysteamine (Fig. 2), the most widely avail-
able of which is the (R)-cysteine methyl ester.
We have previously reported a stereoselective synthesis
of spiro-b-lactams obtained from N-(phenylmethyl-
ene)benzenesulfonammide 2d and the ketene generated
from (2S,4R)-4-acyloxy-N-acyl-L-prolines in the pres-
ence of acetic anhydride. In this case the stereocentre
at the 4-position of the proline induced complete stereo-
selectivity for the new C-4 spiranic stereocentre, but not
for the C-3 stereocentre: the imine attacks the ketene
exclusively from the less hindered side of the proline
ring, thus leading to a mixture of the cis- and trans-
isomer with an (S)-absolute configuration at the C-4
spiranic carbon.12a We have also used chiral imines that
bear a stereocentre in the a-position at the nitrogen
atom, but the degree of diastereo- and enantioselectivity
was low.16
The (2S,4R)-1,3-thiazolidine-2,3,4-tricarboxylic acid 3-
(1,1-dimethylethyl) 4-methyl ester 1d was synthesised
as described in Scheme 2.
(R)-Cysteine methyl ester hydrochloride and glyossilic
acid were reacted in the presence of pyridine and, after
24 h at room temperature, afforded a mixture of the
two amino acid diastereoisomers (2S,4R)-1 and
(2R,4R)-10 in a ratio of 58:42, as determined by 1H
NMR spectroscopy. Crystallisation of the mixture from
water only allowed us to obtain the diastereoisomer
trans-1. The relative (and subsequently absolute) config-
urations were assigned to compounds 1 and 10 by com-
paring the proton chemical shifts with those reported for
the corresponding 1,3-thiazolidine-2,4-dicarboxylic
acids.18 This assignment was confirmed by means of
NOE experiments using a mixture of the two diastereo-
isomers insofar as it was not possible to isolate the more
soluble diastereoisomer 10 because the two compounds
are in equilibrium.18 The NOE experiments revealed a
relationship between H-2 and H-4 in the less abundant
diastereoisomer 10 thus confirming a relative cis-config-
uration. Subsequently, compound 1 was treated with
(BOC)2O to afford 1d. The N-Boc protecting group
was introduced on the thiazolidine-2-carboxylic acid in
Bearing in mind these previous results, we synthesised
enantiomerically pure 1,3-thiazolidine-derived spiro-b-
lactams by means of a Staudinger ketene–imine reaction
COOtBu
COOtBu
N
H
iPr
N
COOH
CH3OOC
H
COOH
H
S
S
1d
1e
Figure 1.
COR
N
H
N
R
R
NH2
SH
R
CHO
∗
∗
+
∗
COOH
COOH
COOH
S
S
Figure 2.

G. Cremonesi et al. / Tetrahedron: Asymmetry 16 (2005) 3371–3379
3373
H
H2
H
CH3OOC
H4
CH3OOC
H4
CH3OOC
NH2
SH
. HCl
COOH
N
S
EtOH
N
S
CHO .
COOH
H2O
+
+
Py
rt, 24 h
COOH
H2
NOE
1'
1
COR
H2
CH3OOC
H4
(i) or (ii) or (iii)
N
S
1
COOH
1d R = Ot Bu (i)
1f R = CH3 (ii)
1g R = Ph (iii)
(i) (BOC)2O, Et3N, CH3CN, ∆
(ii) CH3COCl, Et3N, CH2Cl2, rt
(iii) PhCOCl, Py, rt
Scheme 2.
order to remove it and facilitate the opening of the
ring.14b
DMSO-d6. The Staudinger reaction proceeded with
total stereoselectivity, giving both the b-lactams with a
relative cis-disposition of N-Boc and the phenyl group
(trans according to the CIP rules).
The reaction of an equimolar quantity of amino acid 1d,
imine 2a and 2-chloro-1-methylpyridinium iodide
(MukaiyamaÕs reagent) in the presence of triethylamine
in refluxing CH2Cl2 for 8 h gave the spiro-b-lactams as
a 1.8:1 mixture of diastereoisomers 3h and 3h0, which
were separated by means of column chromatography
(Scheme 3).
The absolute configuration of the stereocentres of spiro-
b-lactams was assigned on the basis of the generally
accepted mechanism of the Staudinger ketene–imine
reaction. According to experimental and theoretical
studies,11,19 with a nucleophilic imine such as (E)-2a, this
[2+2] ketene–imine cycloaddition is a two-step reaction
leading to the formation of a zwitterionic intermediate.
The mechanism involves the attack of the imine lone
pair from the less hindered side of the ketene opposite
the N-acyl group. The presence of a stereocentre in the
ketene differentiates the two faces of the thiazolidine
ring and, depending on which face is attacked, allows
The relative configuration of C-3 and C-4 of the azetid-
1
inone ring was established by comparing the H NMR
spectra with those of the previously obtained com-
1
pounds.14 The H NMR spectra were complicated by
the existence of rotamers (64:36 ratio) arising from the
N-Boc group, and so were recorded at 80 ꢁC in
CH3OOC
CH3OOC
COOt Bu
Ph
N
COOt Bu
O
Ph
Cl
COOt Bu
N
N
I
Me
CH3OOC
CH
+
N
+
S
S
N
H
N
Et3N
CH2Cl2
COOH
N
Ph
S
CH2Ph
CH2Ph
CH2Ph
O
H
∆
1d
2a
3h
3h'
Scheme 3.
H
H
H
CH3OOC
N
t BuOOC
CH3OOC
CH3OOC
N
90 ˚
flip
H
Ph
3h
Ph
N
Ph
H
S
N
t BuOOC
S
t BuOOC
S
H
C
O
N
C
N
CH2Ph
C
O
CH2Ph
O
CH2Ph
β1
β1'
H
H
H
CH3OOC
N
CH3OOC
N
CH3OOC
N
90 ˚
flip
t BuOOC
Ph
N
t BuOOC
t BuOOC
3h'
S
S
S
H
C
C
CH2Ph
CH2Ph
C
O
O
N
O
N
CH2Ph
Ph
H
β2
Ph
H
β2'
Figure 3.

3374
G. Cremonesi et al. / Tetrahedron: Asymmetry 16 (2005) 3371–3379
the zwitterionic intermediates b1 or b2 to be obtained.
After a 90ꢁ flip to the corresponding b01 and b20 , the con-
rotatory ring-closure of these zwitterionic intermediates
leads to b-lactams 3h and 3h0, which, respectively, have
the absolute (3R,4R,7R)- and (3S,4S,7R)-configurations
(Fig. 3).
. HCl
NH2
. HCl
CHO . H2O EtOH
H
+
N
S
rt
COOH
SH
5
COOH
COOt Bu
N
(BOC)2O
Et3N
CH3CN
∆
COOH
There was therefore also an asymmetric induction
because the diastereoisomer 3h derives from the attack
of the imine on the face of the ketene opposite the 4-met-
oxycarbonyl group. These assignments were confirmed
by means of the X-ray structure determination of the
more abundant diastereoisomer 3h (Fig. 4).
S
1e
Scheme 4.
1H NMR analysis showed that a single diastereoisomer
was obtained, but its relative configuration was not
determined because the stereochemistry at C-2 of the
thiazolidine ring is lost during the cycloaddition. The
reaction of 1e and imine 2a under the usual experimental
conditions affords a single diastereoisomer 3i, to which
the absolute (3S,4S,7S)-configuration was assigned on
1
the basis of the H NMR spectra and the above mecha-
nistic considerations (Scheme 5).
As previously reported,11b,c the Staudinger ketene–imine
reaction depends on the steric hindrance of the ketene
intermediate. In our cycloadditions, we also noted a
decrease in the total yield going from the 4-unsubstituted
1,3-thiazolidine-2-carboxylic acid (91%)14b to the more
encumbered 4-substituted 1,3-thiazolidine-2-carboxylic
acid (63% for 1d and 42% for 1e). On the other hand,
the presence of this substituent makes the reactions
more diastereoselective because a 100:0 = trans:cis ratio
was obtained. Furthermore, the formation of only one
spiro-b-lactam in the reaction of 1e shows that the iso-
propyl group generates a greater steric hindrance than
the methoxycarbonyl group on the thiazolidine ring.
Amino acids 1d and 1e were also reacted with N-(phen-
ylmethylene)benzenesulfonamide 2d, but no spiro-b-
lactams were detected in the reaction mixtures. With this
electron-poor imine, a concerted [2+2] cycloaddition
rather than a two-step mechanism mainly affording the
cis-isomer was proposed to explain the opposite diaste-
reoselectivity with substrates 1a and b.14b The complete
lack of reactivity may be due to the fact that a concerted
mechanism prevents an approach between the imine and
the more crowded ketenes derived from 1d and 1e (with
both the N-Boc and 4-methoxycarbonyl or 4-iso-propyl
groups present). To confirm this hypothesis, amino acid
1 was transformed into the 3-acetyl 1f and 3-benzoyl 1g
derivatives using conventional methods (Scheme 2), and
reacted with imine 2d. The reactions afforded spiro-b-
Figure 4. ORTEP plot of 3h with atom numbering scheme. Displace-
ment ellipsoids at 20% probability level.
A similar result was obtained using the (4S)-4-(1-meth-
ylethyl)-1,3-thiazolidine-2,3-dicarboxylic acid 3-(1,1-
dimethylethyl) ester 1e, which has a substituent with
different electronic and steric properties. Product 1e
was prepared by condensing (2S)-2-(1-methylethyl)-cys-
teamine hydrochloride20 5 and glyoxylic acid, followed
by treatment with (BOC)2O (Scheme 4).
Ph
COOt Bu
COOH
N
Cl
COOt Bu
O
N
I
Me
CH
N
S
+
S
N
Et3N
CH2Cl2
N
Ph
CH2Ph
CH2Ph
H
∆
1e
2a
3i
Scheme 5.

G. Cremonesi et al. / Tetrahedron: Asymmetry 16 (2005) 3371–3379
3375
CH3OOC
COR
N
Ph
Cl
COR
I
N
H
CH3OOC
Me
CH
N
S
+
Ph
S
COOH
N
Et3N
CH2Cl2
N
SO2Ph
SO2Ph
O
∆
1f,g
2d
3l : R = CH3
3m : R = Ph
Scheme 6.
lactams 3l and 3m in only 8% and 5% yield, respectively,
thus showing a close relationship with the steric hin-
drance of the N-substituent (Scheme 6).
3. Conclusions
We stereoselectively synthesised enantiomerically pure
1,3-thiazolidine-derived spiro-b-lactams by means of
the [2+2] cycloaddition reaction of non-symmetrical,
optically active cyclic ketenes with an imine, thus con-
firming the generality of the reported 1,3-thiazolidine-
derived spiro-b-lactam synthesis. The presence of the
stereocentre afforded complete diastereoselectivity (only
trans diastereoisomers) and enantioselectivity (with sub-
strate 1e). When two stereoisomers were obtained (sub-
strate 1d), they were separated and transformed into the
enantiomer pair of 4-phenyl-1-(phenylmethyl)azetidine-
2,3-dione. In this way, the Staudinger ketene–imine
cycloaddition, followed by thiazolidine ring cleavage,
proved to be a general method for obtaining these
heterocycles.
The relative cis-configuration was assigned to com-
1
pounds 3l and 3m on the basis of the H NMR spectra.
It was not possible to determine the absolute configura-
tion but the (3S,4R,7R) configuration was proposed on
the basis of an attack of the imine on the face of the
ketene opposite the 4-metoxycarbonyl group,14b as
already verified in our previous research.12c
Finally, our protocol for opening the thiazolidine ring14b
was applied to spiro-b-lactams 3h and 3h0, which
were, respectively, transformed into the corresponding
(4R)-4-phenyl-1-(phenylmethyl)azetidine-2,3-dione
7
and (4S)-4-phenyl-1-(phenylmethyl)azetidine-2,3-dione
70. In this transformation, we observed a steric influence
of the methoxycarbonyl group on the reaction times:
compound 3h was deprotected at the thiazolidine-N-
atom under anhydrous conditions with gaseous HCl in
AcOEt to 60 ꢁC for 24 h, thus affording the correspond-
ing spiro-b-lactam hydrochloride 6 (Scheme 7).
4. Experimental
4.1. General
Melting points were measured using a Buchi apparatus
¨
1
After heating 6 to 60 ꢁC in a CHCl3/DMSO solution for
60 h, the (4R)-4-phenyl-1-(phenylmethyl) azetidine-2,3-
dione 7 was obtained in 58% total yield from 3h; simi-
larly, the spiro-b-lactam 3h0 afforded 70 in a 54% total
yield. The enantiomeric excess of b-lactams 7 and 70
(and therefore the absence of epimerisation during the
transformation or a keto-enol tautomerism) were deter-
and are uncorrected. H and 13C NMR spectra were
recorded in CDCl3 (unless otherwise specified) on a
Bruker AC 300 spectrometer; chemical shifts (d) are
given in parts per million relative to TMS and all of
the coupling constants are in Hertz. Optical rotation
values were measured at 25 ꢁC on a Perkin–Elmer 241
spectropolarimeter. The MS spectra were determined
using a VG Analytical 7070 EQ mass spectrometer with
an attached VG analytical 11/250 data system. The IR
spectra were determined using a Perkin–Elmer 1725X
FT-IR spectrometer in reciprocal centimetres.
1
mined by means of H NMR spectroscopy using (+)-
Eu(hfc)3 as a chiral shift reagent.
In this way, both of the enantiomers of this useful b-lac-
tam21 were synthesised for the first time. Furthermore,
the (R)-cystine dimethyl ester dihydrochloride could be
recycled as a chiral auxiliary after its reduction to (R)-
cysteine methyl ester hydrochloride.22 This method is a
mild and general procedure for the preparation of
monocyclic azetidine-2,3-diones, which are useful inter-
mediates in organic synthesis.
Compound (2S)-2-(1-methylethyl)-cysteamine hydro-
chloride 520 was prepared according to the reported
method. Imines 2a and d, 2-chloro-1-methylpyri-
dinium iodide (MukaiyamaÕs reagent) and the shift
reagent (+)-Eu(hfc)3 were obtained from commercial
sources.
CH3OOC
CH3OOC
. HCl
Ph
COOt Bu
Ph
H
N
Ph
H
O
O
N
N
HCl g
DMSO
S
S
N
AcOEt
60˚
CHCl3
60˚
H
N
H
CH2Ph
CH2Ph
CH2Ph
O
O
3h
6
7
Scheme 7.

3376
G. Cremonesi et al. / Tetrahedron: Asymmetry 16 (2005) 3371–3379
4.2. (2S,4R)-1,3-Thiazolidine-2,4-dicarboxylic acid
4-methyl ester, 1
7 h. After evaporation of the solvent, the residue was
treated with 30 mL of a cold 10% aq HCl solution and
extracted with toluene. The organic layer was dried over
Na2SO4 and the solvent evaporated under reduced pres-
sure. The residue yellow oil was treated with dichloro-
methane and a 5% aq NaHCO3 solution. The aqueous
phase was separated, acidified with acetic acid and
extracted with dichloromethane. The organic phase
was dried over Na2SO4 and the solvent evaporated
under reduced pressure. Compound 1e was obtained
To a stirred solution of (R)-cysteine methyl ester hydro-
chloride (4 g, 23.3 mmol) and glyoxylic acid monohy-
drate (2.15g, 23.3 mmol) in ethyl alcohol (50 mL),
pyridine ( 3.76 mL, 46.6 mmol) was added. After being
stirred for 24 h at room temperature, the solvent was
evaporated off and the residue treated with water: the
crystalline mass was filtered and dried. Product 1 was
obtained as a colourless solid (2.85g, 64%). Mp 133–
134 ꢁC. 1H NMR: d 3.07 (dd, 1H, H-5, Jgem = 10.5,
Jvic = 5.3); 3.18 (dd, 1H, H-5, Jgem = 10.5, Jvic = 6.7);
3.72 (s, 3H, OCH3); 4.41 (t, 1H, H-4, J = 6.0); 5.04 (s,
1H, H-2). 13C NMR: d 36.7 (t, C-5); 52.0 (q, OCH3);
1
as a pale yellow oil (0.72 g, 45%). H NMR: d 0.87 (d,
3H, (CH3)2C, J = 6.7); 0.97 (d, 3H, (CH3)2C, J = 6.7);
1.39 (s, 9H, (CH3)3C); 2.05(m, 1H, C H(CH3)2); 2.91
(dd, 1H, H-5, Jgem = 11.3, Jvic = 6.6); 2.99 (dd, 1H,
H-5, Jgem = 11.3, Jvic = 6.2); 4.06 (m, 1H, H-4); 5.39
20
65.3 (d, C-4); 65.8 (d, C-2); 171.1, 171.9 (s, CO).
(s, 1H, H-2). ½aŠ ¼ 56:4 (c 0.15, CH3OH). IR (Nujol):
D
20
½aŠ ¼ À216:8 (c 1.03, CH3OH). IR (Nujol): 1703
(mCDO, COOH), 1742 (mCO, COOCH3), 3220 (mOH). Anal.
Calcd for C6H9NO4S: C, 37.69; H, 4.74; N, 7.33. Found:
C, 37.67; H, 4.76; N, 7.40. MS-EI (m/z): 191 (M+), 160,
146, 132, 59, 45.
1650 (mCO, N–CO); 1710 (mCO, COOH). Anal. Calcd
for C12H21NO4S: C, 52.36; H, 7.64; N, 5.09. Found:
C, 52.31; H, 7.44; N, 4.95.
4.5. (2S,4R)-3-Acetyl-1,3-thiazolidine-2,4-dicarboxylic
acid 4-methyl ester, 1f
4.3. (2S,4R)-1,3-Thiazolidine-2,3,4-tricarboxylic acid
3-(1,1-dimethylethyl) 4-methyl ester, 1d
To a stirred suspension of acid 1 (1.5g, 7.85mmol) in
dichloromethane (8 mL), Et3N (2.4 mL, 17.3 mmol)
was added, after which acetyl chloride (0.62 mL,
8.65mmol) in dichloromethane (4 mL) was added drop-
wise. The obtained solution was stirred for 24 h. After
evaporation of the solvent, the residue was treated with
15mL of 10% aq HCl. The precipitate was filtered and
recrystallised from i-PrOH–i-Pr2O to afford a colourless
A mixture of 1 (1.2 g, 6.28 mmol), (BOC)2O (2.74 g,
12.56 mmol) and Et3N (1.74 mL, 12.56 mmol) in
40 mL of acetonitrile was refluxed for 7 h. After evapo-
ration of the solvent, the residue was treated with 30 mL
of a cold 5% aq HCl solution and extracted with tolu-
ene. The organic layer was dried over Na2SO4 and the
solvent evaporated under reduced pressure. Compound
1d was obtained as an amorphous solid (1.68 g, 92%).
1H and 13C NMR show the presence of rotamers about
the carbamate bond in a 79:21 ratio. 1H NMR: d 1.38 (s,
9H, (CH3)3C); 3.15(d, 1H, H-5, Jgem = 12.5); 3.39 (dd,
1H, H-5, Jgem = 12.5, Jvic = 7.2); 3.73, 3.85(s, 3H,
OCH3); 4.95, 5.03 (m, 1H, H-4); 5.25, 5.30 (s, 1H, H-
2). 13C NMR: d 28.0, 28.3 (q, (CH3)3C); 32.5, 33.8 (t,
C-5); 52.7 (q, OCH3); 59.7, 60.4 (d, C-4); 62.4, 62.7 (d,
1
solid (1.05g, 56%). Mp 186–188 ꢁC. H and 13C NMR
show the presence of rotamers about the amide bond
in a 72:28 ratio. 1H NMR: d 2.14, 2.16 (s, 3H, COCH3);
3.21, 3.42 (d, 1H, H-5, J = 12.3, 11.9); 3.60, 3.70 (dd,
1H, H-5, Jgem = 12.3, 11.9, Jvic = 6.3, 7.2); 3.78, 3.85
(s, 3H, OCH3); 4.93, 5.17 (d, 1H, H-4, J = 7.2, 6.3);
5.33, 5.39 (s, 1H, H-2). 13C NMR: (DMSO-d6) d 22.3,
23.0 (q, COCH3); 32.3, 34.3 (t, C-5); 52.6, 53.3
(q, OCH3); 60.8 (d, C-4); 62.5, 63.3 (d, C-2); 168.7,
20
C-2); 82.3 ((CH3)3C); 170.4, 173.7, 174.3 (s, CO).
169.6, 170.2, 170.7, 171.2, 171.9 (s, CO). ½aŠ ¼
D
20
½aŠ ¼ À72:7 (c 0.22, CH3OH). IR (Nujol): 1660 (mCO
,
À133:0 (c 0.79, CH3OH). IR (Nujol): 1610 (mCO
,
D
N–CO); 1708 (mCO, COOH), 1741 (mCO, COOCH3).
Anal. Calcd for C11H17NO6S: C, 45.36; H, 5.84; N,
4.81. Found: C, 45.31; H, 5.63; N, 4.70. MS-FAB+
(m/z): 291 (M+), 247, 192.
N–CO); 1725( mCO, COOH), 1738 (mCO, COOCH3).
Anal. Calcd for C8H11NO5S: C, 41.20; H, 4.75; N,
6.01. Found: C, 41.15; H, 4.53; N, 5.92. MS-EI (m/z):
188 (M+ÀCOOH), 174, 146.
4.4. (4S)-4-(1-Methylethyl)-1,3-thiazolidine-2,3-
dicarboxylic acid 3-(1,1-dimethylethyl) ester, 1e
4.6. (2S,4R)-3-Benzoyl-1,3-thiazolidine-2,4-dicarboxylic
acid 4-methyl ester, 1g
To a stirred solution of (2S)-2-(1-methylethyl)-cyste-
amine hydrochloride 5 (1.0 g, 6.42 mmol) in ethyl alco-
hol (25mL), glyoxylic acid monohydrate (0.59 g,
6.42 mmol) was added under a nitrogen atmosphere.
After 24 h at room temperature, the solvent was evapo-
rated off and the residue treated with water and dichlo-
romethane. The aqueous phase was separated and
evaporated affording (4S)-4-(1-methylethyl)-1,3-thiaz-
olidine-2-carboxylic acid hydrochloride as a yellow oil,
which was used without further purification (1.23 g,
90%). A mixture of this compound (1.23 g, 5.8 mmol),
(BOC)2O (2.54 g, 11.6 mmol) and Et3N (1.78 mL,
12.76 mmol) in 70 mL of acetonitrile was refluxed for
To a stirred solution of acid 1 (1.0 g, 5.2 mmol) in pyr-
idine (4 mL), benzoyl chloride (0.6 mL, 5.2 mmol) was
added dropwise. The obtained solution was stirred at
room temperature for 18 h. After evaporation of the
solvent, the residue was treated with 10% aq HCl and
extracted with dichloromethane. The organic layer was
dried over Na2SO4 and the solvent evaporated under
reduced pressure. The residue was purified by column
chromatography (SiO2, CH2Cl2/CH3OH = 98/2–50/
50). Product 1g was obtained as a colourless solid after
recrystallisation from trichloroethylene (1.07 g, 70%).
Mp 143–145 ꢁC. 1H NMR: d 3.30 (d, 1H, H-5,
J = 11.9); 3.64 (dd, 1H, H-5, Jgem = 11.9, Jvic = 6.4);

G. Cremonesi et al. / Tetrahedron: Asymmetry 16 (2005) 3371–3379
3377
20
D
3.71 (s, 3H, OCH3); 4.84 (d, 1H, H-4, J = 6.4); 5.58 (s,
1H, H-2); 7.42 (s, 5H, Ph). 13C NMR show the presence
of rotamers about the amide bond: (DMSO-d6) d 31.7,
33.8 (t, C-5); 51.8, 52.6 (q, OCH3); 60.2, 61.1 (d, C-4);
151.8, 165.9, 170.5 (s, CO). ½aŠ ¼ þ59:6 (c 0.98,
CHCl3). IR (Nujol): 1690 (mCO, NCOOt-Bu), 1747
(mCO, COOCH3), 1766 (mCO, N–CO). Anal. Calcd for
C25H28N2O5S: C, 64.08; H, 6.02; N, 5.98. Found: C,
64.95; H, 5.92; N, 5.95. MS-FAB+ (m/z): 469 (M+),
413, 367, 335, 309, 277.
62.3, 64.0 (d, C-2); 126.3–132.8 (Ph); 166.5, 168.6,
20
170.5(s, CO). ½aŠ ¼ 191:9 (c 1.03, CH3OH). IR (Nu-
D
jol): 1644 (mCO, N–CO); 1697 (mCO, COOH), 1742 (mCO
,
COOCH3). Anal. Calcd for C13H13NO5S: C, 52.87; H,
4.44; N, 4.74. Found: C, 52.58; H, 4.24; N, 4.73. MS-
EI (m/z): 295(M +), 264, 250, 236, 190.
4.10. (3S,4S,7S)-8-(tert-Butoxycarbonyl)-7-(1-methyl-
ethyl)-3-phenyl-2-(phenylmethyl)-5-thia-2,8-diaza-
spiro[3,4]octan-1-one, 3i
4.7. General procedure for the reactions of 1d–g with
2a and 2d and Mukaiyama’s reagent
(Yield: 42%). Mp 120–121 ꢁC (i-Pr2O/hexane). 1H
NMR: d 0.83 (d, 3H, (CH3)2CH, J = 7.0); 0.93 (d, 3H,
(CH3)2CH, J = 7.0); 1.22 (s, 9H, (CH3)3C); 2.49 (m,
1H, (CH3)2CH); 2.96 (d, 1H, H-6, J = 12.0); 3.23 (dd,
1H, H-6, Jgem = 12.0, Jvic = 7.1); 3.87 (dd, 1H, H-7,
J = 7.1, 4.4); 4.23 (d, 1H, CH2Ph, J = 15.0); 4.75 (s,
1H, H-3); 5.21 (d, 1H, CH2Ph, J = 15.0); 7.23–7.56
(m, 10H, Ph). 13C NMR: d 17.7 (q, (CH3)2CH); 20.1
(q, (CH3)2CH); 27.8 (q, (CH3)3C); 30.2 (t, C-6); 30.5
(d, (CH3)2CH); 45.7 (t, CH2Ph); 66.7 (d, C-7); 75.0 (d,
A mixture of 1d–g (1.0 mmol), imine 2a and 2d (1.0
mmol), 2-chloro-N-methylpyridium iodide (1.16 mmol)
and Et3N (3.0 mmol) in dry CH2Cl2 (15mL) was heated
at reflux temperature for 8–12 h under a nitrogen atmo-
sphere. After cooling, the solution was washed with
H2O, 5% aq HCl, and then with H2O. The organic layer
was dried over Na2SO4 and the solvent removed under
reduced pressure. The crude products were purified by
column chromatography (SiO2, toluene/AcOEt = 95:5)
and recrystallised as indicated.
C-3); 81.1 (s, (CH3)3C); 84.0 (s, C-4); 126.1–135.0 (Ph);
20
151.8, 166.4 (s, CO). ½aŠ ¼ þ159:2 (c 1.03, CHCl3).
D
IR (Nujol): 1694 (mCO, NCOOt-Bu), 1772 (mCO, N–
CO). Anal. Calcd for C26H32N2O3S: C, 69.00; H, 7.13;
N, 6.19. Found: C, 68.92; H, 7.05; N, 6.15. MS-ESI
(m/z): 475(M ++Na), 397, 375.
4.8. (3R,4R,7R)-8-(tert-Butoxycarbonyl)-7-methoxy-
carbonyl-3-phenyl-2-(phenylmethyl)-5-thia-2,8-diaza-
spiro[3,4]octan-1-one, 3h
4.11. (3S,4R,7R)-8-Acetyl-7-methoxycarbonyl-3-phenyl-
2-(phenylsulfonyl)-5-thia-2,8-diazaspiro[3,4]octan-1-
one, 3l
(Yield: 40.5%). Mp 108–109 ꢁC (i-Pr2O). 1H NMR
(DMSO-d6, T = 80 ꢁC): d 1.17 (s, 9H, (CH3)3C), 3.31
(dd, 1H, H-6, Jgem = 12.6, Jvic = 1.1); 3.65(s, 3H,
OCH3); 3.69 (dd, 1H, H-6, Jgem = 12.6, Jvic = 7.8); 4.30
(d, 1H, CH2Ph, J = 15.2); 4.30 (d, 1H, H-7, J = 7.1);
4.75(s, 1H, H-3); 4.92 (d, 1H, C H2Ph, J = 15.2); 7.24–
7.38 (m, 10H, Ph). 13C NMR show the presence of rota-
mers about the carbamate bond in a 64:36 ratio: d 27.7
(q, (CH3)3C); 31.8, 32.7 (t, C-6); 45.2, 45.6 (t, CH2Ph);
52.5 (q, OCH3); 63.3, 64.1 (d, C-7); 75.3 (d, C-3); 81.4
Oil. (Yield: 8%). 1H NMR: d 2.07 (s, 3H, COCH3); 2.77
(dd, 1H, H-6, Jgem = 11.8, Jvic = 6.0); 3.05(d, 1H, H-6,
J = 11.8); 3.81 (s, 3H, OCH3); 4.67 (d, 1H, H-7,
J = 6.0); 5.51 (s, 1H, H-3); 7.23–7.39 (m, 5H, Ph); 7.56
(t, 2H, HmPhSO2); 7.69 (t, 1H, HpPhSO2); 8.00 (d, 2H,
HoPhSO2). Anal. Calcd for C21H20N2O6S2: C, 54.77;
H, 4.38; N, 6.08. Found: C, 54.65; H, 4.30; N, 5.92.
(s, (CH3)3C); 83.2 (s, C-4); 125.9–134.9 (Ph); 151.1,
20
164.1, 170.4 (s, CO). ½aŠ ¼ À180:2 (c 0.95, CHCl3). IR
(Nujol): 1690 (mCO, NCDOOt-Bu), 1766 (mCO, COOCH3,
N–CO). Anal. Calcd for C25H28N2O5S: C, 64.08; H,
6.02; N, 5.98. Found: C, 63.81; H, 5.89; N, 5.85. MS-
FAB+ (m/z): 469 (M+), 413, 367, 335, 309, 277. Single
crystals suitable for X-ray structure determination were
obtained by precipitation from i-Pr2O.
4.12. (3S,4R,7R)-8-Benzoyl-7-methoxycarbonyl-3-phen-
yl-2-(phenylsulfonyl)-5-thia-2,8-diazaspiro[3,4]octan-1-
one, 3m
(Yield: 5%). Mp 221–223 ꢁC (Toluene). 1H NMR: d 2.91
(dd, 1H, H-6, Jgem = 11.6, Jvic = 5.8); 3.11 (dd, 1H, H-6,
Jgem = 11.6, Jvic = 2.5); 3.63 (s, 3H, OCH3); 4.85(dd,
1H, H-7, Jgem = 5.8, Jvic = 2.5); 5.66 (s, 1H, H-3);
7.28–7.47 (m, 10H, Ph); 7.57 (t, 2H, HmPhSO2); 7.69
(t, 1H, HpPhSO2); 8.06 (d, 2H, HoPhSO2). 13C NMR:
d 32.7 (t, C-6); 53.1 (q, OCH3); 66.0 (d, C-7); 67.9 (d,
4.9. (3S,4S,7R)-8-(tert-Butoxycarbonyl)-7-methoxy-
carbonyl-3-phenyl-2-(phenylmethyl)-5-thia-2,8-diaza-
spiro[3,4]octan-1-one, 3h0
C-3); 86.6 (s, C-4); 127.5–137.4 (Ph); 163.2, 168.8,
20
(Yield: 22.5%). Mp 102–103 ꢁC (i-Pr2O/hexane). 1H
NMR (DMSO-d6, T = 80 ꢁC): d 1.31 (s, 9H, (CH3)3C),
3.25(dd, 1H, H-6, Jgem = 11.7, Jvic = 7.1); 3.39 (s, 3H,
OCH3); 3.44 (dd, 1H, H-6, Jgem = 11.7, Jvic = 6.7);
4.19 (d, 1H, CH2Ph, J = 15.2); 4.70 (s, 1H, H-3); 4.75
(t, 1H, H-7, J = 6.9); 4.80 (d, 1H, CH2Ph, J = 15.2);
7.20–7.40 (m, 10H, Ph). 13C NMR show the presence
of rotamers about the carbamate bond in a 66:34 ratio:
d 28.3 (q, (CH3)3C); 32.0, 32.9 (t, C-6); 45.3 (t, CH2Ph);
52.5 (q, OCH3); 65.0, 65.6 (d, C-7); 74.3, 74.9 (d, C-3);
82.6 (s, (CH3)3C); 83.9 (s, C-4); 127.1–135.2 (Ph);
170.3 (s, CO). ½aŠ ¼ À85:3 (c 0.30, CHCl3). IR (Nujol):
D
1663 (mCO, N–COPh); 1747 (mCO, COOCH3), 1806 (mCO
,
N–CO). Anal. Calcd for C26H22N2O6S2: C, 59.76; H,
4.24; N, 5.36. Found: C, 59.69; H, 4.10; N, 5.13. MS-
EI (m/z): 522 (M+), 491, 463, 417, 381.
4.13. (4R)-4-Phenyl-1-(phenylmethyl) azetidine-2,3-
dione, 7
A solution of 3h (200 mg, 0.43 mmol) in 8 mL of
2 M HCl in AcOEt, was heated at 60 ꢁC for 24 h under

3378
G. Cremonesi et al. / Tetrahedron: Asymmetry 16 (2005) 3371–3379
a nitrogen atmosphere. After evaporation of the
solvent, the residue was treated with 10 mL of CHCl3
and 0.1 mL of DMSO and heated at 60 ꢁC for 60 h.
After evaporation of the solvent, the residue was
treated with a mixture of methyl alcohol/diethyl ether
and (R)-cystine dimethyl ester dihydrochloride was
collected by filtration (81 mg, 55%). The solution was
evaporated to dryness and compound 7 purified by
flash chromatography (SiO2, hexane/AcOEt = 3/1).
Product 7 was obtained as an oil (63 mg, 58%). 1H
NMR: d 4.1 (d, 1H, CH2, J = 14.5); 4.85 (s, 1H, H-4);
5.13 (d, 1H, CH2, J = 14.5); 7.11–7.32 (m, 10H, Ph).
Crystallographic data (excluding structure factors) for
3h have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication num-
ber CCDC 279055. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (fax: +44-1223-
336033; e-mail: deposit@ccdc.cam.ac.uk).
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13C NMR: d 45.7 (t, CH2); 73.8 (d, C-4); 126.4–
20
133.7 (Ph); 164.0, 202.0 (CO). ½aŠ ¼ À21:9 (c 0.59,
D
CHCl3), Ee >99% [1H NMR with (+)-Eu(hfc)3]. IR
(Nujol): 1743 (mCO, CO-3); 1825( mCO, CO-2). Anal.
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4.14. (4S)-4-Phenyl-1-(phenylmethyl) azetidine-
2,3-dione, 70
1
(Yield 54%). H NMR: d 4.12 (d, 1H, CH2, J = 14.4);
4.85(s, 1H, H-4); 5.12 (d, 1H, CH 2, J = 14.4); 7.10–
7.32 (m, 10H, Ph). 13C NMR: d 45.8 (t, CH2); 73.7 (d,
20
D
C-4); 126.4–133.7 (Ph); 164.0, 202.0 (CO). ½aŠ
¼
þ20:35( c 0.50, CHCl3), Ee >99% [1H NMR with (+)-
Eu(hfc)3]. IR (Nujol): 1740 (mCO, CO-3); 1822 (mCO
,
CO-2). Anal. Calcd for C16H13NO2: C, 76.48; H, 5.21;
N, 5.57. Found: C, 76.28; H, 5.00; N, 5.33. MS-FAB+
(m/z): 252 (M+), 194.
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4.15. Single crystal X-ray structural determination
of 3h
The intensity data for 3h were collected on a Bruker
Smart Apex CCD area detector using graphite-mono-
˚
chromated Mo-Ka radiation (k = 0.71073 A). Data
reduction was made using SAINT programs; absorption
corrections based on multiscan were obtained by
SADABS.23 The structures were solved by SIR-9224
and refined on F2 by full-matrix least-squares using
SHELXL-97.25 All the non-hydrogen atoms were
refined anisotropically, hydrogen atoms were included
as ÔridingÕ and not refined. The ORTEP-III program
was used for molecular diagrams.26
13. Dalla Croce, P.; La Rosa, C. Heterocycles 2000, 53, 2653.
14. (a) Cremonesi, G.; Dalla Croce, P.; La Rosa, C. Tetra-
hedron 2004, 60, 93–97; (b) Cremonesi, G.; Dalla Croce,
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16. Farina, M. Thesis, University of Milan, 2004.
17. Lalezari, I.; Schwartz, E. L. J. Med. Chem. 1988, 31, 1427–
1429.
Crystal data and results of the refinement: colourless
plate 0.35 · 0.32 · 0.05mm, Mr = 468.55, orthorhombic,
˚
˚
space group P212121, a = 10.722(2) A, b = 14.398(3) A,
3
˚
˚
c = 15.979(3) A, V = 2466.9(9) A , Z = 4, T = 293(2) K,
l = 0.168 mmÀ1. 30,123 measured reflections, 4859
independent reflections, 4084 reflections with I > 2r(I),
3.80ꢁ < 2h < 52.00ꢁ, Rint = 0.0777. Refinement on 4859
reflections, 298 parameters. Flack parameter27 for
determination of the absolute configuration = 0.09(11).
Final R = 0.0578, wR = 0.1272 for data with F2 >
2r(F2), S = 1.099, (D/r)max = 0.001, Dqmax = 0.18,
18. Pellegrini, N.; Refouvelet, B.; Crini, G.; Blacque, O.;
Kubicki, M.; Robert, J. F. Chem. Pharm. Bull. 1999, 47,
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´
19. (a) Venturini, A.; Gonzalez, J. J. Org. Chem. 2002, 67,
À3
Dqmin = À0.20 e A . The puckering analysis28 of the
˚
´
9089–9092; (b) Arrieta, A.; Lecea, B.; Cossıo, F. P. J. Org.
five-membered ring gives the parameters Q =
Chem. 1998, 63, 5869–5876; (c) Arrieta, A.; Cossio, F. P.;
Lecea, B.; Ugalde, J. M. J. Am. Chem. Soc. 1994, 116,
´
2085–2093; (d) Lopez, R.; Sordo, T. L.; Sordo, J. A.;
˚
0.478(3) A, u = 322.3(4)ꢁ, corresponding to a nearly
envelope conformation.

G. Cremonesi et al. / Tetrahedron: Asymmetry 16 (2005) 3371–3379
3379
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25. Sheldrick, G. M. SHELX-97. Program for the Refinement
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26. Burnett, M. N.; Johnson, C. K. ORTEP-III: Oak Ridge
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28. Cremer, D.; Pople, J. A. J. Am. Chem. Soc. 1975, 97,
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Hegedus, L. S.; Montgomery, J.; Narukawa, Y.; Snustad,
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Tetrahedron 2001, 57, 4629–4635.
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Prakt. Chem. 2000, 342, 585–590; (b) Palomo, C.; Aizpu-
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